Dermatologic

Cryosurgery

William Abramovits
Gloria Graham
Yaron Har-Shai
Renata Strumia
Editors

123
Dermatological Cryosurgery
and Cryotherapy
William Abramovits • Gloria Graham
Yaron Har-Shai • Renata Strumia
Editors

Dermatological
Cryosurgery
and Cryotherapy
Editors
William Abramovits Yaron Har-Shai
Dermatology Treatment The Unit of Plastic Surgery
and Research Center Carmel Medical Center
Dallas, TX Haifa
USA Israel

Gloria Graham Renata Strumia

Eastern Dermatology and Pathology St Anna Hospital
Morehead City, NC University of Ferrara
USA Ferrara
Italy

ISBN 978-1-4471-6764-8 ISBN 978-1-4471-6765-5 (eBook)

DOI 10.1007/978-1-4471-6765-5

Library of Congress Control Number: 2015960385

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Preface

In dermatologic cryotherapy and cryosurgery, localized cold is used to

improve some skin conditions or destroy and remove abnormal tissue. It uti-
lizes cryogens to treat various benign non-cancerous, pre-cancerous, and can-
cerous lesions.
The advantages of cryosurgery include high success rates, few side effects
of significance, relatively short recovery times, ease of performance, and rea-
sonable cost. The disadvantages include frequent morbidity, lack of accurate
margin of destruction control, and operator dependency.
Solid scientific grounds nowadays support the indications for cryosurgical
and cryotherapeutic procedures, starting with understanding the mechanisms
of action, the cellular and vascular events that occur during the processes of
cooling and freezing, thawing and recovery, and ending with the statistical
evidence of cure or relief.
This book is titled Cryosurgery and Cryotherapy for Skin Diseases and
Conditions because in this way we address from the start semantic issues with
the word cryotherapy, which we consider to be misused interchangeably with
cryosurgery. For our purpose, the term “cryosurgery” is used to denote a pri-
marily destructive procedure involving temperature reduction (such as for
skin cancer), while “cryotherapy” is used to denote a therapeutic procedure
where the tissues are taken to low temperature but are expected to survive
(such as in pain reduction). A terminology compromise was accepted for
those procedures where mechanisms of action where destruction and the
involvement of immunity overlapped. We often respected the choice of words
by the chapter authors.
An example of cryosurgery is the treatment of epithelial skin neoplasms
by lowering them to temperatures that selectively destroy the cancer cells
within them, while their surrounding tissue is spared lethal damage. Examples
of cryotherapy include lowering skin temperature to induce anesthesia, pre-
serving a severed finger for reattachment, or cooling a wart for a few seconds
just to induce an immune response that hopefully will get rid of it.
It was 3 years ago that Mr. Grant Weston from Springer Publishers
approached me after my almost yearly lecture on cutaneous cryosurgery at an
Annual Meeting of the American Academy of Dermatology to suggest that I
write the “definitive textbook” on the subject. That year another textbook
(albeit not the definitive) on the same topic was just published, so I felt that
the timing was suboptimal; the seed had been placed in nourishing ground.
For the daunting task, it was tremendously gratifying to obtain the support of

v
vi Preface

luminaries like Gloria Graham, MD; Renata Strumia, MD; and Yaron Har-
Shai, MD, who became my co-editors.
Gloria needs no introduction in the world of dermatology, and she is with-
out a doubt the Doyenne of Cryosurgery, having written many articles, edited
textbooks, lectured innumerable times all over the world, treated many, and
mentored a large cadre of practitioners of the trade. Dr. Graham kept motivat-
ing us by example; although she struggled with health issues, she never quit
pressing us to edit and her many friends in the field to contribute.
Renata was introduced to me by Grant. He suggested that I read a book on
cryosurgery she had just published in Italian. Dr. Strumia wrote that book
pretty much all by herself, and it was very much to my liking. I contacted her,
met her at congresses, learned firsthand of her competence, and asked her to
join us as editor and contributor; she did so with remarkable eagerness and
efficiency.
Yaron’s name I kept running into while reviewing cryosurgery on PubMed;
Dr. Har-Shai is a plastic surgeon in Israel who has a keen interest in the reduc-
tion of keloids and has developed innovative techniques. He was also a most
efficient deliverer of contributions to our text, and he helped us recruiting
erudite authors for several chapters. I would also want to give a special thanks
to Dr. Robert Schwartz for his help in the final stretch of this book. He dedi-
cated a lot of his time and his team’s effort to complete chapters for which we
had difficulties finding willing contributors.
I am in great debt to my co-editors for their efforts and collaboration. They
all actively participated in the development of the content, wrote a great num-
ber of the chapters, and helped me greatly in the selection of contributors of
the highest quality, expertise, and recognition in their respective fields.
Finally, I must acknowledge the valuable participation and intense dedica-
tion and efforts of the team Alba Quiñones, MD (from Dermatology Treatment
and Research Center) and Michael D. Sova (Developmental Editor for
Springer Science) to whom this text owes its crystallization.
Hopefully the readers will find this book to be of value, as complete as
possible, and enjoyable to read; it may not be the “definitive textbook” on the
subject, but hopefully that is because the field continues to expand and
progress.

Dallas, TX, USA William Abramovits

Contents

Part I History

1 The History of Dermatologic Cryosurgery . . . . . . . . . . . . . . . . 3

William Abramovits
Part II Physics

2 Principles of Cryoablation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
John G. Baust, Andrew A. Gage, and John M. Baust
3 Cryogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
William Abramovits
4 The Effect of Cold Temperatures on Biological Systems . . . . . 19
Jeunghwan Choi, Saravana B. Kumar,
Silvia Jiang-Hughes, and John C. Bischof
5 Mechanism of Cellular Damage from Cryosurgery . . . . . . . . . 37
Carlos Horacio Gonzalez Rojas
6 Effects of Cold Temperature on the Skin. . . . . . . . . . . . . . . . . . 39
Kenneth R. Diller, Sepideh Khoshnevis,
and Matthew Brothers
Part III Immunology

7 Immunology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Michael Scott Sabel
Part IV Equipment

8 Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
William Abramovits
9 In-Office Generators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
C. Lee Asplund
10 Storage Units/Dewars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
William Abramovits and Ana M. Prato-Guia
11 Withdrawal Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Carmen I. Hernandez Lara

vii
viii Contents

12 Stands/Roller Bases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Alba G. Quiñones
13 Gloves and Aprons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
William Abramovits
14 Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
William Abramovits
15 Dispensing Units (Carbon Dioxide,
Nitrous Oxide, etc.) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
William Abramovits
16 Thermos/Vacuum-Insulated Bottles/Flasks. . . . . . . . . . . . . . . . 95
William Abramovits
17 Cups ............................................. 99
William Abramovits
18 Tips ............................................. 101
William Abramovits
19 Cotton/Rayon Tipped Applicators . . . . . . . . . . . . . . . . . . . . . . . 105
William Abramovits
20 Sprayers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
William Abramovits
21 Open Cones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Carmen I. Hernandez Lara
22 Closed Probes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
William Abramovits
23 Cryochambers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
William Abramovits
24 Cryoneedles (for Extra and Intra-lesional Use) . . . . . . . . . . . . 121
William Abramovits
25 Miscellaneous (Adaptors, Extensions,
Protectors, Tubing, etc.). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
William Abramovits
26 Cryotweezers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
William Abramovits
27 Other Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
William Abramovits
28 Tissue Temperature Monitors. . . . . . . . . . . . . . . . . . . . . . . . . . . 135
William Abramovits
29 Monitorization Instrumentation with Ultrasound . . . . . . . . . . 137
William Abramovits
Contents ix

30 MRI/CAT Scanners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

William Abramovits
31 Confocal Microscopes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
William Abramovits
Part V Therapeutic Principles and Techniques

32 Therapeutic Principles and Techniques. . . . . . . . . . . . . . . . . . . 147

Gloria F. Graham and Sara Moradi Tuchayi
33 Patient Selection and Related Contraindications . . . . . . . . . . . 151
Gloria F. Graham and Sara Moradi Tuchayi
34 Lesion Selection and Related Contraindications . . . . . . . . . . . 157
Manisha J. Patel, Alice He, and Gloria F. Graham
35 Method and Equipment Selection . . . . . . . . . . . . . . . . . . . . . . . 163
Gloria F. Graham and Sara Moradi Tuchayi
36 Cryosurgeon Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Gloria F. Graham
Part VI Methods

37 Spray . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Gloria F. Graham
38 Cotton Tipped Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
Renata Strumia
39 Segmental and Fractional Cryotherapy. . . . . . . . . . . . . . . . . . . 183
Renata Strumia
40 Cryopeeling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
Janyana M.D. Deonizio
41 Cryo-massage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Renata Strumia
42 Controlled Cold Induced Lipolysis. . . . . . . . . . . . . . . . . . . . . . . 193
Jennifer Peterson and Suzanne Bruce
43 Solid Carbon Dioxide: Usage in Slush or Block
Form as Therapeutic Agent in Dermatology. . . . . . . . . . . . . . . 201
Harold J. Brody
Part VII Results

44 Expected Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

Christopher M. Scott, Gloria F. Graham,
and Ronald R. Lubritz
45 Evolution of the Cryo-lesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Christopher M. Scott, Gloria F. Graham,
and Ronald R. Lubritz
x Contents

46 Recovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
Christopher M. Scott, Gloria F. Graham,
and Ronald R. Lubritz
47 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Christopher M. Scott, Ronald R. Lubritz,
and Gloria F. Graham
48 Acute Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
Christopher M. Scott, Gloria F. Graham,
and Ronald R. Lubritz
49 Chronic Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
Gloria F. Graham, Christopher M. Scott,
and Ronald R. Lubritz
50 Prevention and Management of Complications . . . . . . . . . . . . 235
Christopher M. Scott, Ronald R. Lubritz,
and Gloria F. Graham
Part VIII Cryosurgery in Special Populations

51 The Management of the Pediatric Patient

and Adolescent During Skin Cryosurgery. . . . . . . . . . . . . . . . . 243
Nir Gal Or and Yaron Har-Shai
52 Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
William Abramovits and Kimberly Dawn Vincent
53 Cutaneous Lesions of HIV-Positive Patients . . . . . . . . . . . . . . . 257
Ann M. John, Heather M. Holahan,
and Robert A. Schwartz
Part IX Special Indications and Contraindications

54 Special Indications and Contraindications . . . . . . . . . . . . . . . . 265

Yaron Har-Shai
55 Aesthetic/Cosmetic Cryosurgery . . . . . . . . . . . . . . . . . . . . . . . . 269
Oliverio Welsh, Esperanza C. Welsh,
and Jesús Alberto Cárdenas
56 Palliative Cryosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
Divya Sharma, Robert A. Schwartz,
and William Abramovits
57 Oral Mucous Membrane Cryosurgery . . . . . . . . . . . . . . . . . . . 283
Carlos Horacio Gonzalez Rojas
58 Basal Cell Carcinoma of the Eye Area. . . . . . . . . . . . . . . . . . . . 295
Bobby L. Limmer
Contents xi

59 Cryosurgery for External Ear Pathology. . . . . . . . . . . . . . . . . . 299

Carlos Horacio Gonzalez Rojas
60 Cryosurgery of the Nose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
Marcial Oquendo, William Abramovits,
and Alba G. Quiñones
Part X Cryosurgery in Combinations

61 Combination Cryosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311

Michael Thomas Jennings and William Abramovits

Part XI Cryosurgical Treatment of Benign

Skin Conditions

62 Acne ............................................. 319

Gloria F. Graham and Sara Moradi Tuchayi
63 Alopecia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
Renata Strumia
64 Angiokeratoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
Stephanie Saxton-Daniels
65 Angiolymphoid Hyperplasia with Eosinophilia . . . . . . . . . . . . 331
Stephanie Saxton-Daniels
66 Callosities, Corns, Clavi, Tylomata . . . . . . . . . . . . . . . . . . . . . . 333
Renata Strumia
67 Cryosurgery of Plantar Lesions . . . . . . . . . . . . . . . . . . . . . . . . . 335
Michelle A. Nguyen, Jennifer Krejci-Manwaring,
and Bobby L. Limmer
68 Cheilitis and Miscellaneous Benign Lip Lesions . . . . . . . . . . . . 339
Marcia Ramos-e-Silva, Cleide Eiko Ishida,
and Stella Ramos-e-Silva
69 Chromoblastomycosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
Ted Rosen, Alexandro Bonifaz, Leonel Fierro-Arias,
Amelia Peniche-Castellanos,
and Denisse Vázquez-González
70 Clear Cell Acanthoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
Jacqueline Guidry and Ted Rosen
71 Condyloma Acuminatum (Genital Warts). . . . . . . . . . . . . . . . . 361
Renata Strumia
72 Dermatofibroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
Renata Strumia
73 Dermatosis Papulosa Nigra. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
Neiraja Gnaneswaran, Eshini Perera,
and Shobhan Manoharan
xii Contents

74 Elastosis Perforans Serpiginosa . . . . . . . . . . . . . . . . . . . . . . . . . 373

Luciana Samorano, Eugênio Raul de Almeida Pimentel,
and Marcello Menta Simonsen Nico
75 Epidermal Nevi. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
Antonios Panagiotopoulos
76 Fibrous Papules of the Nose . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
Renata Strumia
77 Granuloma Annulare. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
Renata Strumia
78 Granuloma Faciale. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
Basil Patel, Robert A. Schwartz, William Abramovits,
and Kimberly Dawn Vincent
79 Granuloma Fissuratum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
Renata Strumia
80 Hemangiomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
William Abramovits and Kimberly Dawn Vincent
81 Herpes Simplex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
Renata Strumia
82 Post-herpetic Neuralgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399
Jacqueline Guidry and Ted Rosen
83 Hyperkeratosis of the Nipple and Areola . . . . . . . . . . . . . . . . . 403
Christina M. Ring and Robert A. Schwartz
84 Idiopathic Guttate Hypomelanosis. . . . . . . . . . . . . . . . . . . . . . . 407
Prasad Kumarasinghe
85 Cryosurgical Treatment of Keloids
and Hypertrophic Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
Christos C. Zouboulis, Yaron Har-Shai,
and Constantin E. Orfanos
86 Intralesional Cryosurgery for the Treatment
of Hypertrophic Scars and Keloids . . . . . . . . . . . . . . . . . . . . . . 453
Yaron Har-Shai and Christos C. Zouboulis
87 Cutaneous Larva Migrans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
Stefano Veraldi, Ermira Çuka, and Fabrizio Vaira
88 Hidradenitis Suppurativa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
Calogero Pagliarello, Giuseppe Fabrizi,
Claudio Feliciani, and Sergio di Nuzzo
89 Leishmaniasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
Antonio Rondón Lugo
90 Lentigo and Solar Lentigines . . . . . . . . . . . . . . . . . . . . . . . . . . . 491
Leon Neumann
Contents xiii

91 Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503

Heather M. Holahan and Robert A. Schwartz
92 Lichen Sclerosus et Atrophicus. . . . . . . . . . . . . . . . . . . . . . . . . . 507
Hee Jin Kim and Robert A. Schwartz
93 Lichen Simplex Chronicus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511
Renata Strumia
94 Lupus, Discoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513
Martina Brandner and Angelika Klein-Theyer
95 Lymphangioma Circumscriptum . . . . . . . . . . . . . . . . . . . . . . . . 517
Jessica Alexis Savas and Gloria F. Graham
96 Lymphocytoma Cutis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521
Hee Jin Kim, Brian W. Lee, and Robert A. Schwartz
97 Molluscum Contagiosum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525
Chante Karimkhani, Lindsay N. Boyers,
Ryan Gamble, and Robert P. Dellavalle
98 Milia en Plaque. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529
Giuseppe Noto
99 Digital Mucoid Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
Alba G. Quiñones
100 Nevus Sebaceus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535
Marc Zachary Handler and Robert A. Schwartz
101 Orf ............................................. 537
Jorge Ocampo-Candiani and Kristian Eichelmann
102 Pearly Penile Papules. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541
Jorge Ocampo-Candiani and Kristian Eichelmann
103 Porokeratosis of Mibelli. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545
Selçuk Özyurt and Tuğrul Dereli
104 Porokeratosis, Linear. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549
Renata Strumia
105 Cryosurgery for Disseminated Superficial
Actinic Porokeratosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553
Vijay Vanchinathan and Robert A. Schwartz
106 Cryosurgery for Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557
Mohammad-Ali Yazdani Abyaneh, Robert Griffith,
Leyre Falto-Aizpurua, and Keyvan Nouri
107 Prurigo Nodularis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563
Renata Strumia
108 Cryosurgery for Pruritus Ani . . . . . . . . . . . . . . . . . . . . . . . . . . . 567
Parmvir Singh and Robert A. Schwartz
xiv Contents

109 Pyogenic Granuloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571

Renata Strumia
110 Rhinophyma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575
Renata Strumia
111 Rosacea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579
Renata Strumia
112 Cutaneous Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
Ann M. John, Brian W. Lee, and Robert A. Schwartz
113 Seborrheic Keratosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589
Kimberly Dawn Vincent and William Abramovits
114 Acrochordons (Skin Tags) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595
Kimberly Dawn Vincent and William Abramovits
115 Steatocystoma Multiplex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
Renata Strumia
116 Syringoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
Renata Strumia
117 Sebaceous Gland Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . 605
Rivka C. Stone and Robert A. Schwartz
118 Cryosurgery for Tattoo Removal . . . . . . . . . . . . . . . . . . . . . . . . 609
Christina M. Ring and Philip J. Cohen
119 Tick Removal with Liquid Nitrogen. . . . . . . . . . . . . . . . . . . . . . 611
Mira Pavlovic
120 The Tuberous Sclerosis Complex . . . . . . . . . . . . . . . . . . . . . . . . 615
Carmelo Schepis
121 Venous Lakes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619
Renata Strumia
122 Cryosurgery of Common Warts . . . . . . . . . . . . . . . . . . . . . . . . . 621
Noah Scheinfeld
123 Cryosurgery for Verruca Palmaris. . . . . . . . . . . . . . . . . . . . . . . 625
Nancy S. Handler, Marc Zachary Handler,
and Robert A. Schwartz
124 Verruca Plana (Flat Viral Warts) . . . . . . . . . . . . . . . . . . . . . . . . 629
Renata Strumia
125 Verruca Filiformis (Filiform Wart) . . . . . . . . . . . . . . . . . . . . . . 631
Renata Strumia
126 Cryosurgery for Xanthomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
Parmvir Singh, Marc Zachary Handler,
and Robert A. Schwartz
Contents xv

Part XII Pre-malignant and Malignant Skin Conditions

127 Cryosurgery for Premalignant and Malignant

Skin Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639
Parmvir Singh, Rivka C. Stone, Robert A. Schwartz,
and Giuseppe Micali
128 Actinic Keratosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 645
Leonard H. Goldberg, Diane Trieu, and Anna Drosou
129 Bowenoid Papulosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655
Thomas J. Jasterzbski and Robert A. Schwartz
130 Basal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
Eshini Perera and Rodney Sinclair
131 Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
Gloria F. Graham and Sara Moradi Tuchayi
132 Verrucous Carcinoma (Oral) . . . . . . . . . . . . . . . . . . . . . . . . . . . 675
Marcello Menta Simonsen Nico and Silvia Vanessa Lourenço
133 Kaposi Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681
Renata Strumia
134 Keratoacanthoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 685
Renata Strumia
135 Cutaneous Leiomyosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689
Ann M. John, Shilpa Agarwal, and Robert A. Schwartz
136 Lentigo Maligna and Lentigo Maligna Melanoma . . . . . . . . . . 695
Raymond Cornelison
137 Malignant Melanoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
Pedro Redondo
138 Leukoplakia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713
Marcia Ramos-e-Silva, Cleide Eiko Ishida,
and Stella Ramos-e-Silva
139 Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 719
Patricia L. Myskowski
140 Chronic Radiodermatitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723
Francesco Feletti and Renata Strumia

Part XIII Socioeconomic Issues

141 Cryosurgery for Non-melanoma Skin

Cancer: A Cost Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 729
Howard W. Rogers
142 A Photographic Walk in Veterinary Cryosurgery . . . . . . . . . . 737
Bobby L. Limmer
xvi Contents

Part XIV The Future of Cryosurgery

143 The Future of Cryosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749

William Abramovits
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751
Contributors

William Abramovits, MD, FAAD Department of Dermatology,

Baylor University Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology, The University of Texas
Southwestern Medical School, Dallas, TX, USA
Department of Internal Medicine, Texas College of Osteopathic Medicine,
University of North Texas Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas Medical Branch,
Dallas, TX, USA
Texas Tech University, Health Sciences Center, Lubbock, TX, USA
Texas A&M Health Science Center College of Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center, Dallas, TX, USA
Mohammad-Ali Yazdani Abyaneh, BS Department of Dermatology
and Cutaneous Surgery, University of Miami Miller School of Medicine,
Miami, FL, USA
Shilpa Agarwal, MD Department of Dermatology, Rutgers New Jersey
Medical School, Newark, NJ, USA
C. Lee Asplund, BSc, MS Independent Sales, Marketing, and Business
Development Consultant and former Director of Sales and Marketing for
MMR Technologies, Inc., Sacramento, CA, USA
John G. Baust, PhD Department of Biological Sciences,
Institute of Biomedical Technology, Binghamton, NY, USA
John M. Baust, PhD Department of Research and Development,
CPSI Biotech, Owego, NY, USA
John C. Bischof, PhD Department of Mechanical and Biomedical
Engineering, University of Minnesota, Minneapolis, MN, USA
Alexandro Bonifaz, PhD Department of Dermatology/Mycology,
Hospital General de México, Mexico City, DF, Mexico
Lindsay N. Boyers, BA Yale-Waterbury Department of Internal Medicine,
Waterbury, CT, USA

xvii
xviii Contributors

Martina Brandner, MD Department of Ophthalmology,

Medical University Graz, Graz, Austria
Harold J. Brody, MD Department of Dermatology,
Emory University School of Medicine, Atlanta, GA, USA
Matthew Brothers, PhD Department of Kinesiology and Health Education,
The University of Texas at Austin, Austin, TX, USA
Suzanne Bruce, MD Suzanne Bruce & Associates, Katy, TX, USA
Jesús Alberto Cárdenas, MD Department of Dermatology,
Centro de Especialidades Medicas, Monterrey, Nuevo León, Mexico
Jeunghwan Choi, PhD Department of Engineering,
East Carolina University, Greenville, NC, USA
Philip J. Cohen, MD Department of Dermatology, VA New Jersey Health
Care System, Rutgers New Jersey Medical School, Newark/East Orange,
NJ, USA
Raymond Cornelison, MD OKC Dermatology Associates,
Oklahoma City, OK, USA
Ermira ౪uka, MD Department of Pathophysiology and Transplantation,
Universita’ degli Studi di Milano, I.R.C.C.S. Foundation,
Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Robert P. Dellavalle, MD, PhD, MSPH Department of Dermatology,
Veteran Affairs Medical Center, Denver, CO, USA
Janyana M.D. Deonizio, MD Department of Dermatology,
Hospital das Clinicas, Curitiba, Parana, Brazil
Tuğrul Dereli, PhD, MD Department of Dermatology, Ege University,
İzmir, Turkey
Sergio Di Nuzzo, MD, PhD Department of Clinical and Experimental
Medicine, University of Parma, Parma, Italy
Kenneth R. Diller, ScD Department of Biomedical Engineering,
The University of Texas at Austin, Austin, TX, USA
Anna Drosou, MD Department of Dermatology, Derm Surgery Associates,
Houston, TX, USA
Kristian Eichelmann, MD Department of Dermatology,
University Hospital “José E. González”, Monterrey, Nuevo León, Mexico
Giuseppe Fabrizi, MD, PhD Department of Clinical and Experimental
Medicine, University of Parma, Parma, Italy
Leyre Falto-Aizpurua, MD Department of Dermatology and Cutaneous
Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
Francesco Feletti, MD Local Health Trust of Romagna, Department of
Diagnostic Imaging, S. Maria delle Croci Hospital, Ausl della Romagna,
Ravenna, Italy
Contributors xix

Department of Electronics, Information and Bioengineering Polytechnic

University of Milan, Milan, Italy
Claudio Feliciani, MD, PhD Department of Clinical and Experimental
Medicine, University of Parma, Parma, Italy
Leonel Fierro-Arias, MD Department of Dermatology,
Hospital General de México, Mexico City, DF, Mexico
Andrew A. Gage, MD Department of Surgery (Emeritus),
State University of New York at Buffalo Medical School, Buffalo, NY, USA
Ryan Gamble, MD Department of Dermatology, University of Colorado,
Aurora, CO, USA
Neiraja Gnaneswaran, MBBS, BMedSci Department of Plastic
and Reconstructive Surgery, Queensland Health, Southport, QLD, Australia
Leonard H. Goldberg, MD Department of Dermatology,
Derm Surgery Associates, Houston, TX, USA
Gloria F. Graham, MD Department of Dermatology, Wake Forest University
School of Medicine, Winston Salem, NC, USA
Robert Griffith, MD Department of Dermatology and Cutaneous Surgery,
University of Miami Miller School of Medicine, Miami, FL, USA
Jacqueline Guidry, MD Department of Internal Medicine,
Baylor College of Medicine, Houston, TX, USA
Marc Zachary Handler, MD Department of Dermatology,
Rutgers University New Jersey Medical School, Newark, NJ, USA
Nancy S. Handler, MD Department of Dermatology,
Rutgers University New Jersey Medical School, Newark, NJ, USA
Yaron Har-Shai, MD Department of Plastic Surgery,
The lady Davis Carmel Medical Center, Linn Medical Center, Haifa, Israel
Alice He, BS, BA Department of Dermatology, Johns Hopkins School
of Medicine, Baltimore, MD, USA
Heather M. Holahan, MD Department of Dermatology, Rutgers New
Jersey Medical School, Newark, NJ, USA
Cleide Eiko Ishida, MD Sector of Dermatology and Post-Graduation
Course, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Thomas J. Jasterzbski, MD Department of Dermatology,
Rutgers University New Jersey Medical School, University Hospital,
Newark, NJ, USA
Michael Thomas Jennings, BS Paul L. Foster School of Medicine,
MS2 Texas Tech University, El Paso, TX, USA
Silvia Jiang-Hughes, PhD Department of Regulatory Affairs,
Abbott Laboratories, Alameda, CA, USA
xx Contributors

Ann M. John, MD Department of Dermatology, Rutgers New Jersey

Medical School, Newark, NJ, USA
Chante Karimkhani, BA University Hospitals Case Medical Center,
New York, NY, USA
Sepideh Khoshnevis, MD, PhD Department of Biomedical Engineering,
The University of Texas at Austin, Austin, TX, USA
Hee Jin Kim, MD Department of Dermatology, Rutgers University
New Jersey Medical School, Newark, NY, USA
Angelika Klein-Theyer, MD Department of Ophthalmology,
Medical University Graz, Graz, Austria
Jennifer Krejci-Manwaring, MD Department of Dermatology,
University of Texas Health Science Center, San Antonio, TX, USA
Saravana B. Kumar, PhD Department of Mechanical Engineering,
University of Minnesota, Minneapolis, MN, USA
Prasad Kumarasinghe, MBBS, MD, FAMS, FACD Department
of Dermatology, Royal Perth Hospital, Perth, WA, Australia
Carmen I. Hernandez Lara, BS, PhD Department of Research
and Development, Laboratorio Behrens, Caracas, Miranda, Venezuela
Brian W. Lee, MD Department of Dermatology, Rutgers University
New Jersey Medical School, Newark, NJ, USA
Bobby L. Limmer, MD Department of Dermatology, Plastic Surgery,
University of Texas Health Science Center, San Antonio, TX, USA
Silvia Vanessa Lourenço, DDS Department of Pathology,
Faculdade de Odontologia da Universidade de São Paulo,
São Paulo, São Paulo, Brazil
Ronald R. Lubritz, MD, FACP Department of Dermatology,
Tulane University School of Medicine, Hattiesburg Clinic, Hattiesburg,
MS, USA
Antonio Rondón Lugo, MD Instituto de Biomedicina, Universidad
Central de Venezuela, Calle Venezuela, Quinta Natilse, Terrazas Club
Hipico, Caracas, Miranda, Venezuela
Shobhan Manoharan, MBBS, FACD Department of Dermatology,
Westside Dermatology, Taringa, QLD, Australia
Giuseppe Micali, MD Department of Dermatology, University of Catania,
Catania, Italy
Patricia L. Myskowski, MD Department of Dermatology,
Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College,
New York, NY, USA
Leon Neumann, MD Department of Dermatology, ABC Hospital,
Mexico City, DF, Mexico
Contributors xxi

Michelle A. Nguyen, BS University of Texas Health Science Center

at San Antonio, San Antonio, TX, USA
Marcello Menta Simonsen Nico, MD Department of Dermatology,
Medical School, University of São Paulo, Brazil, Hospital das Clínicas,
São Paulo, São Paulo, Brazil
Giuseppe Noto, MD Unit of Dermatology, Department of Oncology,
La Maddalena, Palermo, Italy
Keyvan Nouri, MD Department of Dermatology and Cutaneous Surgery,
University of Miami Miller School of Medicine, Miami, FL, USA
Jorge Ocampo-Candiani, MD Department of Dermatology,
University Hospital “José E. González”, Monterrey, Nuevo León, Mexico
Marcial Oquendo, MD Department of Pediatrics,
Driscoll Children’s Hospital, Corpus Christi, TX, USA
Nir Gal Or, MD Department of Plastic Surgery, The Lady Davis Carmel
Medical Center, Haifa, Israel
Constantin E. Orfanos, MD, Emeritus The Free University of Berlin,
Berlin, Germany
Selçuk Özyurt, MD Department of Dermatology, Izmir Atatürk Education
and Research Hospital, İzmir, Turkey
Calogero Pagliarello, MD, PhD Department of Clinical and Experimental
Medicine, University of Parma, Parma, Italy
Antonios Panagiotopoulos, MD Department of Cryosurgery,
Andreas Syggros, Athens, Greece
Basil Patel, BS Department of Dermatology, Rutgers University New
Jersey Medical School, Newark, NJ, USA
Manisha J. Patel, MD Department of Dermatology, Johns Hopkins School
of Medicine, Baltimore, MD, USA
Mira Pavlovic, MD Department of Dermatology, Hospital Tenon,
Paris, France
Amelia Peniche-Castellanos, MD Department of Dermatology,
Hospital General de México, Mexico City, DF, Mexico
Eshini Perera, MBBS, BMedSci Sinclair Dermatology, Department
of Medicine, Dentistry and Health Sciences, University of Melbourne,
East Melbourne, VIC, Australia
Jennifer Peterson, MD Suzanne Bruce & Associates, Katy, TX, USA
Eugênio Raul de Almeida Pimentel, MD Department of Dermatology,
Medical School, University of São Paulo, Hospital das Clínicas, São Paulo,
São Paulo, Brazil
Ana M. Prato-Guia, MD Dermatology Treatment and Research Center,
Dallas, TX, USA
xxii Contributors

Alba G. Quiñones, MD Dermatology Treatment and Research Center,

Dallas, TX, USA
Marcia Ramos-e-Silva, MD, PhD Sector of Dermatology
and Post-Graduation Course, Federal University of Rio de Janeiro,
Rio de Janeiro, Brazil
Stella Ramos-e-Silva, MD Sector of Dermatology and Post-Graduation
Course, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Pedro Redondo, MD, PhD Department of Dermatology,
University Clinic of Navarra, Pamplona, Navarra, Spain
Christina M. Ring, BS Department of Dermatology,
Rutgers New Jersey Medical School, Newark, NJ, USA
Howard W. Rogers, MD, PhD Advanced Dermatology, Norwich,
CT, USA
Carlos Horacio Gonzalez Rojas, MD Clinica del Café, Armenia,
Quindio, Columbia
Ted Rosen, MD Department of Dermatology, Baylor College of Medicine,
Houston, TX, USA
Michael Scott Sabel, MD, FACS Department of Surgery,
University of Michigan, Ann Arbor, MI, USA
Luciana Samorano Department of Dermatology, Medical School,
University of São Paulo, , Hospital das Clínicas, São Paulo,
São Paulo, Brazil
Jessica Alexis Savas, BS, MD Department of Dermatology
& Cutaneous Surgery, University of Miami Miller School of Medicine,
Miami, FL, USA
Stephanie Saxton-Daniels, MD Dermatology Treatment and Research
Center, Dallas, TX, USA
Noah Scheinfeld, MD, JD Department of Dermatology-Weil Cornel
Medical College, New York Hospital, New York, NY, USA
Carmelo Schepis, MD Unit of Dermatology, Oasi Institute for Research
on Mental Retardation and Brain Aging, Troina, Sicily, Italy
Robert A. Schwartz, MD, MPH, DSc (Hon), FRCP (Edin) Dermatology
and Pathology, Rutgers University New Jersey Medical School, Rutgers
University School of Public Affairs and Administration, Newark, NJ, USA
Christopher M. Scott, MD Department of Dermatology,
University of Virginia, Charlottesville, VA, USA
Divya Sharma, MD Department of Dermatology, Rutgers University
New Jersey Medical School, Newark, NJ, USA
Contributors xxiii

Rodney Sinclair, MBBS, MD, FACD Sinclair Dermatology,

Department of Medicine, Dentistry and Health Sciences,
University of Melbourne, East Melbourne, VIC, Australia
Parmvir Singh, MD Department of Dermatology, University Hospital,
Newark, NJ, USA
Rivka C. Stone, MD, PhD Department of Dermatology,
Rutgers-New Jersey Medical School, Newark, NJ, USA
Renata Strumia, MD Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University of Ferrara, Ferrara, Italy
(Former)
Diane Trieu, MD Department of Dermatology, Derm Surgery Associates,
Houston, TX, USA
Sara Moradi Tuchayi, MD, MPH Department of Dermatology,
Wake Forest University School of Medicine, Winston Salem, NC, USA
Fabrizio Vaira, MD Dermatology Unit, Department of Medical,
Surgical Diagnostic and Pediatric Science, University of Pavia,
Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Vijay Vanchinathan, MD Department of Dermatology,
Rutgers University New Jersey Medical School, University Hospital,
Newark, NJ, USA
Denisse Vázquez-González, MD Department of Dermatology,
Hospital General de Mexcio “Eduardo Liceaga” O.D., Mexico City, Mexico
Stefano Veraldi, MD, PhD Department of Pathophysiology
and Transplantation, Universita’ Degli Studi di Milano,
IRCCS FOUNDATION, Ca’ Granda Ospedale Maggiore Policlinico,
Milan, Italy
Kimberly Dawn Vincent, MD, FAAD Belle Meade Dermatology,
Nashville, TN, USA
Esperanza C. Welsh, MD Department of Dermatology,
Centro de Especialidades Medicas, Monterrey, Nuevo León, Mexico
Oliverio Welsh, MD, DSc Department of Dermatology,
University Hospital, UANL, San Pedro, Nuevo León, Mexico
Christos C. Zouboulis, PhD, MD Departments of Dermatology,
Venereology, Allergology and Immunology, Dessau Medical Center,
Dessau, Germany
 Part I
History
 The History of Dermatologic
Cryosurgery
1
William Abramovits

Abstract
The therapeutic use of “extreme” cold dates from the mid nineteen cen-
tury. For over a hundred years cryosurgery has been used to treat skin
cancer; also skin infections, benign tumors, and a myriad of other condi-
tions. Understanding of the mechanism by which cold affects the skin and
other organs has led to the development of progressively better delivery
systems, cryogens and monitorization equipment; all this thanks to the
contributions of many bright medical and other scientific minds which we
attempted to recognize in this chapter.

Keywords
History • Liquid air • Carbon dioxide • Liquid oxygen • Liquid nitrogen •
Isotherms • Monitorization • Cryotherapy • Cryosurgery

W. Abramovits, MD, FAAD

Department of Dermatology, Baylor University Although the history of the use of lowered tem-
Medical Center, Dallas, TX, USA
peratures for therapeutic purposes may go as
Department of Internal Medicine, University of North far back as ancient Egypt and Greece its early
Texas Health Science Center, Texas College of
Osteopathic Medicine, Fort Worth, TX, USA
use, was intended to provide analgesia and
inflammation relief. Frostbite, an injury due to
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
ice crystal formation in superficial and deep tis-
sues was appreciated long before; a 5,000-year-
The University of Texas Southwestern Medical
School, Dallas, TX, USA
old mummy found in Chilean mountains
represents the earliest documentation of its
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
occurrence [1, 2].
Dermatologic cryosurgery textbooks and schol-
Texas A&M Health Science Center College of
Medicine, Bryan, TX, USA
arly reviews credit James Arnott, with the first
publication on the destruction of skin tissue by
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160, Dallas,
means of “extreme” cold (circa 1851), which he
TX 75230, USA achieved by mixing finely crushed ice and sodium
e-mail: DrA@dermcenter.us chloride, recommending it in acne, neuralgia and

© Springer-Verlag London 2016 3

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_1
4 W. Abramovits
to anesthetize skin preoperatively; and supposed
the curability of cancers by congelation [3].
Campbell White, in articles published in 1899
and 1901 advocated the use of liquid air for the
treatment of a variety of skin conditions includ-
ing lupus, herpes zoster, chancroid, nevi, warts,
leg varicosities, carbuncles and epitheliomata.
About the latter he said that treated early it will
always be cured [4].
Whitehouse, H in 1907 reported on the use of
liquid air on vascular nevi, lupus erythematosus
and epitheliomata; about the latter he found it to
be more successful at eradicating recurrences
than repeat radiotherapy; that same year Bowen,
JT and Towle, HP reported on the successful use
of liquid air on vascular lesions [4–6].
Hall-Edwards, J in 1911 reported on the use of
carbon dioxide (CO2) in many conditions, but
most notably on “rodent ulcers” [7] an old term
for ulcerated basal-cell carcinomas and on the
same year Cranston-Low explained the results of
cryosurgery as the sum of its directly injurious,
thrombotic and inflammatory effects [3–5].
Gold, J in 1910 reported on the comparison of
the effects of liquid air versus CO2 stating with “no
hesitancy” that the former is “far preferable” [8].
In the 1920s and 1930s liquid oxygen was
used for the treatment of acne.
Irvine, H and Turnacliffe, D in 1929 favored
liquid air and oxygen over CO2, reporting on the
use of the former in seborrheic and senile kerato-
sis, lichen simplex, poison ivy dermatitis and her-
pes zoster; and of liquid oxygen for warts,
including plantar [9, 10].
Pussey, W in 1935 popularizes the use of CO2
snow derived from steel cylinders that kept it in
liquid state, which when allowed to escape, turns
into a fine snow that can be compressed into
shapes for particular treatments; Pussey success-
fully treated a large black hairy nevus on a girl’s
face, as well as warts, nevi and lupus erythemato-
sus. He also recognized the low scarring potential
of cryosurgery [6].
Allington, HV in 1950 is the first to publish on
the satisfactory use of liquid nitrogen in the treat-
ment of warts, keratosis, superficial hemangio-
mas, leukoplakia, keloids, acute contact
dermatitis, lichen simplex and planus, pyogenic
granulomas, discoid lupus and acne. His cure
rates treating common warts surpassed 90 % in
three treatments done dipping cotton swabs into
thermos bottles containing liquid nitrogen.
Besides his elegant description of the method he
used, histologic findings of post-cryosurgery
were reported in the article [11].
In the 1960s several reports are made of the
use of CO2 from dry ice, pulverized and wrapped
into bags (golf ball size) lined with gauze, some-
times mixed with precipitated sulfur, and doused
with acetone, in acne therapy.
Cooper, IS in 1963 reported on the use of liq-
uid nitrogen to destroy or extirpate benign and
malignant skin lesions; he had developed an
apparatus to deliver liquid nitrogen targeted for
neurosurgical use [13].
Torre, D [14] in 1965 and Zacarian, S [15] in
1967 presented hand held devices to spray liquid
nitrogen that were particularly well suited to the
dermatology practice; later on both dermatologists
wrote extensively on the subject, particularly
Zacarian who published a textbook on Cryosurgery
of Skin Cancer, and Cryogenic Techniques in
Dermatology in 1969 and two other in 1977 and
1985 [16–18]. Torre edited an issue of the Journal
of Dermatologic Surgery and Oncology wholly
dedicated to cryosurgery in 1983 [19].
Gage, AA in 1965 [20] writes on cryosurgery
of the lip and oral cavity, later on benign and
malignant lesions of the mouth; then on its use
for pilonidal cysts, basal and squamous cell car-
cinoma, lentigo maligna, and on ear cancer. His
body of work exceeds 70 papers listed in the
PubMed database and many textbook chapters.
Gage has made major contributions to the
field of cryobiology, the understanding of the
mechanisms by which cryosurgery works, and to
its monitorization.
Graham, GF in 1971 [21] reviews the use of
cryosurgery in the treatment of malignant lesions
of the skin and later publishes on the success
rates of this modality for the ablation of basal cell
carcinomas. Graham, GF writes and lectures
extensively; in 1994 she was the Chair of the
Task Force that developed the American
Academy of Dermatology Guidelines of Care of
Cryosurgery.
1 The History of Dermatologic Cryosurgery
Other distinguished and contemporaneous
contributors to the field of dermatologic cryosur-
gery include: Emmanuel Kuflik, Rodney Dawber,
Gilberto Castro-Ron, Reimo Suhonen, Ronald
Lubritz, Lazlo Biro, José M. Férnandez-
Vozmediano, Peter Nordin, CC Zouboulis, José
Carlos d’Almeida-Gonçalves and my co-editors
and chapter writers for this textbook.
A PubMed review of a cross search of cryo-
surgery and dermatology found the following list
of diseases as one time or another since 1963
when the database began to have been reported as
amenable to cryosurgery treatment [12]:
Molluscum Contagiosum, Actinic Keratosis,
Elastosis Perforans Serpiginosa, Basal and
Squamous Cell Carcinomas, Lentigo Maligna,
Lentigo Maligna Melanoma, Melanoma Maligna,
Hemangiomas, Trichoepitheliomas, Porokeratosis
of Mibelli, Kaposi’s Sarcoma, Mucous Cyst,
Hemorrhoids, Pilonidal Cysts, Nevus Flammeus,
Condyloma, Cylindroma, Herpes Simplex,
Telangiectasia, Atypical Fibroxanthoma, Bowen’s
Disease, Angiofibromas of Tuberous Sclerosis,
Cherry and Capillary Angiomas, Cavernous
Hemangiomas, Epidermal Nevus, Keloids,
Lichen Sclerosus and Atrophicans, Erythroplasia
of Queyrat, Verruciform Epidermodysplasia
of Lewandowski and Lutz, Extramammary
Paget’s Disease, Actinic Comedonal Plaque,
Prurigo Nodularis, Tattoos, Pigmented Nevi,
Carbuncles, Clear Cell Acanthomas, Trichiasis,
Dermatofibromas, Sebaceous Hyperplasia,
Angiolymphoid Hyperplasia, Tricoepithelioma,
Chalazion, Neurodermatitis, Bowenoid Papulosis,
Leishmaniasis, Lupus Erythematosus, Idiopathic
Guttate Hypomelanosis, Lymphocytoma
Cutis, Leukoplakia, Hypertrophic Scars,
Xanthogranulomas, Cutaneous Larva Migrans,
Granuloma Annulare, Facial Eosinophilic
Granuloma, Xanthelasma, Leiomyosarcoma,
Actinic Cheilitis, Pearly Penile Papules,
Venous Lakes, Granuloma Faciale, Giant
Cell Tumor, Milia, Rhinophyma, Pyogenic
Annulare, Chomomycosis, Epidermodysplasia
Verruciformis, Verrucous Hyperplasia and
Carcinoma, Acrokeratosis Verruciformis of Hopf,
Seborrheic Keratosis, Merkel Cell Carcinoma,
Keratocanthoma, Myasis, Multinucleate Cell
5
Angiohistiocytoma, Blue Rubber Bleb Nevus
Syndrome, Lobomycosis, PTEN Hamartoma
Tumor Syndrome, Oral and Acral Pigmentation
of Laugier-Hunziker Syndrome, Xeroderma
Pigmentosa, and Kindler Syndrome.
The same review found the following as com-
plications of cryosurgery: Pruritus, neuropathy,
residual tumor, relapses and recurrences, loss of
pigment, reactive lentiginous hyperpigmentation,
delayed wound healing, hypopigmented, hyper-
trophic and depressed scars, retraction at the free
margins of lips and eyelids, pseudoepithelioma-
tous hyperplasia, hyperemia, erythema, edema,
bullae, loss of lashes, hairs and meibomian
glands, damage to the lacrimal system, bacterial
and viral transfer risk, erosive pustular dermato-
sis of the scalp, amelanotic melanoma at
recurrence.
A progressive understanding of the mode of
action of cryosurgery includes reports on cryo-
gen induced low temperatures on animal and
human skin, measurements of temperatures
below the skin surface, the influence of blood
flow on freezing and thawing times [13], the
evaluation of circulatory events during and after
cryosurgery versus before it, the histopathology
of the cryo-lesion, the finding of the minimal
temperature lowering leading to epidermal
necrosis, the effect of cryoprotective agents, the
determination of the temperatures lethal do dif-
ferent cells, comparative histologic observations
between thermo and cryonecrosis, vascular
induction of cryolesions by thrombotic events,
the mediators of pain during and post-
cryosurgery, the effect of anesthesia and epi-
nephrine on cryolesions, the detection of
antibodies to epidermal cytoplasmatic antigens
and cell mediated immunity post procedure,
induction of stress (heat shock) proteins, immu-
nomodulatory effects of cryosurgery on mela-
noma response, wound healing and scarring
from different freezing protocols, long-term
effects of cryosurgery on cutaneous sensation,
the ablative effects of freeze-thaw times and
cycle repetition, the use of clobetasol [14] and
antimicrobials to reduce inflammation and infec-
tions post-procedure, the differential effects of
various refrigerants.
6 W. Abramovits
An array of methods have evolved from the
times that a simple thermometer was used to read
the skin temperature at the site of application of
cryogens or of the cryogens themselves; monitor-
ization has progressed from the visual and tactile
estimation of frozen skin margins, and the dura-
tion of freeze and thaw times, to the use of ther-
mocouple needles that allow for more accurate
estimation of temperatures below the surface and
at expected lesion depth [15, 16]. Other modali-
ties currently being used to estimate depth and
intensity of freeze and to match those to targets
include: Measurements of electrical impedance
[17] and current flow, ultrasound and echography
to estimate tumor extent, increase the precision
of thermocouple placement and detection of a
match of cryodestructive isotherms and tumor
extension [18], The use of magnetic resonance
imaging (MRI) [19], optical coherence and
impedance tomography, real time infrared guid-
ance, second-harmonic generation microscopy
and in vivo reflectance confocal microscopy.
Other ways to optimize the success of cryosur-
gery evolving over the years include combinations
with supervoltage, curettage and radiofrequency
for preoperative debulking, the use of epinephrine
in the local anesthetics, retinoids orally and
topically, chemotherapeutic agents, non-steroidal
anti-inflammatories, immune-stimulatory agents
including imiquimod and tumor necrosis factor
alpha, and tagging tumor cells with metallic
nanoparticles, and sclerosing agents.
The incessant understanding of the mecha-
nisms of action of lower temperatures and of the
imaging technologies lead the way to increasing
success for cryotherapy and cryosurgery.
References
1. Zonnevylle JA, Zwaveling A. The influence of cryo-
surgery and electrocoagulation upon metastatic
spread. J Surg Oncol. 1984;27(2):131–4.
2. Sguazzi A, Bracco D. A historical account of the tech-
nical means used in cryotherapy. Minerva Med.
1974;65(70):3718–22.
3. Cooper SM, Dawber RP. The history of cryosurgery.
J R Soc Med. 2001;94(4):196–201.
4. Fraunfelder FW. Liquid nitrogen cryotherapy for sur-
face eye disease (an AOS thesis). Trans Am
Ophthalmol Soc. 2008;106:301–24.
5. Ahmed L, Ahmed S, Davies J. History of cryosurgery.
J Endourol/Endourol Soc. 2006;20(7):471–4.
6. Hall AF. Advantages and limitations of liquid nitrogen
in the therapy of skin lesions. Arch Dermatol.
1960;82:9–16.
7. Jh E. The therapeutic effects of carbon dioxide snow:
methods of collecting and application. Lancet.
1911;ii:87–90.
8. Kile RL, Welsh AL. Liquid oxygen in dermato-
logic practice. Arch Derm Syphilol. 1948;57(1):
57–62.
9. Turnacliff DD, Irvine HG. Liquid oxygen in derma-
tology. Arch Derm Syphilol. 1929;19(2):270–80.
10. Laymon CW, Balogh CJ. The use of liquid oxygen in
dermatology. Minn Med. 1956;39(3):151–2; contd.
11. Allington HV. Liquid nitrogen in the treatment of skin
diseases. Calif Med. 1950;72(3):153–5.
12. PubMed Search. 2014. URL: http://www.ncbi.nlm.
nih.gov/pubmed/?term=cryosurgery+AND+dermatol
ogy. Accessed 14 May 2014.
13. Gage AA, Guest K, Montes M, Caruana JA, Whalen
Jr DA. Effect of varying freezing and thawing rates in
experimental cryosurgery. Cryobiology.
1985;22(2):175–82.
14. Hindson TC, Spiro J, Scott LV. Clobetasol propionate
ointment reduces inflammation after cryotherapy. Br
J Dermatol. 1985;112(5):599–602.
15. Abramovits W, Pruiksma R, Bose S. Ultrasound-
guided thermocouple placement for cryosurgery.
Dermatol Surg Off Publ Am Soc Dermatol Surg
[et al]. 1996;22(9):771–3.
16. Zacarian SA. How accurate is temperature monitoring
in cryosurgery and is there an alternative? J Dermatol
Surg Oncol. 1980;6(8):627–32.
17. Hartov A, Lepivert P, Soni N, Paulsen K. Using
multiple-electrode impedance measurements to moni-
tor cryosurgery. Med Phys. 2002;29(12):2806–14.
18. Hahn M, Pavlista D, Danes J, et al. Ultrasound guided
cryoablation of fibroadenomas. Ultraschall Med.
2013;34(1):64–8.
19. Caviezel A, Terraz S, Schmidlin F, Becker C, Iselin
CE. Percutaneous cryoablation of small kidney
tumours under magnetic resonance imaging guidance:
medium-term follow-up. Scand J Urol Nephrol. 2008;
42(5):412–6.
20. Gage AA, Koepf S, Wehrle D, Emmings
F. Cryotherapy for cancer of the lip and oral cavity.
Cancer. 1965;18(12):1646–51.
21. Graham GF. Cryosurgery of skin tumors. N C Med
J. 1971;32(3):81–7.
 Part II
Physics
 Principles of Cryoablation
2
John G. Baust, Andrew A. Gage,
and John M. Baust

Abstract
This chapter describes the development of the use of freezing tempera-
tures in therapy. The principles of biological freezing were established in
early work on frostbite and on cryopreservation protection. These led to an
understanding of the tissue response to freezing, the mechanism of cryo-
genic injury, and the techniques of cryosurgery. Modern cryosurgery
requires monitoring by temperature measurement and by diverse imaging
techniques, which continue to evolve.

Keywords
Cryosurgery • Cryotherapy • Cryoablation • Adjunctive therapy • Tissue
freezing • Tissue ice

Introduction BC describe the therapeutic use of cold [1]. The

The use of low temperature to palliate pain and to
manage inflammation has been exploited since the
dawn of history. The written records of the
Egyptian surgeon Imhotep dating back to 2600
J.G. Baust, PhD
Department of Biological Sciences, Institute of
Biomedical Technology, Binghamton, NY, USA
A.A. Gage, MD
Department of Surgery (Emeritus), State University
of New York at Buffalo Medical School,
Buffalo, NY, USA
J.M. Baust, PhD (*)
Department of Research and Development,
CPSI Biotech, 2 Court St., Owego, NY 13827, USA
e-mail: jmbaust@cpsibiotech.com
first use of freezing as a debulking and potentially
curative process was extensively described by
Arnott in the mid-1800s following the use of
“salted ice” mixtures (~ −24 °C) to treat visible
tumors of the breast and uterus [2]. Half a century
later stepwise advancements in cryogenic engi-
neering would permit access for medical use to
ultracold cryogens. Key developments included
the discovery of the Joule-Thomson effect in 1853,
cryogen liquefaction (Caillete 1877; von Linde
1895) and Dewar’s 1892 invention of the vacuum
insulated thermos (dewar) essential to maintaining
and handling a volume of liquefied gas.
Liquid cryogens found their earliest therapeu-
tic use at the turn of the twentieth century when
White reported on the successful treatment of

© Springer-Verlag London 2016 9

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_2
10
various dermatologic conditions [3, 4]. Over the
next half-century numerous cryogens were
employed including liquid CO2, N2O, liquid air,
liquid oxygen and ethers. LN was first employed
in 1950 as a non-combustible cryogen to replace
liquid oxygen [5]. To this point in time dermato-
logic applications of freezing were limited to sur-
face treatments with cryogen sprays or topical
liquid application. In 1961, Cooper and Lee [6]
developed the first cryoprobe that could be
inserted through the skin for treatment of bulky
skin lesions and or visceral tumors. With this
development dermatologists had access to a mul-
tiplicity of cryosurgical tools supportive of rela-
tively precise tumor treatment.
Principles of Biological Freezing
With the growing interest in diverse cryoablative
strategies, a need to understand underlying prin-
ciples of freezing and its consequential mecha-
nisms of action in tissue became apparent.
Numerous studies of the damaging effects related
to frostbite along with a developing understand-
ing of cellular freeze protection during cryo-
preservation procedures established a base line of
relevant knowledge.
The application of a cryogen in various forms
(i.e. metallic probe, fibrous wick, surface spray,
etc.) to a targeted tissue, once “activated,” acts as
a heat sink to remove thermal (heat) energy. As
tissue cooling progresses, water molecules slow,
tend to aggregate into a structured lattice and
form an ice crystal. Ice growth proceeds out-
wardly from the “cryoprobe” by accretion of
water ahead of the freeze front at a rate dependent
on the heat extraction capabilities of the cryogen.
The rate of freezing is always more rapid proxi-
mal to the “cryoprobe.” Hence, the rate of freez-
ing varies over the radius of the freeze zone
resulting in less damaging effects in the periph-
ery of the frozen tissue mass. This discontinuity
may yield cell survival within the distal regions
of the tissue target or in those cells near active
vasculature. For this reason, a second freeze fol-
lowing the first thaw is common practice since a
second “partially lethal” freeze yields an additive
J.G. Baust et al.
destructive outcome. The second freeze, while
use has been historically empirical, gains signifi-
cance as it is now recognized that indolent cancer
cells and cancer stem cells are far more resistant
to varied therapeutic assaults and are no doubt
the foci of cancer recurrence [7].
Tissue Response to Freezing
Depending upon the severity of the freezing dur-
ing a cryosurgical procedure, the tissue’s
responses to cold injury may range from revers-
ible inflammation to cellular destruction. This
difference is the basis for a selective therapeutic
response. Short duration freezing at elevated sub-
zero temperatures produces only a mild inflam-
matory response with limited therapeutic uses
such as the treatment of retinal detachment.
Severe freezing produces destruction of cells
through two processes: (1) physical effects of cell
rupture due to osmotic shock and intracellular ice
formation and (2) activation of stress signaling
cascades that launch numerous molecular mecha-
nisms of cell death (i.e. apoptosis, autophagy and
necrosis). Some differences in the sensitivity of
diverse cell types to cold injury and even freezing
have been reported which may be exploited for
therapeutic purpose [8].
The cryogenic lesion is characterized by a
central portion of coagulation necrosis, which
collectively consists of death via physical trauma,
rapid-onset apoptosis, and necrotic populations.
With a relatively thin peripheral zone or freeze
margin cell destruction is uncertain. Shortly after
thawing, the tissue appears hyperemic within the
border region of the previously frozen volume
with an edematous central zone. Maximal levels
of apoptosis are evident within the core within
1–2 h following thawing, whereas elevated levels
are seen in the periphery several hours later while
necrosis is observed immediately post-thaw
(primary necrosis) and in the following days
(secondary necrosis). The border of the previ-
ously frozen tissue may be critical to therapeutic
management. In this region tissue temperatures
ranged from 0 to −20 °C, yielding some live
cells, some dead, and others partially damaged
2 Principles of Cryoablation
hovering between life and death [9, 10]. It is
within this region that high numbers of delayed
apoptotic and secondary necrotic cells are evi-
dent. Hence, the therapeutic challenge is to
ensure the death of all cells in this region. While
a challenge, the involvement of molecular mech-
anisms of cell death offers the potential for com-
bination strategies to enhance death [7].
The injured tissue begins the repair process
quickly with the infiltration of inflammatory cells
migrating through the necrotic tissue. Over the
following weeks to months, a fibrous, pliable col-
lagen scar laid down by fibroblasts slowly replaces
the necrotic tissue The preservation of the collag-
enous matrix helps retain the tissue architecture
which facilitates tissue repair, and healing.
Mechanisms of Cryogenic Injury
The mechanism of tissue injury from freezing is
complex as the numerous consequences of a
freeze-thaw cycle have a global impact on cellu-
lar homeostasis. Direct injury to the cells caused
by ice crystal formation might also include
microcirculatory failure. The cascade is com-
pleted with the post-thaw induction of apoptosis
and cellular necrosis. Extracellular ice crystal
formation, especially in the peripheral region of
the freeze zone, removes water from the cells
causing major deleterious metabolic disequilibria
related to solute concentration, the “solution
effects”. Ice crystals also cause mechanical dam-
age due to cell membrane disruption, intracellu-
lar ice crystal formation and shearing forces,
especially in highly organized tissues. The vascu-
lar stasis that follows thawing constitutes a major
mechanism of injury within the volume of previ-
ously frozen tissue thereby increasing the proba-
bility that cells die. While the relative importance
of these two mechanisms of injury has long been
debated, the two are clearly synergistic in cryoin-
jury leading to cell death from freezing [11–14].
Apoptosis or programmed cell death has been
identified as a mechanism of cell death associated
with thermal injury [15]. In investigations with
human prostate cancer cells in vitro, Hollister
et al. described cells dying from apoptosis some
11
days after freezing [16, 17]. Experiments in vitro
have shown that apoptosis occurs following expo-
sure to modest freezing temperatures and that
cells are susceptible to apoptotic initiation events
up to 12–24 h after thawing [18–21]. Clarke et al.
observed cell rupture and necrosis immediately
post-thaw, while apoptotic cell death was promi-
nent 12-h post-freeze [19]. Subsequent studies,
apoptotic death showed this to be partially regu-
lated through the mitochondria [21–23]. The
mitochondria play an important role in the apop-
totic death cascade, most notably through the
influence of the Bcl-2 family of proteins, regula-
tors of apoptosis [23–28]. More recently, Robilotto
et al. identified a temporal wave of apoptosis
induction initiating within an hour post-thaw at
the core of the frozen mass when ultra-low tem-
peratures are attained followed by the movement
of apoptotic induction outward towards the
periphery over the next 18–24 h [22]. Further, this
study revealed that the rapid induction of apopto-
sis at ultra-low temperatures progressed through a
membrane-mediated pathway whereas the
delayed apoptosis in the periphery progressed
through a mitochondrial-mediated pathway.
The Freeze-Thaw Cycle
Cryosurgical technique requires that tissue be
rapidly frozen, thawed slowly and completely,
and then exposed to a second freeze cycle so that
the goal of achieving a temperature in the tar-
geted tissue is attained along with a safe margin
around the tumor [12, 14, 29]. Each of the multi-
ple phases of the freeze-thaw cycle (i.e. cooling
rate, tissue temperature, freezing duration, and
thawing rate contribute to tissue injury) are
highly damaging to cells. Repetition of the
freeze-thaw cycle subjects the tissues to a repeat
injurious paradigm important to complete tumor
destruction. The characteristics of each of these
phases of the cycle vary in relation to the distance
from the cryosurgical probe. This cycle of freez-
ing also allows for the driving of ablative iso-
therms (−20 °C or −40 °C) further out from the
cryoprobe region helping increase the level of
cell destruction [30].
12
Rate of Tissue Cooling
Rapid cooling increases the probability of lethal
intracellular ice crystal formation. Intracellular
ice formation typically occurs at cooling rates
greater than 20 °C per minute [29, 31]. In clinical
practice, the cryosurgical probe should always be
used at the lowest attainable temperature to
obtain a greater probability of intracellular ice
formation since much of the frozen tissue volume
will be subjected to only slow cooling rates.
Additionally, studies have shown that the rapid
induction of membrane mediated apoptosis at
ultra-cold temperatures and rapid-cooling rates
starts the cancer cell down an irreversible path to
death therefore increasing the possibility of can-
cer destruction [22].
Target Tissue Temperature
Tissue temperature is the critical factor in the
application of a cryosurgical technique. Cell death
occurs in greater numbers as the tissue tempera-
ture is lowered toward a nadir. Cells from differ-
ent tissue sources demonstrate different lethality
ranges [8, 16, 32]. Those of dermatologic origin
are typically the most sensitive to freezing while
those of the prostate are far hardier. Most skin
lesions are fully ablated at temperatures between
−10 and −20 °C while certain prostate cancers
require a range between −40 and −80 °C. Studies
have also demonstrated that the molecular dispo-
sition of a specific cancer type can also influence
the cells response to freezing. For instance,
Klossner et al. demonstrated that early stage
androgen responsive prostate cancer is more resis-
tive to freezing injury than the late stage androgen
non-responsive prostate cancer cells [32].
Duration of the Freeze-Thaw Cycle
Studies that would definitively establish the dura-
tion of freeze cycle (i.e. duration of nadir tempera-
ture holds during a single or double freeze and
interval between first and second freeze cycle) are
wanting. While longer durations are intuitively
beneficial, only limited in vitro research [30, 33]
J.G. Baust et al.
provides quantitative data supporting physician
practice. Hence, anecdotal evidence and physi-
cian instinct guide timing in regard to clinical
practice. Hold times of a “few minutes” at the
nadir temperature is thought to be adequate to
assure that the targeted lesion is fully involved at
the nadir and that local circulation is arrested. To
this end, Klossner et al. demonstrated that hold
times of 1–2 min at target temperature were ade-
quate to result in cell death [30]. Holds of shorter
duration resulted in less effective cell death where
holds longer than 2 min at a given temperature did
not increase the level of death. When a dual
freeze-thaw cycle is applied, the thaw interval
should be of adequate duration to assure passive
thawing of the outer margin of the freeze zone.
Passive thawing allows for prolonged exposure to
the nadir temperature, which is elevated in com-
parison with the inner mass of the freeze zone.
The repeat freeze cycle provides a double stress
event to the cell population as well as allows for
critical temperatures to be driven further from the
cryoprobe thereby increasing the overall kill zone.
Thermocouple Monitoring
The use of thermocouples to monitor tissue tem-
perature during freezing has emerged as an impor-
tant adjunct to the imaging techniques.
Needle-mounted thermocouples have proven accu-
rate and useful for thermal monitoring, especially
when inserted in critical areas [34]. Their use
allows for the confirmation that lethal temperatures
have been achieved in the target tissue or that inju-
rious temperatures have not been reached in critical
areas, such as in the wall of the rectum. It is impor-
tant to note that thermocouples measure point
sources of temperature within the tissue. As such,
these temperatures cannot be extrapolated easily to
the entire volume of the cryosurgical lesion.
Adjuncts to Cryoablation
Cytotoxic drugs when used as adjunctive agents
offer a promising approach to increase the kill
efficacy of cryotherapy along the margin of the
ice ball [19–21, 23, 28]. Sub-toxic exposure to
2 Principles of Cryoablation
agents such as 5-Flurouracil or Taxotere prior to
the freezing insult can increase the lethal affect of
freezing at the elevated sub-freezing temperatures
found within the freeze zone periphery [19, 28].
The combined benefit of 5-FU and freezing is to
increase the rate of apoptosis in the targeted tissue
margin [19, 28, 35]. Other studies have shown
that other agents such as Taxotere [23], cisplatin
[16], vitamin D3 [36, 37], TNF [38, 39], and
TRAIL [40], among others, providing a synergis-
tic benefit when used in conjunction with cryoab-
lation raising the lethal temperature necessary
from the −20 °C to −30 °C range to around −10 °C
or warmer. These adjunctive strategies have
shown promise to significantly improve tumor
ablation.
Cryoablative Technologies
Beginning in the mid-1960s, cryoablation under-
went a significant technical advancement [6] and
now serves as an effective treatment modality for
a number of cancers. Further technical modifica-
tions were realized in the 1990s including the
development of new cryosurgical apparatus,
imaging techniques, and adjunctive devices to
improve the applicability and efficacy of cryo-
therapy. Technical improvements, such as the use
of new multi-probe devices and the development
and utilization of a protective urethral warming
catheter may be cited as significant milestones in
the evolution of cryosurgical technique [41–47].
Better selection of patients, with appropriate
staging of disease, has substantially improved
overall results.
Cryogen selection provides option to support
diverse treatment of diverse clinical indication
ranging from de-bulking to total ablation. Carbon
dioxide, a cryogen with the most limiting ablative
action (−78.5 °C), and nitrous oxide (−88.5 °C)
find limited use. Argon (−185.8 °C) and liquid
nitrogen (−195.8 °C) are more widely adopted in
cryosurgical devices that operate with closed-end
cryoprobes. LN is a conveniently managed liquid
utilized in spray, wick and probe configurations.
Recently, a next generation class of devices has
been developed utilizing critical and supercritical
cryogens, poised to provide far more rapid and
13
effective freezing tissue thereby increasing the
level of death while reducing the time and col-
lateral damage associated with the freeze thaw
process [48].
Modern Cryosurgery
The application of cryosurgery often relies on
guidance from information derived from the
imaging techniques. Ultrasound, allows for mon-
itoring of ice ball growth progression, but has
significant limitations because the practitioner
cannot see beyond the nearest ice plane of frozen
tissue. The resulting image is two-dimensional
because acoustic shadowing precludes visualiza-
tions of the extent of freezing behind the ice front
[45]. Three-dimensional ultrasound may well
alleviate this problem [46, 47, 49, 50]. Another
limitation of ultrasound occurs because the image
provides no information about target tissue tem-
perature, which causes difficulty in making real-
time determination of where the critical −40 °C
isotherm is within the ice ball. To address the
issue of thermal monitoring, the use of thermo-
couples, in conjunction with ultrasound, has
added an increased level of certainty of the
success.
New directions in imaging for cryosurgery
include computerized tomography (CT), mag-
netic resonance imaging (MRI), and electrical
impedance tomography (EIT). CT has the benefit
of showing the entire cross sectional image of the
frozen tissue. The images are made at intervals of
a minute or two, which is not real time but still
within the realm of usefulness [51]. MRI pro-
vides a three dimensional view of the volume of
frozen tissue and has shown promise as a clini-
cally valuable monitoring technique in cryosur-
gery [52–55]. MRI data allow the temperature
within the frozen volume to be established using
mathematical models [56–59]. The techniques
and tools for use with MRI are still evolving, as
are the MRI contrast agents [60]. Harada et al.
recently demonstrated the usefulness and safety
of MRI-guided cryosurgery for renal tumors
[61]. The probability of extensive or routine clin-
ical use of MRI-guided cryosurgery in the near
future is remote because of expense. Electrical
14
impedance tomography (EIT) has been proposed
as a method of monitoring the freezing of tissue
[62]. EIT provides a global image by introducing
low amplitude AC currents into the body, thus
measuring the electrical potentials on the body
surface. These potentials are then recorded and
analyzed to create a tomographic image [63–65].
This approach to imaging is new and needs fur-
ther development prior to use in clinical-based
cryosurgical procedures.
Summary
Tissue injury is produced by a sequence of
destructive effects, beginning with prolonged tis-
sue cooling, metabolic disruption, ice crystal for-
mation and cellular rupture. After thawing,
microcirculatory failure and the associated isch-
emia add to cell death, resulting in a coagulative
necrosis. Physical processes of destruction are
effective immediately, but physiological-based
detrimental effects, including cytokine release
and induction of apoptosis and secondary necro-
sis, produce a damaging effect over several days.
The basic principles of cryosurgery for tumors
are fast cooling of the tissue to a cell-lethal tem-
perature, slow thawing, and repetition of the
freeze-thaw cycle. Ideally a temperature of
−40 °C should be produced at the tumor margin
to ensure that all portions of the tumor are sub-
jected to lethal conditions. Repetition of freezing-
thaw cycle elevates the cell-lethal temperature
due to additive cellular stress, as does an increased
duration of freezing.
In vitro and in vivo experiments on the molec-
ular basis of cell death associated with cryosur-
gery have demonstrated the potential value of
adjunctive cytotoxic chemotherapy. The idea is to
increase the extent of injury to cells in the periph-
eral portion of the cryogenic lesion with the
expectation that differences in cell sensitivity to
freezing may be mitigated. The objective of these
strategies is to “make ice lethal at 0 °C”. This
would provide for an ablative event throughout
the entire target region, markedly reducing the
potential of disease reoccurrence from satellite
populations of cancer cells surviving within the
J.G. Baust et al.
targeted frozen region. Further research should
lead to a better understanding of the molecular
mechanisms involved in cryosurgery and adjunc-
tive therapy, which in turn should increase the
efficacy of cryosurgery for tumors.
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2 Principles of Cryoablation
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16
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 Cryogens
3
William Abramovits

Abstract
Cryogens are used to produce cold temperatures, for this discussion, for
therapeutic purposes. Liquid nitrogen is currently the cryogen of choice
for most dermatological applications; other cryogens may be of use.

Keywords
Cryogen • Liquid nitrogen • Carbon dioxide • Helium • Nitrous oxide •
Argon

The etymology of cryogen, Greek in origin, is

simple and sensical: cryo meaning very cold or
W. Abramovits, MD, FAAD
freezing, and gen meaning to produce. The dis-
Department of Dermatology,
Baylor University Medical Center, cussion of cryogens and their use in dermatologic
Dallas, TX, USA therapy is, however, not so straight forward.
Department of Internal Medicine, Following is a list of cryogens used for derma-
University of North Texas Health Science Center, tologic therapy over the years:
Texas College of Osteopathic Medicine,
Fort Worth, TX, USA Boiling point
Department of Dermatology, Ice/water 100 °C = 373 K = 212 °F
University of Texas Medical Branch, Liquid air −195 °C = 078 K = −319 °F
Dallas, TX, USA Liquid oxygen −183 °C = 090 K = −297 °F
The University of Texas Southwestern Medical Liquid nitrogen −196 °C = 077 K = −321 °F
School, Dallas, TX, USA Carbon dioxide/dry ice −057 °C = 217 K = −070 °F
Texas Tech University, Health Sciences Center, Liquid helium −269 °C = 004 K = −452 °F
Lubbock, TX, USA Nitrous oxide −088 °C = 185 K = −126 °F
Texas A&M Health Science Center College Liquid argon −186 °C = 085 K = −309 °F
of Medicine, Bryan, TX, USA Dichlorodifluoromethane −030 °C = 243 K = −022 °F
(Freon™)
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160,
Dallas, TX 75230, USA The first cryogen with dermatologic therapeu-
e-mail: DrA@dermcenter.us tic intent was a mixture of salt and crushed ice,

© Springer-Verlag London 2016 17

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_3
18
with which temperatures of −24 °C = 249 K =
−11 °F could be achieved [1]. Liquid air became
in vogue for the treatment of a variety of diseases
during the 1880s to the 1920, followed by liquid
oxygen until the 1930s [2–6]. Liquid carbon
dioxide was then used to generate a fine snow
that was easy to compress into a solid shape; able
to lower the skin surface temperature to
−79 °C = 194 K = −110 °F [7].
Multiple factors make liquid nitrogen (LN)
the ideal cryogen for the dermatology office: low
boiling point, transport not requiring pressuriza-
tion, low production cost, lack of fume toxicity,
lack of flammability, and storage in minimally-
or non-pressurized containers. It also seems to be
the cryogen that freezes tissue at the most appro-
priate speed (50–100 °C/min.) for the most effi-
cient and selective destruction of targeted
pathologies. LN spray is able to induce the rapid
freeze/thaw cycle that kills cancer cells most
effectively; repeated cycles of freeze and thaw
may enhance that effect. However, dispensing
LN from a flask, using a cotton bud does not
allow the cells below the immediate skin surface
to reach cryodestructive isotherms and should not
be used for skin cancer therapy.
LN is also not practical for use in closed cir-
cuit thin tubing, nor with the needles used for
deep organ lesion destruction (prostate and breast
cancer indications), as it tends to crystalize and
obstruct its own flow; liquid argon finds use in
those applications. Recently, a supercritical form
of LN is finding its way into equipment for such
localizations, and maybe it will be used to destroy
some skin tumors, like keloids, where volume
reductions without skin surface disruption may
be advantageous.
Gynecologists, until recently, utilized mostly
carbon dioxide and nitrous oxide gas for cervix
atypia, with a reportedly 85 % success rate; LN
may likely replace those gasses. Dermatologists
rarely use carbon dioxide or nitrous oxide nowa-
days. Urologists prefer argon based cryosurgery,
sometimes aided by helium thawing, for prostate
enlargement and cancer, perhaps because small
diameter needles allow those gasses to circulate;
supercritical nitrogen may replace those soon.
W. Abramovits
Canisters for home use, some claiming to
freeze down to −70 °C (some containing
dimethyl ether, propane and ether or other pro-
prietary fluoroethane combinations with boiling
points down to −47 °C = 226 K = −54 °F) exist
for uses that may not require the lower tempera-
tures achievable with LN. As a rule, issues of
inefficiency and technical problems such as drip-
ping make such devices unworthy in the derma-
tology practice.
Other devices are promoted as practical, based
on their small size and shape, some use of nitrous
oxide cartridges intended for single or disposable
use. The editors have little experience with these
devices and find them of little significant practi-
cal value in dermatology. Finally, there are pen-
like sticks covered by insulating sleeves; these do
not require gas and claim to sustain a temperature
of −90 °C = 183 K = −130 °F (similar to nitrous
oxide) at the tip. The same opinion applies.
Over 90 % of dermatologists use LN equip-
ment in their practices; most use canisters filled
daily from a central tank. The amount supplied to
each practice depends on patient volume, number
of providers and rooms. Canisters hold a day’s
worth of usable LN under adequate pressure to be
sprayed efficiently. Most currently available
equipment is able to dispense the LN in a predict-
ably efficient way, at a reasonable cost to the phy-
sician and patient.
References
1. Arnott J. On the treatment of cancer by the regulated
application of an anaesthetic temperature. London:
Churchill; 1851.
2. Cailletet L. Recherches sur la liquéfaction des gaz.
Ann Chim Phys. 1878;15:132–44.
3. White AC. Liquid air: its application in medicine and
surgery. Med Rec. 1899;56:109–12.
4. White AC. Possibilities of liquid air to the physician.
JAMA. 1901;36:426–9.
5. Whitehouse H. Liquid air in dermatology: its indica-
tions and limitations. JAMA. 1907;49:371–7.
6. Bowen JT, Towle HP. Liquid air in dermatology. Med
Surg J. 1907;157:561.
7. Pusey W. The use of carbon dioxide snow in the treat-
ment of naevi and other lesions of the skin. JAMA.
1935;49:1354–6.
 The Effect of Cold Temperatures
on Biological Systems
4
Jeunghwan Choi, Saravana B. Kumar,
Silvia Jiang-Hughes, and John C. Bischof

Abstract
The mechanisms of cold injury to biosystems are investigated at the cel-
lular, tissue, and systemic levels, with details concerning the related exper-
imental methods. Cellular level studies have shown a direct relationship
between biophysical changes versus freeze-thaw survival. Advances in
experimental and analytical methods have resulted in qualitatively similar
results for native and artificial tissue systems, with several important cave-
ats relating to cell-cell, cell-ECM effects. While these biophysical events
have informed a better understanding of immediate injury after freezing at
the cell and tissue level, further understanding of delayed injury effects
after cryosurgery including at the cellular (i.e. apoptosis) and host medi-
ated (i.e. vascular and immunological) events remain important areas of
research and an opportunity to improve the technique.

Keywords
#RYOBIOLOGY s &REEZE INJURY s "IOPHYSICS s &REEZE THAW s #RYOMICROSCOPY s
$IFFERENTIAL SCANNING CALORIMETRY s &REEZE SUBSTITUTION s &REEZING MODEL s
Cryosurgery

J. Choi, PhD
Department of Engineering, East Carolina University,
Greenville, NC, USA
3" +UMAR 0H$
Department of Mechanical Engineering,
University of Minnesota, Minneapolis, MN, USA
S. Jiang-Hughes, PhD
Department of Regulatory Affairs,
Abbott Laboratories, Alameda, CA, USA
*# "ISCHOF 0H$ *)
$EPARTMENT OF -ECHANICAL AND "IOMEDICAL %NGINEERING
University of Minnesota, 111 Church St. SE,
Minneapolis, MN 55455, USA
e-mail: bischof@umn.edu
Introduction
Cryobiology is the study of biological materials
or systems at low temperatures where controlled
freezing is used for either the preservation
(cryopreservation) or the destruction (cryosur-
gery) of biological systems. The first reported
successful cryopreservation of sperm was
reported in 1949 by Polge et al. [1]. The cryo-
preservation of cells has since been reported for
many cell types [2–7= &REEZING IS ALSO USED TO

© Springer-Verlag London 2016 19

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_4
20
70
60
Solution Effects IIF
50
Survival
Survival (%)
40
30
Cell Suspensions
20
10
Cooling Rate
10–1
Fig. 4.1 (Left) A schematic representation of the “two
factor” hypothesis of cell injury. Slow freezing results in
cell dehydration and is linked to “solution effects” of
hypertonic injury, whereas rapid freezing injury is attrib-
destroy malignant cells or tissues using cryosur-
gery [8, 9]. Detailed reviews of cryopreservation
or cryosurgical applications can be found else-
where [6, 10–14].
This chapter discusses the destructive capa-
bilities of freezing on biological systems and ini-
tially describes the fundamental mechanisms of
freezing injury at the cellular level. The second
part focuses on the mechanisms of cryosurgery,
with comparisons between immediate cell injury
vs. delayed vascular and immunological events
that dictate the final lesion size.
The Mechanisms of Cellular
Freeze Injury
While injury can occur at any temperature below
0 °C, it is now generally accepted that range
between 0 and −60 °C is the most lethal to cells
[15]. During many freezing events, a cell must
traverse this range twice during freezing and then
again during warming. Ice initially forms in the
larger extracellular space leading to intracellular
supercooling. This occurs due to the plasma
membrane which at higher sub-zero temperatures
of 0 to −5 °C can block ice crystals from entering
the cell [16]. This supercooling also drives an
osmotic imbalance between the inside and
J. Choi et al.
MARROW
RBC
YEAST HAMSTER
1 10 102 103 104
COOLING VELOCITY
uted to the lethality of intracellular ice formation (IIF).
(Right) The “two factor” relation is cell type dependent
(Adapted from Mazur et al. [27]. With permission from
John Wiley & Sons)
outside of the cell leading to the outflow of water
from the cell through the plasma membrane. The
rate of water movement is dependent on the cool-
ing rate – slow freezing allows cell dehydration
whereas rapid freezing traps water that eventu-
ally forms intracellular ice [17= "OTH EXTREME
dehydration and intracellular ice formation are
well documented forms of cell injury driven by
biophysics [18, 19].
Cellular freezing biophysics is linked to cell
injury by the “two factor” hypothesis as origi-
nally proposed by Mazur [17, 19]. An inverted U
curve relation between cell injury and cooling
rate is purported to result from two opposing
damaging factors. Slow freezing rates are linked
to “solution effects” or hypertonic injury, and cell
injury at rapid freezing rates is attributed to lethal
))& &IG 4.1) [17, 19]. An optimal freezing rate
SHOULD BE LOW ENOUGH TO AVOID ))& BUT HIGH
enough to minimize solution effects injury. This
optimal cooling rate is dependent on cell type as
SHOWN IN &IG 4.1. Cell biophysics and injury
(“two factor” hypothesis) has been well studied
for multiple cell types in the unattached state
(suspensions) [4, 5, 7, 15, 17, 20–26]. However,
the effect of cell attachment on the “two factor”
hypothesis is not well understood, as the majority
of cells studied were in suspension and not
ATTACHED TO SURFACES 3EE &IG 4.1 [27]).
4 The Effect of Cold Temperatures on Biological Systems
Cell Biophysics
As mentioned, the “two factor” hypothesis has
been well studied for cells in suspension. The
biophysical response that leads to these two fac-
tors depends on the ability of water to move
across the cell membrane (or cell permeability).
"IOPHYSICAL MODELS ARE THUS USEFUL TO DETERMINE
and predict cell membrane permeabilities for
imposed thermal conditions. A discussion of cel-
lular freezing biophysical models and experi-
mental techniques follows.
Cell Dehydration
Extracellular ice concentrates the extracellular
media, creating an osmotic pressure difference
across the semipermeable cell membrane that
drives water out of the cell. Slow freezing rates
allow adequate time for intracellular water to
move out, thus dehydrating the cell [15]. The rate
of water movement is affected by the cell mem-
brane permeability and the chemical potential
gradient. A simplified model for cell dehydration
was proposed by Mazur [15] in 1963 (Eq. 4.1).
dV L A
= − p ( Δp ) (4.1)
dT B of the loss of cell membrane integrity and not
Here, V is the cell volume (μm3); T is the tem-
PERATURE +  Lp is the cell membrane permeabil-
ity; A is the cell surface area (μm2); B is the
cooling rate (°C/min); and Δπ is the osmotic pres-
sure difference across the cell membrane.
Osmotic water transport is limited by the tem-
perature dependence of the cell membrane per-
meability. This is modeled using an Arrhenius
relation as proposed by Levin et al. [28] as given
below.
⎡ −E ⎛ 1 1 ⎞⎤
L p = L pg exp ⎢ Lp ⎜ − ⎟⎟ ⎥ (4.2)
⎜
⎢⎣ R ⎝ T Tref ⎠ ⎦⎥
Here, Lpg (μm/min atm) is the membrane
hydraulic permeability at a reference tempera-
ture Tref + ELp is the activation energy for
water transport (kcal/mol); and R is the gas
CONSTANT  *MOL +  7ATER TRANSPORT
21
across the cell membrane can then be predicted
using these cell specific biophysical parameters
(i.e. Lpg & ELp). In general, changes to permea-
bility (Lp) shift the dehydration curves from left
to right without affecting their overall profile
&IG 4.2). A change to activation energy (ELp)
affects the profile and shifts the curve.
Mazur’s water transport model was originally
proposed for cell suspensions [15]. It does not
account for interactions that would occur in
attached cellular systems. The modeling as shown
IN &IG 4.2 does not show the impact of intracel-
lular ice formation. Other limitations to the model,
are discussed in detail elsewhere [15, 29–31].
Other biophysical models have been proposed
that attempt to address limitations of Mazur’s
original model [16, 32–35= 3EE &IG 4.2 [36]).
Intracellular Ice Formation
)NTRACELLULAR ICE FORMATION ))& RESULTS FROM
intracellular water supercooling faster than it can
exosmose out of the cell. Three major theories
DESCRIBE HOW ))& OCCURS IN CELLS
s Membrane damage theory
4HIS THEORY CONTENDS THAT ))& IS A CONSEQUENCE
a precursor to membrane damage [37].
s Pore theory
The theory postulates that at a particular freez-
ing temperature, extracellular ice crystals are
small enough to advance through aqueous
pores (protein pores or gap junctions) in the
plasma membrane and nucleate the intracel-
lular media [38–40= "ASED ON CALCULATIONS AN
ice crystal was deemed small enough to pass
through 0.8 nm pores below −10 °C if the con-
tact angle of ice-water interface with the pore
wall was ~75o [38–41].
s Surface catalyzed nucleation (SCN) theory
The SCN theory postulates that the plasma
membrane, interacting with extracellular ice,
acts as an intracellular nucleation site [16].
Toner et al. proposed this mechanistic model
TO ASSESS ))& IN BIOLOGICAL CELLS ;16, 42]. The
model assumes that the nucleation rate I
 22 J. Choi et al.

a b
1.0

1,000°/min

0.8
RELATIVE VOLUME OF CELL WATER

100°/min

0.6

10°/min

1°/min
0.4

1,000°/min

5,000°/min

10,000°/min
Eq.

0.2

Eq.

0
0 –4 –8 –12 –16 –20 –24 –28 –4 –8 –12 –16 –20 –24
TEMPERATURE (°C)

Fig. 4.2 Cellular dehydration during freezing as visual- temperature at indicated cooling rates (Adapted from
ized by the fraction of intracellular water remaining in Mazur [36]. With permission from The American
yeast (a), and human red blood cells (b) as a function of Association for the Advancement of Science)

depends on the kinetic (Ωo) and thermody- not account for cell attachment effects like cell-cell
namic (κo) coefficients of nucleation. The interactions. There have been other models pro-
PROBABILITY OF INTRACELLULAR ICE FORMATION 0)& POSED TO STUDY ))& IN CELL SUSPENSIONS WHICH
is then predicted as given below. include both mechanistic and phenomenological
⎛ t ⎞ models [19, 43–45]. Though fundamentally differ-
PIF SCN = 1 − exp ⎜ − ∫ AI SCN dt ⎟ (4.3) ent in their approaches, the end results are reported
⎝ 0 ⎠ to be similar [33].

Here A is the membrane surface area. The SCN

MODEL FOR ))& IN CELLS HAS ASSUMPTIONS AND LIMITA-
tions to its application. The nature of the interaction
of ice with the plasma membrane is broad – chemi-
cal, physical, electrical, ionic, thermal or mechani-
cal. It is unknown if a particular underlying
interaction is predominant or if a combination of
the above plays a critical role. Definitive experi-
mental evidence showing the plasma membrane as
THE ORIGINATOR OF ))& IS LACKING !DDITIONALLY THIS
model was developed for cell suspensions and does
Experimental Techniques
Cell freezing biophysics is commonly studied
using a cryomicroscope [42, 46–48]. The histori-
cal development of the cryomicroscope and its
applications to cryobiology is discussed else-
where [49–54]. Current designs of the cryomi-
croscope are modifications of the initial work by
Diller and Cravalho who invented the convection
based cryomicroscope where cooling rate and
4 The Effect of Cold Temperatures on Biological Systems
temperature are microprocessor controlled and
can be programmed independently [55]. A modi-
fied version of the stage based on radial conduc-
tion was later proposed by McGrath as an
enhancement to the original design [56]. A more
detailed review of the engineering contributions
to cryobiology can be found elsewhere [57, 58].
A cryomicroscope is used to track cell volume
(using projected area) as a function of tempera-
ture during freezing. An important assumption is
that the cells are circular, and cell volume can be
calculated using a simple circle-sphere relation.
Cell volume measurement during freezing are
obtained either manually or using algorithms
developed to automatically track and calculate
volume changes [59–61]. A major limitation of
the cryomicroscope is its inability to map cell
volume as a function of temperature for non-
spherical cells (e.g. sperm), and attached cells.
4HE CRYOMICROSCOPE CAN ALSO BE USED TO TRACK ))&
IN CELLS &IG 4.3 [62=  ))& IS CLASSICALLY DESCRIBED AS
a sudden “flashing” of the cell attributed to a change
in the optical transparency of light as cellular water
CONVERTS TO ICE ))& IS SOMETIMES DESCRIBED AS
“twitching” – a “very sudden and small volume
increase” – of the cell with no perceptible darkening
of the cytoplasm [20, 63]. There is a degree of subjec-
TIVITY ASSOCIATED WITH TRACKING ))& USING A CRYOMICRO-
scope since “flashing” is affected by the experimental
setup (amount of water/ice in the system), and user
interpretation of optical changes to the cell during
freezing. Additionally, it is difficult to ascertain if the
MECHANISTIC EVENTS CAUSING ))& PRECEDE OR SUCCEED
the “flashing or twitching” of the cells.
Technological advances to the cryomicros-
COPY METHOD HAVE AIDED IN THE STUDY OF ))& BIO-
physics in cells. Recent work by, Stott and
+ARLSSON USED HIGH SPEED VIDEO CRYOMICROSCOPY
in micropatterned tissues challenge the conven-
tional acceptance of “flashing” as an indication
OF ))& ;64]. Using high frame rates (8,000–16,000
frames/s), they showed that intracellular ice
growth originated at a point source within the
cell, which then manifests as a single advancing
FRONT 4HE TYPICAL hmASHINGv ASSOCIATED WITH ))&
was then shown to be a secondary event that
occurred after the ice front had traversed the cell
[64].
23
Amongst other available experimental tech-
niques, the differential scanning calorimeter
(DSC) can also be used to quantify cell biophys-
ics (especially water transport) during freezing.
Changes to the cell volume are tracked by mea-
suring the difference in the heat release between
intact and lysed cells [65]. The DSC technique is
not limited by the size or shape of the cells (non-
SPHERICAL  &OR INSTANCE $3# IS ONE OF THE ONLY
techniques that can be used to assess sperm bio-
physics during freezing. More recently it has
BEEN USED TO ASSESS WATER TRANSPORT AND ))& IN CELL
SUSPENSIONS &IG 4.4) [66, 67]. A detailed review
of the applicability, technical advantages and
limitations of the DSC for biophysical evaluations
is provided elsewhere [67, 68]. A further tech-
nique that has been used to study water transport
IN NON SPHERICAL SYSTEMS IS &OURIER 4RANSFORM
)NFRA RED 3PECTROSCOPY OR &4)2 ;69, 70].
Specifically, membrane (CH2) dehydration and
water peak changes have been used to assess
overall cell dehydration and correlated to water
TRANSPORT &IG 4.5). This technique has now been
applied to numerous sperm systems [71, 72].
Other experimental techniques that have been
used to study cell dehydration in non-isotonic
solutions (not freezing) include diffusion and
perfusion chambers [73–75], spectrophotometers
[76–78], photomicroscope [79], and electronic
particle counters [80–83].
Effect of Cell Attachment
on Biophysics
Cell attachment is anticipated to affect the bio-
physics of freezing in comparison to cells in sus-
pension. This could be a result of the differences
in the environment and interactions of the cell
with its surroundings. Cell attachment is known
to affect the morphology, and the phenotype
[84–86]. The extracellular matrix (ECM) is
known to provide structural integrity and func-
tional assistance to cells. In fact, it is argued that
the ECM is an extension of the cells and an active
participant in the regulation of cell function
[85, 86]. Currently, substantial evidence has been
obtained showing cell-cell and cell-ECM
24 J. Choi et al.

Fig. 4.3 Cell dehydration during freezing of one-cell CELL IS SEEN TO FORM ))& DARKENS AT – —# WHICH SPREADS
mouse embryos as seen using a cryomicroscope. Ice was rapidly as temperature declines further (Adapted from
nucleated at −1 °C and the cooling rate is 2 °C/min. One Toner et al. [48]. With permission from Elsevier)

interactions are essential organizing principles the cell membrane, morphology, membrane ten-
that define the nature of tissue [87]. In addition, sion, mechanical properties and osmotic
the cytoskeleton of the cell affects the structure of responses [88–91]. Actin is a major protein
4 The Effect of Cold Temperatures on Biological Systems 25

0 0

–10
q [mJ/mg]

q [mJ/mg]
–10
(a) 0.5 °C/min (b) 10 °C/min
–20 α=0 α=0
α = 0.2 –20 α = 0.2
α = 0.4 α = 0.4
α = 0.8 α = 0.8
–30

–30
0 –2 –4 –6 –8 –10 0 –10 –20 –30
Temperature [°C] Temperature [°C]

0 0

–5
q [mJ/mg]

q [mJ/mg]

–10
(c) 20 °C/min (d) 50 °C/min
α=0 α=0
α = 0.2 –10 α = 0.2
α = 0.4 α = 0.4
–20 α = 0.8 α = 0.8

–15
0 –10 –20 –30 0 –10 –20 –30 –40 –50
Temperature [°C] Temperature [°C]

Fig. 4.4 Heat release thermograms of Human Dermal which is more pronounced with faster cooling rates as
&IBROBLASTS OBTAINED USING A $IFFERENTIAL 3CANNING #ALORI well as with higher cytocrit (α, cell concentration within
meter show a primary peak related to water transport and suspension) (Adapted from Mori et al. [69]. With permis-
a secondary peak related to intracellular ice formation sion from Elsevier)

present in the cytoskeleton of cells, and is known
to play a critical role in cell volume regulation
[90, 92]. Defects to the cytoskeleton are known to
cause membrane instability [93]. Hence, events
that can cause extensive depolymerization of the
actin cytoskeleton may increase the vulnerability
of cells to injury [94= &REEZING COULD DISRUPT
these interactions, and currently there is minimal
understanding of the impact of cytoskeletal
changes on the “two factor” hypothesis. This has
generated new work on both experimental mea-
surement and prediction of biophysics in the
attached state as discussed below.
Experimental Approaches
4HE PROPAGATION OF ))& IS INmUENCED BY CELL CELL
and cell-matrix interactions. This was first
reported in plant tissues where a strong relation-
SHIP BETWEEN CELL INTERACTIONS AND INCREASED ))&
was noted [37, 54, 95, 96]. Subsequently, this
phenomenon has been reported for other cellular
systems [80, 97]. Acker et al. demonstrated the
EFFECT OF ATTACHED CELL INTERACTIONS ON ))& USING
four different in vitro cellular systems of hamster
lBROBLASTS &IG 4.6). These systems included
cells in suspension, attached to a glass surface
(cell-surface interactions), colonies of cells
attached to glass with both cell-cell and cell-
surface interactions, and multi-cellular spheroids
with extensive cell-cell interactions [98]. A sig-
NIlCANT INCREASE IN ))& WAS NOTED IN THE PRESENCE
of cell-cell contact. In addition, a significant
DECREASE IN THE TIME TO REACH   ))& FOR CELLS IN
suspension as compared to attached cells was
observed [98]. This data showed that cell-cell and
CELL SURFACE INTERACTIONS ALTER ))& BIOPHYSICS AS
26 J. Choi et al.

2853 800
a b
NT = –3°C NT = –3°C
2852 NT = –10°C NT = –10°C
600

H2O band area (AU)

2851
υCH2 (cm–1)

2850 400

2849

200
2848

2847 0
–80 –60 –40 –20 0 20 40 –80 –60 –40 –20 0 20 40

Temperature (°C) Temperature (°C)

c
1.0 Cryomicroscope 1.0
FTIR
Normalized Cell Volume

0.8 0.8
Water Band Area

0.6 0.6

0.4 0.4

0.2 0.2

0.0 0.0
0 –5 –10 –15 –20 –25 –30
Temperature (°C)

Fig. 4.5 &4)2 RESULTS OF FREEZING HUMAN DERMAL lBRO-
blasts. (a) Larger shift in symmetric vCH2 stretching band
(~2,850 cm−1) is observed under greater dehydration con-
ditions (nucleation at −3 °C versus −10 °C). (b) The
increase in H2O spectral band area with ice formation is
greater for NT = −3 °C indicating that there is more total
ice formation under greater dehydration conditions.
(c) Comparison of cellular volumetric changes as a result
OF FREEZE INDUCED DEHYDRATION AS PREDICTED FROM &4)2
versus cryomicroscopy measurements (Adapted from
"ALASUBRAMANIAN ET AL ;71]. With permission from
Elsevier)

compared to cell suspensions. One reason for the
INCREASE IN ))& WAS ATTRIBUTED TO THE PRESENCE OF
gap junctions, which have been shown to facili-
tate ice propagation through intercellular interac-
tions [41].
Though cell attachment was clearly shown
TO INCREASE THE PROBABILITY OF ))& IN COMPARISON
to suspensions, its effect on cell damage
remains unclear. Acker and McGann showed
THAT -$#+ CELL SURVIVAL IN MONOLAYER IS GREATER
than 65 % even though the cells exhibited
  ))& ;99]. The authors attributed this to
the protective action of intracellular ice formed
by propagation through gap junctions. In con-
trast, the tenets of the “two factor” hypothesis
would have predicted a higher percentage of
CELL INJURY )N CONTRAST )RIMIA AND +ARLSSON DID
not observe a benefit to cell viability in the
presence of intercellular ice propagation [100].
Observed discrepancies may be partially due to
4 The Effect of Cold Temperatures on Biological Systems 27

a b 100

spheroids
80

PREVALENCE OF IIF (%)

cells in colonies

60 individual attached cells

cells in suspension

40
c d

20

0
0 –2 –4 –6 –8 –10 –12 –14 –16
TEMPERATURE (ºC)

Fig. 4.6 The impact of cell attachment state on freezing (d) Cells forming a spheroid. (Bottom panel) – Probability
biophysics was evaluated using four model systems. OF ))&  AS A FUNCTION OF TEMPERATURE IN THE MODEL SYS-
(Top panel) – Hamster fibroblasts in (a) Suspension; tems evaluated (Adapted from Acker et al. [99]. With per-
(b) Individual cells attached to glass; (c) Cells in colonies; mission from Elsevier)

differences in cell type, attachment methods, 100

** * **
culturing conditions, and the use of enzymatic Suspension cells
*
digestion. 80 Attached cells
There are very few studies that have been
**
reported for water transport biophysics for
viability (%)

60 *
attached cells during freezing. One main reason
**
is the limitation of experimental techniques that
40 *
are currently incapable of measuring cell vol-
ume changes in the 3D configuration for
attached cells. This limits the scope of both 20
experimental and numerical methods in predict-
ing attached cell dehydration biophysics. 0
2ECENTLY #HOI AND "ISCHOF STUDIED THE hTWO 0.0 0.1 1.0 10.0 100.0 1000.0
cooling rate (ºC/min)
factor” biophysics of freezing fibroblasts in sus-
pension vs. monolayer [101]. Water transport is Fig. 4.7 Comparison of post-thaw survival of human der-
predicted to be higher for fibroblasts in mono- mal fibroblasts in suspension versus attached state. Error
layer as compared to suspensions at slow freez- bars represent standard deviations. *, P < 0.1; **, P < 0.05,
significant difference in viability between suspension vs.
ing rates. This would indicate that “solution
attached cell systems at given cooling rate (Adapted from
effects” injury should be higher for the cells in Choi et al. [102]. With permission from Elsevier)
monolayer per the “two factor” hypothesis.
However, cell survival is significantly higher in
MONOLAYER VS SUSPENSION &IG 4.7). A possible Biophysical Models
explanation is that cells in suspension are
squeezed into unfrozen channels and exposed to The water transport model proposed for cell sus-
high solute concentrations but not all the cell pensions has limitations in its application to
surface area may be accessible to solutes in the attached cells. The model does not account for
case of attached cells. This indicates that the cell-cell and cell-ECM interactions, and is con-
slow freezing biophysics of attached cells might strained by experimental techniques since they
be mechanistically different when compared to are unable to measure cell volume in 3D configu-
suspensions. ration. In spite of these limitations, the cellular
28
biophysical model for water transport can still be
reasonably used to assess the dehydration kinet-
ics of attached cells and is useful in assessing
how the biophysical parameters and hence the
kinetics change between suspension versus
attached cell states.
Yarmush et al. used the cellular models to pre-
dict attached cell biophysics by decoupling the
KINETICS OF ))& FROM CELL DEHYDRATION AT RAPID
FREEZING RATES 4HIS PROVIDED RELEVANT ))& BIO-
physical parameters, which were then assumed as
constant at lower freezing rates. Cell dehydration
biophysical parameters were then predicted using
COUPLED WATER TRANSPORT AND ))& MODELS ;102].
Other biophysical models for attached cell water
transport have been proposed but they are limited
to specific applications or cellular systems [28,
103–108= -ORE RECENTLY (IGGINS AND +ARLSSON
applied a fluorescence quenching method to
determine the membrane permeability parame-
ters of attached cells [109, 110]. Similarly, the
BIOPHYSICAL MODELS OF ))& DEVELOPED FOR CELL SUS-
pensions have been used to study cells in the
attached state [102]. Other approaches have been
PROPOSED TO MODEL ))& KINETICS IN THE ATTACHED
state by accounting for cell-cell interactions.
)RIMIA AND +ARLSSON USED MICROPATTERNED CELLS TO
PROPOSE A THEORETICAL MODEL TO PREDICT THE ))&
kinetics in a group of cell pairs based on Singlet/
Doublet states [100]. More recently, Higgins and
+ARLSSON USED A FOUR STATE -ARKOV CHAIN MODEL
TO DESCRIBE ))& KINETICS IN ATTACHED CELLS ;111].
In summary, a review of literature shows
good understanding of the biophysics of freezing
cells in suspension and a growing understanding
of behavior in the attached state and especially
for water transport. Additionally, the cell attach-
ment state affects the molecular expression of
cells (e.g. lipids and proteins). Differences in the
state of the proteins and lipids are expected to
contribute to observed differences in biophysics
between cell suspensions and attached cells.
Therefore a clearer understanding of the bio-
physics of freezing cells in an attached state will
require further studies of changes and events at
the molecular level, beginning with variables
defined in simpler cellular systems (i.e. cell sus-
pensions). Recent studies investigating changes
J. Choi et al.
to lipids and proteins due to freezing include the
works of Wolkers et al. [69, 70, 112].
Tissue Freezing
The freezing of tissue is a more complicated phe-
nomenon compared with freezing of single cells in
either suspension or attached state. While the same
biophysical events observed in simple cell systems
(dehydration and intracellular ice formation) affect
the biological outcome of tissue systems, difficul-
ties in visualizing and quantifying the dynamics of
freezing in tissue have hindered the direct correla-
tion of biophysical events with post-freeze viabil-
ity [103]. It is noted that several models describing
tissue level biophysical response do exist [105,
106], but the data required to test the models are
currently lacking. Some of the earliest findings on
the mechanisms of freezing in vertebrate tissues
include those reported by Chambers and Hale
(frog) [96], Meryman [113], Trump et al. (liver)
[114], and Love [115]. Subsequent work by
Rubinsky et al. also provide supporting evidence
to this mechanism of freezing in liver [116].
The experimental methods used to study tissue
response to freezing need to address the fact that
these systems are generally opaque to optical
interrogation and also experience a greater varia-
tion in cooling history within the system. One
method used to aid in maintaining a more uniform
cooling rate during tissue freezing is directional
solidification, which involves sliding a thin tissue
sample between two isothermal surfaces at a con-
trolled rate [117–122]. Several microscopy tech-
niques exist that allow for the biophysical
assessment of frozen tissue without compromise
to tissue morphology, such as cryo scanning elec-
tron microscopy (Cryo-SEM) [116, 118, 123,
124] or freeze substitution followed by light
microscopy [120–122, 125, 126]. An example of
freezing response of tissue (rat liver) by direc-
TIONAL SOLIDIlCATION IS SHOWN IN &IG 4.8 where the
cooling rate was varied from very fast (>1,000 °C/
MIN &IG 4.8a TO VERY SLOW  —#MIN &IG 4.8d).
It can be seen that the intracellular ice crystals
formed during fast cooling (A) are so small that
they are not distinguishable from the darkly
4 The Effect of Cold Temperatures on Biological Systems 29

a b

c d

Fig. 4.8 Controlled-rate freezing behavior of rat liver.
Light micrographs show rat liver tissue frozen by (a) Slam
freezing (>10,000 °C/min) or by directional solidification
at (b) 400 °C/min, (c) 50 °C/min, or (d) 5 °C/min to −20 °C,
followed by immersion in liquid nitrogen. Scale bar is
50 μm, dark areas (starred) correspond to tissue compo-
nents, transparent areas (arrows) correspond to sinusoids or
to extracellular ice crystals that form within the liver
!DAPTED FROM 0AZHAYANNUR AND "ISCHOF ;126]. With per-
mission from ASME publications)

staining cellular compartment. At intermediate

cooling rates (B, C) some of the water remains
trapped in the cells to form intracellular ice while
some water is also transported to the extracellular
space. The intracellular ice grow to sufficient size
at these intermediate cooling rates to be visible in Ac
addition to the large extracellular crystals. During ΔX rv
very slow cooling (D) most of the cellular water is
transported to the extracellular space resulting in
very large extracellular ice crystals.
L
The principles upon which water within the
cell is transported to the extracellular space dur- ΔX
ing tissue freezing are similar to those for simple
CELL SYSTEMS &OR MANY SITUATIONS THE BIOPHYSICAL Fig. 4.9 +ROGH CYLINDER MODEL 4HE CYLINDER REPRESENTS
equations used for single cells can be adapted to the extracellular/vascular compartment, and the box is the
cellular compartment. The characteristic dimensions of
tissue systems if appropriate changes are made the model are described in the text (Adapted from
TO THE MODEL GEOMETRY 4HE +ROGH CYLINDER 0AZHAYANNUR AND "ISCHOF ;126]. With permission from
&IG 4.9) is one such geometry in which the ASME publications)
30
extracellular and vascular compartment of the
tissue is represented as a cylinder, while the box
surrounding the cylinder is considered the cellu-
lar compartment [127= )N &IG 4.9, the vascular
and extracellular space is the cylinder with ini-
tial vascular radius rv, axial length L, and surface
Ac. With ΔX defined as the distance between vas-
cular and extracellular spaces, the cellular space
is then calculated to be (ΔX2 – πrv2) × L. The
modeling of water transport in liver tissue during
freezing was done by Rubinsky and Pegg by
APPLYING THE +ROGH CYLINDER GEOMETRY TO THE
single cell biophysics equations described previ-
ously in Cell Biophysics [105]. It is noted that
WHILE THE TWO COMPARTMENT +ROGH SYSTEM IS USE-
ful as a tissue freezing model, it has many limita-
tions which need to be specifically worked out,
including a better description of the surface area
through which freezing occurs, possible cell-cell
dehydration mechanisms, and mechanical effects
of ice crystals [103].
Cell Death from Tissue Freezing:
Cryosurgery
The freezing of tumor tissues is a complicated
phenomenon usually analyzed within pre-clinical
models by histology. Immediately after cryosur-
gery, a central necrosis area caused by direct cell
injury is observed [128, 129]. The same immedi-
ate cell injury mechanisms that destroy tumor cells
also destroy endothelial cells of the microvascula-
ture. This results in post-thaw platelet aggregation
and vascular stasis. In vitro tests show that endo-
thelial cells are in general more sensitive to freeze
injury than cancer cells [46, 121]. Thrombosis and
ultimately ischemia occur within the treated area,
leading to ischemic necrosis of the frozen tumor
within few hours post cryosurgery [130, 131]. At
the peripheral zone of the cryolesion, where the
temperature may not have been cold enough to kill
all the cells, some of the cells show signs of apop-
tosis in vitro which peak at 24 h [132, 133]. A dis-
tinct inflammatory zone also appears at the
demarcation of the frozen and untreated tissue
from 6 h to day 3 [128]. Wound repair begins at the
periphery of the cryolesion from day 7 to a few
J. Choi et al.
weeks, followed by inflammatory cells infiltrate
and new blood vessels grow in to the injured tissue
from surrounding viable tissue, and ultimately
fibroblasts and new collagen formation within the
lesion [134, 135]. The evolution of the histological
changes as the lesions progress over time post
cryosurgery is highly correlated with the immedi-
ate and delayed mechanisms of cryoinjury [8, 136,
137= &URTHER READING ON THE PROGRESSION OF CRYO-
surgical injury and it’s manipulation can be found
in the literature [137–139], and are discussed
briefly below.
Immediate Injury
Cellular Effects
The immediate effects of freezing injury at the
cellular level include intracellular ice formation
))& OR DEHYDRATION MECHANISMS AS DESCRIBED IN
DETAIL IN PREVIOUS SECTIONS &IG 4.10). This direct
cell injury occurs during freezing. One of the
most important factors in affecting this mecha-
nism is the cooling rate, although end-temperature
(i.e. critical isotherms), hold-time and thawing
rate are also important [8].
Tissue Effects
4HE ))& AND DEHYDRATION NOT ONLY DESTROY THE
tumor cells, but also can destroy the endothelial
cells along the blood vessel, the circulating eryth-
rocytes and leukocytes within the vessel or in the
interstitial space. This is manifested in histology
as a large central necrotic area around the cryo-
probe with an intense eosinophilic staining of
cells, a loss of nuclear and cytoplasmic detail
[140]. This is often referred to as the complete
destruction zone (below −40 °C) where all types of
cells experience a severe freezing procedure. In
the partially damaged zone (between −40 and
−0.5 °C), these direct injury mechanisms can also
happen. However, endothelial cells are shown to
be more cryosensitive to direct cell injury than sev-
eral tumor cell lines [46]. Therefore, even though
the tumor cells experiencing the mild freezing are
not completely destroyed, the ice crystals form
and propagate along the vascular system and
mechanically induce damage to the blood vessel
4 The Effect of Cold Temperatures on Biological Systems
Fig. 4.10 Mechanisms of
cryosurgical injury – direct
CELL INJURY "ASED ON DATA
from Ref. [8])
Intracellular Ice Formation
Lipid
Peroxidation
Phase Separation
Fluidity / Permeability
Injury and Possible Death (Apoptosis and Necrosis)
wall causing endothelial sloughing, subsequently
leading to delayed ischemia injury as described in
the next section. These immediate destructive
effects lead to significant cell debris and cytokines
in the injury site, sending out a signal for host
inflammatory cells recruitment and adaptive
immunological response; which are a part of the
delayed injury response described below.
Delayed Injury
In addition to the immediate effects of ice forma-
tion in vivo (cellular and vascular ice formation
and dehydration), the tissue continues to be
injured by several delayed mechanisms from
hours to days after cryosurgery, which are con-
sidered to be critical to determine the extent of
the cryolesion. At the cellular level, there is
in vitro evidence that apoptosis (a delayed onset
damage mechanism) destroys some but certainly
not all the tumor cells at the periphery of artificial
tissue systems [141–143]. In native tissues, this
picture is more complicated. It appears that some
apoptosis can occur within endothelial cells lin-
ing the microvasculature of tumors [138].
However, few careful studies have been able to
distinguish necrosis from apoptosis in vivo, and
31
I. Water Biophysics
Dehydration Injury
(Solute Effects)
II. Lipid / Protein Biophysics
Protein
Protease Activity
Denaturation / Inactivation
Aggregation
Synergy
no evidence currently suggests that apoptosis is
dominant over necrosis as an in vivo cryosurgical
mechanism of destruction. In the case of necro-
sis, which is classically termed “ischemic necro-
sis” in the early cryosurgical literature [8], it
results directly from microvasculature shut down
secondary to vascular thrombosis. At the edge of
the lesion where the microvasculature thaws and
then flows, there is ischemia/reperfusion. This in
turn leads to the recruitment of inflammatory and
immune cells and an adaptive host mediated
immune response. Relevant reviews in this area
INCLUDE THE WORK OF (OFFMANN AND "ISCHOF ;8] as
well as that of Sabel [144].
Interaction of Mechanisms
It is worth noting that immediate and delayed
injury mechanisms (local vs. host mediated
injury) are highly interrelated and overlapping in
THEIR EFFECTS &OR INSTANCE INmAMMATORY CELL
infiltrate is considered a key step in enhancing
local injury through a host-local interaction at the
vascular level, and also an important linkage to
activate a tumor-specific immunological
response. In addition, as mentioned above, imme-
diate cell damage due to freezing causes release
32
of certain chemotactic factors, which direct
inflammatory cells to the site of injury. These
cells then produce more free radicals, adhere to
the endothelium and plug microvessels, further
amplifying the damage to endothelium and there-
fore tissue ischemia [145]. Recruitment of
inflammatory cells and release of inflammatory
cytokines modify the tumor microenvironment
facilitating the activation of the adaptive immune
response.
Conclusion
The effect of cold temperature on biological
systems was briefly reviewed in this chapter
within the context of cryosurgery. It has been
shown that biophysics (i.e. phase-change-
induced dehydration and intracellular ice for-
mation) can qualitatively account for the
resulting survival outcome at the cellular
level. Important changes are noted between
suspended cells and attached cells, which have
a more tissue-like phenotype (i.e. cell-cell and
cell-CEM attachment). Experimental and the-
oretical methods to assess these attached cells
are still being developed. Importantly, similar
biophysical trends have also been observed at
the tissue level, however, the resolution of the
data is quite poor due to the opacity of most
TISSUE SYSTEMS &URTHER TOOLS AND STUDIES ARE
thus needed to better elucidate the biophysical
changes in the variety of cell types that make
up a tissue with cell-cell, cell-ECM and vascu-
LAR AND LYMPHATIC EFFECTS &INALLY IN THE
assessment of how freezing affects in vitro or
in vivo cells, one needs to consider both the
immediate injury (i.e. biophysics) as well as
the delayed injury at the cellular level (i.e.
apoptosis) and at the tissue level (vascular and
immunological) host mediated response.
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 Mechanism of Cellular Damage
from Cryosurgery
5
Carlos Horacio Gonzalez Rojas

Abstract
The cryosurgery of skin lesions produces physical, chemical, micro-
circulatory and immunological events. The fast freezing is more destruc-
tive and slow thawing is more lethal. The tissue destruction increases with
repetition of the freeze-thaw cycles.

Keywords
Freezing • Cryosurgery • Crystals • Thawing • Cell compression

Introduction The damage of the cell membrane generates

Cellular damage in cryosurgery of skin lesions
is mainly determined by freeze speed, achieved
final temperature, thaw time, and the size,
form and nature of the cell. Intra- and extra-
cellular cooling of water leads to the forma-
tion of crystals that exert physical effects on
cells. Larger crystals tend to locate in the
extra-cellular space while smaller ones do it
intra-cellular. Both are harmful; their forma-
tion pattern depends on the speed of freeze.
Smaller crystals are thermodynamically less
stable and tend to merge and re-crystallize
harming the cell during the freeze-thaw cycle.
C.H.G. Rojas, MD
Clinica del Café, cra 0 number 12-75 of 420,
Armenia, Quindio 63001, Colombia
e-mail: cahora@yahoo.com
harmful physical events because when the
selective barrier function is lost there is
increased flux of intracellular liquids that may
lead to cell blowup or to dehydration, changes
in ph and enzymatic damage. Immunological
events observed in vivo and in vitro studies
suggest that necrosis induced by cryosurgery
could model the analysis of the interaction
between the amount of necrosis and the
immune response [1]. In Dr. Paul F. Bradley’s
book, Crysurgery of the Maxillofacial Region,
Dr Colin J. Green [2] exposes in a magisterial
way the mechanisms of the cellular damage
caused by freezing and thawing. The physical,
chemical, micro-circulatory and immunologi-
cal events after cryosurgery relate to the vari-
able lability to tolerate coldness in the various
cellular populations. For the ultimate erudite
discussion on the subject the reader is refered
to the preceeding chapter.

© Springer-Verlag London 2016 37

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_5
38
Summary of Damage Mechanisms
Cell compression by extracellular ice.
Increased concentration of intra and extracellular
electrolytes.
Decreased cellular volume due to intracellular water
loss, from increased membrane permeability.
Damaged cellular lipoproteins.
Rupture of cell membranes due to fast water loss.
Pathological ph changes from changes in ionic
concentration at the liquid phase.
Mechanical rupture of cell structures by
micro-crystals.
Thermal shock.
Release of toxic free-radicals during thawing and
reflux.
Microcirculatory events lead to ischemia and
necrosis after freezing.
Possible production of antibodies and generation
of immune cellular response.
Factors to Optimize Cryosurgery
Having met all the points above, to perform a
good cryosurgical practice various factors must
be taken into consideration:
The nature of the damage.
The effect of cold on the cell population to be
treated.
C.H.G. Rojas
The boundaries of the lesion.
The adequate selection of methods and
accessories.
In benign lesion, do not freeze the healthy
tissue.
In malignant lesion, freeze to a margin of safety.
That the tissue destruction increases with the rep-
etition of the freeze-thaw cycles.
Full thawing should be allowed to happen before
repeating a cycle.
Fast freezing is more destructive.
Slow thawing is more lethal.
Protect underlying structures, tumescent anesthe-
sia creates “a third space” under the lesion [3].
Biopsy to rule-out residual disease when healing
is incomplete.
References
1. Gazzaniga S, Bravo A, Goldszmid SR, Maschi F,
Martinelli J, Mordoh JA, et al. Inflammatory changes
alter cryosurgery – induced necrosis human melanoma
xenografted in nude mice. J Invest Dermatol.
2001;116:664–71.
2. Green CJ, et al. The biophysical responses of tissues to
extreme temperature changes. In: Bradley PF, editor.
Cryosurgery of the maxillofacial region, vol. I. Boca
Raton: CRC Press; 1986. p. 17–32.
3. Zanini M. Criocirugía sob anesthesia tumescente no
manejo de carcinomas em área de risco do nervo
facial. Med Cután IberLat Am. 2006;34(6):309–11.
 Effects of Cold Temperature
on the Skin
6
Kenneth R. Diller, Sepideh Khoshnevis,
and Matthew Brothers

Abstract
The response of skin to the application of surface cooling is manifested
primarily as a local vasoconstriction and reduced blood flow. Major func-
tions of skin blood flow (SBF) are to sustain the metabolic process of the
skin cells and to facilitate heat transfer between the body core and the envi-
ronment via the cutaneous circulation. One consequence of surface cooling
is to insulate the body core from the environment by reducing the magni-
tude of SBF. The magnitude of vasoconstriction has a nonlinear dose
response to the applied temperature so that even mild cooling can cause the
loss of a significant fraction of SBF. Other thermally sensitive processes are
also influenced, in particular metabolism, which decreases with falling
temperature. So long as a cold state is maintained, both the blood flow and
metabolism remain depressed. When the skin is rewarmed, metabolism
will likewise increase proportionately. However, in the absence of an exter-
nally applied stimulation, the SBF will remain at depressed levels for many
hours, presumably due to the action of locally expressed humoral vasomo-
tive agents that block the vasodilation process. The consequences may be
prolonged exposure to an ischemic state in conjunction with a high meta-
bolic rate, which may exacerbate the potential for nonfreezing cold injury
(NFCI) expressed as tissue necrosis and neuropathy. The decoupling of
temperature and SBF during rewarming gives rise to a hysteresis effect that
is independent of the speed of the cooling and warming processes.

K.R. Diller, ScD (*) • S. Khoshnevis, MD, PhD

Department of Biomedical Engineering,
The University of Texas at Austin,
107 West Dean Keeton St., BME 4.202A,
Austin, TX 78712, USA
e-mail: kdiller@mail.utexas.edu
M. Brothers
Department of Kinesiology and Health Education,
The University of Texas at Austin, Austin, TX, USA

© Springer-Verlag London 2016 39

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_6
40
Keywords
Cooling • Hysteresis • Ischemia • Nonfreezing cold injury • Skin • Skin
blood flow • Temperature • Thermoregulation • Vasoconstriction
Overview
In normal physiological function, the temperature
of skin is tightly coupled to the local level of blood
perfusion. At the highest levels of SBF, skin tem-
perature may approach that of the body core, minus
1–2 °C to account for convective heat loss as blood
flows to peripheral regions. In addition, environ-
mental heat transfer boundary conditions may exert
a large influence to either augment or depress skin
temperatures. The typical range of skin tempera-
tures encountered in neutral thermal environments
covers approximately 24–34 °C, depending on the
region of the body surface; the local air tempera-
ture, velocity and humidity; the clothing ensemble
worn; the recent thermal history experienced by a
person including level of physical exertion; current
state of in the circadian cycle; and features unique
to a person’s intrinsic thermoregulatory function.
Temperatures outside this range may be produced
under special circumstances such as the application
of energy based therapeutic devices and extremes
in environmental temperature. Of particular inter-
est in this chapter are the consequences of an overt
cooling of the skin for therapeutic purposes to tem-
peratures significantly below the normal physio-
logical continuum.
Reducing the temperature of skin to
suprafreezing levels causes multiple physiologi-
cal alterations. The primary response is a reduc-
tion in SBF that is proportional to the imposed
cutaneous temperature [1–5]. When the initial
skin temperature is above 30 °C, a reduction even
into the high twenties (°C) may cause a drop in
blood flow, and at 20 °C half of the baseline flow
may be lost [6, 7]. Further reduction to the low
teens (°C) may drive the blood flow down to
20 % of baseline. The blood flow will remain at a
diminished level so long as the temperature is
depressed and for an extended time thereafter if
there is no active stimulation intervention [8].
Eventually, if vasoconstriction is maintained
K.R. Diller et al.
sufficiently long, an ischemic state is created that
may precondition the tissue for reperfusion injury
if and when blood flow is reestablished [9].
A prolonged exposure to low temperatures
and ischemia is known to potentiate NFCI [6, 10,
11]. This condition is a consequence of starvation
of the tissue of oxygen and nutrients under condi-
tions at which the metabolic demands are greater
than is supplied by local blood flow. Typical man-
ifestations are tissue necrosis [12–14] and neu-
ropathy [9, 15–18] associated with accumulated
cell death. The clinical manifestation of NFCI
may appear to be similar to injury caused by
freezing, and it is frequently characterized as
frostbite, even in the archival literature [12–14].
However, the mechanisms and time sequence of
the damage processes for freezing and nonfreez-
ing causation are quite different. Cooling at
above freezing temperatures can lead to injury
based on ischemic stress. In contrast, cooling to
subfreezing temperatures can lead to injury based
on the local formation of ice crystals that may
cause concentration of aqueous solutes and intra-
cellular ice formation [19–22]. If protocols are to
be designed to achieve specific physiological out-
comes via the application of cooling to tissues, it
is important to understand and accommodate the
differential in response to temperatures above
and below the freezing point.
Experimental Data
Hundreds of experiments have been conducted in
the authors’ laboratory in which carefully regu-
lated cooling sources were applied to the skin of
subjects to reduce the temperature to values above
0 °C, and local SBF was monitored before, during,
and after cooling. All experimental protocols were
reviewed and approved by the University of Texas
Institutional Review Board (2011-05-0106). The
experimental protocol starts with an initial period
6 Effects of Cold Temperature on the Skin 41

a b
35

Skin Perfusion (%Change

O1|
O2|
50

from Baseline)
30

0
25
Temperature (Oc)

–50

20
0 30 60 90 120 150 180
32

Skin Temperature (Oc)

O1.
30
15 O2.
28
26
24
10
Tcooling pad 22
T1 20
T2 18
5 T3
0 30 60 90 120 150 180 0 30 60 90 120 150 180

Time (mln) Time (mln)

Fig. 6.1 Temperature (a) and blood perfusion (b) data for
a cryotherapy trial with an Össur Cold Rush cryotherapy
system and dedicated knee pad with a central opening so
that the patella is not cooled directly. The three tempera-
ture plots in (a) in addition to the cooling pad surface are:
two on the skin surface underlying the pad (T1 and T2)
and room air (T3). The laser Doppler probes embody a
thermistor on the sensor tip to monitor temperature (01T
and 02T) and blood flow (01P and 02P) at the same site, as
shown in (b). Probe 1 was under the cooling pad; probe 2
was on the patella in an area without direct cooling but
surrounded by the circulating ice water pad

of at least 30 min for environmental equilibration
in the testing room during which thermocouples
and laser Doppler probes are applied to the skin at
the testing site to monitor temperature and
SBF. Subjects are clothed in shorts and a tee shirt
and remain motionless in a supine or reclining
position throughout a protocol. Supplemental cov-
ering with a blanket is available on demand for
comfort and to avoid vasoconstriction induced by
the environmental factors.
Subsequently, cooling is accomplished by the
circulation of cold water through a flexible pad
placed at the test site. A remote refrigeration
source, typically an insulated container contain-
ing an ice water bath with an immersion pump, is
used to induce a flow of cold water through the
bladder. The temperature applied to the skin sur-
face is adjusted by placing a layer of thermal insu-
lating material between the pad and skin. Data
acquisition is initiated during an initial baseline
period of approximately 30 min with no water
flow. Next, water flow is started for a predeter-
mined time that may be varied from a few minutes
to several hours. Finally, the water flow is termi-
nated, but the pad and instrumentation are left in
place while the test site and pad warm passively
by parasitic heat transfer from the underlying tis-
sue and room air. Data acquisition consists of time
series records for temperature and SBF at multi-
ple sites on the skin beneath the pad, plus tem-
peratures at other control and environmental sites.
Figure 6.1 presents temperature and SBF data
for an exemplar experiment in which an Össur
Cold Rush cryotherapy system (Össur Americas,
Foothill Ranch, CA) with the associated knee pad
was applied to the right knee of a healthy male
subject. The knee-pad design explicitly excludes
the patella area for direct exposure to the circulat-
ing ice water. A single layer of loose Ace ban-
dage was applied over the skin underlying the
cooling bladder as a thermal insulation barrier.
The protocol consisted of a 30 min baseline
period prior to the start of cooling, 60 min of ice
water circulation through the cooling pad, and
120 min of passive rewarming.
Although Fig. 6.1 presents data for only a sin-
gle trial with a single cryotherapy unit (CTU), the
analysis of a multitude of trials has shown that
the primary thermal and blood flow features of
this data are within statistically significant bounds
42
Fig. 6.2 Hysteresis effect
between temperature and
blood perfusion during a
cooling and warming cycle.
Cooling data is shown in blue
and warming in red. Blood
flow is presented in terms of
CVC (% of baseline)
cutaneous vascular
conductance (CVC), which is
defined as the output signal
from the laser Doppler system
divided by the mean arterial
blood pressure [24]
for the performance of other CTU devices and
their operation [7, 8]. Of greatest relevance is that
with the commencement of ice water flow
through the cooling pad, its surface temperature
drops very rapidly to a value between 0 and
10 °C. The skin temperature follows with a con-
siderable time lag and thermal offset. Both of
these effects are influenced by the insulating
properties of the thermal barrier and are readily
explained in terms of heat transfer fundamentals
[23]. When ice water flow is terminated, both the
pad and the skin begin to rewarm owing to heat
transfer from the ambient air and from the under-
lying tissue that still has a residual blood flow and
metabolism. Blood perfusion clearly follows the
temperature during cooling, in this case loosing
about 75–80 % of the baseline value. Preliminary
data yet to be reported indicate that the reduction
in blood perfusion is dose dependent on the
applied temperature. Directly under the cooling
pad the drop in temperature and blood flow are
both rapid and pronounced. In the patella area
that is only surrounded by cooling, the drop in
temperature is much smaller and slower.
Likewise, the decrease in blood flow is also
delayed, but eventually the extent of vasocon-
striction nearly matches that underneath the cool-
ing pad. In contrast, during the 2-h period of
K.R. Diller et al.
140
120
100
80
60
40
20
14 16 18 20 22 24 26 28 30 32
Temperature (oC)
passive rewarming, although the skin temperature
recovers approximately two-third of the tempera-
ture loss from baseline incurred during cooling,
the local blood perfusion remains largely
unchanged. Independent studies by our research
group indicate that there is a humoral agent
released during cooling that blocks vasodilation
and that remains active for an extended time fol-
lowing the cessation of active cooling.
Decoupling between temperature and SBF
during the cooling and warming cycle may be
illustrated clearly in terms of a hysteresis plot [8].
Figure 6.2 illustrates this effect.
The data in Fig. 6.2 is derived from a single
cooling trial in which the skin temperature was
reduced to 15 °C prior to passive rewarming. The
hysteresis occurred as the blood flow was pro-
gressively reduced to about 30 % of its baseline
during cooling and then remained depressed dur-
ing rewarming until there was a upward trend
after the temperature reached about 26 °C. The
duration of the trial was not sufficiently long to
allow the blood flow to recover to its original
state. Note that there is no time element in this
plot. However, trials have been conducted for
various combinations of slow and rapid cooling
and rewarming, and in all cases the temperature
and blood flow follow this hysteresis relationship.
6 Effects of Cold Temperature on the Skin
A comprehensive set of trials is being evaluated
to prepare a future paper to present and discuss
this phenomenon in much greater detail.
Summary
The cooling of skin to temperatures deeply
depressed below the physiological range, but
above the conditions for ice crystallization, causes
a strong reduction in local blood flow. If the cold
temperature is sustained, vasoconstriction will
produce an ischemic condition and may lead to a
nonfreezing cold injury. The thermal history dur-
ing a cooling and warming cycle may be manipu-
lated to control the level of blood flow in a target
tissue and thereby to regulate the injury outcome.
Acknowledgements This research was sponsored by
National Science Foundation Grants CBET 0828131,
CBET 096998, and CBET 1250659, National Institutes of
Health Grant R01 EB015522, and the Robert and Prudie
Leibrock Professorship in Engineering at the University
of Texas at Austin.
Author Disclosure Statement Patent applications have
been submitted by Dr. Diller, Dr. Khoshnevis, and Dr.
Brothers to the United States Patent and Trademark
Office the cover certain aspects of the technologies dis-
cussed herein. Ownership rights to these patents reside
with The University of Texas System. Dr. Diller has
served as an expert witness for both plaintiff and defen-
dant counsel since 2000 in numerous legal cases regarding
the safety and design of existing cryotherapy devices.
References
1. Johnson JM. Mechanisms of vasoconstriction with
direct skin cooling in humans. Am J Physiol Heart
Circ Physiol. 2007;292:H1690–1.
2. Johnson JM, Kellogg DL. Local thermal control of the
human cutaneous circulation. J Appl Physiol. 2010;
109:1229–38.
3. Sendowski I, Savourey G, Besnard Y, Bittel J. Cold
induced vasodilatation and cardiovascular responses in
humans during cold water immersion of various upper
limb areas. Eur J Appl Physiol. 1997;75:471–7.
4. Taber C, Contryman K, Fahrenbruch J, LaCount K,
Cornwall MW. Measurement of reactive vasodilation
during cold gel pack application to nontraumatized
ankles. Phys Ther. 1992;72:294–9.
5. Yanagisawa O, Homma T, Okuwaki T, Shimao D,
Takahashi H. Effects of cooling on human skin and skel-
etal muscle. Eur J Appl Physiol. 2007;100:737–45.
43
6. Francis TJ. Non freezing cold injury: a historical
review. J R Nav Med Serv. 1984;70:134–9.
7. Khoshnevis S, Craik NK, Diller KR. Experimental
characterization of the domains of coupling and
uncoupling between surface temperature and skin
blood flow. Intl J Transport Phenom. 2014;13:
277–301.
8. Khoshnevis S, Craik NK, Diller KR. Cold-induced
vasoconstriction may persist long after cooling ends:
an evaluation of multiple cryotherapy units. Knee Surg
Sports Traumatol Arthrosc. 2015;23(9):2475–83.
DOI:10.1007/s00167-014-291-y.
9. Jia J, Pollock M. Cold nerve injury is enhanced by
intermittent cooling. Muscle Nerve. 1999;22:
1644–52.
10. Francis TJ, Golden FS. Non-freezing cold injury: the
pathogenesis. J R Nav Med Serv. 1985;71:3–8.
11. Thomas JR, Oakley EHN. Nonfreezing cold injury.
In: Textbooks of military medicine: medical aspects
of harsh environments. Falls Church: Office of the
Surgeon General, U. S. Army; 2002. p. 467–90.
12. Brown WC, Hahn DB. Frostbite of the feet after cryo-
therapy: a report of two cases. J Foot Ankle Surg.
2009;48:577–80.
13. Lee CK, Pardun J, Buntic R, Kiehn M, Brooks D,
Buncke HJ. Severe frostbite of the knees after cryo-
therapy. Orthopedics. 2007;30:63–4.
14. McGuire DA, Hendricks SD. Incidences of frostbite
in arthroscopic knee surgery postoperative cryother-
apy rehabilitation. J Arthrosc Relat Surg. 2006;22:
1141–e1.
15. Large A, Heinbecker P. Nerve degeneration following
prolonged cooling of an extremity. Ann Surg. 1944;
120:742–9.
16. Schaumburg H, Byck R, Herman R, Rosengart C.
Peripheral nerve damage by cold. Arch Neurol. 1967;
16:103–9.
17. Bassett 3rd FH, Kirkpatrick JS, Engelhardt DL,
Malone TR. Cryotherapy-induced nerve injury. Am
J Sports Med. 1992;20:516–8.
18. Irwin MS. Nature and mechanism of peripheral nerve
damage in an experimental model of non-freezing
cold injury. Ann R Coll Surg Engl. 1996;78:372–9.
19. Mazur P. Kinetics of water loss from cells at subzero
temperatures and the likelihood of intracellular freezing.
J Gen Physiol. 1963;47:347–69.
20. Hoffmann NE, Bischof JC. The cryobiology of cryo-
surgical injury. Urology. 2002;60(2A):40–9.
21. Han B, Bischof JC. Engineering challenges in tissue
preservation. Cell Press Technol. 2004;2:91–112.
22. Balasubramanian SK, Wolkers WF, Bischof JC.
Membrane hydration correlates to cellular biophysics
during freezing in mammalian cells. Biochim Biophys
Acta Biomembr. 2009;1788:945–53.
23. Roselli RJ, Diller KR, editors. Biotransport: princi-
ples and applications. New York: Springer; 2011.
1286 pp.
24. Clough G, Chipperfield A, Byrne C, de Mul F, Gush R.
Evaluation of a new high power, wide separation laser
Doppler probe: potential measurement of deeper tissue
blood flow. Microvasc Res. 2009;78:155–61.
 Part III
Immunology
 Immunology
7
Michael Scott Sabel

Abstract
The clinical application of cryosurgery in dermatology is expanding,
including the treatment of skin cancers. At the same time, cryosurgery is
increasingly being used to treat other solid tumors. Early experience with
tumor cryoablation noted an abscopal effect, where treatment of one lesion
led to the regression of distant, non-treated lesions. These anecdotal
reports led to pre-clinical and clinical studies of cryo-immunology; the
impact that cryoablation has on immune recognition and eradication of
malignant disease. However, this relationship is complex and while the
mechanism by which cryoablation triggers immune recognition can the
augmentation of an anti-tumor response, under different conditions it can
lead to anergy and immune suppression. This chapter will review the data,
both pre-clinical and clinical, that documents the existence of a
cryoablation-induced immune response and examines the mechanism by
which this occurs. In addition, this chapter reviews promising adjuvants
that, in combination with cryoablation, can lead to a more robust immune
response that may have a significant clinical impact on the progression of
metastatic disease.

Keywords
Cryoablation • Cryo-immunology • Immune response • Tumor ablation

M.S. Sabel, MD, FACS
Department of Surgery, University of Michigan,
3302 Cancer Center 1500 Medical Center Drive,
Ann Arbor, MI 48109-5932, USA
e-mail: msabel@umich.edu
Introduction
While cryosurgery has several benefits as a local
therapy for skin malignancies, another potential
benefit may be the generation of distant effects,
specifically, the initiation of a tumor-specific

© Springer-Verlag London 2016 47

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_7
48
immune response. In this manner, cryosurgery
may trigger an abscopal effect, where treatment
of one site of disease could have effects on
untreated sites of disease far from the ablated tis-
sue. The abscopal effect has primarily been
described with radiation, where non-irradiated
tumors resolve following localized radiation
therapy. This has been described in melanoma
[1–3], and activation of an anti-tumor immune
response is often proposed as the mechanism.
However, the abscopal effect can be seen with
other forms of local therapy. Several reports of
various intralesional therapies for in-transit dis-
ease in melanoma describe regression of
untreated lesions, and the term distant bystander
effect is often used to describe this effect [4–6].
There are multiple reports of distant bystander
effects after tumor cryoablation. Ablin et al. [7]
reported on several cases where cryoablation of
the prostate led to regression of distant disease,
including lymph node, pulmonary and bone
metastases. One of the patients had anti-prostatic
antibodies detected in their serum after cryosur-
gery, suggesting a humoral anti-tumor immune
response may have been the cause [8]. Horan
et al. [9] also reported on distal tumor regression
after prostate cryoablation in a small number of
patients. Uhlschmid et al. [10] described the
results of 30 patients who underwent cryoablation
of pulmonary metastases from various cancers.
Four patients had evidence of an abscopal effect.
Reports of similar effects in breast cancer and
other tumor types have been reported from Japan,
where cryoablation was examined as a palliative
therapy for locally advanced disease [11–13].
These clinical reports prompted basic science
studies of the potential for cryosurgery to gener-
ate an anti-tumor immune response and exhibit
distant effects. The mixed results of these studies
not only served to dampen excitement for cryoab-
lation as a form of immunotherapy, but raised
questions about its clinical use. Since that time,
however, our knowledge of the components of the
immune system and their interactions in the stim-
ulation and/or suppression of an immune response
has increased exponentially. This has led to a bet-
ter understanding of how cryoablation may gener-
ate or suppress the immune recognition of tumor,
M.S. Sabel
and how we can modulate that in order to use
cryoablation as both a local and a systemic ther-
apy. This chapter will review the mechanisms by
which the in situ freezing of malignant tissue may
influence the immune system’s recognition of
unique tumor antigens, and the research examin-
ing how to augment that response for maximum
clinical benefit.
How Does Cryoablation Kill Cells?
There are a variety of methods that cryoablation
can be used to ablate cancer. For most solid
tumors this often involves using image guidance
to insert one or more cryoprobes in or around a
tumor. Cryoprobes cool rapidly, removing heat
via conduction. In other cases, particularly in
dermatologic surgery, cryoablation is often per-
formed by applying LN with a cotton applicator
stick or an aerosol spray. There are different pro-
cesses by which cooling leads to cell death, and
the method by which tissue is frozen can impact
the fractions of cells killed by one process over
another. Rates of temperature change, target tem-
peratures, and distance from the freezing center
will change the relative fractions of necrosis and
apoptosis, and potentially alter the way the
immune system responds.
The mechanisms by which cryoablation kills
cells are multiple and complex, and can be cate-
gorized as either direct cellular injury and indi-
rect cellular injury, the latter being related to
changes in the cellular microenvironment
induced by the cold [14, 15]. Direct cellular
injury is related to the sequelae of freezing water.
When ice crystals form in the extracellular space,
free water is sequestered, increasing tonicity.
This has the effect of increasing osmotic tension
and drawing more free water out of the cells-
leading to dehydration and destabilization of the
cell membrane [16]. Osmotic injury doesn’t just
occur during freezing, but also during thawing.
When the ice melts, tonicity decreases, osmotic
forces reverse, and the cells can swell and burst.
One can see, therefore, how the speed by which
cooling occurs can impact this effect. Rapid cool-
ing does not allow for these osmotic shifts, trapping
7 Immunology
water within the cells and leading to intracellular
ice crystal formation [15]. Instead of osmotic
injury, this results in a physical damage known as
disruptive necrosis (different from the coagulative
necrosis one sees with heat based ablations) [16,
17]. As high extracellular colute concentrations
lower the freezing point of water, the influx of free
water into the intracellular space during thawing
can also increase the growth of intracellular ice
crystals, magnifying their effect [14, 17].
These direct effects are primarily necrotic, but
many cells will also die by apoptosis. For exam-
ple, cells with intact membranes but with damage
to mitochondria will see activation of caspases,
which leads to programmed cell death, or apopto-
sis [18]. Cells that don’t die, particularly those
more distant from the freezing center, but have
irreversible cellular injury will also die by apop-
tosis [19]. A handful of studies showed that cell
death by necrosis is evident in the central part of
the cryogenic lesion, while apoptosis is evident
8–16 h later at the periphery of the lesion [18,
20–22]. The freeze-thaw process will also dam-
age blood vessels, leading to indirect cellular
injury. Vascular endothelial cell are damaged,
and when reperfusion brings in platelets, they
contact the damaged endothelium and thrombo-
sis. This ischemia will then lead to additional
necrosis and apoptosis [23].
Cell Death and the Immune System
Why is it important whether a cancer cell dies
by coagulative necrosis, disruptive necrosis,
apoptosis or some other mechanism? How a
cell dies will impact the response from the
immune system [24]. Necrosis, particularly dis-
ruptive necrosis, is characterized by release of
intracellular contents, many of which are
immunostimulatory, such as heat shock pro-
teins, uric acid or the chromosomal protein
HMGB1 (high mobility group box chromo-
somal protein 1). These “danger signals” serve
to activate the innate immune response [25].
The disruption and exposure of tissue architec-
ture, such as fibrinogen, oligosaccharides of
hyaluronan, extra domain A (EDA)-containing
49
fibronectin and heparin sulfate proteoglycan,
has a similar effect [26–29]. In contrast, apop-
totic cells tend not to release their contents.
Instead they are engulfed by macrophages,
mediated by a number of receptors and opso-
nins, which bind to cellular ligands exposed on
the surface of apoptotic cells. This not only pre-
vents the release of the intracellular contents,
but modulates phagocyte function, inhibiting
pro-inflammatory cytokine release and increas-
ing TGF-B1 production [30, 31]. Dendritic
cells that take up apoptotic cells have sup-
pressed cytokine production and do not mature
[32, 33]. These non-mature DC not only fail to
stimulate an immune response, they can trigger
clonal deletion and anergy [34]. Physiologically,
this makes sense given the fact that apoptosis is
a natural event in most tissues, as the genera-
tion of an immune response against these cells
could lead to autoimmune disease, which can
be seen when there are defects in the manner by
which apoptotic cells are cleared [29]. The con-
tinual transport of apoptotic “self” cells and
presentation of self-antigen may relate to
peripheral tolerance [35, 36].
The impact on the immune response initiated
by the type of cell death moves beyond the “self
vs. non-self” concept of immune recognition.
The generation of an immune response not only
requires the identification of “non-self” but also
needs a signal that there is “danger” [37, 38].
Thus, three signals are actually needed to trigger
an immune response; (1) recognition of a peptide
antigen, presented on an antigen presenting cell
(APC), by a T-cell receptor, (2) interaction of co-
stimulatory molecules on the APC cell surface
and T-cell, and (3) a “danger” signal that can
either be a foreign substance (exogenous) or
intracellular contents (endogenous). Apoptosis of
normal cells, in the absence of any danger sig-
nals, would lead to the release of immunosup-
pressive signals and development of tolerance.
Looking at the three-signal theory and how it
may relate to cryoablation, one might surmise that
complete necrosis of a malignant lesion would gen-
erate the strongest immune response. However,
there is evidence that apoptotic tumor cells may
also contribute to a more robust anti-tumor response
50
[39–42], as phagocytosis by dendritic cells of
tumor cell-derived apoptotic bodies, leads to cross-
presentation of antigens to CD8+ T-cells [41, 43].
In the absence of cross-presentation, and the gen-
eration of only CD4+ T-cells, the response is pri-
marily humoral and the T-cell response is less
robust. Therefore, while pure apoptotic death might
lead to tolerance, the combination of necrosis (for
the generation of danger signals) and apoptosis (for
apoptotic bodies to be taken up by DC activated by
these signals) may lead to the most significant anti-
tumor immune response.
As described above, cell death in cryoabla-
tion is achieved by the relative contributions of
osmotic shifts, extracellular and intracellular
ice formation, and vascular injury to cell death,
and these in turn result in varying fractions of
apoptosis and necrosis. These can vary depend-
ing on the technique used to treat, as well as the
local anatomy. While temperatures below
−20 °C efficiently kill cancer cells, most inves-
tigators suggest the lethal temperature should
be in the −40 °C to −50 °C range, and some
studies suggest temperatures below −60 °C are
required [44]. Decreasing temperature leads to
more direct cell injury, and a wider area of indi-
rect injury further from the source. It is not just
how low the temperature goes, but how quickly
that occurs. Tissue close to the source of the
cold has a very rapid cooling rate, while further
away the cooling is slower. The cooling rate has
significant impact on extracellular and intracel-
lular ice formation and osmotic changes [45,
46]. While the cooling rate is in part set by the
operator, it is also in part determined by the tis-
sue type and proximity to blood vessels. While
the cooling rate may have less impact on
whether the cells are killed, it may have more
significant impact on the type of immune
response generated [47, 48].
While we tend to focus on freezing, thawing
can be equally destructive. The longer the dura-
tion of the thaw, the greater the damage to the
cells primarily due to an increase in the solute
effects as well as increased size of the intracellu-
lar ice crystals [47, 49]. Cancer cells can be more
resistant to freezing than non-neoplastic cells,
M.S. Sabel
and may suffer cell membrane damage but not
death. These cells, however, are more susceptible
to a second round of freezing, so that more than
one freeze-thaw cycle can greatly increase cell
killing, and several early cryo studies demon-
strated the clinical importance of more than one
freeze-thaw cycle [50–52]. A second cycle leads
to a larger volume of frozen tissue, and a more
lethal effect in the warmer freezing zone at the
periphery of a target [44, 53], which may also
serve to increase necrosis and decrease apoptosis
within this peripheral zone.
Preclinical Studies of the Presence
and Mechanism of the Immune
Response to Cryoablation
Prompted by observations of distant bystander
effect in patients undergoing clinical cryoablation,
early studies documented the humoral response
triggered by cryoablation across several animal
models, showing the induction of serum antibodies
that recognized tumor specific antigens [54–61].
These investigations were the first to suggest that
cancer cryoablation could potentially be a form of
immunotherapy such as a vaccine. Therefore, freez-
ing a tumor and leaving it in place could render the
animal resistant to a re-challenge. Tanaka et al. [10],
Neel et al. [62] and Blackwood [63] all demon-
strated this tumor-specific resistance to re-challenge
was present after cryoablation, but not surgery, in
multiple animal models. Sabel et al. [64] looked at
MT-901 mammary adenocarcinoma tumors in
BALB/c mice treated by cryoablation or surgical
resection. After re-challenge, 86 % of mice treated
by surgery developed second tumors compared
with only 16 % of mice treated by cryosurgery. This
was tumor-specific, as cryosurgery offered no pro-
tection against challenge with another cell line. Not
all studies, however, have demonstrated this vac-
cine-type effect. Several studies attempted to docu-
ment an immune response to cryoablation but failed
to do so, or had mixed results [46, 65–68]. Other
studies showed that not only was there no benefit,
there was a negative effect to cryoablation [69–74].
Many of these studies involved fibrosarcoma cell
7 Immunology
lines in rats. Hayakawa et al. [69], using a chemi-
cally induced fibrosarcoma, found mice treated by
cryoablation had a decreased resistance to a second-
ary tumor challenge, as well as increased growth
and metastatic rates of secondary tumors. Shibata
et al. [71], using a similar animal model, found
cryoablation enhanced pulmonary metastases.
Several studies demonstrated varying results,
depending on the timepoint examined. Misao
et al. [75] compared cryosurgery and surgical
resection in Sprague-Dawley rats implanted with
a metastasizing comedo-type breast adenocarci-
noma (MRMT-1). Mice were re-challenged after
successful local therapy. When mice were exam-
ined 1–3 weeks after treatment, the surgical
group demonstrated a superior rejection rate.
However, by week 10, mice treated by cryosur-
gery demonstrated significantly better tumor
rejection (80 %) compared to mice that had surgi-
cal excision (18 %). Looking at several measures
of immune response in the regional nodes of
mice treated by surgery or cryo, Maya et al. [76]
found while hyperplasia and sinus histiocytosis
in the nodes increased and remained high after
cryosurgery, PHA-induced proliferation of
T-cells in the regional lymph nodes increased
with cryoablation, but decreased in the peripheral
blood, not fully recovering to preoperative levels
until 6 weeks. The authors concluded that there
was an early tumor suppression that took place
systemically as a result of cryosurgery, although
this eventually reversed, leading to a high resis-
tance to re-challenge with time.
Beyond the timing of when you look for the
response, differences in response may be related to
how much tumor was frozen. Blackwood and
Cooper [63] described prevention of re-challenge
and regression of second tumors after cryoablation
but found that the immunologic response was more
robust when only a small amount of frozen tissue
was left behind, compared to the bulk of the frozen
tumor tissue. Hanawa et al. [72] had similar results.
Rats whose tumors had been completely ablated
were more susceptible to a subsequent challenge
than rats that had the tumors incompletely frozen.
Urano et al. [77] ablated metastatic colon tumors in
the liver and found that ablation of a single nodule
51
in the liver led to a significant reduction in the num-
ber of metastatic deposits. However, cryoablation of
multiple nodules actually eradicated this effect,
resulting in a greater number of lesions. These
results suggested the degree of tumor freezing
might modulate the systemic immune response and
possibly there was a threshold of antigenic stimu-
lant whereby excess antigen might prove detrimen-
tal to the immune response. This may be supported
by a study from Miya et al [73], who examined the
route and time course of tumor antigens in local
lymphatic and hematogenous vessels around cryo-
ablated tissue. The authors suggested that the large
release of tumor antigens via lymphatic routes
might act as a blocking factor and participate in
depressing anti-tumor immunity in the early post-
operative period. These mixed results not only
raised questions regarding the clinical implementa-
tion of cryosurgery, but also encouraged mechanis-
tic studies of how cryoablation interacts with the
immune system. These studies provide some insight
into the mechanisms by which cryoablation can
augment the critical steps required for the genera-
tion of a tumor-specific response (Fig. 7.1).
Although the interest lies primarily in the adaptive
response; the generation of tumor specific antibod-
ies and cytotoxic T-cells, the initial immunologic
result of cryoablation is inflammation and the initia-
tion of the nonspecific innate response. The inflam-
matory changes in the hours and days after
cryoablation have been documented in animal stud-
ies [78, 79]. Within hours, leukocytes are seen intra-
vascularly, eventually infiltrating the peritumoral
area. By day 3, these have reached their maximal
concentrations and macrophages begin to appear.
By day 14 there is a significant infiltration of neu-
trophils and macrophages in the parenchyma, blood
vessels and perivascular areas. For the adaptive
response to occur, the innate response needs to
progress to the attraction and activation of antigen-
presenting cells (APC). APC, such as macrophages
and dendritic cells, drive the activation, differentia-
tion and proliferation of T-cells, and are also in part
responsible for tamping down that response.
To activate tumor specific T-cells, dendritic
cells require tumor antigen, and the cryoablated
tumor provides an excellent source. Den Brok
52
Cryoprobe
Necrosis Apoptosis
Tumor
Antigens
C
D MHC-1
Apoptotic
Bodies
B RESPONSE
A
Danger
Signals
Polymorphonuclear Cells
Macrophages
INNATE
RESPONSE
Fig. 7.1 Methods by which cryoablation initiates and
drives an anti-tumor immune response. (a) Shortly after
cryoablation, the innate response leads to an influx of
PMNs and macrophages. Cytokines released by these
cells lead to additional inflammation and drive the adap-
tive response. (b) Intracellular contents are released
from necrotic cells, acting as ‘danger signals’ to activate
the innate response and lead to DC activation and matu-
ration. (c) Tumor antigens released from necrotic cells
et al. [80] injected 111Indium-labeled KLH or
OVA tracer proteins into B16/OVA tumors prior
to cryoablation and demonstrated that cryoabla-
tion, as compared to untreated mice, showed a
significant uptake of the labeled antigens in
CD11c+ dendritic cells. Cryoablation also
induced maturation of these DC, and outper-
formed both radiofrequency ablation or conven-
tional dendritic cell vaccines. Given the rapid
uptake of antigen within the DC, it seems more
likely the antigens traveled from the lymphatics
to DC within the nodes, rather than DC migrating
to the ablated tumor, taking up antigen, and then
travelling to the lymph nodes.
M.S. Sabel
E
BT CO28 CD8+
T-cell
(Cytotoxic)
Dendritic Cell receptor T-cell
ADAPTIVE
Monoclonal
Antibodies
MHC-2 87
T-cell CO28
receptor
F
CD4+
(Helper) B-Cell
T-cell
are taken up by DC in the tumor draining lymph nodes.
Exogenous antigens are primarily processed and pre-
sented on Class II MHC, leading to CD4+ T-cells. (d)
Apoptotic bodies phagocytized by antigen-presenting
cells (in the presence of danger signals) lead to cross
presentation to Class I MHC and (e) the activation of
tumor-specific CD8+ cytotoxic T-cells. (f) With help
from CD4+ T-cells, B-cells produce tumor specific
antibodies
Several murine studies clearly document the
generation of tumor-specific T-cells after cryoab-
lation. Bagley et al. [81] harvested splenic lym-
phocytes at weekly intervals after either
cryoablation or surgery for cytotoxicity assays.
Mice undergoing cryoablation had significantly
higher cytotoxicity than mice undergoing surgery
or untreated mice, and these were tumor specific,
as cytotoxicity assays against other tumor types
showed no effect. Sabel et al. [64, 82] showed
that cryoablation, but not surgery, lead to an
increase in tumor-specific CD4+ and CD8+
T-cells within the tumor draining lymph nodes.
Urano et al. [77] demonstrated an increased
7 Immunology
activity of tumor specific T-cells after cryoablation
of colon cancer metastatic to the liver of BALB/c
mice. Ming et al. [22] performed cryoablation of
C6 gliomas in Wistar rats. Compared with sur-
gery that caused significant reductions in CD3+
and CD4+ cell percentages within the blood,
cryosurgery increased these percentages.
Not all T-cells are the same, however, and in
addition to helper and cytotoxic T-cells, there are
regulatory T-cells that serve to dampen an immune
response. Some studies have demonstrated the
capability of cryoablation to increase these regula-
tory T-cells [48, 83]. Shibata et al., who had dem-
onstrated a negative effect of cryoablation, showed
that the adoptive transfusion of splenocytes from
tumor-bearing mice treated by cryoablation would
diminish anti-tumor resistance, suggesting that the
immunosuppression following cryosurgery might
be caused by regulatory T-cells (which at the time
were known as suppressor T-cells). This finding
was supported by another study of fibrosarcoma
cryoablation in Sylvian golden hamsters, showing
an increase in regulatory T-cells following cryo-
surgery [83]. The presence of regulatory T-cells
after cryoablation may be associated with the
immunologic and clinical outcomes [84].
Sabel et al. [48] sought to determine whether
different methods of cryoablation might impact
the T-cell response. Breast cancer bearing mice
were treated by surgical excision and two types
of cryoablation; a rapid freeze or a slow freeze,
which may result in less necrosis and more apop-
tosis. Compared to surgical excision, the rapid
freeze resulted in a significant increase in IFN-γ
producing T-cells, a significant decrease in pul-
monary metastases and improvement in survival.
In contrast, there was no improvement in the
tumor specific immune response nor pulmonary
metastases and survival with the slow freeze.
Looking at T-cell subsets, regulatory T-cells
(CD4+ CD25 high) decreased with the rapid
freeze compared to surgical excision, but
increased with the slow freeze. These results con-
firmed not only that the degree of immune
response can be altered by changes in the cryo-
surgical technique, but suggested that some
approaches to cryoablation may actually cause
immune suppression.
53
Documentation of the Cryo-immune
Response after Clinical Cryoablation
The mechanism for a cryo-immunologic response
proposed in animal studies is to some degree sup-
ported by immune studies in patients undergoing
clinical cryosurgery. Early, isolated studies in the
1970s and 1980s demonstrated increases in non-
specific markers of inflammation in patients
undergoing cryoablation of oral cavity cancers
[85–87], rectal cancers [88, 89] or breast cancer
[12]. Since that time, the clinical application of
cryoablation for cancer has expanded dramati-
cally, but there have been relatively few studies of
the immunologic consequences in humans. The
majority of work has been focused on document-
ing changes in serum cytokine levels. Much of
this has been driven by the recognition of “cryo-
shock,” a potentially fatal cytokine release syn-
drome that can lead to thrombocytopenia,
disseminated intravascular coagulation (DIC),
and pulmonary failure [90–92]. This syndrome is
primarily seen when large volumes of the liver
are cryoablated, and Seifert et al. [90, 93] demon-
strated elevations of TNF-α and IL-6 in this situ-
ation. Elevations of pro-inflammatory cytokines
have also been described after cryoablation of
prostate, bone and soft tissue tumors [94, 95].
Changes in the cytokine levels induced by cryo-
ablation may correlate with the immune response.
After hepatic cryoablation, Osada et al. [96, 97]
reported that patients who had both local and
abscopal effects had elevations of TNF-α and
increases in the Th1/Th2 ratio (IFN-γ/IL-4),
while patients without evidence of an abscopal
effect had elevations of IL-10 levels after
cryosurgery.
There have been several studies documenting
the generation of a tumor-specific response.
Ravindranath et al. [98] measured both the level
of serum tumor gangliosides and their antibody
titers after cryosurgery, radiofrequency ablation
(RFA) or surgical excision of colorectal metasta-
ses in the liver. Cryoablation, but not surgery or
RFA, led to an increase in both serum ganglio-
sides and in the IgM titer against tumor ganglio-
sides. This led the authors to conclude that
cryosurgery-induced necrosis of the tumor both
54
released these gangliosides and initiated a
humoral response. Si et al. reported increases in
both IFN-γ producing T-cells and tumor specific
cytolytic activity after prostate cancer cryoabla-
tion [94, 99]. There are also several studies of
increases in T-cell populations following cancer
cryoablation [87, 100]. Weyer et al. [101] per-
formed a randomized study of cryosurgery versus
conventional surgery for patients with melanoma.
In both the skin and blood of patients undergoing
cryoablation, an increase in total T-cells, helper
T-cells and the helper/suppressor T-cell ratio was
seen. In the patients treated by surgery, these
parameters either decreased or remained the
same.
Cryoablation as a Component
of Combination Immunotherapy
The available evidence suggests that cryoablation
of malignant tumors has the potential to stimulate
an anti-tumor immune response, but this is response
may only be clinically significant in a fraction of
cases, and in some situations, related to multiple
variables, the response may be suppressive. As we
examine a multitude of immunotherapies, we are
becoming increasingly aware that harnessing the
potential of immunotherapy in cancer will require a
multipronged approach- combining therapies that
initiate an immune response with not only pro-
inflammatory adjuvants, but also therapies directed
at quashing immunosuppressive factors.
Several immune adjuvants have been examined
as potential adjuvants to augment the immunologic
impact of cryoablation. Urano et al. [77] found that
Krestin, a protein-bound polysaccharide preparation
widely used in Japan as a biological response modi-
fier, could enhance the antitumor effects of cryoabla-
tion. This approach was subsequently used clinically
for unresectable hepatic tumors with some success
[97]. Granulocyte-macrophage colony stimulating
factor (GM-CSF) is a protein secreted by immune
cells (T-cells, NK cells, mast cells), endothelial cells
and fibroblasts. GM-CSF regulates the proliferation,
differentiation and function of granulocytes and
macrophages, and is thought to stimulate DC to
uptake and process antigens [102]. GM-CSF has
M.S. Sabel
been a popular adjuvant to immunotherapies such as
vaccines, and has also been used in combination
with cryoablation with promising results. In a trial of
patients with metastatic prostate cancer, the combi-
nation of cryoablation and GM-CSF resulted in
increased tumor-specific T-cell responses [103]. In a
pilot study of cryoablation and GM-CSF in renal cell
carcinoma, the combination therapy led to the induc-
tion of tumor specific cytotoxic T-cells and antibody,
and these responses appeared to be associated with
clinical response [104].
Toll-like receptors (TLRs) are transmembrane
proteins expressed by cells of the innate immune
system, which activate signaling pathways that
launch a variety of immune and inflammatory
responses. The most well known TLR agonist is
Imiquimod, a TLR-7 agonist, is currently used in
dermatology for the treatment of human papillo-
mavirus infection, basal cell carcinoma and
actinic keratosis. It has also been examined as a
treatment for melanoma, albeit with mixed
results. In murine studies; Redondo et al. [105]
demonstrated that cryosurgery followed by daily
topical treatment with imiquimod for 10 days
dramatically improved resistance to re-challenge
over cryoablation alone or surgery, and a robust
T-cell response in the tumor draining lymph
nodes. This has been used clinically as well, with
the combination of imiquimod and cryosurgery
used to successfully treat lentigo maligna [106],
and basal cell carcinoma. Using TLR-9 stimula-
tion using CpG-oligodeoxynucleotides (CpG-
ODN), den Brok et al. [107, 108] also showed
that resistance to re-challenge was significantly
enhanced by the combination therapy compared
to ablation or CpG-ODN alone. There were
increased tumor antigen containing dendritic
cells within the TDLN, as well as increased DC
maturation, cross-presentation and tumor-
specific T-cells [103].
As opposed to adjuvants meant to ramp up an
immune response (stepping on the gas), the same
goal can be achieved by removing immunosup-
pressive factors (cutting the brakes).
Cyclophosphamide is a chemotherapeutic agent
that depletes regulatory T-cells. Levy et al. [109]
found that when combined with cryoablation, the
result was a greater anti-tumor immune response.
7 Immunology
Other methods to deplete regulatory T-cells have
also resulted in increased cryoablation-induced
tumor immunity [80].
Monoclonal antibodies that block the function
of CTLA-4 are an extremely promising anti-
cancer therapy, presently used in the treatment of
stage IV melanoma. CTLA-4 is a transmembrane
protein expressed by activated T-cells, which
serves to end an on-going immune response.
CTLA-4 binds B7 at the surface of the APC, and
this interaction serves to inhibit T-cell activation.
Ipilimumab is an FDA-approved monoclonal
antibody to CTLA-4 that diminishes the inhibi-
tory process, allowing a more robust T-cell
response, and this has a significant clinical impact
in the treatment of metastatic melanoma [110,
111]. Several pre-clinical studies have demon-
strated that administration of anti-CTLA-4 mAb
during the cryoablation of a primary tumor
improves the generation of a systemic immune
response. In their examination of antigen loading
of DC by cryoablation, den Brok and colleagues
also studied whether modulating suppressive reg-
ulation could augment the immune response to
cryoablation [80]. The authors found that the
combination of CTLA-4 blockade with cryosur-
gery led to increased IFN-γ producing tumor spe-
cific T-cells as well as an increased resistance to
re-challenge. Likewise, depletion of regulatory T
cells prior to ablation also enhanced tumor immu-
nity. Neither anti-CTLA-4 antibodies or Treg
depletion had a significant effect of primary
tumors or re-challenges in the absence of cryo-
therapy. Other studies have confirmed the potent
immune stimulation with this combination [112,
113]. These results have led to a clinical trial of
Ipilimumab combined with cryoablation in early
stage breast cancer [114].
Another promising approach in tumor immu-
notherapy is the introduction of antibodies that
block programmed cell death-1 (PD-1) receptors,
which are expressed on activated T and B-cells.
The ligand for this receptor, PD-L1 (or B7-H1) is
inducible on monocytes, DC and can be expressed
to cancer cells. This serves to suppress T-cell
responses by inducing apoptosis, anergy and
functional exhaustion of T-cells and may be one
mechanism by which cancer escapes immune
55
recognition [115–117]. Upregulation of circulat-
ing PD-L1/PD-1 has also been associated with
poor post-cryoablation response in hepatocellu-
lar carcinoma [118]. Clinical trials of monoclonal
antibodies that block the binding of PD-1 to
PD-L1 have demonstrated impressive clinical
results in a variety of malignancies, including
melanoma [119]. Combination of cryoablation
and anti-PD-1 antibodies may be a potent combi-
nation for augmenting the clinical benefit of the
cryo-immunologic response.
Conclusion
The majority of pre-clinical and clinical data
reveals than a systemic anti-tumor immune
response can be generated through the use of
cryoablation. In the majority of pre-clinical
studies comparing cryoablation to other modali-
ties, the systemic immune response is substan-
tially greater with freezing than surgical
excision, radiofrequency ablation or other heat-
based ablation technologies. This supports the
existing evidence from clinical cryosurgery sug-
gesting a clinically relevant anti-tumor immune
response being responsible for distant bystander
effects. The immune mediated ablation of dis-
tant micrometastatic disease and a reduction in
distant disease recurrence associated with a pri-
mary therapy is the holy grail of cancer therapy;
greatly improving outcomes while decreasing
the cost and morbidity of treatment. While this
is a strong motivator for the clinical application
of cryosurgery, a better understanding of the
complex relationship between cell death and
immune recognition reveals the potential for
immune suppression. Given these complexities,
it is imperative that we continue to dissect the
methods by which cryoablation can influence
the individual components of the immune sys-
tem. A better understanding of how cryosurgical
technique can not only impact efficacy, but also
the resultant immune modulation, are necessary
so that we assure both adequate tumor ablation
and at the very least, avoid immune suppres-
sion. More importantly, this information will
also help guide the appropriate selection of
immune adjuvants to be delivered in concert
with cryoablation. As it seems unlikely that
56
cryoablation alone will generate enough of an
immune response to be clinically relevant, cryo-
ablation may be a single component in a multi-
step approach to immunotherapy. These
treatment paradigms will also need to be studied
in the context of standard adjuvants, such as
chemotherapy and radiation therapy, as these
treatments can be immunosuppressive and the
timing of these could counter the immunologic
benefit gained from cryoablation.
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 Part IV
Equipment
 Equipment
8
William Abramovits

Abstract
Liquid nitrogen (LN) is the most commonly used cryogen for dermatologic
cryosurgery and cryotherapy. The equipment used for the therapeutic deliv-
ery of this and other refrigerants is discussed in the following chapters.

Keywords
Equipment • Production • Storage • Delivery • Monitorization • Cryosurgery •
Cryotherapy

W. Abramovits, MD, FAAD

Department of Dermatology,
Baylor University Medical Center,
Dallas, TX, USA
Department of Internal Medicine,
University of North Texas Health Science Center,
Texas College of Osteopathic Medicine,
Fort Worth, TX, USA
Department of Dermatology,
University of Texas Medical Branch,
Dallas, TX, USA
The University of Texas Southwestern Medical School,
Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College
of Medicine, Bryan, TX, USA
Dermatology Treatment and Research Center,
5310 Harvest Hill Road, Suite #160, Dallas, TX
75230, USA
e-mail: DrA@dermcenter.us
Introduction
Over the last 50 years, LN has become the most
common refrigerant used in dermatologic cryo-
therapy and cryosurgery. Equipment has been
designed for the efficient production, storage and
delivery of LN to effectively treat skin lesions. To
optimally perform cryosurgery it is essential to
have a solid understanding of the materials
(equipment) and methods (techniques) to be
used.
What follows is a compilation, as complete as
we could put together from literature, technical
exhibits at dermatology and cryosurgery meet-
ings, Internet vendors and searches, etc. Still,
new products surprise us every time we think we
included all the relevant products; others disap-
pear from the market as quickly. Every attempt

© Springer-Verlag London 2016 63

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_8
64 W. Abramovits

has been made not to favor or miss the products review, but they are further discussed by the
of any brand or distributor. authors that use them in their corresponding
Equipment that utilizes gasses other than LN chapters.
as refrigerants may be underrepresented in this
 In-Office Generators
9
C. Lee Asplund

Abstract
Liquid nitrogen (LN) has become a critical tool in dermatology practices –
used in a variety of procedures and tissue assessments. Sourcing of liquid
nitrogen is being evaluated more critically – due to artifacts present in the
delivered LN. The availability of in office, on-demand, generators allows
doctors to know where the LN came from, and to know they will always
have a supply on hand.

Keywords
Liquid nitrogen • LN2 • LN2 generation • Cryosurgery • Cryogen

LN is usually produced in manufacturing plants compressor/dehumidifier and a liquefier. Room

from where it is sold and transported in various
quantities to institutions and clinics. Performing
high volumes of cryosurgical procedures requires
a steady supply of LN and adequate storing at the
site; in some areas LN vendors may not supply a
dependable, uninterrupted source. For such
places, in-office generators may provide a solu-
tion. This equipment extracts nitrogen from the
surrounding air and converts it to clean LN, at the
doctor’s offices. LN generators are clean, safe,
reliable and convenient. One such unit, from
MMR Technologies™ is composed of an air
C.L. Asplund, BSc, MS
Independent Sales, Marketing, and Business
Development Consultant and former Director of Sales
and Marketing for MMR Technologies, Inc., 1004 Silver
Lake Drive, Sacramento, CA 95831, USA
e-mail: LeeAsplund@gmail.com
air is extracted through a particle filter, com-
pressed, dehumidified, and purified to nitrogen
gas; this gas is condensed to liquid and transferred
to either an internal or external storage container.
MMR Technologies™ offers two LN genera-
tors, differing only in the method of storage. The
elan2™ Office Station Liquid Nitrogen Generator
stores LN in an internal 1.0 L dewar to await dis-
pensing into external proprietary MMR dewars.
The production of LN automatically stops when
the internal dewar is full. The elan2 Autotransfer
Station Liquid Nitrogen Generator has an inter-
nal dewar that automatically transfers LN to en
external 20 L dewar when full [1] (Fig. 9.1).
It is possible to locate other manufacturers of
LN generators on the Internet but those were
mostly marketed to industrial and research facili-
ties and not specifically to dermatology offices.

© Springer-Verlag London 2016 65

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_9
66 C.L. Asplund

Fig. 9.1 The elan2 Office

Liquid Nitrogen Generator
Office Generator (right)
and the elan2 Autotransfer
Station (left)

Reference
1. elan2™ Liquid Nitrogen Generators. Retrieved from
http://www.elan2.com/product_elan2office.asp.
 Storage Units/Dewars
10
William Abramovits and Ana M. Prato-Guia

Abstract
Liquid Nitrogen (LN) is commonly stored in dewars (double lined flasks)
separated by a vacuum or other temperature insulation. Dewars come in a
variety of sizes depending on the intended use; these go from a fraction of
a liter to over 50 l. This section deals with those dewars intended for stor-
age, and some representatives are presented.

Keywords
Dewar • Storing • Dispensing

W. Abramovits, MD, FAAD

Department of Dermatology, At dermatology offices LN is commonly stored
Baylor University Medical Center, Dallas, TX, USA in dewars. Dewars are double lined containers
Department of Internal Medicine, with walls separated by an insulator and/or a
University of North Texas Health Science Center, vacuum space. They are usually constructed of
Texas College of Osteopathic Medicine, stainless steel, with or without a fiberglass neck
Fort Worth, TX, USA and may come with handles to facilitate tilting or
Department of Dermatology, displacing and a pouring spout or a lid.
University of Texas Medical Branch, At −196 °C LN boils and transforms into its
Dallas, TX, USA
gaseous phase expanding rapidly. In a closed
The University of Texas Southwestern Medical School, environment, this leads to an increase in pressure.
Dallas, TX, USA
Containers must safely accommodate this poten-
Texas Tech University, Health Sciences Center, tially expanding gas. Since LN explodes if kept
Lubbock, TX, USA
in an absolutely closed container, dewars are
Texas A&M Health Science Center College designed to allow for minimal evaporation.
of Medicine, Bryan, TX, USA
Dewars can work in two configurations: open,
Dermatology Treatment and Research Center, in contact with the atmosphere via a loose-fitting or
Dallas, TX, USA
vented lid to allow for the equilibration of pressure
A.M. Prato-Guia, MD (*) of the gaseous content with its surroundings, or
Dermatology Treatment and Research Center,
Dallas, TX, USA closed, sealed from the atmosphere and incorporat-
e-mail: anamprato@gmail.com ing a valve to vent beyond a determined pressure.

© Springer-Verlag London 2016 67

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_10
68
Fig. 10.1 Taylor Wharton
liquid nitrogen dewars
Dewars are designed to hold differing
amounts of LN and to last differing numbers of
days respectively. A 10-l capacity dewar should
be able to hold enough LN as to last around
50 days, a 30-l dewar the LN should hold enough
LN as to last over 120 days. Dewars come in
sizes from less than 1 l to 80 l and larger, each
having a manufacturer-provided specific static
evaporation rate (SER, usually expressed in
liters/day), that being the rate at which the LN
will evaporate in the container closed, with the
efficiency of the dewar being inversely propor-
tional to SER.
Spouts for withdrawal may be fitted over the
mouths of dewars, or they may be placed in
stands that tilt to facilitate pouring (see below).
Representative dewars are listed and depicted.
The Taylor Wharton dewars LD Series,
designed for storing and dispensing small
amounts of LN, include a beaker style with a
wide mouth (LD5) and pitcher-style for easy
pouring (LD4). Features (per the manufacturer)
include: High-performance, modern and rugged
construction and advanced insulation materials
assure high thermal efficiency, superior vacuum
performance provide maximum holding times.
Ribbed high strength aluminum body, mag-
niformed neck-tube design, durable paint and
conveniently located handles allow for easy oper-
ation – a snap-on cap and necktube assure tight
closure and easy access (Fig. 10.1).
W. Abramovits and A.M. Prato-Guia
Taylor Wharton Liquid Nitrogen
Dewars: The 4 l LD4 weighs empty:
6.6 lbs, full: 13.7 lbs, a height of 17 in. and
outside diameter 7.6 in. The 5 l LD5 weighs
empty: 6.9 lbs, full: 15.8 lbs, a height of
17.5 in. and outside diameter of 7.6 in. The
10 l LD10 weighs empty: 14.5 lbs, full:
32.3 lbs, a height of 23.5 in. and outside
diameter of 11.4 in. The 25 l LD25 weighs
empty: 23.2 lbs, full: 67.7 lbs, a height of
25.8 in. and outside diameter of 15.6 in.
The 35 l LD35 weighs empty: 35.1 lbs,
full: 97.4 lbs, a height of 26.3 in. and out-
side diameter of 18.8 in. The 50 l LD50
weighs empty: 38.7 lbs full: 127.7 lbs, a
height of 32.4 in. and outside diameter of
18.8 in.
The MVE Lab Series, (per the manufacturer) is
named for their acceptance in laboratories and med-
ical offices worldwide. These are most convenient
and economical. Many can be fitted with pouring
spouts, pressurized dispensing devices or dippers.
MVE10 unit has a 2.2″ throat size. MVE20, 30 and
50 have a 2″ throat size. Easy maintenance lid
design and a high strength neck tube reduces LN
loss. An Advanced Chemical Vacuum Retention
System is offered for superior vacuum performance
10 Storage Units/Dewars
Fig. 10.2 MVE® dewars
over the life of the product. Superior strength, light-
weight aluminum construction (Fig. 10.2).
MVE Lab Series Liquid Nitrogen Dewar:
4 l MVE4 has a liter static holding time of
2–3 weeks, weighs empty: 6 lbs, full: 13 lbs,
a height of 16.8 in. and outside diameter of
7.3 in. The 5 l MVE5 has a static holding
time of 4–5 weeks; it weighs empty: 8 lbs,
full: 17 lbs, has a height of 18.2 in. and an
outside diameter of 8.8 in. The 10 l MVE10
has a static holding time of 6–8 weeks;
weighs empty: 13 lbs, full: 30 lbs, has a
height of 21.5 in. and an outside diameter of
69
10.3 in. The 20—l MVE20 has a static hold-
ing time of 8–12 weeks; weighs empty:
19 lbs, full: 53 lbs, a height of 24.7 in. and an
outside diameter of 14.5 in. Storage Dewars
The 20SC Liters – Long Lasting has a static
holding time of 200 days, weighs empty:
19 lbs, full: 53 lbs, and has a height of
24.7 in. The 30 l MVE30 has a static holding
time of 14–16 weeks, weighs empty: 26 lbs,
full: 77 lbs, a height of 24.1 in. and outside
diameter of 17 in. The 50 l MVE50 has a
static holding time of 14–17 weeks, weighs
empty: 34 lbs, full: 123 lbs, a height of
30.7 in. and an outside diameter of 17 in.
 Withdrawal Devices
11
Carmen I. Hernandez Lara

Abstract
Withdrawal Equipment includes devices utilized to obtain liquid nitro-
gen (LN) from a container or dewar. There are several types of with-
drawal devices depending on the technology for LN storage and delivery.
Less sophisticated devices include dippers, which are long thin steel
rods attached to a steel cup. This device is immersed into the dewar to
obtain small quantities of liquid nitrogen. Withdrawal tubes with a filter
are also available for small quantities of LN. More sophisticated with-
drawal devices include faucets with a switch and a LN filter. Withdrawal
devices come in different sizes depending on the amount of LN that the
dewar can store.
Withdrawal equipment are complimented with many accessories
ranging from withdrawal stands in order to pour LN from larger dew-
ars, to filters attached to the withdrawal device that clean the liquid
nitrogen. Other accessories include replacement dewar caps and
cores for dewars of different sizes that range from 4 to 50 l, dewar
dippers for dispensing small quantities of LN, pouring spouts for
dewars of all sizes and dewar dippers for dispensing bigger quantities
from up to 35 l dewars. The dewar measuring rod is a helpful device
that indicates the level of LN in the dewar and is available for the
different dewar sizes.

Keywords
Withdrawal devices • Dewar • Liquid nitrogen • Dipper

Withdrawal equipment includes devices to draw

C.I.H. Lara, BS, PhD
Department of Research and Development,
Laboratorio Behrens,
Calle Principal de Chapellin Edificio Behrens,
Caracas, Miranda, Venezuela
e-mail: carmenhernandezphd@gmail.com
LN from a container or dewar. Less sophisticated
devices include dippers, long thin steel rods with
a steel cup at the bottom end to immerse into the
dewar and obtain small quantities of LN. More

© Springer-Verlag London 2016 71

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_11
72 C.I.H. Lara

sophisticated devices include faucets with a

switch and a filter. They come in sizes that depend
on the amount of LN the dewar can store.
Accessories range from withdrawal stands
that allow pouring LN from larger dewars to fil-
ters that clean the LN, replaceable caps with
cores, pouring spouts, etc. A measuring rod is a
helpful device that indicates the level of LN still
in the dewar.
Smaller dewars can be carefully tilted by hand
to allow pouring, but larger dewars require stands
that can tilt or devices with which to withdraw.
Several types of withdrawal devices are on the
market; some have stems that reach deep into the
container while the outer portion (resembling a
lid), has a spout; increased pressure within the
container due to the expansion of LN, or manu-
ally introduced via a pump, propels the LN from
the container through the spout. These devices
vary according to sophistication (i.e. incorporat-
ing a safety valve and pressure gauge on the
device itself), how they attach to the dewar, flow
rate through the spout, and necessity to warm up
in between uses. Examples of withdrawal devices
are shown below.

Fig. 11.1 Withdrawal device for dewars of 20 l and over.

(Brymill™): Conveniently fills multiple delivery units at a
time. Affixes to the top of the dewar (i.e., is not removed
after each use), has a simple on/off switch, and works like
a faucet. Includes a filter that helps clean the LN before it
is withdrawn
11 Withdrawal Devices 73

Fig. 11.3 Filters for withdrawal devices. (Brymill™)

Fig. 11.2 Withdrawal tube for dewars of 5–20 l.

(Brymill™): Simple and efficient way to extract LN from
a storage dewar. Fills one to a few delivery units at a time.
The tube is removed from the dewar after each use. Offers
quick pressurization. Includes a filter that helps clean the
LN before it is withdrawn
74 C.I.H. Lara

Fig. 11.5 Dippers rigid and swivel small for MVE®

Dewars: 5, 10, 20, 30 and 50 l

Fig. 11.4 On the left: Dipper for 10LD, LD10, or any

2 in. throat dewar (1 1/4 oz). On the right: Dipper for
25LD, LD25, 35LD, LD35, or any 2 1/2 in. throat dewar
(2 oz). Rigid dippers are also available for the MVE5,
MVE10, MVE20 and MVE50
11 Withdrawal Devices 75

Dewar Caps and Cores MVE® Replacement Caps and Cores

Fig. 11.6 Replacement cap for 4LD and LD4 T&W, 5LD
and LD5 T&W, 10LD and LD10 T&W, 25LD and LD25
T&W, 35LD, LD35, 50LD and LD50 T&W dewars

Fig. 11.7 On the left: replacement cap and core for MVE4, MVE5, MVE10, and MVE20. On the right: replacement
cap and core for the MVE30 and MVE5o
76 C.I.H. Lara

Measuring Rods Low conducting plastic mea- Pouring Spouts

suring rods clearly show LN level in a dewar (in
inches and centimeters). 42″ long.

Fig. 11.9 Pouring spout MVE5/PS for MVE5 and

MVE10, MVE20/PS for MVE20, and MVE30/PS for
MVE30 and MVE50 (MVE®)
Fig. 11.8 Measuring rod for all size dewars DO-31
 Stands/Roller Bases
12
Alba G. Quiñones

Abstract
Stands and roller bases are designed to help mobilize dewars and to pour
liquid nitrogen (LN) from the dewar to the storage tank in a safe manner.

Keywords
Stands • Roller bases • Dewars • Transportation • Storage

Besides facilitating transport of larger storage Dewar Roller Bases

dewars, stands may reduce the chance of inad-
vertently tipping a dewar over, damaging it or
spilling the LN, which could be a serious matter.
Some stands are ball-bearing swivel wheeled.
Tipping stands suspend and stabilize dewars;
this allow users to easily tilt them for controlled
pouring. They are available in sizes to accom-
modate the different storage dewars. Examples
below (Figs. 12.1, 12.2, and 12.3).

Fig. 12.1 Roller base for Taylor Wharton® 25LD, LD25,

LD35, LD50, DO-23 and DO- 24

A.G. Quiñones, MD
Dermatology Treatment and Research Center,
5310 Harvest Hill Rd., Suite 160, Dallas,
TX 75230, USA
e-mail: albagquinones@gmail.com

© Springer-Verlag London 2016 77

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_12
78 A.G. Quiñones

Fig. 12.2 5-caster roller base for MVE20, MVE20/RB,

MVE30, MVE30/RB, and MVE50. Two of the casters
have breaks (MVE®)

Dewar Tipping Stands This example is for use

with the Taylor Wharton 25 l dewar only. Easily
tips with one hand. Five wheels allow maximum
handling convenience. Tipping stand height
(without dewar) is 27″.

Fig. 12.3 Tipping stand for Taylor Wharton DO-25

 Gloves and Aprons
13
William Abramovits

Abstract
To avoid contact with liquid nitrogen (LN) personnel handling it should
wear gloves able to withstand extreme cold and be waterproof. None is
available for submersion in LN. Aprons protecting from extreme low tem-
peratures are available.

Keywords
Gloves • Aprons • Protection • Personnel

Nitrogen is liquid at atmospheric pressure at tem-

W. Abramovits, MD, FAAD
Department of Dermatology,
Baylor University Medical Center,
Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical School,
Dallas, TX, USA
Department of Internal Medicine,
Texas College of Osteopathic Medicine,
University of North Texas Health Science Center,
Fort Worth, TX, USA
Department of Dermatology,
University of Texas Medical Branch,
Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College
of Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160,
Dallas, TX 75230, USA
e-mail: DrA@dermcenter.us
peratures between 63 K and 77.2 K (−210 °C and
−195.8 °C, respectively), thus it is extremely impor-
tant that the LN and the equipment carrying it does
not come into direct contact with the handler’s skin.
One way to avoid this is by using cryogenic
gloves specially made to withstand extreme cold
temperatures, and that are either water resistant
or water proof. Offering protection from cold
temperatures down to −160 °C, waterproof
gloves help protect from splashes as well, but are
still not made to withstand submersion in LN. At
actual LN temperature there is some stiffening of
the material, but it still remains flexible enough
for use. Cryogenic gloves come in varying sizes
and lengths, from wrist-length to arm-length,
depending on the provider (Figs. 13.1 and 13.2).
Cryogenic aprons are used to further help pro-
tect the body from the extreme temperatures of
LN. These aprons offer protection up to −160 °C
and are splash resistant (Fig. 13.3).

© Springer-Verlag London 2016 79

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_13
80 W. Abramovits

Fig. 13.1 Brymill CryoGloves®

Fig. 13.3 Cryo-Apron® Tempshield Cryo-ProctectionTM

Fig. 13.2 Delasco CryoGuard® waterproof gloves

 Delivery Systems
14
William Abramovits

Abstract
Delivery systems for spray and probe use are available to dermatologists
and other practitioners. Their body is a small dewar or double lined flask,
the lid features a release valve, a trigger, and a nozzle to which tips and
probes are to adapt. One manufacturer adds a temperature monitor. In this
section we present some of the systems available for liquid nitrogen (LN)
delivery and the attachments with which they come.

Keywords
Delivery system • Dewar • Flask • Lid • Trigger • Valve • Nozzle • Tip
• Probe

LN must be delivered to lesions in a deliberate,

W. Abramovits, MD, FAAD controlled manner to ensure sufficient freezing of
Department of Dermatology, Baylor University the target area to the necessary depth while sparing
Medical Center, Dallas, TX, USA
as much surrounding healthy tissue as possible.
Department of Internal Medicine, University of North Spray-release systems are the most commonly
Texas Health Science Center, Texas College of
used in dermatology. Known for convenient, easy
Osteopathic Medicine, Fort Worth, TX, USA
to use design, these small metal vacuum flasks
Department of Dermatology, University of Texas
contain a valve delivery system sealed under
Medical Branch, Dallas, TX, USA
pressure that releases LN in an efficient and eas-
The University of Texas Southwestern Medical
ily regulated manner. Several commercial LN
School, Dallas, TX, USA
delivery units are available virtually all share a
Texas Tech University, Health Sciences Center,
few common features:
Lubbock, TX, USA
They are handheld, accommodating 300 ml,
Texas A&M Health Science Center College of
350 ml, or 500 ml of LN. Holding times, average
Medicine, Bryan, TX, USA
12 h but can be up to 24; frequent usage will obvi-
Dermatology Treatment & Research Center,
ously decrease them. The body of the unit is a small
5310 Harvest Hill Road, Suite #160, Dallas,
TX 75230, USA dewar, with a tight-fitting screw-on lid that has a
e-mail: DrA@dermcenter.us safety pressure valve to avoid excess pressure

© Springer-Verlag London 2016 81

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_14
82
buildup. A stem on the lid underside extends to the
bottom of the inside of the canister when closed. A
nozzle extends perpendicularly out of the top of the
lid, with its tip having a mechanism to allow to
interchange tips and probes. A trigger extends from
the top of the lid downwards somewhat parallel to
the canister. Evaporation of LN within the canister
increases pressure; this pressure propels a stream
of LN through the nozzle and spray tip or probe
when the trigger is squeezed. The tip unit is held
anywhere from less than one to a few centimeters
from the surface of the skin when spraying.
Units vary by the ergonomics and shape of the
canister itself and the shape and placement of the
trigger and spray nozzle. Most have a fixed noz-
zle, one branded unit has a replaceable nozzle,
which may be advantageous if the canister is
dropped or tipped over. Recently, a manufacturer
introduced an electronic attachment for certain
spray units to provide visual indication of skin
temperature and freezing levels.
Fig. 14.1 Cry-Ac® 3 and
Cry-Ac®
W. Abramovits
Cotton tipped applicators can be soaked with
LN and placed directly on lesions for freezing but
may be less efficient in delivering coolant.
Handheld delivery systems for liquid nitrous
oxide (N2O) are smaller than LN spray units,
barely larger than a fountain pen. Some N2O
units are cylindrical, accept a twist-in cartridge of
NO2 in their base, and have a button that releases
N2O when depressed. The N2O escapes the car-
tridge and travels out through an interchangeable
tip. The unit is held perpendicular to the lesion
when used, and unlike LN spray units, the tip of
the N2O unit should contact the lesion directly
during therapy because it is the liquid phase of
N2O that is the coolant. An cartridge once
inserted can hold a charge for up to 3 months
without use.
Examples of the above-described systems are
shown below:
CRY-AC® and CRY-AC® 3 Brymill™
14 Delivery Systems
Product Features and Information:
• Slender, fingertip trigger for maximum
control and ease of viewing – also
rotates easily for left-handed users.
• Streamlined relief valve maintains a
constant operating pressure to ensure
consistent and accurate freezing.
• Patented safety Autovent design maxi-
mizes safety by allowing internal pres-
sure to gradually vent, as the cap is
unscrewed.
• Durable collar and cap cover insulates
the user’s hand and reduces
condensation.
• Stainless steel and brass construction
for long life.
• Sturdy base for extra stability.
Cry-Ac®-3
Smaller size for easier handling Weight
Full: 618 g (24.0 oz.) Weight Empty:
412 g (14.5 oz.) Static Holding Time:
10–12 h Capacity: 300 ml.
Cry-Ac®
Larger size for greater capacity and longer
holding time; Weight full: 895 g
(31.6 oz.) weight empty: 540 g (19.0 oz.)
Static Holding Time: 20–24 h. Capacity
500 ml.
Both the CRY-AC and CRY-AC-3 sets come
complete with manual, 3 year uncondi-
tional warranty (both parts and labor),
four regular tips: A (1 mm), B (0.8 mm),
C (0.55 mm), and D (0.4 mm), a 20 gauge
× 3″ bent extension spray needle and a 20
gauge × 1″ straight spray needle. All
probes and sprays may be sterilized by
steam or hot bead sterilizers.
The main valve body is made of stainless
steel and a top is cover made of blue
plastic to prevent sweating. It also has a
narrow and slim design easing one-
handed operation.
83
Delasco FrigiSpray® Liquid Nitrogen Spray
Apparatus The FrigiSpray® features include an
attached, black, sturdy base for better stability, a
permanent, laser-etched label to keep contact infor-
mation and caution statements in front of the user
for the life of the unit and it comes in a custom-fitted
sturdy canvas carrying bag, ideal for storing the unit
or transporting it from one office to the next.
Other dermatologist-requested features
include: a replaceable nozzle, which screws on
and off the top of the FrigiSpray; a unique trigger
sports an insulated and formed hand grip, to help
with user control and handle temperature; a black
plastic molding covers the top one third of the
flask, protecting your hand better from the frigid
temperatures of the nitrogen; and the screw-type
connector allows any cryo-tip or probe to easily
attach. Adapters are available to use Cry-AC tips
on the FrigiSpray unit or to attach Luer-lockTM
fitted tips such as probes.
FrigiSpray unit comes with a set of standard
spray tips #1 extra small (0.4 mm), #2 small
(0.5 mm), #3 medium (0.6 mm), #4 large
(0.8 mm), bent extension spray, autoclavable tip
tray and canvas carrying bag. It is a three hundred
fifty milliliter flask with an average holding time
of 12 h. One-year warranty.
CryoPro® Liquid Nitrogen Apparatus
CryoPro Liquid Nitrogen 500 ml (MAXI)
and CryoPro Liquid Nitrogen 350 ml
(MINI) units include six tips, tip/probe
stand and unit base
Both offer cutting-edge design features creat-
ing ease of operation and reliability.
Spray tips and contact probes from other sys-
tems may be used with the CryoPro, making it a
versatile addition to current LN equipment.
Each unit includes standard spray tips: A
(1 mm), B (0.75 mm), C (0.55 mm), C (0.55 mm),
D (0.45 mm), one bent extension spray tip, black
plastic probe stand, and attached black base.
Three-year worldwide warranty.
84
a b
Fig. 14.2 (a) FrigiSpray® (b) Apparatus
Nitrospray Plus Nitrospray Plus, 16 oz and
Nitrospray Plus Lite, 10 oz come with 5 Spray
Tips (16, 17, 18, 19 and 20 gauge). Also comes
with tip protector and base holder.
A lightweight self-pressurized, and easy-to-
handle LN device simple to operate for fast and
efficient treatments. It is trigger activated to per-
mit perfect alignment of the outflow spray with
the treatment site. The grooved neck makes the
units easy to hold, and the position and shape of
the trigger allows for unobstructed view of the
area or lesion to be treated. Uses luerlock tip
attachments. Has a 3-year warranty.
W. Abramovits
Frigitronics® Cryo-Plus™ Surgical System
This system has everything needed to per-
form cryosurgery procedures, from excel-
lent thermoconductivity to temperature and
pressure gauges. By monitoring the actual
tip temperature with every freeze, you are
assured an adequate freeze with each treat-
ment. The Cryo-Plus System features inter-
changeable probes with safety pressure
seals. All probes can be autoclaved for
sterilization.
14 Delivery Systems 85

The compact, lightweight UltraFreeze is the

new, easy-to-use, portable cryosurgical system
ideal for most office skin procedures. A newly
designed ergonomic handle offers comfort and
control. Completely self-contained, the system
delivers controlled spray. UltraFreeze is supplied
with an assortment of easily attached Luer-lock
closed tip or open apertures. It features:

• Available in two sizes (0.35 and 0.5 l).

• Ergonomically designed comfort handle.
• New smooth flow spray technology.
• Enhanced performance.
• New five spray apertures offer precision accu-
racy of liquid nitrogen spray for better control.
• Uniform pattern on skin.
• Three-year warranty.
• Available stand.
• Flat closed tips of 2 mm, 3 mm, 5 mm, 6 mm.
• Accu-shields to concentrate the LN spray
within a limited area (six cones).
• 14 gage – 3 in. in length straight/ blue
• 14 gage –3 in. in length curved/blue
• 16 gage – 1 ½″ in. in length straight/green
• 16 gage – 1 ½″ in. in length curved/green

Fig. 14.3 CryoPro®: cryo/maxi and cryo/mini

Wallach. UltraFreeze Liquid Nitrogen

Cryosurgical Sprayer Combines a cost-
effective cryosurgical system with Wallach’s
proven reliability.
86 W. Abramovits

a b

Fig. 14.4 (a) Nitrospray Plus®, (16 oz capacity) and (b) Nitrospray Lite® (10 oz capacity)
14 Delivery Systems 87

Fig. 14.5 Frigitronics® Cryo-Plus™ surgical system

Fig. 14.6 UltraFreeze®

 Dispensing Units (Carbon Dioxide,
Nitrous Oxide, etc.)
15
William Abramovits

Abstract
Besides for liquid nitrogen (LN), equipment to deliver other cryogens for
dermatological purposes is available. Carbon dioxide can be shaped to
adapt to lesions or areas to be frozen for cryotherapy and ablation; Carbon
dioxide gas dispensing units are available. Nitrous oxide dispensing equip-
ment is in the market. Some units as small as pens, using cartridges of the
above gasses compressed are also available. So are units that dispense
cryogenic mixtures. A unit that externally cools tips is featured as well.

Key words
Carbon dioxide • Nitrous oxide • Cryogenic mixtures • Gas cylinders

W. Abramovits, MD, FAAD

Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical
School, Dallas, TX, USA
Department of Internal Medicine, Texas College
of Osteopathic Medicine, University of North Texas
Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College of
Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160,
Dallas, TX 75230, USA
e-mail: DrA@dermcenter.us
In addition to the LN, carbon dioxide based equip-
ment is available. Carbon dioxide snow could give
good results eliminating benign lesions and small
superficial carcinoma. Equipment intended to tar-
get internal lesions in gynecology; oral surgery and
ophthalmology using nitrous oxide is rarely used in
dermatology. The technique and use of probes for
nitrous oxide surface freezing is somewhat similar
to the LN one.
Nitrous Oxide Cryosurgical Systems
According to the manufacturer the Wallach
LL100® unit gives physicians the fastest freeze
and defrost; an exclusive two-trigger design
allows for precise control of both freeze and

© Springer-Verlag London 2016 89

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DOI 10.1007/978-1-4471-6765-5_15
90 W. Abramovits

defrost. With twice the freezing power of other

systems it performs both functions more effi-
ciently. Freeze and defrost only occur when trig-
gered. A light-weight, well-balanced,
maneuverable unit provides full view of the tar-
get tissue. A gas hose allows for unimpeded sur-
gical movement.
Nitrous oxide cylinders (20 lb.) offer approxi-
mately 80 min of freeze time. Cylinders are pro-
vided empty and may be filled locally at a medical
gas supplier. A sturdy rolling cart offers a vehicle
for transporting the cylinders.
Per its manufacturer the Wallach WA100B®
offers the ideal combination of easy-to-use con-
trols and built in safety features. It uses the pow-
erful LL100 two-trigger freezer for nitrous oxide.
Freeze and defrost only occur when triggered and
can be stopped instantly. A console-mounted
switch must be activated to permit gas to flow
into the LL100 and a color-coded gauge provides
gas pressure reading at a glance. The temperature
indicator gives cryosurgeons unparalleled control
and efficiency during procedures. Precise read-
out of tip temperature on thermocouple tips are
displayed. The depth of freeze can be read using
an independent hypodermic thermocouple.
Audible freeze timer starts when freezing tem-
perature is reached and records the total time the
tip is actually freezing.
Fig. 15.1 WA1000B Cryosurgical Console System
Large selection of reusable, sterilizable cryo-
tips with disposable plastic shields are available
for the LL100 and WA1000B Cryosurgical conductivity to temperature and pressure gauges.
Systems (Fig. 15.1), offering safety and conve- Monitoring the actual tip temperature with every
nience. Disposable plastic shields act as insulator freeze assures an adequate freeze with each treat-
to prevent the tip from adhering to tissue in ment (Fig. 15.2). The Cryo-Plus System features
unwanted areas. The shield also assures proper interchangeable probes with safety pressure
attachment of the tip by serving as a positive seals. All probes can be autoclaved.
stop, provided tabs on shield are correctly fitted
into grooves on the metal tip.
Wallach LLCO2 Cryosurgical System

Carbon Dioxide Cryosurgical
Systems
Per the manufacturer, the Frigitronics® Cryo-
Plus™ System has everything needed to perform
cryosurgery procedures, from excellent thermo-
Fast freeze and defrost. The LLCO2 is specifi-
cally designed to handle the challenges posed
by carbon dioxide, a gas, liquid and solid within
a narrow temperature range. Freeze and defrost
only occur when triggered. Light weight, well
balanced and maneuverable the unit provides
15 Dispensing Units (Carbon Dioxide, Nitrous Oxide, etc.)
Fig. 15.2 Frigitronics® Cryo-Plus™ System
full view of the target tissue. The gas hose
allows for unimpeded surgical movement.
Cryotips can be changed at any time without
venting. A large selection of highly conductive
reusable, sterilizable cryotips and disposable
plastic shields are available. The LLCO2 system
is designed differently due to the properties of
the gas.
Handheld Delivery Systems
for Liquid Nitrous Oxide
Nitrous oxide units just a bit larger than a foun-
tain pen exist. Some are cylindrical, accept a
twist-in cartridge of nitrous oxide inside, and
feature a button that when depressed releases
the gas, which then travels out through
interchangeable tips of different widths. The
described units are to be held perpendicular to
the lesion when used, and the tip should practi-
cally contact it during therapy because it is the
91
liquid phase of nitrous oxide that is the cool-
ant. Once inserted a cartridge can hold charge
for up to 3 months without use. Examples
below.
Miltex® CryoSolutions™
Miltex® CryoSolutions™ complete set includ-
ing unit with standard 1 mm wide tip, one car-
tridge (23.5 g), metal pin (which acts as a
fulcrum to insert cartridge), a user manual, and
plastic case. Replacement Cartridges (23.5 g
N2O), Pack of four or ten, and Tips including a
standard 1 mm wide glass tip and dermatology
2 mm, 3 mm, and 4 mm wide glass tips are avail-
able. Per its manufacturer, this innovative yet
simple device allows the clinician to pinpoint the
treatment site for rapid freezing (−127 °F) and
efficacious destruction of unwanted tissue.
CryoSolutions™ is a convenient, in-office treat-
ment for either or superficial malignant lesions.
It does not necessitate repeated freeze-thaw
cycles since the extreme cold of the liquefied
nitrous oxide is delivered directly onto the treat-
ment site. Difficult lesions, such as plantar warts,
may require more than a single application. An
“average” application time of 6 s for a single
lesion would provide approximately 50 treat-
ments per cartridge – an economical patient care
product (Fig. 15.3).
Fig. 15.3 Miltex® CryoSolutions™
92 W. Abramovits

The CryOmega™

This ‘Disposable Cryosurgical Device’, per its

manufacturer, provides clinically effective direct
application of liquid nitrous oxide in a conve-
nient, and economical device (Fig. 15.4).
Delivers a continuous, direct spray of nitrous
oxide (−89 °C) to treatment site. With a lower
operating temperature compared to canister-
based systems it provides clinically effective
freezing with pinpoint precision. Simple, low-
cost, hassle-free operation. Operators are
instructed to activate the internal 16 g cartridge
once and the disposable device is ready for use.
No need for additional accessories or replace-
ment cartridges. Thirty to 45 5-second sprays per
device. Difficult lesions may require longer
treatment.

CryoProbe™

Per it’s manufacturer, this is an innovative, effi-

cient and portable cryosurgical device, which
treats benign skin lesions with pinpoint accuracy
using disposable nitrous oxide cartridges. The
gas is applied to the tissue by the spray from the
applicator tips, varying in the range of 1–15 mm.
As it easily adapts to every lesion regardless
shape or size, only abnormal tissue will be
treated avoiding collateral damage to adjacent
tissue. The CryoProbe™ is FDA cleared as a
Class ll device and can only be sold to physi-
cians (Fig. 15.5).
Fig. 15.4 CryOmega

CryoPen™
The CryoPen Surgical System® features “pen-
point” precision, consistent effective freeze
temperature ensured by using the temperature
indicator, and simple non-technique dependent
procedure. Per the manufacturer, CryoPen uses
a state-of-the-art, linear compression cooling
technology that does not require handling of
dangerous cryogenic gases and liquids. In
addition, the CryoPen reduces the risks of
serious burns. It also makes cryosurgery safer
and easier for office staff. Plus, the treatment
has a minimal scarring and no need for anes-
thetic (Fig. 15.6).
15 Dispensing Units (Carbon Dioxide, Nitrous Oxide, etc.) 93

Fig. 15.5 The CryoProbe™. Blue applicator for 1–3 mm applications, white applicator for 2–5 mm applications, green
applicator for 4–8 mm applications, yellow applicator: 7–15 mm applications

Fig. 15.6 The CryoPen

Surgical System®
94 W. Abramovits

Dermapen CryoTM

Per its manufacturer, this device uses a very pre-

cise jet of highly compressed liquefied nitrous
oxide to destroy benign lesions, and penetrate up
to 1 mm per 5 s of application, making it an
extremely versatile machine, treating anything
from extremely superficial sunspots to lesions up
to 5 mm in depth. The applicator tips facilitate to
target the treatment on the lesion and protect the
surrounding healthy skin (Fig. 15.7).

Fig. 15.7 Dermapen Cryo™

 Thermos/Vacuum-Insulated
Bottles/Flasks
16
William Abramovits

Abstract
These are double lined flasks separated by a vacuum or other form of ther-
mal insulation. Usually these units are small and intended to carry aliquots
of liquid nitrogen (LN) adequate enough for a bud applicator to be dipped
and transferred onto small or benign lesions. Examples are shown.

Keywords
Flasks • Vacuum • Insulated • Holding time • Cross-contamination

These comprise flasks designed as LN carrying

W. Abramovits, MD, FAAD
systems for the cotton-wool bud applicator tech-
Department of Dermatology, Baylor University nique. They are usually small metal or plastic
Medical Center, Dallas, TX, USA cannisters to be used individualized in ways to
Departments of Family Practice and Dermatology, reduce the risk of cross-contamination with
The University of Texas Southwestern Medical viruses (human papilloma, herpes, hepatitis, etc.)
School, Dallas, TX, USA from the LN supply. Cryosurgery thermos-like
Department of Internal Medicine, units are available in different designs and sizes,
Texas College of Osteopathic Medicine, depending in the provider.
University of North Texas Health Science
Center, Fort Worth, TX, USA
Department of Dermatology, University
of Texas Medical Branch, Dallas, TX, USA
Delasco Cryo-Tainer®
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
A properly labeled glass thermos container that
may be used to transfer LN to cups; it reduces
Texas A and M Health Science Center College
of Medicine, Dallas, TX, USA
liability over generic unlabeled LN point-of-use
containers. Provided with a non-spout cap triple
Dermatology Treatment and Research Center,
5310 Harvest Hill Road, Suite #160,
perforated for proper venting. A relatively inex-
Dallas, TX 75230, USA pensive product for cryosurgery, it holds 12 oz of
e-mail: DrA@dermcenter.us LN (Fig. 16.1).

© Springer-Verlag London 2016 95

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_16
96 W. Abramovits

Warning: This unit uses a glass liner that is

extremely fragile. Any hairline cracks in the liner
(caused by accidentally dropping, unit tipping
over, etc.) can cause the container explode. Use
this container with extreme caution at all times.

Delasco Stainless Steel Cryo-Tainer®

For those concerned about using glass lined vac-

uum containers, Delasco offers safety labeled
stainless steel vacuum containers that do not
carry the risk of cracking if accidentally fall over.

CTS-4

A 16 oz (0.47 l) unit. Approximate nominal hold-

ing time is 24 h. (Actual holding time with usage
is about 8–12 h) (Fig. 16.2).

CTS-5

A 33.8 oz (1 l) unit. Approximate nominal hold-

ing time is 36 h. (Actual holding time with usage
is about 12–18 h).

Fig. 16.1 Delasco stainless steel Cryo-Tainer® CTS-4

16 Thermos/Vacuum-Insulated Bottles/Flasks 97

Fig. 16.2 Delasco Cryo-Tainer®

 Cups
17
William Abramovits

Abstract
Cups are vessels that can briefly hold nitrogen in liquid phase just long
enough for applicators to be dipped in them and then be transferred onto
lesions to treat. They can be of stainless steel, which requires placing them
on an insulated base. Molded plastic like styrofoam or other cups may be
used, if they provide enough insulation to protect personnel and patients.

Keywords
Cup • Stainless steel • Applicators • Base • Organizer

Cups are used as part of the Asepticator® for the

W. Abramovits, MD, FAAD
Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical School,
Dallas, TX, USA
Department of Internal Medicine, Texas College of
Osteopathic Medicine, University of North Texas
Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College of
Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160, Dallas,
TX 75230, USA
e-mail: DrA@dermcenter.us
dipstick (cotton-wool bud) technique. LN is
poured into small stainless steel cups (see picture
below) that are suitable for holding small amounts
of LN for manual application of skin lesions
using cotton- or rayon-tipped applicators. Once
done the surplus of LN is allowed to evaporate, or
is disposed, and a new cup is placed in the proper
well of the Asepticator. This system protects the
LN supply from cross-contamination with viruses
(See Fig. 17.1).
Cross-contamination has been demonstrated
to occur through LN therapy; the modality is sub-
ject to the general rules of isolation and steriliza-
tion that govern the rest of surgical practices.
The Asepticator is a handy organizer which
has an insulated well to accept a stainless steel
vessel, which can be removed and sterilized
between patients, thus interrupting any possible
chain of cross-contamination.

© Springer-Verlag London 2016 99

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_17
100 W. Abramovits

Fig. 17.1 Asepticator system:

insulated holder by Frigiderm
and four stainless steel
vessels – distributed by
Delasco

The stainless steel vessels are of 2 oz. capa- most patients, dissipating in about 20 s. The full
city, which when filled hold enough LN for long LN supply is workable for about 20 min, but it
enough to treat multiple non-cancerous lesions in may take 45 min to completely evaporate.
 Tips
18
William Abramovits

Abstract
Cryosurgery tips adapt to the end of the units to deliver cryogens. They
can be open or closed. Open tips have apertures of different diameters that
permit the outwards flow of liquid nitrogen (LN). Spray needles are a type
of open tip. Closed tips are at the end of internally circulating probes that
vent backwards. Cryochambers work as a sort of closed system when
pressed over an area or lesion to treat.

Keywords
Tips • Open • Closed • Probes • Cones • Chambers

Cryosurgery tips are metal accessories that

W. Abramovits, MD, FAAD
Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical School,
Dallas, TX, USA
Department of Internal Medicine, Texas College of
Osteopathic Medicine, University of North Texas
Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College of
Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160, Dallas,
TX 75230, USA
e-mail: DrA@dermcenter.us
screw-in and attach to delivery systems. They are
available in diverse size apertures and lengths –
to be selected depending on their intended use.
Several companies offer a wide range of tips
in two basic categories: open and closed. Open
tips have an aperture through which LN escapes
towards the skin. These spray tips are available
in apertures that dictate the flow of LN exiting
the nozzle. Some spray tips are constructed with
a vent, a small tube that allows some LN to exit
backwards; in this manner they release a more
uniform stream with less intermittence and clog-
ging. Slit-shaped or micro-perforated tips deliver
diffuse, highly vaporized LN suitable for acne
and peels, and to cover broad areas. Spray nee-
dles are thin, elongated extensions that allow for
more precise delivery to the target. Due to their
length, they may require insulation. Some may

© Springer-Verlag London 2016 101

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_18
102 W. Abramovits

be bent to facilitate freezing lesions at difficult to
reach areas such as the oral cavity. Luer-lock™
adaptors make it possible to attach disposable
needles or other compatible devices to the noz-
zle. Straight, right angle, and malleable exten-
sions are available that connect to the nozzle at
one end and accommodate a spray tip or adapter
at closed.
Closed tips, known as probes, circulate LN
within them, resulting in a frozen probe at the
end. Instead of by spraying LN on the lesion
cooling is achieved via direct contact with the
frozen tip. Closed probes are available in shapes
and sizes to suit many different situations; for
instance, hemi ball-shaped probes may be more
useful to treat ulcerated or concave-shaped
tumors, while concave probes can be used in
raised lesion.
Cryochambers are similar to open cones but
comprise a partly closed system. They attach to
the unit tip at one end while the opposite open-
end has a chamber to be pressed against the skin
surrounding a lesion. The spray is thus confined
to the chamber and causes the LN to pool on the
lesion.
Representative examples of open tips follow:
Spray tips with varying sized apertures
(0.04–0.016 in.) a 1″ × 20 g Straight Spray and a
20 gauge bent spray. These CryoPro® spray tips
are included with CRY-AC® and CRY-AC®-3
(Brymill) units (Fig. 18.1a). Tip trays are offered
(Fig. 18.1b–d).

a b

Fig. 18.1 (a) 6 spray tips included with CRY-AC® and CRY-AC®-3 units. (b) Bent Extension Spray Tip. (c) Soft
Spray Acne Tip. (d) Standard Spray Tips: “A” (1 mm), “B” (0.75 mm), “C” (0.55 mm), and “D” (0.45 mm)

FrigiSpray® Spray Tip #1 Extra Small

(0.4 mm), #2 Small (0.5 mm), #3 Medium
(0.6 mm), and #4 Large (0.8 mm)
(Fig. 18.2). FrigiSpray® also offers bent
extentions and a Tip Tray.
18 Tips 103

Fig. 18.2 FrigiSpray® spray tip

 Cotton/Rayon Tipped Applicators
19
William Abramovits

Abstract
Applicators conformed of a cotton-wool or rayon tip on a thin wooden
stick are used for dipstick technique cryosurgery. The tip is submerged in
LN contained in a cup or flask and transferred to a lesion. Significant loss
of cooling is lost in the process, making it less efficient than spray. Sticks,
cotton-wool and rayon can be bought separately to improvise large tip
applicators.

Keywords
Applicator • Cotton-wool • Rayon • Stick • Swab

W. Abramovits, MD, FAAD

Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical School,
Dallas, TX, USA
Department of Internal Medicine, Texas College of
Osteopathic Medicine, University of North Texas
Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College of
Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160, Dallas,
TX 75230, USA
e-mail: DrA@dermcenter.us
Cotton/rayon tipped applicators are used in the
simple dipstick technique. Applicators are con-
formed of a cotton-wool tip bound to a wooden
stick. Customized applicators can be made
attaching a wad of cotton-wool to an orange
stick. The cotton tip of the applicator is dipped
into a cup or partly filled Thermos™ and then
transferred repeatedly as needed onto the lesion
to be treated.
Rayon Applicators 8″ solid paper sticks are
sold by Delasco™. Tips are rayon, and free of
sizing to allow modeling of the tip to the precise
shape needed. For versatility they are pointed on
one end and blunt on the other. Slightly ridged for
good cotton adhesion. Stems can be 6–10″ long
and 2.3 mm diameter (Figs. 19.1a–c).
Rayon/Cotton Balls Package of 300. Rayon
balls of 1 1/8″ diameter combine the best qualities

© Springer-Verlag London 2016 105

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DOI 10.1007/978-1-4471-6765-5_19
106 W. Abramovits

of cotton and rayon (Fig. 19.2). 6″ pointed sticks unwind without falling apart, and large or small
they are ideal for making custom tipped applica- tips can be quickly fashioned to meet the needs of
tors. As opposed to cotton balls, rayon balls the specific lesion(s) (Fig. 19.3).

a c

Fig. 19.1 (a) Rayon applicator swabs, 8″ long, pack of 100. (b) Pointed applicator sticks, 6″ and 10″ long, pack of 100.
(c) Cotton tipped wood applicators, 6″ long, box of 100

Fig. 19.2 Rayon/cotton balls package of 300

Fig. 19.3 Rayon balls, medium size, bag of 200

 Sprayers
20
William Abramovits

Abstract
Sprayers are open tips that deliver LN in a fan-like pattern onto the skin.
This can be used to induce a superficial peel.

Keywords
Spray • Sprayer • Peel • Cryopeel

Sprayers are described as a type of cryosurgery

tip that delivers the LN in a fan-like pattern over
the skin. Sprayers are available with different
W. Abramovits, MD, FAAD sized apertures depending on the region to receive
Department of Dermatology, Baylor University the treatment. They may be indicated to induce a
Medical Center, Dallas, TX, USA peel over a large area, for example a hand dorsum
Departments of Family Practice and Dermatology, with many actinic keratosis, or to treat rhytides
The University of Texas Southwestern Medical and lentigos on the forehead (See Fig. 20.1).
School, Dallas, TX, USA
Department of Internal Medicine, Texas College
of Osteopathic Medicine, University of North Texas
Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College of
Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160,
Dallas, TX 75230, USA
e-mail: DrA@dermcenter.us

© Springer-Verlag London 2016 107

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DOI 10.1007/978-1-4471-6765-5_20
108 W. Abramovits

Fig. 20.1 Advance Acne Aperture®. The Advanced

Acne Aperture is great for acne and cryopeel. Gives a soft,
vaporized spray for superficial desquamation of cheeks,
forehead, and back
 Open Cones
21
Carmen I. Hernandez Lara

Abstract
Open Cones are conical instruments helpful in dermatologic cryosurgery
by accumulateing liquid nitrogen (LN) in the designated area for the treat-
ment of a skin lesion. Open cones are made of different materials such as
transparent plastic or synthetic rubber, such as neoprene. Open cones are
available in many different types of conical opening, meaning variations in
diameter of the conical opening, to fit the size of the lesion to be treated.
The diameter of the conical opening range from as small as 3 mm to as big
as 38 mm. Open Cones are especially helpful for the treatment of lesions
that require a rapid rate of temperature decrease for greater localization of
the freezing area, making these instruments very efficient and destructive.
Open cones are utilized to treat lesions in sensitive or hard to reach areas,
or of irregular shaped and profile. Open cone sets consist of a number of
open cones of different opening diameter and a LN spray container ready
to use. Open cone sets are also known as cryoplates, or cryocones, depend-
ing on the brand.

Keywords
Open cones • Diameter • Conical opening • Neoprene

Large warts and deep tumors may require signifi-

C.I.H. Lara, BS, PhD
Department of Research and Development,
Laboratorio Behrens,
Calle Principal de Chapellin, Edificio Behrens, Calle
Kemal Ataturk, 0TA Merecure Valle Arriba, Caracas,
Miranda, Venezuela
e-mail: carmenhernandezphd@gmail.com
cantly more freezing than superficial ones. Open
cones are especially helpful for lesions that
require rapid rate of temperature decrease and
greater localization of the freezing. They are con-
ical devices open at the base and apex. The apical
opening is placed directly over the lesion, and LN
is sprayed into the cone to accumulate over the
lesion. One version is the cryoplate/cryodisk, a
circular, clear, Lexan™ disc with four conical

© Springer-Verlag London 2016 109

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_21
110
openings of different diameter. The apex of a
selected opening is placed directly on the lesion
to surround it, while holding on to the rest of the
disk; this allows the user to spray into the cone
over the lesion, concentrating the freezing effects
of the coolant on it while sparing surrounding tis-
sue. Other open cones are made of rubber, such
as Neoprene™. They too are available in a variety
of diameters at the apical opening, as to fit the
Fig. 21.1 Four transparent cryoplates with conical open-
ings of 3, 5, 8 and 10 mm
Fig. 21.3 Example of the application of the transparent Lexan™ plate in a skin lesion near the eyes (Courtesy of Gloria
Graham MD)
C.I.H. Lara
size of the lesion to be treated. Because of their
malleability Neoprene™ cones can be com-
pressed to fit irregularly shaped lesions. It is pos-
sible to estimate the extent of freeze by watching
the ice ball extend beyond the outer margin of the
cone pressed against the peri-lesional skin.
Moistening the apical opening, Neoprene™
cones makes them quickly attach to the skin by
the lesion (Figs. 21.1, 21.2, and 21.3).
Fig. 21.2 Example of the use of conical cryoplates in a
skin lesion (Courtesy of Gloria Graham MD)
21 Open Cones
Transparent Lexan™ plate with four conical
openings of various diameters (3, 5, 8 and
10 mm). This Cryoplate® (Brymill™) provides
localization of freezing and protection of sensi-
tive areas such as the eyes (Figs. 21.4 and 21.5).
Fig. 21.4 Neoprene™ cones of various diameters
(Courtesy of Gloria Graham MD)
111
Neoprene™ cones. Set of six (inside narrow
diameter): 5 mm, 11 mm, 16 mm, 22 mm, 31 mm
and 38 mm Set of five: 11 mm, 16 mm, 22 mm,
31 mm and 38 mm. Set of four: 16 mm, 22 mm,
31 mm and 38 mm.
Fig. 21.5 Example of the application of the Neoprene™
cone in a skin lesion
 Closed Probes
22
William Abramovits

Abstract
In this probes, the cryogens, usually liquid nitrogen (LN), circulate within
and then escape through a back vent. Their tips are placed in contact with the
condition to be treated; such tips come in a vast array of shapes to be matched
to the type and profile of lesions to be pressed upon or just contacted.

Keywords
Closed • Probe • Tip • Contact

This type of probe is closed, the LN circulates

W. Abramovits, MD, FAAD
Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical School,
Dallas, TX, USA
Department of Internal Medicine, Texas College
of Osteopathic Medicine, University of North Texas
Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College
of Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160,
Dallas, TX 75230, USA
e-mail: DrA@dermcenter.us
within, and treats by being pressed against a
lesion. Depending on shape, they can be adapted
to treat a variety of lesions from hemorrhoids to
large ulcerated epithelial carcinomas, as well as
recurrent or metastatic lesions. They are also use-
ful to treat eyelid lesions or wherever LN splat-
ters would be problematic. All closed probes may
be sterilized by autoclave or cold sterilization.
Examples follow (Figs. 22.1 and 22.2a, b):
Ball probes can be used for ulcerated tumors,
large tumors, concave lesions, underlying bony
structures, or for a dome-like symmetrical freeze
of soft tissue (Fig. 22.2c).
The concave probe can be used to treat large,
raised vascular lesions (Fig. 22.2d, e).
Conical probes may be inserted into large or
ulcerated lesions, markedly increasing the sur-
face area of the freeze (Fig. 22.2f, g).
Cryogun Conical Probes, Set of 7 2085/S
(Fig. 22.3).

© Springer-Verlag London 2016 113

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DOI 10.1007/978-1-4471-6765-5_22
114 W. Abramovits

a b

Fig. 22.1 CryoPro® contact probes, (a) Sharp-pointed conical bolt probe, (b) 1 mm contact CryoPro probe, (c) Gold
plated contact probe: 1, 2, 3, 4, 5, 6, 8, 10, 15, 20, and 30 mm

Mini probes range in size from a sharp point to
a 6 mm diameter. They give very precise control
of marginal spread whilst also giving a fast, deep
freeze. Mini probes are practical to treat eyelid
margins, sebaceous hyperplasia, angiomas, len-
tigines, small flat warts, trichiasis and lesions
near the eyes or in the ear canal. All come fitted a
silicone exhaust tube to ensure the vented LN is
directed away from the user and patient
(Fig. 22.4).
By applying pressure onto a lesion with a con-
tact probe one can reduce its vascular flow,
creating a quicker deeper freeze thus reducing the
freeze time. In this manner closed probes can
treat larger lesions sometimes faster than open
spray can (Fig. 22.5).
22 Closed Probes 115

a b c d

e f

Fig. 22.2 CRY-AC® probes. (a) Flat round probe: 1, 2, probe, 1 cm. (e) Round probes: 1, 2, 3, 4, 5, and 6 mm. (f)
and 3 cm. (b) Gentle probe with rounded edges, 8 mm. (c) Conical probes: 1, 2, 3, 4, 5, and 6 mm. (g) Sharp-pointed
Ball round probe: 6 and 8 mm, 1 and 2 cm. (d) Elliptical probe
116 W. Abramovits

Fig. 22.2 (continued)

Fig. 22.3 Nitrospray Plus™ contact probes

Fig. 22.4 Mini contact probe: 1, 2, 3, 4, 5, and 6 mm

22 Closed Probes 117

a b

c d

Fig. 22.5 (a) Basal cell carcinoma. (b) Closed probe technique applying pressure curettage. (c) Lesion after cryosur-
gery. (d) Post-op at 1 month
 Cryochambers
23
William Abramovits

Abstract
Cryochambers allow liquid nitrogen (LN) to pool over the area within
their rim, for deep ablation of thick lesions.

Keywords
Chambers • Cryochambers • Deep

These types of open probes are used for the treat-

W. Abramovits, MD, FAAD
Department of Dermatology, Baylor University ment of large skin lesions such as some thick
Medical Center, Dallas, TX, USA plantar warts and epithelial carcinomas. They
Departments of Family Practice and Dermatology, screw-in and attach to the LN source for deep
The University of Texas Southwestern Medical School, cryosurgery in the specific area under the cham-
Dallas, TX, USA ber. Cryochambers permit profound and precise
Department of Internal Medicine, Texas College destruction of tissue by allowing a confined spray
of Osteopathic Medicine, University of North of LN to pool continuously over deep lesions
Texas Health Science Center, Fort Worth, TX, USA (Fig. 23.1).
Department of Dermatology, University
of Texas Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College
of Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160,
Dallas, TX 75230, USA
e-mail: DrA@dermcenter.us

© Springer-Verlag London 2016 119

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_23
120 W. Abramovits

Fig. 23.1 Cryochambers are

available in the following
sizes: 6 mm, 10 mm, 15 mm,
18 mm, 31 mm
 Cryoneedles (for Extra and Intra-
lesional Use)
24
William Abramovits

Abstract
Needles come as open, closed, where the liquid nitrogen (LN) circulates
through, and may be blunt or beveled sharp like a hypodermic needle, straight
or bent. The open ones are ideal for spraying into body cavities that are other-
wise hard to reach; the sharp ones can be passed through the bulk of a tumor
or a keloid to ablate it from within. Bent needles can spray over lesions at
awkward locations behind structures not reachable with straight ones.

Keywords
Needles • Straight • Bent • Open • Closed • Blunt • Sharp • Intralesional

W. Abramovits, MD, FAAD
Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical School,
Dallas, TX, USA
Department of Internal Medicine, Texas College
of Osteopathic Medicine, University of North Texas
Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College
of Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160,
Dallas, TX 75230, USA
e-mail: DrA@dermcenter.us
Blunt needles are used to extend the conventional
spray tips. Intralesional needles are used for
cryosurgical treatment of a variety of skin disease
including hypertrophic scars and keloids, as well
as hard to reach skin and mucosal lesions such as
those found in the oral, perianal, rectal or vaginal
areas. For intralesional indications the needle is
inserted through the lesion and LN circulates
down the length of the needle exiting to the open
air at its distal end; some are designed so that the
LN will circulate internally and go back to the
base, where it exits through a small vent. The cir-
culating LN freezes the needle and thus the
lesion. This method requires more freezing time
(5–20 min, depending on size) than superficial
lesions. The chapters on keloid cryosurgery also
illustrate their use. Lumbar puncture needles
have been used under the same concept.

© Springer-Verlag London 2016 121

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_24
122 W. Abramovits

Cryosurgery needles are available in different Brymill

lengths and configurations to be efficient at
reaching the internal skin lesions.

a b a

Fig. 24.2 Original bent spray extension. (a) Bent sprays

can be rotated 360° for greater precision when treating
hard-to-reach lesions. (b) 3 in. × 20 g bent spray. (c)
1.5 in. × 20 g bent spray

Fig. 24.3 Histology package: the Brymill histology

package consists of a 10 in. malleable spray extension and
a wide spray aperture. Used in Mohs Labs

Fig. 24.1 (a) Original straight spray extension. (b) 3 in.

straight spray needle, available in 16, 18, and 20 g. Used
to reach condylomata in the perianal, rectal or vaginal
areas. 1 in. straight spray needle available in 16, 18 and
20 g
 Miscellaneous (Adaptors,
Extensions, Protectors,
25
Tubing, etc.)

William Abramovits

Abstract
To assist in the delivery of liquid nitrogen (LN) on-to lesions that may be hard
to reach by conventional probes and tips; an array of extensions exists that may
be adapted to the original equipment that comes with delivery units. Adaptors
with or without exhaust, extensions, tubing and protectors are marketed. Some
adaptors allow for attachments of a particular brand to be used with another.

Keywords
Adaptors • Extensions • Protectors • Tubing

Some adaptors (or adapters) are used to increase

W. Abramovits, MD, FAAD
Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical
School, Dallas, TX, USA
Department of Internal Medicine, Texas College
of Osteopathic Medicine, University of North Texas
Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College
of Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160,
Dallas, TX 75230, USA
e-mail: DrA@dermcenter.us
the flow of LN particularly when contact probes
or tips of smaller apertures are attached to the
spray gun. This is usually accomplished by
means that vent the flow outwards. Silastic® tub-
ing may be attached to a vent pipe to direct the
exhaust of LN away from patient and operator.
Other adapters are intended to allow the use of
one brand of attachments to other brand of units.
Extensions are used to distance the canisters
from the target lesions. Bent or bendable exten-
sions can be bent to adjust the angle of spray in
consideration to where the skin lesion is located.
They are particularly useful to reach lesions
inside the mouth or the female genitalia.
Examples of these parts follow:
CRY-AC® Back-Vented Adapter Eliminates
intermittent spray and increases LN flow when
used with contact probes and smaller aperture

© Springer-Verlag London 2016 123

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_25
124 W. Abramovits

Fig. 25.1 Back vented adapter for cryogun

probes. This adapter is CE marked and fits both the

CRY-AC and the CRY-AC 3. May be sterilized by
autoclave or cold sterilization.
Fig. 25.2 CRY-AC malleable extension

CRY-AC® Malleable Extension This probe can

be used with any spray tip or contact probe to
change angle of spray while keeping unit upright.
It is CE marked and fits both the CRY-AC and the
Mini CRY-AC 3. They may be sterilized by auto-
clave or cold sterilization.
CRY-AC® Right Angle Adapter Primarily used
with cryo-chambers to keep the chamber vertical by
holding the unit upright. The adapter is CE marked
and fits both the CRY-AC and the CRY-AC 3.
Can be used with any spray tip, cryochamber,
or contact probe to change the angle of spray
while keeping the CRY-AC® unit upright.
CRY-AC® Foam Protector Replacement blue
foam protector piece for the previous model
CRY-AC unit.
Silastic® tubing for accessories. Available in
small, medium, or large sizes.
CRY-AC® Luer-Lock® Adapter Fits dispos-
able needles or other tips to screw-on units.
CryoPro® Luer Lock Adapter
Nitrospray™ Plus Accessories
25 Miscellaneous (Adaptors, Extensions, Protectors, Tubing, etc.) 125

Fig. 25.5 Small Silastic® tubing for cryogun accessories

Fig. 25.3 90° extension/adapter

Fig. 25.6 Medium Silastic® tubing for cryogun

accessories

Fig. 25.7 Large Silastic® tubing for cryogun accessories

Fig. 25.4 45° extension/adapter
126 W. Abramovits

Fig. 25.8 Luer lock adaptor for CRY-AC

25 Miscellaneous (Adaptors, Extensions, Protectors, Tubing, etc.) 127

Fig. 25.9 CryoPro®

Luer-lock adapter. Fits Luer
lock type needles or probes to
the CryoPro LN unit

a b c

Fig. 25.10 (a–c) Luerlok adapter for use of probes on FrigiSpray

a b c

Fig. 25.11 (a–c) Adapter for Frigispray to accept Brymill tips

128 W. Abramovits

a b c

Fig. 25.12 (a–c) Adapter for Brymill to accept FrigiSpray tips

Fig. 25.15 Rigid needle extender for nitrospray

Fig. 25.13 Screw-on accessory adapter for nitrospray

Fig. 25.14 (a–d) bent spray extension tip for nitrospray Fig. 25.16 Spray tip protector for nitrospray
 Cryotweezers
William Abramovits
Tweezers and forceps have been designed for
cryosurgery to obtain more control in the treat-
ment of protruding skin lesions such as skin tags.
The idea is to control the freeze by grabbing only
the protruding fleshy region of the lesion with the
forceps or tweezer, for a more precise cryosur-
gery while avoiding damage to healthy skin sur-
rounding the lesion.
Cryosurgery tweezers have added mass to
Teflon-coated tips, and a narrow neck, both to
conserve the low temperature achieved when the
tweezers are submerged in LN for 15–30 s. The
extra bulk engineered at the tip allows for longer
freeze duration compared with standard tweezers
or forceps. The narrow neck prevents the cold
W. Abramovits, MD, FAAD
Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical School,
Dallas, TX, USA
Department of Internal Medicine,
Texas College of Osteopathic Medicine,
University of North Texas Health Science Center,
Fort Worth, TX, USA
© Springer-Verlag London 2016
W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_26
26
from the tweezer heads to transfer along the main
body of the instrument. The Cryo-Tweezers are 5″
long from end to end. The handle is made of stain-
less steel, the tips of brass; the entire tweezer is
Teflon-coated (Figs. 26.1 and 26.2).
The correct technique for ablating skin tags is
to freeze only the fleshy part protruding from the
surface of the skin while taking care not to extend
the ice formation to surrounding base tissue,
which could result in pigmentation change. This
may occur if trying to freeze a skin tag using
open spray techniques.
To clean the tweezer before sterilization, use
rubbing alcohol; other types of cleaning solution
may remove the Teflon coating.
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College
of Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160,
Dallas, TX 75230, USA
e-mail: DrA@dermcenter.us
129
130 W. Abramovits

Fig. 26.1 Brymill Cryo Tweezers™: designed for local-

ized treatment of skin tags supplied with a Delrin™ cup Fig. 26.2 Cryo tweezer
holder and ten foam cups
 Other Delivery Systems
27
William Abramovits

Abstract
Several canisters that dispense refrigerants other than liquid nitrogen
(LN), carbon dioxide and nitrous oxide are sold at pharmacies and
distributors of medical supplies. Their efficacy is limited.

Keywords
Cryogen • Refrigerant • Canister

Histofreezer®

A patented cryogenic liquid mixture of com-

pressed gas comprised of dimethyl ether and pro-
W. Abramovits, MD, FAAD pane. This gas mixture does not harm the ozone
Department of Dermatology, Baylor layer. The cryogen is released into a foam applica-
University Medical Center, Dallas, TX, USA tor cooling it to an effective freezing temperature
Departments of Family Practice and Dermatology, of −57 °C/−70.6 °F. May be left in travel bag for
The University of Texas Southwestern Medical School, nursing home or other situations in which it is not
Dallas, TX, USA
convenient to take LN. It is distributed by Delasco
Department of Internal Medicine, Texas College and has a shelf life of 2 years (Fig. 27.1a, b).
of Osteopathic Medicine, University of North
Texas Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University
of Texas Medical Branch, Dallas, TX, USA
Verruca Freeze ®
Texas Tech University, Health Sciences Center,
Hand held aerosol canisters containing a proprie-
Lubbock, TX, USA
tary, highly optimized formulation of refrigerants
Texas A&M Health Science Center College
that medical professionals can use for cryotherapy
of Medicine, Dallas, TX, USA
in an outpatient setting to freeze a lesion down to
Dermatology Treatment & Research Center,
−70 °C (−94 °F) at the surface. The packaging for
5310 Harvest Hill Road, Suite #160,
Dallas, TX 75230, USA Verruca Freeze® is designed for hand held use,
e-mail: DrA@dermcenter.us and is completely portable. Shelf life is of at least

© Springer-Verlag London 2016 131

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_27
132 W. Abramovits

a b

Fig. 27.1 (a) Histofreezer®, (b) 36 and 60 mixed application kits, (one 80 ml can with twelve 2 mm and twenty-four
5 mm applicators or two 80 ml cans with twenty-four 2 mm and thirty-six 5 5 mm applicators)

6 years. It is non-flammable, non toxic, and envi-
ronmentally friendly. Cleared to treat 21 common
benign skin lesions including common warts,
plantar warts, sunspots, and age spots. Starter kits,
as well as refill canisters at small, medium, and
large sizes include a complete set of re-usable
cryoCones®, a pack of CryoBuds®, practice pad,
an insulator for the canister, and useful resources
including how to materials. CryoCones® can be
placed over the lesion to create a seal so that only
the lesion is sprayed. CryoBuds® can be used like
a swap to apply the cryogen (Figs. 27.2 and 27.3).
27 Other Delivery Systems 133

Fig. 27.2 Cryosurgery VFC65 65 freeze canister 162 ml

134 W. Abramovits

a b

Fig. 27.3 Other products for self therapy of warts, including plantar warts, such as Compound W Freeze Off TM and
Dr. Scholl’s Freeze AwayTM may be available at pharmacies
 Tissue Temperature Monitors
28
William Abramovits

Abstract
Tissue temperature monitors with thermocouple needles detect the tem-
perature within lesions being frozen in real time. Units using infrared
lasers detect surface temperatures during the cryoablative process.
Monitors allow for accurate delivery of lower temperatures.

Keywords
Monitor • Thermocouple • Sensor • Ultrasound

Tissue temperature monitors allow direct obser-

W. Abramovits, MD, FAAD
Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical School,
Dallas, TX, USA
Department of Internal Medicine, Texas College
of Osteopathic Medicine, University of North Texas
Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College
of Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160,
Dallas, TX 75230, USA
e-mail: DrA@dermcenter.us
vation of the temperature to which a lesion is
being frozen. Some use thermocouples (i.e.
temperature-sensing) needles. The thermocouple
needle is inserted into the lesion to provide real-
time measurements of its temperature. This helps
the cryosurgeon achieve the desired temperature
during freezing.
Thermocouples are perhaps the most com-
monly used instruments for temperature
measurement during cryosurgery. They are inex-
pensive, small, simple to use, and remarkably
accurate when used understanding their pecu-
liarities [1].
Thermocouple wires can be inserted into a
standard syringe needle, or similar metallic tub-
ing, and the thermocouple junction located adja-
cent to the needle’s tip, forming a “temperature
sensing needle” also known as “thermocouple
needle”. Such needles provide a simple and con-
venient means of temperature sensor localization;

© Springer-Verlag London 2016 135

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_28
136 W. Abramovits

to evaluate the freezing front propagation and

correlate the thermal history with the resulting
cryoinjury, seeking to define the “lethal tempera-
ture”. For dermatological purposes placement of
thermocouple needles may be best done for accu-
racy under ultrasound control [5].
Another type of tissue temperature monitor, is
the Tracker Cam® (Brymill™), which uses infra-
red sensors connected to a camera to detect the
temperature of the lesion at the surface. It uses
infrared sensors and a built-in camera to get a
clear, precise view of the lesional area. Operators
can record video and audio treatment data for the
patient’s electronic medical record files, as well
as create program applications by skin tempera-
ture and freeze time for better control. The infra-
red light sensor continuously and safely monitors
skin temperature while color-coded lights shine
on the lesion to indicate how fast skin tempera-
ture is decreasing and when the desired skin tem-
perature is reached. Benefits include: consistent
achievement of desired skin temperatures, ability
to record video and audio of treatments, more
accurately perform cryosurgery knowing how
long to spray and when to stop. It can be used to
train others to reliably do cryosurgery (Fig. 28.1).

References
Fig. 28.1 Brymill CRY-AC Tracker Cam®
they can be placed straightforwardly or guided
by an imaging technique such as ultrasound.
Thermocouple needles used singly or as one of an
array, are routinely applied in cryosurgery for the
purpose of recording the thermal history [2–4].
Temperature data from the procedure is compiled
1. Benedict RP, editor. Fundamentals of temperature,
pressure, and flow measurements. New York: Wiley-
Interscience; 1984.
2. Baust J, et al. Minimally invasive cryosurgery –
technological advances. Cryobiology. 1997;34:
373–84.
3. Dilley AV, et al. Laboratory and animal model evalua-
tion of the Cryotech LCS 2000 in hepatic cryotherapy.
Cryobiology. 1993;30(1):74–85.
4. Hewitt PM, et al. A comparative laboratory study of
liquid nitrogen and argon gas cryosurgery systems.
Cryobiology. 1997;35:303–8.
5. Abramovits W, Pruiksma R, Bose S. Ultrasound-
guided thermocouple placement for cryosurgery.
Dermatol Surg. 1996;22(9):771–3.
 Monitorization Instrumentation
with Ultrasound
29
William Abramovits

Abstract
Ultrasound (US) can be used intraoperatively to detect freeze fronts during
cryosurgery; also for diagnosis and for thermocouple placing.

Keywords
Ultrasound • Isotherms • Thermocouples • Freeze front • Diagnosis
• Monitorization

Intraoperative ultrasound has been used as a

W. Abramovits, MD, FAAD
Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical
School, Dallas, TX, USA
Department of Internal Medicine, Texas College
of Osteopathic Medicine, University of North Texas
Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College
of Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160,
Dallas, TX 75230, USA
e-mail: DrA@dermcenter.us
monitoring technique. However, ultrasound
imaging does not accurately provide information
on the temperature isotherms in the frozen area.
Therefore, when ultrasound is used to monitor
cryotherapy, the tissue destroying isotherms may
not correspond to the ultrasound image but be
4–10 mm away from the edge of the hypoechoic
image [1].
Ultrasound scanning has become a diagnostic
resource in dermatology. Advantages displayed
by ultrasound scanning include being easy and
safe to use, as well as, it provides important diag-
nostic information. 20-MHz scanning can be
used to measure tumor thickness and/or skin
thickness when treating inflammatory diseases
such as scleroderma or psoriasis. Real-time
sonography with 7.5- to 10-MHz probes has
assumed an increasingly important role, since it
is used to search for and image lymph nodes and
subcutaneous tumors in a variety of clinical

© Springer-Verlag London 2016 137

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_29
138
a b
Fig. 29.1 (a) Dermascan C USB complete 2D system with cradle and probeholder. (b) Sonographic image highlight-
ing a dermal nevus
settings, including preoperative staging and fol-
low-up of melanoma [2] (Fig. 29.1a, b).
Recently available high-frequency digital
20-MHz B-scan ultrasound equipment enables
precise definition of tumor depth and extent of the
cryonecrosis. The healing processes after cryosur-
gery can also be visualized. It is thus a suitable
tool for the in vivo measurement of wound heal-
ing [3]. Freeze fronts have been detected with the
Dermascan C ver.3 traveling through exenterated
skin and needles as thin as 30 gauge can be pre-
cisely located with this equipment making it suit-
able for thermocouple placement [4, 5].
A new and practical multipurpose instrument
that includes ultrasound is the Dermalab® Combo.
It offers a 20 MHz, high frequency, focused ultra-
sound able to penetrate 3.4 mm. Images are dis-
playable on computer tablets or laptop. Data may
be exported to spreadsheets. It generates read-out
of intensity scores and skin thickness among other
features; it is offered by Cortex Technology of
Denmark.
W. Abramovits
Another unit for this purpose is available from
Taberna Pro Medicum.
The cost of US equipment varies from $10.000
to 20.000.
References
1. Theodorescu D. Cancer cryotherapy: evolution and
biology. Rev Urol. 2004;6 Suppl 4:S9–19.
2. Schmid-Wendtner M-H, Burgdorf W. Ultrasound
scanning in dermatology. Arch Dermatol.
2005;141(2):217–24.
3. Winkler K, Hoffman K, el-Gammal S, Karmann B,
Almetyer P. The influence of hyaluronic acid on
wound healing controlled by a standardized model for
humans. In: Marks R, Plewing G, editors. The envi-
ronmental threat to the skin. London: Martin Dunitz;
1992. p. 319.
4. Abramovits W, Pruiksma R, Bose S. Ultrasound-
guided thermocouple placement for cryosurgery.
Dermatol Surg. 1996;22(9):771–3.
5. Abramovits W, Goldstein AM, Gonzalez S. Confocal
microscopy oriented cryosurgery. Int J Dermatol.
2002;41(5):284–5.
 MRI/CAT Scanners
30
William Abramovits

Abstract
Magnetic resonance imaging (MRI) detects ice ball expansion during
freezing and can be used to monitor cryosurgery. It can also be used to
stage the depth of vascular lesions. Percutaneous cryoablation of osteomas
in children under computerized tomography has been reported as success-
ful and safe.

Keywords
Magnetic resonance • Tomography • Ultrasound • Vascular lesion
• Osteoma

In experimental studies magnetic resonance imag-

W. Abramovits, MD, FAAD
Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical
School, Dallas, TX, USA
Department of Internal Medicine, Texas College
of Osteopathic Medicine, University of North Texas
Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College
of Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160,
Dallas, TX 75230, USA
e-mail: DrA@dermcenter.us
ing (MRI) proved to be an excellent tool for the
imaging of ice ball extension during freezing
[1–3]. MRI monitorization of cryosurgery has
some important advantages over ultrasound (US)
and computerized tomography (CT); it has
multiplanar imaging capabilities – allowing the
operator to choose an anatomically optimal field of
view of the treated area; it is less operator depen-
dent than US and has superior soft tissue contrast,
which provides better characterization of the target
lesion during treatment and follow-up. In particu-
lar, MRI can accurately differentiate frozen from
nonfrozen tissue. Due to an extremely short T2
relaxation time, frozen tissues exhibit a signal void
on MR images, whereas the adjacent tissue remains
visible [2, 4]. MRI has been used to stage the depth
of vascular lesions in situations like where orbital
involvement was suspected as well as to guide the

© Springer-Verlag London 2016 139

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_30
140
insertion of cryosurgery needles and monitor the
freeze [5, 6]. An integrated probe for MRI to moni-
tor skin cryosurgery has been developed [7].
Cryoablation with CT guidance has been tech-
nically and clinically successful in the treatment of
osteomas in children. In a study, six children with
osteoid osteoma were treated with CT-guided per-
cutaneous cryoablation. CT guidance was used for
procedural planning, instrument guidance, and
monitoring. An argon-based cryoablation system
was used. Each cryoablation included two freeze-
thaw cycles. Follow-up assessed technical and
clinical outcome for a minimum of 12 months.
The study concluded that percutaneous cryoabla-
tion with CT guidance was safe and effective for
the treatment of osteoid osteoma in children [8].
References
1. Gilbert J, Rubinsky B, Roos MS, Wong ST, Brennan
KM. MRI-monitored cryosurgery in the rabbit brain.
Magn Reson Imaging. 1993;11(8):1155–64.
W. Abramovits
2. Matsumoto R, Oshio K, Jolesz FA. Monitoring of
laser and freezing-induced ablation in the liver with
T1-weighted MR imaging. J Magn Reson Imaging.
1992;2(5):556–62.
3. Rubinsky B, Gilbert JC, Onik GM, Roos MS, Wong
ST, Brennan KM. Monitoring cryosurgery in the brain
and in the prostate with proton NMR. Cryobiology.
1993;30(2):191–9.
4. Tacke J. MRI-guided cryotherapy. Interv Magn Reson
Imaging Med Radiol. 1998;195–201.
5. Tronina SA, Bobrova NF, Khrinenko VP. Combined
surgical method of orbital and periorbital
hemangioma treatment in infants. Orbit. 2008;27(4):
249–57.
6. Littrup PJ, Jallad B, ChandiwallMody P, D’ Agostini
M, Adam BA, Bouwman D. Cryotherapy for breast
cancer: a feasibility study without excision. J Vasc
Interv Radiol. 2009;20(10):1329–41.
7. Pease GR, Rubinsky B, Wong ST, Roos MS, Gilbert
JC, Arav A. An integrated probe for magnetic reso-
nance imaging monitored skin cryosurgery. J Biomech
Eng. 1995;117(1):59–63.
8. Wu B, Xiao YY, Zhang X, Zhao L, Carrino
JA. CT-guided percutaneous cryoablation of osteoid
osteoma in children: an initial study. Skelet Radiol.
2011;40(10):1303–10.
 Confocal Microscopes
31
William Abramovits

Abstract
Confocal Microscopes generate histologic images in vivo down to a few
millimeters that rival ex vivo sections to a significant extent, but mostly in
shades of gray. For the purpose of cryosurgery they intervene in the pro-
cesses of diagnosing lesions and following their post-op looking for
incomplete ablation or recurrence.

Keywords
Confocal • Laser • Microscopy • In vivo • Histology

Confocal microscopes offer a cellular level view

W. Abramovits, MD, FAAD
Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical
School, Dallas, TX, USA
Department of Internal Medicine, Texas College
of Osteopathic Medicine, University of North Texas
Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College
of Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160,
Dallas, TX 75230, USA
e-mail: DrA@dermcenter.us
of the patient’s skin at the bedside, allowing for
immediate tissue characterization and treatment.
Confocal microscopes consist of a laser light
source that penetrates the skin and is reflected by
cellular structures thus detecting what is happen-
ing deeper in the skin, not just the surface. A
series of images are displayed on a computer
screen. By manipulating the laser, the physician
can zoom in and capture still or moving images of
certain areas and depths. A site can be monitored
over time since the confocal microscope is able to
get a cellular level view of the skin without
destroying the tissue, allowing to compare images
of the same area before and after treatment to
determine the effect treatment have had. An
in vivo examination with the confocal microscope
is a painless procedure that takes a few minutes to
complete. To generate an image on a monitor
there is no need for special tissue preparation.

© Springer-Verlag London 2016 141

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_31
142
Representative products are described below:
VivaScope® 1500
The VivaScope® System is intended to acquire,
store, retrieve, display and transfer in vivo
images of tissue, including blood, collagen
and pigment, in exposed unstained epithelium
and the supporting stroma with cellular reso-
lution for review by physicians to assist in
forming a clinical judgment (Fig. 31.1).
Combining reflectance and fluorescence imag-
ing, the VivaScope 1500 Multilaser includes
wavelengths of 785 nm (near infrared),
658 nm (red) and 488 nm (blue), integrated
into a single device; this creates unparalleled
imaging potentials. The laser wavelengths are
applied to the skin one at a time, eliminating
the possibility of bleed-through from other
fluorophores. An organism-compatible dye
can be applied to the tissue of interest prior to
Fig. 31.1 VivaScope® 1500
W. Abramovits
its use. The respective laser light excites a
fluorophore, and the emitted fluorescence pro-
duces a contrast during the imaging process
that can help identify dynamic reactions that
are not visible during reflectance imaging.
The VivaScope 2500 system is intended to
acquire, store, retrieve, display, and transfer
electro-optically enlarged reflectance and flu-
orescence images of unsectioned excised sur-
gical tissue for medical purposes (Fig. 31.2).
The VivaScope 3000, because its lightweight and
single handed operation is ideally suited for
rapid examination of multiple areas of interest
in the same subject, even in areas anatomically
difficult to access, like around the eyes, nose
and ears. A small diameter probe tip enables
the VivaScope 3000 to reach sites that are
impossible to reach with other non-invasive
imaging modalities, including dermoscopy [1]
(Fig. 31.3).
31 Confocal Microscopes 143

Fig. 31.2 VivaScope 2500

Fig. 31.3 VivaScope 3000

144 W. Abramovits

Reference
1. Abramovits W, Goldstein AM, Gonzalez S. Confocal
microscopy oriented cryosurgery. Int J Dermatol.
2002;41(5):284–5.
 Part V
Therapeutic Principles and Techniques
 Therapeutic Principles
and Techniques
32
Gloria F. Graham and Sara Moradi Tuchayi

Abstract
Cryosurgery is based on removing heat from a tissue by applying cold
and this is accomplished by using a cryogen with a probe, spray or cot-
ton swab. The selection depends on the depth of freeze needed to accom-
plish removing a lesion and a cotton swab may be used for a wart but is
inadequate for a skin cancer. The size of the target is also important as
lesions over 2 cm may be treated in stages or referred for excision or
MOHS surgery.
Alterations following freezing are dependent on (1) temperature fall (2)
the rate of re-warming (3) solute concentration (4) length of time cells are
exposed to below freezing temperatures (0 to −50 °C) and (5) coldest tem-
perature reached in the target tissue (generally minus 50 °C).
While benign lesions require brief freezing of 5–10 s, malignant
lesions generally require 1 min of freezing and the use of a double freeze
thaw cycle.

Keywords
Cryosurgery • MOHS surgery • Probe • Spray • Cotton swab • Apoptosis •
Microemboli

Introduction

Cryosurgery is based on removing heat from a

G.F. Graham, MD (*) • S.M. Tuchayi, MD, MPH
Department of Dermatology, Wake Forest University
School of Medicine, Winston Salem, NC, USA
e-mail: ggfgraham@aol.com
particular tissue by applying cold. This may be
accomplished by means of a cryogen delivered
with a probe, spray, or cotton swab. Introductory
chapters in this textbook discuss the fundamen-
tals in cryoequipment.

© Springer-Verlag London 2016 147

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_32
148 G.F. Graham and S.M. Tuchayi

Techniques

How this is best done depends on the size of the

target, the composition of the target, and the tem-
perature differential. Cryosurgery results in
injury to the cells and in vascular stasis after
thawing; and it is postulated that an immune
response may develop. There is ample proof of
this in the literature [1].
Partial anesthesia results from freezing, so
numerous lesions can be treated at a single office
visit, making cryosurgery a most cost effective
and efficient procedure and, from an insurance
point of view, a very economical one.
Fig. 32.1 A thermocouple needle is inserted to measure
Tissue alterations following freezing are depth of cold below the lesion. Freeze time is around
dependent on several factors, including: 1 min to −50° C. Note the levels of cold as shown by the
isotherms (Reprinted from Graham and Barham [8]. With
permission from Elsevier)
1. Speed of temperature fall.
2. Rate of rewarming.
3. Solute concentration.
4. Length of time during which cells are exposed
to below freezing temperatures (0 to −50 °C
or 32 to −58 °F range).
5. Coldest temperature reached at the target tis-
sue [2, 3].

The treatment of benign and superficial pre-

cancerous lesions often requires a brief freeze of
5–10 s; that leads to separation the epidermis
from the dermis above the basement membrane.
This allows for removal of many benign such
lesions, including actinic keratoses. There is
rapid re-epithelialization at the site with epithe-
lial cells lining the epidermal appendages and the
surrounding epidermis.
When treating deeper tumors and malignan-
cies, the better results that can be obtained from
freezing over heat come from the fact that the cel-
lular components of the tumor are more suscepti-
ble to the freezing than are the stromal components.
Tissue is to be frozen rapidly for skin malignan-
cies, generating the lowest needed temperature
within 1 min or less, rather than a slower freeze
that would take 2–3 min. Slow cooling produces
extracellular ice formation whereas rapid cooling
produces intracellular ice formation and thus
more cell damage due to rupture of the cells dur-
ing thawing [4]. For malignant lesions, a fast
Fig. 32.2 After biopsy of BCC, cryosite following freez-
ing of BCC with halo of 5 mm; halo thaw time 1 min and
clinical thaw time 4 min. A repeat freeze-thaw cycle was
used
freeze to lethal temperatures of −50 °C followed
by a slow but complete thaw and, after a short
interval, a repeat freeze-thaw cycle brings about
the greatest destruction (Fig. 32.1).
A halo of 0.5 cm is needed beyond the tumor
margin. The ice ball should include a −50 °C iso-
therm. If a thermocouple is used it should register
at −50 °C. The freeze time is generally around
1 min and the thaw to the halo time 1–1 min 30 s.
The complete thaw time of the tumor may be
from 3 to 5 min (Fig. 32.2).
32 Therapeutic Principles and Techniques 149

Pigment cells are particularly sensitive to

destruction at −4 to −7 °C [4]. Keratinocytes are
more resistant to cell death at −20 to −30 °C. The
most resistant cells to freezing are fibroblasts,
which undergo cell death at −30 to −35 °C [4].
Longer freeze duration may increase the cell
death rate. Apoptosis is induced by cryosurgery
[5, 6]. Cell death may be enhanced by modulat-
ing this response.
Freezing leads to ischemic necrosis from
vascular stasis and deprivation of oxygen.
After two hours microemboli form inside cap-
illaries and arterioles, and in 5–8 h focal necro-
sis of blood vessels develop. These irreversible
changes help destroy the tumor. Since large
vessels remain patent there is rapid neovascu-
larization leading to healing. Local inflamma-
tory response aids in final cellular destruction.
Immunity may be stimulated by local and sys-
temic immune response [1], discussed in a
separate chapter. Cryosurgery destroys malig-
nant cells while preserving normal tissue.
Fig. 32.3 Eschar, 3 weeks following freezing of BCC on
Long-term memory cells may develop and pro-
lower leg
tect from further disease. The immune effect is
of a systemic nature, it may aid in destroying
tumor cells beyond the freezing site and thus
have potential therapeutic value beyond that of
other treatment modalities [1].
Clinical effects of cryosurgery should be
explained to the patients so that they know what
to expect. First, there is erythema, and then a
wheal may develop due to histamine release a
few minutes after starting the procedure. With
the blood vessel damage some edema will
develop, which peaks at about 12–36 h post
cryosurgery. A vesicle develops after the wheal,
which can be serous or hemorrhagic. Exudate
and some sloughing of tissue may be noted fol- Fig. 32.4 Hypopigmention following freezing of multi-
lowed by eschar in a few days (Fig. 32.3). The ple BCCs on the chest. Note: hypertrophic scar from elec-
trodessication and curettage
depth of freeze determines how long the crust-
ing may last, this can be from 1 to 4 weeks or at
times, especially on the back and lower leg, up Summary
to 2 months. Melanocytes are most susceptible
to freezing, which can lead at times to hypo- or Freezing effects tumor destruction by inducing:
depigmentation [7] (Fig. 32.4). Repigmentation direct cell damage, ischemic necrosis, and apopto-
occurs from the melanocytes that may migrate sis with the help of local inflammatory responses
from the epidermal margin or from the hair [1, 5, 6]. A fast freeze to lethal temperatures of
follicles. −50 °C, a slow complete thaw, an interval between
150
cycles, and a repeat freeze-thaw cycle is needed
for maximum destruction. Cryosurgery produces a
selective destruction of tissue. Epithelial cells are
more susceptible to freezing than the stroma they
are within; this allows for destruction of tumors
overlying bone and cartilage. Large blood vessels
may freeze without rupturing, and regeneration
occurs after freezing. On rare occasions superficial
nerve damage may develop.
References
1. Johnson JP. Immunologic aspects of cryosurgery:
potential modulation of immune recognition and effec-
tor cell maturation. Clin Dermatol. 1990;8(1):39–47.
G.F. Graham and S.M. Tuchayi
2. Zacarian SA. Cryosurgery for skin cancer and cryo-
genic techniques in dermatology. Springfield: CC
Thomas; 1969. p. 11–21.
3. Shephard J, Dawber RP. The historical and scientific
basis of cryosurgery. Clin Exp Dermatol. 1982;
7(3):321.
4. Gage AA. Experimental cryogenic injury of the pal-
ate: observations pertinent to cryosurgical destruction
of tumors. Cryobiology. 1978;15(4):415–25.
5. Baust JG, Gage AA. The molecular basis of cryosur-
gery. BJU Int. 2005;95(9):1187–91.
6. Baust JG, Gage AA, Robilotto A, Baust JM. The
pathophysiology of thermoablation: optimizing cryo-
ablation. Curr Opin Urol. 2009;19(2):127–32.
7. Gage AA, Meenaghan MA, Natiella JR, Greene Jr
GW. Sensitivity of pigmented mucosa and skin to
freezing injury. Cryobiology. 1979;16(4):348–61.
8. Graham GF, Barham KL. Cryosurgery. Curr Probl
Dermatol. 2003;15(6):229–50.
 Patient Selection and Related
Contraindications
33
Gloria F. Graham and Sara Moradi Tuchayi

Abstract
Selecting the proper patients for cryosurgery is as important as a proper
technique. Cold has the ability to reduce pigment and redness of rosacea
or other vascular changes these must be given prime consideration.
Consider the Fitzpatrick skin type, general health, anticoagulant medica-
tion, presence of flushing from rosacea, marked lentiginous skin and
severe dispigmentation from photo damage or melasma. Problems associ-
ated with cryofibrogenemia, cryoglobulinemia and cryourticaria are
important conditions to ask about in the history. While pacemakers were a
reason in the past for selecting freezing, many today are solid state and are
no longer prone to be altered by the electrocautery or electrolysis.

Keywords
Cryosurgery • Excision • Electrodessication • Laser • Imiquimod
• Fitzpatrick skin types I–VI

Introduction mod and ingenol are all successful in treating

Most dermatologists are well trained in the use of
cryosurgery, electrodessication and curettage,
excision, laser and more are becoming skilled in
Mohs surgery. Topical agents such as
5-fluorouracil, glycolic acid, retinoids, imiqui-
actinic keratosis [1]. Photodynamic therapy is
being used more widely [2]. Decision for select-
ing one technique or one medication may depend
on the physician and his expertise with an indi-
vidual technique, with the individual patient and
his personal experiences with the various treat-
ments, his skin type and general health.

Patient Selection
G.F. Graham, MD (*) • S.M. Tuchayi, MD, MPH Patients with multiple skin cancers, actinic kera-
Department of Dermatology, Wake Forest University
School of Medicine, Winston Salem, NC, USA toses or seborrheic keratoses are often the best
e-mail: ggfgraham@aol.com candidates for cryosurgery (Figs. 33.1a–c).
© Springer-Verlag London 2016 151
W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_33
152
a b
Fig. 33.1 (a) Middle age white female, addicted to sun
exposure and tanning beds, has had many squamous cell
carcinomas on her legs arising from actinic keratoses over
Excellent candidates for cryosurgery include cer-
tain patients on an anticoagulants, those with
older pacemakers, and those with skin that has
been damaged by ultraviolet light where poor
wound healing may be predictable [5]. Diabetics
with small vessel disease and arteriosclerosis
may show slow healing, particularly on the lower
leg thus they should be treated with care by all
methods. Venous disease with tendency to ulcer-
ation and stasis dermatitis may cause the skin to
take 2 months to heal [3, 4] (Fig. 33.2a, b). Skin
that has been X-irradiated can be treated effec-
tively with cryosurgery.
Infected sites can be managed by freezing.
Tumors not deeper than 4–5 mm can fairly accu-
rately be treated using thermocouple or electric
impedance monitoring. Tumors with well-defined
margins, select tumors on the tip of the nose,
around the eyes or ear are also amenable to cryo-
G.F. Graham and S.M. Tuchayi
25 years. (b) Secondary pyoderma following cryosurgery
of multiple actinic keratosis. (c) Post cryosurgery for mul-
tiple actinic keratoses on the ankle
surgical treatment (Fig. 33.3a, b). Cartilage is tol-
erant of cold and then cryosurgery may be
preferable to excision, unless the tumor margins
are indefinite; in that case Mohs technique may
be treatment of choice. There is preservation of
the lacrimal duct even with freezing to – 70 °C,
which justifies cryosurgery for some eyelid
lesions [5, 6] (Fig. 33.4a, b).
Patients with allergies to local anesthetics may
tolerate freezing well. In the US South, where I
practice in a coastal fishing area, many patients
present with multiple squamous cell carcinomas
on the lower leg, from years of sun exposure on
the beach and boating.
One such patient with rheumatoid arthritis
addicted to tanning beds and immunosuppressed
from being on several biologic medications for
years has had many squamous cell carcinomas on
her lower legs (Fig. 33.5). She responded nicely
33 Patient Selection and Related Contraindications 153

a b

Fig. 33.2 (a) Patient with venous disease and multiple squamous cell carcinomas chose cryosurgery over excision. (b)
During cryosurgery, 1 min freeze time, 1 min halo thaw time. Lesion healed as expected

a b

Fig. 33.3 (a) Post biopsy squamous cell carcinoma in the hairline treated by cryosurgery. (b) Double freeze thaw cycle.
Halo thaw time over 1 min, each cycle

to cryosurgery and the use of imiquimod for
actinic keratosis. She is seen monthly and lesions
treated when early. Deeper lesions are excised.
Patients on anticoagulants have been treated
effectively with freezing. With the increasing per-
centage of elderly patients there is a rising preva-
lence of premalignant and malignant skin lesions.
Use of sunscreens in this population has helped to
stem the tide of the increasing number of skin
cancers. Many of our patients who are in their
70–90s are high-risk surgical candidates and
poorly suited for more invasive treatments. The
effectiveness of freezing has proven itself; a num-
ber of practices in our area use cryosurgery for the
treatment of malignances, actinic keratoses and
lentigines. Patients who are followed regularly
have tumors diagnosed and treated when they are
3–5 mm; the many large tumors that were seen in
the past are less frequent nowadays. There are
many more tumors nowadays that are small
enough to be managed by cryosurgery [7].
Smaller, more superficial tumors also respond
to shave excision, curettage and electrodessica-
tion, as well as to excision. Even many large
tumors, which are superficial, such as Bowen’s
disease and superficial basal cell carcinoma are
competently managed by cryosurgery if they are
not over 2.0 cm; treating larger lesions in stages,
over several weeks is an effective way to resolve
them without significant morbidity. Patients in
nursing homes can be well cared for by physi-
cians who do cryosurgery beyond their offices;
154
Fig. 33.4 (a) Squamous cell carcinoma extending into
the eyebrow. Patient chose cryosurgery over MOHs sur-
gery because of the multiple number of tumors he has had
treated by cryosurgery. (b) Follow up, 1 year later. Good
cosmetic result
the portability of modern cryosurgery equipment
becomes an important benefit to that group of
patients [8].
Advantages and Disadvantages
Patients with certain underlying medical conditions
may represent both advantages and disadvantages
for cryosurgery. While the post-radiation patient
may respond well, and so may the patient with
human immunodeficiency virus; the advantage of
cryosurgery is that it can be a bloodless procedure,
especially in the treatment of warts, molluscum
contagiosum, and Kaposi’s sarcoma [8, 9].
In contrast, freezing should be avoided in
some patients with severe arteriosclerosis of the
lower extremities and in diabetics with known
circulatory problems. Patients with cryofibrino-
genemia and cold urticaria should be treated with
caution due to edema or necrosis and poor heal-
ing. Edema is not generally a problem treating
small lesions, but treating a large lesion around
the neck could lead to airway obstruction.
G.F. Graham and S.M. Tuchayi
Fig. 33.5 Immune suppressed patient now has only a few
small squamous cell carcinomas remaining on the right
leg. Most cleared by cryosurgery and actinic keratoses
with imiquimod
Cryosurgery is useful in treating tumors over car-
tilage such as the pinna of the ear and the postau-
ricular sulcus. Notching of the ear can occur
when treating the helix of the ear so patients
should be cautioned about this.
Today, propranolol or rapamycin and then
laser are usually preferred over freezing for port-
wine stains and other vascular lesions, but
patients with multiple lentigines may respond to
freezing as well as to laser, and the former is
more cost effective.
Indications for cryosurgery are extensive and
a list is included in this text. The choice of this
over another method may depend on numerous
factors. Cost/effectiveness of freezing is a signifi-
cant benefit; the fact that the treatment of many
lesions may be done on the day the patient is seen
and reschedule is not necessary, is in itself a great
cost saving measure.
Contraindications
A relative contraindication is marked facial red-
ness such as that seen in patients with rosacea as
removing a cancer or even a seborrheic keratosis
in very erythematous telangiectatic skin may
cause a lighter skin area. I tell patients that if I
have to freeze more than 10–15 s that hypopig-
mentation may result and longer freezes may
leave a spot as white as their abdominal skin,
33 Patient Selection and Related Contraindications
since the darker color of their tanned skin will not
return after freezing. Patients whose skin is a
Fitzpatrick Type I or II are not often concerned
about the pigment loss, but with Type III to VI
any pigment loss will be more apparent and
depending on the location and the type skin, and
although it may be temporary this may end up
being more unsightly than an excisional scar.
Similarly, patients with multiple lentigines on
the skin may have an unsightly spot from the
removal of a seborrheic keratosis or a skin can-
cer. Excision, laser or even electrodessication and
curettage may provide a better cosmetic result. It
may be worth a trial of liquid nitrogen (NL) in an
inconspicuous location before using it on a larger
area since it may be more obvious. Patients that
have had freezing done are quite familiar with
how it affects their skin; nevertheless treating a
different location may result in a less than satis-
factory cosmetic outcome although the cure may
be satisfactory. Always consider the final cos-
metic result as well as the cure rate when select-
ing the best therapy in any given patient.
Summary
Consider carefully the skin type including color,
quality and vascularity when in selecting patients
for cryosurgery. Caution patients if you believe
155
there may be significant pigment or vascular risk
from the freezing. In the past patients would be
content with some pigment change but today,
more choices for treatment have raised the bar for
cosmetic results.
References
1. Sarnoff D. Therapeutic update on actinic keratosis.
J Drugs Dermatol. 2014;13(7):785.
2. Ericson MB, Wennberg AM, Larko O. Review of pho-
todynamic therapy in actinic keratosis and basal cell
carcinoma. Ther Clin Risk Manag. 2008;4(1):1–9.
3. Graham, G. Cryosurgery. Textbook of dermatologic
surgery. 1st ed. Philadelphia: Lippincott-Raven; 1998.
p. 440.
4. Graham G. Cryosurgery. Techniques in dermatologic
surgery. London: Mosby; 2003. p. 185.
5. Kuflik E, Gage A. Cryosurgical treatment for skin
cancer. 1st ed. New York: Igaku-Shoin; 1990.
p. 44–6.
6. Liu D, Natiella J, Schaefer A, et al. Cryosurgical treat-
ment of the eyelids and lacrimal drainage ducts of the
rhesus monkey. Course of injury and repair. Arch
Opthamol. 1984;102:934–9.
7. Rigel DS, Friedman RJ, Dzubow LM, Reintgen DS,
Bystryn J, Marks R. Cancer of the skin. 1st ed.
Philadelphia: Elsevier Saunders; 2005. p. 493.
8. Jackson A, Colver G, Dawber R. Cutaneous cryosur-
gery. 3rd ed. New York: Taylor & Francis; 2006.
p. 113.
9. Graham GF. Cryosurgery. Clin Plast Surg. 1993;
20(1):133.
 Lesion Selection and Related
Contraindications
34
Manisha J. Patel, Alice He, and Gloria F. Graham

Abstract
Cryosurgery is used commonly to treat both benign and malignant skin
lesions: the medical professional treating the condition must select the
best method from among the many available today. This chapter deals
with selection of lesions that are best suited for cryosurgery. Though there
are hardly strict confines to what can or cannot be treated this chapter will
discuss lesions commonly treated by cryosurgery and general contraindi-
cations as well as some lesions where cryosurgery is not the best
recommendation.
General factors when considering cryosurgery as treatment for a lesion
are site, cosmetic impact of treatment, and skin type. Those with more
melanocytes are at higher risk of hypopigmentation following cryosurgi-
cal treatment as the freezing will damage pigment production often times,
permanently. For skin cancers in particular one must consider size, depth,
delineation, tumor type, and age and health of patient.
The senior author has been using freezing in various ways since her
residency days in 1961. Other contributing authors to this book are at
Johns Hopkins and offer varied and current viewpoints.
In this chapter we consider where cryosurgery is optimized, as in the
treatment of actinic keratoses, and where it is relatively contraindicated,
although may be used, with care, in small lesions such as patients with
cryosurgery in cryourticaria. Confining what can and cannot be treated is

M.J. Patel, MD • A. He, BS, BA

Department of Dermatology, Johns Hopkins
School of Medicine, Baltimore, MD, USA
G.F. Graham, MD (*)
Department of Dermatology, Wake Forest University
School of Medicine, Winston Salem, NC, USA
e-mail: ggfgraham@aol.com

© Springer-Verlag London 2016 157

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_34
158 M.J. Patel et al.

relative to the medical professional’s experience, knowledge, and comfort

level in utilizing cryosurgery. What I may consider treatable, another may
not. In this chapter I hope to generally clarify common encounters in the
office that would be considered for treatment.

Keywords
Hypopigmentation • Cryosurgery • Monotherapy • Arteriosclerosis •
Bloodless technique • Electrodessication • Curettage • Raynaud’s disease

Introduction effective in treating lesions overlying cartilage as

cartilage necrosis is uncommon with the freeze
Cryosurgery is a common method to treat both times used in clinical practice [4, 5]. For example,
benign and malignant skin lesions. Because there lesions on the pinna of the ear and the postauricu-
are several treatment modalities in practice today, lar sulcus have been shown to have successful
it is important to carefully consider many factors treatment results [4, 5] (Fig. 34.2).
when deciding on one, as each has specific risks
and benefits in addition to varying efficacy rates.
This makes skin lesion selection an important
skill to have in clinic.
Most skin lesions can be treated with any one
of several treatment options (cryosurgery, exci-
sion, electrodessication curettage), each with
advantages and disadvantages [1]. Cosmesis, cost,
and patient convenience should be factored in
when deciding on a treatment modality [1]. The
patient should be informed about all options so
they can choose from the reasonable alternatives
[1]. Because cryosurgery is often times more cost-
effective and can produce a cosmetically pleasing
result it is commonly used in practice to success- Fig. 34.1 Very elongated seborrheic keratoses in a diffi-
cult location for excision
fully treat a wide range of skin lesions [2].
The following considerations are intended to
highlight scenarios in which cryosurgery can be
optimized and those scenarios in which it is rela-
tively contraindicated.

Factors Involved in Lesion Selection

First, cryosurgery can be utilized for lesions on all

body sites; however, certain locations are more
suitable to improved outcomes. Flat surfaces allow
for a more even freeze cycle (Fig. 34.1). Lesions
crossing beyond one cosmetic unit, such as the
nasolabial fold, can make freeze cycles difficult Fig. 34.2 Typical actinic keratoses on the helix of the ear
given the uneven contours [3]. Cryosurgery is is frequently treated with cryosurgery
34 Lesion Selection and Related Contraindications
Second, consider the skin type underlying the
lesion. As melanocytes are more sensitive to
freezing than keratinocytes, hypopigmentation is
a known possible side effect [2]. Cryosurgery
may not be a suitable option for well-tanned or
darker skinned individuals if they are unwilling
to accept the potential cosmetic effects of treat-
ment [6]. For the same reason, cryosurgery is
well suited on Fitzpatrick skin types I–III [7].
Cryosurgery is a suitable option for sun-damaged
skin, especially in the instance of actinic kerato-
sis as the cosmetic result blends well with the
surroundings [1, 2] (Fig. 34.3).
Third, cryosurgery is suitable for lesions of
various sizes and depths (Fig. 34.4a, b). Staged
Fig. 34.3 Multiple actinic keratoses on the lower leg may
be treated with liquid nitrogen spray since they are super-
ficial and despite her varicose veins presented little
problem
a b
Fig. 34.4 (a) Patient with multiple possible squamous cell carcinomas and prurigo nodularis. (b) Patient with biopsy-
proven keratoacanthoma and prurigo nodularis is a good candidate for cryosurgery
159
treatment may be required for lesions greater
than 2 cm in diameter. Ideal as monotherapy for
superficial lesions, cryosurgery may be com-
bined with shave removal or curettage for
deeper ones.
Fourth, when treating malignant lesions, one
must consider the natural history of the tumor
and its growth pattern. Cryosurgery is commonly
utilized when treating primary, well circum-
scribed, and superficial skin cancers [8] (See
Fig. 34.4a, b). Cryosurgery demonstrated a
5 year disease free survival rate of 99 % for non-
melanoma skin cancer in a review of 2,932 cases
treated by a single clinician [9]. However, as
cure rates may be lower, superficial therapies,
such as cryosurgery as monotherapy, should be
reserved for those patients where surgery or radi-
ation is contraindicated or impractical [9]. In
patients with low-risk shallow cancers, such as
SCC in situ or low-risk sBCC, cryosurgery may
be considered even though the cure rate may be
lower [9].
Ultimately, the clinician must consider many
factors beyond the lesion when choosing therapy.
General health including, but not limited to: aller-
gies to local anesthesia, ability to care for sutured
wounds, severe arteriosclerosis of the lower legs,
desire for “bloodless” techniques, limited access
to care, such as transportation or distance to med-
ical facilities, which make cryosurgery often pre-
ferred given its portability and that it can often be
accomplished in a single visit [10].
160 M.J. Patel et al.

Table 34.1 Contraindications There are several diseases that are exac-
Relative erbated by extremely cold temperatures.
Absolute contraindications contraindications Cryoglobulinemia is a disease in which there
Lesions for which tissue Cryoglobulinemia are abnormal proteins in the blood that become
pathology is required
insoluble at low temperatures [12]. These pro-
Patient unable to accept Raynaud’s disease
possibility of pigmentary
teins can occlude blood vessels and deposit in a
changes variety of tissues, ultimately leading to end-organ
Proven sensitivity or adverse Cold intolerance damage [12]. Patients with Raynaud’s disease are
reaction to cryosurgery also sensitive to cold temperatures. Raynaud’s
High risk basal cell or Cold urticaria disease is a disorder of small arteries and capil-
squamous cell carcinoma laries, in which the blood vessels narrow and con-
(poorly defined, recurrent,
prior history radiation, strict upon exposure to cold temperatures [13]. In
immunosuppression, severe cases, loss of blood flow can lead to tissue
death. Patients with pathological cold intolerance
and cold urticarial should also be counseled spe-
Contraindications cifically on treatment with cryosurgery.
Due to the common side effect of hypopig-
There are few absolute contraindications for mentation, heavily pigmented skin is often cited
cryosurgery. With such, another modality should as a relative contraindication [1]. Of course, this
be utilized to maximize the success of skin lesion depends entirely on the comfort and preferences
removal and patient satisfaction. of the patient; performing cryosurgery on dark
There are relative contraindications to cryo- skin is not in and of itself harmful to the patient.
surgery. These may make alternative treatment
modalities more suitable, but cryosurgery can
still be performed in these instances depending Summary
on the severity of the condition and the comfort
of the physician. Patients often prefer cryosurgery over alternative
Possible absolute and relative contraindica- strategies because of its cost, convenience, and
tions to cryosurgery are shown in Table 34.1. cosmetic results. However, some skin lesions are
better suited for cryosurgery than others.
Several factors should be considered when
Absolute Contraindications selecting a lesion for therapy. These include but
are not limited to, location, skin type, size, and
Cryosurgery should only be used when the skin depth of penetration, type of malignancy.
lesion is precisely diagnosed [11]. It should not Always consider patient’s comorbidities and
be used when a biopsy is required for diagnosis preference. The contraindications for cryosur-
as no specimen is obtained as a result of the pro- gery cited in literature are primarily concerned
cedure [1]. High risk malignancies are generally with underlying patient characteristics that may
not to be treated with cryosurgery because deeper prevent optimal healing, or with diseases exacer-
invasion can be masked and histological margin bated under extreme cold temperatures.
cannot be confirmed [8]. While there are certainly situations that favor
cryosurgery treatment over alternative modalities,
and vice versa, each lesion should be evaluated
Relative Contraindications on a case-by-case basis.
Ultimately, deciding on a procedure should be
Most of the relative contraindications for cryo- a collaborative decision between patients and
surgery involve either the intolerance to freezing their physicians to determine the best method of
temperatures or the triggering of underlying cold treatment, all lesion characteristics and contrain-
induced conditions. dications considered.
34 Lesion Selection and Related Contraindications 161

References 7. Raziee M, Balighi K, Shabanzadeh-Dehkordi H,

Robati RM. Efficacy and safety of cryotherapy vs. tri-
chloroacetic acid in the treatment of solar lentigo.
1. Andrews MD. Cryosurgery for common skin condi-
J Eur Acad Dermatol Venereol. 2008;22:316–9.
tions. Am Fam Physician. 2004;69:2365–72.
doi:10.1111/j.1468-3083.2007.02409.x.
2. Zimmerman EE, Crawford P. Cutaneous cryosurgery.
8. Trost, LB, Bailin, PL. Dermatologic surgery.
Am Fam Physician. 2012;86:1118–24.
Philadelphia: Elsevier Limited; 2009.
3. Wetmore SJ. Cryosurgery for common skin lesions.
9. National Comprehensive Cancer Network (NCCN).
Treatment in family physicians’ offices. Can Fam
Practice guidelines in oncology: basal cell and squa-
Physician. 1999;45:964–74.
mous cell skin Cancers., <http://www.nccn.org/pro-
4. Nordin P, Stenquist B. Five-year results of curettage-
fessionals/physician_gls/pdf/nmsc.pdf. > (2013).
cryosurgery for 100 consecutive auricular non-
10. Rigel DS, et al. Cancer of the skin. 2 ed. Philadelphia:
melanoma skin cancers. J Laryngol Otol.
Saunders; 2011.
2002;116:893–8. doi:10.1258/00222150260369390.
11. Dawber RP. Cryosurgery: complications and contra-
5. Burge SM, Shepherd JP, Dawber RP. Effect of freez-
indications. Clin Dermatol. 1990;8:108–14.
ing the helix and the rim or edge of the human and pig
12. Berenson JR. Cryoglobulinemia: better treatments
ear. J Dermatol Surg Oncol. 1984;10:816–9.
with brighter outcomes. Oncology (Williston Park).
6. Seirafi H, Fateh S, Farnaghi F, Ehsani AH,
2013;27:1125–6. 1128.
Noormohammadpour P. Efficacy and safety of long-pulse
13. Landry GJ. Current medical and surgical management
pulsed dye laser delivered with compression versus cryo-
of Raynaud’s syndrome. J Vasc Surg. 2013;57:1710–
therapy for treatment of solar lentigines. Indian J Dermatol.
6. doi:10.1016/j.jvs.2013.03.012.
2011;56:48–51. doi:10.4103/0019-5154.77552.
 Method and Equipment Selection
35
Gloria F. Graham and Sara Moradi Tuchayi

Abstract
Main methods to deliver cryogens include the cryospray and the cryo-
probe techniques. A flat cryoprobe applied with pressure can result in a
deeper freeze in relation to lateral spread than obtained with the spray
method. A pointed cryo probe tip produces an ice ball that is deeper than
its radius on the surface whereas a round probe produces a hemisphere-
shaped ice ball. Open-ended cryoprobes are devices where a central open-
ing sprays nitrogen on center of a lesion rather than near the enclosed
periphery. This is best used with a pyrometer or electrical impedance nee-
dle. When selecting a cryosurgical unit find one that is well constructed
and has a good safety record. The cryogen of choice is generally LN. Solid
carbon dioxide can be used for treatment of benign lesions. Nitrous oxide
units are available but have disadvantages and are not recommended for
treatment of malignant lesions. Fluorocarbon sprays can be used for treat-
ment of acne pustules and cysts and for peeling of the skin surface, for
acne scarring as well as treating plaques of psoriasis, actinic or seborrheic
keratoses.

Keywords
Cryospray • Cryoprobe • Cone spray • Cryosurgical unit • Cryogen

Introduction

While day-to-day advance in technology offers

G.F. Graham, MD (*) • S.M. Tuchayi, MD, MPH
Department of Dermatology, Wake Forest University
School of Medicine, Winston Salem, NC, USA
e-mail: ggfgraham@aol.com
different cryosurgery instruments, certain meth-
ods of applying cryogens has not changed a lot.
Cryospray, cryoprobe and cones are still champi-
ons. Some continue to use cotton swabs
(Fig. 35.1a). Lesion type, size, and depth are
important factors to consider before selecting the

© Springer-Verlag London 2016 163

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_35
164 G.F. Graham and S.M. Tuchayi

a b

c d

e f

Fig. 35.1 Spray, and probe tip are all commonly used
techniques in cryosurgery. (a) Various size hand-held cry-
ounits and multiple size probe and spray tips. (b) Blue
forceps used for treating skin tags. (c) Use a cone similar
to size of the lesion for spraying cryogen using an inter-
mittent spray. This process may reduce freeze time by a
few seconds. (d) Cone is surrounding basil cell carcinoma
so that spray is directed onto the lesion. (e) A 5 mm halo
is noted beyond the lesion. (f) A central direct spray, cir-
cular and paint-brush techniques are commonly used
while spraying cryogen. T target, H halo around the
lesion. (g) Probe tip is in place and a 5 mm halo is noted
around the probe for skin cancer, but only a 1–2 mm halo
is needed for benign lesion. (h) A 2 mm halo produced by
a small probe tip when treating benign lesion. (c, f)
(Reprinted from Graham and Barham [2]. With permis-
sion from Elsevier)
35 Method and Equipment Selection
g h
Fig. 35.1 (continued)
appropriate technique. There are few cryogens to
choose from, LN remaining the most commonly
used. Different methods of cryosurgery are dis-
cussed in detail in this chapter (Fig. 35.1b) [1].
Cryosurgery Method
Two main methods used for delivering cryogens
include the cryospray and the cryoprobe; the
cone spray technique is also used frequently
with varying size plastic cones (Fig. 35.1c) that
can be made to fit around lesions in a most con-
venient way.
Cryogen is generally applied through an open
spray tip or through the use of a variety of cryo-
probes attached to a hand held cryosurgical unit
[2, 3] (Fig. 35.1d–f).
A flat cryoprobe applied with significant pres-
sure can result in a deeper depth of freeze in com-
parison to the lateral spread of freeze obtained
with the spray method. Probes can either be
dipped into a cryogen or the cryogen can circu-
late within the tip. It is well to have various size
probes so that one that is approximately the size
of the lesion to be treated can be selected. Each
type of cryoprobe produces a slightly different
shaped ice ball; a pointed tip produces an ice ball
that is deeper than its radius on the surface
165
whereas a round probe produces a hemisphere-
shaped ice ball. Flat probes at 5–25 mm applied
with gentle pressure produces an ice ball that has
a lateral spread of freeze approximately equal to
the central depth of freeze [1] (Fig. 35.1g, h).
After freezing, the halo should be of 1–2 mm for
benign lesion and of 5 mm for malignant lesion.
When estimating, depth of freeze equals lateral
spread [1].
One can practice using the different probes on
either a potato cut in half or an agar plate.
Freezing is carried out until there is a 5 mm halo
of ice beyond the margin. This is timed, and the
model is transected so the cross-section of the
depth of freeze can be seen. The area may turn
brown after 30–60 s; in the potato model the area
frozen will turn brown about 30 min later. It is
also possible to place thermocouple needles in
the model to register temperature in relation to
the freezing pattern. The potato model is not the
same as measuring electrical resistance in the
skin because the electrolytes are different. To
compare the lateral spread of freeze and depth of
freeze using electrical resistance measurements a
meat model is preferable. Lateral spread of freeze
and depth of ice ball may be measured. A ther-
mocouple may be used to determine the iso-
therms (Fig. 35.2) within the ice ball that forms
in the agar gel [1–3].
166
Fig. 35.2 A thermocouple needle is inserted to measure
depth of cold below the lesion. Freeze time is around
1 min to −50 °C. Note the levels of cold as shown by the
isotherms (Reprinted from Graham and Barham [2]. With
permission from Elsevier)
Following the freezing of skin cancer urtica-
tion will develop within about 10 min; at 24 h a
deep vesiculation will be noted; at 48 h there is a
gelatinous mass that can be peeled back showing
a granulomatous base [1].
Cryosurgery Equipment
The cryosurgical equipment has been discussed
in detail in earlier chapters. It is well to have
more than one cryosurgical unit in case one
should malfunction while treating a malignant
lesion. Dr. Graham prefers various size cones,
either plastic, neoprene cones by Arthur
H. Thomas Company, or otoscope cones.
A plastic Jaeger retractor for eye protection or
plastic eye shields are essential for treating
lesions around the eye, a set of cryoprobes and a
pyrometer and /or electrical monitoring unit.
Open-ended cryoprobes are devices with a
central opening spray; the central opening should
be aimed as to spray LN onto the center rather
than near the periphery of the lesion. This should
be done with a pyrometer or electrical impedance
needle [1].
When selecting a cryosurgical unit find one
that is well constructed, has a good safety record,
and is easy to handle. Check several at meetings
G.F. Graham and S.M. Tuchayi
and get the feel of different units. When LN is
placed inside a cryosurgical instrument the con-
tents are then under pressure, which can force it
out in the form of a spray. A safety valve can pre-
vent excessive pressure build-up. A trigger mech-
anism can allow the pressure to force the LN out
of the delivery unit through a flow valve and
nozzle tip. While most people today seem to
prefer handheld units, in the past table top porta-
ble units, and small floor models were available.
The handheld units are lightweight and hold
0.5–1.5 l of liquid nitrogen. Most are self-
pressurizing and operate at a low pressure for
immediate use. Interchangeable Luer-lock tips
are available for many units. A table-top unit, the
CF 76, that was used in the 1970s was made by
Frigitronics, it was excellent for treating larger
tumors. It produced a continuous spray for longer
time than handheld units. Its two tank system is
difficult to fill [1–3].
Smaller units are made by Brymill; the one
referred to as the Cryospray is excellent for those
treating a variety of lesions. Other units are the
WSL Nitrospray, the Cryopt by Gilmore, and the
Cryosurge by Frigitronics. Various sized spray
tips and probes are also available from different
companies. There are rounded-end probes for
treating mucous membranes and myxoid cysts,
flat-end cylindrical probes for tumors, and
pointed probes for sebaceous hyperplasia, milia,
and small flat warts, rounded end probes for
mucous cysts of the lips, myxoid cysts on the fin-
gers and toes, and certain vascular lesions.
Next is thermocouple pyrometer system mea-
suring the tissue temperature below the tumor or
electrical tissue resistance monitors.
The next is eye shields and other protective
devices such as plastic spoons or tongue blades
[1–3].
Transfer of Liquid Nitrogen
The cryogen of choice is generally LN available
at a welding supply company, delivered to the
office approximately once every 2 weeks. It is
poured into a large holding container, a dewar,
often holding 25–35 l with a withdrawal device
35 Method and Equipment Selection 167

a b

Fig. 35.3 (a) Nurse is using a withdrawal device to remove liquid nitrogen from dewar. (b) Nurse is pouring liquid
nitrogen with an assistant from a 35 l dewar and wearing gloves for protection of her hands

or a tilt stand (Fig. 35.3a). The larger and more
expensive dewars have a longer holding time. In
a 34 l dewar the evaporation rate is around 0.1 l
per day [1].
The authors’ nurses prefer pouring LN from
the storage dewar using one of the pouring stands.
Pouring of LN from small dewars of 10 l by tilting
them is acceptable, for larger containers pouring
stands are available (Fig. 35.3b). A dipper can
also be used or a spigot-type device [2, 3].
Other Cryogens
off and fly onto other areas of skin, and droplets
need to be surrounded by using a cup-shaped
device allowing them to vaporize on the skin sur-
face. The minimum temperature reached with
this is around −80 °C. It is not recommended for
treatment of malignant lesions although some of
these have been made [1].
Fluorocarbon sprays are available primarily
for use as local anesthesia. It can be used for
treatment of acne pustules and cysts and for peel-
ing of the skin surface for acne scarring as well as
treating plaques of psoriasis, actinic or seborrheic
keratoses.

If LN is not available solid carbon dioxide can be

References
used for treatment of benign lesions. Dry ice can
be used to make a pencil shaped cryogen from
cylinders or from the KIDDE apparatus with
miniature cylinders. Nitrous oxide units are also
available but have some disadvantages. When
nitrous oxide is sprayed onto a surface there is a
buildup of a snow-like substance that can break
1. Torre D, Lubritz RR, Kuflik EG. Practical cutaneous
cryosurgery. Norwalk: Appleton and Lange; 1988.
p. 1–41.
2. Graham GF, Barham K. Cryosurgery. Curr Probl
Dermatol. 2003;15(6):223–50.
3. Zacarian SA, editor. Cryosurgery for cancer of the
skin. St Louis: Mosby; 1984. p. 3–54.
 Cryosurgeon Selection
36
Gloria F. Graham

Abstract
The selection of the cryosurgeon is very important especially for the treat-
ment of skin cancers and rarer conditions. While warts, actinic keratosis
and other superficial benign lesions are frequently treated by dermatolo-
gists as well as family physicians, plastic surgeons, and ENT (ear nose and
throat) specialists, the most experienced are often dermatologists.

Keywords
Dermatologist • ENT specialist • Pediatrician • Pediatric dermatologist

As discussed by Dr. William Abramovits at
the January 16, 2014 American College of
Cryosurgery meeting, “Cryosurgery is very
operator-dependent; it requires fundamental
knowledge in the physics of cryobiology, skin
anatomy and physiology, pathology, and the
clinical acumen that is to be expected only from
a dermatologist”. I know that there are Family
Physicians who are well trained in cryosur-
gery and that do an excellent job, In fact, Mark
Andrews, a Family Physician, has written an arti-
cle for family physicians about cryosurgery, con-
tributing greatly to the education of other family
physicians on cryosurgery procedures [1].
G.F. Graham, MD
Department of Dermatology, Wake Forest University
School of Medicine, Winston Salem, NC, USA
e-mail: ggfgraham@aol.com
However, since the cure rate from cryosurgery
depends on the skill of the operator, the cure rate
may be affected by a lack of careful understanding
of cryosurgical techniques, or what tumors cryo-
surgery could be beneficial for, knowledge most
afforded by experienced dermatologists. Dawber
et al. [3] states that “One of the most important
contraindications is the lack of a proper diagno-
sis” [2]. For example in this country, melanoma,
other than lentigo maligna, has not been treated
with cryosurgery, but in certain parts of the world,
it has been. Breitbart developed the original tech-
nique for treatment of melanoma with cryosur-
gery [4]. He performed a study with Johnson [5]
comparing the immunoreactivity of melanomas
that were surgically treated versus freezing. From
this comparison study it was determined that If a
tumor is excised, there is no immune response.
If it is frozen, there can be an immune response
and frequently is [4]. Until more significant

© Springer-Verlag London 2016 169

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_36
170
comparisons have been made with freezing of
melanoma, MOST Cryosurgeons probably limit
cryosurgery only to those superficial tumors that
fall in the lentigo maligna category.
Many other specialties are now involved in
cryosurgery, just look at the abstracts in The
American College of Cryosurgery meeting cryo-
surgery is now being used in the heart for atrial
fibrillation, the liver, prostate, kidney and even
the bronchial tree. Ear, nose and throat special-
ists, along with gynecologists have used cryosur-
gery in the past extensively.
Summary
Selection of the Cryosurgeon relies on a few fac-
tors including the number of dermatologists in an
area and how many utilize cryosurgery [6, 7].
“Cryosurgery is an art as well as a science. Of
course just as a sculptor or painter must learn about
stone, wood, canvas, paper, chisels, rasps, paint-
brushes, and other materials, the cryosurgeon must
understand the science underlying cryosurgery. He
or she must learn the properties of the various cryo-
gens, the apparatus for applying them, the three-
dimensional extent of the lesions to be treated, and
the tissue content of these lesions. He or she should
also know the susceptibility of various portions of
the target lesion and surrounding tissues to varying
insults with cold”.
Cryosurgical equipment can be purchased for
under a thousand dollars including monitoring
devices. This rather low expense can make
G.F. Graham
cryosurgery widely available. In a coastal area like
the one in which I work, there are usually several
physicians trained in freezing including family
physicians, internists, and pediatricians, pediatric
dermatologists who also are well trained in laser
use, plastic surgeon, some surgeons, ear, nose and
throat specialists, as well as dermatologists. Mohs
surgeons may limit themselves to their main prac-
tice of Mohs surgery, however, many use excision,
electrodessication, curettage, and cryosurgery.
When considering freezing, it is wise to select a
physician with enough cryosurgical experience to
determine if the patient and or lesion in question
will be suitable for freezing, and will tolerate the
post procedural edema, weeping, and crusting.
References
1. Andrews M. Cryosurgery for common skin condi-
tions. Am Fam Physician. 2004;69(10):2365–72.
2. Abramovits W. American College of Cryosurgery
(meeting). Key Largo, Florida. 16 Jan 2014.
3. Dawber R, Colver G, Jackson A. Cutaneous cryosur-
gery principals and clinical practice, vol. 7. 1st ed.
London: Martin Dunnitz; 1992. p. 149.
4. Breitbart E, Dachow-Siwiec E, editors. Clinics in
dermatology: advances in cryosurgery, vol. 8.
New York: Elsevier; 1990. p. 96–100.
5. Johnson JP, Dachow-Siwiec E, editors. Clinics in der-
matology: immunologic aspects of cryosurgery:
potential modulation of immune recognition and
effector cell maturation, vol. 8. New York: Elsevier;
1990. p. 39–48.
6. Torre D. The art of cryosurgery. Cutis Cutan Med
Pract. 1994;54(5):354.
7. Graham GF. Cryosurgery. Clin Plast Surg. 1993;20(1):
131–47.
 Part VI
Methods
 Spray
37
Gloria F. Graham

Abstract
This chapter focuses on the spray technique and conditions amenable to
cryospray. Equipment needed will be discussed, as well as different tech-
niques for the spray application. Attention will be given to freeze time,
halo thaw time, and complete thaw time. Cure rates discussed for actinic
keratoses and non-melanoma skin cancers. Spray is preferred by many
cryosurgeons.

Keywords
Cryospray • Cryoprobe • Curettage • Tangential shave • Cryopattern
• Freeze time • Halo thaw time • Complete thaw time

Introduction contact with the site being treated and allowing

Though the cryoprobe method has many indica-
tions for application and is widely used, the spray
method is preferred by most cryosurgeons.
Studies performed by Kuflik and Gage [1] have
shown spray to be a very preferred and beneficial
application of cryosurgery with high cure rates
[2], low rates of recurrence, and positive
cosmetic results [3].
The advantage of using the spray method
include allowing the cryosurgeon to keep visual
G.F. Graham, MD
Department of Dermatology, Wake Forest University
School of Medicine, Winston Salem, NC, USA
e-mail: ggfgraham@aol.com
them to determine the depth of freeze (with a
probe only the halo is visible), higher cure rates,
low recurrence rates and positive cosmetic out-
comes. The spray method is the preferred method
in my practice. The probe is best used primarily
around the eyelid in small deep tumors.
Combined Methods
Frequently, it is beneficial to combine methods of
treatment with cryospray. Shave is best used for
obtaining the biopsy and curettage is often fol-
lowed to debulk the tumor. The spray is then
applied to the tumor bed. On the trunk and the
lower leg, a single freeze is sufficient when com-
bined with shave, curettage and cryosurgery.

© Springer-Verlag London 2016 173

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_37
174
Conditions Amenable to Cryospray
There are many diseases that indicate spray
method cryosurgery. These include Benign
lesions such as : Acne vulgaris, angiolymphoid
hyperplasia, angiokeratoma, angiomas, chon-
drodermatitis nodularis chronicus helicis, der-
matofibroma, disseminated superficial actinic
prokeratosis, granuloma faciale, granuloma fis-
suratum, hemangiomas, hidredentitis suppura-
tiva, keloids, leishmaniasis, lentigines, lichen
planus, lichen sclerosus, lichen simplex croni-
cus, lymphocytoma cutis, mucocele, myxoid
cyst, nevi, porokeratosis of mibelli, porokera-
tosis plantarus discretus, prurigo nodularis,
psoratic plaques, pyogenic granuloma, rosa-
cea, sebaceous hyperplasia, sebhorreic kera-
tosis, steastocystoma multiplex, syringoma,
trichiasis, venous lake, verrucae and precan-
cerous lesions such as: actinic chelitis, actinic
keratoses, keratoacanthoma, lentigo maligna,
bowenoid papulosis. Malignant lesions such
as: basal cell carcinoma, Bowen’s Disease,
Kaposi’s sarcoma, metastatic melanoma,
selected squamous cell carcinoma excluding
most adenoid and de novo type [4].
Methodology and Equipment
for Spray Treatment
After identifying the lesion for treatment some
doctors prefer to outline the area with a mark-
ing pen [5], (Figs. 37.1a–c) however darker
pigmented lesions (Fig. 37.2) will provide a
cryopattern outlining the border making this
unnecessary. There are a several main ways to
apply spray, in a circular pattern, paintbrush
pattern (see Fig. 37.1f) or with a cone selected
(see Fig. 37.1c) for the diameter of the lesion
[6]. The circular pattern is applied by starting
the spray in the center of the lesion and moving
out in a circular motion. This is best for lesions
that are 0.5–2.0 cm in diameter. The paintbrush
pattern is applied by sweeping back and forth
across the lesion as if one is using a paintbrush,
this method is preferred for irregular shaped
lesions from 2.0 to 3.0 cm in diameter. The
G.F. Graham
cone method utilizes a cone, selected for the
diameter of lesion and provides a concentrated
area for the spray and a defined outline, and
reduces necessary spray time by 2–3 s provid-
ing a nicer cosmetic outcome and higher cure
rate.
When starting out with cryosurgery it is rec-
ommended that you use a thermocouple inserted
at the base of the tumor to determine the depth of
freeze, (Fig. 37.3a–c) once one has gained
enough experience depth of freeze can be deter-
mined by judging the thaw of the freeze halo
around the lesion. For some lesions you may
need a repeat freeze thaw cycle to effectively
eradicate it. You may also freeze a lesion in sec-
tions if it is larger than 2.0 cm, or if it is exten-
sive, it may be frozen in stages over a longer time
span to avoid a thick eschar that may take up to
3 months to separate.
To apply the spray method one will need a
cryosurgical spray unit, thermocouple, pyrome-
ter, spray and probe tips, and cones. Details on
equipment can be found in Chap. 40.
Freeze times that I have used as a teaching
tool to give novices in cryosurgery a place to
start. These are averages, and each person should
develop their own techniques which may require
different freeze times. See Table 37.1 [4].
Cure Rate
Thai Ke performed a multicenter prospective
study on actinic keratosis of the face and scalp
between 1.0 and 5.0 mm in diameter. Patients
with a total of 421 actinic keratoses were fol-
lowed for 3 months and individual complete
responses were 67.2 %, 39 % for lesions treated
under 5 s, 69 % if treated 5–20 s, and 89 % if
treated over 20 s [7]. My experience has shown
that, and even higher for lesions treated for lon-
ger than 20 s. Some comedonal actinic kerato-
ses require 30 s of freeze because of the depth
of follicle (Fig. 37.4a, b). Kuflik performed a
review of records from 2,932 patients with
4,406 new and recurrent basal cell carcinomas
and squamous cell carcinomas treated with the
open spray technique using two to three thaw
37 Spray
a b
Fig. 37.1 (a) Elderly patient with a presumed seborrheic
keratosis prior to biopsy on the helix of the ear. (b) After
biopsy confirmed squamous cell carcinoma, lesion out-
Fig. 37.2 Cryopattern shown after freezing a hyperpig-
mented seborrheic keratoses
cycles, some monitored with a thermocouple to
−50/−60° C, the rest monitored clinically,
175
lined and frozen for 1 min. Halo thaw time was 1 min, and
complete thaw time was 3 min. (c) Follow up shows satis-
factory cosmetic result
showed a 30 year cure rate of 98.6 %. Kuflik
also presented a study showing a 5 year cure
rate of 522 cases at 99 % with only five
recurrences.
Summary
The spray method allows a better visual contact
with lesions being frozen and a high cure rate
making it the preferred method of treatment by
many cryosurgeons. The cryopattern is useful
when spray is being used, since the outline of the
lesion is better visualized. In my hands, the spray
time has been very useful for obtaining a higher
cure rate and better cosmetic result.
176 G.F. Graham

a b

Fig. 37.3 (a) Large superficial basel cell carcinoma on confirming −50°°C with thermocouple needle. (c) Linear
the upper arm with satellite lesion was divided into sec- hypertrophic scar at 6 weeks, subsided after several
tions. (b) Tumor was frozen using paintbrush method and months

Table 37.1 Freeze times of common conditions

Spray Spray Spray
Lesion type time Lesion type time Lesion type time
Verruca plana 5s Lentigo 7s Sebaceous adenoma 5–10 s
Actinic keratosis 5–10 s Sebhorreic keratosis 10 s Verruca vulgaris 15–20 s
Prurigo nodularis 30 s Keloids 30 s Hemangioma 60+ s
Keratoacanthoma 30 s Dermatofibroma 60+ s Granuloma faciale 30 s
Granuloma annulare 20 s Chondrodermatitis 30 s Plaque of psoriasis 15–30 s
Cherry angiomas 10 s Nevus 10 s Leukoplakia 15 s
Mucocele 30 s Molluscum contagiosum 5–10 s – –
37 Spray 177

a b

Fig. 37.4 (a) Patient has amazing response following photodynamic therapy. (b) Despite the response, patient still has
multiple comedonal actinic keratoses that require 30 s of freezing using local anesthesia for eradication

surgery. 1st ed. Philadelphia: W.B. Saunders; 1994.

References
1. Kuflik E, Gage A. Cryosurgical treatment for skin can-
cer. 1st ed. New York: Igaku-Shoin; 1990.
2. Graham GF. Cryosurgery. Clin Plast Surg. 1993;
20(1):143.
3. Dawber R, Colver G, Jackson A. Cutaneous cryosur-
gery principals and clinical practice. London: Martin
Dunitz; 1992. p. 53.
4. Graham G. Cryosurgery for benign, premalignant, and
malignant lesions. In: Wheeland R, editor. Cutaneous
p. 840.
5. Graham G. Cryosurgery. In: Nouri K, Leal-Khouri S,
editors. Techniques in dermatologic surgery. 1st ed.
Edinburgh: Mosby; 2003. p. 183.
6. Dawber R, Colver G, Jackson A. Cutaneous cryosur-
gery principals and clinical practice. London: Martin
Dunitz; 1992. p. 20–1.
7. Thai K, Fergin P, Freeman M, Vinciullo C, Francis D,
Spelman L, Murrell D, Anderson C, Weightman W,
Reid C, Watson A, Foley P. Int J Dermatol. 2004;
43:687–92.
 Cotton Tipped Application
38
Renata Strumia

Abstract
The dipstick applicator method is the original method used to apply LN to
lesions. LN is applied by means of an instrument, usually a wooden stick
6 in. long, the end of which is covered with cotton according to the size of
the lesion. The cotton-tipped dipstick is dipped into the cryogen placed in
a container and then applied firmly onto the lesion until a halo of ice forms
around it. A ‘gentler’ treatment than the one utilizing LN may be carried
on using dimethyl ether and propane. This mixture is sprayed through a
narrow tube to a cotton applicator, which is applied to the lesion.

Keywords
Liquid nitrogen • Cotton-tipped dipstick method • Dimethyl ether and
propane • Cryosurgery

Dipstic Applied Liquid Nitrogen
The dipstick applicator method (Figs. 38.1 and
38.2) is the original method used to apply LN to
lesions [1]. It is still popular in the management
of common benign lesions, in some European
countries; in other countries it is being supplanted
by spray techniques.
LN is applied to the lesion by means of an
instrument, usually a wooden stick 6 in. long, the
end of which is covered with cotton-wool accord-
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital,
University of Ferrara, (Former) Ferrara, Italy
e-mail: restrumi@tin.it
ing to the size of the lesion. The cotton-tipped dip-
stick is dipped into the cryogen within a cup or
insulated bottle and then applied firmly onto the
lesion until a halo of ice forms around the bud.
The depth of freeze can be increased by applying
pressure on the lesion. The method has the advan-
tage of not needing a spray or probe equipment
and is therefore cheap. However, repeated appli-
cations may be necessary to achieve a proper
freeze thaw. Low temperatures are not achieved in
the dipstick applicator method deep or efficiently
as they are in the spray technique; therefore, this
method is suitable only for benign lesions. It is
important to appreciate the respective roles of the
duration and of the pressure of applications of LN
on lesions of different depths.

© Springer-Verlag London 2016 179

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_38
180
Fig. 38.1 Cotton-tipped dipstick
The cotton-tipped dipstick method is particu-
larly useful in the treatment of lesions located is
areas not easily reachable by spray or probes or
close to the eye and in the auricle concha.
A comparative study about the effectiveness
of LN cryotherapy with cryo-spray vs. cotton
wool bud for hand and foot warts showed both
to be equally effective [2]. The cotton-tipped
dipstick method has the advantage of not need-
ing a spray or probe equipment and may there-
fore be cheaper than buying spray or probe
apparatus.
In benign lesions and skin tags which require
a light freeze the forceps and cotton applicator
method may be used. The cotton applicator is
dipped in LN until it becomes frosted. The benign
lesion is pinched with forceps, then the applicator
is pressed against the lesion until a 15-s frost is
achieved. This process is repeated once more.
The forceps lifts the lesion from the background
skin so less collateral damage occurs; this gives
the cotton-tip a better surface for contact. The
lesion freezes first, then the surrounding skin, the
same principle as a bridge freezing before the
surrounding road freezes, reducing collateral
damage which results in less discomfort [3].
The possibility of transmission of virus parti-
cles from patient to patient by multi-use silver
nitrate sticks and styptic pencils and by cotton
wool swabs that have been dipped repeatedly
R. Strumia
Fig. 38.2 Cryotherapy for a plantar wart. Liquid nitro-
gen is applied to the lesion by means of an instrument,
usually a wooden stick 6 in. long, the end of which is cov-
ered with cotton-wool according to the size of the lesion
into dewar flasks of LN has been proven. It is
often not recognized that, LN is an agent for
cryo preservation of biologic material (e.g., for
forensic analysis) and, in particular, of infectious
microorganisms (including viruses). Therefore,
without adherence to correct infection control,
including adequate sterilization, one could trans-
mit infection from patient to patient. For exam-
ple, if a receptacle filled with LN is used for
every patient throughout a clinic and multiple
swabs are dipped into it, the receptacle can be
contaminated with patients’ microbial flora.
Moreover, if any unused liquid nitrogen is
returned to the main storage container, the entire
tank can become contaminated.
LN was implicated in cases of HPV cross-
infection when swabs were used to treat patients
with warts and then used to treat other patients
with dermatological lesions [4, 5]. Therefore
wabs should not be dipped repeatedly into the
flask of liquid nitrogen but, instead, a small ali-
quot of nitrogen should be decanted into a smaller
‘clean’ vessel, a cup for example, and a new cot-
ton swab used for each patient.
Dipstic Applied Dimethyl Ether
and Propane
May be a gentler treatment than LN because a
lesser drop in temperature is achieved. It may be
38 Cotton Tipped Application
less expensive and is easier to store. Small units
that contain a liquid gas mixture of dimethyl
ether and propane are retailed. The mixture is
sprayed through a narrow tube to a cotton appli-
cator, which is applied to the lesion. The mixture
evaporates and freezes the lesion. A temperature
of −50 °C is reached at the cotton tip. In a ran-
domized trial comparing LN and dimethyl ether
and propane cryotherapy for the treatment of
hand warts, the percent of patients cured was 67
and 35 (P = 0.01) and the percentage of warts that
resolved was 66 and 49 (P = 0.08) respectively
[6]. The treatments were about equally effective
in dorsal nonprotuberant and small (<5 mm)
warts, but the overall results with LN were
better.
181
References
1. Lubritz RR. Cryosurgical approach to benign and pre-
cancerous tumors of the skin. In: Zacarian SA, editor.
Cryosurgery for skin cancer and cutaneous disorders.
St. Louis: Mosby; 1985. p. 283–97.
2. Ahmed I, Agarwal S, Ilchyshyn A, Charles-Holmes S,
Berth-Jones J. Liquid nitrogen cryotherapy of com-
mon warts: cryo-spray vs. cotton wool bud. Br
J Dermatol. 2001;144:1006–9.
3. Kuwahara RT, Craig SR, Amonette RA. Forceps and
cotton applicator method of freezing benign lesions.
Dermatol Surg. 2001;27:183–4.
4. Jones SK, Darville JM. Transmission of virus particles
by cryotherapy and multi-use caustic pencils: a problem
to dermatologists? Br J Dermatol. 1989;121:481–6.
5. Charles CR, Sire DJ. Transmission of papovavirus by
cryotherapy applicator. JAMA. 1971;218:1435.
6. Sharma VK, Khandpur S. Guidelines for cryotherapy.
IJDVL. 2009;75:90–100.
 Segmental and Fractional
Cryotherapy
Renata Strumia
Abstract
Segmental cryosurgery makes cryosurgical eradication of larger cancers
possible by segmenting the lesion and treating it in stages, on average,
3–4 weeks a part.
Keywords
Segmental cryosurgery
Segmental cryosurgery is a methodical technique
to destroy tumor segments or in separate sec-
tions, going on centripetally.
The segmental cryosurgical procedure was
first suggested by Zacarian [1] to treat large
tumors that could not be treated in one session.
Albright [2] and Kuflik [3] developed the tech-
nique further. It makes cryosurgical eradica-
tion of larger cancers possible by segmenting
the lesion and treating it in stages, on average,
3–4 weeks a part. In one version the first treat-
ment freezes part of the tumor’s contour plus
adjacent safety margin using two freeze–thaw
cycles. The criteria to decide which segments
of the tumor’s contour will be treated first
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara, (Former) Ferrara, Italy
e-mail: restrumi@tin.it
© Springer-Verlag London 2016
W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_39
39
depend on the shape and architecture of the
lesion. Two points must be considered; seg-
mental cryosurgery should start at the periph-
ery of the lesion; the resulting ulceration slowly
heals by second intention over the following
3–4 weeks. After healing, the remaining lesion
is reduced in diameter or, at least, in thickness,
and its measurements are compared with the
initial ones and recorded. If its size indicates
that there is no more danger of retraction, the
second procedure is performed in the standard
way (two freeze–thaw cycles with adequate
safety margin). If the tumor is still too large,
the first procedure is repeated. The aim of this
technique is to obtain progressive reductions in
the size of the tumor, with as many procedures
as necessary, until it is reduced to a size that
permits complete freezing, with safety margin
with a reduced risk of retraction. Although it is
an excellent method to treat elongated lesions,
it seems inadequate for lesions around the eyes
and for smaller, rounded tumors.
183
184
In 1999 Almeida Gonçalves [4] reported his
protocol of fractional cryosurgery that is the
opposite of segmental cryosurgery. In fractional
cryosurgery, the treatment begins at the center of
the tumor and continues centrifugally outwards,
the safety margin being the last segment to be
treated. Fractional cryosurgery is indicated for
roundish tumors near important physiognomic
features. The tumor is progressively reduced in
size, and the final treatment is performed only
when it is evident that it will no longer produce a
deforming scar.
R. Strumia
References
1. Zacarian SA. Cryosurgery for cancer of the skin. In:
Zacarian SA, editor. Cryosurgery for skin cancer and
cutaneous disorders. St Louis: CV Mosby, Co; 1985.
p. 96–162.
2. Albright III SD. Case report: prolonged cure of extensive
primary and recurrent cancers of the skin by aggressive
cryosurgery. J Dermatol Surg Oncol. 1983;9:231–4.
3. Kuflik EG. The “field-fire” basal cell carcinoma: treat-
ment by cryosurgery. J Dermatol Surg Oncol. 1980;6:
247–9.
4. Almeida Gonçalves JC. Fractional cryosurgery for
skin cancer. Dermatol Surg. 2009;35:1788–96.
 Cryopeeling
40
Janyana M.D. Deonizio

Abstract
Although focal ablative methods are considered effective options for
actinic keratoses, treatment of the “field of cancerization” has guided the
treatment of multiple actinic keratoses. Cryopeeling is a technique that
uses cryotherapy not only on actinic keratoses lesions but also over the
photodamaged skin where they reside. Cryopeeling is well tolerated and
effective in the treatment of actinic keratoses, with evidence of clinical
benefit in improving the surface appearance of the affected skin. Despite
clinically apparent cosmetic benefits on photodamaged skin and efficient
treatment of actinic keratoses lesions, cryopeeling was not able to induce
measurable histological changes in solar elastosis, epidermal organiza-
tion, or epidermal and Grenz zone thicknesses. Mind the risk of hypopig-
mentation when choosing this modality for photodamaged skin.

Keywords
Cryopeeling • Cryo-peel • Photodamage • Liquid nitrogen • Actinic
keratoses • Cryotherapy • Skin aging

Cryosurgery with LN is the most common form
of treatment of actinic keratoses [1]. It is an easy
access option for dermatologists with good cost
J.M.D. Deonizio, MD
Department of Dermatology, Hospital das Clinicas,
Rua General Carneiro, 181 – Curitiba/PR – CEP
80.060-900, Curitiba, Parana 80.060-900, Brazil
e-mail: janyanadd@yahoo.com.br
benefits [2–4]. A portable system (PS) is a more
recent alternative for cryotherapy, it uses dimeth-
ylether, propane and isobutane in a portable plas-
tic canister where the tip may achieve a
temperature of −55 °C, not enough to deliver
proper destructive isotherms for beyond the most
superficial lesions. With LN, which has a boiling
point of −196 °C, the temperature to be achieved
in the tissue, adequate for the treatment of malig-
nancies, is between −50 and −60 °C several mil-
limeters deep [5].

© Springer-Verlag London 2016 185

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_40
186
Despite of the fact that focal ablative methods
are considered effective options for actinic kera-
toses, the treatment of the entire “field of cancer-
ization” has guided the treatment of multiple
actinic keratoses. The entire photodamaged area
that, although without clinical lesions, demon-
strates precancerous changes and genetic muta-
tions, which precede tumor development defines
the field of cancerization. Considering this, other
treatments may be chosen for the treatment of
actinic keratoses as photodynamic therapy and
topical medications, in order to treat larger areas
and those with subclinical changes. The topical
use of 5-fluorouracil, diclofenac and imiquimod
are alternatives following this approach strategy
to these lesions [4]. After photodynamic therapy,
histological evaluation demostrate an reduction
in histologic signs of photodamage, including
both proliferation marker Ki-67 and early carci-
nogenesis marker p53 [6]. Interestingly, despite
the improvement of basal keratinocytes dyspla-
sia, there is still some degree of dysplasia in 45 %
of the cases, suggesting that one single treatment
is not sufficient to completely clear the signs of
photodamage [6].
Following the concept of field of canceriza-
tion, cryopeeling for actinic keratoses and photo-
damage might be interesting in order to improve
the skin appearance and, combined with inten-
sive photoprotection, to prevent the occurrence of
malignant lesions [4]. Cryopeeling is a technique
that uses cryotherapy in a diffuse manner
throughout the skin region affected by sun dam-
age in order to promote cell renewal and desqua-
mation, with possible benefits in appearance of
new lesions caused by photodamage. A detailed
methodology for the performance of cryopeeling
is discussed towards the end of the chapter on
Keloids and scars by Zouboulis, Har-Shai and
Orfanos, in this textbook.
Although cryosurgery is widely used in clini-
cal practice, few studies using cryopeeling have
been conducted [3, 7–9]. In them the results
obtained with cryopeeling treating actinic kerato-
ses were satisfactory and more effective than
5-fluorouracil. It seems that cryopeeling is effi-
cient, affordable and easy to apply [3]. A study of
16 patients 50–80 years old (mean age
J.M.D. Deonizio
68.5 ± 9.6 years), compared a portable system
(PS) and liquido nitrogen (LN); the PS’s cryogen
was applied to one forearm and LN to the other,
selected randomly. An occlusive topical anes-
thetic (lidocaine 5 % and prilocaine 5 %) was
applied 2 h before the procedure. To guide the
application, quadrants and demarcation of actinic
keratoses lesions to be individually treated were
made. The cryopeeling was performed by apply-
ing the freezing substance with brush movements
along the extension of the forearm until the area
was frozen [7]. After this, actinic keratoses
lesions were individually treated with variable
freezing times set by the investigator (Fig. 40.1a,
b [9]). Curettage was previously performed to
very hyperkeratotic lesions. Following manufac-
turer's guidelines for the use of PS, the valve was
pressed until a few drops of cryogen came out
from the tip. The applicator was then rotated 90°
followed by a 15 s wait for the tip to freeze. The
tip was slid with rotational movements over the
skin causing transitory blanching (Fig. 40.1a).
The day following the procedure patients used
petrolatum topically to moisturize the skin and
reduce discomfort.
Cryopeeling done with LN achieved higher
efficiency in treating actinic keratosis lesions
when compared to PS (74 % vs 62 %, p = 0.019).
Evaluating the procedure discomfort, the mean
visual analogue scale (0–10) was significant
higher with LN than PS. There was no significant
statistical difference between the two methods in
terms of researcher and patient preferences. The
photographic analysis showed skin appearance
improvement with both methods. Treatment with
LN obtained some degree of improvement in
62.5 % of the cases, while treatment with PS
obtained some degree of improvement in 52 % of
the cases. It was concluded that PS technique
showed better tolerance, but less efficacy in treat-
ing actinic keratoses than LN [8].
Histologic changes due to photoaging are
highly debated in literature. It is believed that
there is a reduced turnover rate of the stratum
corneum, epidermal atrophy, increased healing
time and less effective scaling. An accumulation
of corneocytes makes the skin surface rougher.
The dermis shows a reduction of about 20 % of
40 Cryopeeling
Fig. 40.1 Patients received cryopeeling treatment using
the PS to one forearm (a) and using LN to the other fore-
arm (b), randomly. The cryopeeling was performed by
applying the freezing substance with brush movements
along the extension of the forearm until the area was fro-
its thickness, with disorganization of collagen
fibers and accumulation of abnormal elastin-
containing material [10]. Collagen fibers,
responsible for skin strength and support,
become disorganized and arranged in rope-like
bundles. In contrast to the proportion of 80 % of
type I collagen and 15 % of type III collagen in
young skin, in aged skin the amount of type III
collagen increases [10–12]. Exposure to ultravi-
187
zen. After this, actinic keratoses lesions were individually
treated. PS portable system, LN liquid nitrogen (Adapted
from Deonizio et al. [9]. With permission from Hindawi
Publishing Corporation)
olet radiation induces transcription factors
involved in gene activation of matrix metallopro-
teinases and consequent production of collage-
nases, gelatinases and stromelysin, perhaps the
responsible mechanism for decreased collagen
levels. Photodamage is also marked by elastosis:
changes in elastic fibers characterized by the
accumulation of amorphous elastin material and
thick elastic fibers in the papillary dermis. The
188
initial response to sun damage is hyperplastic,
resulting in increased amounts of elastic fibers.
However, it is believed that, subsequently,
degenerative response takes place resulting in a
decrease of the skin elasticity. Additionally,
there is a change in the normal pattern of imma-
ture oxytalanic elastic fibers located in the papil-
lary dermis. This delicate ascendant network,
which extends perpendicularly from the upper
section of the dermal papilla until just beneath
the basal membrane, gradually tends to disap-
pear. All glycosaminoglycans (hyaluronic acid,
dermatan sulfate and chondroitin sulfate) are
decreased in photodamaged skin, specially hyal-
uronic acid [10].
Medium peels with trichloroacetic acid
induce an increase of elastic fibers in the papil-
lary dermis, establishing what is called Grenz
zone [13]. The real meaning of Grenz is “fron-
tier” and this term is also used to designate the
area that separates the epidermis from subepi-
dermal area of severe elastosis in the dermis [8].
Grenz zone also designates the area spared by
subepidermal inflammatory infiltrate in granu-
loma annulare.
Despite evidence of clinical benefits, this was
not reflected proportionally to the histological
analysis of the skin treated with cryopeeling. It
was not possible to demonstrate histological
improvements in solar elastosis, epidermal orga-
nization and thickness or Grenz zone thickness
after cryopeeling treatment. Histological analysis
showed a decrease in pigment after cryopeeling
but this difference was only significant with the
PS. With the use of the PS for actinic keratoses
treatment an unexpected increase of the frozen
area is often observed; this may affect the size of
consequent hypopigmentation. The impossibility
to predict which sample underwent which proce-
dure indicates the inconsistency, if present, of
histological improvement after treatments. The
highest density of elastic fibers, although found
in many cases after treatment, also failed to reach
a statistically significant difference [9].
Cryopeeling, by definition, is a superficial
peel that does not reach deeper levels in the der-
mis. Despite evident surface appearance and tex-
ture improvements in all patients, measurable
J.M.D. Deonizio
histological changes did not reflect them.
Probably, the improvement of skin appearance is
due to the treatment of actinic keratoses, and not
to that of the entire photodamaged skin. Although
some studies have demonstrated a hyperplastic
response of epidermis after several peeling sec-
tions, only one treatment session fails to induce
the same response [13]. This consequently raises
a discussion about the real benefit of using
cryopeeling under the inherent hypopigmenta-
tion risk. Only long term follow up studies would
be able to evaluate the real long term benefit in
new lesions development in those patients treated
with cryopeeling.
Conclusions
Despite cosmetic benefits on photodamaged
skin and efficient treatment of actinic kerato-
ses lesions, cryopeeling was not able to induce
measurable histological changes in solar elas-
tosis, epidermal organization, or epidermal
and Grenz zone thicknesses. Keep in mind the
risk of hypopigmentation risk when consider-
ing this method.
References
1. McIntyre WJ, Downs MR, Bedwell SA. Treatment
options for actinic keratoses. Am Fam Physician.
2007;76(5):667–71.
2. Shoimer I, Rosen N, Muhn C. Current management of
actinic keratoses. Skin Ther Lett. 2010;15(5):5–7.
3. Chiarello SE. Full-face cryo- (liquid nitrogen) peel.
J Dermatol Surg Oncol. 1992;18(4):329–32.
4. Fenske NA, Spencer J, Adam F. Actinic keratoses:
past, present and future. J Drugs Dermatol. 2010;9(5
Suppl ODAC Conf Pt 1):s45–9.
5. Rigel DS, Cockrell CJ, Carucci J, et al. Actinic kerato-
sis, basal cell carcinoma and squamous cell carci-
noma. In: Bolognia JL, Jorizzo JL, Rapini RP, editors.
Dermatology. 2nd ed. Spain: Mosby; 2008.
p. 1641–59.
6. Bagazgoitia L, Cuevas Santos J, Juarranz A, Jaén
P. Photodynamic therapy reduces the histological fea-
tures of actinic damage and the expression of early
oncogenic markers. Br J Dermatol. 2011;
165(1):144–51.
7. Chiarello SE. Cryopeeling (extensive cryosurgery) for
treatment of actinic keratoses: an update and compari-
son. Dermatol Surg. 2000;26(8):728–32.
40 Cryopeeling
8. Deonizio JM, Mulinari-Brenner FA. Cryopeeling for
treatment of photodamage and actinic keratosis: liq-
uid nitrogen versus portable system. An Bras
Dermatol. 2011;86(3):440–4.
9. Deonizio JMD, Werner B, Mulinari-Brenner
FA. Histological comparison of two cryopeeling
methods for photodamaged skin. ISRN Dermatology.
2014. p. 5.
10. Baumann L. Skin ageing and its treatment. J Pathol.
2007;211(2):241–51.
11. Griffiths CE, Russman AN, Majmudar G, Singer RS,
Hamilton TA, Voorhees JJ. Restoration of collagen
189
formation in photodamaged human skin by tretinoin
(retinoic acid). N Engl J Med. 1993;329(8):530–5.
12. Fisher GJ, Wang ZQ, Datta SC, Varani J, Kang S,
Voorhees JJ. Pathophysiology of premature skin aging
induced by ultraviolet light. N Engl J Med. 1997;
337(20):1419–28.
13. Nelson BR, Fader DJ, Gillard M, Majmudar G,
Johnson TM. Pilot histologic and ultrastructural study
of the effects of medium-depth chemical facial peels
on dermal collagen in patients with actinically dam-
aged skin. J Am Acad Dermatol. 1995;32(3):
472–8.
 Cryo-massage
41
Renata Strumia

Abstract
Cryomassage is used when a slight freeze over a large surface is desired.
A cotton-tipped dipstick or a probe are applied on the lesion using the
rotary or spiral pattern of the paintbrush method. The cotton-wool or probe
stays in contact with the skin for 1–3 s until it blanches momentarily. Main
indications are facial erytrosis, rosacea, alopecia areata and large solar
lentigo.

Keywords
Cryomassage • Erytrosis • Rosacea • Alopecia areata • Solar lentigo

Variations of the cotton-tipped dipstick and probe The main indications are facial erytrosis, rosacea,
method of liquid nitrogen application include alopecia areata and large solar lentigo. Cryomassage
“cryomassage”. This technique is used when a can be repeated every 20–30 days for months.
slight freeze on a large surface is requested. Only
benign lesions can be treated in this manner.
A cotton-tipped dipstick or a probe is applied
on the lesional skin with a rotary or spiral pattern
or a paintbrush method (Fig. 41.1). The cotton-
wool or the probe stays in contact with the skin
for 1–3 s until it blanches momentarily from
freezing. In older people and in those with thin
skin, cryomassage should be light and rapid;
younger people may benefit more from a heavier
slower massage.

R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara, (Former) Ferrara, Italy Fig. 41.1 The cotton-tipped dipstick is rolled over the
e-mail: restrumi@tin.it lesion using a rotary or spiral pattern

© Springer-Verlag London 2016 191

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_41
 Controlled Cold Induced Lipolysis
42
Jennifer Peterson and Suzanne Bruce

Abstract
While liposuction is still the gold standard for body contouring, controlled
cold induced lipolysis is an effective option for patients interested in non-
surgical procedures. Controlled cold lipolysis is produced via a proprietary
device that cools tissue to approximately 0 °C and results in crystallization
of intracellular lipids within adipocytes with subsequent apoptosis, pan-
niculitis, and reduction of adipocytes. Reduction in adipose tissue apparent
by improvement in body surface contours is clinically evident 2–4 months
following treatment. Controlled cold lipolysis received its FDA clearance
for treatment of flanks in 2010, abdomen in 2012, and thighs in 2014.
Studies have reproducibly shown high patient satisfaction with this tech-
nology and the incidence of severe side effects is low. The ideal candidate
for this device is a patient with discrete area(s) of redundant adipose tissue
and skin without laxity. We feel appropriate patient selection is the key to
obtaining best results following controlled cold induced lipolysis.

Keywords
Cryolipolysis • Fat reduction • Body contouring • Cold induced lipolysis •
Noninvasive

Introduction liposuction is still the gold standard for body

Historically a sign of beauty and wealth, the
presence of excess adipose tissue is now con-
sidered to be aesthetically objectionable. While
J. Peterson, MD (*) • S. Bruce, MD
Suzanne Bruce & Associates,
23510 Kingsland Blvd., Katy, TX 77494, USA
e-mail: jpeterson@sba-skincare.com
contouring, many patients are opposed to surgi-
cal downtime and its risks and are instead look-
ing for noninvasive treatments. Noninvasive
body contouring has been reported with radio-
frequency, laser therapy, focused ultrasound,
or a combination of these devices. However,
many of these treatments require multiple
treatment sessions and results are often highly
variable [1, 2].

© Springer-Verlag London 2016 193

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_42
194 J. Peterson and S. Bruce

Small Small, Slightly Large Small, Flat,

curved curved applicator straight conformable
applicator applicator applicator applicator

Applicator of Best matches Pulls in 2.5x as Ideal for longer, Ideal for non-
choice for with the contour much volume as vertical areas pinchable
flanks of the abdomen other vacuum of fat (i.e. areas of fat (i.e.
Curved cup Most commonly applicators abdomen, abdomen,
design allows used applicator flanks, arms and flanks, and
Suggested for
for better used for inner outer things)
large volume
abdomen thights )
Placement and reduction or
fit on curved or de-bulking,
narrow parts especially on
of the body the abdomen

Fig. 42.1 The controlled cold lipolysis console unit fea-
tures wheels enabling it to be transported easily between
rooms. The applicator is connected via a cord to the con-
sole unit and features touch buttons to operate the unit.
The applicators containing vacuum suction are equipped
with two parallel cooling plates to optimize tissue cooling.
The non-vacuum assisted applicator utilizes a conform-
able cooling plate design. The five controlled cold lipoly-
sis applicators and their most common areas of utilization
are described here

The first reports of cold induced panniculitis
were described in infants sucking on popsicles and
coined “popsicle panniculitis”. Other reports of
cold induced panniculitis were later described
involving the lateral thighs of equestrians riding in
cold weather [3]. These occurrences led to the dis-
covery adipocytes are more sensitive to the effects
of cooling than the epidermis and dermis. Thus,
the quest for a device that could selectively target
adipocytes through cold exposure was begun.
Controlled cold lipolysis is produced via
a noninvasive proprietary device (Zeltiq,
Pleasanton, CA) that cools tissue to approxi-
mately 0 °C and results in crystallization of
intracellular lipids within adipocytes with sub-
sequent apoptosis, panniculitis, and reduction
of adipocytes [4]. Reduction in adipose tissue
apparent by improvement in body surface con-
tours is clinically evident 2–4 months following
treatment. Ischemia-reperfusion injury is felt to
be one of the triggering events leading to apop-
tosis [2] in controlled cold induced lipolysis. The
device’s console allows the attachment of one of
five different applicators composed of cooling
plates (Fig. 42.1). The console is equipped with
a thermoelectric cooling element to maintain the
target temperature of 0 °C throughout the treat-
ment cycle via sensors contained within the cool-
ing plates. Energy extraction is measured by the
controlled intensity factor or CIF in milliwatts
per centimeter squared [3].
Controlled cold lipolysis received its FDA
clearance for treatment of flanks in 2010, abdo-
men in 2012, and thighs in 2014. It is indicated
for patients with a body mass index (BMI) of 30
or less. Optimal results are seen in patients with
discrete area of redundant adipose tissue and skin
that lacks significant laxity [3].
Early Animal Studies
The original studies of controlled cold induced
lipolysis were conducted on Yucatan and
Yorkshire pigs. During these initial studies, up to
25–30 % of the pigs’ total body surface areas were
treated at a time with a variety of time points and
energy extraction rates. Three months following
treatment, improvements in skin surface contours
were noted along with a 33 % decrease in adipose
layer thickness (measured via ultrasound and
gross anatomical tissue [2]. Histological studies
42 Controlled Cold Induced Lipolysis
showed inflammation and adipocyte apoptosis
beginning 2 days post-treatment. The inflamma-
tory cell infiltrate present at this time interval was
composed of neutrophils and mononuclear cells.
The intensity of inflammation increased over
the next 7–14 days. Phagocytosis of lipids was
present between days 14–30 [2, 5]. By day 90,
inflammation had begun to decrease in its inten-
sity. Of note, the epidermis, dermis, and adnexal
structures showed no evidence of erosions, ulcer-
ation, or necrosis [2]. Analysis of serum lipids
showed no significant changes throughout the
study. Investigators discovered the most dramatic
reductions in adipose layer thickness correlated
with longer and more intense treatments [2, 5].
Human Studies
Following the porcine studies, investigations on
the flanks of human subjects were begun.
Coleman et al. performed a split flank study on
ten subjects and found an average 20.4 % reduc-
tion in the adipose tissue thickness as measured
by ultrasound 2 months following a single treat-
ment of controlled cold lipolysis. At 6 months
post treatment, the average reduction of adipose
tissue increased to 25.5 % [6]. A split-flank study
on 32 patients by Dover et al. found fat layer
thickness decreased an average of 22.4 % as mea-
sured by ultrasound 4 months after treatment [7].
Caliper measurements on 49 patients showed an
average 23 % reduction in the thickness of adi-
pose tissue in the study by Dierickx et al. [8].
Volumetric analysis of 3-D imaging was used
to analyze changes in adipose tissue in a split-
flank study on 11 patients conducted by Garibyan
et al. Measurements were calculated in cubic
centimeters. Two months post-treatment, the
average reduction on the treated side was 56.2 cc
and 16.6 cc on the untreated side. The mean
absolute difference was 39.6 between the treated
and untreated sides. Though this is a small change
in volume, over 80 % of patients were satisfied
with the results of their treated flank [9].
The only study to investigate the effects of
two treatments on adipose reduction was
195
performed by Shek et al. on 33 Chinese patients.
Patients received either a single treatment or two
treatments spaced 3 months apart. Areas that
were treated were either the abdomen or flanks.
Caliper reading showed a mean 14.67 % reduc-
tion in the adipose tissue at 2 months following a
single treatment. In subjects who received two
treatments on the abdomen, a mean 14.0 %
reduction was seen 2 months after first treatment
and additional 7.0 % reduction 2 months after
the second treatment. On the flanks, there was
13.4 % reduction 2 months after the first treat-
ment and 4.3 % reduction after the second treat-
ment. This study demonstrated the results of a
second procedure promoted further reduction in
adipose tissue, but not to the same degree as the
original procedure. Additionally, a second treat-
ment was more beneficial to the abdomen as
compared to the flanks [10].
Two case studies reported by Bernstein
addressed the long-term sustainability of the
results of controlled cold induced lipolysis. Two
men were treated in a split flank manner, with
one flank serving as a controlled. In one patient
2 years after treatment, he still maintained a
diminished amount of adipose tissue on his
treated flank despite gaining 10 lb. The other
patient also maintained his results 5 years post-
treatment [11].
Klein et al. sought to investigate the effects
of controlled cold lipolysis on serum triglycer-
ides, cholesterol, and liver function tests. Forty
patients received treatment to the flanks and
were followed with serial serum testing at base-
line, day 1, and 1, 4, 8, and 12 weeks post-treat-
ment. No significant changes in any of these
serum levels were encountered throughout the
duration of the study [12].
Patient satisfaction with controlled cold
induced lipolysis has been favorable. In the above
study by Shek et al. 81 % of 33 patients reported
moderate to good improvement and 80 % were
satisfied or very satisfied with their results after a
single treatment [10]. A larger study of 518
patients showed 73 % of patients were satisfied
or extremely satisfied with the results of their
treatment and 82 % would recommend the treat-
ment to a friend [8].
196
Indications and Contraindications
Controlled cold lipolysis received its FDA clear-
ance for treatment of flanks (2010), abdomen
(2012), and thighs (2014) in patients with a body
mass index (BMI) of 30 or less (Figs. 42.2 and
42.3). Other off label areas amendable to treat-
ment include the arms, back, male breasts, but-
tocks, and hips.
We do not treat patients with a history of cold
sensitizing disorders including cold-induced
urticarial, cryoglobulinemia, cryofibrinogen-
emia, Raynaud’s disease, or paroxysmal cold
Fig. 42.2 (a, b) 47-year-old male before and 2 months
after a single treatment to the flanks and lower abdomen.
The largest applicator was utilized for the lower abdomen
and the small curved applicator was applied to the flanks.
J. Peterson and S. Bruce
hemoglobinuria. Treatment should be avoided
over an area with a hernia, abdominal wall
defect, or diastasis recti. Any surgeries in the
proposed treatment area should also be eluci-
dated from the patient. We recommend women
wait 3 months following vaginal delivery and
6 months after cesarean delivery before under-
going controlled cold induced lipolysis on their
abdomen. Patients should not receive treat-
ment if they are pregnant. Finally, improvement
from cold induced cryolipolysis is diminished
in patients with significant skin laxity and/or
adipose tissue. These patients are often better
Note the anterior projection of the lower abdomen and the
lateral projection of the flanks are dramatically reduced in
the post-treatment photographs
42 Controlled Cold Induced Lipolysis
Fig. 42.3 (a, b) This is a case of a 45-year-old female
before and 2.5 months after a single treatment to the abdo-
men and flanks using the larger and small slightly curved
served by surgical procedures such as liposuc-
tion, abdominoplasty, and other surgical lifting
procedures.
Procedure Technique
The device can be used with one of five applica-
tors, four of which employ a vacuum assisted
technology to draw the skin into the applicator
(Fig. 42.1). The largest applicator can draw in 2.5
times the amount of tissue of the smaller applica-
tors and is most commonly used to treat redun-
dant adipose tissue on the upper or lower
abdomen. The three smaller vacuum assist appli-
cators are designed with either a straight, slightly
curved, or curved surface to conform to a variety
of skin surfaces such as the abdomen, flanks, and
inner thighs. The most recent applicator has a
flat, yet conformable, design and was developed
to treat non-pinchable adipose tissue on the abdo-
men and thighs. Often times multiple applicators
197
applicators, respectively. A notable reduction of adipose
tissue is noted along with improvement in her contours
are needed per patient in order to fully treat all of
the areas of concern.
Prior to treatment, the areas of redundant adi-
pose tissue are marked in a topographic manner.
The patient is then positioned comfortably on the
treatment bed and a thermal coupling gel sheet is
applied to the skin surface [3] to maintain thor-
ough coupling between the plates [13]. Next, the
applicator is applied. If a vacuum assisted appli-
cator is utilized, the skin tissue is drawn between
to cold plates for a time of 1 h at a CIF of 41.6.
After the treatment has begun, the clinician is not
needed for the duration of the cycle.
After 1 h, the cycle is completed and the appli-
cator is removed. At this time the tissue is ery-
thematous and firm. Manual massage for 2 min
immediately following treatment has been shown
to further improve the adipose tissue loss by
68 % at 2 months [14]. We routinely incorporate
this technique into our procedure.
Recently, a flat, conformable applicator was
introduced. This new applicator does not require
198
vacuum suction. Instead, straps are utilized to
maintain the position of the applicator through-
out the duration of the treatment. Unlike the vac-
uum assisted applicators, the flat, conformable
applicator requires 2 h of placement on the skin
surface and a colder temperature of −10 °C dur-
ing the procedure [15].
Post-Procedure Care
We recommend our patients wear an over the
counter compressive garment during the daytime
for 2 weeks following controlled cold lipolysis.
Anecdotally, we have found patients report less
pain and swelling with their compressive gar-
ments. Mild discomfort can be managed with
over the counter nonsteroidal anti-inflammatories
and/or acetaminophen. For more severe pain,
which does not respond to conservative treat-
ment, patients are instructed to call our office.
Patients are able to return to their activities the
same day and follow-up is arranged for 8 weeks.
Side Effects
Erythema and edema are the most common side
effects, affecting 100 % of subjects [8, 9]. Bruising
is a common side effect of the vacuum assisted
applicators occurring in 9.5–9.8 % of patients,
and may persist for a week or more [3, 10]. Rare
episodes of vasovagal reaction during treatment
have been reported [8]. In their large study of 518
patients, Dierickx et al. reported nodular or dif-
fuse infiltration of the skin tissue within a few
days after treatment in 2.5 % of patients, which
resolved within weeks. Decreased sensation and
numbness has occurred in up to 73 % of patients
and can persist for weeks to months [9]. Using the
proprietary controlled cold induced lipolysis
device, no episodes of scarring, ulceration, or
necrosis have been encountered [3].
During the procedure, the majority of patients
experience minimal to mild pain localized to the
applicator site when vacuum suction is employed.
This discomfort resolves with in 5 min of begin-
ning the treatment as the skin is cooled [8]. Pain
J. Peterson and S. Bruce
Table 42.1 Management of post-treatment pain
Mild discomforta Acetaminophen 1,000 mg po q 6 h
Ibuprofen 400–800 mg po q 6 h
Camphor/menthol topical cream
Compression garment
Moderate Lidocaine 5 % patch applied up to
discomforta 12 h daily
Significant Gabapentin 300 mg po daily – TID
discomforta Consider narcotics
a
Consider combination therapy
occurring immediately after the procedure is
often mild and lasts a few days; however, severe,
debilitating pain lasting a few weeks has been
reported in approximately 0.04 % of patients
[16]. Mild pain can be improved with menthol
based creams, compression garments, non-
steroidal anti-inflammatories, and acetamino-
phen (Table 42.1).
Severe pain following controlled cold induced
lipolysis does not begin until 3–4 days after the
procedure and has been described as a level of 10
on a pain scale of 0–10. A variety of symptoms
have been reported including stabbing, burning,
shooting, and “pins and needles”-like sensations.
Severe pain often fails to respond to topical men-
thol creams and over the counter analgesics.
Instead, topical lidocaine patches, narcotics, and
GABA analogs (gabapentin) used to treat neuro-
pathic pain can provide the necessary reduction
of symptoms for these patients (Table 42.1). With
in 2 weeks, the pain spontaneously resolves in the
majority of patients [16].
Following the reports of numbness and severe
pain associated with the procedure, Coleman et al
investigated the affect of controlled cold lipolysis
on the function of peripheral nerves. Ten subjects
received treatment with controlled cold lipolysis
to their flanks, one flank was randomized to
receive treatment, while the other served as a
control. A board certified neurologist performed
sensory neurological exams on nine subjects at
baseline and weekly for 8 weeks following con-
trolled cold lipolysis. A single patient underwent
nerve biopsy at the control and treatment site 3
and 6 weeks post-procedure. At the conclusion of
their study, a temporary decrease in sensory func-
tion was noted in six patients 1 week after their
42 Controlled Cold Induced Lipolysis
procedure. However, sensory function was
restored to baseline an average of 3.6 weeks post-
treatment. Nerve biopsy did not demonstrate any
long-term changes to the sensory nerve fibers [6].
A phenomenon called paradoxical adipose
hyperplasia (PAH) has been reported to occur in
0.0051 % of patients post treatment. Patients who
have experienced PAH have shown a gradual
reduction in adipose tissue for the first 2–3 months
after treatment followed by an increase in the
presence of adipose tissue at months 3–5.
Histology on these patients has demonstrated
increased septal thickening and vascularity along
with adipocytes of variable shapes and sizes.
PAH may be more common in male patients,
though larger studies are needed to draw this con-
clusion. PAH can be treated with liposuction,
abdominoplasty, or excision [4].
Conclusions
While liposuction is still the gold standard for
body contouring, controlled cold induced
lipolysis is an effective option for patients
interested in nonsurgical procedures. Studies
have reproducibly shown high patient satis-
faction with this technology and the incidence
of severe side effects is low. The ideal candi-
date for this device is a patient with discrete
area(s) of redundant adipose tissue and skin
without laxity. We feel appropriate patient
selection is the key to obtaining best results
following controlled cold induced lipolysis.
References
1. Avram MM, Harry RS. Cryolipolysis for subcutane-
ous fat layer reduction. Lasers Surg Med. 2009;
41:703–8.
2. Zelickson B, Egbert BM, Preciado J, et al.
Cryolipolysis for noninvasive fat cell destruction:
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initial results from a pig model. Dermatol Surg.
2009;35:1–9.
3. Nelson AA, Wasserman D, Avram MA. Cryolipolysis
for reduction of excess adipose tissue. Semin Cutan
Med Surg. 2009;28:244–9.
4. Jalian HR, Avram MM, Garibyan L, et al. Paradoxical
adipose hyperplasia after cryolipolysis. JAMA
Dermatol. 2014;150:317–9.
5. Manstein D, Laubach H, Watanabe K, et al. Selective
cryolipolysis: a novel method of non-invasive fat
removal. Lasers Surg Med. 2008;40:595–604.
6. Coleman SR, Sachdeva K, Egbert BM, et al. Clinical
efficacy of noninvasive cryolipolysis and its effects on
peripheral nerves. Aesth Plast Surg. 2009;33:482–8.
7. Dover J, Burns J, Coleman S, et al. A prospective
clinical study of noninvasive cryolipolysis for subcu-
taneous fat layer reduction – interim report of avail-
able subject data. Lasers Surg Med. 2009;41:S21–43.
8. Dierickx CC, Mazer JM, Sand M, et al. Safety, toler-
ance, and patient satisfaction with noninvasive cryoli-
polysis. Dermatol Surg. 2013;39:1–8.
9. Garibyan L, Sipprell WH, Jalian HR, et al. Three-
dimensional volumetric quantification of fat loss fol-
lowing cryolipolysis. Lasers Surg Med. 2014;46:
75–80.
10. Shek SY, Chan NPY, Chan HH. Non-invasive cryoli-
polysis for body contouring in Chinese – a first commer-
cial experience. Lasers Surg Med. 2012;44:125–30.
11. Bernstein EF. Longitudinal evaluation of cryolipoly-
sis efficacy: two case studies. J Cosmet Derm.
2012;12:149–52.
12. Klein KB, Zelickson B, Riopelle JG, et al. Non-
invasive cryolipolysis for subcutaneous fat reduction
does not affect serum lipid levels or liver function
tests. Lasers Surg Med. 2009;41:785–90.
13. Sasaki GH, Abelev N, Tevez-Ortiz A. Noninvasive
selective cryolipolysis and reperfusion recovery for
localized natural fat reduction and contouring. Aesth
Surg J. 2014;34:420–31.
14. Boey GE, Wasilenchuk JL. Enhanced clinical out-
come with manual massage following cryolipolysis
treatment: a 4-month study of safety and efficacy.
Lasers Surg Med. 2014;46:20–6.
15. Stevens WG. Feasibility study of a cryolipolysis sur-
face applicator for non-invasive fat reduction in the
outer thigh. Presented at the American Society of
Lasers in Surgery and Medicine annual meeting; 2–6
Apr 2014.
16. Avram M, Dover J, Horowitz S, et al. Late onset pain
associated with cryolipolysis procedures. White paper
from Zeltiq Company. 16 June 2011.
 Solid Carbon Dioxide: Usage
in Slush or Block Form
43
as Therapeutic Agent
in Dermatology

Harold J. Brody

Abstract
The use of solid carbon dioxide (CO2) in dermatology is valuable to treat
acne vulgaris, acne excoriee and as an adjunct in chemical peeling for the
treatment of photo-aging and depressed scarring. This cryosurgical option
is a cost-effective, viable treatment in the twenty-first century in the face
of a flood of expensive devices for contemporary consideration. At −78 °C,
a block of solid dry ice can be slushed in acetone and alcohol to efface
comedones and promote more even healing of excoriated lesions. In addi-
tion, the combination of solid carbon dioxide followed immediately by
trichloroacetic acid as a medium depth chemical peel has a place in the
armamentarium of treatment in a series of over 4000 cases with a wide
margin of safety in lighter skin types.

Keywords
CO2 • Solid carbon dioxide • CO2 slush • Cryosurgery • Cryotherapy •
Chemical peeling • Neurotic excoriations • Acne vulgaris • Acne excoriee

Solid Carbon Dioxide solid block temperature of −78.5 °C allow it to be

Solid CO2 (dry ice) is a physical modality used in
dermatology for the treatment of acne vulgaris,
acne scarring, freckling and other cutaneous dis-
orders for almost a century. Its properties and
H.J. Brody, MD
Department of Dermatology, Emory University
School of Medicine, 1218 West Paces Ferry Rd.,
NW, Atlanta, GA 30327, USA
e-mail: drb@atlantadermatology.com
used alone or to amplify chemical peeling.
CO2 snow is prepared traditionally either by
releasing the gas from a cylinder through a cham-
ois leather bag and then transferring it to wood or
Bakelite-funneled tubes in which the snow is
hammered hard or by means of a “Sparkle”
machine in which individual cylinders discharge
the gas through a small opening into a collecting
tube [1]. Pusey in 1907 introduced the use of
solidified CO2 whittled to appropriate shape and
held onto a lesion from 2 s to as long as 60 s for
destruction of skin lesions such as hemangiomas,

© Springer-Verlag London 2016 201

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_43
202 H.J. Brody

Fig. 43.2 Dipping of solid CO2 into a 3:1 ratio of acetone

Fig. 43.1 Storage of solid CO2 in ice chest after twice to isopropyl alcohol solution for antiseptic slippage across
weekly delivery and breaking for application to the skin the skin

prior to the development of LN. Dry ice is more

easily obtained in the twenty-first century and
may be found in grocery stores in large cities. It
may be purchased from ice plants, ice cream
manufacturers, dairies, food-packing plants, fish-
ing bait supply houses, and pharmaceutical sup-
ply companies in smaller towns. Solid blocks can
be delivered to offices twice weekly and stored in
standard ice chests or coolers (Fig. 43.1). Five- or
10-lb blocks of ice are broken to hand size for
slushing in acetone, ethyl acetate, or precipitated
sulfur with or without alcohol before application
to the skin in the treatment of acne [2–4].
Fig. 43.3 Moving CO2 across the skin for 6 s with illumi-
Alternatively, the ice can be pulverized using a nation of comedones
mortar to make a slush similar to a paste with the
appropriate slushing agent selected and dabbed
over the skin. Acetone serves to dissolve sebum by the pressure of application. Five to 8 s of mod-
and lowers the temperature of the CO2 by accel- erate pressure per acne area is adequate to freeze
erating the change of CO2 from a solid to a gas comedones (Fig. 43.3). Solid CO2 applied to the
[5]. If the snow is released from a cylinder of gas skin for 15 s produces complete epidermal necro-
in the physician’s office, hand packing to a hard sis with pronounced dermal edema. A mixed
solid form may be difficult and therefore less inflammatory infiltrate is seen without collagen
effective for a solid destruction mode as opposed destruction (Fig. 43.4). Varying pressure is applied
to slush for acne treatment. Ideally, a block of to the skin by the ice block to induce microepider-
solid CO2 is broken to hand size, wrapped in a mal vesiculobullous formation where desired
small hand towel and continually dipped in a 3:1 (Figs. 43.5 and 43.6). Pressure by the operator
solution of acetone and alcohol so that the dry ice determines depth, and this may be noted on a dia-
will move freely over the skin and kill surface gram of the areas being treated in the patient’s
bacteria [6] (Fig. 43.2). record. Mild pressure is 3–5 s, moderate pressure
Either an individual lesion or the entire face is 5–8 s, and hard pressure is 8–15 s (Table 43.1).
may be easily slushed using slow, even strokes; The seconds given are general guidelines, and
varying epidermal depths of cool will be produced the actual time and pressure will vary slightly
43 Solid Carbon Dioxide: Usage in Slush or Block Form as Therapeutic Agent in Dermatology 203

Fig. 43.5 Epidermal vesicular formation, 8 h later

Fig. 43.4 Histology of solid CO2 applied to the skin for

15 s, after 2 days producing epidermal necrosis with pro-
nounced dermal edema, a mixed inflammatory infiltrate
and no collagen destruction. After reepithelialization, Fig. 43.6 Scaling and erythema with resolution of com-
neither collagen nor elastic fibers in the dermis show any edones, 6 days later
architectural changes, confirming epidermal injury only
(Hematoxylin-eosin [H & E] stain) (no elastic stain
shown here) Table 43.1 Solid CO2 administration
CO2 pressure Time (s) Skin reaction
Mild 3–5 Erythema
with patient tolerance and the dermatologist. The Moderate 5–8 Erythema, edema and peeling
skin reaction ranges from mild erythema to vesic- Hard 8–15 Vesiculobullous reaction
ulobullae formation. All areas of the face may be
iced to treat acne and mild photo-pigmentation,
with defect size and patient tolerance being the hard pressure. An electric fan or assistant’s man-
chief limiting factors. The cheeks are less sensi- ual fanning to blow away the acetone vapors can
tive, and the glabella is more sensitive. Insertion facilitate patient breathing and reduce discomfort
of gauze into the mouth between the lips facili- when freezing around the nose, mouth, and gla-
tates hard freezing over the upper lip onto the bella (Fig. 43.7).
vermilion. The crow’s feet and lower periorbital The dry ice is dipped into the solution multi-
area may be frozen hard without difficulty. Care ple times during the treatment to allow easy slip-
should always be taken to apply less pressure page for skin application. This treatment speeds
when freezing over bony prominences where removal of comedones and promotes acne resolu-
post-inflammatory pigmentary changes may be tion. Patients may ask to be “iced” and enjoy the
more likely. Individual scars may be blunted with results of this treatment alone. Less destructive
204
Fig. 43.7 Freezing of upper lip with gauze in mouth to
absorb any dripping and fan on patient to ease breathing
from acetone and alcohol application
than liquid nitrogen, which is over twice as cold
at −186 °C, the margin of safety of solid CO2 is
wide. It may induce transient hyperpigmentation
in darker skinned individuals, but hard pressure
and freezing the skin solid for 12–15 s has not
produced scarring or hypopigmentation in non-
poikilodermatous skin Fitzpatrick I–III type skin
in our experience of over 4000 cases.
Solid CO2 was used in the BioMedic
Micropeel™, a proprietary peel system now
owned by SkinCeuticals™. Shaving of the skin is
followed by the application of 15–30 % glycolic
acid and then by application of selective solid CO2
slush. The now unnamed system is accompanied
by and marketed with an extensive product line
[7]. No clinical or histologic comparisons to other
existing superficial peeling agents are available.
One case of scarring has occurred allegedly from a
Baker’s phenol peel performed 3 days after this
combination was applied to the face, indicating
that the patient had sustained substantial epider-
mal alteration with the initial peel, allowing deeper
penetration with the phenol formula.
Solid CO2 slush is a superlative agent for
facial and non-facial neurotic excoriations or
acne excoriee. A moderate application to excori-
ated areas will serve to keep the patient’s hands
off the lesions long enough to heal and provide
inspiration for the patient not to touch the areas
for a variable length of time (Fig. 43.8). The
result obtained using chemical peeling agents to
excoriated areas is unpredictable in a patient with
a tendency to pick and prematurely remove
H.J. Brody
Fig. 43.8 Focused application of CO2 to treat acne
excoriee for 7 s
exfoliating skin. In our experience, the use of a
physical agent such as solid CO2 is less risky in
this population than chemical wounding agents
and is almost always effective and helpful.
Use of Solid CO2 as a Preliminary
Agent in a Medium Depth
Chemical Peel
Traditionally, the classic peel for a medium depth
peel to correct photodamage in the form of actinic
keratosis, fine wrinkling, hyperpigmentation or
depressed acne scarring was the 50 % trichloro-
acetic acid (TCA) peel, used extensively for
decades as the classic peel for the patient who did
not warrant, tolerate, or desire a “phenol peel.”
Trichloroacetic acid, however, is an agent prone
to produce increased scarring with higher concen-
trations. The need for an intermediate procedure
that would achieve a similar depth but still not
approach the toxicity of the phenol formulas was
the impetus for the development of the procedure
performed initially in 1980 by Brody and Hailey
[8–10]. Insulting the epidermis with a refrigerant
allows a less potent concentration of TCA such as
35 % to penetrate to the depth of a higher-strength
50 % solution. Although the temperature of the ice
block of CO2 is −78.5 °C, the skin temperature is
considerably higher, as demonstrated by clinical
experience and rapid thaw time. LN when used
alone to treat scarring is approximately 100 °C
colder than solid CO2 and can achieve dermal
43 Solid Carbon Dioxide: Usage in Slush or Block Form as Therapeutic Agent in Dermatology
depth destruction and induce melanocyte toxic-
ity, hypopigmentation, and scarring with improper
technique [11]. CO2 alone, however, does not usu-
ally induce scarring or hypopigmentation in lighter
skin types and therefore has a wider margin of
safety when combined with TCA for peeling. Over
4000 combination peels using CO2 followed by
35 % TCA, both applied to the full face, confirm
its effectiveness for photodamage and selected
scars. The combination of two superficial agents
to reach the depth of one single agent to increase
safety is the rationale of all medium-depth peeling.
CO2 plus TCA has the greatest wound depth and
histologic correction of elastotic changes with the
widest papillary dermal Grenz zone after peeling
of any published medium depth peel combination.
Jessner’s solution followed by TCA and glycolic
acid followed by TCA are slightly less deep in pen-
etration [12].
When freezing an individual depressed scar, it
is permissible to freeze the rims for 10–15 s to
afford greatest TCA penetration so that the scar
edges will be clinically blunted. Immediately after
freezing a deep scar, the skin may be wiped dry of
flammable acetone, and the rim may be electrodes-
sicated with monopolar current for further efface-
ment. This is painless because of attendant CO2
cryo-anesthesia. TCA can be applied after CO2 to
treat individual scar rims, solitary rhytides or kera-
toses, or areas at the vermilion border, for exam-
ple. If freezing hard is absolutely necessary on the
forehead, a nerve block may be helpful. Facial
freezing with CO2 makes immediate application of
TCA more tolerable. The burning sensation that
accompanies the application of the TCA is less-
ened by the CO2 slush applied immediately before
and can be minimized further by the immediate
application of an ice pack or cold gel pack (3M)
after adequate frosting has occurred. After 5 min,
a soothing emollient can be used.
Complications of Solid CO2: Cold
Sensitivity or Cold Urticaria
When using solid CO2 (dry ice) to freeze the skin
either alone or in combination with TCA in
medium-depth peeling, transient swelling or urti-
caria can be produced in distant areas [13]. We
205
have seen this in only one patient in a series of
over 4000 CO2 + TCA peel patients. Because
CO2 has minimum temperature of only −78.5 °C
and because it is rarely concentrated in any one
area for more than 20 s, it is limited in its ability
to produce cold reactions. The freons, LN, and
prolonged cold immersion with ice water are
more common precipitating factors [14]. The
application of a 10-s LN spray to the entire face
for acne scar treatment has resulted in full-
thickness necrosis and scarring as a result of the
presence of occult cryofibrinogenemia [15].
Increased serum levels of cryofibrinogens are
found in about 4 % of apparently normal indi-
viduals and may signal collagen-vascular dis-
ease, malignancy, pregnancy, oral contraceptive
use, excessive smoking, or thromboembolic phe-
nomena. Cryofibrinogenemia may be a transitory
condition. This necrosis has not been reported
with solid CO2. Transient stinging and burning
sensations may occur during any freeze phase,
and treatment to the forehead, especially if pro-
longed, may produce a headache that may persist
for several hours. This responds to acetamino-
phen or ibuprofen.
There is limited evidence published in peer-
reviewed medical literature that addresses the
efficacy of comedo removal for the treatment of
acne, despite its long-standing clinical use.
However, it is the opinion of the Guidelines of
Care Work Group of the American Academy of
Dermatology that comedo removal may be help-
ful to the management of comedones resistant to
other therapies [16]. While it cannot affect the
clinical causes of the disease, it can improve the
patient’s appearance, which may positively
impact compliance with the treatment program.
References
1. Rook A, Wilkinson DS, Ebling FJG. Textbook of
dermatology. Oxford: Blackwell Scientific; 1972.
p. 2099.
2. Dobes WL, Keil H. Treatment of acne vulgaris by
cryotherapy (slush method). Arch Dermatol Syph.
1940;42:547.
3. Zugerman I. A formula for cryotherapy for acne and
postacne scarring. Arch Dermatol Syph. 1946;54:209.
4. Dobes WL. A simplified method of cryotherapy for
acne vulgaris. South Med J. 1951;44:546.
206
5. Moseley JC, Katz SI. Acne vulgaris: treatment with
carbon dioxide slush. Cutis. 1972;10:429–31.
6. Wolf R, Landau M, Berger SA, et al. Transfer of bacte-
ria associated with cryotherapy. Cutis. 1993;51:276–7.
7. Biomedic distributor. SkinCeuticals. http://www.skin-
ceuticals.com.
8. Brody HJ. Medium-depth chemical peeling of the
skin: a variation of superficial chemosurgery. Adv
Dermatol. 1988;3:205–20.
9. Brody HJ. Chemical peeling. 3rd ed. Atlanta, Georgia:
Emory University Publications; 2008. http://www.ama-
zon.com.
10. Brody HJ, Hailey CW. Medium depth chemical peel-
ing of the skin: a variation of superficial chemosur-
gery. J Dermatol Surg Oncol. 1986;12:1268–75.
H.J. Brody
11. Graham GF. Cryotherapy in the treatment of acne. In:
Epstein E, Epstein Jr E, editors. Skin surgery. 4th ed.
Springfield: Charles C Thomas; 1977. p. 685–97.
12. Brody HJ. Variations and comparisons in medium
depth chemical peeling. J Dermatol Surg Oncol.
1989;15:953–63.
13. Brody HJ. Complications of chemical peeling.
J Dermatol Surg Oncol. 1989;15:1010–9.
14. Dowd PM. Cold related disorders. Prog Dermatol.
1987;21:1–7.
15. Stewart RH, Graham GF. A complication of cryosur-
gery in a patient with cryofibrinogenemia. J Dermatol
Surg Oncol. 1978;4:743–4.
16. Strauss JS. Guidelines of care for acne vulgaris man-
agement. J Am Acad Dermatol. 2007;56:651–3.
Part VII
Results
 Expected Events
44
Christopher M. Scott, Gloria F. Graham,
and Ronald R. Lubritz

Abstract
Cryosurgery provides numerous advantages for patients in need of skin
surgery including ease of delivery, good cure rate, low cost and patient
tolerance. Selection of lesion by sight is an important decision. For
instance, a hypopigmented site on the face in an area of rosacea may be
even more unsightly than a hypopigmented spot in pigmented skin. Careful
consideration of the entire area of skin can be significant.

Keywords
Poor candidate • Complex medical patients • Anticoagulants • MOHs
surgery • Excisional surgery • Raynaud’s syndrome • Cryoglobulinemia •
Cryofibrinogenemia

Introduction Adequate lesion, site, and patient selection must

occur in advance. Poor decision-making in
Cryosurgery offers numerous advantages in the advance is what leads to complications. Careful
surgical skin patient, including ease of delivery, consideration of the whole patient is often
good cure rates, low cost, and patient tolerance. rewarded with clinical and subjective success.

C.M. Scott, MD Advantages of Cryosurgery

Department of Dermatology, University of Virginia,
Charlottesville, VA, USA
G.F. Graham, MD (*)
Department of Dermatology, Wake Forest University
School of Medicine, Winston Salem, NC, USA
e-mail: ggfgraham@aol.com
R.R. Lubritz, MD, FACP
Department of Dermatology, Tulane University
School of Medicine, Hattiesburg Clinic,
Hattiesburg, MS, USA
Benefits of cryosurgery include cost effective-
ness, good cosmetic results, and high cure rates.
Tumor selection is important. Cryosurgery is best
suited for tumors involving infected sites, tumors
of the chest and back, and multiple or superficial
tumors (Fig. 44.1a–d). As long as the tumor
depth is 4–5 mm, cryosurgery can be quite accu-
rate (Fig. 44.2a, b). Freezing tumors overlying

© Springer-Verlag London 2016 209

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_44
210 C.M. Scott et al.

a d

Fig. 44.1 (a) Well demarcated typical basal cell carci- the margin of the tumor at 1 min. (d) Cryosite is well
noma of the breast. (b) Cone in place around tumor during healed several months later
spray freezing. Freeze time 1 min. (c) Halo thaw time into
44 Expected Events
a b
Fig. 44.2 (a) Large basal cell carcinoma was thought to
be psoriasis plaque for years. On biopsy proven to be a
basal cell carcinoma and was treated by three stages of
cartilage may be preferable to excision since car-
tilage is tolerant of freezing (Fig. 44.3a, b). Also,
if demonstrating well-defined margins, select
tumors of the tip of the nose, eyelid or ear may be
treated by cryosurgery (Fig. 44.4a, b). There is
preservation of the lacrimal duct, even with freez-
ing to −70 °C [1–4].
Patient selection is extremely important in any
surgical procedure. Quite often, patients who are
poor candidates for another surgical modality
will be well-suited for cryosurgery. Complex
medical patients, such as those with congestive
heart failure or kidney disease, may be at poor
risk for excisional procedures. Even those who
have been heavy smokers heal well following
freezing. Patients receiving anticoagulation ther-
apy or with a history of poor wound healing after
standard cutaneous surgery do not have increased
risk of morbidity with cryosurgery. Cryosurgery
has a role in palliation for inoperable lesions. If
poor compliance or loss to follow-up is antici-
pated, cryosurgery is advantageous since mini-
mal post-operative care is required. Follow-up at
211
cryosurgery over 3 months. (b) Final result shows one
small residual area remaining which was the last area
treated
3 and 6 month intervals is recommended. Elderly
patients usually tolerate cryosurgery without dif-
ficulty [5].
Contraindications
Cryosurgery is not the preferred treatment modal-
ity if the tumor is deeply invasive or fixed to
underlying structures. It is strongly recom-
mended that these cases be handled by Mohs
micrographic surgery or wide excisional surgery.
Mohs surgery is ideal for histologically aggres-
sive tumors, or those in an area of high-risk.
Recurrent carcinoma, if deep to the central area
of the original tumor, is often best suited for
Mohs technique. However, marginal recurrences
may be treated with cryosurgery.
Patients with tumors such as large morphea-
form basal cell carcinoma, metatypical basal cell
carcinoma, and de novo squamous cell carcinoma
are not ideal cryosurgical candidates.
Morpheaform basal cell carcinoma has a fibrous
212 C.M. Scott et al.

a b

Fig. 44.3 (a, b) A cutaneous horn treated by liquid base. (c) Cryosurgical procedure carried out, 30 seconds
nitrogen spray is shown with a 5 mm margin since these freeze time and 5 mm halo around the cutaneous horn
lesions may have a small squamous cell carcinoma at the

a b

Fig. 44.4 (a) Small basal cell carcinoma. (b) Treatment with cryosurgery

component that limits adequate curettage. Each Indefinite margins are considered a contrain-
of these tumors responds to freezing when dication to cryosurgery (Fig. 44.5a–d). However,
smaller than 2 cm, but Mohs surgery is the pre- some tumor margins may be delineated by care-
ferred technique for the larger tumors. ful curettage.
44 Expected Events
a b
c d
Fig. 44.5 (a) Fitzpatrick type 1 skin, patient has had mul-
tiple basal cell carcinomas treated by cryosurgery since
1970. See hypopigmented spot on his very erythematous
skin. (b) Patient came last year with a recurrent tumor fol-
If large areas are to be treated, cryosurgery
should not be used in patients with severe cold-
intolerance, such as Raynaud’s syndrome, cryo-
globulinemia, and cryofibrinogenemia. Excision
is the preferred treatment of melanoma. But,
freezing is very effective in lentigo maligna,
especially for larger lesions in elderly patients.
Tumor site also determines the utility versus
potential harm of cryosurgery. Since a common
side-effect of cryosurgery is alopecia, tumors on
the scalp may be best treated by excision.
Extreme care should be taken when freezing
tumors on the eyelid, but this site may be treated
with cryosurgery. There are numerous published
studies of the effectiveness of freezing eyelid and
periocular tumors, especially with well-defined
margins [1, 4].
213
lowing excision on the chin and was referred for Mohs
surgery. (c) Following the procedure. (d) During healing
(Courtesy of Richard Lewis, MD, Mohs surgeon, Eastern
Dermatology, Greenville, NC)
References
1. Zacarian SA. Cryogenics: the cryolesion and the
pathogenesis of cryonecrosis. In: Zacarian SA, editor.
Cryosurgery for skin cancer and cutaneous disorders.
St. Louis: CV Mosby; 1985. p. 2–3.
2. Torre D. Cradle of cryosurgery. NY State J Med.
1967;67:465–7.
3. Graham GF. Cryosurgery for benign, premalignant,
and malignant lesions. In: Wheeland RG, editor.
Cutaneous surgery. Philadelphia: WB Saunders;
1994. p. 835–67.
4. Kuflik EG, et al. Millenium paper: history of dermato-
logic cryosurgery. Dermatol Surg. 2000;26:715–22.
5. Lubritz RR. Cryosurgical approach to benign and pre-
cancerous tumors of the skin. In: Zacarian SA, editor.
Cryosurgery for skin cancer and cutaneous disorders.
St. Louis: CV Mosby; 1985. p. 44–8.
 Evolution of the Cryo-lesion
45
Christopher M. Scott, Gloria F. Graham,
and Ronald R. Lubritz

Abstract
Expected results after freezing are erythema, urtication, and edema which
may last for several days. If freezing is superficial, vesicles or bullae
developed. Bullae may become hemorrhagic. When treating malignances,
a more gelatinous appearance may result. The stroma is more resistant to
freezing than the cellular elements. Healing for most lesions takes place
within 2 weeks for benign or premalignant lesions to 4–6 weeks for malig-
nant lesions. Systemic steroids may be used to prevent swelling around the
periorbital area.
Hemorrhaging should be controlled by aluminum chloride, Monsel’s
solution or electrodessication. Anti-inflammatory and anti-coagulants
have rarely caused prolonged bleeding. Secondary infection is rare but
responds to topical or systemic antibiotics.

Keywords
Cryosurgery • Hemorrhagic bullae • Edema • Urtication • Erythema

Introduction

C.M. Scott, MD The cryosurgical site demonstrates a fairly pre-

Department of Dermatology, University of Virginia,
Charlottesville, VA, USA
G.F. Graham, MD (*)
Department of Dermatology, Wake Forest University
School of Medicine, Winston Salem, NC, USA
e-mail: ggfgraham@aol.com
R.R. Lubritz, MD, FACP
Department of Dermatology, Tulane University
School of Medicine, Hattiesburg Clinic,
Hattiesburg, MS, USA
dictable course. Recognizing the normal physio-
logical response to extreme cold will help the
clinician recognize whether a more significant
adverse event is occurring [1–3]. While cryosur-
gery is considered quite safe, several well-defined
complications have been linked to cutaneous
freezing [4]. In many instances, complications
are extensions or accentuations of normal physi-
ologic events. Knowledge of these serves not

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_45
216
only to assure that cryosurgical procedures
proceed correctly, but is also necessary to discern
complications from normal expectations [5–7].
Immediate Clinical Effects
After cryosurgery, it is common to experience
pain and edema acutely. Within a few minutes,
erythema and urtication are observed, followed
by edema. Erythema and urtication may last a
few days. If freezing is superficial, vesicles or
bullae develop. Bullae may be serous or hemor-
rhagic. Hemorrhagic bullae may occur with
deeper freezes; however occurrence may be
unpredictable [2, 8] (Figs. 45.1a, b and 45.2a–c).
Even deeper freezing, as used in treatment of
malignancies, may not elicit bullae formation,
but present a more gelatinous appearance [2].
Stromal elements are more resistant to freezing
than cellular elements. Edema is observed after
almost every cryosurgery [3–5]. The patient’s
normal response to cold temperatures, the dura-
tion of cryogen application, the cryosurgical
modality, and the location of the lesion may help
predict the severity of resultant edema. Swelling
may persist for 1–2 weeks. Edema is more pro-
nounced after freezing loose skin, such as perior-
bital tumors, the forehead, the mandibular area,
and around the ears. Periorbital edema may be
a b
Fig. 45.1 (a) Actinic keratoses treated by cryosurgery, hemorrhagic bullae that appeared to be also secondarily infected
and was treated with antibiotics. (b) Shown well healed a month later
C.M. Scott et al.
prolonged, up to 5 days, but systemic steroids
tend to suppress this edema [9]. However, delayed
wound healing may result from topical steroid
use (Fig. 45.3). Cold water compresses are suffi-
cient for symptomatic relief.
Hemorrhage may occur if a biopsy is per-
formed in conjunction with freezing. This was
also reported when freezing a wart in a patient
with hemophilia [10] (See Fig. 48.2). Ulcerated
or edematous tumors also may bleed after cryo-
gen delivery. Therefore, adequate hemostasis
prior to cryosurgery is important. Aluminum
chloride, Monsel’s solution or electro surgery
provides improved hemostasis after debulking
malignancies or biopsy acquisition. Anti-
inflammatory and anti-coagulant drugs such as
those which inhibit cyclooxygenase increase the
likelihood of acute hemorrhage, but rarely neces-
sitate drug discontinuation. If incidentally frozen,
large blood vessels have rarely been reported to
experience injury.
Over the course of 2 weeks to 3 months, the
cryosurgical site continues to evolve. Healing
occurs by secondary intention. Deeper freezes,
as seen when using a probe, may take more
time to heal. Vascular tissues, such as the face,
tend to heal quite quickly. Relatively poorly
vascularized tissues, such as lower legs
(Fig. 45.4) with marked edema, can take several
months to heal.
45 Evolution of the Cryo-lesion 217

a b

Fig. 45.2 (a) Patient with multiple actinic keratoses Bullous reaction 4 days after treatment of multiple actinic
occurring in plaques of psoriasis treated for months with keratoses on dorsum of hand, 3 cm in size. (c) Two days
topical steroid without regression. Cryosurgery 20 s later, eschars are beginning to form where the bulla had
applied to the actinic keratoses throughout the lesion. (b) been

Fig. 45.3 Ulcerations developed when patient mistak-

enly used a potent steroid cream on bullous lesions fol-
lowing treatment of actinic keratoses

Fig. 45.4 Post cryosurgery squamous cell carcinoma,

1 month prior, leaving an ulcerated site that required
6 weeks to heal. At this stage, an ointment may be used to
soften eschar. All of her many squamous cell carcinomas
treated by freezing have healed well within 4–6 weeks
218
In general, the overlying eschar forms a sterile
biologic dressing [11]. This eschar should be left
intact to allow secondary intention healing below.
Conclusion
The expected course for the typical cryosurgi-
cal site includes erythema, pain, edema, bulla,
and eschar formation. The appearance is often
quite typical, but one’s clinical experience is
key to determining normal versus pathologic
changes [12].
References
1. White AC. Liquid air in medicine and surgery. Med
Rec. 1899;56:109–12.
2. Torre D, Lubritz RR, Kuflik EG. Practical cutaneous
cryosurgery. Norwalk: Appleton and Lange; 1988.
p. 1–41.
3. Scott CM, Lubritz RR, Graham GF. Complications of
cryosurgery. In: Nouri K, editor. Complications of der-
matologic surgery. New York: Mosby; 2008. p. 119–36.
C.M. Scott et al.
4. Kuflik EG, Gage AA, Lubritz RR, Graham
GF. Millennium paper: history of dermatologic cryo-
surgery. Dermatol Surg. 2000;26:715–22.
5. Baust JG, Gage AA. The molecular basis of cryosur-
gery. BJU Int. 2005;95:1187.
6. Hanai A, Yang WL, Ravikumar TS. Induction of
apoptosis in human colon carcinoma cells HT29 by
sublethalcryoinjury: medication by cytochrome C
release. Int J Cancer. 2001;93:26–33.
7. Grimmett R. Liquid nitrogen therapy: histologic
observations. Arch Dermatol. 1961;83:563–7.
8. Zacharian SA. Cryosurgical advances in dermatology
and tumors of the head and neck. Springfield: Charles
C Thomas; 1977. p. 20–5. 1.
9. Kuflik EG, Webb W. Effects of systemic corticoste-
roids on post-surgical edema and other manifestations
of the inflammatory response. J Dermatol Surg Oncol.
1985;11:464.
10. Hancox JG, Graham GF, Yosipovitch G. Hemorrhagic
bullae after cryosurgery in a patient with hemophilia
A. Dermatol Surg. 2003;29:1084–6. 12.
11. Graham GF. Cryosurgery for benign, premalignant,
and malignant lesions. In: Wheeland RG, editor.
Cutaneous surgery. Philadelphia: WB Saunders;
1994. p. 835–67.
12. Elton RF. Complications of cutaneous surgery. J Am
Acad Dermatol. 1983;8:513.
 Recovery
46
Christopher M. Scott, Gloria F. Graham,
and Ronald R. Lubritz

Abstract
Little intervention is required for the usual cryosurgical patient. The origi-
nal pain and edema give way to a bullas reaction. After 1–2 weeks, an
eschar forms. When the eschar peels away, cure still takes longer to
complete.
Pain or burning may follow freezing. When treating malignancies, local
anesthesia is advised; especially if a debulking of the tumor preceeds treat-
ment. The mucous membranes, forehead, temple, distal fingers and nose
are more susceptible to pain. Migraine type headaches occur occasionally
after treating lesions on the forehead or temple. Syncope, while rare, does
occur. The patient may be put in the supine or Trendelenburg position for
recovery.
While dressings are not generally required after freezing, an absorbent
pad that can stick to clothing may be used to prevent drainage on clothing.
Pressure of a bullae may be relieved with a sterile needle or scalpel blade.

Keywords
Cryosurgery • Syncope • Migraines • Vasovagal • Intervention

C.M. Scott, MD Introduction

Department of Dermatology, University of Virginia,
Charlottesville, VA, USA
Pain and edema tend to give way to a modest bul-
G.F. Graham, MD (*) lous reaction. Eventually an eschar forms, and
Department of Dermatology, Wake Forest University
School of Medicine, Winston Salem, NC, USA
further secondary intention healing ensues. When
e-mail: ggfgraham@aol.com the eschar peels away, cure may still take time to
R.R. Lubritz, MD, FACP
present clinically [1].
Department of Dermatology, Tulane University
School of Medicine, Hattiesburg Clinic,
Hattiesburg, MS, USA

© Springer-Verlag London 2016 219

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_46
220
Methodology
While freezing benign and pre-cancerous lesions
is relatively painless, malignancies require deeper
freezing, resulting in more intense discomfort. A
burning sensation may be experienced during
treatment, exaggerated during the thaw period.
Immediate intense pain usually remits after the
first 20–30 min. Since treatment of cutaneous
malignancies may be augmented by initially deb-
ulking the tumor, local anesthetic is often used
prior to incision and cryosurgery. Some physi-
cians pre-treat these patients with acetamino-
phen, continuing analgesic use up to 24–48 h
post-operatively. Be aware that mucus mem-
branes, the forehead, temporal areas, distal fin-
gers, and distal nose are more susceptible to pain.
A migraine-type headache may result from freez-
ing preauricular tumors, as well as lesions involv-
ing the forehead or temples [1–3].
Syncope may occur during or immediately after
cryosurgery [1]. Special consideration should be
given to elderly patients or when freezing is espe-
cially uncomfortable. Patients should remain
seated or supine post-operatively. Cryosurgical
syncope is likely a vasovagal response. Deeper
freezing may cause more intense pain, increasing
the probability of a vasovagal reaction. Local
anesthesia is more often used in these instances.
Place these patients in a supine or Trendelenburg
position for recovery [1, 3].
The cryosurgical site may be tender for sev-
eral days. Patients may desire to place a dressing
over the site for comfort, but this is not required
for normal healing. Soap and water cleansing of
the site is all that is usually required [2]. An
absorbent pad can be attached to clothing and
serves as an effective dressing without requiring
tape around the site (Fig. 46.1).
If a patient experiences acute pain with a tense
bulla, the pressure may be relieved with a sterile
needle or scalpel blade. It is important to note
that this manipulation disrupts the sterile blister
roof, possibly introducing pathogens. While not
C.M. Scott et al.
Fig. 46.1 Patient with multiple basal cell carcinomas
developing years after burn at age 5 and radiation for the
very thick scars at age 8. Eschars may be covered with
absorbent pads attached to clothing so that tape is avoided.
Healing was excellent considering the thick scarring she
had in the site
often required, the site may be covered with anti-
biotic ointment and a dressing to prevent contam-
ination. Graham prefers avoiding this type of
dressing to soap and water cleansing [2].
Conclusion
Soap and water cleansing of the treatment site
is frequently all that is required during the
post-operative period. Some cryosurgeons
prefer topical ointments, while others do not.
If dressing is required, use absorbent pad that
can be attached to clothing to avoid the use of
tape [2].
References
1. Elton RF. Complications of cutaneous surgery. J Am
Acad Dermatol. 1983;8:513.
2. Graham GF. Cryosurgery for benign, premalignant,
and malignant lesions. In: Wheeland RG, editor.
Cutaneous surgery. Philadelphia: WB Saunders;
1994. p. 835–67.
3. Dawber RPR. Cryosurgery: complications and con-
traindications. In: Breitbart EW, Dachow-Siwiec E,
editors. Clinics in dermatology: advances in cryosur-
gery. New York: Elsevier; 1990. p. 108–14.
 Adverse Events
47
Christopher M. Scott, Ronald R. Lubritz,
and Gloria F. Graham

Abstract
Cryosurgery for the treatment of proven and documented dermatologic
conditions has known possible complications or adverse events. Certain
patient considerations should be addressed when considering this tech-
nique for treatment. Proper patient selection, communication of potential
risks given site location, noted contraindications and their possible impact
on the results, and clinician’s experience in understanding proper treat-
ment duration are equally important matters to assure positive results.

Keywords
Alopecia • Erythematous • Telangiectasia • Cryoglobulinemia • Myeloma
• Lymphoma

Introduction

Site-specific complications and patient expecta-

tions must be addressed with each individual
patient. Cryosurgery with probes and sprays can
deeply penetrate into human tissues, and compli-
cations may result. For a macular actinic kerato-
C.M. Scott, MD sis 7–10 s is required. For a basal cell carcinoma
Department of Dermatology, University of Virginia, of the superficial type of 5 mm in diameter,
Charlottesville, VA, USA 30–45 s is sufficient. For a 3–4 mm in depth basal
R.R. Lubritz, MD, FACP cell carcinoma, 60 s with a double freeze thaw
Department of Dermatology, Tulane University cycle may be required A halo of 5 mm around the
School of Medicine, Hattiesburg Clinic, tumor has been shown to result in higher cure
Hattiesburg, MS, USA
rates than a 2 mm halo which is used for most
G.F. Graham, MD (*) pre-cancerous lesions [1]. The minimal degree of
Department of Dermatology, Wake Forest University
School of Medicine, Winston Salem, NC, USA cryosurgery to accomplish the therapeutic inter-
e-mail: ggfgraham@aol.com vention should be the goal.

© Springer-Verlag London 2016 221

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_47
222
Pre-treatment Considerations
To lessen the likelihood of adverse events related
to cryosurgery, patient selection for this tech-
nique as well as site consideration are critical.
There are known collateral effects of this type of
treatment including hypopigmentation, alopecia,
transient numbness and potential changes to the
complexion. These should be discussed with the
patient.
When treating darkly pigmented skin,
hypopigmentation has a higher possibility than
when treating lightly pigmented skin. Where
freckles are prevalent, very erythematous skin
and/or telangiectasia on the face, hypopigmented
skin is a possible result and may lead to patient
dissatisfaction (Fig. 47.1). An increased risk of
scarring (See Fig. 32.4) and/or pigment loss
(Fig. 47.2) may result from deeper freezing in
treatment of malignancies. Patient education is
important.
Fig. 47.1 Very fair skinned golfer with multiple skin
cancers treated by cryosurgery since 1970. Some have
resulted in hypopigmentation in his very erythematous
skin of the face
C.M. Scott et al.
Fig. 47.2 Patient with multiple superficial basal cell car-
cinomas on the back. Because of her Parkinson’s disease,
other treatments were more difficult and many of her
tumors were treated by cryosurgery and/or 5-fluorouracil
for the earliest tumors
Cryosurgical technique is of equal importance
to patient and lesion selection. As Wheeland has
cautioned, there are pitfalls to treating all actinic
keratoses as squamous cell carcinomas [2].
Tables provide only an estimated duration of
freezing that may be required for treatment, the
art of effective cryosurgery with minimal adverse
events is learned with experience (See Table 37.1).
Some side effects are unavoidable, even for the
most experienced cryosurgeon.
There are relatively few contraindications to
cryosurgery. The decision to treat neoplasm of
uncertain behavior may need to be deferred until
after the biopsy results are received. Benign mel-
ancytic nevi can respond favorably to cryosur-
gery [3]. If the biopsy is performed after
treatment, the histopathology of the lesion may
be harder to interpret. Where contraindications
are documented, patient follow up is critical to
timely patient healing and satisfaction. The most
important contraindication is prior adverse reac-
tion to cryosurgery, such as anaphylaxis or severe
cold articaria [4]. When treating patients with
cold urticaria, caution is recommended, espe-
cially when treating a large tumor on the neck.
Severe sequellae, such as scar contracture, may
appear in larger periorbital or perioral tumors as
these are predisposed location for scar contrac-
ture [5, 6].
Relative contraindications relevant to cryosur-
gery include autoimmune disorders including
47 Adverse Events
pyoderma gangrenosum, myeloma, Raynaud’s
disease, cryoglobulinemia, intake of immunosup-
pressive drugs, and areas of vascular compro-
mise. A patient with hemophilia A suffered
hemorrhagic bullae following the freezing of ver-
ruca vulgaris (See Fig. 48.3). Care should be
taken when treating patients with bleeding disor-
ders [7].
Summary
Knowledge of the art of cryosurgery, the poten-
tial for and understanding ways to avoid certain
adverse events, managing patient expectations,
and awareness of patient’s medical history are all
important elements when considering cryosur-
gery. A well-informed clinician will achieve pos-
itive results more often than not if all of these
areas are given careful consideration.
223
References
1. Graham GF. Cryosurgery for benign, premalignant,
and malignant lesions. In: Wheeland RG, editor.
Cutaneous surgery. Philadelphia: WB Saunders;
1994. p. 835–67.
2. Wheeland RG. The pitfalls of treating all actinic kera-
toses as squamous cell carcinomas. Semin Cutan Med
Surg. 2005;24:152–4.
3. Elton RF. Complications of cutaneous cryosurgery.
J Am Acad Dermatol. 1983;8:513.
4. Scott CM, Lubritz RR, Graham GF. Complications of
cryosurgery. In: Nouri K, editor. Complications of der-
matologic surgery. New York: Mosby; 2008. p. 119–36.
5. Smith V, Walton S. Treatment of facial basal cell car-
cinoma: a review. J Skin Cancer. 2011;2011, 380371.
7 pages.
6. Thissen MRTM, Nieman FHM, Ideler AHLB,
Berretty PJM, Neumann HAM. Cosmetic results of
cryosurgery versus surgical excision for primary
uncomplicated basal cell carcinomas of the head and
neck. Dermatol Surg. 2000;26(8):759–64.
7. Hancox JG, Graham GF, Yosipovitch G. Hemorrhagic
bullae after cryosurgery in a patient with hemophilia
A. Dermatol Surg. 2003;29:1084–6.
 Acute Complications
48
Christopher M. Scott, Gloria F. Graham,
and Ronald R. Lubritz

Abstract
Following cryosurgery, acute complications may be accentuated physio-
logic events. One must know how to handle these exaggerated occur-
rences. Pain, edema, and bullae are expected and hemorrhage, while it
may occur, is not an expected event. There exists a continuum between
expected tissue damage and more exaggerated responses. Edema, espe-
cially around the eye and neck, may be more than is anticipated due to
laxness of the tissue. Depending on the lesion size, large bullae may be
noted. Secondary infection, while rare may occur. Nitrogen gas insuffla-
tion around biopsy site and syncope are occasionally observed.

Keywords
Hemorrhagic bullae • Cryosurgery • Paresthesia • Edema • Hemorrhage •
Nitrogen gas insufflation • Syncope • Pyogenic granuloma

Introduction

Awareness of the normal expected events associ-

ated with cryosurgery is important. The expected
events may surface as complications if the patient
C.M. Scott, MD has not been informed of the expected changes,
Department of Dermatology, University of Virginia, but are often in fact normal physiologic events.
Charlottesville, VA, USA Knowledge of these anticipated outcomes is nec-
G.F. Graham, MD (*) essary to distinguish between actual complica-
Department of Dermatology, Wake Forest University tions that require intervention and normal
School of Medicine, Winston Salem, NC, USA
outcomes that simply require time to heal.
e-mail: ggfgraham@aol.com
Immediately following cryosurgery, pain and
R.R. Lubritz, MD, FACP
edema are expected. Deeper freezing may cause
Department of Dermatology, Tulane University
School of Medicine, Hattiesburg Clinic, hemorrhaging. Freezing tissue on the face and
Hattiesburg, MS, USA finger sometimes results in syncope or, on the

© Springer-Verlag London 2016 225

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_48
226
arms and hands, nitrogen gas insufflation. There
exists a continuum between expected and exces-
sive reactions.
Delayed reactions may occur within hours and
up to weeks post freezing. Bullae are expected
but infection and delayed bleeding are uncom-
mon complications, and systemic reactions and
pyogenic granuloma are very rare.
Immediate Clinical Effect
Tissue exposure to a cryogen reacts with ery-
thema and urtication within a few minutes, with
edema following. Within 12–36 h, edema peaks
followed by occasional hemorrhaging. For
superficial freezing, vesicles or bullae develop.
In the treatment of malignancies, freezing is
deeper and bullae may not be seen but may
appear as a more gelatinous reaction (Fig. 48.1a).
After a few additional days of healing, depend-
ing on the depth of the freeze, eschar may occur
and can last several weeks or longer (Fig. 48.1b).
Regrowth of the epidermis usually starts within
24–48 h, as cryosurgery destroys certain tissues
with cellular elements more than stromal tissue.
The difference in temperature tolerance allows
for effective destruction of tumors overlying
bone and cartilage. If large blood vessels are fro-
zen, they usually do not rupture. Injury from
cold allows for nerve regeneration within
3–6 months, as with the selective destruction
a b
Fig. 48.1 (a) A gelatinous type reaction 5 days post freezing of a squamous cell carcinoma on the dorsum of the hand.
(b) Eschar formation 9 days post freezing
C.M. Scott et al.
associated with cryosurgery. Rarely, immediate
and prolonged paresthesia has been observed.
Pain
Freezing has some anesthetic effect; pain is usu-
ally limited in most cryosurgical procedures.
During the freezing process, the patient may
experience a burning sensation. This sensation
may elevate during the thaw cycle, especially
observed when treating malignancies. The deeper
the freeze, the greater the pain. Freezing viral
warts for 10 s after five treatments has resulted in
a higher cure rate versus the traditional end-point
of a halo of ice. The trade-off results, as expected,
in significantly more pain [1]. Once the lesion is
completely thawed, discomfort may be mild to
moderate for a short period of time but reduces
after the first few minutes. Certain patients with
lower pain thresholds may have local anesthetic.
Also note that a migraine-type headache some-
times manifests when working around the fore-
head, temples, and in front of the ear. This headache
may last for several hours after the procedure.
Edema
Urtication occurs within minutes following cryosur-
gery. Edema or swelling also occurs immediately to
some degree. The severity depends on the extent
48 Acute Complications 227

a b

Fig. 48.2 (a) Edema post- cryosurgery. (b) Edema has subsided and eschar has formed at about 1 week (Pictures
courtesy of William Abramovitz MD)

and intensity of freezing, the location of the proce-

dure, and the lesion response to cold. Periorbital and
mandibular areas, around the ears, and in areas
where loose skin is apparent may present exagger-
ated edema. Periorbital edema often lasts for
3–5 days, and occasionally longer (Fig. 48.2a, b).

Hemorrhage

Acute hemorrhaging is uncommon except when

a biopsy is conducted in concert with the cryosur-
gery. Ulcerated lesions may bleed after freezing,
though minimally. If these conditions exist, the
cryosurgeon should obtain hemostasis prior to
initiating the procedure. While very rare, a deeper
hemorrhage caused by rupturing blood vessels
has been observed. After minimal cryosurgery
for verruca vulgaris in a patient with hemophilia
A, a hemorrhagic bullae developed, causing com-
plication [2, 3] (Fig. 48.3).
Fig. 48.3 Hemorrhagic bullae secondary after warts
freezing. Requires Factor VIII concentrate if drainage is
needed (Reprinted from Graham and Barham [3]. With
permission from Elsevier)
opening for the nitrogen gas. While uncommon,
nitrogen gas insufflation surfaces with immediate
swelling around the site, greatly distending the tis-
sue. This is most common in the periorbital area
and the dorsum of the hand in elderly patients
where there is loose skin.

Nitrogen Gas Insufflation

When using the open spray method, nitrogen gas
insufflation may occur. A fissure or fistula may
exist between the surface and the underlying tissue.
This leaves a natural or traumatic (i.e., biopsy site)
Syncope
When treating the elderly or in areas where
increased pain is anticipated, syncope has been
observed during or immediately following
228 C.M. Scott et al.

cryosurgery. The cause of syncope in cryosurgi-

cal treatment is unknown. In reality, this event
may be a mild form of vasovagal response, as the
patient sometimes becomes nauseated, slightly
dizzy and develops a cold sweat.

Bullae Formation

Superficial freezing frequently results in the for-

mation of bullae, particularly when treating
benign lesions. This formation is due to the sepa-
ration of the dermo-epidermal junction. This
reaction is most common on loose skin areas
such as the dorsum of the hands and arms. A ves-
icobullous reaction is less likely with deeper Fig. 48.4 Pyogenic granuloma after cryosurgery
cryosurgery (See Figs. 48.2 and 48.3).

Infection

Infection is not common after surgery; however, Systemic Reactions

it can develop in slow healing lesions or under-
neath those with a thick crust (See Fig. 48.1a).
Bleeding
Bleeding can be observed as a tumor becomes
necrotic; however, it is an uncommon occur-
rence. When the cellular elements of a treated
tumor are destroyed and the stromal elements
remain, a small blood vessel may be invaded.
Once this small blood vessel separates from the
tumor and damaged tissue, delayed bleeding may
occur.
Pyogenic Granuloma
Several weeks after treatment, a benign vascular
tumor can develop at the treated site. Pyogenic
granulomata has been observed when combining
cryoablation and salicylic acid treatment of ver-
ruca vulgaris [4] and with cryosurgery alone [5].
This complication has also been documented
following cryosurgery of a venous lake [6]
(Fig. 48.4).
If a febrile reaction develops after cryosurgery, it
is most often within a few hours and subsides
within 24–36 h. This reaction is similar to a flu-
like episode. Patients who have had treatment for
large or multiple lesions at one sitting may pro-
duce this reaction.
Summary
Acute complications are many times extensions
of physiologic events. Experience gained by
freezing multiple type lesions in various loca-
tions and in younger, middle-aged and older
patients helps to gain the experience that
cryosurgeons need to inform patients of the
expected events that may occur.
Pain and edema followed at times by hemor-
rhage, occasionally by nitrogen gas insufflations,
and rarely syncope may be events that are
expected. Bullae, infection and delayed bleeding
may also occur, as may pyogenic granuloma and
rarely febrile systemic reactions.
48 Acute Complications 229

References 3. Graham GF, Barham K. Curr Probl Dermatol.

2003;15:247.
4. Greer KE, Bishop GE. Pyogenic granuloma as a com-
1. Connolly M, Bazmi K, O’Connell M, Lyons JF,
plication of cutaneous cryosurgery. Arch Dermatol.
Bourke JF. Cryotherapy of viral warts: a sustained
1975;111:1536–7.
10-s freeze is more effective than the traditional
5. Elton RF. Complications of cutaneous cryosurgery.
method. Br J Dermatol. 2001;145:554–7.
J Am Acad Dermatol. 1983;8:513.
2. Hancox JG, Graham GF, Yosipovitch G. Hemorrhagic
6. Cecchi R, Giomi A. Pyogenic granuloma as a compli-
bullae after cryosurgery in a patient with hemophilia
cation of cryosurgery for venous lake. Br J Dermatol.
A. Dermatol Surg. 2003;29:247.
1999;140:373–4.
 Chronic Complications
49
Gloria F. Graham, Christopher M. Scott,
and Ronald R. Lubritz

Abstract
Incomplete treatment may not show up for 1–2 years and may be in the
center of the lesion or at the periphery. Pigmentary changes are the most
common chronic changes seen after freezing especially after more than
15–20 s of freeze time. A cancerdial dose of freezing of 60 s often repeated
for a second time will almost always result in some pigment loss. The
darker skinned patients show the most change in pigmentation. Fortunately
Fitzpatrick Types I and II skin types show the least pigment change and
have the most skin cancer.
Pseudoepitheliomatous hyperplasia, an infrequent occurrence most
often seen 3–6 weeks after the eschar sheds, may mimick a recurrence.
A neuropathy may be occasionally noted after freezing a tumor overly-
ing a superficial nerve. Alopecia is expected if freezing a skin cancer on
the scalp. Many seborrheic keratoses, however, may be treated resulting
in little or no hair loss. Scar formation is usually noted more after longer
freeze times, but in certain locations hypertrophic scarring may be noted
especially on the chest and back and atrophic scarring on the forehead
and temple.

Keywords
Pseudoepitheliomatous hyperplasia • Milia • Alopecia • Pseudotumor
recidive • Hyperpigmentation

G.F. Graham, MD (*)

Department of Dermatology, Wake Forest University
School of Medicine, Winston Salem, NC, USA
e-mail: ggfgraham@aol.com
R.R. Lubritz, MD, FACP
C.M. Scott, MD Department of Dermatology,
Department of Dermatology, University of Virginia, Tulane University School of Medicine,
Charlottesville, VA, USA Hattiesburg Clinic, Hattiesburg, MS, USA

© Springer-Verlag London 2016 231

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_49
232
Introduction
Chronic complications, unlike acute, are not
apparent once the procedure is complete. These
complications surface over time, some appearing
within several hours while others after weeks have
passed. As the eschar heals, patients may report
unexpected physiologic events. To resolve these
complications, additional dermatologic surgery
may be required even with other modalities to
improve patient satisfaction and overall success.
Incomplete Treatment
Incomplete treatment of certain lesions, while not
a true complication, may confuse both patients and
clinicians. When treating verruca centrally and
superficially, the “halo wart” phenomenon may
surface. Incomplete treatment of an actinic kerato-
sis may allow a squamous cell carcinoma to
develop. The most experienced clinician, while
balancing the risks and benefits of cryosurgery for
treatment of a condition, may undertreat a certain
lesion. These findings stress the importance of
understanding patient selection, freeze times, and
proper utilization of certain tools and methods.
Pigmentation Changes
Changes in the color and texture of certain pig-
mented areas may occur. Melanocytes are more
likely to be affected by freezing than keratinocytes.
As melanocytes are pigment producing cells,
destruction may lead to varied cosmetic effects.
After longer freezes, there is an absence of mela-
nosomes in keratinocytes, but melanocytes are still
present. Thus, hypopigmentation does not necessar-
ily mean an absence of melanocytes. If one is freez-
ing a malignant melanocytic tumor, the loss of
pigment may not mean that there is a cure [1].
Hyperpigmentation is relatively common after
freezing, more noticeable after inflammation has
subsided. This change in pigmentation may last
from several months to greater than a year; how-
ever, this reaction slowly fades. This visible
G.F. Graham et al.
change in pigmentation typically consists of a
central area of hypopigmentation and a surround-
ing halo of hyperpigmentation. This incident is
commonly observed after the use of metal cones.
Patients with vitiligo may develop a depigmented
halo following freezing of a wart [2].
Localized hypopigmentation is expected after
cryosurgical procedures. Pigment cells are
destroyed at −4° to −7 °C [3]. Proper treatment of
malignant tumors requires temperatures of −40° to
−60 °C, so it is expected that melanocytes become
ablated. Re-pigmentation begins from various
points within the site, such as hair follicles and
adnexal tissue. Long-term and even permanent
hypopigmentation may occur (Fig. 49.1a, b). The
extent of dyschromia is unpredictable; however, the
loss of pigmentation, long-term, is more common in
darker skinned patients. For non-malignant sites,
freezing for 10–15 s minimizes hypopigmentation.
Pseudoepitheliomatous
Hyperplasia
This uncommon inflammatory reaction requires
no treatment. Condition is occasionally observed
3–6 weeks after cryosurgery, mimicking an
invasive neoplasm. Pseudotumor recidive is most
observed after treating the nose. After a few
months, this phenomena improves and is not
indicative of recurrence. Of primary concern to
the clinician is distinguishing this self-limited
reaction from a rapid recurrence of the tumor [4].
Milia
Milia may appear long after the surgical lesion has
healed, and is often mistaken for recurrence. Milia
is occasionally observed following deep cryosur-
gery for malignancies, and has been reported to
appear as milia en plaque in a recent review [5].
The use of the cone spray may increase inci-
dence of this purely cosmetic complication. This
condition is neither serious nor permanent; clini-
cian needs to reassure the patient when this con-
dition appears.
49 Chronic Complications
Nerve Damage
Neuropathy can occur post-operatively, espe-
cially in areas where nerves are superficial [4, 6].
Permanent damage is rare, but possible. Freezing
cutaneous nerves leads to hypesthesia, an effect
utilized in cryotherapy of lichen simplex chroni-
cus and prurigo nodularis. In a study assessing
treatment of trigeminal neuralgia with cryother-
apy, sensation returned in 4–8 months in 19
patients, and pain recurred in 13 of 19 patients
within 6–12 months [7]. Nerves which are
directly frozen most often regain sensation, and
inadvertant cooling will rarely result in perma-
nent loss [8]. Sensory loss of varying degree is
the most common form, but motor weakness has
been reported.
Areas which require special caution include
the pre- and post-auricular areas, lateral aspects
of the fingers, lateral aspect of tongue, and ulnar
fossa [8]. Risk of nerve damage may be dimin-
ished by manually moving the area to be treated
away from the underlying tissue. In addition,
injection of local anesthetic or saline beneath the
target tissue, or “ballooning,” can distance the
lesion from the nerve.
The key to regeneration is the neural sheath; it
is relatively resistant to freezing. If the neural
sheath is not permanently damaged, neural regen-
eration is likely to occur. Anesthesia and
paresthesia are temporary, usually resolving
spontaneously over a period of many months.
a b
Fig. 49.1 (a) Cryosurgery of multiple basal cell carcinomas on the back. (b) Pigment loss and hypertrophic scarring is
noted following treatment
233
Alopecia
Permanent alopecia is expected if freezing
extends to, and destroys, the hair follicles, as hap-
pens when treating a skin cancer (See Fig. 50.1).
Successful treatment of malignant lesions often
requires cryosurgery to this depth. Squamous cell
carcinoma in-situ and lentigo malgna often fol-
low adnexal structures deep into tissue. Freezing
for 15–20 s may cause permanent hair-loss. All
hair-bearing areas can be affected, including the
eyelashes [4].
Scar Formation
Scar formation is inevitable after deeper freez-
ing (See Fig. 49.1a, b). It is usually cosmeti-
cally acceptable and the treated sites usually
heal rather smoothly. Preserved dermal fibrous
network usually aids in regeneration of the epi-
dermis. A degree of atrophy is expected with
normal skin grossly destroyed by the tumor
(See Fig. 49.1). However, excessive atrophy
can follow treatment of skin cancers. The helix
of the ear and the rim of the ala nasi are
especially sensitive to developing post-
treatment atrophy.
Full thickness freezing, as required in many
malignancies over nasal and otic cartilage, results
in cartilage necrosis and notching. Perforation
can also occur. These complications develop
234
most commonly on the ears, the free edge of the
nares and the eyelids, where cartilage lies super-
ficially and is covered by thin areas of skin.
Because of this anatomy, notching and perfora-
tion are sometimes unavoidable, especially if the
tumor has already invaded the cartilage structure.
Patients should be forewarned of this complica-
tion when a tumor is located in the areas
mentioned.
Hypertrophic scarring may also develop
4–6 weeks post-surgically, usually occurring
at the center of the treated site. The resulting
lesion appears in a linear fashion, mimicking a
sutured site. As with other surgical proce-
dures, hypertrophic scarring is more prevalent
on the back and the chest, with fewer occur-
rences on the forehead, temples, and mandibu-
lar areas.
Retraction scars occur in certain areas [9].
Most commonly, they are seen around the lips,
and are occasionally observed in the area between
the medial canthus and the nasal bridge. Ectropion
may uncommonly be seen on the lower lid. Those
who have so-called “lazy lids” are most prone to
develop this complication.
A type of possible scarring of the lower eye-
lids has been reported by Lazlo Biro (personal
communication). It consists of long-term to per-
manent reddish papules which occur after freez-
ing of basal cell carcinomata on the tarsal plate.
To date, it is not known why this uncommon
complication develops.
G.F. Graham et al.
Summary
Chronic complications include incomplete treat-
ment, pigmentary changes, milia, pseudoepithe-
liomatous hyperplasia, neuropathy, alopecia and
scar formation. Patients should be forewarned of
those changes which are most likely to happen,
such as pigment alteration.
References
1. Burge SM, Bristol M, Millard PR, Dawber
RP. Pigment changes in human skin after cryotherapy.
Cryobiology. 1986;23(5):422–32.
2. Takamichi I, Yoshida Y, Adachi K, Furue M,
Yamamoto O. Wart with depigmented halo and gener-
alized vitiligo. Yonago Acta Med. 2012;55(4):81–2.
3. Gage AA, Meenaghan MA, Natiella JR, Greene Jr
GW. Sensitivity of pigmented mucosa and skin to
freezing injury. Cryobiology. 1979;16(4):348–61.
4. Elton RF. Complications of cutaneous surgery. J Am
Acad Dermatol. 1983;8:513–9.
5. Beutler BD, Cohen PR. Cryotherapy-induced milia en
plaque: case report and literature review. Dermatol
Online J, 21(2). pii: 13030/qt4dw7k4nk.
6. Dawber RPR. Cryosurgery: complications and con-
traindications. In: Breitbart EW, Dachow-Siwiec E,
editors. Clinics in dermatology: advances in cryosur-
gery. New York: Elsevier; 1990. p. 108–14.
7. Pradel W, Hlawitschka M, Eckelt U, Herzog R,
Koch K. Cryosurgical treatment of genuine trigeminal
neuralgia. Br J Oral Maxillofac Surg. 2002;40:244–7.
8. Finelli PF. Ulnar neuropathy after liquid nitrogen
cryotherapy. Arch Dermatol. 1975;111:1340–2.
9. Usatine RP, Stulberg DL, Colver GB. Cutaneous
cryosurgery. 4th ed. CRC Press; 2015.
 Prevention and Management
of Complications
50
Christopher M. Scott, Ronald R. Lubritz,
and Gloria F. Graham

Abstract
Prevention of complications is important for all cryosurgeons to fully
understand. Immediate reactions such as erythema, vesicle and bullae may
be decreased if certain steps are followed.
Avoiding over freezing or using several shorter freezes may also
decrease some complications but are not advocated for skin cancers.
Learning freezing using a thermocouple needle or electric monitoring
device will assist in reducing likelihood of complications. Use of cones
decreases excessive lateral freezing.
Short-term conditions may surface following cryosurgery including
pain, syncope, edema, nitrogen gas insufflation, infection and delayed
bleeding. Long term reactions include the formation of a donut wart, milia,
nerve damage, alopecia and scarring. Each of these conditions, though
rare, are discussed in this chapter detailing how to prevent and treat if
these happen. Use of local anesthetics can help with patients who are
prone to syncope that can be produced by pain. Nitrogen gas insufflation
can be reduced by using a cone around the spray or a probe.

Keywords
Alopecia • Milia • Bullae • Nitrogen gas insufflation • Edema • Molluscum
• Syncope

C.M. Scott, MD
Department of Dermatology, University of Virginia,
Charlottesville, VA, USA
R.R. Lubritz, MD, FACP G.F. Graham, MD (*)
Department of Dermatology, Tulane University Department of Dermatology, Wake Forest University
School of Medicine, Hattiesburg Clinic, School of Medicine, Winston Salem, NC, USA
Hattiesburg, MS, USA e-mail: ggfgraham@aol.com

© Springer-Verlag London 2016 235

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_50
236
Introduction
We have discussed numerous complications of
cryosurgery in previous chapters. Now, we
address prevention and intervention for the
potential unintended outcome. It remains of criti-
cal importance to appropriately manage the
patient’s site, and lesion selection in advance of
performing cryodestruction.
Methodology
When treating small superficial lesions, a cotton
swab may produce less side effects than using a
cryoprobe. But time can decrease the swelling
from using a probe, and time should be limited to
5 and not more than 10 s. When treating malig-
nancies, a cotton swab, which only goes 2 mm in
depth into the epidermis is insufficient for many
pre-cancerous and cancerous lesions. A cryo-
spray or probe are required.
Immediate Reactions
Redness, edema, and vesicles may appear imme-
diately after freezing and are dependent on the
degree of freezing and, if a probe is used, the
degree of pressure applied with the probe. Small
superficial lesions require no more than 5–7 s of
spray freezing. Thicker lesions such as sebor-
rheic keratoses may require 10–15 s of spray
freezing.
Prevention and Management
Short-Term Reactions
These effects and complications may occur
over several hours to weeks and include pain,
edema, hemorrhage, syncope, bullae, infec-
tion, and, on rare occasions, pseudoepithelio-
matous hyperplasia, systemic reactions and
pyogenic granuloma.
C.M. Scott et al.
Pain
All patients should be advised of mild, moderate
or severe pain, both during treatment and 30 min
after treatment. While anesthesia is often not
needed, the longer freezing times required for
treating malignancies may require local anesthe-
sia. If using cryosurgery for malignancies, this is
especially needed for debulking the tumor prior
to freezing. Mild analgesics, such as acetamino-
phen, may be required if bullae develop. Proper
patient positioning may help avoid vasovagal
reactions. Post operatively, the patient should
remain seated or in a supine position [1].
In pediatric cases, eutectic lidocaine/prilo-
caine cream 5 % may be considered an hour in
advance of the procedure [2]. Forceps dipped in
liquid nitrogen may be used to treat delicate
areas, including skin tags on the neck, to mini-
mize unintended damage [3]. However, the depth
of freeze will be limited as is the case with cotton-
swab application.
Local trauma and additional discomfort may
occur if frozen mucous membranes are attached
to the probe tip when withdrawn. Pre-chilling
the probe tip or application of lubricating jelly
may reduce the likelihood of adherence to the
probe [4].
The forehead, temples, tips of the fingers and
nose are more susceptible to pain, as are mucous
membranes. Patient may use cold packs
immediately after treatment for relief. Patient
may have discomfort from a headache and use
over the counter analgesics to alleviate the pain.
Edema
A trial of oral vitamin C and vitamin E, free radi-
cal scavengers, does not appear to improve pain,
blistering, erythema or edema volume [5].
Systemic steroids may decrease the amount of
periorbital edema as shown in a study by Kuflik
[6]. Cold water compresses may provide symp-
tomatic relief, but antihistamines offer very little
help for the swelling. This swelling usually
resolves in approximately 5 days. When treating
molluscum in pediatric patients, a small cryo-
probe may be used, protecting the eye with either
a cone or a Jaeger retractor [7, 8].
50 Prevention and Management of Complications
Hemorrhage
Following debulking of a lesion, aluminum chlo-
ride or Monsel’s solution may be used for hemo-
stasis prior to freezing. Patients on anticoagulants
will have a greater likelihood of immediate hem-
orrhage, but stopping these medications prior to
freezing is not necessary [9]. Freezing may be
considered the treatment of choice in patients on
anticoagulants or who have a bleeding disorder
(See Fig. 48.2). Manual pressure followed by a
pressure dressing may be sufficient for control of
hemorrhage if aluminum chloride or Monsel’s
solution is not. Electrocautery may be utilized as
well.
Nitrogen Gas Insufflation
If nitrogen gas insufflation is anticipated, use of a
cryoprobe may eliminate this event. Prevention
may also be accomplished by pressure rings or
cones placed around the opening prior to freezing
or spraying at an angle on the lesion [9, 10].
If nitrogen gas insufflation does occur, the gas
may be manually expelled from the wound site.
This reaction is self-limited to a few hours or up
to 24 h. No permanent side effects have been
observed.
Syncope
Syncope happens especially after freezing warts
around the fingers, more often around periungal
warts. If anticipated, pretreatment with an anal-
gesic or local anesthetic may address this possi-
ble vasovagal reaction. Use of supine or
head-down position will often resolve the vaso-
vagal reaction within a few minutes [9, 10].
Since these are expected results, other than
infection, they are not completely preventable.
By decreasing the freeze time, these reactions
will be reduced; but the freezing may not be long
enough to accomplish eradication of the lesion.
Bullae Formation
Superficial freezing results in bullae formation
due to separation of the epidermis from the der-
mis. It is often more common in areas of loose
tissue, particularly the dorsum of the hands and
arms. Deeper freezing may produce a vesicobullous
237
response, and when treating cancer, a gelatinous
response (See Fig. 48.1a) [8–10].
Formation of a bullae is not preventable except
by decreasing the freeze time which may result in
an insufficient freeze for eradication of the lesion.
Vesicles or bullae are helpful to the curing
process, obtaining removal of the superficial
lesion. The overlying skin serves as a sterile
biologic dressing to help reduce the likelihood
of infection. If evacuation of the contents is
necessary, then an application of antibiotics
may be appropriate since the barrier has been
breached. Healing of bullae should occur
within 3–5 days.
Infection
Following cryosurgery, infection is uncommon.
Infection can develop in a lesion that is slow in
healing or has a thick eschar. Infection has been
noted following topical application of steroid
cream (see Fig. 45.2).
Delay in wound healing as related to patients
with venous stasis or diabetes mellitus should be
a strong consideration to select another form of
therapy. In many instances, however, if the lesion
is not greater than 5–8 mm, healing may take
place in 1–2 months and have no additional
sequellae. Infection is more common in hot,
humid regions such as the Southern United States
(See Fig. 33.1c).
Infection, though rare, may occur in uncom-
plicated patients; antibiotics are indicated for
such treatment, as well as immunocompromised
patients or any patient at high risk for infection. It
may be difficult to distinguish between normal
exudation and sloughing and infection after deep
cryosurgery. A culture may be necessary to deci-
pher, and topical antibiotic ointments may be
used or rarely systematic antibiotics.
Bleeding
The patient may apply pressure for several min-
utes on the bleeding site if delayed bleeding does
occur. Physician intervention and office follow-
up is seldom necessary. If patient’s pressure on
the bleeding site is ineffective, a pressure dress-
ing or suture will control hemorrhage.
238
Pyogenic Granuloma
Pyogenic granuloma are benign vascular tumors
which may occur within 1–2 months following
freezing. These have been described after cryo-
ablation and salicylic acid treatment of verruca
vulgaris [11]. Pyogenic granuloma has also been
observed following cryosurgery alone [12] (see
Fig. 48.4). Interestingly, this has also been seen
after a treatment of a venous lake [13]. Pyogenic
granuloma is not preventable and may be eradi-
cated by additional freezing and/or electrodessi-
cation and curettage [14].
Pseudoepitheliomatous Hyperplasia
Pseudoepitheliomatous hyperplasia is a rare
occurrence where overgrowth of the epidermis
produces a false appearing recurrence. This usu-
ally subsides in just a few months [12]. If in
doubt, a biopsy should be performed. A similar
occurrence can follow radiation therapy.
Systemic Reactions
Within a few hours of cryosurgery, though rare, a
febrile reaction may develop, but it subsides
within 24–48 h. Rest and antipyretics are usually
sufficient treatment for this flu-like reaction [12].
Long-Term Reactions
These effects and complications may occur
within several hours to weeks following cryosur-
gery. However, if these complications do not
improve significantly over time, additional surgi-
cal intervention may be required. These reactions
include the effects of incomplete treatment, pig-
mentation changes, milia, nerve damage, alope-
cia and scar formation.
Incomplete Treatment
A clinician should discern carefully between over
and under treating lesions with freezing. Proper
selection of patients is also important. Freeze
halos and thaw time will help to determine if
treatment is sufficient. A thermocouple with
pyrometer or electrical monitoring can also help
assure adequate treatment.
C.M. Scott et al.
A biopsy is recommended if there is any con-
cern over incorrect diagnosis. Retreating the
cryosurgical site may resolve issues if there is
any doubt in the adequacy of treatment. A donut
or halo of warts may appear around the site fol-
lowing cryosurgery of warts. The use of imiqui-
mod may prevent this unusual happening if used
before and after the freezing. Limiting the freez-
ing of the wart to a 1 mm halo may also help
avoid this complication. Use of a cone around the
wart is helpful.
Mohs surgery is recommended for treating
recurrent basel cell carcinoma and sclerosing
basal cell carcinoma. When patients have a mul-
titude of medical conditions that prohibit large
procedures, cryosurgery has been used for treat-
ment of these tumors. Effectiveness of cryosur-
gery of melanoma has been studied by Breitbart
[15]. Cryosurgery has been used in selected cases
and found effective for certain satellite lesions,
lentigo maligna and recurrent tumors. However,
cryosurgery should not be considered as the first
option for melanoma patients.
Pigmentation Changes
Improved cosmesis has been observed using sev-
eral shorter freeze-thaw treatments [8]. The tip of
the nose, the helix and the trunk are especially
susceptible areas. Local hypopigmentation may
occur following freezing of actinic keratoses
using shortened freeze times. If the cryosurgeon
feels this may present an unacceptable cosmetic
problem for the patient, one of the topical agents
may be used for treatment or PDT.
Treatment option for hypopigmentation are
few, even with shortened freeze cycles. Resection
of the area may be a solution if it is cosmetically
unacceptable to the patient.
Milia
Milia can be removed by piercing the area with a
blood sample disposable lancet or with a pointed
scalpel.
Nerve Damage
Risk of nerve damage can be lessened by moving
the area to be treated away from the underlying
50 Prevention and Management of Complications
Fig. 50.1 A 52-year old white female with area of alope-
cia 6 months following cryosurgery of a basal cell carci-
noma in the vertex
tissue. Special attention should be given to lateral
aspects of the fingers and tongue, pre- and post-
auricular areas, lateral neck, radial aspect of the
wrist and the ulnar fossa. The use of local anesthe-
sia or a saline injection underneath the targeted
area, creating a “ballooning” effect and distancing
from nerve tissue, has proven effective [12, 16].
The regeneration of the neural sheath is impor-
tant, as it is resistant to freezing. If this sheath is
not permanently damage, then neural regenera-
tion is likely. Paresthesia and anesthesia are short
term, and often resolve in 3–6 months.
Nerve injury may occur in athletes treated by
cryotherapy for injuries. In very rare circumstances,
nerve injury has developed, resulting in temporary
or rarely permanent injury of the athlete [17].
Alopecia
Alternative treatment methods should be dis-
cussed fully with the patient if the treatment area
is where hair-loss is likely to be of cosmetic
importance (Fig. 50.1).
Hair loss is common, even with a 15–20 s of
freezing. As with pigmentary changes, there are few
effective treatment methods. Excision of site or pos-
sibly hair transplant could be used if needed [12, 17].
Scar Formation
Freezing should be minimized in the area between
the medial canthus and the nasal bridge to pre-
239
vent retraction scars, as previously discussed.
Site selection and depth of the freeze are critical
considerations to minimize scarring.
Hypertrophic scarring improves over time.
Treatment of these lesions is not necessary (See
Fig. 37.3a–c). If this scarring still exists
6–9 months post treatment and causes patient
concern, an intralesional injection of triamcino-
lone can help to resolve the scarring. Studies are
not conclusive on the effectiveness of topical
immune modulators, such as imiquimod, in
reducing such scarring [18].
Summary
Patient communications regarding expected post-
operative outcomes is key with cryosurgery, as in
all areas of medicine. Bullous and edematous
changes are prominent in many patients. The cli-
nician should have a clear understanding of
patient expectations including hypopigmentation
in dark-skinned patients or alopecia in hair bar-
ing areas. Cryosite complications such as carti-
lage notching and ectropion should also be
discussed, when applicable. As cryosurgery
involves probes and sprays, which may involve
deep penetration, so impact on underlying anat-
omy should be carefully considered and dis-
cussed with the patient.
Potentially minimizing the need for
post-operative therapeutic intervention is
important with cryosurgery as with other
therapeutic approaches. Extended cryogenic
treatment should be performed only with a
clear understanding of anticipated and possible
complications. Cryosurgery is not simply a
technical operation, but instead a keen balance
between sub-therapeutic treatment and exces-
sive ablation. While many of the complications
discussed herein are rare, proper identification
and communication will improve the patient
experience and post-operative outcome [8–10].
An informed patient is much more accept-
ing of an outcome, even if happens to be an
unexpected one.
240
References
1. Keefe M, Dich DC. Cryotherapy of hand warts – a
questionnaire survey of “consumers”. Clin Exp
Dermatol. 1990;15:260–3.
2. Gupta AK, Koren G, Shear NH. A double-blind, ran-
domized, placebo-controlled trial of eutectic lido-
caine/prilocaine cream 5% (EMLA) for analgesia
prior to cryotherapy of warts in children and adults.
Pediatr Dermatol. 1998;15:129–33.
3. Kuwahara RT, Craig SR, Amonette RA. Forceps and
cotton applicator method of freezing benign lesions.
Dermatol Surg. 2001;27:183–4.
4. Scott CM, Lubritz RR, Graham GF. Complications of
cryosurgery. In: Nouri K, editor. Complications of
dermatologic surgery. New York: Mosby; 2008.
p. 119–36.
5. Gach JE, Humphreys F, Berth-Jones J. Randomized,
double-blind, placebo-controlled pilot study to assess
the value of free radical scavengers in reducing
inflammation induced by cryotherapy. Clin Exp
Dermatol. 2005;30:14–6.
6. Kuflik EG, Webb W. Effects of systemic corticoste-
roids on post-surgical edema and other manifestations
of the inflammatory response. J Dermatol Surg Oncol.
1985;11:464.
7. Biro L. Pediatric cryosurgery. Syllabus for basic cryo-
surgery course. Evanston: American Academy of
Dermatology; 1990. p. 21.
8. Lubritz RR. Cryosurgery of benign and premalignant
cutaneous lesions. In: Zacarian SA, editor.
Cryosurgical advances in dermatology and tumors of
the head and neck. Springfield: Charles C Thomas;
1977. p. 55–73.
C.M. Scott et al.
9. Dawber RPR. Cryosurgery: complications and con-
traindications. In: BreitbartE Dachow-Siwiec EW,
editor. Clinics in dermatology: advances in cryosur-
gery. New York: Elsevier; 1990. p. 108–14.
10. Graham GF. Cryosurgery for benign, premalignant, and
malignant lesions. In: Wheeland RG, editor. Cutaneous
surgery. Philadelphia: WB Saunders; 1994. p. 835–69.
11. Greer KE, Bishop GE. Pyogenic granuloma as a com-
plication of cutaneous cryosurgery. Arch Dermatol.
1975;111:1536–7.
12. Elton RF. Complications of cutaneous surgery. J Am
Acad Dermatol. 1983;8:513.
13. Cecchi R, Giomi A. Pyogenic granuloma as a compli-
cation of cryosurgery for venous lake. Br J Dermatol.
1999;140:373–4.
14. Mirshams M, Daneshpazhooh M, Mirshekari A,
Taheri A, Mansoori P, Hekmat S. Cryotherapy in the
treatment of pyogenic granuloma. J Eur Acad
Dermatol Venereol. 2006;20(7):788–90.
15. Breitbart E. Cryosurgery in the treatment of melanoma.
In: Breitbart E, Dachow-Siwiec E, editors. Advances in
cryosurgery. Clinics in dermatology, vol. 8. New York,
Amsterdam, London: Elsevier; 1990. p. 96–100.
16. Zacarian SA. Complications, indications, and contra-
indications in cryosurgery. In: Dekker M, editor.
Roenigk & Roenigk dermatologic surgery principles &
practice. New York, 1996. p. 266–7.
17. Malone TR, Engelhardt DL, Kirkpatrick JS, Bassett
FH. Nerve injury in athletes caused by cryotherapy.
J Athl Train. 1992;27:235–7.
18. Guitanis G, Bassukas ID. Immunocryosurgery for
nonmelanoma skin cancer : applications and practical
tips. In: Pasquali P, editor. Cryosurgery: a practical
manual. Springer: New York; 2015. p. 256.
 Part VIII
Cryosurgery in Special Populations
 The Management of the Pediatric
Patient and Adolescent During
51
Skin Cryosurgery

Nir Gal Or and Yaron Har-Shai

Abstract
Cryosurgery is one of the most common procedures performed in pediatric
dermatology. Health care professionals have a duty to provide compas-
sionate care to all children. Adequate pain control is now considered a
basic human right. The anatomical and physiological characteristics of
neonates, infants and young children are distinct from adults.
The goal of the therapy is to minimize the psychological distress, dis-
comfort and side effects among pediatric patients and adolescents while
maximizing the efficacy of the technical aspects of the procedure. The
reduction of the incidence of chronic pain symptoms is most important.
Research in behavioral approaches to pediatric pain management has pro-
vided various behavioral approaches and recommendations for minimiz-
ing children’s anxiety and pain associated with medical procedures and
cryosurgery of the skin. This chapter is aimed to elaborate and discuss in
a systematic approach the pain management and anxiolytic, including staff
and parent’s education and protocol development which can have a posi-
tive effect on providing comfort to children before, during and following
the cryosurgery treatment.
This Chapter will deal with the physiology of pain during cryosurgery,
pain assessment, the timing of informing the child about the procedure and
the potential discomfort. Non-pharmacologic methods to minimize pain
will be clarified including: distraction, counter stimulation and restraint as

N. Gal Or, MD
Department of Plastic Surgery, The Lady
Davis Carmel Medical Center, Haifa, Israel
Y. Har-Shai, MD (*)
Department of Plastic Surgery, The Lady
Davis Carmel Medical Center, Linn Medical
Center, Haifa, Israel
e-mail: yaron07@yahoo.com

© Springer-Verlag London 2016 243

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_51
244 N. Gal Or and Y. Har-Shai

well as tailoring these non- pharmacologic approaches to each age groups:

neonates and infants, toddlers and preschoolers, school age children and
adolescents. Pharmacological interventions will be discussed including
topical and local anesthetics, NSAIDs, sedation procedures and general
anesthesia which should be performed by safe protocols and practices by
an anesthesiologist who has adequate experience with pediatric patients.
If possible, reassurance or anxiety reduction without sedation is prefer-
able. However, if sedation is required, it is recommended that it will be
administered judiciously and that the pediatric patient be vigilantly moni-
tored for respiratory distress or hemodynamic instability.
Some recommendations and guidelines for procedural pain manage-
ment in neonates and children are offered in this chapter in order to guide
best practice, but strategies can only be effective if acted upon and utilized.
It is the key that all those involved in caring for children undergoing pain-
ful procedures are aware of the importance of procedural pain control, and
ensure that effective interventions are implemented regularly into routine
practice.

Keywords
Pediatric dermatology • Children • Cryosurgery • Skin • Pain management
• Behavioral approaches • Non-pharmacologic methods • Pharmacological
interventions • Sedation • Anesthesia • Recommendations and guidelines

Introduction inflammation and pain. De Souza et al. [2] have

Cryosurgery is one of the most common procedures
performed in pediatric dermatology. The goal of the
therapy is to minimize the discomfort and side
effects while maximizing treatment efficacy.
Common pediatric and adolescent skin condi-
tions treated with cryosurgery include: cutaneous
warts, molluscum contagiosum, syringomas, pig-
mented naevi, hemangiomas, hypertrophic scars
and keloids. Each of these is discussed in detail in
other chapters of this book. The focus of this
chapter is on the various behavioral approaches
to anxiety and pain management of the pediatric
patient during cryosurgery of the skin.
Pain During Skin Cryosurgery
As skin temperature decreases, pain sensation
and tissue damage increase. Pain sensation begins
whenever the skin temperature reaches 5 °C [1].
The application of LN to the skin induces
elaborated on this process. Pain is the result of
two mechanisms. The first mechanism is charac-
terized by mediators, such as kinins and sub-
stance C, that stimulate the free terminals of
neural cells (C fibers) to conduct a direct and
rapid pain signal to the brain. The second mecha-
nism works through mechanical nociceptor
hypersensitivity. Cytokines, released by defense
cells, intensify the pain induced by arachidonic
acid/cyclo-pxygenase products, sympathomi-
metic amines, TNF-α, IL-1 and IL-8.
Pain experienced by the patient can be a limit-
ing factor in the effective use of skin cryosurgery
[3]. We found (unpublished data) that severe pain
(level 6–8 mm in the Visual Analog Scale (VAS)
of 0–10 mm) is reported immediately after con-
tact cryosurgery and is still present, in somewhat
reduced form (4–6 mm), 4 h post treatment.
Gupta et al. [4] reported that pain severity dur-
ing skin cryosurgery ranged between 29.1 and
55.9 mm on the VAS, while the pain score in the
group which has been pre-treated with topical
51 The Management of the Pediatric Patient and Adolescent During Skin Cryosurgery
eutectic lidocaine/prilocaine cream 5 % (EMLA)
was found to be between 22.5 and 47 mm.
Cryosurgery has been reported to be beneficial
for the relief of pain due to post herpetic neural-
gia [5]. This can be explained by the sensitivity
of myelin and axons to cold, while the neural
connective tissue sheaths (perineurium and epi-
neurium) have survived apparently unchanged
which correlates to a second- degree nerve injury
[6]. Scores above 3 mm in the VAS scale is con-
sidered an uncomfortable annoying pain [2].
Pediatric Pain Management
Profound attention should be taken with the chil-
dren population to minimize the pain and dis-
comfort during and after skin cryosurgery.
Pain which accompanies medical procedures in
pediatric patients results in short-term suffering,
but there is data that indicate also long-term detri-
mental effects. Specifically, early painful insults
might have lasting negative effects on neuronal
development, pain threshold and sensitivity, coping
strategies, emotionality and pain perception [7, 8].
Childhood pain during medical interventions has
been linked to later adulthood fear, pain, and avoid-
ance of medical care. In addition, severe pain dur-
ing medical visits predicts missed future medical
appointments and poor health care follow-up [9].
Safe and effective management of pediatric
pain is an art as well as a science. Knowledge of
developmental stages, provision of simple expla-
nations and honesty with children and their par-
ents are essential for success.
Pain Assessment
In the hospital setting, pain and response to treat-
ment, including adverse effects, should be moni-
tored routinely and documented clearly and in a
visible place, such as on the vital sign sheet, to
facilitate treatment and communication among
health care professionals. Pain can be assessed
using self-report, behavioral observation, or
physiologic measures, depending on the age of the
child and his or her communication capabilities.
245
Specific measures vary in validity and useful-
ness. Accurate acute pain assessment requires
consideration of the plasticity and complexity of
children’s pain perception, the influence of psy-
chological and developmental factors, and the
appreciation of the potential severity and specific
types of pain that are experienced [10].
Because pain is a subjective experience, indi-
vidual self-report is often favored; however, it is
important to be sure that children, particularly
those between 3 and 7 years of age, are compe-
tent to provide information before their report of
location, quality, intensity, and tolerability of the
pain are accepted. Observation of behavior
should be used to complement self-report and
can be an acceptable alternative when valid self-
report is not available.
When communication is difficult, personal
assumption by health care professionals on the
meaning of the behavior should be examined
carefully. Pain expression reflects the physical
and emotional state, coping style, and family and
cultural expectations and can be misinterpreted
by the health care professional. For example,
stoic or depressed children with severe pain may
not report or show expected behavioral evidence
of the severity of the pain. Pain experienced by
children with special health care needs or devel-
opmental disabilities may be particularly difficult
to assess accurately. Careful and thorough assess-
ments are necessary when communication with
the patient may be problematic, as may be the
case with children who are cognitively impaired,
severely emotionally disturbed, or impaired in
sensory or motor modalities.
Cultural and language differences between the
child and health care professional also require
additional care during the pain assessment. When
such patients are unable to report pain, credible
assessment usually can be obtained from the par-
ent or another person who knows the child well.
However, there is a relatively pervasive and sys-
tematic tendency for proxy judgments to under-
estimate the pain experience of others.
Physiologic measures should be recognized as
usually reflecting stress reactions during acute
pain and usually are only tenuously correlated
with self-report of pain.
246
Timing
In general the time between informing the child
about potential discomfort and the actual proce-
dure performance should be short. Long delays
between the explanation and the actual procedure
increase anticipatory distress prior to the procedure
[11]. Information provided far in advance of a pro-
cedure is not recommended because it might serve
to increase anxiety; children can dwell on and
exaggerate the event http://www.pediatricsdigest.
mobi/content/122/Supplement_3/S134.full-ref-23
[12] or might forget the pertinent information [13].
Conversely, information provided immediately
before the medical procedure might not allow chil-
dren to have sufficient time to process and handle
the information, which can heighten stress. It is
also important to note that these findings are tied to
the particular procedure. For example, same-day
preparation might heighten distress for major pro-
cedures such as surgery http://www.pediatricsdi-
gest.mobi/content/122/Supplement_3/S134.
full-ref-25 [14] but benefit children undergoing
minor procedures such as ear piercing [15].
Minimizing Pain
during Cryosurgery: Non-
pharmacologic Methods
The pain of cryosurgery can be minimized with
some simple techniques; pain management
begins with creating a comfortable environment
for the parent and child.
Distraction
Distraction of a child during a painful procedure
can help to reduce pain and distress. This includes
having the child perform rhythmic breathing or
blowing bubbles. It also helps to create visual
images for the child in an effort to reduce pain.
One could ask the child to think of the funniest
movie he or she has ever seen and to imagine the
pain getting less intense with each laugh. For
younger children, parents can also help with
singing and storytelling [10].
N. Gal Or and Y. Har-Shai
As for a rationale for the pain-reducing
effects of distraction, McCaul and Malott
http://www.pediatricsdigest.mobi/content/122/
Supplement_3/S134.full-ref-71 [16] hypothe-
sized that the brain has a limited capacity to focus
attention on stimuli; if intentional resources are
devoted to focusing on a distracting task, there
is little left for attending to painful stimuli. It has
also been suggested that distraction alters noci-
ceptive responses by triggering an internal pain-
suppressing system.
Regardless of the reason, distraction seems to
be an excellent pain-management intervention
for children.
A meta-analysis indicated that distrac-
tion for pediatric pain management was most
effective for children under the age of 7 years
old [17]. In selecting the best distracter, data
have been inconclusive. For example, Mason
et al. http://www.pediatricsdigest.mobi/con-
tent/122/Supplement_3/S134.full-ref-70 [18]
found an interactive robot to be more effec-
tive than a story book, whereas MacLaren and
Cohen http://www.pediatricsdigest.mobi/con-
tent/122/Supplement_3/S134.full-ref-21 [19]
showed that movies are superior to an inter-
active toy. Theoretically, optimal distraction
stimuli involve multiple modalities (e.g., vision,
hearing, touch) and produce positive affec-
tive states that are incompatible with distress
http://www.pediatricsdigest.mobi/content/122/
Supplement_3/S134.full-ref-62 [20]. It is also
important to select age-appropriate stimuli and
ones that involve the parents as coaches. The
latter recommendation stems from findings
that children rarely engage in coping without
the assistance of coaches http://www.pediat-
ricsdigest.mobi/content/122/Supplement_3/
S134.full-ref-66 [21]. Fine-grained analyses of
procedural phases have shown that it is critical
that distraction might be used before the proce-
dure to reduce anticipatory anxiety, during the
procedure, and after the procedure to enhance
recovery [22]. The only contraindication for dis-
traction arises in the assumption that it might be
best to match the intervention to coping style.
http://www.pediatricsdigest.mobi/content/122/
Supplement_3/S134.full-ref-44 [23]. As such, if
51 The Management of the Pediatric Patient and Adolescent During Skin Cryosurgery
a child finds that watching and being involved
in the procedure decreases anxiety and pain,
encouraging distraction might not be advis-
able. In general, in the medical literature there
is a strong support for distraction therefore, it
should be routinely used with cryosurgery, espe-
cially for children ≤7 years old.
Counter Stimulation
Counter-stimulation is a technique by which some-
one repetitively and persistently rubs or touches an
area of the body close to the area that is being hurt.
This technique is based on the gate theory of pain.
Transmission of pain information from dorsal horn
cells occurs through a “gate” which opens in
response to signals from the affected small fibers.
The gate can be “closed” by large neurons that are
stimulated by non-painful touching or pressing of
the skin. The theory explains why we rub our
elbows when we hit it against something: the rub-
bing stimulates these large fibers and suppresses
the anticipated painful sensation.
Restraint
Although proper restraint of a child for a painful
procedure does not always reduce fear or anxiety,
it does allow the physician to perform the task
better. This indirectly reduces pain because fewer
attempts may be necessary to accomplish the
task. The need for restraint should be explained
to the parents, who should not be involved in the
actual process. Instead, the child might be
wrapped in sheets with the parents attempting to
calm the child afterward [10].
Non-pharmacologic Methods-
Specific to Each Age Group
Neonates and Infants
Babies under 6 months have no fear of physi-
cians; the level of anxiety experienced by a young
infant is a reflection of parental anxiety. Babies
develop fear of strangers around 7–9 months of
247
age. Parental presence in the room is essential to
minimize the trauma of procedures at this age.
When performing painful procedures on
infants, it is important to take into consideration
the context of the procedure (i.e., is the procedure
really necessary, how many painful procedures has
the infant had in the past, and what was their previ-
ous pain experience [24]. The procedural environ-
ment should also be developmentally sensitive. In
fact, reducing noise and lighting, use of soothing
smells and clustering procedures to avoid over
handling, reduces pain reactions in infants [25].
Distraction techniques used with this age group
are mostly passive. Cognitive strategies used to
reduce pain perception in infants are either visual
or auditory interventions. Visual aids can include
pictures, cartoons, mobile phones, and mirrors
[26]. Auditory aids include music, lullabies sung
by parents or health care professionals [27].
Behavioral strategies are more common for
this age group, and involve either “direct or indi-
rect” interventions that engage the caregivers in
handling the infants [28]. Examples of behavioral
strategies include the following:
A. Non-nutritive sucking, an indirect intervention
involving insertion of a pacifier or a nonlactat-
ing nipple into the infant’s mouth to encourage
sucking behaviors. This was found to stimulate
the orotactile and mechanoreceptors, and
decrease cry durations and heart rate [29].
B. Skin to skin contact with the mother (kanga-
roo care), where the infant is positioned on
the mother’s exposed chest during, or after
the painful procedure [30].
C. Rocking and holding the infant, where the
infant is carried by a parent or caregiver dur-
ing (if possible) and after the painful proce-
dure and gently rocked [31].
D. Swaddling the infant is another similar calm-
ing technique where the infant is wrapped with
its extremities close to their trunk to prevent
him/her from moving around excessively.
Interventions for Young Infants
Distraction has been shown to be an effective
intervention for young children, including infants
248
Table 51.1 Guidelines for sucrose for venous access
1. Administer 2 mL of 25 % sucrose solution by
syringe into the infant’s mouth (1 mL in each cheek)
or allow infant to suck solution from a nipple
(pacifier) for no more than 2 min before the start of
the painful procedure
2. Sucrose may be given for >1 procedure within a
relatively short period of time, but it might not be
effective if administered more than twice in 1 h
3. Sucrose seems to be more effective when given in
combination with a pacifier; nonnutritive suck also
contributes to calming the infant and decreasing
pain-elicited distress
Adapted from Zempsky et al. [51]. With permission from
American Academy of Pediatrics
Contraindications: Avoid use if the patient (1) is under nil-per-os
restrictions, (2) has fructose intolerance, (3) is low birth weight
or preterm (<28 weeks’ gestation) and has not begun oral feeds,
or (4) has a recent history of glucose intolerance
from 1 to 24 months old who are undergoing
brief stressful medical events, http://www.pedi-
atricsdigest.mobi/content/122/Supplement_3/
S134.full-ref-50 [26, 32] but it has not been suffi-
ciently evaluated for younger infants (i.e. birth to
6 months). Evidence-based behavioral methods
for these very young patients include sucrose,
nonnutritive sucking, and skin-to-skin contact.
Sucrose water (12–50 %; typically 1 packet of
sugar in 10 mL of water), given immediately
before an acute painful procedure, has been
shown to decrease pain in neonates and infants
up to Ð4 to 6 months of age [33]. Results from a
systematic review of the literature support using
sucrose to provide pain relief to infants undergo-
ing venous access. As for the mechanism, some
have suggested that sucrose works via the activa-
tion of endogenous opioids [34], although others
have not found support for this hypothesis [35].
Administration is typically done by dipping a
pacifier into a solution, or instilling it directly
into the mouth with a syringe. Although most of
the research has examined neonate and infant
immunizations, there have been some investiga-
tions with venous access, and the findings have
consistently supported the pain-management
effects of sucrose [36]. Table 51.1 provides a sug-
gested protocol for administering sucrose.
Research has also shown that nonnutritive
sucking (at a rate of or exceeding 30 sucks per
N. Gal Or and Y. Har-Shai
minute) is an effective analgesic, especially when
combined with sucrose [37].
Sucrose is recommended primarily for infants’
≤6 months of age, breastfeeding and skin-to-skin
contact should benefit young and older infants
alike.
Toddlers and Pre-schoolers
Toddlers to age 6 have good understanding of
non-pharmacological interventions; simple
explanation, directions, and honesty are the best
tools for success at this age. For young children,
explaining the procedures with age appropriate
information is useful, in addition to providing
them with the opportunities to ask questions [38].
Examples for active distraction used with this age
group include, allowing them to blow bubbles,
providing toys with lots of colors or toys that
light up. Initiating distracting conversation (e.g.,
how many brothers and sisters do you have?
What did you do at your birthday party?) And
deep breathing methods are all helpful for older
children. Passive distraction techniques include:
having the parents read age appropriate books,
sing songs, and practicing “blowing out birthday
candles” with the child [39].
Keep in mind that young children understand
more than they say. Avoid casual teasing, conde-
scension, or talking about the child while exclud-
ing him or her. Do not tell a child that something
will not hurt unless you are sure that it will not, it
is important to be honest with the child about any
pain or discomfort that he or she will experience.
Once a child is surprised by a painful stimulus, he
or she will become more vigilant and less ame-
nable to distraction or relaxation techniques.
School-Age Children
Older children have a better understanding of pro-
cedures and why they are being done, thus provid-
ing them with age appropriate information and a
choice (e.g., sit or lie down, choose which hand),
this helps them to feel in control of the situation.
Asking parents about their child’s previous pain
experiences and coping mechanisms will help
health care professionals identify which appropri-
ate interventions should be used. Educating school-
aged children about the available passive and active
51 The Management of the Pediatric Patient and Adolescent During Skin Cryosurgery 249

techniques will help them to cope with the distress Table 51.2 Suggested language for parents or health
care providers
and anxiety of the procedure [38]. Active tech-
niques for this age group include blowing bubbles, Language to avoid Language to use
singing songs, squeeze balls, relaxation breathing You will be okay; What did you do in school
there is nothing to today? (distraction)
and playing with electronic devices. Passive dis-
worry about
traction can include watching videos, listening to (reassurance)
music on headphones, reading a book to the child This is going to hurt/ It might feel like a pinch
or telling them a story [39]. this won’t hurt (sensory information)
Children aged 7 to adult are more able to com- (vague; negative
focus)
prehend procedures and cooperate, they have
You are acting like a Let’s get your mind off of it;
learned to dissociate their feelings from their baby (criticism) tell me about that movie …
actions [40], they are willing to cooperate provided (distraction)
that they understand what is happening and what is It will feel like a bee Tell me how it feels
expected of them, this is the age at which bargains sting (negative focus) (information)
are the key to success. “If you let me treat this wart, The procedure will The procedure will be shorter
last as long as … than … (television) program or
I will not treat the other wart today” “if you let me
(negative focus) other familiar time for child)
try, I will stop when you tell me to” [41]. (procedural information;
positive focus)
Adolescents The medicine will Some children say they feel a
It is essential to always ensure a private setting for burn (negative focus) warm feeling (sensory
information; positive focus)
procedures with adolescents, especially as they
Tell me when you are When I count to 3, blow the
sometimes tend to deny pain in front of friends, ready (too much feeling away from your body
and family. Giving them the power to choose the control) (coaching to cope; distraction;
type of distraction, or whether they want friends limited control)
and family present is helpful [38]. Striking conver- I am sorry You are being very brave
(apologizing) (praise; encouragement)
sations, using squeeze balls or having them play
Don’t cry (negative That was hard; I am proud of
with electronic devices are examples of active focus) you (praise)
techniques, while passive distractions include It is over (negative You did a great job doing the
watching videos, training them to breathe deeply focus) deep breathing, holding still …
(in from the nose, count to 5 and out through the (labeled praise)
mouth), and listening to music. Regardless of the Reprinted from Cohen [33]. With permission from
procedure performed, the patient’s developmental American Academy of Pediatrics
Words or phrases that are helpful to one child may be
level and acute level of anxiety will directly impact threatening to another; parents and health care providers
on the success of a procedure and the patient’s should select their language carefully
eventual subjective experience.
Adolescents need gentle reassurance and
carefully chosen words to reduce fear and pain and sensory information in a calm voice and with
(Table 51.2). Adolescents should be encour- age-appropriate language.
aged to ask questions and engage in the process
so that their fears might be allayed [42]. It is
also recommended that the information be pre- Minimizing Pain
sented in a detailed rather than vague fashion during Cryosurgery: Pharmacologic
http://www.pediatricsdigest.mobi/content/122/ Interventions
Supplement_3/S134.full-ref-37 [43] and that
emotive language should be avoided, because Topical Anesthetics
it might heighten anxiety [44]. The clinician
should continue to walk the child through the To be effective, topical anesthetics must traverse
steps of the procedure and outline procedural the superficial layers of skin and affect the nerve
250
Table 51.3 Recommended maximum dose and application area of Eutectic Mixture of Local Anesthetics (EMLA;
product insert)
Age and body weight Maximum total dose
requirement of EMLA cream, g
0–3 months or <5 kg 1 10
3–12 months and >5 kg 2 20
1–6 years old and >10 kg 10
7–12 years old and >20 kg 20
endings within the dermis. The thickness of the
stratum corneum and the acid dissociation con-
stant (pKa) of an anesthetic determine how well
the topical anesthetics can penetrate the stratum
corneum [45].
Depending upon the anesthetic used, the prod-
uct is left in place for 30–60 min. Occlusion with
plastic wrap or massaging the cream into the skin
may achieve quicker onset of action if necessary.
Immediately preceding the procedure, the mate-
rial is removed with dry gauze, and the skin is
wiped clean with water-dampened gauze.
Complete removal of residual cream before the
procedure is particularly important with alcohol-
containing topical anesthetics because of their
incendiary potential [46].
Improper application of topical anesthetic
preparations such as benzocaine, lidocaine, and
tetracaine may cause serious complications,
including death.
Prolonged application, use of inappropriately
high concentrations, and application to large sur-
face areas before outpatient procedures increase
the risk of cardiotoxicity and central nervous sys-
tem toxicity [47].
Lidocaine/prilocaine is a eutectic mixture of
equal quantities (by weight) of lidocaine and pri-
locaine. A 5 % emulsion preparation, containing
2.5 % each of lidocaine/prilocaine, is marketed
by APP Pharmaceuticals under the trade name
EMLA (an abbreviation for Eutectic Mixture of
Local Anesthetics). The manufacturer of EMLA
cites broad parameters to be monitored to avoid
systemic toxicity when the cream is applied to
patients with intact skin who have normal renal
and hepatic function.
As an example, patients older than 7 years
who weigh more than 20 kg should have no more
than 20 g of EMLA applied to their skin and
N. Gal Or and Y. Har-Shai
Maximum application Maximum application
area, cm2 time, hours
1
4
100 4
200 4
covering no more than 200 cm2 of surface area
for less than 4 h. On the other hand, newborns
younger than 3 months of age weighing less than
5 kg should have no more than 1 g of EMLA
applied to an area no larger than 10 cm2 and for
less than 1 h (Table 51.3).
Paracetamol and Non-steroidal
Anti-inflammatory Drugs (NSAIDs)
Despite their good side effect and safety profile,
paracetamol and NSAIDs such as Ibuprofen have
insufficient analgesic potency to be useful for
procedural analgesia. They may though have a
place contributing to post-procedural analgesia.
Sedation
In the pediatric population, and especially in
young children, sedation is typically used as a
premedication prior to a general anesthetic.
Sedation can be useful in children who have sig-
nificant separation anxiety, uncontrolled anxiety
concerning the procedure or who are uncoopera-
tive. Typically, sedation is not used as the sole
anaesthetic for young children, although it can be
used for this purpose perhaps in older children
and teenagers. Furthermore, pediatric patients are
especially vulnerable to laryngospasm, which
usually occurs during surgical stimulation.
Commonly used sedatives for pediatric patients
include oral midazolam (0.3–0.5 mg/kg) or oral
ketamine (4–6 mg/kg). As a rule, sedation should
be administered by a second physician, and not by
the surgeon [48]. Ketamine distinctively provides
analgesia, amnesia and reduces anxiety simulta-
neously. It can also induce salivary secretions that
51 The Management of the Pediatric Patient and Adolescent During Skin Cryosurgery
may cause laryngospasm, especially in pediatric
patients. The increase in salivary secretions can
be attenuated by co-administration of glycopyr-
rolate or atropine; the latter at a dose of 10–20 μg/
kg (to a maximum dose of 600 μg) intravenously
or intramuscularly 30 min before application of
ketamine. The utility of ketamine is limited by
emergence delirium. Postoperative hallucinations
which may be induced by ketamine, may be
reduced by co administering a benzodiazepine,
such as midazolam [49]. Ketamine is contraindi-
cated in pediatric patients with upper respiratory
infections, seizure disorders, increased intraocu-
lar pressure or open globe injuries. Despite its
potential adverse effects, ketamine is a unique
agent that does not significantly suppress protec-
tive airway reflexes or depress the cardiorespira-
tory system. Therefore, it is an especially useful
agent in providing sedation prior to dermal proce-
dures in children.
General Anesthesia
General anesthesia may be required if the proce-
dure involves extensive areas of treatment or if
the child is unable to tolerate treatment even
under sedation.
Anesthetic risk is inversely proportional to
age; therefore, neonates are at the highest risk of
perioperative comorbidity. There are physiologi-
cal, pharmacological and anatomical differences
between children and adults. A thorough under-
standing of these differences is necessary, in
order to provide anesthesia for the pediatric
patient safely. In addition, specific pediatric anes-
thesia equipment is often required [50].
Conclusions
Adequate pain control is now considered a
basic human right. Adequate procedural pain
control in children facilitates the technical
aspects of the procedure, may prevent psycho-
logical distress and importantly, reduces the
incidence of chronic pain symptoms.
A number of excellent standards and guide-
lines for procedural pain in neonates and chil-
dren are available to guide best practice, but
251
strategies can only be effective if acted upon
and utilized. It is the key that all those involved
in caring for children undergoing painful pro-
cedures are aware of the importance of proce-
dural pain management, and ensure that
effective interventions are implemented regu-
larly into routine practice.
If possible, reassurance or anxiety reduc-
tion without sedation is preferable. However,
if sedation is required, we recommend that it
be administered judiciously and that the pedi-
atric patient be vigilantly monitored for respi-
ratory distress or hemodynamic instability.
If general anesthesia is required, we
encourage the presence of an anesthesiologist
who has adequate experience with pediatric
patients. Keep in mind that the anatomical and
physiological characteristics of neonates,
infants and young children are distinct from
adults.
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 Special Populations
52
William Abramovits and Kimberly Dawn Vincent

Abstract
Cryosurgery is easily adaptable to the need of many special populations, so
called under legal considerations. These include pediatric populations, the
elderly, the discapacitated, the mentally handicapped, the in prisoned or other-
wise institutionalized, pregnant and lactating women, etc. Specifically for cryo-
surgery, special consideration should be given to people with darker skin tones
for whom the, usually hypochromic, pigmentary sequelae, with relatively
increased contrast, may be carry psychologic, social and other consequences.

Keywords
Special populations • Pregnancy • Discapacitated • Handicapped • Darker
skin tone

W. Abramovits, MD, FAAD (*)

Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical School, Pregnancy
Dallas, TX, USA
Department of Internal Medicine, Texas College There is a remarkable paucity of literature on this
of Osteopathic Medicine, University of North Texas
subject, probably because of a tacit lack of preoc-
Health Science Center, Fort Worth, TX, USA
cupation over the issue.
Department of Dermatology, University of Texas
As a physical method and one that most com-
Medical Branch, Dallas, TX, USA
monly does not require a local anesthetic, cryo-
Texas Tech University, Health Sciences Center,
surgery should represent the safest procedure
Lubbock, TX, USA
optioned to a pregnant patient (though the use of
Texas A&M Health Science Center College
lidocaine for this purpose has been found safe in
of Medicine, Dallas, TX, USA
pregnancy) [1].
Dermatology Treatment & Research Center,
Photodynamic therapy, immunotherapy with
5310 Harvest Hill Road, Suite #160, Dallas, TX
75230, USA intradermal injections of purified protein deriva-
e-mail: DrA@dermcenter.us tive (PPD) and lasers have been used with vari-
K.D. Vincent, MD, FAAD able degrees of success to treat human papilloma
Belle Meade Dermatology, Nashville, TN, USA virus (HPV), herpetic infections and molluscum

© Springer-Verlag London 2016 255

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_52
256 W. Abramovits and K.D. Vincent

contagiosum in pregnant women. The question is
why, when the obvious choice should be cryosur-
gery, with its inherent safety and recognized suc-
cess rate [2, 3].
The authors suggest cryosurgery to be the first
destructive option in pregnant women.
Some patients develop post-inflammatory pig-
mentations over the treated areas. Caution should
be exerted when treating lentigos and melasma
on the face and on the legs, where the hyperpig-
mentation from cryosurgery may look worse than
the original dyschromia and take as long as a year
to resolve (Figs. 52.1 and 52.2).

Mentally Handicapped

Under the right circumstances, which include

from obtaining permission from legal caretakers
to showing proper kindness to these patients,
cryosurgery is a particularly useful treatment
modalities with the same indications it has in the
general population.

Institutionalized Patients
Fig. 52.1 This illustrates that fair-skinned patients with
The portability of cryosurgery delivery systems sun damaged skin should be warned of post-cryosurgery
hypochromia
and their safety make these units optimal for the
treatment of patients in nursing homes, prisons
and other institutions from which transport to an
office or clinic is impractical or risky.

People of Color

Darker skin tones are likely to reflect most notice-

able the exquisite sensitivity to cold of melano-
cytes. Hypo- and a-chromic lesions from
cryosurgery are not uncommon in some areas of
human skin like the face, torso and proximally on
the extremities, while rare on palms and soles. In
actinically damaged chronically erythematous
skin porcelain smooth patches may represent the
original background skin color.
Darker toned patients may be unhappy with
the resulting loss of pigment which may be
thought of as representative of vitiligo as the
unsavory trade from the destruction of a lesion,
which even of more severe consequences, was
less noticeable. Every effort must be made to pre-
pare these patients in advance. Often, these hypo-
chromias vanish over time, but creating falsely
optimistic expectations may work against the
cryosurgeon.
Fig. 52.2 Achromia 1 month post cryosurgery of a wart
on a dark skin patient. This will probably resolve sponta-
neously over a few months
References
1. Gormley DE. Cutaneous surgery and the pregnant
patient. J Am Acad Dermatol. 1990;23(2 Pt 1):
269–79.
2. Yang YG, Zou XB, Zhao H, Zhang YJ, Li HJ.
Photodynamic therapy of condyloma acuminata in preg-
nant women. Chin Med J (Engl). 2012;125(16):2925–8.
3. Eassa BI, Abou-Bakr AA, El-Khalawany MA.
Intradermal injection of PPD as a novel approach of
immunotherapy in anogenital warts in pregnant
women. Dermatol Ther. 2011;24(1):137–43.
 Cutaneous Lesions
of HIV-Positive Patients
53
Ann M. John, Heather M. Holahan,
and Robert A. Schwartz

Abstract
Human immunodeficiency virus (HIV) is associated with several cutane-
ous conditions, including molluscum contagiosum, condyloma acuminata
and, Kaposi sarcoma. Many treatment modalities, including physical abla-
tion, chemical topical agents, immunomodulators, and antiviral treat-
ments, have been employed to treat these. One treatment that has shown
success is cryosurgery. Since recurrence and more aggressive disease is
associated with HIV infection, close monitoring and repetition of treat-
ments are often necessary.

Keywords
Cryosurgery • HIV • Molluscum contagiosum • Condyloma acuminata •
Kaposi sarcoma • Varicella zoster • Plantar verrucae • Squamous cell
carcinoma

Introduction

HIV is associated with a range of cutaneous man-

ifestations in patients. Often, lesions are larger,
more numerous, and more widely disseminated
A.M. John, MD in these immunocompromised patients compared
Department of Dermatology, to their immunocompetent counterparts.
Rutgers New Jersey Medical School,
Newark, NJ, USA Cryotherapy has been well-studied in HIV posi-
tive patients. Its utility is delineated in mollus-
H.M. Holahan, MD
Department of Dermatology, Rutgers New, cum contagiosium, condyloma acuminata,
Newark, NJ, USA Kaposi sarcoma, and several other conditions.
R.A. Schwartz, MD, MPH, DSc(Hon), FRCP(Edin) (*)
Department of Dermatology, Rutgers University
School of Public Affairs and Administration,
185 South Orange Ave., Newark, NJ 07103, USA
e-mail: roschwar@cal.berkeley.edu

© Springer-Verlag London 2016 257

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_53
258
Molluscum Contagiosum
Description of Disease
Molluscum contagiosum virus (MCV) is com-
monly implicated in cutaneous infection in
HIV positive patients. During the HIV epi-
demic in the mid-1980s, this infection was rec-
ognized as a defining feature [1]. A member of
the Poxviridae family, MCV rapidly prolifer-
ates in differentiating cells of the epidermis
before causing a local inflammatory response.
The epidermal growth factor receptor and che-
mokine receptors in epidermal cells may allow
MCV entry. Lesions are waxy, skin-colored,
dome-shaped umbilicated papules with grey-
white discharge upon squeezing; they are usu-
ally located in the genital area, palms and
soles, and mucous membranes, including the
lips, cheeks, and conjunctiva [2–6]. In HIV-
positive patients, lesions are usually larger,
more numerous, and more widely dissemi-
nated. Presence of MCV lesions suggest wors-
ening immune status, with obliteration of
T-helper lymphocytes [7].
The virus is transmitted by direct skin con-
tact, and perhaps via fomites, including towels,
bath sponges, and swimming pools. Contributors
to the spread include shaving and scratching,
unprotected intercourse, topical corticosteroids
and calcineurin inhibitors, and a personal his-
tory of atopic dermatitis [8, 9]. Vertical trans-
mission has been reported [10]. Diagnosis is
usually based on the clinical observation of
umbilicated papules. A dermatoscope can help
identify typical features, including the crown,
punctiform, radial, and mixed-flower patterns of
blood vessels [11]. Histopathology demon-
strates hyperplastic, acanthotic squamous epi-
thelium with a classic central crater filled with
keratin fragments and molluscum bodies. Also
known as Henderson-Paterson bodies, mollus-
cum bodies are eosinophilic and intracytoplas-
mic inclusions. Polymerase chain reaction
sequencing and ELISA may be used in atypical
cases to confirm the diagnosis [2].
A.M. John et al.
Therapeutic Alternatives
While MCV generally causes a self-limiting
infection in immunocompetent hosts, this is strik-
ingly different from its effect in immunocompro-
mised hosts, specifically with HIV. Thus,
aggressive treatment is needed, including physi-
cal ablation, chemical agents, immune stimula-
tors, and antivirals [2]. Curettage after topical
anesthetic and single pulse dye laser to each
lesion, repeated after 2-3 weeks if necessary,
have also shown success. Photodynamic therapy
and electron beam have been specifically applied
to HIV-positive patients; side effects include ery-
thema, hypo- or hyper-pigmentation, bleeding,
pain, pruritus, burning, and scarring [2, 12, 13].
Trichloroacetic acid has been used in HIV-
positive patients with MCV [14]. Immune stimu-
lators including 5 % imiquimod cream,
cimetidine, diphencyprone, and intralesional can-
dida antigen have been used as well [2, 15].
Finally, the antiviral cidofovir topically and intra-
venously been used in HIV positive patients, the
intravenous form being associated with neutrope-
nia and nephrotoxicity [2]. For patients with HIV,
physical ablative therapies seem to be the least
effective.
Cryotherapy
Cryotherapy has shown various rates of success
in HIV positive patients, but it is less effective
than the chemical, immune stimulating, and anti-
viral agents. Liquid nitrogen (LN) is applied for
10–20 s to each lesion in two freeze-thaw cycles,
repeated after a week if necessary [16]. Side
effects include pain, erythema, changes in pig-
mentation, and burning sensation.
A comparative study of 20 HIV patients with
disseminated facial lesions demonstrated an aver-
age reduction in lesion count of 55 % after 8 weeks
of treatment. This study suggested that 100 % tri-
chloroacetic acid is superior to cryotherapy in HIV
positive patients with MCV [14]. Another study
reported recurrence of lesions within 6–7 weeks
53 Cutaneous Lesions of HIV-Positive Patients
after lesion removal, suggesting poor long-term
value of physical ablation in HIV positive patients
[17]. One study demonstrated similar efficacy of
cryotherapy and topical potassium hydroxide in
MCV lesions; however this study was not confined
to HIV positive patients [18]. There was one case
report of the development of Wells syndrome, or
eosinophilic cellulitis, after treating MCV with
repeated cryosurgery [19]. Another demonstrated
disappearance of many MCV lesions with repeated
cryosurgery, although not all lesions were totally
destroyed [20].
Condyloma Acuminata
Description of Disease
Condyloma acuminata are anogenital warts
caused by human papilloma virus. Highest preva-
lence of warts is in sexually active woman
between ages 20 and 24 and sexually active men
between ages 25 and 29 [21]. HIV positive
patients are more likely to develop genital warts
that are generally larger, more numerous, and
more recalcitrant to a variety of treatment modal-
ities, with higher rates of recurrence [22].
Condyloma can present as small, flat papules,
or larger cauliflower-like lesions. The latter can
interfere with defecation, urination, and sexual
intercourse, causing pruritus, bleeding, and mal-
odorous discharge. Diagnosis is based on clinical
observation; atypical cases warrant histological
examination. Differential diagnosis is vast,
including condyloma lata, epidermoid cysts,
Fordyce spots, granuloma annulare, lichen pla-
nus, MCV, seborrheic keratosis, Bowenoid papu-
losis, squamous cell carcinoma, and vulvar
intraepithelial neoplasia [22–25].
Therapeutic Alternatives
Treatment is the same for HIV positive or nega-
tive patients. Regardless of the treatment, recur-
rence rates are high, ranging from 25 % to 67 %
259
[26]. Topical agents for external warts include
imiquimod cream, which enhances immune
response and should be applied until complete
resolution, usually within 16 weeks. Clearance
rate is 37–50 % with a 13 % recurrence rate [27,
28]. Side effects include pruritus, erythema,
burning, tenderness, ulceration, erosion, and pain
[23]. Other topical solutions include 0.5 % podo-
filox, 15 % sinecatechins ointment, 25 % podo-
phyllin solution, and trichloroacetic acid [23].
Surgical treatment includes electrosurgery, which
easily destroys external warts but can result in
significant pain and scarring if the destruction is
too deep [24]. Excision is used, particularly in
pedunculated or exophytic warts. This method is
especially useful when histological examination
is required. Since the warts may actually be squa-
mous cell carcinoma in HIV positive patients,
histological examination is often necessary [23].
Options for recalcitrant lesions include interferon
alpha, cidofovir, photodynamic therapy, carbon
dioxide laser therapy, and fluorouracil.
Preventative methods include vaccination and
circumcision [23].
Cryosurgery
The use of cryosurgery in condyloma acuminata
is well-established. LN is applied to the lesion to
a 1–2 mm margins. Up to three freeze-thaw cycles
are performed and treatment sessions are usually
repeated within 1–2 weeks [23]. Clearance rates
are between 71 % and 79 % and recurrence rates
range from 38 % to 73 % at 6 months [29]. One
study showed that cryosurgery needed to be
repeated about four times before complete resolu-
tion of anogenital warts [30]. In a study of 298
HIV positive patients, cryosurgery was the most
commonly used treatment modality, with an aver-
age of three treatment sessions per patient.
Recurrence rate was 12.9 %, after an average of
9.9 months [25]. A study of the use of cryotherapy
or cryotherapy with adjuvant interferon demon-
strated resolution in 79.7 % of patients, with
higher recurrence rates in HIV-positive patients.
260
Cryotherapy proved a useful tool for large lesions
with good aesthetic results [31].
A study of 80 HIV negative males showed
that cryotherapy had a higher rate of complete
resolution than 5 % imiquimod cream (86.7 %
versus 68.6 %). However, cryotherapy was
associated with more pain and inconvenience
[32]. A study of 140 HIV negative patients
demonstrated equivalence in efficacy between
cryosurgery and combination of cryosurgery
and podophyllotoxin cream, although the
combination resulted in slightly faster resolu-
tion [33].
Kaposi Sarcoma
Description of Disease
Kaposi Sarcoma (KS) may present at any stage
of HIV illness, but usually occurs after recent
suppression of the immune system such as with
opportunistic infection. KS is commonly
described as symmetric and multicentric, with
visceral and cutaneous involvement occurring
concurrently [34–40]. Morphologically, KS
may present with several variants: patch,
plaque, nodular, lymphadenopathic, exophytic,
infiltrative, ecchymotic, telangiectatic, keloi-
dal, and cavernous [36]. Macular lesions are red
to purple, and vary from millimeters to centi-
meters [39]. Trunk lesions may begin expedi-
tiously over a couple days as macules, with
evolution to papules and tumors. Oblong pap-
ules often present on the legs and face and may
cause pain and edema [39]. Distal extremity
involvement may include papules and patches,
which may enlarge into plaques or form tumors
over time. Both morphologies may occur
together as large, violaceous plaques with over-
lying nodules [39]. Cutaneous areas more fre-
quently involved include the nose, post-auricular
area, feet, legs, penis, trunk, and oral cavity
[34–39]. KS may also be complicated by
involvement of the lymphatic system; lymph
nodes should be evaluated on presentation [34–
38, 41].
A.M. John et al.
Therapeutic Alternatives
Optimal curative therapy for KS in HIV does not
exist. No treatment has shown increased longev-
ity of survival, but most patients die from causes
unrelated to KS. Treatment aims to ameloriate
cosmetically disfiguring lesions, unpleasant oral
lesions, and control pain and edema without fur-
ther compromising the immune system [34–39,
42]. It may include surgery, laser ablation, che-
motherapy, radiation, immunotherapy, and anti-
virals [43].
Cryotherapy
Cryotherapy of KS is a viable treatment given its
ease of administration, good outcome, low cost,
and lack of systemic side effects [44]. In 21 patients
with HIV-KS, cryotherapy induced complete or
partial response in greater than 85 % of the cutane-
ous Kaposi’s sarcoma irrespective of morphology
or location [42].
Complete resolution of KS lesions using cryo-
therapy was noted in 19/30 patients, with a mean
number of three sessions needed per patient [44].
Treatment was halted in three patients with sub-
sequent progression of disease, with imiquimod
added to eight partial responders with complete
resolution achieved. Cryotherapy may be most
effective when used for more macular and patchy
lesions [45] or as adjuvant therapy when com-
plete response is not achieved [44].
Cryosurgery in Other Cutaneous
Conditions in HIV Positive Patients
Cryosurgery has been sparsely reported in other
cutaneous conditions in HIV positive patients.
One report demonstrated its efficacy in persistent
herpetic lesions secondary to varicella zoster in a
HIV positive patient previously treated with acy-
clovir, brivudine, and famciclovir without com-
plete resolution [46]. Cryosurgery has been
suggested as a treatment for plantar verrucae, as
53 Cutaneous Lesions of HIV-Positive Patients
it is more aggressively with higher rates of recur-
rence in HIV positive patients [47, 48].
Conclusion
Cryosurgery has shown favorable efficacy in
various cutaneous lesions associated with HIV
positive patients. These include MCV, condy-
loma acuminata, KS, and several other condi-
tions. Immunosuppressed patients are subject
to higher recurrence of cutaneous lesions. As
such, multiple cryosurgery treatments must be
employed for complete resolution. There is no
contraindication to the use of cryosurgery in
HIV, but other treatment modalities show com-
parable or improved efficacy.
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Manuskiatti W. Generalized molluscum contagio-
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17. Robinson MR, Udell IJ, Garber PF, Perry HD,
Streeten BW. Molluscum contagiosum of the eyelids
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18. Handjani F, Behazin E, Sadati MS. Comparison of
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19. Stavropoulos PG, Kostakis PG, Panagiotopoulos
AK, Papakonstantinou AM, Petridis AP, Georgala S.
Molluscum contagiosum and cryosurgery: triggering
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2003;83(5):380–1.
20. Vozmediano JM, Manrique A, Petraglia S, Romero MA,
Nieto I. Giant molluscum contagiosum in AIDS. Int
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 Part IX
Special Indications and Contraindications
 Special Indications
and Contraindications
54
Yaron Har-Shai

Abstract
Cryosurgery is the most commonly performed dermatologic procedure in
the United States.
A long period of follow-up in the field of dermatological cryosurgery
has obtained supportive evidence that cryosurgery is a distinct therapeutic
tool for the management of skin tumors, i.e., benign, pre-malignant and
cancerous and attests to its effectiveness, when properly administered by
the skilled cryosurgeon.
Many of the effects of the skin freezing methods employed in clinical
practice produce inflammatory changes that are probably important for a
successful treatment. Therefore, morbidity, side effects and complications
cannot always be treated as a separate entity. Thus, the treating physician
should be aware of the absolute and relative contraindications of the pro-
cedures in order to prevent harm or make the condition worse.
The contraindications for cryosurgery of the skin can be divided into
three groups i.e. by lesion, by area and by patient. In each of those groups
every disease is categorized as an absolute (A) or relative (R)
contraindication.
It should be stressed that apart from the commonest types of basal-cell
carcinoma, no skin tumor should be treated without histological proof
diagnosis. The relatively few absolute contraindications to cryosurgery
generally are related to concomitant illnesses in which excess reactions to
cold may occur or delayed healing may be anticipated. Some relative con-
traindications may make alternative treatment modalities more suitable.

Y. Har-Shai, MD
Department of Plastic Surgery, The Lady Davis
Carmel Medical Center, Linn Medical Center,
Haifa, Israel
e-mail: yaron07@yahoo.com

© Springer-Verlag London 2016 265

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_54
266
Keywords
Cryosurgery • Skin • Absolute and relative contraindications • Lesion •
Area • Patient • Diagnostic biopsy
Cryosurgery is the most commonly performed der-
matologic procedure in the United States. There
are many different ways to achieve cold tempera-
tures, but clinically, the end result is to freeze the
fluid in the cells, which causes crystals that damage
them, and results in tissue destruction.
Many of the effects of the skin freezing meth-
ods employed in clinical practice produce inflam-
matory changes that are probably important for a
successful treatment. Therefore, morbidity, side
effects and complications cannot always be treated
as a separate entity. Thus, the treating physician
should be aware of the absolute and relative con-
traindications of the procedures in order to prevent
harm or make the condition worse.
Zacarian [1] has published his list of diseases in
which cryosurgery in general should be precluded.
These concurrent diseases may adversely affect
the success rates and healing after cryosurgery.
Dawber [2] has published the complications
and contraindications of cryosurgery. He has
stated that there are no absolute contraindications
to cryosurgery. Furthermore, many of those listed
in cryosurgical and dermatological surgery books
simply imply that for many skin lesions, better
cure rates can be obtained with other modes of
treatment such as for morphoeic basal-cell carci-
noma; also, certain sites and skin types lessen the
usefulness of cryosurgery mainly for cosmetic
reasons i.e. scalp and beard areas and black skin.
Dawber entirely agrees with Zacarian regarding
the preclusion of diseases that affect the success
rate and healing following cryosurgery.
Dawber [2, 3] stated that one of the most
important contraindications is the absence of an
accurate diagnosis; this is not to denigrate clini-
cal judgment, however, which will generally be
adequate. Apart from the commonest types of
basal-cell carcinoma, no skin tumor should be
treated without histological proof diagnosis. This
means that destructive cryosurgery equipment
Y. Har-Shai
that is easy to use must not be put in the hands of
inexperienced physicians without adequate
supervision and training. Nordin advocated that,
for an experienced cryosurgeon, even tumors on
such difficult sites as the ear, eyelids and nose,
are relatively well suited for cryosurgery [4].
The relatively few contraindications to cryo-
surgery generally are related to concomitant ill-
nesses in which excess reactions to cold may
occur or delayed healing may be anticipated.
Some relative contraindications may make alter-
native treatment modalities more suitable.
Andrews [5] and Sharma and Khandpur [6]
divided the contraindications for skin cryosur-
gery into two groups, absolute and relative.
Usatine and Stulberg [7] published the list of
contraindications for skin cryosurgery. They
divided the contraindications into three groups
i.e. by lesion, by area and by patient. In each of
those groups every disease was categorized as
an absolute (A) or relative (R) contraindication.
Since this way of classification is more didactic
and memorable, we hereby revise and update
the list by Usatine and Stulberg, which includes
the condition in which skin cold therapy is abso-
lutely (A) or relatively (R) contraindicated as
follows:
By Lesion
Melanoma – (A)
Lesions in which tissue pathology is
required – (A).
If Mohs is indicated, cryosurgery is not – (A).
Sclerosing BCC, morphoeic BCC, micronodular
BCC, metatypical BCC or Baso-Squamous
carcinoma or moderately or poorly differenti-
ated Squamous Cell Carcinoma – (A).
Tumors over 2 cm in diameter – (R).
BCCs with ill-definable borders – (R).
54 Special Indications and Contraindications 267

Recurrent tumors in the H-zone (with the excep- anaphylaxis, cryoglubulinemia, cryofibrino-
tion of post radiotherapy) – (R). genemia and paroxysmal cold
Recurrent BCCs with secondary sclerosis – (R). hemoglobinuria – (A).
Nevus or any undiagnosed lesion suspicious for Reduced levels of consciousness or impaired
non-melanoma malignancy should not be understanding – (A).
treated with cryosurgery because if a nevus Patients unable to accept possibility of pigmenta-
were to grow back, it might appear malignant tion changes – (A).
and a biopsy could be suspicious for mela- Chills or acute febrile illness – (A).
noma (pseudomelanoma) – (R). Acute skin conditions e.g. rashes, eczema – (A).
Aggressive non-melanoma skin cancers – (R) Angina pectoris or other severe cardiac
diseases – (R).
Arteriosclerosis and impaired peripheral
By Area circulation – (R).
Varicose veins – (R).
Skin malignancy located in high-risk areas like Diabetes especially severe pancreatic (insular)
the temple, upper lip near vermilion borders, diabetes – (R).
ear or nasolabial folds, abutting cartilage or Anemia – (R).
bone or with perineural spread – (A). Cancer – (R).
Very large skin areas. Cryosurgery when applied Rheumatoid arthritis – (R).
to an organ with weight exceeding 7 % of total Blood dyscrasias of unknown origin and platelet
body weight might cause hypothermia and deficiency disease – (R).
DIC – (A). Keloidal tendency – (R).
Impaired circulation. Tissue damage may result Collagen vascular disease – (R).
from vasoconstriction – (A). Pyoderma gangrenosum – (R).
Tumors with a high recurrence rate situated on Collagen and autoimmune diseases – (R).
the nasolabial fold, inner canthus and preau- Concurrent treatment with immunosuppressive
ricular areas – (R). drugs – (R).
Eye lid margins – (R). Concurrent treatment with renal dialysis – (R).
Ala nasi and hair-bearing areas due to a high risk of Multiple Myeloma – (R).
developing alopecia, especially cicatrical – (R). Lymphoma – (R).
Pre-tibial area and shins and scalp in elderly due Impaired sensation or paralysis. Patient can-
to slow wound healing – (R). not report when they become anesthetic
Deep X-ray therapy or other ionizing radiation in from cold. Tissue damage occurs slightly
the last 6 months in the region being below temperatures that produce
treated – (R). numbness – (R).
Open wound after 48 h – (R). Dark-skinned individuals due to high risk of
Regenerating peripheral nerves – (R). developing cosmetically inacceptable pro-
Extensive scar tissue – poor blood supply may tracted hypopigmentation – (R).
lead to ice burns – (R).

By Patient References

Hypersensitivity to cold, such as Raynaud’s phe-
nomenon, especially when lesions are on fin-
gers, toes, nose, ear and penis, cold urticaria,
cold intolerance, cold allergic conditions, cold
1. Zacarian SA. Cryosurgery for skin cancer and cutane-
ous disorders. St. Louis: CV Mosby Co.; 1985.
p. 283–97.
2. Dawber RPR. Cryosurgery: complications and con-
traindications. Clin Dermatol. 1990;8(1):108–14.
268
3. Dawber RPR. The use of cryosurgery in dermatology.
In: Korpan NN, editor. Basics of cryosurgery. Wein:
Springer; 2001. p. 46–87, chap 7.
4. Nordin P. Cryosurgery for epithelial skin cancer. In:
Korpan NN, editor. Basics of cryosurgery. Wein:
Springer; 2001. p. 72–87, chap 7.3.
5. Andrews MD. Cryosurgery for common skin condi-
tions. Am Fam Physician. 2004;69:2365–72.
Y. Har-Shai
6. Sharma VK, Khandpur S. Guidelines for cryosurgery.
Indian J Dermatol Venereol Leprol. 2009;75:
90–100.
7. Usatine RP, Stulberg DL. Cryosurgery. In: Usatine
RP, Pfenninger JL, Stulberg DL, Small R, editors.
Dermatologic and cosmetic procedures in office
practice. Philadelphia: Saunders, Elsevier Inc.; 2012.
p. 182–98, chap 15.
 Aesthetic/Cosmetic Cryosurgery
55
Oliverio Welsh, Esperanza C. Welsh,
and Jesús Alberto Cárdenas

Abstract
Cryosurgery is a useful office therapeutic method for treating diverse
benign unaesthetic skin diseases. Treatment of acne, acne scars, idiopathic
gutatte hypomelanosis, infantile hemangiomas, flat warts, freckles, lentigo
simplex, photoaging, pyogenic granuloma, rhinophyma, sebaceous hyper-
plasia, seborrheic keratosis, skin tags, solar lentigo, spider nevi, trichoepi-
thelioma, and venous lakes is addressed. Most conditions require a single,
less than 30 s long, 1 mm margin treatment cycle. Avoidance of overtreat-
ment and careful patient selection can minimize potential adverse effects
such as hypopigmentation or scarring. Combination with other treatment
modalities can improve aesthetic outcome. Cryolipolysis is a non-invasive
subcutaneous fat-reduction technique indicated for the flanks and abdo-
men that needs further evaluation. When properly applied, cryosurgery is
a fast, safe, effective and economical tool for the treatment of most unaes-
thetic dermatoses.

Keywords
Cryosurgery • Cryotherapy • Sebaceous hyperplasia • Warts • Hemangioma
• Lentigo • Acne • Scars • Aging • Cryolipolysis

Abbreviations

O. Welsh, MD, DSc (*) CP Cryoprobe

Department of Dermatology, FTC Freeze-thaw cycle
University Hospital, UANL,
Magallanes 105 Oriente Colonia Mirasierra, OS Open spray
San Pedro, Nuevo León 66240, Mexico s Seconds
e-mail: owelsh@yahoo.com
E.C. Welsh, MD • J.A. Cárdenas, MD
Department of Dermatology,
Centro de Especialidades Medicas,
Monterrey, Nuevo León, Mexico

© Springer-Verlag London 2016 269

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_55
270
Introduction
Cryosurgery is a technique that uses freezing
temperatures, via the delivery of a cryogen, to
destroy abnormal tissue. In the past, different
cryogens such as liquid air, solidified carbon
dioxide, and liquid oxygen have been used.
Liquid nitrogen (LN) has been the leading agent
for dermatological therapy in the last 50 years.
Allington popularized liquid nitrogen in 1950 for
the treatment of warts, keloids, hemangiomas and
leukoplakia using a cotton swab for delivering
the cryogen [1]. Modern cryosurgery started with
the development by Cooper and Lee of a cryosur-
gical probe to transmit cold temperature to neural
tissue for the treatment of different neurological
diseases such as Parkinson [2]. Afterwards,
Douglas Torre modified Cooper and Lee’s probe
to treat cutaneous lesions [3]. A new era began
when Setrag Zacarian, working with engineer
Michael Bryne, developed and constructed a
handheld unit for the application of LN, which
became the first commercially available device
for therapeutic use in dermatology [4].
Properly trained physicians that know its pre-
cise indications, correct application techniques,
and side effects should be the ones using LN for
cosmetic dermatology. It is important to not for-
get that it is better to undertreat than overtreat
because of potentially unpleasing adverse effects.
This chapter will focus on benign dermatoses,
usually located on the hands, neck and face that
can be improved aesthetically by proper cryosur-
gical management.
Infantile Hemangiomas
Treatment of infantile hemangiomas includes
wait-and-see, topical or systemic steroids, topical
imiquimod, cryosurgery, laser and propanolol
therapy. Topical propranolol is used for small
lesions and systemic propranolol for larger ones
for several months with good results [5–8].
Cryosurgery is indicated for hemangiomas up to
1.5 cm. Cryosurgical treatment is done with a
cryoprobe, adjusted to the size of the hemangi-
oma, is applied on the lesion using pressure to
O. Welsh et al.
collapse the underlying blood vessels. A freeze-
thaw cycle (FTC) can vary from 40 s up to 2 min
depending on its size and depth with a 1 mm mar-
gin. Immediate effects of the treatment include
edema and erythema. If necessary, a second FTC
can be administered 4 weeks later but one cycle
tends to be sufficient (Fig. 55.1a, b).
Venous Lakes
Venous lakes of the lips are common lesions
found in elderly patients. They are caused by
dilation of venules and present as soft blue eleva-
tion [9]. Venous lakes of the lips can be treated
with CP adapted to the size of the lesion and just
as with infantile hemangiomas, compression is
required [10]. A freezing time of 10–20 s and a
1–2 mm margin is needed. Immediate edema and
erythema appears with crusting several days after
treatment. If needed, a second freeze-thaw cycle
can be administered 4 weeks later.
Spider Nevi
Spider nevi, also known as spider angiomas or
vascular spiders, are small vascular lesions
appearing in 10–15 % of adults and children [11].
These lesions can be treated with laser, sclero-
therapy, and electrosurgery [12]. In selected
patients, cryosurgery can represent an effective
alternative. The center of the spider nevi is frozen
with CP for 5–10 s with a 1 mm margin and,
depending on the evaluation of results 4 weeks
later, the freeze-thaw cycle can be repeated.
Skin Tags (Acrochordons)
Skin tags are flesh-colored, often pedunculated,
benign lesions usually encountered in the neck,
axilla, eyelids and groin. The techniques for treat-
ing skin tags include surgical removal under
topical anesthesia, electrocauterization, and cryo-
surgery [13]. A practical way to treat small skin
tags is to limit the base of the lesion with small
scissors and freeze the acrochordon with a C tip
55 Aesthetic/Cosmetic Cryosurgery
a b
Fig. 55.1 (a, b) Infantile hemangioma before and after one cycle of cryosurgery
open spray technique all the way to the base and
then cutting it with scissors. This technique pro-
tects the surrounding skin from cryodamage and
has the advantage of not requiring anesthesia.
Sebaceous Hyperplasia
Sebaceous hyperplasia is a benign proliferation of
sebaceous glands that appear as soft, yellow and
umbilicated papules. Its size varies from 1–2 mm
to 1–1.5 cm. Their treatment includes electrodes-
sication, shaving, laser, and cryosurgery [14].
Properly selected patients with Fitzpatrick skin
types 2–4 can benefit from one freeze-thaw cycle
between 7 and 15 s with a CP and a 1 mm margin;
a second cycle can be administered 6 weeks later
in case of incomplete remission (Fig. 55.2).
Trichoepithelioma
Trichoepithelioma is a benign follicular tumor that
mainly affects young women. Surgery is the treat-
ment of choice for solitary trichoepitheliomas.
Cryosurgery, electrosurgery, carbon dioxide lasers,
dermabrasion, curettage and electrodesication rep-
resent alternative options for multiple lesions. FTC
until ice formation is recommended. Multiple ses-
sions 1 month apart are usually needed. Recurrence
is common in most treatment modalities [15, 16].
Seborrheic Keratosis
Seborrheic keratosis is an extremely common,
benign tumor of the epidermis. Caucasians are
271
more frequently affected. Its prevalence is superior
to 60 % in people over 50 years of age. Its color can
range from white/gray and brown to black.
Diagnosis is based on clinical appearance.
Histological examination is needed when diagnosis
is unclear. Despite its benign nature, many patients
seek treatment for cosmetic reasons especially
when they are located on the face, neck and arms.
Several treatment modalities exist of which curet-
tage, cryosurgery, and shaving are usually preferred.
Cryosurgery offers the advantages of requiring less
wound care and no anesthesia. For small, flat,
superficial lesions a C tip OS technique with FTC
of 5 s yields an excellent cosmetic result. Thick
lesions require combined treatment methods. Open
spray with a B size tip for 7–25 s followed by curet-
tage and hemostatic solution application offers a
good treatment alternative without the need of topi-
cal or intralesional anesthesia. A single test lesion
can be treated to evaluate aesthetic outcome before
treating multiple keratosis (Fig. 55.3a, b) [17, 18].
Flat Warts
Infection by human papillomavirus can produce
multiple flat warts on places like the arms and face.
Cryosurgery is considered an option after medical
treatment has failed. The application of LN with
open spray on the wart for 3–4 s with 1–2 mm mar-
gin is well tolerated and cosmetic results tend to be
good especially in Fitzpatrick skin types 2–4. A
second cycle 3–4 weeks later achieves greater
remission rates [19]. After treatment, sun exposure
prevention with sunblock is recommended for at
least 1–2 months. Topical tretinoin cream is used
as an adjuvant to prevent recurrence.
272
Fig. 55.2 Sebaceous
hyperplasia before and after
one cycle of cryosurgery
Freckles (Ephelides)
Freckles response to cryosurgery is variable. Best
results are obtained in Fitzpatrick skin type 2 and
3. Treatment with open spray and a C tip cover-
ing a 1 mm margin for 2–3 s is sufficient. An
alternative regimen which uses a closed probe
until uniform ice is formed is also recommended
[16]. In big freckles, it is necessary to combine
treatments to prevent recurrence and achieve best
cosmetic results. Appropriate sunscreen, antioxi-
dants, and avoiding sun exposure are convenient
recommendations. In cases of incomplete
response, a light hypopigmenting agent can be
added to obtain best outcome.
Idiopathic Gutatte Hypomelanosis
Hypopigmented lesions that often appear on the
dorsum of the forearms and legs characterize this
acquired leucoderma. It’s more frequently
encountered in individuals with chronic sun
exposure. Cryosurgery application with an open
spray tip C for 2–5 s for 1 cycle and a 1 mm
O. Welsh et al.
margin is often sufficient to obtain over 50 %
improvement of skin color. Results are best eval-
uated 4–8 weeks after treatment. Sun exposure
protection and sunscreen are indicated [20].
Lentigo Simplex
These hyperpigmented melanocytic lesions often
appear on the dorsum of hands, forearms and
face. Treatments include laser, topical therapy,
and cryosurgery. Patient selection is important.
One cycle with open spray with a C tip to a 1 mm
margin for 5–10 s is often enough for clearing the
lesion. It is important to apply the cryogen evenly.
Temporary cryotherapy effects include burning
sensation and minimal pain. Epicutaneous or
intralesional anesthesia is administered in over-
sensitive patients [21].
Actinic (Solar) Lentigo
This sun-induced pigmented light to dark brown
dermatoses often appears on the face. When the
55 Aesthetic/Cosmetic Cryosurgery
a process of the pilosebaceous complex may
b and pustules are treated with open spray tipped
Fig. 55.3 (a, b) Seborrheic keratosis before and after one
cycle of cryosurgery
lesion is solitary and unevenly pigmented, it is
necessary to distinguish it from malignant enti-
ties, sometimes using dermatoscopy. In case of
diagnostic uncertainty, a biopsy is necessary to
exclude malignancy before therapy. One freeze-
thaw cycle with open spray for 5–10 s, 2 mm
margin with a paintbrush or circular evenly
applied technique is sufficient. When treating
multiple lesions, a test site is useful to evaluate
skin response to the cryogen. Adverse effects are
similar to those encountered when treating len-
tigo simplex. Post-procedure care is essential to
prevent recurrence. Irregular hypopigmentation,
a peripheral pigmented ring and leucodermic
areas can be a consequence of an uneven appli-
cation [22].
Acne
Acne is one of the most common cosmetic
problems. This multifactorial inflammatory
273
develop comedones, papules, pustules,
abscesses, nodules, and induce scarring. Acne
and its sequelae can cause a significant negative
impact on quality of life. The use of cryosur-
gery is a useful adjuvant in acne’s therapeutic
and cosmetic results. Treatment with cryosur-
gery contributes to a decreased number of com-
edones, involution of papules, pustules and
nodules, as well as improvement of post-acne
scars. In the inflammatory phase, the papules
C for 2–3 s and nodules for 3–4 s, applying the
cryogen exclusively on the lesion. Patient selec-
tion is important to avoid pigmentary changes
[16, 23].
In Fitzpatrick skin types 2 and 3, mild and
moderate acne atrophic scars can be treated
with closed probes. Prior to treatment, a small
test site can show the patient the technique, evo-
lution and pigmentary changes. Before treat-
ment, all makeup and creams should be removed
and the area to be treated carefully delimited
with a skin marker. In patients with a low pain
threshold, previous oral analgesics or epicuta-
neus anesthesia should be administered. A door
knob probe is applied with pressure over the
scars for 10–12 s depending on the scar type.
Borders are treated with a cotton swab with liq-
uid nitrogen to achieve a blending effect over
the surrounding skin. This procedure can be
applied on some or all affected cosmetic regions
of the face. Erythema, pain, and edema are
expected manifestations (Fig. 55.4). Patients
should be previously informed of immediate,
mediate and long-term manifestations. Cold
compresses can help lessen edema, pain and
decrease vesicle formation. Post-acne hypertro-
phic and queloid scars are more frequent in men
on the inferior maxillary, chest, and back.
Cryotherapy is an effective option in patients
with Fitzpatrick skin types 2–4; better results
are obtained in small lesions less than 1-year
evolution. Two to three freeze-thaw cycles of
25 s with open spray B tip on each lesion is rec-
ommended. Cryosurgery plus intra-lesional ste-
roids can accelerate the involution of the scar
and decrease the pain associated with the corti-
coid injection [24, 25].
274
Fig. 55.4 Post-acne scars before, immediately after cryosurgery and 3 months later
Rhinophyma
Rhinophyma is the hyperplasia and hypertrophy
of sebaceous glands and connective tissue of the
nose in patients with chronic advanced rosacea.
Medical treatment is adequate for the early
stages and surgical modalities reserved for late
ones. Cryosurgery alone or with surgery and
oral treatment, represents an inexpensive low-
risk option that offers improvement. The entire
nose is covered with open spray for 15–30 s for
two freeze-thaw cycles 1–4 min apart. Additional
sessions 2–8 weeks apart can be given. Strict
sun exposure avoidance is recommended
[26–28].
Pyogenic Granuloma
Pyogenic granuloma is a benign, acquired, vas-
cular proliferation found on mucosa and skin that
usually appears as a red, solitary papule on the
head, neck and upper extremity. Many treatment
modalities exist, of these; surgical excision,
curettage, and cryotherapy offer the best results.
A closed probe or dipstick technique is used in
the lesion until a 2 mm margin of frozen tissue is
achieved. To obtain complete remission, most
lesions require one to two cycles, which can be
administered monthly. LN carries an overall
recurrence rate of 1.63 % compared to 2.94 % of
surgical excision and 9.55 % of curettage.
Dyschromias are frequent adverse effects that
can be cosmetically unacceptable in dark-skinned
patients [29, 30].
O. Welsh et al.
Photoaging
In photoaging, Fitzpatrick skin types 2–3 can ben-
efit from cryosurgery on light to medium rhytides
around the lips and other areas on the face. The
cryogen can be applied by face units, using a
freeze-thaw cycle of 5–15 s with a closed probe in
a homogenous distribution. The clinical effects can
be comparable to those of a medium trichloroacetic
acid-peel. Edema and erythema are the first mani-
festations. Thereafter, blisters and crust formation
appear. One to 2 weeks later, a red homogenous
skin surface appears. Sun exposure should be
strictly avoided including exposure while driving
around peak sun hours. Sunscreen agents that pro-
tect from A and B ultraviolet radiation are required.
Adverse Effects and Complications
Immediate edema, erythema, vesicle formation,
and crusting are expected tissue responses to
freezing. They usually disappear 1–2 weeks after
treatment.
Topography and freezing time are related to the
duration of the above symptoms. Pain is usually
tolerable and seldom requires treatment with anal-
gesics. In case of being necessary, prescription of
non-steroidal anti-inflammatory drugs for 1–2 days
is sufficient. Bacterial infection of treated sites is
very rare. The treated area needs to be reviewed the
following day and, afterwards, as many times
needed depending on its evolution. If the patient
has a history of recurrent herpes infection, preven-
tive administration of acyclovir is prescribed.
55 Aesthetic/Cosmetic Cryosurgery
Prolonged or permanent adverse effects in
cosmetic cryosurgery are uncommon due to the
short duration of the treatment (<30 s). However,
hypopigmentation and hyperpigmentation, as
well as irregular pigment distribution can appear.
Using a test site previous to treatment on hands
and face is advisable to foresee individual
response to the cryogen [16]. The compliance of
post-cryosurgery indications must be followed
strictly. Of particular importance, sun exposure
avoidance can prevent dyschromias.
Benign lesions usually heal between 10 and
20 days with the exception of post-acne scars that
can take between 3 and 6 weeks depending on the
freezing depth and time. Treated lesions on the
face heal faster than the ones treated on the trunk
and extremities.
We have to remember that in benign non-
esthetic lesions, we seek the best cosmetic results.
Therefore, overtreatment must be avoided to
decrease long-term adverse effects. The proper
selection of patients and correct pre- and post-
procedure guidelines will minimize unaesthetic
results. Informed consent must be obtained
before treatment. A good doctor-patient relation-
ship is essential in all cosmetic procedures.
Cryolypolisis is another cosmetic use of cryo-
therapy; it is extensively discussed in another
chapter in this textbook.
Conclusions
Cryosurgery is a useful therapeutic tool in the
dermatological armamentarium. If applied
by a properly trained physician, treatment
outcome of unaesthetic dermatoses can be
quite satisfactory. The equipment and sup-
plies are relatively inexpensive, durable, and
of easy maintenance. Its use in the office for
treating unaesthetic skin conditions is fast,
effective and rewarding. Selecting the ade-
quate patients, following the correct tech-
nique and post-cryosurgery care compliance
are essential to obtain the best therapeutic
results.
Acknowledgments We thank Dr. Sergio Lozano for his
help in reviewing and editing the manuscript.
275
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 Palliative Cryosurgery
56
Divya Sharma, Robert A. Schwartz,
and William Abramovits

Abstract
There are many palliative indications for cryosurgery. Thoracic surgeons
find it useful in managing central airway obstruction from tumors and
mesothelioma; neurosurgeons use it in metastatic disease to the spine, if
just for pain; urologists in prostate and renal cell carcinoma; gastrointesti-
nal and oncology surgeons in esophageal cancer, colonic cancer, and met-
astatic liver disease. Dermatologists find it of value in melanoma and
epithelial tumors, primary or metastatic. Cryosurgery has advantages over
other ablative modalities such as radiofrequency, microwave, laser, and
high-intensity focused ultrasound ablation.

Keywords
Cryosurgery • Cryotherapy • Cryoablation • Palliative • Cancer

D. Sharma, MD Departments of Family Practice and Dermatology,

Department of Dermatology, Rutgers University
New Jersey Medical School, Newark, NJ, USA
R.A. Schwartz, MD, MPH, DSc (Hon),
FRCP (Edin) (*)
Dermatology and Pathology, Rutgers University New
Jersey Medical School, Rutgers University School of
Public Affairs and Administration,
185 South Orange Ave, Newark, NJ 07103, USA
e-mail: roschwar@cal.berkeley.edu
W. Abramovits, MD, FAAD
Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
The University of Texas Southwestern Medical School,
Dallas, TX, USA
Department of Internal Medicine, Texas College
of Osteopathic Medicine, University of North Texas
Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College
of Medicine, Dallas, TX, USA

© Springer-Verlag London 2016 277

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_56
278
Introduction
Cryosurgery can be palliative for patients with
advanced disease, inoperable tumors, or contrain-
dications to other ablative modalities. The intent
is to improve quality of life, reduce suffering, and
offer therapy based on the needs and goals of the
patient. A patient may choose palliative cryosur-
gery for symptom-relief, freedom from side
effects of other treatment modalities, and as a less
risky and less invasive form of therapy; if options
are limited by comorbidities, psychological rea-
sons, functional problems, desire to avoid social
isolation, or if there was an insufficient response
to previous treatments.
Cryosurgery can be performed solo or in
conjunction with other modalities; usually pal-
liation can be achieved in one session and it can
be administered to bed- or wheelchair-bound
patients. Sometimes, even though cure is not the
objective, cryosurgery can completely resolve a
lesion.
Description of the Disease
Cryosurgery may be performed for tumors unre-
sectable due to location [1]; to treat solid tumors
on the skin, nasopharynx, breast, lung, heart,
liver, pancreas, adrenal gland, kidney, uterus, cer-
vix, prostate, rectum, and bone; for pain relief, in
patients with tumors adjacent to the spinal cord,
sciatic nerve; to relieve obstruction caused by
tumors in the gastrointestinal tract, urinary organs
[2–7], and airways [8].
Therapeutic Alternatives
Percutaneous ethanol injection (PEI) was utilized
for treating hepatocellular carcinoma until ran-
domized trials confirmed that radiofrequency
ablation (RFA) is superior [9–14]. RFA involves
high frequency, alternating current with a wave-
length of 460–500 kHz, to generate frictional
heat by electron flow [1]; at 49 °C cell death hap-
pens in minutes, at 60 °C, it occurs instantly. RFA
is relatively safe and straightforward to perform
for small tumors encompassed by parenchyma,
D. Sharma et al.
and separated from major vasculature, the gall-
bladder, and the central large bile duct. However,
it has a high local recurrence rate and may require
general anesthesia [15, 16]. PEI may be used for
patients whose tumors are not candidates for per-
cutaneous RFA [17]. Microwave ablation utilizes
900–2,450 MHz energy to realign water mole-
cules and generate heat that induces cell death via
coagulative necrosis [1]. In theory it is superior to
RFA, but more data is needed to support its use
[18–21]. Laser ablation involves light energy
delivered through a laser fiber to cause tumor
necrosis and thrombosis. High-intensity focused
ultrasound uses sonic waves to generate heat that
destroys targeted tissues: outcomes are similar to
other ablation methods [22–28].
Cryosurgery
Cryosurgery has many advantages over heat-based
treatments; in these, the temperature flow cannot
be precisely visualized intraoperatively and may
be transferred through the vasculature, resulting in
a larger than intended zone of destruction [1, 29,
30]. Cryosurgery has greater accuracy, as it can be
paired with US, CT, or MRI for tissue identifica-
tion. Multiple cryoprobes can be placed at once
for tumor coverage, and there is less concern of
inadvertent transference through the vasculature;
it has less risk of thrombosis as blood vessels are
less sensitive to damage and causes less pain so it
can be performed under local anesthesia with mild
sedation. Furthermore, it can induce anti-tumor
immunity due to the rupture of tumor cell mem-
branes, exposing antigens [31–34]. Disadvantages
of cryosurgery include the possibility of tumor
seeding as well as the risk of bleeding and rupture
of target tissue during thawing [1].
Methodology (How I Do it)
Cryosurgery can be performed in the office set-
ting, hospital, or nursing home as general anes-
thesia or premedication is usually not required
and the procedure is relatively straightforward
[35]. Cryosurgery may be administered during
56 Palliative Cryosurgery
open-surgery or via minimally invasive image-
guided methods such as endoscopy or percutane-
ous approach. Intraoperative approaches may
also be paired with image-guidance.
A cryoprobe is advanced until it reaches the
target for maximal circumferential freezing.
Argon gas or LN is administered to cool and irre-
versibly destroy a tumor. Palliative treatment of
advanced cancers may necessitate extensive
freezing in order to destroy large amounts of
tumor. After freezing and thawing surface tumors,
several days are needed for the necrotic tissue to
slough off, and an ulcerating wound remains.
Healing time varies based on the size, depth of
invasion, and location of the tumor [35, 36].
Persistent disease may be present at the periphery,
but if the goal is achieved, no further intervention
is necessary; if the goal is unmet, cryosurgery can
be repeated with caution and consideration of
alternative therapies, as the risks of creating a
larger cavity may outweigh the benefits.
Success Rates
Surgeons report cryosurgery as useful in the
management of central airway obstruction from
tumors [8, 37], metastatic disease to the bone
[38], mesothelioma [39], metastatic renal carci-
noma [40], esophageal and rectal cancer [41, 42],
and for many lesions where a relatively mini-
mally invasive procedure is of choice; quite often
with surprisingly gratifying results.
Dermatologists find it useful in melanoma
[43, 44], when cure is not to be expected, squa-
mous cell carcinoma of the nose and nasal pas-
sages when the smell of the lesion tortured the
patient, for large necrotic tumors where malodor
permeates the room and dressing changes become
a labor of intense love for the caretakers and rela-
tives, for painful lesions amenable to size reduc-
tion and direct or indirect anesthetic effects [45];
and these are only a few examples.
Fear of medico-legal consequences of pallia-
tive cryosurgery should be surpassed by the per-
ceived benefits to the patients.
In advanced skin cancer, if cure is not possible
or curative treatment is declined, cryosurgery
279
may ameliorate distressing symptoms, decrease
tumor bulk, improve cosmesis, reduce malodor,
control bleeding, and relieve pain [36]. Palliative
cryosurgery has been reported to be of benefit for
skin cancers involving the ear, orbit, nose, breast,
perineum, and buttocks [35, 36, 46–55]. In these
cases, the need for aggressive surgical interven-
tion, reconstructive procedures, or deep radiation
therapy was mitigated.
Cryosurgery in advanced melanoma has been
used to achieve palliation [56–61]. It has been
directed at large lesions, primary or metastatic, to
control growth and alleviate associated symp-
toms. Expected length of survival is usually
unchanged. Cryosurgery with LN has been used
for the treatment of cutaneous metastatic mela-
noma, however large-scale studies demonstrating
its value are lacking [62, 63]. In one study, 30
patients with metastatic melanoma treated with
palliative cryosurgery achieved remission for an
average of 36 months [64]. Cryotherapy-induced
local trauma would cause tumor antigen release,
which would then trigger systemic anti-melanoma
immune mediators, as was seen in vitro [65].
Recently, this associated anti-tumor response (as
compared to the anti-tumor response generated by
iron particles and magnetic field application in an
in situ study) was found to be inferior [66].
Conclusions
Cryosurgery has shown success as curative
and palliative therapy. It can be performed to
reduce tumor burden, provide symptom alle-
viation, and serve as an alternative to more
invasive or heat-based treatment modalities.
Cryoablation is a developing technique; its
role continues to be defined.
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 Oral Mucous Membrane
Cryosurgery
57
Carlos Horacio Gonzalez Rojas

Abstract
The cryosurgery is the first method in diverse oral mucous pathologies,
principally tumors and vascular malformations and traumatic lesions by
orthodontic appliance. There is fast healing and low morbidity.

Keywords
Cryosurgery • Oral mucous • Open technique • Solid • Freeze • Probe

Introduction Why Cryosurgery in the Oral Cavity?

All the mucous membranes are cryo-sensible Methodology

because of their humidity and texture. The oral
cavity has moving structures, like the tongue,
inside a limited space that makes the traditional
surgical technique difficult. The mucous mem-
branes are vascular and their healing is fast by
second intention, keeping their form and low
morbidity [1, 2] (Fig. 57.1).
Protection is a priority when we operate on lesions
in the oral cavity with LN [3]. The closed tech-
nique or contact is preferable due to safety and
comfort. If we have to use the open technique or
spray, we must avoid accidental burns caused by
LN dripping onto adjacent structures. The spray
causes atomization of vapors which obstruct
vision and reduce the precision of the procedure
in the oral cavity. This situation may be resolved
using a hair dryer some distance away from the
treated area. The hot air facilitates the vision.

How to Do It?
C.H.G. Rojas, MD
Clinica del Café, cra 0 number 12-75 of 420,
Always protect the lips and tongue with a wooden
Armenia, Quindio 63001, Colombia tongue depressor. Place the wooden tongue
e-mail: cahora@yahoo.com depressor on the lower side of the probes along

© Springer-Verlag London 2016 283

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_57
284 C.H.G. Rojas

Humidity

Cryosensibility Vascularity

Texture

Fig. 57.1 Cryo-sensibility factors

Fig. 57.3 Sarcoma covering the entire palate

Fig. 57.2 Protect the tongue and floor of the mouth by

using spray technique

with the venting tube. When using spray on the

upper palate, avoid LN dripping on the lower
parts by placing a wooden spatula on the mouth
floor (Fig. 57.2). Do not use gauze or cotton
because their freezing can damage the structures
they intend to protect (Figs. 57.3 and 57.4). Fig. 57.4 Result 1 month after procedure

Diseases by Living Agents (Fig. 57.5)
We advise to use spray to avoid contamination
and dissemination of infections (Fig. 57.6).
treatment with probes impossible due to their
irregular morphology.
Closed Techniques with Probes

Extensive Lesion Delimited Tumors (Fig. 57.8)

In large pathologies, the use of the open tech- Whenever a lesion has defined borders, the halo
nique with tips allows covering of the whole freezing achieved with a probe indicates greater
lesion. therapeutic safety limits.

Irregular Forms (Fig. 57.7) Vascular Pathologies Palate (Fig. 57.9)

It is common to find lesions in the oral mucous The vascular lesions should be compressed by
that endanger several plans which makes their the probe during freeze time (Fig. 57.10).
57 Oral Mucous Membrane Cryosurgery 285

Fig. 57.5 Condiloma acominatum

Fig. 57.8 Venous vascular malformations

Fig. 57.6 Open technique

Fig. 57.9 Hemangioma

Fig. 57.7 Actinic cheilitis

Fig. 57.10 Venous vascular malformations

286
For tumors in the salivary glands and in vascu-
lar lesions, the probe’s maneuverability makes
for a more practical and secure technique.
Benign Salivary Gland Tumors (Fig. 57.11)
Mucocele of Blandin-Nuhn Glands
(Figs. 57.12, 57.13, and 57.14)
Mucocele by Orthodontic Appliance
(Figs. 57.15, 57.16, 57.17, and 57.18)
Major Salivary Glands Ranula
(Figs. 57.19, 57.20, 57.21, and 57.22)
MAJOR MINOR
Parotid Oral Cavity
Submaxillary Except Rhagades
Sublingual Palate
Ranulas Mucoceles
Fig. 57.11 Salivary glands
Fig. 57.12 Cryosurgery closed technique
C.H.G. Rojas
Hemangiolymphangioma
A case treated with probes using solid freeze
cycles by direct contact on the buccal mucous
and the skin (Figs. 57.23, 57.24, 57.25, and
57.26).
Bone Cyst
Bone cyst treated with cone in four frozen solid
previous regional blocking (Figs. 57.27, 57.28,
and 57.29).
Telangiectasic Granuloma
Extensive granuloma treated with closed probe
technique. Note the post-surgery necrosis and the
conservation of the healthy tissue (Figs. 57.30
and 57.31). The use of the traditional surgical
techniques would leave aftermaths.
Venous Vascular Malformation
The pressure and torsion to vacate the vessels by
deep-freezing without trespassing the limits of
the lesion guarantee a successful result
(Figs. 57.32, 57.33, and 57.34).
57 Oral Mucous Membrane Cryosurgery 287

Fig. 57.13 Cryosurgery closed technique

Fig. 57.14 Mucocele of Blandin-Nuhn glands post

treatment
288 C.H.G. Rojas

Fig. 57.15 Mucocele treatment with probe

Fig. 57.16 Mucocele by orthodontic appliance

Fig. 57.17 Post treatment with probe technique

57 Oral Mucous Membrane Cryosurgery 289

Fig. 57.18 Closed technique, halo freezing limited, edema and healing

Fig. 57.21 One week later

Fig. 57.19 Ranula mouth floor

Fig. 57.20 The probe for effective and secure therapy

290 C.H.G. Rojas

Fig. 57.25 Cryosurgery with probe

Fig. 57.22 One month later

Fig. 57.26 Final result

Fig. 57.23 Hemangiolymphangioma left cheek

Fig. 57.24 Caviar eggs hemangiolymphangioma

57 Oral Mucous Membrane Cryosurgery 291

Fig. 57.29 Cryosurgery with cone

Fig. 57.27 Bone cyst

Fig. 57.30 Telangiectasic granuloma

Fig. 57.28 Biopsy of bone cyst

292 C.H.G. Rojas

Fig. 57.31 Pre-treatment and final result

Fig. 57.32 Venous vascular malformation

Fig. 57.33 Solid cryosurgery with probe
57 Oral Mucous Membrane Cryosurgery 293

Fig. 57.34 Necrosis post cryosurgery and final result

Conclusions xenografted in nude mice. J Invest Dermatol.

Oral cryosurgery eases treatment of most 2001;116:664–71.
2. Green CJ. The biophysical responses of tissues to
pathologies in difficult-to-access places and extreme temperature changes. In: Bradley PF, editor.
allows for anatomical and functional Cryosurgery of the maxillofacial region, vol. I. Boca
conservation. Raton: CRC Press; 1986. p. 17–32.
3. Zanini M. Biophysical responses of tissues to extreme
temperature changes. In: Bradley PF, editor.
Cryosurgery of the maxillofacial region. Boca Raton:
References CRC Press, Inc.

1. Gazzaniga S, Bravo A, Goldszmid SR, Maschi F,

Martinelli J, Mordoh JA, et al. Inflammatory changes
alter cryosurgery induced necrosis human melanoma
 Basal Cell Carcinoma of
the Eye Area
58
Bobby L. Limmer

Abstract
Although surgical procedures with margin control are preferred by most
surgeons for the treatment of eyelid epithelial cancers, among dermatolo-
gists Mohs being the method of choice, cryosurgery remains a valid
important option.

Keywords
Mohs • Eyelid • Basal cell carcinoma

Introduction after tumor removal. Cryosurgery remains a via-

Because of the potential consequences of failure
to cure an invasive malignancy of the eyelid,
most dermatologist and surgeons of today lean
heavily toward the use of microscopically con-
trolled removal techniques; favorite of such
procedures being Mohs micrographic technique.
Surgeons not trained in Mohs might utilize fro-
zen sections at the time of surgery. Fixed tissue
histologic analysis of the margins of excised tis-
sue may be used by other surgeons. The consen-
sus is that some form of microscopic analysis of
the margins is highly preferred to assure much as
possible the certainty of a clear surgical margin
ble option for the treatment of eyelid neoplasms
and benign conditions such as trichiasis.
Therapeutic Alternatives
Besides the treatments described in the introduc-
tion, radiation, electrodessication and curettage,
and combinations such as surgical removal fol-
lowed by radiation of the perimeter are all meth-
ods that while still providing a very high cure
rate, do not provide histologic control of the mar-
gin after treatment of the tumor.

Cryosurgery
B.L. Limmer, MD
Department of Dermatology, Plastic Surgery,
University of Texas Health Science Center, Cryosurgery has been used widely and exten-
14615 San Pedro, Suite 245, San Antonio, sively throughout the world for the destruction of
TX 78232, USA malignant tissue. The method of LN application
e-mail: carolelimmer@icloud.com

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_58
296 B.L. Limmer

by either direct spray or probe technique is well

accepted as suitable for the destruction of malig-
nant cells. Other cryogens are typically not uti-
lized because of their lesser abilities to rapidly
reduce tissue temperature or cost and handling
requirements. LN is readily available and reason-
ably inexpensive throughout the world.

Metodology (How I Do It)

The standard and accepted method of LN cryo-

surgery involves either spray or probe application Fig. 58.2 Post-op at 1 week
to the surface of the lesion until a margin of tissue
3 mm removed from its clinical margin is reduced
to a −40 °C, as measured by a thermocouple.
When −40 °C is registered at the selected margin
of treatment, the delivery of LN is stopped. The
frozen ice ball is then allowed to thaw in unas-
sisted fashion. After the lesion has thawed in its
entirety, the sequence is repeated. This method of
double freeze slow thaw cycle is generally
accepted principle for the maximal destruction of
tissue (Figs. 58.1, 58.2, 58.3, 58.4, and 58.5).

Success Rates Fig. 58.3 Post-op at 6 weeks

In most instances cryosurgery accomplishes cure

rates in the range of 95–99 % for all cutaneous
basal cell carcinomas (BCC). Although cryosur-
gery is very effective for the destruction of BCC,
most physicians with experience in the treatment

Fig. 58.4 Post-op at 6 months

of periocular lesions would limit its use for those

Fig. 58.1 Basal cell carcinoma of the eyelids before
cryosurgery
lesions with well-defined margins and reason-
ably small diameter. Fraunfelder and other
would suggest that the selection of lesions best
be limited to those BCC of less 1 cm in diameter
and of nodular or nodular-ulcerative type with
58 Basal Cell Carcinoma of the Eye Area
Fig. 58.5 Post-op at 5 years
sharp clinical margins [1]. BCC with infiltrative
characteristics have a lower cure rate by virtue of
the difficulty in clinically defining the presumed
margins of the tumor. Without reasonably
defined clinical margins, it is difficult to deter-
mine the desired endpoint of the cryosurgical
destructive isotherm. By carefully selecting
smaller, nodular BCC and by the use of appro-
priate technique, a cure rate equal to, or in excess
of 97 % is reasonably expected. Two significant
contributions to the field of cryosurgery of BCC
on the eyelids were published recently; a series
of 781 lesions averaging less than 1 cm, in 768
patients treated over 30 years and prospectively
followed for over 10 years – those operated on
the first 20 years of the study, and for at least a
year the rest – showed recurrences in only three
patients [2]; a series of 220 patients followed for
at least 5 years showed recurrences in only 5.1 %
after a first attempt and of 0.6 % after a second
cryosurgery [3].
Complications
Significant eyelid and periocular edema is a natu-
ral and accepted consequence of cryosurgery in
the periocular zone. The edema may reach such
level in the immediate postoperative days as to
occlude vision. This can be reduced through the
use of postoperative systemic steroids and cold
297
compresses to the area. The edema typically
resolves within 7 days.
If a tumor involves the full thickness of the
lash margin, a rounded defect may occasionally
occur. Loss of lashes within the treated part is to
be expected. Ectropion may occur but not com-
monly. If innercanthal lesions are treated, punctal
and canalicular occlusion may occur. Avoidance
of that area is strongly recommended.
Hyperthophic scars occur highly uncommonly.
Ectropion as result of scar retraction may happen
and is more common if the lesion treated is
located in an inferotemporal location. Most of the
scars resulting from cryosurgery are cosmetically
acceptable. Rarely, pseudoepitheliomatous
hyperplasia develops in the months following
treatment; typically, it resolves spontaneously.
Should regrowth suggestive of recurrence occur,
a repeat biopsy should be promptly done.
Healing after cryosurgery typically requires
4–8 weeks, depending upon the size of the lesion;
it may be associated with edema, serous dis-
charge, and scar formation if the wound is
allowed to remain dry. Depigmentation may be a
problem particularly after healing in darkly pig-
mented skin.
Conclusion
Although the complications from cryosurgery
may seem an obstacle, the good cosmetic
results and high cure rates in the hands of
well-trained cryosurgeons, make the treat-
ment, in most instances, highly satisfactory.
References
1. Fraunfelder FT, Zacarian SA, Wingfield DL, et al.
Results of cryotherapy for eyelid malignancies. Am
J Ophthalmol. 1984;97:184–8.
2. Lindgren G, Larkö O. Cryosurgery of eyelid basal cell
carcinomas including 781 cases treated over 30 years.
Acta Ophthalmol. 2014;92(8):787–92.
3. Buschmann W. A reappraisal of cryosurgery for eye-
lid basal cell carcinomas. Br J Ophthalmol. 2002;
86(4):453–7.
 Cryosurgery for External Ear
Pathology
59
Carlos Horacio Gonzalez Rojas

Abstract
The cryosurgery on external ear is an effective, easy and secure technique
due to the cartilage is cryo-resistant and it is possible delimit the damage
and the conservation of anatomic structures.

Keywords
Keloid • Cone technique • Angiolymphoid hyperplasia • Cartilage

Introduction tube may fall on these structures in an impercep-

The external ear, due to its cartilaginous struc-
ture, which resists low temperatures, is one of the
places where it is appropriate to perform cryosur-
gery for benign to malignant lesions (Fig. 59.1).
How to Freeze the External Ear
When using an open technique, the medium and
internal ear must be protected with a wooden
tongue depressor. Gauze and cotton should be
avoided because when in contact with nitrogen,
they may prolong the freezing front. Usually the
LN drippings coming from the tips or venting
tible way.
Freeze without surrounding margins the
benign lesions. When possible, use the closed
technique with probes. In malignant lesions,
curette to define the freezing field and leave some
safety margin.
Nordin P and Stenquist B performed a study
[1] between 1983 and 1996 in 100 patients with
non-melanoma skin carcinomas of the external
ear. Patients were treated with a double cycle of
cryosurgery post-curettage, it showed that of 81
treated tumors only 1 showed recurrence after
5 years of treatment. Nineteen patients followed
for 2 years died due to causes unrelated to the
tumor and didn’t have recurrences.

Keloids
C.H.G. Rojas, MD
Clinica del Café, cra 0 number 12-75 of 420,
Armenia, Quindio 63001, Colombia Cryosurgery performed on keloids of the external
e-mail: cahora@yahoo.com ear using the open cone technique is a classic

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_59
300 C.H.G. Rojas

Fig. 59.1 Anatomy of the Helix

ear
Antihelix Pillars

Auricular tubercle
Triangular Fossa

Helix Branch
Antihelix
Cymba Tragus
Ear-shell cymba
cavity Cavity Intertragic Incisure

Antitragus

Ear lobe

Fig. 59.2 The use of open cone technique, tissue protection by a wooden tongue depressor, and healthy skin
conservation

example where we may see the destruction of the Angiolymphoid Hyperplasia

lesion and conservation of the anatomic cartilagi-
nous structure. In these cases, the healthy skin
must be respected and their necrotic tissue not be
scraped. Crust removal, stimulates the prolifera-
tion of fibroblasts and keloid recurrence
(Figs. 59.2, 59.3, 59.4, 59.5, 59.6, 59.7, 59.8, and
59.9).
Kimura Sickness (1948). Angiolymphoid
Hyperplasia with Eosinophilia (Wells 1969).
Pyogenic Pseudogranuloma (Wilson Jones
1969). Papular angioplasia (Wilson Jones
1970). Atypical Pyogenic Granuloma (Peterson
1977). Nodular Angioblastic Hyperplasia with
59 Cryosurgery for External Ear Pathology 301

Fig. 59.3 Recurrent retroauricular keloid and normal post-inflammation reaction

Fig. 59.4 Cryosurgery with cone and solid freezing during 5 min
302 C.H.G. Rojas

Fig. 59.5 Necrosis post surgery

Fig. 59.7 Pre-treatment photo and final result

Fig. 59.6 Pre-treatment photo and final result

59 Cryosurgery for External Ear Pathology 303

Fig. 59.8 Pre-cryosurgery painful keloid and solid freezing spray

Fig. 59.9 Second intention cicatrization and final result with no recurrence

Eosinophilia and Lympholiculosis (Bend
1977).
Histiocytoid Hemangioma (Rosai 1979).
Epithelium Hemangioma (Ezinger 1983)
(Figs. 59.10 and 59.11).
Methodology (How I Do It)
The cone is ideal to achieve solid freezings.
The cartilage is cryo-resistant but it must
be avoided so that the freezing halo passes
from side to side and not through, because it
might cause perforation. Perform: anesthe-
sia (depending on the location of the lesion,
it may be by infiltration or by nerve block),
a solid freeze of the lesion but do not involve
the healthy skin, do freeze-thaw cycles three
times, do not take off the crust.
Conclusions
It is very difficult to achieve permanent results
in auricular keloids by methods other than
cryosurgery.
304 C.H.G. Rojas

Fig. 59.10 Recurrent retro-auricular tumor lesion and biopsy

Fig. 59.11 Post cryosurgery cicatrization and final result

Reference
1. Nordin P, Stensuist B. Five ncyclesmanent results in
auricular keloids with those methods different from the
cryosurgery tology [internet article]. Londres.
2002;116(11):893–9. http://proquest.umi.com/pqd
web?did=243980071&sid=1&Fmt=4&clien.
 Cryosurgery of the Nose
60
Marcial Oquendo, William Abramovits,
and Alba G. Quiñones

Abstract
The nose is an area that is particularly susceptible to sun damage and skin
cancers often occur. Many malignant and non-malignant skin lesions on
the nose have been successfully treated with cryotherapy methods similar
to that of facial lesions and has also been successfully used by otorhinolar-
yngology to treat intranasal lesions. Cryosurgery of the nose, as mono-
therapy or in combination with other techniques has been proven to be safe
and appropriate management of malignant and non-malignant lesions with
high cure rate and usually pleasing cosmetic results.

Keywords
Cartilage • Halo • Ballooning • Nose • Mohs

Department of Internal Medicine, Texas College

of Osteopathic Medicine, University of North Texas
M. Oquendo, MD (*) Health Science Center, Fort Worth, TX, USA
Department of Pediatrics,
Department of Dermatology,
Driscoll Children’s Hospital,
University of Texas Medical Branch, Dallas, TX, USA
3533 S Alameda St., Corpus Christi, TX 78411, USA
e-mail: dr.oquendo@gmail.com Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
W. Abramovits, MD, FAAD
Department of Dermatology, Texas A&M Health Science Center College
Baylor University Medical Center, Dallas, TX, USA of Medicine, Dallas, TX, USA
Departments of Family Practice and Dermatology, The A.G. Quiñones, MD
University of Texas Southwestern Medical School, Dermatology Treatment and Research Center,
Dallas, TX, USA Dallas, TX, USA

© Springer-Verlag London 2016 305

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_60
306 M. Oquendo et al.

Introduction and hypertrophic scars, granuloma faciale and

The nose is an area that is particularly susceptible
to sun damage and skin cancers often occur.
Cartilaginous tissues such as the nose and ears
are considered relatively safe and appropriate
sites for cryosurgery because cartilage necrosis,
connective tissue damage and disfiguring scars
are uncommon with routine techniques.
Patient Selection
Many malignant and non-malignant skin lesions
on the nose have been successfully treated with
cryotherapy methods similar to that of facial
lesions [1]. Among those reported in the litera-
ture we have: basal cell carcinoma (BCC) [2]
(Fig. 60.1), hemangioma [3], rhinophyma [4],
lupoid leishmaniasis [5], nasoalveolar cyst [6],
actinic keratosis, cutaneous horns, squamous cell
carcinoma (Fig. 60.2), keratoacanthomas, angio-
fibromas, angiomas, dermatofibromas, keloids
dermatosis papulosis nigra. However, Mohs
micrographic surgery may be preferred to treat
malignant lesions method due to its higher cure
rates and cosmetic results and can be used in
combination with cryosurgery [7].
Cryosurgery has also been successfully used by
otorhinolaryngology to treat intranasal lesions
such as: epistaxis, hemorrhagic telangiectasia,
nasopharyngeal angiofibromas and carcinomas,
nasal polyposis, chronic allergic rhinitis, hypertro-
phic rhinitis, Osler disease, chronic vasomotor rhi-
nitis and chronic hypertrophied turbinates [8–11].
Technique
The treatment of malignancies on the nose is gen-
erally similar to that of facial lesions. Axiom in
the use of cryosurgery when treating malignant
lesions is “first treatment should be the final treat-
ment” as no malignant cells should survive after
a successful application. The goal for tissue

a b

Fig. 60.1 (a) Pigmented BCC. (b) During cryosurgery showing a 5 mm halo of freeze. (c) Cosmetically pleasing
results at 6 months (Photos courtesy of William Abramovits, MD)
60 Cryosurgery of the Nose
a b
c d
Fig. 60.2 (a, b) Squamous cell CA. Patient requested
palliation and relief from malodor. (c) Aggressive
cryosurgery encompassing the entire visible tumor.
temperature should be between −40 and −60 °C
and the application time will depend on exten-
sion, depth and consistency of the lesion, typical
times range from 30 to 60 s. In the case of malig-
nancy, a halo of freeze of about 3–5 mm should
surround the lesion and sustain for another
30–60 s after the freezing ends; two cycles sepa-
rated by 1 min of complete thaw is appropriate.
More extensive lesions could require multiple
freeze-thaw cycles and segmental freezing to
cover extensive areas. Palpation or biopsy can be
used to determine whether the tumor is fixed to
the cartilage which will require more aggressive
treatment [12].
LN is the most effective cryogen for treatment
of malignant and pre/malignant lesions. Local
anesthetic is frequently used to lift the lesion
(ballooning) away from the cartilage or bone.
The contact probe technique is useful when
307
(d) Clinical cure at 1 year. Patient declined plastic surgery
repair (Photos courtesy of Gilberto Castro-Ron, MD and
William Abramovits, MD)
needing to protect the underlying structures or to
avoid splatter towards the eyes.
Conclusions
Cryosurgery of the nose, as monotherapy or in
combination with Mohs micrographic surgery,
vismodegib, imiquimod, and radiation therapy
[1, 13–16] is a safe and appropriate treatment
for skin malignant and non-malignant lesions
on the nose, as well as for intranasal pathol-
ogy. It results in high cure rates and usually
pleasing cosmetic results [7].
References
1. Richard UP, Daniel LS, Colver GB. Cutaneous cryo-
surgery. 4th ed. Boca Raton: CRC Press; 2014.
308
2. Zribi H, Cherif F, Zakraoui H, Cheikhrouhou R,
Mokni M, Ben Osman Dhahri A. Cryosurgery for
nose basal cell carcinoma. Series of 17 tumors. Tunis
Med. 2006;84(8):473–6.
3. Olariu B, Olariu D, Raducanu D, Cristescu G, Laky
D. A case of hemangioma of the nasal pyramid treated
by cryotherapy with liquid nitrogen in an infant. Rev
Chir Oncol Radiol ORL Oftalmol Stomatol Oto-
Rino-Laringol. 1988;33(3):205–11.
4. Wiecko J, Sonnenberg Z. Nasal rhinophyma.
Combined surgical treatment and cryotherapy.
Otolaryngol Pol Pol Otolaryngol. 1985;39(3):
204–10.
5. Benmously Mlika R, Hammami H, Sioud A, Mokhtar
I, Fenniche S. Lupoid leishmaniasis of the nose
responding well to cryotherapy. Dermatol Ther.
2011;24(3):378–9.
6. Janardhan N, Venkateswarlu V, Rajesh Kumar S,
Narasimharaju BG. Role of cryosurgery in the surgical
management of nasoalveolar cyst. Indian J Otolaryngol
Head Neck Surg: Off Publ Assoc Otolaryngol India.
2013;65 Suppl 2:376–9.
7. Nordin P, Larko O, Stenquist B. Five-year results of
curettage-cryosurgery of selected large primary
basal cell carcinomas on the nose: an alternative
treatment in a geographical area underserved
by Mohs’ surgery. Br J Dermatol. 1997;136(2):
180–3.
M. Oquendo et al.
8. Hartley C, Willatt DJ. Cryotherapy in the treatment of
nasal obstruction: indications in adults. J Laryngol
Otol. 1995;109(8):729–32.
9. Kim JY, Oh JH, Kim GT, Kwon JH. Endoscopic cryo-
therapy for the treatment of epistaxis due to hereditary
hemorrhagic telangiectasia. J Craniofac Surg.
2014;25(2):e120–2.
10. Liu H, Zhu P. Morphological study on chronic hyper-
trophic rhinitis treated with cryosurgery. Zhonghua Er
Bi Yan Hou Ke Za Zhi. 1999;34(1):36–7.
11. Rakover Y, Rosen G. A comparison of partial inferior
turbinectomy and cryosurgery for hypertrophic infe-
rior turbinates. J Laryngol Otol. 1996;110(8):732–5.
12. Fortuno-Mar A. Cryosurgery: a practical manual.
New York: Springer; 2014.
13. Gaitanis G, Kalogeropoulos C, Bassukas ID. Imiquimod
can be combined with cryosurgery (immunocryosur-
gery) for locally advanced periocular basal cell carcino-
mas. Br J Ophthalmol. 2011;95(6):890–2.
14. Nordin P. Skin cancer around the nose and ears: careful
curettage followed by cryosurgery is a cheap and safe
therapeutic method. Lakartidningen. 1991;88(43):3550.
15. Nordin P. Curettage and cryosurgery as a safe method
for treatment of non-melanoma skin cancer of the nose
and ear. Lakartidningen. 1991;88(30–31):2523–5.
16. Kuflik EG. Learning the basics #2: debulking the
lesion before cryosurgery. J Dermatol Surg Oncol.
1986;12(4):321–2.
 Part X
Cryosurgery in Combinations
 Combination Cryosurgery
61
Michael Thomas Jennings
and William Abramovits

Abstract
For selected patients prospective outcomes can be enhanced using cryo-
surgery in combination with other surgical procedures, some destructive
as well, hyperthermia, sclerosing agents, topical chemotherapy or immu-
notherapy, and possibly systemic agents like vismodegib, etc.

Keywords
Curettage • Mohs • Excision • Radiofrequency • Imiquimod • 5-fluorouracil
• Diclofenac • Retinoids • TNF-α • Hyperthermia • Nanoparticles •
Vismodegib

M.T. Jennings, BS
Paul L. Foster School of Medicine,
MS2 Texas Tech University, El Paso, TX, USA
W. Abramovits, MD, FAAD (*)
Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical School,
Dallas, TX, USA
Department of Internal Medicine, Texas College
of Osteopathic Medicine, University of North Texas
Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College
of Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160,
Dallas, TX 75230, USA
e-mail: DrA@dermcenter.us
Introduction
Cryosurgery is an effective method for treat-
ing various skin lesions; however, in some
cases the desired results cannot be achieved.
Many individuals may have refractory lesions
when treated with cryosurgery alone.
Prospective outcomes may be enhanced
through combination therapy, which has the
following goals: increase lesion clearance
rate, decrease lesion size, decrease recur-
rences, protect healthy tissue, or reduce pain.
Combined treatments may work to either
enhance the inherent mechanisms of cryosur-
gery, or to induce unique, local changes at the
site of the targeted lesion.

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DOI 10.1007/978-1-4471-6765-5_61
312
Combinations with Surgery
Surgical combinations act as debulking measures
in cryosurgery. Reduction of lesion size allows
the LN to penetrate into deeper levels of affected
tissue. Structural alterations due to surgical deb-
ulking may also enhance the intrinsic properties
of LN freezing.
Curettage
Preoperative curettage is useful in preparation for
cryosurgery. By exposing the inferior aspects of
the lesion through curettage, LN is able to cool
deeper levels of tissue to induce more targeted
freezing.
A prospective study of 726 subjects evaluated
the long-term efficacy of curettage-cryosurgery
for scalp and face skin cancers. After 14 years,
recurrence free rate/cure rate was calculated as
>97 % [1].
Mohs Surgery
Cryosurgery has been shown to be an effective
adjuvant therapy to Mohs. In the event that nega-
tive margins are not achieved through Mohs,
cryosurgery could help reduce the number of lin-
gering tumor cells at the periphery [2]. This
should improves clearance and recurrence rates.
The advantage of Mohs surgery is that it spares
the stromal tissue. Complementation of cryosur-
gery with Mohs may be ideal for hand and facial
lesions. Out of the invasive, surgical approaches,
Mohs surgery should produce the most desired,
long-term cosmetic results.
Surgical Excision
Complete surgical excision functions in a similar
manner to curettage; however, excision may be a
more thorough approach than curettage due to the
greater amount of tissue that is removed. Surgical
excision is more likely to result in negative mar-
gins; however, this is in consequence to healthy
M.T. Jennings and W. Abramovits
tissue damage and scar formation, which may ulti-
mately result in late cosmetic concerns. Consider
excision for clothed and thicker skin regions [3].
Supervoltage and Radiofrequency
Supervoltage and radiofrequency act as non-
invasive, preoperative debulking techniques. In
addition to priming targeted lesions for cryosur-
gery, they may reduce lesional bleeding during
biopsy collection or surgical intervention [4].
Combinations with Topical Agents
Non-surgical combinations alter the local, cellu-
lar response. They address the underlying patho-
physiology of the lesion. Adjuvant therapy with
various drugs has demonstrated marked improve-
ments over cryosurgery alone.
Antimetabolites and DNA Replication
Inhibitors
Inhibitors of DNA replication, like fluorouracil
(5-FU), prevent cells from developing into
tumors. Specifically, 5-FU induces thymineless
death of cells in targeted tissue. Combining 5-FU
postoperatively with cryosurgery should reduce
lesion recurrence. A study of 144 patients with
actinic keratosis demonstrated that fluorouracil
cream combined therapy was superior to cryosur-
gery alone. Mean lesion count reduction was
67.0 % (complete clearance – 33 %) in the com-
bined group and 45.6 % (complete clearance –
7.7 %) in the non-combined group [5].
The early reaction induced by 5-FU on actinic
keratosis has been used to disclose subclinical
lesions, thus guide cryosurgery.
Immune-Stimulatory Agents
The postoperative addition of immune-stimulatory
agents, such as imiquimod cream, elicits the
recruitment of a leukocyte-rich inflammatory
61 Combination Cryosurgery
infiltrate. In doing so, imiquimod increases the
cellular response to tumor cells present at the site
of the lesion. It has been suggested that imiqui-
mod “turns the treated tumor lesion into an autol-
ogous tumor vaccine” [6]. It is recommended to
start imiquimod a few days to weeks before the
cryosurgical approach to take advantage of com-
bined immune stimulation and disclosure of sub-
clinical lesions. A study of 247 subjects compared
the effects of cryosurgery/3.75 % imiquimod
cream to cryosurgery/vehicle in the treatment of
actinic keratoses. Median total reductions were
86.5 % and 50 % respectively. The data suggest
that cryosurgical supplementation with imiqui-
mod is more effective than cryosurgery alone [7].
Intralesional Steroid Injections
The use of intralesional steroid injections, such
as triamcinolone, in combination with cryosur-
gery has proven to be an effective means of
increasing scar clearance. Most often used in the
treatment of keloids and hypertrophic scars, cor-
ticosteroids exert anti-inflammatory effects that
reduce the size of targeted lesions. Injected corti-
costeroids also have the benefit of ameliorating
pain and pruritus in many cases [8]. A study of 21
patients with 60 small keloids showed a 66.7 %
‘excellent response’ in the group receiving com-
bined therapy as opposed to a 43.3 % response in
the group receiving cryotherapy alone [9].
Non-steroidal Anti-inflammatory
Drugs (NSAID)
Increases in cyclooxygenase-2 (COX-2) have been
implicated in the development of actinic keratoses.
Postoperative administration of a topical NSAID,
such as diclofenac sodium gel, inhibits COX-2 and
subsequently diminishes further genesis of actinic
keratoses. A prospective study of 521 subjects
compared the efficacy of diclofenac-cryosurgery
with cryosurgery alone. Subjects who received
combined therapy achieved 100 % lesion clear-
ance; those who received cryosurgery alone
achieved 21 % lesion clearance [10].
313
Retinoids
While much remains uncertain about the mecha-
nisms of retinoid action, treatment of actinic ker-
atoses and other lesions with vitamin A
derivatives has shown some promise. Retinoids
may be used as preoperative agents due to their
exfoliating, thus lesion and field thickness reduc-
ing, properties. The use of retinoids in the treat-
ment of hypertrophic scars and keloids is
controversial as retinoids upregulate collagen
formation, which may exacerbate the lesion to
treat. Literature regarding the synergy between
cryotherapy and retinoids is sparse. In one
instance, the combination resulted in the counter-
productive formation of a hypertrophic scar [11].
Sclerosing Agents
Sclerosing agents should be considered when
dealing with vascular malformations.
Reduction of flow to the lesion may assist in
cell death. It may also function in a similar
manner to vasoconstricting agents by prolong-
ing freeze time [12].
TNF-α
Similar in function to imiquimod cream, the
introduction of TNF-α preoperatively primes the
lesion through pro-inflammatory processes and
leukocyte recruitment. Effects may last several
days and ultimately enhance the degree of clear-
ance from cryosurgery. TNF-α also increases the
temperature threshold of necrosis, meaning less
negative temperatures are required to induce cell
death [13, 14].
Hyperthermia
The combination of heat in a treatment based
upon freezing may seem counter-intuitive; how-
ever, hyperthermia has been used as adjuvant to
chemotherapy in various types of cancer.
Increased temperatures at the site of a lesion may
314
induce cell death through inhibition of S-phase
cells [15].
In the case of a 70-year-old female who pre-
sented with metastatic breast cancer manifesting
as two enlarging nodules, the patient had been
refractory to standard cryosurgical methods. The
subsequent addition of a disposable body warmer
for 12 h following further cryosurgery resulted in
nearly complete flattening of the tumor. It is
unclear if this result correlates to the hyperthermic-
induced state or to the alterations in the applica-
tion of secondary cryosurgical attempts. Further
research is necessary to determine the correlation
and efficacy of combinative hyperthermia [16].
Procedural Agents
Nanoparticles
Nanoparticles facilitate faster and more pro-
nounced iceball formation; reduction of the nec-
essary freezing time limits damage to surrounding
tissues. Nanoparticles may also elicit the forma-
tion of ice nuclei that could further enhance cryo-
damage to the targeted cells. Historically, chronic
administration of nanoparticles has been associ-
ated with high levels of toxicity; new develop-
ments have produced biodegradable, non-toxic
MgO nanoparticles that have shown success in
clinical applications. In order to ensure maximal
coverage, nanoparticles are typically introduced
after some degree of excision or shaving [17].
Vasoconstricting Agents
The use of vasoconstricting agents, particularly
epinephrine, has been shown to increase
cryosurgery-induced cell death. Vasoconstriction
prolongs freeze time by reducing blood flow to
the site of the lesion [18].
Conclusions
There are several ways to enhance the benefits
expected from cryosurgery; one is by using
it in combination with other treatment
modalities.
M.T. Jennings and W. Abramovits
References
1. Lindemalm-Lundstam B, Dalenbäck J. Prospective
follow-up after curettage-cryosurgery for scalp and
face skin cancers. Br J Dermatol. 2009;161(3):
568–76.
2. Ruiz Santiago H, Morales-Burgos A. Cryosurgery as
adjuvant to Mohs micrographic surgery in the man-
agement of subungual squamous cell carcinoma.
Dermatol Surg. 2011;37(2):256–8.
3. Kuijpers DI, Thissen MR, Berretty PJ, Ideler FH,
Nelemans PJ, Neumann MH. Surgical excision versus
curettage plus cryosurgery in the treatment of basal
cell carcinoma. Dermatol Surg. 2007;33(5):579–87.
4. Gonçalves JC, Martins C. Debulking of skin cancers
with radio frequency before cryosurgery. Dermatol
Surg. 1997;23(4):253–7. Jorizzo J, Weiss J, Furst K,
VandePol C, Levy SF. Effect of a 1-week treatment
with 0.5% topical fluorouracil on occurrence of
actinic keratosis after cryosurgery: a randomized,
vehicle-controlled clinical trial. Arch Dermatol.
2004;140(7):813–6.
5. Redondo P, del Olmo J, López-Diaz de Cerio A,
Inoges S, Marquina M, Melero I, Bendandi
M. Imiquimod enhances the systemic immunity
attained by local cryosurgery destruction of mela-
noma lesions. J Invest Dermatol. 2007;127(7):
1673–80.
6. Jorizzo JL, Markowitz O, Lebwohl MG, Bourcier M,
Kulp J, Meng TC, Levy S. A randomized,
double-blinded, placebo-controlled, multicenter, effi-
cacy and safety study of 3.75% imiquimod cream fol-
lowing cryosurgery for the treatment of actinic
keratoses. J Drugs Dermatol. 2010;9(9):1101–8.
7. Stücker M, Grape J, Bechara FG, Hoffmann K,
Altmeyer P. The outcome after cryosurgery and intra-
lesional steroid injection in vulvar lichen sclerosus
corresponds to preoperative histopathological find-
ings. Dermatology. 2005;210(3):218–22.
8. Sharma S, Bhanot A, Kaur A, Dewan SP. Role of liq-
uid nitrogen alone compared with combination of liq-
uid nitrogen and intralesional triamcinolone acetonide
in treatment of small keloids. J Cosmet Dermatol.
2007;6(4):258–61.
9. Berlin JM, Rigel DS. Diclofenac sodium 3% gel in the
treatment of actinic keratoses postcryosurgery.
J Drugs Dermatol. 2008;7(7):669–73.
10. Peck GL. Hypertrophic scar after cryotherapy and topi-
cal tretinoin. Arch Dermatol. 1973;108(6):819–22.
11. Stavropoulou E, Korfitis C, Christofidou E, Tzilalis
VD, Rallis E. Blue rubber bleb nevus syndrome suc-
cessfully treated with polidocanol sclerotherapy and
cryosurgery. Dermatol Surg. 2009;35(9):1442–4.
12. Goel R, Swanlund D, Coad J, Paciotti GF, Bischof
JC. TNF-alpha-based accentuation in cryoinjury –
dose, delivery, and response. Mol Cancer Ther.
2007;6(7):2039–47.
13. Chao BH, He X, Bischof JC. Pre-treatment inflamma-
tion induced by TNF-alpha augments cryosurgical
61 Combination Cryosurgery
injury on human prostate cancer. Cryobiology.
2004;49(1):10–27.
14. Hachisuka J, Doi K, Furue M. Combination cryosur-
gery with hyperthermia in the management of skin
metastasis from breast cancer: a case report. Int J Surg
Case Rep. 2012;3(2):68–9.
15. Zagar TM, Oleson JR, Vujaskovic Z, Dewhirst MW,
Craciunescu OI, Blackwell KL, Prosnitz LR, Jones
EL. Hyperthermia for locally advanced breast cancer.
Int J Hyperthermia. 2010;26(7):618–24.
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16. Di DR, He ZZ, Sun ZQ, Liu J. A new nano-
cryosurgical modality for tumor treatment using bio-
degradable MgO nanoparticles. Nanomedicine.
2012;8(8):1233–41.
17. Myers B, Donovan W. The effect of local anesthesia and
epinephrine on the size of cryolesions in the experimen-
tal animal. Plast Reconstr Surg. 1981;68(3):415–21.
18. Ernst FD, Kuoch HG. The functional behavior of
peripheral circulation in cryogenic surgery. Z Exp
Chir. 1979;12(3):171–80.
 Part XI
Cryosurgical Treatment
of Benign Skin Conditions
 Acne
62
Gloria F. Graham and Sara Moradi Tuchayi

Abstract
Acne vulgaris is the most common dermatologic diagnosis in the United
States. Almost 20 % of these young people endure moderate to severe
acne. It is a multifactorial disorder of the sebaceous glands characterized
by inflammation, comedones, and lesions of the skin. There are several
methods for grading acne, but to assess the severity of acne for clinical
reasons a four categories measure is part of many methods like global acne
grading system (GAGS). Based on the multifactorial nature of the disease
current guidelines agree on necessity of combination therapy. Topical reti-
noids are cornerstone of therapy for most patients except those with the
most severe disease. Antimicrobial agents such as benzoyl peroxide or
antibiotics help with inflammatory lesions. Nowadays a topical retinoid
plus an antimicrobial agent is considered first-line therapy for acne. Oral
antibiotics or hormone therapy should be added to treatment regimen for
moderate acne cases. For many patients with lower grade acne outbreaks
these treatments have a high success rate. Isotretinoin is preferred for
severe acne patients. Although it has undeniably great effects in acne treat-
ment, severe birth defect risk remains the main concern. Karp introduced
cryotherapy for treatment of acne and acne scars in 1939. Allington used
liquid nitrogen applied with a cotton swab for treatment of different skin
disorders including acne in late 1940s. In 1971 Graham reported liquid
nitrogen to be effective in treating acne. Coherent Anti-Stokes Raman
Scattering (CARS) microscopy has proved a gradual loss of subcellular

G.F. Graham, MD (*) • S.M. Tuchayi, MD, MPH

Department of Dermatology, Wake Forest University
School of Medicine, Winston Salem, NC, USA
e-mail: ggfgraham@aol.com

© Springer-Verlag London 2016 319

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_62
320 G.F. Graham and S.M. Tuchayi

structures in sebocytes after cold exposure. Cryosurgical treatment of acne

is a simple procedure and produces quick results with no scarring, patients
seeing clearing of pustules and papules in as early as 3 days. The more
severe the individual case of acne, the more beneficial cryospray treatment
proves to be.

Keywords
Acne vulgaris • Cryosurgery • Crospray • Retinoid • Isotretionoin •
Benzoyl peroxide • Hormone therapy • Phototherapy • Laser •
Hypopigmentation

Introduction pustules accompanied by erythema and slight

Acne vulgaris, or more commonly, acne is the most
common dermatologic diagnosis in the United
States [1]. While acne affects almost 85 % of teen-
agers, more common in teenage boys than girls,
greater numbers of women struggle with the dis-
ease into their adulthood [2]. Almost 20 % of these
young people endure moderate to severe acne [3].
Although acne is not a life threatening disease it
can cause serious undesirable effects on patients’
quality of life, [4] as it has been revealed that acne
vulgaris caused the fourth greatest US skin disabil-
ity (0.25 % of total US DALYs) in 2010 [5].
Description
It is a multifactorial disorder of the sebaceous
glands characterized by inflammation, comedo-
nes, and lesions of the skin. It is generally caused
by the over activity of sebaceous glands with
inadequate shedding of epithelial tissue leading
to blockages of the follicle and sebum creating an
excess of the naturally occurring propionibacte-
rium [6]. This results in the surface reaction of
comedones, pustules, papules, and in worse cases
cysts. There are several methods for grading
acne, but to assess the severity of acne for clinical
reasons a four categories measure is part of many
methods like global acne grading system
(GAGS). Grade I is presence of minor breakouts
of occasional papules but mostly open comedo-
nes. Grade II shows increased open comedones,
few papules and occasional pustules. Furthermore
Grade III shows many open comedones, papules,
edema. Grade IV shows cysts and most likely
scarring from tissue damage [7].
Therapeutic Alternatives
Treating acne relies heavily on the actions of the
patient. In the past treatments for acne included
options like ultraviolet therapy and direct injec-
tion of corticosteroids into the lesions.
Based on the multifactorial nature of the disease
current guidelines agree on necessity of combina-
tion therapy [8]. Topical retinoids are cornerstone of
therapy for most patients except those with the most
severe disease. Antimicrobial agents such as ben-
zoyl peroxide or antibiotics help with inflammatory
lesions. Nowadays a topical retinoid plus an antimi-
crobial agent is considered first-line therapy for
acne, and benzoyl peroxide remains the most desir-
able antimicrobial agent due to antibiotic resistant
concerns. Oral antibiotics should be added to treat-
ment regimen for moderate acne cases for short
periods. Hormone therapy is very effective in
women with moderate acne. For many patients with
lower grade acne outbreaks these treatments have a
high success rate. Isotretinoin is preferred for severe
acne patients. Although it has undeniably great
effects in acne treatment, severe birth defect risk
remains the main concern. Other therapeutic
options are various forms of light treatments includ-
ing visible light, specific narrowband light, intense
pulsed light (IPL), pulsed dye laser (PDL), and pho-
todynamic therapy (PDT). These optical treatments
can improve inflammatory acne in the short-term,
but long-term studies are still needed [8, 9].
62 Acne 321

Cryospray and the Treatment a

of Acne

Karp introduced cryotherapy for treatment of

acne and acne scars in 1939. He used a mixture of
solid carbon dioxide, acetone, and precipitated
sulfur for freezing [10, 11]. A similar mixture
was used as a “slush” by Dobes and Keil 1 year
later [12]. Allington used liquid nitrogen applied
with a cotton swab for treatment of different skin
disorders including acne in late 1940s [13]. In
1971 Graham reported liquid nitrogen to be
effective in treating acne [14].
Coherent Anti-Stokes Raman Scattering
(CARS) microscopy has proved a gradual loss of
subcellular structures in sebocytes after cold
exposure, [15] which is consistent with previous
findings. Although recovery of most of sebaceous
glands started 1–2 weeks after treatment, some of
the glands never recovered within the course of
the experiment, which suggests that some seba-
ceous glands may be permanently damaged by
cooling [16].
b
Cryosurgical treatment of acne is a simple
procedure and produces quick results, with
patients seeing clearing of pustules and papules
in as early as 3 days.
This treatment produces no scarring;
Cryotherapy is only mildly painful for a brief
amount of time. Shortly after freezing erythema
and edema are likely accompanied by peeling,
and this can be unappealing to some patients.
Cryotherapy in combination with other topical
treatments have been shown to provide rapid and
desired results.

Methodology
Cryospray of acne is performed using a hand held
device such as the CRYAC. A spray nozzle
appropriate for the size of the lesion(s) should be
selected. In my method I mark the skin in a rect-
angular pattern and lesions are targeted by the
spray for short bursts of 5 s. Treatment of the
entire face can take place in less than two minutes
[17] (Fig. 62.1).
Fig. 62.1 (a) A young man was attempting to get into a
branch of service that required his acne to be cleared with-
out isotretinoin. He was treated with tretinoin and oral
antibiotics. He had papules, comedones, pustules and
cysts. Grade 4 acne. After 2 months and use of intrale-
sional steroids on his cysts, he still did not have sufficient
clearing to enter the service. He was treated with liquid
nitrogen spray, and was subsequently accepted into the
service. The results are seen in figures (c, e, f). (b) Right
cheek prior to freezing. (c) Right cheek after freezing. (d)
Left cheek prior to freezing. (e) Left cheek after freezing.
(f) Facial clearing after treatment completed
322
c d
e
Fig. 62.1 (continued)
Success Rates
The more severe the individual case of acne,
the more beneficial cryospray treatment proves
to be. A split-face controlled trial study of 25
patients in which liquid nitrogen was applied
to acne lesions on one side of the face and
other topical therapies were used on the other
side showed liquid nitrogen to be effective
against pustular but not comedonal and papular
acne. It was most effective in treating superfi-
G.F. Graham and S.M. Tuchayi
f
cial cystic lesions and least effective against
deeper lesions [10, 18].
Author’s study of 150 acne patients reported
good to excellent results in 95 % of cases
[19–21].
Conclusions
Due to chronic nature [8] and multifactorial
causality of acne, which result in various pat-
terns of the disease and differences in patients’
preference several methods should be consid-
62 Acne
ered to insure best therapeutic results. There is
not a single effective safe method applicable
for all acne patients yet; with every method
having its own benefits and limitations.
Cryospray if used precisely and in appro-
priate cases has wonderful results. Risk of
hypopigmentation should always be consid-
ered, especially in dark skinned patients.
References
1. NAMCS Factsheet for Dermatology. NAMCS_2010_
factsheet_dermatology.pdf. 2014 [cited 2014
October 23rd]. Available from: http://www.cdc.gov/
nchs/data/ahcd/NAMCS_2010_factsheet_dermatol-
ogy.pdf. 2010.
2. Zeichner JA. Evaluating and treating the adult female
patient with acne. J Drugs Dermatol. 2013;12(12):
1416–27.
3. Bhate K, Williams HC. Epidemiology of acne vul-
garis. Br J Dermatol. 2013;168(3):474–85.
4. Rapp DA, Brenes GA, Feldman SR, Fleischer AB,
Graham GF, Dailey M, et al. Anger and acne: implica-
tions for quality of life, patient satisfaction and clini-
cal care. Br J Dermatol. 2004;151(1):183–9.
5. Karimkhani C, Boyers LN, Margolis DJ, Naghavi M,
Hay RJ, Williams HC, et al. Comparing cutaneous
research funded by the National Institute of Arthritis
and Musculoskeletal and Skin Diseases with 2010
Global Burden of Disease results. PLoS One.
2014;9(7):e102122.
6. Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology.
London: Elsevier Health Sciences UK; 2012.
7. Doshi A, Zaheer A, Stiller MJ. A comparison of cur-
rent acne grading systems and proposal of a novel
system. Int J Dermatol. 1997;36(6):416–8.
8. Thiboutot D, Gollnick H, Bettoli V, Dréno B, Kang S,
Leyden JJ, et al. New insights into the management of
acne: an update from the Global Alliance to Improve
323
Outcomes in Acne group. J Am Acad Dermatol.
2009;60(5 Suppl):S1–50.
9. Williams HC, Dellavalle RP, Garner S. Acne vulgaris.
Lancet. 2012;379(9813):361–72.
10. Taub AF. Procedural treatments for acne vulgaris.
Dermatol Surg. 2007;33(9):1005–26.
11. Karp FL, Nieman HA, Lerner C. Cryotherapy for
acne vulgaris. Arch Dermatol Syphilol.
1939;39:995–8.
12. Dobes WL, Keil H. Treatment of acne vulgaris by
cryotherapy (slush method). Arch Dermatol Syphilol.
1940;42:547–58.
13. Torre D. New York, cradle of cryosurgery. N Y State
J Med. 1967;67(3):465–7.
14. Graham GF. Liquid nitrogen spray found useful in
treating acne. JAMA. 1971;215:1901–4.
15. Jung Y, Tam J, Jalian HR, Anderson RR, Evans
CL. Longitudinal, 3D in vivo imaging of seba-
ceous glands by coherent anti-stokes Raman scat-
tering microscopy: normal function and response
to cryotherapy. J Invest Dermatol. 2015;135(1):
39–44.
16. Gage AA, Meenaghan MA, Natiella JR, Greene
GW. Sensitivity of pigmented mucosa and skin to
freezing injury. Cryobiology. 1979;16(4):
348–61.
17. Graham GF. Cryosurgery in treatment of acne and
specific cutaneous neoplasia. In: Zacarian SA, editor.
Cryosurgical advances in dermatology and tumors of
the head and neck. Springfield: Thomas; 1977.
p. 74–82.
18. Goette DK. Liquid nitrogen in the treatment of acne
vulgaris: a comparative study. South Med
J. 1973;66(10):1131–2.
19. Graham GF. Liquid nitrogen and nitrous oxide sprays
in the treatment of acne vulgaris. Proceedings, latest
developments in cryosurgery. Vienna: International
Congress of Cryosurgery;1972. p. 351–5.
20. Graham GF. Cryosurgical treatment of acne. Cutis.
1975;16:509–13.
21. Graham GF. Cryosurgery in the treatment of acne. In:
Epstein E, editor. Skin surgery. 4th ed. Springfield:
Thomas; 1976.
 Alopecia
63
Renata Strumia

Abstract
Cryotherapy in not generally used in alopecias. There are only some
reports of cryotherapy in alopecia areata. Superficial cryotherapy has been
proposed as a first-line treatment for patients with a milder form, espe-
cially in children who are vulnerable to therapeutic side effects and pain.
Superficial cryotherapy of alopecia areata in eyebrows can be an effective,
safe and easy mode of treatment. The supposed mechanism is that cryo-
therapy dilates the vessels around hair follicles, thus improving follicular
nutritional status.

Keywords
Alopecia • Cryotherapy

Introduction syphilis), pyogenic infections, protozoal infections

Alopecias include androgenetic alopecia, distur-
bances of hair cycle (telogen effluvium), alopecia
of chemical, nutritional and metabolic origin,
chronic diffuse alopecia, alopecia in central ner-
vous system disorders, alopecia areata, traumatic
alopecia. Cicatricial alopecia includes broad groups
such as developmental and hereditary disorders,
physical injuries, medicaments, fungal infections
(kerion), bacterial infections (tuberculosis,
(leishmaniasis), virus infections (herpes zoster,
varicella), tumors (basal/squamous cell carcinomas
and others), clinical syndromes and dermatoses of
uncertain etiology (pseudopelade, folliculitis
decalvans, lichen planus, lupus erythematosus and
many others).
Cryotherapy is not generally used in alope-
cias. There are only some reports of cryotherapy
in alopecia areata (AA).

Description of the Disease

R. Strumia, MD
Unit of Dermatology, Department of Clinical and
AA is a complex genetic, immunomediated dis-
Specialistic Medicine, S. Anna Hospital, University
of Ferrara, (Former) Ferrara 44121, Italy ease that targets anagen hair follicles, character-
e-mail: restrumi@tin.it ized by non-scarring hair loss. AA is a relatively

© Springer-Verlag London 2016 325

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_63
326
common disease. It affects both males and
females of all ages and races in all parts of the
world. The typical patient presents with one or
few nonscarred, hairless patches of round or oval,
sharply demarcated, shape [1]. Mild limited
involvement of the scalp is the most common
presentation; multiple patches may become con-
fluent over time. Spontaneous regression occurs
often, with new hair growth taking place; ran-
domly sized and located recurrences may occur.
Sometimes, the patient can tell when the hair fell
out but in many the exact disease duration is
unclear.
The skin of the affected patches appears nor-
mal and smooth, or a pinkish coloration can be
observed. A soft, cushion like infiltration may
rarely be felt.
Usually, the patches are symptomless. But
occasionally, patients describe some tingling,
itching, or dysesthesia, at times preceding the
hair loss. Different clinical types of AA can be
observed. Patchy AA is the most common
form, occurring in up to 75 % of patients. The
reticularis variant presents multiple active, sta-
ble or regrowing patches which may merge to
form a mosaic pattern. A subset of patients
(10–20 %), have complete alopecia on the
scalp, i.e., alopecia totalis. When all scalp and
body hairs are lost, the type is called alopecia
universalis. The latter includes loss of eye-
brows, eyelashes, nose, and ear hairs. Oophiasis
(Greek for snake) is a peculiar band-like pat-
tern of AA that winds along the occipital hair-
line extending toward the temples. It usually
has a more difficult prognosis. Rarely, inflamed
areas such as psoriatic lesions are spared from
AA [1].
The course of AA is practically unpredictable;
in most cases, taking a chronic but mild course
with episodic patches. In up to 50 % of patients
with patchy AA, spontaneous regrowth occurs
within 12 months, in 66 % within 5 years.
However, the risk of recurrence is 85 %. Severity
at the time of first consultation is an important
prognostic factor. In alopecia totalis and univer-
salis, the chance of full recovery is less than
10 %. Children with severe and long-lasting AA
have the most difficult prognosis.
R. Strumia
Histology
A histopathologic hallmark of alopecia areata is
the presence of perifollicular inflammation and in
particular, a peribulbar infiltrate of predomi-
nantly lymphocytes around anagen follicles. This
infiltrate is commonly referred to as a “swarm of
bees” and is typically seen in patients with active
disease.
Therapeutic Alternatives
First-line therapies for AA include intralesional
or topical corticosteroids, and in some institu-
tions, topical immunotherapy. There are no ran-
domized trials of intralesional corticosteroids for
AA; however, there are several published studies
on the efficacy of topical corticosteroids in the
treatment of this disease. Second-line therapies
include topical minoxidil, anthralin, and photo-
therapy with psoralen plus near ultraviolet light
(PUVA); also, systemic glucocorticoids, sul-
fasalazine, cyclosporine, methotrexate, and com-
binations. Other therapies that have shown some
efficacy include the excimer laser, topical bexar-
otene, photodynamic therapy, prostaglandin ana-
logs, and fractional photothermolysis.
Aromatherapy, a natural option, has been reported
as effective in some. Although there are recent
isolated case reports of different biologics being
effective in the treatment of AA, attempts to treat
this disease with biologic agents that alter T cell
function have not proven to be successful in clini-
cal trials [2].
Cryotherapy
There are some reports that superficial cryother-
apy of AA could be effective and has many
advantages [3–9]. It is simple and convenient,
and has relatively good therapeutic response with
few side effects. Superficial cryotherapy using
LN spray for 2–3 s onto the alopecic patches,
repeated three or four times per session causes no
significant side effects, except slight pain, swell-
ing and erythema. Lei et al. [4] propose it as
63 Alopecia
first-line treatment for patients with milder forms
of AA, especially in children who are vulnerable
to therapeutic side effects and pain. Superficial
cryotherapy of alopecia areata in eyebrows can
be an effective, safe and easy mode of treatment
mode of treatment [9]. The proposed mechanism
is vessel dilatation around hair follicles, thus
improving follicular nutritional status.
Methodology (How I Do It)
I perform cryotherapy in AA both of the scalp,
and of the eyebrows and beard with cotton-tipped
dipstick with the technique of cryomassage. The
cotton-wool stays in contact with the skin for
1–2 s until it turns white momentarily from freez-
ing. Slight pain and mild erythema are the only
side effects. Two sessions a month are performed
for 2 months, followed by one session a month
until regrowth is achieved.
Success Rates
One investigation studying both children and
adults showed hair regrowth in more than 60 % of
affected areas in 70 of 72 patients; after 6 months
only 3 of 66 patients had relapses [4]. In another
study [6] the overall response rate was 66.7 %. In
a more recent study [8], 23 % of lesions had a good
response (regrowth of more than 75 % terminal
hairs) and 33.5 % showed only moderate improve-
ment with cryotherapy treatment.
Conclusions
The best mechanisms explaining the efficacy
of cryotherapy in AA are vascular changes
and immunomodulation. The supposable
mechanism is dilatation of the vessels around
hair follicles, which improves follicular
327
nutritional status. On the whole, LN cryother-
apy in AA can be effective. It is a simple and
convenient method, and has a relatively good
therapeutic response with few side effects. It
is also readily available. We recommend
superficial cryotherapy for patients with a
mild, patchy form of AA, especially in chil-
dren as they are particularly vulnerable to the
long-term side effects of immunosuppressive
drugs. Cryotherapy can be performed alone or
in association with other treatments.
Unfortunately, an accurate evaluation of the
efficacy of cryotherapy in AA is difficult
because the course of the disease is so
unpredictable.
References
1. Finner AM. Alopecia areata: clinical presentation,
diagnosis, and unusual cases. Dermatol Ther.
2011;24:348–54.
2. Hordinsky MK. Treatment of alopecia areata: ‘what is
new on the horizon?’. Dermatol Ther.
2011;24:364–8.
3. Lee BJ, Lee WS, Yoo MS, Ahn SK. Cryotherapy of
alopecia areata. Korean J Dermatol. 1994;32:416–20.
4. Lei Y, Nie Y, Zhang JM, Liao DY, Li HY, Man
MQ. Effect of superficial hypothermic cryosurgery
with liquid nitrogen on alopecia areata. Arch
Dermatol. 1991;127:1851–2.
5. Hong SP, Jeon SY, Oh TH, Lee WS. A retrospective
study of the effect of superficial cryotherapy on alope-
cia areata. Korean J Dermatol. 2006;44:274–80.
6. Hyung OK, Seok D, Won S. Effect of cryotherapy
with liquid nitrogen on alopecia areata. Korean
J Dermatol. 1994;32:421–6.
7. Faghihi G, Radan M. Liquid nitrogen cryotherapy vs.
betamethasone lotion in the management of alopecia
areata. J Clin Med Res. 2013;5:18–22.
8. Faghihi G, Radan M. Jet cryotherapy vs clobetasol
proprionate lotion in alopecia areata. Skinmed.
2014;12:209–11.
9. Jeon SY, Ahn BK, Lee S, Lee WS. Superficial cryo-
therapy of alopecia areata in eyebrows. Korean
J Dermatol. 2004;42:1024–7.
 Angiokeratoma
64
Stephanie Saxton-Daniels

Abstract
Angiokeratomas are benign vascular tumors that have an overlying hyper-
keratotic surface.
Angiokeratomas may be localized or generalized, ranging in size from
1 to 10 mm. Treatment options include cryosurgery, electrocoagulation,
excisional surgery, sclerotherapy and laser.

Keywords
Angiokeratoma • Angiokeratoma of Fordyce • Angiokeratoma of Mibelli
• Angiokertoma corporis diffusum • Fabry disease • Fucosidosis

Introduction Description

Angiokeratomas are benign tumors of ectatic
vessels from the papillary dermis with overlying
hyperkeratosis. The different types of angiokera-
toma include: solitary papular, cicumscriptum,
Mibelli, Fordyce and coporis diffusum.
Angiokeratomas may be localized or general-
ized. The generalized form is associated with an
underlying metabolic disorder such as Fabry dis-
ease or fucosidosis.
S. Saxton-Daniels, MD
Dermatology Treatment & Research Center,
5310 Harvest Hill Rd. Suite 160, Dallas,
TX 75230, USA
e-mail: saxtondaniels@gmail.com
Angiokeratoma are small dark red, blue or purple
papules or plaques, ranging in size from 1 to
10 mm. They are composed of ectatic thin-walled
vessels from superficial dermis with overlying
epidermal hyperkeratosis and acanthosis.
Therapeutic Alternatives
Treatment options include cryosurgery, electro-
coagulation, excisional surgery, sclerotherapy [1]
and laser. The various lasers include: neodynium
YAG [2, 3], copper [4], argon [5], 532-nm KTP
[6], pulsed-dye [7, 8], CO2 and intense pulsed
light lasers [9].
For cryosurgery, an open spray technique with
two 15–20 s freeze-thaw cycles may be utilized.

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_64
330 S. Saxton-Daniels

References 6. Bechara FG, Jansen T, Wilmert M, Altmeyer P,

Hoffmann K. Angiokeratoma Fordyce of the glans
penis: combined treatment with erbium: YAG and
1. Seo SH, Chin HW, Sung HW. Angiokeratoma of
532nm KTP (frequency doubled neodynium: YAG)
Fordyce treated with 0.5% ethanolamine oleate or
laser. J Dermatol. 2004;31(11):943–5.
0.25% sodium tetradecyl sulfate. Dermatol Surg.
7. Burnett CT, Kouba DJ. A rare case of congenital
2010;36(10):1634–7.
angiokeratoma of the glans penis treated using a 595-
2. Ozdemir M, Baysal I, Engin B, Ozdemir S. Treatment
nm pulsed dye laser. Dermatol Surg. 2012;38(12):
of angiokeratoma of Fordyce with long-pulse
2028–30. doi:10.1111/j.1524-4725.2012.02546.x. Epub
neodymium-doped yttrium aluminium garnet laser.
2012 Aug 3.
Dermatol Surg. 2009;35(1):92–7.
8. Lapidoth M, Ad-El D, David M, Azaria R. Treatment
3. Civas E, Koç E, Aksoy B, Aksoy HM. Report of two
of angiokeratoma of Fordyce with pulsed dye laser.
angiokeratoma of Fordyce cases treated with a
Dermatol Surg. 2006;32(9):1147–50.
1064nm long-pulsed Nd:YAG laser. Photodermatol
9. Ichikawa R, Furue M. Successful treatment of scrotal
Photoimmunol Photomed. 2009;25(3):166–8.
angiokeratomas (Fordyce type) with small-spot narrow-
4. Lapins J, Emtestam L, Marcusson JA. Angiokeratomas
band intense pulsed light. Dermatol Surg.
in Fabry’s disease and Fordyce’s disease: successful
2013;39(10):1547–8. doi:10.1111/dsu.12282. Epub 2013
treatment with copper vapour laser. Acta Derm
Jul 29.
Venereol. 1993;73:133–5.
5. Occella C, Bleidl D, Rampini P, Schiazza L, Rampini
E. Argon laser treatment of cutaneous multiple angio-
keratomas. Dermatol Surg. 1995;21(2):170–2.
 Angiolymphoid Hyperplasia
with Eosinophilia
65
Stephanie Saxton-Daniels

Abstract
Angiolymphoid hyperplasia with eosinophilia (ALHE) is a benign condi-
tion with unknown etiology. They may be solitary or multiple and most
commonly occur on the head and neck. Treatment options include surgical
excision, cryosurgery, intralesional corticosteroids or chemotherapy, oral
retinoids, photodynamic therapy, pulsed dye or ND:YAG laser, imiqui-
mod, electrodessication, radiotherapy and pentoxifylline. Treatment with
cryosurgery is reviewed.

Keywords
Angiolymphoid hyperplasia with eosinophilia • ALHE

Introduction solitary or multiple. It is most common in middle-

Angiolymphoid Hyperplasia with Eosinophilia
(ALHE) is an uncommon benign tumor, or pos-
sibly, a reactive process. The cause is unknown.
aged Caucasian women. Lesions can be pruritic
or painful and do not resolve on their own.
Therapeutic Alternatives

Description of the Disease There are many reported treatment options, the
most common being surgical excision. Other
Patients present with red-brown or pink dome- options include cryosurgery, intralesional corti-
shaped dermal papules or nodules, most com- costeroids or chemotherapy, oral retinoids, pho-
monly located on the head and neck, particularly todynamic therapy, pulsed dye or ND:YAG laser,
periauricularly, and on the scalp. ALHE can be imiquimod, electrodessication, radiotherapy and
pentoxifylline [1–11].
S. Saxton-Daniels, MD
Dermatology Treatment & Research Center,
5310 Harvest Hill Rd. Suite 160, Dallas,
TX 75230, USA
e-mail: saxtondaniels@gmail.com

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DOI 10.1007/978-1-4471-6765-5_65
332
Cryosurgery/Methodology
Wozniacka et al. reported the successful treat-
ment of recalcitrant ALHE with cryosurgery [1].
One patient was treated in four sessions at 4-week
intervals, using an open spray technique, each
lesion received 20 s of LN. Slight erythema was
observed 2 weeks after last session; 1-year later
there was no recurrence.
Conclusions
Cryosurgery can be used to successfully treat
ALHE, that results in a good cosmetic out-
come. It represents an inexpensive, widely
available and easy to perform alternative to
other treatment modalities.
References
1. Wozniacka A, Omulecki A, Torzecka J. Cryotherapy
in the treatment of angiolymphoid hyperplasia with
eosinophilia. Med Sci Monit. 2003;9(1):CS1–4.
2. Lembo S, Balato A, Cirillo T, Balato N. A long-term
follow-up of angiolymphoid hyperplasia with eosino-
philia treated by corticosteroids: when a traditional
therapy is still up-to-date. Case Rep Dermatol.
2011;3(1):64–7.
S. Saxton-Daniels
3. Shenefelt PD, Rinker M, Caradonna S. A case of
angiolymphoid hyperplasia with eosinophilia treated
with intralesional interferon alfa-2a. Arch Dermatol.
2000;136(7):837–9.
4. Carlesimo M, Mari E, Tammaro A, Persechino S,
Camplone G. Angiolymphoid hyperplasia with eosin-
ophilia treated with isotretinoin. Eur J Dermatol.
2007;17(6):554–5.
5. Isohisa T, Masuda K, Nakai N, Takenaka H, Katoh
N. Angiolymphoid hyperplasia with eosinophilia
treated successfully with imiquimod. Int J Dermatol.
2014;53(1):e43–4.
6. Redondo P, Del Olmo J, Idoate M. Angiolymphoid
hyperplasia with eosinophilia successfully treated
with imiquimod. Br J Dermatol. 2004;151:1110–1.
7. Vanhooteghem O, Flagothier C, Brassinne M.
Angiolymphoid hyperplasia with eosinophilia of the
scalp: promising results of long-pulsed tunable dye
laser treatment. J Eur Acad Dermatol Venereol.
2009;23(8):954–5.
8. Abrahamson TG, Davis DA. Angiolymphoid hyperpla-
sia with eosinophilia responsive to pulsed dye laser. J Am
Acad Dermatol. 2003;49(2 Suppl Case Reports):S195–6.
9. Sotiriou E, Apalla Z, Patsatsi A, Panagiotidou DD,
Ioannides D. Angiolymphoid hyperplasia with eosin-
ophilia: good response to photodynamic therapy. Clin
Exp Dermatol. 2009;34(8):e629–31.
10. Kadurina MI, et al. Angiolymphoid hyperplasia with
eosinophilia: successful treatment with the Nd:YAG
laser. J Cosmet Laser Ther. 2007;9(2):107–11.
11. Akdeniz N, et al. Intralesional bleomycin for angio-
lymphoid hyperplasia. Arch Dermatol. 2007;143(7):
841–4.
 Callosities, Corns, Clavi, Tylomata
66
Renata Strumia

Abstract
Callosities, corns, clavi, tylomata on the feet may be extremely painful
lesions and a treatment is requested. Medical treatment usually includes
applications of salicylic acid plasters and curettage of the central core.
One or more sessions of cryosurgery for about 5–15 s each, are recom-
mended in most cases to reduce pain. Topical anesthesia with a cream is
usually requested. After cryosurgery, interdigital corns require toe separa-
tion for months to avoid their recurrence.

Keywords
Callosities • Corns • Clavi • Tylomata

Introduction Description of the Disease

Callosities (tylomata) are circumscribed plaques
of hyperkeratosis induced by repeated frictional
trauma. Corns (clavi) arise from persistent con-
tinuous or intermittent pressure where there is an
insufficient amount of soft tissue between skin
and the underlying bone, usually on the feet or
toes. Pain from corns results from their hard coni-
cal corn pointing towards the bone. Foot defor-
mity and improper footwear are the most common
causes. Hereditary callosities are reported [1].
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara, (Former) Ferrara, Italy
e-mail: restrumi@tin.it
Corns (clavi) consist of a central hyperkeratotic
spike projecting downwards and forming a hard
core on the surface, which is surrounded by a
wider semi-opaque area of hyperkeratosis. The
adyacent skin may be reddened. Direct pressure
evokes pain. Soft corns are extremely painful
lesions that can develop between any of the toes
but most commonly between the fourth and fifth
toes (Fig. 66.1). Soft corns can lead to macera-
tion and cellulitis, especially in old people.
Thought corns are usually diagnosed without dif-
ficulty, verrucae may at times coexist with or
underlie callosities; the wart may be revealed by
paring or curettage [2, 3].

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334
Fig. 66.1 Soft corn
Therapeutic Alternatives
As plantar corns can be disabling, treatment is rec-
ommended. Most mechanical lesions can be conser-
vatively managed with adequate footwear. Patients
should be advised to wear low-heeled shoes with a
soft upper portion and a roomy toebox. Excision is
usually not indicated since the rate of recurrences is
as high as with conservative therapy and the result-
ing scars may lead to the same complaints.
Medical treatment usually includes applica-
tions of salicylic acid plasters and curettage of
the central core. Callosities require more pro-
longed treatment. As both callosities and corns
on the feet are the result of deformity associated
with dynamic changes in the function of the foot,
correction can be achieved by the use of suitable
orthotic devices that fix the deformity and main-
tain the correction.
Cryosurgery
It allows for the removal the corn in one or more
sessions [4]. One application is usually enough to
create a blister that will eliminate a lesion.
Recurrence is prevented with adequate footwear
and by applications of salicylic acid plasters.
R. Strumia
Fig. 66.2 After cryotherapy, interdigital corns require the
separation of the toes for months to avoid their
recurrence
Methodology (How I Do It)
One or more sessions of cryosurgeryy of about
5–15 s are adequate in most cases. Topical anes-
thesia with a cream may be requested. After
cryosurgery, interdigital corns require toe sepa-
ration for months to avoid recurrences
(Fig. 66.2).
Conclusions
Cryosurgery is useful in the management of
callosities and corns of the foot.
References
1. Baden HP, Bronstein BR, Rand RE. Hereditary cal-
losities with blisters. J Am Acad Dermatol.
1984;11:409–15.
2. Haneke E. Differential diagnosis and therapy of cal-
luses, corns and plantar warts. Z Hautkr.
1982;57:263–72.
3. Singh D, Bentley G, Trevino SG. Callosities, corns,
and calluses. BMJ. 1996;312:1403–6.
4. Sheard C. Simple management of plantar clavi. Cutis.
1992;50:138.
 Cryosurgery of Plantar Lesions
67
Michelle A. Nguyen, Jennifer Krejci-Manwaring,
and Bobby L. Limmer

Abstract
Several lesions affecting the soles are amenable to be treated with cryosur-
gery. Following the suggested method results in high cure rates and mini-
mal if any scarring.

Keywords
Porokeratosis • Plantaris • Wart • Plantar

Porokeratosis Plantaris Discreta distributed primarily on pressure – bearing areas

Porokeratosis plantaris discreta is a localized
plantar hyperkeratosis first studied in detail by
Taub and Steinberg [1] whose original work has
been expanded by subsequent authors [2, 3]. It is
often mistaken for a wart. There are certain clini-
cal and histological features, which set this lesion
apart from all other hyperkeratotic lesions com-
monly found on plantar surfaces. This lesion is
M.A. Nguyen, BS
University of Texas Health Science Center at San
Antonio, San Antonio, TX, USA
J. Krejci-Manwaring, MD
Department of Dermatology, University of Texas
Health Science Center, San Antonio, TX, USA
B.L. Limmer, MD (*)
Department of Dermatology, Plastic Surgery,
University of Texas Health Science Center,
14615 San Pedro Suite 245, San Antonio, TX 78232,
USA
e-mail: carolelimmer@icloud.com
of the plantar surface, such as, underlying the sub
metatarsal head or on the heel. It is often dispro-
portionately painful when compared to the size
and innocuous appearance of the lesion itself. A
central keratin plug and surrounding callosity or
hyperkeratosis characterized the lesion. The cen-
tral keratin plug is sharply marginated, rarely
more than 3 mm in diameter, rubbery in consis-
tency, opaque in color, and devoid of blood ves-
sels. Histologically, the conical hyperkeratotic
plug possesses a central parakeratotic column,
suggesting a cornoid lamella. Absence of the epi-
dermal granular layer, cystic dilatation of the
eccrine sweet gland apparatus, and chronic
inflammation with dermal fibrosis distinguish it
from standard verrucae.
Porokeratosis plantaris discrete have previ-
ously been described as resistant to therapy by
conservative methods such as chemical cautery.
Taub and Steinberg recommended complete exci-
sion to include the underlying sweat gland,

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
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336
whereas Montgomery suggested removal of the
central keratin plug and electrosurgical destruc-
tion of the base of the lesion [1, 2]. For years,
surgical management was advocated as the only
therapy for the treatment of porokeratosis plan-
taris discrete. However, in 1979, Limmer [4] and
Waller [5] reported on the successful therapy of
porokeratosis plantaris discreta using cryosur-
gery. Limmer reported 21 cases that showed an
excellent response to cryosurgery in combination
with surgical paring [4]. This combination of
cryosurgery and surgical paring is now the treat-
ment of choice for this condition.
Plantar Warts
Plantar warts (verrucae) have a rough surface that
may protrude only from the skin and there may
be a surrounding horny collar. These lesions may
be painful, particularly if the keratin builds up.
When pared down, warts are easily distinguished
by the typical papillary bleeding points visual-
ized. Epidermal ridges do not cross the verruca
and this helps to distinguish them from the corns.
Plantar warts remain a common and challeng-
ing therapeutic problem. The list of measures
applied to this problem range from witchcraft to
immunotherapy. No one method is uniformly
successful. Cryosurgery treatment of verrucae of
plantar surfaces had previously been insufficient
for primary eradication, with recurrences
reported at a rate of over 50 %. Pain often pre-
cludes subsequent procedures as its difficult to
freeze deeply enough without exquisite pain to
eradicate a substantial percentage of plantar ver-
rucae with multiple sessions. This is particularly
true with spray freezing. Limmer reported sig-
nificantly higher cure rates in the treatment of
plantar warts with his combination of cryosur-
gery and surgical paring to the treatment of hun-
dreds of plantar warts. The initial 89 lesions he
treated with this technique, all of which had an
average follow-up period of 17.5 months, were
studied. No lesions were treated more than three
times. The recurrence rate using his method was
9 %. The remaining plantar warts revealed no
evidence of recurrence, constituting a cure rate
of 91 % [6]. Plantar warts are therefore also
M.A. Nguyen et al.
amenable to cryosurgical techniques when
adhering to Limmer’s method.
The Cryosurgical Technique (How
We Do It)
The first step is to obtain adequate local anesthe-
sia, either by direct sublesional infiltration or pos-
terior tibial nerve block. Few patients are able to
tolerate adequate initial cryosurgery of the plantar
surface without local anesthesia. The hyperkerato-
sis of the lesion is then superficially pared to delin-
eate the margin of the lesion. In the case of
porokeratosis plantaris discreta, the central keratin
plug is removed using a sharp (11 Bard Parker™)
blade, leaving a central conical cavity 1–3 mm in
depth. A continuous spray of LN is then directed at
the center of the lesion through an 18-gauge nee-
dle tip attached to the cryosurgical instrument. For
the porokeratosis plantaris discrete lesion, the
spray is directed into the conical cavity created by
removal of the central keratin plug. Holding the
spray on the center of the lesion allows the ice ball
to expand peripherally, encompassing the entire
lesion, and ensures adequate depth of freeze.
Movement of the point of spray over the surface of
the lesion will give the false impression that the
entire lesion has been frozen when, in fact, only a
very superficial freeze will have been achieved.
The spray of LN is continued at a steady rate
until the visible ice ball has advanced to 2 mm
beyond the margin of the lesion.
A blister, often hemorrhagic in nature, will occur
within 24–48 h after the initial freeze. Some dis-
comfort is associated with this period of blister for-
mation and may require analgesia, but most patients
are able to continue about their normal activities
including their work. This discomfort progressively
lessens over the ensuing days. Reabsorption of the
blister fluid will be complete in 10–14 days.
Secondary infections should be watched for in these
lesions although this is uncommon.
The patient is to return at 14 days after the ini-
tial freeze. This is because epithelium will regen-
erate along the blister floor within 14 days after
the freeze, allowing the blister roof to be removed.
The blister roof is removed by sharp dissection.
Care must be exercised to be certain that the
67 Cryosurgery of Plantar Lesions
plane of dissection is such that only the roof of
the blister is removed, leaving behind the newly
formed epidermis covering the floor of the previ-
ous blister. This can be accomplished by grasping
the roof of the blister with a forceps and applying
gentle traction as sharp dissection is carried out
along its margin; such removal is painless.
Residual plantar warts are present in a high per-
centage of treated sites. Most plantar warts will
require more than one treatment to effect cure, in
contrast to porokeratosis which generally require
only one treatment. If there is evidence of resid-
ual keratin or wart remaining after removal of the
blister roof, this should be retreated by superficial
freezing at this time. Repeat cryosurgery can usu-
ally be done without local anesthesia. The freeze
time will be less than 10 s. A great depth of freeze
is not necessary as the residual keratin plug or
wart is usually quite superficial and rarely greater
than 1 mm in thickness. Blister formation will
not occur in the case of a second freeze because
of the thinness of the epidermis. A small serous
crust formation will result, which should be
debrided at the next visit in 14 days. If cryosur-
gery was repeated, the debridement should be
repeated in 14 days. At this time, remove any
crust formation that occurs from the second
freeze since the crust will in its own right become
tender between 2 and 4 weeks after treatment if
left in place. This process is repeated every
14 days until there is no visible callus. Plantar
warts usually require anywhere between one and
three treatments. Adherence to this method mini-
mizes morbidity and enhances the cure rate.
Success Rates
This technique achieves cure rates greater than
90 % in both porokeratosis plantaris discreta and
plantar warts [5, 6]. Recurrences are associated
337
with deviation from this method, usually the
results of patient non-compliance with
follow-up.
Conclusion
Cryosurgical treatment of plantar lesions
appears to offer advantages in addition to an
acceptable cure rate. The technique is rela-
tively simple and safe. Complicated equip-
ment is not needed since simple, inexpensive
cryosurgical instruments are readily avail-
able. Postoperative morbidity is mild but
may consist of pain, leakage of blister fluid
and rarely a secondary infection. Most
patients are able to continue their usual
daily routine and work following this
method of treatment. The uncomplicated
procedure appears to be free from scarring.
A minimal amount of scar production is
seen after secondary infection. Achievement
of satisfactory results requires strict adher-
ence to the established methodology and
patient compliance with appropriately timed
follow-up.
References
1. Taub J, Steinberg MD. Porokeratosis plantaris dis-
creta, a previously unrecognized dermatologic entity.
Int J Dermatol. 1970;9:83.
2. Montgomery RM. Porokeratosis plantaris discreta.
Cutis. 1977;20:711–3.
3. Weisfeld M. Understanding porokeratosis plantaris
discreta. J Am Podiatry Assoc. 1973;63:138.
4. Limmer BL. Cryosurgery of porokeratosis plantaris
discreta. Arch Dermatol. 1979;115:582–3.
5. Waller J. Porokeratosis plantaris discreta (conical cal-
lus): cone spray freeze method. Paper presented at
First Annual American College of Cryosurgery
Meeting, New Orleans, 13 Mar 1978.
6. Limmer BL, Bogy LT. Cryosurgery of plantar warts.
J Am Podiatry Assoc. 1979;69:713–6.
 Cheilitis and Miscellaneous Benign
Lip Lesions
68
Marcia Ramos-e-Silva, Cleide Eiko Ishida,
and Stella Ramos-e-Silva

Abstract
This chapter deals with lesions on the lip that may be treated by
cryosurgery.

Keywords
Cheilitis • Lips • Benign • Cryosurgery • Cryotherapy

Introduction most common are hemangioma, papilloma, pyo-

Diagnosis of the wide variety of lesions that
occur in the oral cavity is possible with careful
examination. The lips reveal a heterogeneous
group of lesions ranging from congenital abnor-
malities to benign and malignant neoplasms, yet
members of both medical and dental professions
often neglect them. Constant exposure to irritants
can lead to alterations in normal tissue histology
or in trauma. Lip lesions may be part of the clini-
cal presentation of a systemic disease.
Anatomically, the lips form the border between
skin and mucosa; this increases the risk for devel-
oping alterations in comparison to other areas of
the head and neck [1]. Of the benign lesions, the
M. Ramos-e-Silva, MD, PhD (*) • C.E. Ishida, MD
S. Ramos-e-Silva, MD
Sector of Dermatology and Post-Graduation Course,
Federal University of Rio de Janeiro,
Rua Dona Mariana, 143 - Botafogo, Rio de Janeiro
22280-020, Brazil
e-mail: ramos.e.silva@dermato.med.br
genic granuloma and mucocele. The main site of
presentation is the lower lip, followed by the
upper lip and finally the commissure. The
increased percentage of involvement of the lower
lip as a site of presentation highlights the fact of
their greater exposure to environmental irritants
and trauma. Of pre-malignant lesions actinic
cheilitis is the most important and frequent.
Cryosurgery in the Oral Mucosa
Cryosurgery is a very useful technique for treat-
ment of oral lesions because of the characteristics
of the oral mucosa. By presenting a smooth and
humid surface, the oral mucosa becomes ideal for
freezing, making cryosurgery the first choice or a
good alternative to conventional surgery, which is
often made more complex by local vascularity
and difficulty of addressing lesions that are hard
to reach. It has several advantages over other
treatment modalities, especially in terms of

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340
convenience, as it is relatively inexpensive and
does not require the operator skill level for proce-
dures such as vermilionectomy. It has proven to
be a valuable alternative method at any stage of
oral lesions whether benign or malignant. It is
recommended for simplicity, absence of risks and
side effects, mild to moderate pain, possibilities
of retreatment, no carcinogenicity inducing resis-
tance, good healing, and low cost [2]. It does
require good illumination with a cold lamp that
will not interfere with thawing time [3]. Steam
aspiration is needed if the spray technique is
used. Combinations with other techniques, such
as shaving or radiosurgery, reduces the size of the
lesion and improves the effectiveness of treat-
ment, as well as enables the performance of a
biopsy for histopathological examination, essen-
tial for pre-cancerous lesions.
Although some clinicians use nitrous oxide,
helium, freons, fluorocarbonated sprays, and
solid carbon dioxide, LN is widely accepted as
the ideal cryogen because its low temperature
(−195.8 °C) and certified efficiency in malignant
disease. Nowadays it is used for both superficial
and deep freezing; the number of freeze-thaw
cycle needed depending on the size and nature of
the lesion.
The spot freeze technique involves the use of a
spray gun, which, through an appropriate nozzle,
emits an open spray of LN. In general, the nozzle
size is chosen according to the size of the lesion;
however, a ‘D nozzle’ will be suitable for most
benign lesions. The dipstick technique involves
dipping a cotton wool bud into a cup containing
LN and firmly applying the bud to the lesion until
a narrow halo of ice forms around the bud.
Cryoprobes may be attached to LN spray guns.
The probe is applied directly to the lesion [4].
Open-system cryosurgery is carried out by the
direct application of the NL to lesions via cotton
swabs or open spray. Special spray equipment
such as a cryogun can deliver a relatively large
amount of LN onto the lesional surface thereby
maintaining a more constant, lower temperature
in lesional tissues being treated. The cotton swab
carries only a small amount of LN, thus it cannot
maintain a constant low tissue temperature; for
that, cryogun cryosurgery seems more efficient
M. Ramos-e-Silva et al.
for oral lesions, needing about half the number of
sessions to achieve complete remission in nearly
equal-sized lesions. Open spray and cone spray
are most useful for lips, while cryoprobes are
preferred for deeper and fluid-filled tumours [4,
5]. The closed system involves the use of a com-
plex and delicate apparatus, the cryoprobe.
Freezing is performed by tissue contact with a
probe through which cryogen circulates; con-
trolled temperatures need to be maintained. In
lesions at the base of the tongue, the patient must
undergo general anesthesia and intubation due to
inflammation and edema that may cause diffi-
culty breathing. It is necessary to protect the
openings of the salivary glands and parotid
glands to avoid sialoadenitis, which is usually
transient.
For benign lesions, cryosurgery is indicated
mainly in cases of angioma, lymphangioma, pyo-
genic granuloma, mucous cysts (mucocele),
fibroma, HPV lesions and labial lentiginous mac-
ules. For pre-malignant lesions it is indicated for
actinic cheilitis, leukoplakia, lichen planus,
actinic stomatitis, among others.
Actinic Cheilitis
Also known as cheilitis exfoliativa, solar cheilo-
sis, solar keratosis, and actinic keratosis of the
lips, is a pre-invasive, malignant lesion of the lips
that is caused by solar radiation. It occurs more
commonly in fair-skinned individuals who work
outdoors or spend too much time in the sun; and
on the lower lip vermilion, as this area is more
directly exposed to sunlight than the upper lip
[2]. Clinically, the lesions can manifest as areas
of dryness, desquamation, color variation on the
lips, atrophy, swelling, erythema, ulceration, and
loss of the limit between the true and the cutane-
ous lip. Vertical folds of the lips can become
more pronounced, and gray-white discoloration
can become apparent [2].
In early stages, due to slow evolution, patients
usually attribute the process to aging and neglect
the lesion until it reaches advanced stages. This
may lead to the development of squamous-cell
carcinoma. Squamous-cell carcinoma of the lip
68 Cheilitis and Miscellaneous Benign Lip Lesions
metastasize much more frequently than analo-
gous lesions elsewhere on the skin and for this
reason, aggressive treatment of actinic cheilitis is
crucial for its prevention [6].
Actinic cheilitis has been successfully treated
by cryosurgery as the smooth surface and mois-
ture of mucous membranes allow for rapid freez-
ing. The high vascularity of the lip causes rapid
thawing, allowing multiple freeze-thaw cycles at
a cellular level, causing crystallization and subse-
quent rupture of cells by metabolic flux. At a vas-
cular level the freeze causes thrombosis,
ischemia, and cell necrosis. The injury to the epi-
dermis causes it to separate from the dermis,
effectively treating the non-invasive epithelium
comprising actinic cheilitis [2]. Open-spray,
cone-spray or closed-system technique can be
used, including on their area of action the entire
lesion and surrounding tissue to a margin of
3–4 mm. The application time is between 30 and
60 s. Defrosting lasts 60–120 s. One more cycle
and the freezing is done. None of the methods
requires anesthesia. A biopsy specimen can be
obtained as the analgesia produced by first freez-
ing allows a punch biopsy, since the material
does not present any histological change even
after it was frozen. After thawing, another cycle
of freezing is performed, this way there is no
change in the progress of healing of the site
where the biopsy was made (Figs. 68.1 and 68.2).
Miscellaneous Benign Lip Lesions
Hemangiomas
Oral hemangiomas are relatively common lesions
classified as either cavernous or capillary type,
depending on their vascular pattern. They can be
red or blue, reflecting both the venous character
of the blood within them and their frequent, deep
mucosal position. Hemangiomas of the lip,
because of their accessibility, are ideally suited to
cryosurgical management. The affected sites are
readily observed during treatment and postopera-
tive periods, and may easily be retreated if neces-
sary. The vascular tissue is very sensitive to the
cold [7]. For superficial hemangiomas the closed-
341
system is preferred. A probe is pressed to empty
the lesion and reduce the blood flow; one freeze-
thaw cycle is enough. Freezing of the superficial
part combined with steroid intralesional infiltra-
tion and local anesthesia in the deep part of hem-
angiomas with deep components can be used.
Freeze time is related to the size and depth of the
lesion. In some patients 2–3 min is enough, while
in others it can be over 5 min [8, 9] (Fig. 68.3).
Depending on the location of the hemangioma
and suspicion of mixed malformations, patients
should undergo an evaluation to determine the
extent of the lesion and vessel diameter, in order
to avoid damage in deep vessels [8].
Venous Lakes
A common variation of venous ectasia that occur
on the lips. Clinically they are red-blue to black
cyst-like venous dilatations on the lower lip lined
by a thin layer of epithelial cells. Some authors
do not consider them true hemangioma but rather
simple venous dilatations. They are common in
the elderly. Their importance is not limited to the
cosmetic aspect as trauma may result in profuse
bleeding [10]. Cryosurgery offers good cosmetic
result using the cryoprobe technique. Anesthesia
is not usually required. A flat or round probe of
the same or slightly smaller diameter than the
lesion should be selected and applied with firm
pressure to the center of the lesion to squeeze out
the blood content. The probe used to freeze is not
removed until a 1–2 mm margin is seen to the
outside of the lesion. After 3–4 min of total thaw-
ing, a second freeze-thaw cycle is applied. It is
important to know that, to avoid a retractile scar,
the ice front should not be allowed to extend
beyond the vermilion border. It heals in
3–4 weeks, and sometimes a second session is
necessary [8, 9].
Mucoceles
A mucocele or mucous cyst is a common benign
lesion of the minor salivary gland mucosa. It has
a bluish translucent color and most frequently
342 M. Ramos-e-Silva et al.

a b

c d

e f

Fig. 68.1 (a): Actinic cheilitis – before treatment (b): cryosurgery (e): Actinic cheilitiis – 10 days after cryosur-
Actinic cheilitis – with markings (c): Actinic cheilitis – gery after cleaning the treated area (f): Actinic cheilitiis –
right after the freezing (d): Actinic cheilitis – 10 days after 2 months after therapy

affects children and young adults [11]. Cryopobe
or cotton-swab technique is used for the treat-
ment of most mucous cysts. Using the cryopobe,
four to five cycles, of 10–30 s of freezing and
thawing, is usually enough to make these lesions
disappear in 2–4 weeks after one or two courses
of cryosurgery. In the cotton-swab technique,
direct application of LN with a cotton swab for
one to ten freeze-thaw cycles, each of 5–10 s,
begin freezing at the center of the lesion, until all
borders appear white and frozen. Anesthesia is
not required [8, 12, 13].
68 Cheilitis and Miscellaneous Benign Lip Lesions 343

a b

c d

Fig. 68.2 (a): Actinic cheilitis – before treatment (b): Actinic cheilitis – with markings (c): Actinic cheilitis – 9 days
after cryosurgery (d): Actinic cheilitis – 9 days after cryosurgery

Oral Lichen Planus Pyogenic Granuloma

Chronic autoimmune disease that involves a
type IV hypersensitivity reaction to antigens in
the mucosal lining and the skin. The oral form
may occur in combination with other variants.
Six clinical forms of oral lichen planus are rec-
ognized: reticular, erosive/ulcerative, papular,
plaque-like or hypertrophic, atrophic and bul-
lous. On the lips, the most common is the
plake-like. It is diagnosed clinically and con-
firmed by histopathologic analysis [14]. The
treatment is performed using the cryopobe or
the open-spray technique for two cycles of
20–30 s of freezing until completely covering
of the lesion and a margin of at least 4 mm [8]
(Fig. 68.4).
A benign neoplasm most often evident as a
rapidly developing solitary, sessile, or polyp-
oid vascular nodule or tumor prone to ulcer-
ation or hemorrhage. Bleeding may be
episodic, copious, and refractory to pressure,
mandating treatment, particularly when on the
lip [15]. Open-spray, cone-spray and cryopobe
can be used; 30–90 s of doble cycles of freez-
ing and thawing. The association to other tech-
niques, such as electrosurgery, can improve
results. After local anesthesia the tumor is res-
sected by electrosurgery and the contact spray
nozzle is applied at the base, performing two
cycles of freezing and thawing for about
20–30 s [8].
344 M. Ramos-e-Silva et al.

a b

c d

Fig. 68.3 (a): Angioma – before treatment (b): Angioma – during freezing (c): Angioma – right after the freezing (d):
Angioma- 1 month after Cryosurgery

Labial Lentiginous Macules (LLM)
This is the clinical term used to describe brown or
black melanotic macules of the oral mucosa that
are not a manifestation of racial pigmentation,
nor classifiable into the recognized types of mel-
anotic lesions and not associated with any sys-
temic disease or syndrome. Usually single and
smaller than 1 cm, they may also occur as multi-
ple lesions. They are asymptomatic and appar-
ently have no malignant potential. Differential
diagnosis includes early superficial melanomas
and, if they are multiple, Peutz-Jeghers syndrome
and Addison’s disease. Biopsy may be needed to
establish a definitive diagnosis. It occurs most
frequently in young women. On histology an
increase of melanin is seen at the basal layer,
such as in freckles. Those melanotic macules
located on the vermilion border of the lips are of
most concern to the patients because of their
unpleasant appearance. The dermatoscopic fea-
tures of the LLM are rather characteristics,
revealing diffuse pigmentation with peculiar par-
allel to dark brown streaks, and melanoma-
specific criteria have not been found on these
benign lesions [16, 17] (Fig. 68.5).
Surgical excision for a single lesion is easy.
However, for multiple lesions it becomes more
complicated. Cryosurgery makes the treatment
easier, more comfortable, and more acceptable to
the patient. Simple cryosurgery needs no sophisti-
cated equipment because LN and cotton-swabs
are inexpensive and readily obtainable. The LN
spray with C, D, or E open tips, double freeze-
thaw cycle to a 1 mm margin, gives good to excel-
lent results in usually one session [8, 9, 16, 17].
68 Cheilitis and Miscellaneous Benign Lip Lesions
a b
Fig. 68.4 (a): Lichen planus – before treatment (b): Lichen planus – during freezing (c): Lichen planus – 1 month after
therapy
HPV Oral Warts
HPV infection of oral and oropharyngeal mucosa
are associated with oro-genital sex and high-risk
sexual behavior with numerous partners, particu-
larly when initiated at an early age. Warts are one
of the most common infections on the oral
mucosa, mainly in children. It is usually seen on
lips, hard palate, gingiva and dorsal surface of
tongue. Use of cryosurgery on warts will be
guided by surface. LN is the only cryogen that
should be used. For flat lesions two cycles of 20 s
of spray should be applied. In condyloma acumi-
nata, association to previous radiosurgery or
electrosurgery under local anesthesia improves
the results, so the application of two cycles of
20-s spray on the site after radiosurgery or elec-
trosurgery [4, 9].
345
Laugier-Hunziker Syndrome (LHS)
This is an acquired, benign pigmentary skin con-
dition involving oral cavity including lower lip in
the form of brown black macules 1–5 mm in size,
frequently associated with longitudinal melano-
nychia. Treatment is sought mainly for cosmetic
reasons and cryosurgery as for LMM conveys
good results [18].
Lipoid Proteinosis
This is a rare hereditary metabolic disorder trans-
mitted as an autosomal recessive trait character-
ized by the deposition of an amorphous
hyaline-like material (glycoprotein) in the
mucous membranes, skin and various internal
346 M. Ramos-e-Silva et al.

a b

c d

Fig. 68.5 (a): Labial lentiginous macules – before treatment (b): Labial lentiginous macules – dermoscopy (c): Labial
lentiginous macules – during freezing (d): Labial lentiginous macules – 1 month after cryosurgery

organs. Cryosurgery can be used to remove the
lip lesions. LN applied for 1 min re-shapes some
areas of the lip. After the procedure the lips feel
softer and have better appearance. Cryosurgery
offers advantages over surgery in reshaping the
lip lesions in this syndrome, since suturing is not
feasible in the rigid mucosa of these patients
[19].
platelet alterations or multiple myeloma. Relative
contraindications exist where treatment by
another method will yield better outcomes [3].
Deep freezing is not recommended for lesions on
the corner of the mouth or the vermilion border,
because occasional permanent cryosurgical com-
plications, as retractions and hypopigmentation,
can be expected [17].

Contraindications Side Effects

These generally relate to illness, such as cold
intolerance or urticaria, poorly controlled diabe-
tes, Raynaud’s disease, cryoglobulinemia, agam-
maglobulinemia, dysfribrinogenemia, blood
dyscrasia of unknown origin, pyoderma gan-
grenosum, collagen and autoimmune disease,
hemodialysis or immunosuppressive therapy,
The incidence of complications after cryosurgery
is very low. It is important to distinguish between
complications and expected signs or symptoms
that represent the normal progression of the pro-
cess of freezing tissue [16]. The potential adverse
effects of cryosurgery include short-term postop-
erative erythema, urtication, edema, pain during
68 Cheilitis and Miscellaneous Benign Lip Lesions
and after treatment, bulla formation, induction of
headache, delayed bleeding. Long-term reactions
in the oral cavity include nerve damage. Edema
may be partially alleviated by the application of a
potent topical steroid immediately following
treatment. If a severe reaction is anticipated, a
systemic corticosteroid may be prescribed.
Topical or systemic antibiotics are indicated in
cases of secondary infection. The cosmetic
results should be evaluated after 4–6 months of
treatment [3, 4, 8, 9, 19].
References
1. Ntomouchtsis A, Karakinaris G, Poulolpoulos A,
et al. Benign lip lesions. A 10-year retrospective
study. Oral Maxillofac Surg. 2010;14(2):115–8.
2. Shah AY, Doherty SD, Rosen T. Actinic cheilitis: a
treatment review. Int J Dermatol.
2010;49(11):1225–34.
3. Ishida CE, Ramos-e-Silva M. Cryosurgery in oral
lesions. Int J Dermatol. 1998;37(4):283–5.
4. Thai KE, Sinclair RD. Cryosurgery of benign skin
lesions. Australas J Dermatol. 1999;40(4):175–84.
5. Yu CH, Lin HP, Cheng SJ, Sun A, Chen
HM. Cryotherapy for oral precancers and cancers.
J Formos Med Assoc. 2014;113(5):272–7.
6. Cavalcante AS, Anbinder AL, Carvalho YR. Actinic
cheilitis: clinical and histological features. J Oral
Maxillofac Surg. 2008;66(3):498–503.
7. Tal H. Cryosurgical treatment of hemangiomas of the
lip. Oral Surg Oral Med Oral Pathol.
1992;73(6):650–4.
8. Ishida CE. Criocirurgia. In: Ramos-e-Silva M, Castro
MCR, editors. Fundamentos de Dermatologia. Rio de
Janeiro: Atheneu; 2010. p. 2201–20.
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9. Turjanski E, Stolar E. Criocirugia em lesiones de
boca. In: Turjanski E, Stolar E, editors. Lesiones de
Piel y Mucosas. Técnicas Terapeuticas. Buenos Aires:
Edama; 1995. p. 121–9.
10. Suhonen R, Kuflik EG. Venous lakes treated by liquid
nitrogen cryosurgery. Br J Dermatol.
1997;137(6):1018–29.
11. de Moraes PC, Teixeira RG, Thomaz LA, Arsati F,
Junqueira JL, Oliveira LB. Liquid nitrogen cryosur-
gery for treatment of mucoceles in children. Pediatr
Dent. 2012;34(2):159–61.
12. Toida M, Ishimaru JI, Hobo N. A simple cryosurgical
method for treatment of oral mucous cysts. Int J Oral
Maxillofac Surg. 1993;22(6):353–5.
13. Marcushamer M, King DL, Ruano NS. Cryosurgery
in the management of mucoceles in children. Pediatr
Dent. 1997;19(4):292–3.
14. Pimentel MIF, Ramos-e-Silva M. Líquen Plano, erup-
ções liquenóides e liquen nítido. In: Ramos-e-Silva
M, Castro MCR, editors. Fundamentos de
Dermatologia. Rio de Janeiro: Atheneu; 2010.
p. 371–90.
15. Al-Qubati Y, Janniger EJ, Schwartz RA. Pyogenic
granuloma of the lip -treatment with carbon dioxide
slush cryosurgery as an approach in a resource-poor
country. Adv Clin Exp Med. 2014;23(1):5–7.
16. Yeh CJ. Simple cryosurgical treatment of the oral
melanotic macule. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod. 2000;90(1):12–3.
17. Ishida CE. Cryosurgery. In: Tosti A, Hexsel D, edi-
tors. Update in cosmetic dermatology. Berlin:
Springer; 2013. p. 145–63.
18. Sachdeva S, Sachdeva S, Kapoor P. Laugier-Hunziker
syndrome: a rare cause of oral and acral pigmentation.
J Cutan Aesthet Surg. 2011;4(1):58–60.
19. Shirani AM. Cryosurgery (N2O) application to
remove lip lesions of lipoid proteinosis syndrome: a
case report. J Dent Res Dent Clin Dent Prospects.
2008;2(2):68–70.
 Chromoblastomycosis
69
Ted Rosen, Alexandro Bonifaz, Leonel
Fierro-Arias, Amelia Peniche-Castellanos,
and Denisse Vázquez-González

Abstract
Chromoblastomycosis (CBM) is an implantation or subcutaneous mycosis
caused by several species of black or melanized fungi, being the most
important agents: Fosecaea pedrosoi and Cladophialophora carrionii.
CBM is frequently located in lower limbs and is a polymorphic disease,
being the most important: nodular, verrucous, tumoral, superficial plaque
and cicatrizal; is a chronic disease. There is no therapy of choice, the best
results is with combination of systemic antifungals (itraconazole and ter-
binafine) with cryosurgery, this must be individualized considering the
location of the lesions, their extension and number. In general, it is recom-
mended for small lesions, especially those far from the folds to avoid sec-
ondary fibrosis and retractile scars. The cryosurgery combined with
antimycotics is a very effective alternative in CBM, especially for patients
with multiple lesions or after reduction of these.

Keywords
Chromoblastomycosis • Fonsecaea pedrosoi Cladophialopora carrionii •
Itraconazole • Terbinafine • Cryosurgery

T. Rosen, MD (*)
Department of Dermatology,
Baylor College of Medicine, L. Fierro-Arias, MD • A. Peniche-Castellanos, MD
1977 Butler Ave., Suite E6.200, Houston, Department of Dermatology, Hospital General de
TX 77030, USA México, Mexico City, DF, Mexico
e-mail: vampireted@aol.com
D. Vázquez-González, MD
A. Bonifaz, PhD Department of Dermatology, Hospital General de
Department of Dermatology/Mycology, Hospital Mexcio “Eduardo Liceaga” O.D.,
General de México, Mexico City, DF, Mexico Mexico City, Mexico

© Springer-Verlag London 2016 349

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_69
350
Introduction
Chromoblastomycosis is an implantation or sub-
cutaneous mycosis caused by several species of
black or melanized fungi (dematiaceous) which
belong to Chaeotothyriales, being the most
important agents: Fosecaea pedrosoi and
Cladophialophora carrionii. In a less proportion
other isolations are: Phialophora verrucosa,
Rhinocladiella aquaspersa and Fosecaea
monophora, among others; is a classic chronic
mycosis due to implantation, and is practically
limited to the subcutaneous tissue [1–4].
Although reported all around the world; it pre-
dominates in tropical and subtropical climates.
The causative fungi live in warm and humid cli-
mates, and are present on the soil, plants, wood,
vegetal detritus, etc. this can explain why the dis-
ease is much more frequent in farmers and rural
workers; cases caused by C. carrionii generally
occurs in semi desert areas. The country with
more case report is Brazil, but there are also
important: Dominican Republic, Costa Rica,
Cuba, Puerto Rico, Guatemala, Honduras,
Venezuela and Colombia. Out American conti-
nent there are important reports in Africa
(Madagascar and Congo), Asia (China and
Thailand), and Australia. In Europe reports are
scarce. Majority of cases occur in adult age
(between 20 and 40 years), in children the dis-
ease is exceptional [1, 5–8]. There is a remark-
able predominance on males (a relation 4:1) over
females; maybe this is caused due to certain hor-
monal factors the influences the adaptation of the
fungus [1, 2, 4, 8].
Diagnosis is made with mycological and histo-
pathological studies. Direct examination is per-
formed with potassium hydroxide (KOH), where
muriform cells are observed, arranged in clusters
around 4–12 μm in size. Cultures are performed
in Sabouraud dextrose agar with and without anti-
biotics. The development corresponds to slow
growth black fungi, and its classification is based
on micromorphology and genetic sequentializa-
tion. The histopathological findings are those of
tuberculoid and sometimes suppurative granulo-
mata. Muriform cells are distinguishable in the
corneum layer of the skin, and within the
T. Rosen et al.
granulomatous process, inside the giant cells with
common hematoxillin-eosin stains [1, 4, 5, 9].
Description of the Disease
The usual clinical topography of chromoblasto-
mycosis is in lower limbs (75 %); the rest affect
upper limbs and rarely on the face and ears [1, 8].
This is a polymorphic disease, and presents the
following clinical pictures: nodular, verrucous or
vegetant; tumoral, superficial plaque (or psoriasi-
form) and cicatrizal [1]. The initial lesion appears
one or several months after inoculation of the
fungus (due trauma), as a papule, that grows and
spreads in the surface of the skin, leading to well-
defined erythemato-squamous and pruriginous
plaques. Lesions are asymmetric and unilateral,
slow growing until the formation of erythema-
tous nodules covered by scales; later lesions
appear like verrucous or vegetant plaques, cov-
ered by abundant scales and sanguine crusts and
sometimes ulcers, resembling the aspect of a
“cauliflower” (nodular or tumoral variety); in
some cases the plaques remain flat and superfi-
cial (superficial form or psoriasis-like lesions).
Symptomatology varies, most of patients refer
pruritus and pain during palpation [1, 3, 6, 8]. As
the disease becomes chronic atrophic and achro-
mic scars appear in the center of the plaques;
lymphostasis is a common manifestation in some
areas. Complications are caused by the extension
of the lesions, specially due to fibrosis and lym-
phostasis, which promotes the bacterial over-
infection, and in the most chronic cases,
squamous cell carcinomas can develop due to the
chronicity of lesions [1, 4] (Fig. 69.1).
Therapeutic Alternatives
Chromoblastomycosis is considered the most
“superficial” of the deep mycosis, and regularly
is limited to the subcutaneous tissue, only in
exceptional cases it gets deeper, affecting mus-
cles or bones. There is no therapy of choice, but a
series of options follow. For authors like Esterre
& Queiroz-Telles [10], they depend on three
69 Chromoblastomycosis
a b
c d
Fig. 69.1 Chromoblastomycosis: general aspects. (a)
Chromoblastomycosis in foot. (b) Muriform cells, direct
examination (KOH, ×40). (c) Biopsy, accumulation of
conditions: the etiologic agent, for example, it is
well known that C. carrionii and Phialophora
verrucosa are more sensitive (in vitro) to antifun-
gals that F. pedrosoi; in second place, the severity
of the disease, for example: its extension, the
clinical variant (high edema, fibrosis and lym-
phostasis) of the nodular or tumoral forms are
much more complicated, and difficult for the
drugs to get in the lesions: and finally the selec-
tion of the drug [10–12]. It is very difficult to
achieve clinical and mycological cure, the rates
of cure are very variable (15–80 %) and depend
on the therapeutic scheme selected. Generally,
low index of cure are reached, and the percentage
of recurrence is high, especially in chronic and
extensive cases. Treatment can be divided in
three groups: physical methods, chemotherapy
and combined therapy [12, 13].
Physical Methods
Local Heat
Any kind of dispositive that produces heat and
keeps the skin temperature around 43 °C can be
351
muriform cells (H&E, ×40). (d) Microscopy of Fonsecaea
pedrosoi (Erythrosin 2 %, ×40)
used. For example, Tagami et al. [13] reported
the use of two constant heat emission devices, the
time period of the treatment was 2–12 months
[14]. It is important to highlight that the use of
humid heat (hot water baths) are not useful
because promotes the spreading of the disease.
Surgery
Recommended in circumscribed, small lesions; it
should include a safety margin (0.5–2.0 cm) for
curettage and electrodessication [1, 4]. There are
some reports of the use of Mohs’ micrographic
surgery, especially in the not well-limited lesions;
the advantage of this technique is the histologic
control of the margins [15]. There are also some
reports of the use of photocoagulation with CO2
laser and photodynamic therapy [16–18].
Chemotherapy
Along the time several drugs have been used to
treat chromoblastomycosis, the ones which offer
better results are: 5-fluorocitosine (5-FC), itra-
conazole and terbinafine. 5-FC is used orally in a
352
dosage of 100–150 mg/kg per day divided in four
doses around 6–12 months. Results vary, in some,
complete cure is reached in few months, in other,
improvement occurs at the beginning but thereaf-
ter there is no more progress. It is important to
know the demonstrated resistance in vitro of some
strains of F. pedrosoi [1, 4, 19]. Itraconazole is
one of the drugs with better results. Recommended
doses are high, although some cases respond well
with 100 mg/day over a long period (15 months)
[20–23]. In one of the largest series [21] the dos-
age was 200–400 mg/day, resulted in total cure in
42 % of the cases, with an average time period of
7.2 months. Itraconazole can be used as single or
combined therapy, especially with cryosurgery
[1, 22, 23]. Terbinafine is dosed at 250–500 mg/
day. Like itraconazole, terbinafine has great
activity in vitro against strains causative of chro-
moblastomycosis [24–28]. There are some
reports with therapeutic success using low doses
(250 mg/day) [24], however, the most adequate
dosage is 500 mg/day. Esterre et al. [25], obtained
mycological and clinical cure in 74.2 % of the
cases after 12 months of therapy, with adequate
tolerance to medication. It is also recommended
as single therapy or in association with cryosur-
gery [27].
Cryosurgery
This technique belongs to the group of physical
therapies, and is one with the best results; some
authors consider it as the therapy of choice, par-
ticularly in combination with systemic antifun-
gals like terbinafine and itraconazole [13, 22, 23].
The first case series showed the topical applica-
tion of the LN using cotton swabs, considering
this way of application as cryotherapy instead
cryosurgery [29, 30]. Current LN application
devices, open technique (spray) and quantifica-
tion of tissular temperature bring better results
[12, 22]. Castro et al. [31] reported their about
15 years experience with this technique in 22
cases of chromoblastomycosis, obtaining myco-
logical and clinical cure in 40.9 %. Technique
must be individualized considering the location of
the lesions, their extension and number. In general,
T. Rosen et al.
it is recommended for small lesions, especially
those far from the folds to avoid secondary fibro-
sis and retractile scars [32–34]. The principal
undesirable effects of cryosurgery are pain,
important local edema, vesicles or blisters, crusts,
ulcers and bacterial infections; post-inflammatory
or residual hypopigmentation during healing is
secondary to damage and destruction of melano-
cytes during lesion freezing [12, 22, 35–37]. It is
important to emphasize that cryosurgery must be
applied in combination with drug systemic anti-
fungals, due to the risk of lymphatic dissemina-
tion of the disease when used alone. Even in small
cases, the recommendation is to give an impreg-
nation dose with systemic antifungals (itracon-
azole or terbinafine) at least 1 month before
application on cryosurgery [1, 3, 12].
Methodology (How I Do It)
The most important step is proper patient selec-
tion. In small lesions (plaques smaller than
10 cm2), the procedure can be performed in one
session. As cryosurgery can cause lymphatic dis-
semination of the disease if used alone, we
always begin with impregnation pharmacother-
apy, consisting in two previous months of itra-
conazole (200 mg/day) or terbinafine (250 mg/
day) and continues after the surgical procedure
[1, 12, 22]. For single plaques between 10 and
20 cm2, after pharmacotherapy impregnation, the
lesion is divided in segments (depending the size)
perform in and cryosurgery is performed on each
[22]. For extensive lesions, the first step aims to
reduce the size with the mentioned antifungals,
and after that a cryosurgery plan is performed in
the most clinical and mycological active areas of
the lesion. The general strategy is as follows:
1. Associated infections, such as bacterial, must
be solved before the use of cryosurgery.
Optimal aseptic conditions must be reached,
prior to performing the cryosurgery, prefera-
bly in an operating room under sterile
conditions.
2. It is desirable the use of local anesthesia because
cryosurgery is painful; we use subcutaneous
69 Chromoblastomycosis 353

infiltrations of 2 % lidocaine with epinephrine.
The whole procedure must be performed by
an experienced cryosurgeon due to the risk of
disseminating the disease and other possible
side effects.
3. The LN is applied under pressure using a
manual container Brymill® type or similar,
with open technique (spray) using open spray
tips A or B. The lesions are delimited by their
clinical activity and a secure peripheral mar-
gin is established (0.5–1 cm). We apply the
LN from the center to the periphery with a spi-
ral motion until total freezing of the lesion is
reached. The therapeutic effect will be opti-
mal when the thaw time doubles the freeze
time. We recommend that, plaques larger that
10 cm2 be divided in quadrants that will
receive cryosurgery under the same parame-
ters [12, 35–37].
4. Within the next 24–48 h the inflammatory and
edematous process will be evident, with for-
mation of serohematic blisters, consequent
exulcerations, crusts and finally re-
epithelization of the area. After 3–4 weeks the
case must be re-evaluated to determine the
need of another cycle [12, 35–37] (Figs. 69.2
and 69.3).
Success Rates
There are no precise rates of cure for the use of
cryosurgery; results depend on the extension of
the lesions and the particular conditions of the
patient (fibrosis). In general, for lesions smaller
than 10 cm2, previously treated with systemic
antifungal, the majority reach total cure in one
single session, and a minor percentage require

a b

c d

Fig. 69.2 (a) Basal chromoblastomycosis. (b) After 4 months of terbinafine treatment (impregnation period).
(c) Division in four quadrants. (d) Cryosurgery process
354
a b
c d
Fig. 69.3 (a) Basal chromoblastomycosis. (b) After cryosurgery (one session). (c) After 1 week after cryosurgery. (d)
After 4 months, with clinical and mycological cure
two or more sessions. For extensive cases there
are no precise numbers, some authors mention
very low percentages like 10–15 % cures, how-
ever, for cases with small lesions (<10 cm2) the
combination can reach clinical and mycological
cure rates as high as 80 % [12, 38].
References
1. Queiroz-Telles F, Esterre P, Perez-Blanco M, Vitale
RG, Salgado CG, Bonifaz A. Chromoblastomycosis:
an overview of clinical manifestations, diagnosis and
treatment. Med Mycol. 2009;47(1):3–15.
2. Rosen T, Joseph LM. Chromoblastomycosis. Int
J Dermatol. 1979;18(3):226–7.
T. Rosen et al.
3. Bonifaz A, Vázquez-González D, Perusquía-Ortiz
AM. Subcutaneous mycoses: chromoblastomycosis,
sporotrichosis and mycetoma. J Dtsch Dermatol Ges.
2010;8(8):619–27.
4. Torres-Guerrero E, Isa-Isa R, Isa M, Arenas R.
Chromoblastomycosis. Clin Dermatol. 2012;30(4):
403–8.
5. Santos AL, Palmeira VF, Rozental S, Kneipp LF,
Nimrichter L, Alviano DS, et al. Biology and patho-
genesis of Fonsecaea pedrosoi, the major etiologic
agent of chromoblastomycosis. FEMS Microbiol Rev.
2007;31:570–91.
6. Elgart GW. Chromoblastomycosis. Dermatol Clin.
1996;14:77–83.
7. Pérez-Blanco M, Hernandez Valles R, Garcia-
Humbria L, Yegres F. Chromoblastomycosis in chil-
dren and adolescents in the endemic area of the Falcon
State, Venezuela. Med Mycol. 2006;44:467–71.
69 Chromoblastomycosis
8. López-Martínez R, Méndez-Tovar LJ.
Chromoblastomycosis. Clin Dermatol. 2007;25:
188–94.
9. Uribe JF. Histopathology of chromoblastomycosis.
Mycopathologia. 1989;105:1–6.
10. Esterre P, Queiroz-Telles F. Management of chromo-
blastomycosis: novel perspectives. Curr Opin Infect
Dis. 2006;19:148–52.
11. Bonifaz A, Carrasco-Gerard E, Saúl A.
Chromoblastomycosis: a clinical and mycological
experience of 51 cases. Mycoses. 2001;44:1–7.
12. Bonifaz A, Paredes-Solis V, Saul A. Treating chromo-
blastomycosis with systemic antifungals. Expert Opin
Pharmacother. 2004;5:247–57.
13. Tagami H, Ginoza M, Imaizumi S, Urano-Suehisa
S. Successful treatment of chromoblastomycosis with
topical heat therapy. J Am Acad Dermatol. 1984;10(4):
615–9.
14. Hiruma M, Kawada A, Yoshida M, Kouya
M. Hyperthermic treatment of chromomycosis with
disposable chemical pocket warmers. Report of a suc-
cessfully treated case, with a review of the literature.
Mycopathologia. 1993;122:107–14.
15. Pavlidakey G, Snow S, Mohs F. Chromoblastomycosis
treated by Mohs micrographic surgery. J Dermatol
Surg Oncol. 1986;12:563–6.
16. Kuttner BJ, Siegle RJ. Treatment of chromomycosis with
a CO2 laser. J Dermatol Surg Oncol. 1986;12:965–8.
17. Hira K, Yamada H, Takahashi Y, Ogawa H. Successful
treatment of chromomycosis using carbon dioxide
laser associated with topical heat applications. J Eur
Acad Dermatol Venereol. 2002;16:273–5.
18. Lyon JP, Pedroso e Silva Azevedo Cde M, Moreira
LM, de Lima CJ, de Resende MA. Photodynamic
antifungal therapy against chromoblastomycosis.
Mycopathologia. 2011;172(4):293–7.
19. De Clercq D, De Vroey C. Treatment of a Zairian case
of chromomycosis with oral 5-fluorocytosine and
5-fluorouracil ointment in association. Int J Dermatol.
1987;26:333.
20. Smith CH, Barker JN, Hay RJ. A case of chromoblas-
tomycosis responding to treatment with itraconazole.
Br J Dermatol. 1993;128:436–9.
21. Queiroz-Tellez F, Purim K, Fillus JN, Bordignon GF,
Lameira RP, Van Custem J, Cawenbergh G. Itraconazole
in the treatment of chromoblastomycosis due to
Fonsecaea pedrosoi. Int J Dermatol. 1992;31:805–12.
22. Bonifaz A, Martínez-Soto E, Carrasco E, Peniche
J. Treatment of chromoblastomycosis with itracon-
azole, cryosurgery and combination of both. Int
J Dermatol. 1997;36:542–7.
23. Kullavanijaya P, Rojanavanich V. Successful treat-
ment of chromoblastomycosis due to Fonsecaea
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pedrosoi by the combination of itraconazole and cryo-
therapy. Int J Dermatol. 1995;34:804–7.
24. Esterre P, Inzan C, Ramarcel ER, Andrianstimahavandy
A, Ratsioharama M, Pecarrere JL, Roig P. Treatment
of chromomycosis with terbinafine: preliminary
results of an open pilot study. Br J Dermatol. 1996;134
Suppl 46:33–6.
25. Esterre P, Ratsioharama M, Roig P. Potential use of
terbinafine in the treatment of chromoblastomycosis.
Rev Contemp Pharmacother. 1997;8:357–61.
26. Bonifaz A, Saúl A, Paredes-Solís V, Araiza J, Fierro-
Arias L. Treatment of chromoblastomycosis with ter-
binafine. Experience with four cases. J Dermatol
Treat. 2005;16:47–51.
27. Bassas-Vila J, Fuente MJ, Guinovart R, Ferrándiz
C. Chromoblastomycosis: response to combination
therapy with cryotherapy and terbinafine. Actas
Dermosifiliogr. 2013. doi:pii: S0001-7310(13)
00105-1.
28. Xibao Z, Changxing L, Quan L, Yuqing H. Treatment
of chromoblastomycosis with terbinafine: a report of
four cases. J Dermatol Treat. 2005;16:121–4.
29. Ramirez MM. Treatment of chromomycosis with liq-
uid nitrogen. Int J Dermatol. 1973;12(4):250–4.
30. de Souza Sittart JA, Valente NY. Treatment of chro-
momycosis with liquid nitrogen. Med Cutan Ibero Lat
Am. 1986;14(4):227–32.
31. Castro LG, Pimentel ER, Lacaz CS. Treatment of
chromomycosis by cryosurgery with liquid nitrogen:
15 years’ experience. Int J Dermatol. 2003;42:
408–12.
32. Lubritz RR, Spence JE. Chromoblastomycosis: cure
by cryosurgery. Int J Dermatol. 1978;17(10):830–2.
33. Nobre G, Oliveira Ada S, Verde SF, Martins O, Picoto
AS. Chromomycosis: report of a case and manage-
ment by cryosurgery, topical chemotherapy, and con-
ventional surgery. J Dermatol Surg Oncol.
1980;6(7):576–8.
34. Pimentel ER, Castro LG, Cucé LC, Sampaio
SA. Treatment of chromomycosis by cryosurgery
with liquid nitrogen: a report on eleven cases.
J Dermatol Surg Oncol. 1989;15(1):72–7.
35. Zouboulis CC. Cryosurgery in dermatology. Eur
J Dermatol. 1998;8(7):466–74.
36. Graham GF. Cryosurgery in the management of cuta-
neous malignancies. Clin Dermatol. 2001;19(3):
321–7.
37. Abramovits W, Losornio M, Marais G, Perlmutter
A. Cutaneous cryosurgery. Dermatol Nurs. 2006;
18(5):456–9.
38. Queiroz-Telles F, Santos DW. Challenges in the ther-
apy of chromoblastomycosis. Mycopathologia. 2013;
175(5–6):477–88.
 Clear Cell Acanthoma
70
Jacqueline Guidry and Ted Rosen

Abstract
Clear cell acanthoma (CCA) is a benign epidermal lesion occurring most
frequently on the lower extremities of adults in the fifth to seventh decade
of life. The etiology is unclear; it most likely is a benign neoplastic or a
reactive inflammatory process. CCA is a slow growing, papular or nodular
lesion, most often dome-shaped and red to brown in color. Diagnosis can-
not be made clinically, given its similarity in appearance to other more
common skin lesions. Histological examination demonstrates a well-
demarcated collection of clear cells containing intracytoplasmic glycogen,
which give this lesion its name. For single lesions, surgical excision is
often the treatment of choice. However, cryosurgery is a very effective
alternative, especially beneficial for patients with multiple lesions, lesions
located over bony prominences not readily amenable to excision, or in
situations where surgery is relatively contraindicated (neutropenia, antico-
agulation) or not desired.

Keywords
Clear cell acanthoma • Clear cell acanthosis • Cryotherapy • Cryosurgery

Introduction

(CCA) is a benign, generally asymptomatic skin

lesion of unucertain etiology [1]. Arguments for
an origin in the epidermis, hair follicles and
J. Guidry, MD sweat glands have all been proposed with incon-
Department of Internal Medicine, Baylor College of clusive results [1]. Several features of CCA
Medicine, Houston, TX, USA favor a benign neoplastic process including
T. Rosen, MD (*) sharp demarcation clinically and histologically,
Department of Dermatology, Baylor College of normal appearance of adnexal structures within
Medicine, 2815 Plumb, Houston, TX 77005, USA the lesion, and lack of spontaneous regression
e-mail: vampireted@aol.com

© Springer-Verlag London 2016 357

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_70
358
[2]. However, more recently, the description of
CCA as a reactive inflammatory dermatosis has
been favored given similarities on cytokeratin
immunohistochemical staining to known epi-
dermal inflammatory disorders, such as psoria-
sis [1]. In addition, CCA is sometimes seen on
top of preexisting conditions, which favors an
inflammatory mechanism. Associations have
been reported with psoriasis, varicose veins, sta-
sis dermatitis, atopic dermatitis, insect bites and
skin injury or trauma [1, 2]. Based on this evi-
dence, it has been suggested that the name is
changed to clear cell acanthosis to reflect the
inflammatory nature of the disease [2].
Historically, it has been referred to as Degos
acanthoma or pale acanthoma [1].
Description of Disease Entity
The lesion initially presents as a insidiously
enlarging, 3–20 millimeter (mm) red to brown
papule or nodule [1]. Well-demarcated plaques
have also been described [2]. The lesions grow
slowly over several years, with reports of lesions
present for 50 years or more [1, 3]. Clinically,
there are several clues to suggest CCA, which
include a dome-shaped appearance and multiple
vascular puncta on the surface of the lesion [1].
However none of these findings are pathogno-
monic for the disease. The lesion has also been
described with a fine collarette of scale, moist
appearance, crusting, vascular blush, or firm,
elastic consistency [1, 3, 4].
The majority of cases of CCA are present in
middle-aged adults with no particular gender pre-
dominance [1]. Lesions are seen with much
higher frequency on the lower extremities, though
the back, abdomen, and chest have been affected.
Rare cases of CCA on the nipple, lips, umbilicus
and other uncommon locations have also been
documented in the literature [1]. The majority of
lesions are asymptomatic, except for a tendency
to bleed with minor trauma [1]. Pruritus and
sweating of the affected region have been uncom-
monly noted [1, 5]. Single lesions are most com-
mon; however, multiple lesions have been
described [1]. In patients with multiple lesions,
J. Guidry and T. Rosen
CCA is classified into two subtypes: discrete and
eruptive [4]. A diagnosis of eruptive CCA
requires at least 30 lesions, but as many as 400
have been described in one patient [1, 4].
There are several other types of CCA, includ-
ing giant, polypoid or pedunculated, pigmented,
atypical and cystic, all of which are exceedingly
rare [1]. Giant clear cell acanthoma describes
lesions greater than 40 mm [1].
Diagnosis
Histopathological diagnosis is required to con-
firm CCA, as the appearance of the lesion is rela-
tively non-specific and can resemble many other
more common lesions (i.e. basal cell carcinoma,
seborrheic keratosis, pyogenic granuloma, and
eczema) [1, 2, 4]. The hallmark finding of an
acanthotic epidermis with clear cells containing
intracytoplasmic glycogen confirms the diagno-
sis of CCA [1, 2]. Additionally, the cells stain
positive for Periodic-Acid-Schiff (PAS) and dia-
stase [1].
The lesion is well-demarcated from the sur-
rounding epidermis and often has dilated inter-
spaces between cells [1, 6]. Associated histologic
changes include neutrophilic exocytosis, neutro-
philic microabscesses in the stratum corneum,
decreased number of melanocytes, and dilated
blood vessels in the upper dermis [1–3].
Therapeutic Alternatives
CCA is a relatively easy to treat lesion and rarely
recurs. Only one case of spontaneous regression
has been reported, but this was only a few of
many lesions in a case of eruptive CCA [1]. If
one solitary lesion is present, surgical excision is
preferred. Other therapeutic alternatives include
Mohs micrographic surgery, curettage, electrof-
ulguration, carbon dioxide laser ablation, and
topical 5-fluoruracil [1, 4]. Carbon dioxide laser
may be especially beneficial in patients who can-
not tolerate the discomfort associated with cryo-
surgery, like children and the elderly, or patients
on anticoagulation [2, 7].
70 Clear Cell Acanthoma
Cryosurgery
The application of LN has been used with good
success in the treatment of CCA. The mechanism
of action is likely cellular damage as a direct con-
sequence of freezing or onset of vascular stasis
[2]. Cryosurgery may be the ideal treatment if
there are multiple lesions, large lesions, or if the
location of the lesion is not amenable to excision
[1, 8]. The latter is especially true in areas overly-
ing bony prominences where excision is difficult
(Figs. 70.1 and 70.2).
Methodology (How I Do It)
Cryosurgery can be performed using the open
spray technique [7]. Lesions should be frozen for
a duration of 60 s, which should provide adequate
spread of freezing to encompass a 2–5 mm rim of
Fig. 70.1 Clear cell acanthoma on anterior foreleg,
pre-treatment
Fig. 70.2 Same lesion following a single session of liq-
uid nitrogen cryosurgery
359
surrounding normal tissue [7]. Often three to four
sessions with at least two freeze-thaw cycles per
session are required for cure of CCA; however,
resolution of a solitary lesion has been reported
following a single cryotherapy session [3, 6]. No
local anesthesia is required prior to cryosurgery
treatment [2]. Most cases of CCA treated with
cryosurgery utilize an open spray technique;
however, one cotton wool swab application of
LN can be used as well [4]. Using this method,
LN should be applied two times for 15–20 s each
with a thaw time of 1 min in between freeze-thaw
cycles [3, 4]. This modality also usually requires
four distinct sessions for cure [4].
Success Rates
Although regression of a CCA has been achieved
with only one cryosurgery session, treatment
consisting of three to four sessions is more widely
recommended to insure complete resolution [9].
Treatment of CCA with cryosurgery has a very
high success rate; if a lesion persists after four
sessions, an alternative treatment modality should
be considered [2]. Cryosurgery has many
expected side effects, which include edema, ves-
icles, bullae, weeping, and hypopigmentation [2].
These usually resolve spontaneously approxi-
mately 10 days after cryosurgery, and patients
typically experience minimal residual scarring
[2, 4].
References
1. Tempark T, Shwayder T. Clear cell acanthoma. Clin
Exp Dermatol. 2012;37(8):831–7.
2. Chi C, Wang S, Huang H. Clear cell acanthoma suc-
cessfully treated with a carbon dioxide laser. Dermatol
Surg. 2005;31(10):1355–8.
3. Betti R, Bruscagin C, Inselvini E, Palvarini M, Crosti
C. Successful cryotherapic treatment and overview of
multiple clear cell acanthomas. Dermatol Surg.
1995;21(4):342–4.
4. Monari P, Farisoglio C, Gualdi G, Botali G, Ungari
M, Calzavara-Pinton P. Multiple eruptive clear cell
acanthoma. J Dermatol Case Rep. 2010;4(2):25–7.
5. Degos R, Civatte J. Clear cell acanthoma. Br
J Dermatol. 1970;83(2):248–54.
360
6. Fernandez-Obregon A. Residents’ corner: cryosur-
gery of clear cell acanthoma. J Dermatol Surg Oncol.
1986;12(7):689–92.
7. Altman AR, Basler E, Rosen T. Cryosurgical treat-
ment of clear cell acanthoma. Int J Dermatol.
1989;28(5):334–5.
J. Guidry and T. Rosen
8. Wang SH, Chi CC. Clear cell acanthoma occurring on
the hallux: the first case report. J Eur Acad Dermatol
Venereol. 2006;20(9):1144–6.
9. Kavanagh GM, Marshman G, Burton JL. Multiple
clear cell acanthomas treated by cryotherapy. Australas
J Dermatol. 1995;36(1):33–4. Abbreviations.
 Condyloma Acuminatum (Genital
Warts)
71
Renata Strumia

Abstract
Condyloma Acuminatum (CA), is probably the most common of infec-
tions that can be sexually transmitted. There is no one specific therapy for
CA; some treatments are based on long-standing use and are supported by
historical practice, small trials, and case-series data. Recently developed
treatment modalities are supported by more rigorous research. Commonly
used destructive modalities include cryosurgery, podophyllin,
5-fluorouracil, electrodesiccation with or without curettage, and laser sur-
gery. Medical treatments include interferon, both intralesionally and sys-
temically, and imiquimod. Cryotherapy is an option to treat CA but
recurrence rates range from 20 % to 30 %.

Keywords
Condyloma acuminatum • Genital warts • Cryotherapy • Cryosurgery

Introduction 31 and 33 are often found in lesions with neo-

Condyloma Acuminatum (CA), also called geni-
tal wart, is probably the most common of the
infections that can be sexually transmitted and is
an important public health problem because of its
clear association with cervical cancer in women
and its potential association with other anogenital
malignancies. Benign CA are usually caused by
HPV types 6 and 11, whereas HPV types 16, 18,
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara, (Former) Ferrara 44121, Italy
e-mail: restrumi@tin.it
plastic transformation.
Description of the Disease
CA lesions are usually asymptomatic, but
depending on the size and anatomic location,
they can be painful or pruritic. Morphological
types include lesions that have the shape of cau-
liflower, smooth papular warts that are dome-
shaped, keratotic genital warts with a thick horny
layer, resembling common warts or seborrheic
keratosis, and slightly raised, flat-topped pap-
ules. CA occur commonly at certain anatomic

© Springer-Verlag London 2016 361

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_71
362 R. Strumia

sites, including around the introitus in women,
under the foreskin of the uncircumcised penis,
and on the shaft of the circumcised penis. CA
can also occur at multiple sites in the anogenital
epithelium or within the anogenital tract (e.g.,
cervix, vagina, urethra, perineum, perianal skin,
and scrotum). Intra-anal warts are observed pre-
dominantly in persons who have had receptive
anal intercourse, but they can also occur in men
and women who do not have a history of anal
sexual contact. Diagnosis is usually clinical, by
visual inspection. CA can be confirmed by
biopsy, which might be indicated if (1) the diag-
nosis is uncertain; (2) the lesions do not respond
to standard therapy; (3) the disease worsens dur-
ing therapy; (4) the lesion is atypical; (5) the
patient has comprised immunity; or (6) the warts
are pigmented, indurated, fixed, bleeding, or
ulcerated.
Therapeutic Alternatives
desiccation with or without curettage, and laser
surgery. Medical treatments include: interferon,
both intralesional and systemic, and imiquimod.
A literature review indicates that no single proce-
dure is markedly superior, with recurrence rates
of approximately 30 % for all techniques [1–5].
Recurrences are probably related to the subclini-
cal infection surrounding the warts. Even sys-
temic interferon does not appear to lower the viral
nucleic acid content in warts.
Cryotherapy
LN cryotherapy is widely used. Its advantages
include a short duration of therapy (3–4 weeks
for up to 6 weeks), with relatively rapid healing.
Only topical anaesthesia is needed and the tech-
nique is suitable for vaginal, urethral and anal
warts. The disadvantages include local side
effects, mainly pain and scarring (Figs. 71.1,
71.2, 71.3, 71.4, and 71.5).

There is no one specific therapy for CA. Some

treatments are based on long-standing use and
are supported by historical practice, smaller tri-
als, and case-series data, whereas recently devel-
oped treatment modalities are supported by more
rigorous research.
Factors that influence selection of treatment
include wart size, wart number, anatomic site of
the wart, wart morphology, patient preference,
cost of treatment, convenience, adverse effects,
and provider experience. Factors that might affect
response to therapy include the presence of
Fig. 71.1 Condyloma acuminatum
immunosuppression and compliance with ther-
apy, which can consist of either a single treatment
or complete course of treatment. In general, warts
located on moist surfaces or in intertriginous
areas respond best to topical treatment. The treat-
ment modality should be changed if a patient has
not improved substantially after a complete
course of treatment or if side effects are severe.
Most genital warts respond within 3 months of
therapy. The response to treatment and any side
effects should be evaluated throughout the course
of therapy.
Commonly used destructive modalities include
cryotherapy, podophyllin, 5-fluorouracil, electro- Fig. 71.2 Cryotherapy
71 Condyloma Acuminatum (Genital Warts)
Fig. 71.3 Post-op at 1 week
Fig. 71.4 Post-op at 2 weeks
Fig. 71.5 Post-op at 3 months
Methodology (How I Do It)
Topical lidocaine/prilocaine preparation is rec-
ommended to reduce the pain of cryotherapy in
the removal of CA. This combination anesthetic
363
may possibly allow for a more complete freezing
of the lesions and a more cooperative patient.
Two to three cycles of freezing with LN, each of
10 s should be performed in the same session.
Repeat applications every 1–2 weeks.
Success Rates
Eron et al. [5] reported data for comparison
groups who received cryotherapy plus placebo;
wart clearance was 40 % at 3 months and 27 %
at 6 months, respectively, for these groups.
Data have suggested that recurrence rates may
be 38–73 % by 6 months after treatment [4].
Clearance rates range from 50 % to 80 % with
published recurrence rates ranging from 20 %
to 30 %.
Conclusions
Cryotherapy is an option to treat CA; but
recurrence rates range from 20 % to 30 %.
References
1. Jablonska S. Traditional therapies for the treatment of
condylomata aeuminata (genital warts) Australasian.
J Dermatol. 1998;39(Suppl):S2–4.
2. French L, Nashelsky J. Clinical inquiries. What is the
most effective treatment for external genital warts?
J Fam Pract. 2002;51:313.
3. Menter A, Black-Noller G, Riendeau LA, Monti
KL. The use of EMLA cream and 1% lidocaine infil-
tration in men for relief of pain associated with the
removal of genital warts by cryotherapy. JAAD.
2013;37:96–100.
4. Handley JM, Horner T, Maw RD, Lawther H,
Dinsmore WW. Subcutaneous interferon alpha 2a
combined with cryotherapy vs cryotherapy alone in
the treatment of primary anogenital warts: a ran-
domised observer blind placebo controlled study.
Genitourin Med. 1991;67:297–302.
5. Eron LI, Alder MB, O’Rourke JM, Ritlweger R,
DePamphilis J, Pizutti DJ. Recurrence of condylo-
mata acuminata following cryotherapy is not pre-
vented by systemically administered interleron.
Genitourin Med. 1993;69:91–3.
 Dermatofibroma
72
Renata Strumia

Abstract
Dermatofibromas or histiocytomas are common, benign, skin tumours.
Open spray or cryoprobe techniques may be used to improve the cosmetic
appearance of dermatofibromas.

Keywords
Dermatofibroma • Histiocytoma • Cryotherapy

Introduction variants have been described: cellular benign

Dermatofibroma (DF) or histiocytoma is a com-
mon, benign, skin tumour.
Description of the Disease
DF usually appears as slow-growing, firm der-
mal nodules with a predilection for the legs of
middle-aged women. Although DF is as a rule
only a few millimeters in diameter, it occasion-
ally measures 2–3 cm. Most lesions have a red
color but they may be red-brown because of
hyperpigmentation of the overlying skin, or
blue-black because of large amounts of hemo-
siderin within the tumor [1]. Many histological
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara, (Former) Ferrara 44121, Italy
e-mail: restrumi@tin.it
fibrous histiocytoma, aneurysmal benign fibrous
histiocytoma, atypical (pseudosarcomatous)
benign fibrous histiocytoma, epithelioid benign
fibrous histiocytoma. Generally, the clinical and
histologic diagnosis is straightforward, but dif-
ferentiation other cutaneous tumors can be diffi-
cult in atypical cases and rare variants. DF
usually persists indefinitely, although spontane-
ous involution has been observed [2]. Treatment
is usually requested on cosmetic grounds, and,
occasionally, pruritus.
Therapeutic Alternatives
Most authors advocate excision of the lesion
when required, despite reports of successful ther-
apy with liquid nitrogen [3]. Excision of tumours
on the leg, particularly on the shin, can result in
wide atrophic scarring, and the result may be cos-
metically unacceptable.

© Springer-Verlag London 2016 365

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_72
366
Cryosurgery
Open spray or cryoprobe techniques may be used
to improve the cosmetic appearance of dermato-
fibromas [2, 4].
Methodology (How I Do It)
Each DF is treated by LN spray, probe or cotton-
tipped dipstick method to produce a visible freez-
ing of the tumor to a 1 mm halo for 20 s. Patients
are checked 4 weeks after this treatment to
decide, based on the clinical response, whether
further freezing is required.
Success Rates
In many patients the DF does not completely
resolve, but the therapy produces marked flatten-
ing of the lesion, which remains palpable, with
R. Strumia
softening of the surface color. In pruritic or pain-
ful lesions, cryosurgery improves or resolves the
symptoms.
Conclusions
Cryosurgery is a good option in the treatment
of pruritic or painful lesions and in cosmeti-
cally not acceptable blue-black lesions.
References
1. Elder D, Elenitsas R, Jaworsky C, Johnson Jr
B. Lever’s histopathology of the skin. Philadelphia:
Lippincott-Raven Publishers; 1997. p. 847–53.
2. Niemi KM. The benign fibroistiocytic tumours of the
skin (review). Acta Derm Venereol (Stockh).
1970;50:66.
3. Lanigan SW, Robinson TWE. Cryotherapy for derma-
tofibromas. Clin Exp Dermatol. 1987;12:121–3.
4. Hill AC, Dougherty JW, Torre D. Cryosurgical treat-
ment of dermatofibromas. Cutis. 1975;16:517–8.
 Dermatosis Papulosa Nigra
73
Neiraja Gnaneswaran, Eshini Perera,
and Shobhan Manoharan

Abstract
Dermatosis Papulosa Nigra (DPN) is characterized by benign epithelial
tumours resembling seborrheic keratosis in groups of varied numbers, it
occurs commonly in the dark skin population. These pigmented papules or
papillomas develop on the face, neck and upper trunk. They are often
treated for cosmetic reasons. A plethora of treatments exist including
cryosurgery, curettage, electrodessication and fractional thermolysis;
cryosurgery has the advantage of being fast, inexpensive, and minimal
preparation required. Hypopigmentation is a potential side effect of cryo-
surgery. A feathering technique can help disguise the areas of hypopig-
mentation. There is limited literature on the success of cryosurgery in
DPN however from the author’s experience this is a very effective method.
Lesions are likely to increase in numbers as the patient ages, and multiple
treatments may be needed.

Keywords
Dermatosis papulosa nigra • Cryosurgery • Ethnic skin

Introduction

Dermatosis Papulosa Nigra (DPN) is represented

N. Gnaneswaran, MBBS, BMedSci
Department of Plastic and Reconstructive Surgery,
Queensland Health, Southport, QLD, Australia
E. Perera, MBBS, BMedSci
Sinclair Dermatology, Department of Medicine,
Dentistry and Health Sciences, University of
Melbourne, East Melbourne, VIC, Australia
S. Manoharan, MBBS, FACD (*)
Department of Dermatology, Westside Dermatology,
185 Moggill Rd., Taringa, QLD 4068, Australia
e-mail: shobhan@brisbaneskin.com.au
by benign small dark pigmented papules and pap-
illomas that occur on the face, neck and chest,
particularly, in the dark-skinned population.
Multiple lesions often occur in these areas and
can be a source of embarrassment. Given their
benign nature, the treatment of these lesions is for
cosmetic purposes. A number of treatment options
exist for DPN including cryosurgery, curettage,
electrodessication, and fractional thermolysis.

© Springer-Verlag London 2016 367

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_73
368
Cryosurgery has the benefits of being a fast, rela-
tively inexpensive and effective modality for
treating DPN with minimal side effects.
Description of the Disease
DPN is made of benign epithelial tumours,
closely resembling seborrheic keratoses (SK).
The highest prevalence is in darker skinned
adults; up to 10–35 % of adult dark-skinned
patients [1–3]. Despite the significant tropism for
this ethnic group, sporadic case reports of DPN
in the Asian, Hispanic and Caucasian populations
have been published [4, 5]. Previous series sug-
gested predominance in females, occurring three
to four times more frequently in them. Up to
40–54 % of affected patients report a significant
family history, suggesting a genetic element [6].
Classically, the lesions initially develop after the
onset of puberty in the second decade of life with
a peak incidence in the sixth decade [7].
DPN is thought to represent a nevoid develop-
mental defect of the pilosebaceous follicle [3].
Macroscopically, DPN is characterized by small,
firm, pigmented non-tender papules [3] which
commonly occur on the malar regions, forehead,
neck and upper trunk [2]. While DPN usually
presents as macular, papular or papillomatous
lesions, they may present as pedunculated pap-
ules and papillomas. Individual lesions are often
between 1 and 5 mm in diameter and occur in
groups, their number often increasing with age
(Fig. 73.1). DPN lesions are considered to be a
Fig. 73.1 Dermatosis Papulosa Nigra of the forehead
N. Gnaneswaran et al.
variant of SK; recent studies examining the
genetic profile of DPN demonstrated similar
mutations, suggesting that they have a common
genetic background [8].
Diagnosis may be confirmed by biopsy.
Histopathologically, DPN lesions resemble SK,
displaying hyperkeratosis, irregular acanthosis,
keratin filled invaginations of the epidermis and
marked hyperpigmentation of the basal layer. A
study observing the microscopic pattern in DPN
demonstrated features consistent with the “ade-
noid type” of SK [3].
DPN shows no malignant potential, however
the course is chronic and progressive with more
lesions appearing with age. Despite its benign
nature, consultation and treatment is often sought
for the resulting cosmetic disfigurement and
source of embarrassment [9]. At times the lesions
may be symptomatic, with a proportion of
patients reporting pruritus.
Therapeutic Alternatives
Several different treatment modalities have been
reported in the literature. These options include
curettage, electrodissecation, photothermolysis
and cryosurgery. Despite the prevalence of the
disease, few robust studies have reported out-
comes of such treatments. As such, in reviews of
textbooks of dermatology [10–12], there is no
recommended treatment plan and further, no sug-
gestion between treatment modality. It is cur-
rently accepted that regardless of the modality,
aggressive treatment may be associated with
post-therapeutic dyspigmentation, scarring or
keloid formation [13].
Light abrasive curettage has been described
as an appropriate therapy that provides cosmeti-
cally acceptable results. Lesions are lightly
abraded with a curette down to the base. This
method allows for the treatment of multiple,
widespread lesions in a single session, without
the use of local anaesthetic. Curettage is thought
to induce inflammatory cell exocytosis and epi-
dermal degeneration, which subsequently
results in involution and regression of the DPN
lesions.
73 Dermatosis Papulosa Nigra
By minimizing procedural trauma the occur-
rence of post-operative inflammatory hypo- and
hyper- pigmentation is reduced. Kauh et al.
reported a series of 20 patients undergoing
curettage as outlined [13]. The resulting aes-
thetic improvement was subjective and appeared
to be optimal at the 8-week follow-up; at the
12-month follow-up, 95 % of the patients were
assessed to have obtained aesthetically accept-
able results with only one reporting persistent
hypopigmentation [8].
Electrodessication is a common method of
treatment for DPN; it utilizes a high frequency
alternating electrical current at various voltages to
destroy abnormal skin growths. An electrode tip
is used to isolate and deliver current until a white
frost forms and destroys the abnormal lesion.
Occasionally, DPN lesions will require retreat-
ment. Electrodessication is highly effective, how-
ever patients often report significant discomfort
with this method. Few studies in recent literature
have reported aesthetic outcomes following this
treatment modality. Garcia et al. published a
series of ten patients undergoing different modali-
ties. In this group, they reported a high clearance
rate following electrodessication of 92.5 %, how-
ever, with high rates of hyperpigmentation [1].
Various methods, frequencies and regimes of
laser therapy (photothermolysis) in the treatment
of DPN and other benign pigmented skin lesions
have been reported in contemporary literature
[14–18]. Across 532 nm and 1,064 nm frequen-
cies, this treatment modality has proven to be
efficacious and results in minimal residual pig-
mentary changes [16–18]. Cellular changes
induced photothermolysis are thought to include
transepidermal elimination, characterised by
elimination of necrotic debris through epidermal
vacuoles [19]. Laser therapy has also been asso-
ciated with excellent patient satisfaction and
minimal morbidity, even in the absence of topical
anaesthetic agents. In a robust, controlled clinical
trial comparing Potassium-Titanyl-Phosphate
laser (KTP) to electrodessication in DPN [15]
aesthetic results were comparable, however a sig-
nificant reduction in discomfort was reported fol-
lowing KTP photothermolysis [15]. Fractional
photothermolysis (FP) delivers fractionated laser
369
beams to a designated area, producing a poten-
tially therapeutic thermal injury. In a report of a
single case of DPN [20] FP was administered
over three treatments separated by 4–5 weeks; a
1,550 nm Fraxel SR laser was utilised with eight
to ten passes during each treatment, obtaining
excellent aesthetic outcomes with minimal mor-
bidity at 1-month follow up. The safety of FP on
facial lesions was validated in a report of hyper-
pigmentation in 0.73 % of patients in a series of
961 patients [21].
Cryosurgery Methodology (How
I Do It)
Cryosurgery is a very effective treatment for
DPN. It is usually used for the macular and papu-
lar type lesions, however it can also be used for the
pedunculated oness. Cryotherapy offers the bene-
fits of being relatively inexpensive and quick to
perform, with minimal down time for the patient.
The area to be treated may be anaesthetized
with local or topical anesthetic prior to the treat-
ment; this is optional.
1. Hold the spray 1 cm away and perpendicular
to the lesion
2. Spray directly into the center of the lesion
until ice forms over it. This should take under
30 s.
3. Allow the lesion to thaw for several seconds
4. Curette the frozen lesion with one or two
strokes; this is optional.
In the case of papular; papillomatous or
pedunculated lesions, a No. 10 scalpel, other
blades or scissors can be used prior to freezing
the base.
Another method that can be used is the dip-
stick method. A small container is filled with liq-
uid nitrogen. A small cotton bud is dipped into
the liquid nitrogen. The cotton bud is then held
against the lesion until ice formation is seen
around it; freeze temperatures obtained with the
dipstick method are not as low as with the spray
method. These higher temperatures may reduce
the risk of hypopigmentation.
370
After the procedure a topical steroid of mild-
moderate potency may be applied for several
days to help minimize any post inflammatory
hyperpigmentation (PIH). A short course of pred-
nisolone may also be prescribed in the short term
to reduce any edema and blistering. It is also use-
ful to advise the patient of sun avoidance, partic-
ularly in the first 24 h, to minimize PIH.
Complications
Cryosurgery should be used cautiously in darker
skin populations as melanocytes are more suscepti-
ble to destruction than keratinocytes by low tem-
peratures, and patients may be left with
post-inflammatory hypo or hyperpigmented
sequelae that can be cosmetically unacceptable.
Shorter freeze-times, of fewer than 15 s may reduce
this side effect. Lightly spraying the margins (feath-
ering) of the lesions may help disguise the transition
in color. Patients should be warned of the dyspig-
mentation risks prior to the procedure, as they can
be as distressing as the lesions themselves.
Pain and edema are also adverse events in
cryosurgery. Edema is particularly common
around the eye region. While these side effects
are extremely common, they do not occur at the
magnitude seen in other cryosurgical procedures
because the freeze-time is much shorter.
Success Rates
There is limited data on the success of cryosur-
gery in DPN. From anecdotal experience cryo-
surgery is very effective, with results comparable
to electrodessication. There are no recorded
recurrence rates for DPN lesions treated with
cryosurgery. What is known, is that lesion num-
bers increase with age and the patient will need
ongoing treatments throughout their life.
Conclusions
Multiple treatment options for DPN include
curettage, electrodessication and fractional
photothermolysis. Cryosurgery is a commonly
used treatment for DPN; short freeze thaw
N. Gnaneswaran et al.
cycles should reduce the risk of pigmentary
sequelae. There is limited data on the success
rates of cryosurgery, however the authors’
experience is that the procedure is less painful
and comparable in its success in DPN as the
already favourable results seen with elec-
trodessication. The patient will need ongoing
treatments regardless of the modality used as
lesion numbers increase with age.
References
1. Garcia MS, Azari R, Eisen DB. Treatment of derma-
tosis papulosa nigra in 10 patients: a comparison trial
of electrodesiccation, pulsed dye laser, and curettage.
Dermatol Surg: Off Publ Am Soc Dermatol Surg
[et al]. 2010;36(12):1968–72.
2. Grimes PE, Arora S, Minus HR, Kenney Jr
JA. Dermatosis papulosa nigra. Cutis. 1983;32(4):385–
6. 92.
3. Hairston Jr MA, Reed RJ, Derbes VJ. Dermatosis
papulosa nigra. Arch Dermatol. 1964;89:655–8.
4. Binazzi M, Simonetti S. A case of dermatosis papu-
losa nigra in a white man. Ann Dermatol Venereol.
1984;111(11):1013–5.
5. Moyed MJMN, Mostaghimi L. Dermatosis papulosa
nigra: report of a case in the Caucasian race. Eur
J Dermatol. 1992;12:333–5.
6. Niang SO, Kane A, Diallo M, Choutah F, Dieng MT,
Ndiaye B. Dermatosis papulosa nigra in Dakar,
Senegal. Int J Dermatol. 2007;46 Suppl 1:45–7.
7. Collyer JCLS. Treatment of dermatosis papulosa
nigra. In: Alam MBA, Kundu RV, Yoo SS, Chan
HH-L, editors. Cosmetic dermatology for skin of
colour. New York: McGraw-Hill; 2009. p. 125–9.
8. Hafner C, Landthaler M, Mentzel T, Vogt T. FGFR3 and
PIK3CA mutations in stucco keratosis and dermatosis
papulosa nigra. Br J Dermatol. 2010;162(3):508–12.
9. Calcaterra R, Franco G, Valenzano M, Fazio R,
Morrone A. Clinical features and treatment of derma-
tosis papulosa nigra in migrants to Italy. Skinmed.
2010;8(4):207–9.
10. Sutton RL, editor. Diseases of the skin. 11th ed. St
Louis: The CV Mosby company; 1956.
11. Moschella SPD, Hurley HJ, editors. Dermatology.
Philadelphia: WB Saunders; 1975.
12. Rook AWD, Ebling FJG, editors. Textbook of dermatol-
ogy. Oxford: Blackwell Scientific Publications; 1979.
13. Kauh YC, McDonald JW, Rapaport JA, Ruschak PJ,
Luscombe HA. A surgical approach for dermatosis
papulosa nigra. Int J Dermatol. 1983;22(10):590–2.
14. Spoor TC. Treatment of dermatosis papulosa nigra
with the 532 nm diode laser. Cosmet Dermatol.
2001;14:21–3.
73 Dermatosis Papulosa Nigra
15. Kundu RV, Joshi SS, Suh KY, Boone SL, Huggins
RH, Alam M, et al. Comparison of electrodesiccation
and potassium-titanyl-phosphate laser for treatment
of dermatosis papulosa nigra. Dermatol Surge: Off
Publ Am Soc Dermatol Surg [et al]. 2009;35(7):
1079–83.
16. Lupo MP. Dermatosis papulosis nigra: treatment
options. J Drugs Dermatol: JDD. 2007;6(1):29–30.
17. Raulin C, Schonermark MP, Greve B, Werner
S. Q-switched ruby laser treatment of tattoos and
benign pigmented skin lesions: a critical review. Ann
Plast Surg. 1998;41(5):555–65.
18. Schweiger ES, Kwasniak L, Aires DJ. Treatment of
dermatosis papulosa nigra with a 1064 nm Nd:YAG
laser: report of two cases. J Cosmet Laser Ther: Off
Publ Eur Soc Laser Dermatol. 2008;10(2):120–2.
371
19. Hantash BM, Bedi VP, Sudireddy V, Struck SK,
Herron GS, Chan KF. Laser-induced transepidermal
elimination of dermal content by fractional photother-
molysis. J Biomed Opt. 2006;11(4):041115.
20. Katz TM, Goldberg LH, Friedman PM. Dermatosis
papulosa nigra treatment with fractional photother-
molysis. Dermatol Surg: Off Publ Am Soc Dermatol
Surg [et al]. 2009;35(11):1840–3.
21. Graber EM, Tanzi EL, Alster TS. Side effects and
complications of fractional laser photothermolysis:
experience with 961 treatments. Dermatol Surg: Off
Publ Am Soc Dermatol Surg [et al]. 2008;34(3):301–
5; discussion 5–7.
 Elastosis Perforans Serpiginosa
74
Luciana Samorano,
Eugênio Raul de Almeida Pimentel,
and Marcello Menta Simonsen Nico

Abstract
Elastosis perforans serpiginosa is an uncommon and chronic dermatosis
characterized by transepidermal elimination of abnormal elastic fibers
originating in the dermis. Diagnosis is based on clinical and histopatho-
logic aspects. Treatment has included various modalities and cryotherapy
is one of the effective options. Favored method includes the use of open
spray timed spot freeze technique and one to two sessions are usually
enough to treat some grouped papules.

Keywords
Elastosis perforans serpiginosa • Cryotherapy • Open spray • Timed spot
freeze technique

Introduction drome, pseudoxanthoma elasticum, Rothmund-

Elastosis perforans serpiginosa (EPS) is a rare
and chronic dermatosis characterized by the tran-
sepidermal elimination of abnormal elastic fibers
originating in the dermis [1]. EPS is associated
with genetic disorders and connective tissue dis-
eases such as Down syndrome, Ehlers-Danlos
syndrome, osteogenesis imperfecta, Marfan syn-
L. Samorano • E.R. de Almeida Pimentel, MD
M.M.S. Nico, MD (*)
Department of Dermatology, Medical School,
University of São Paulo, Hospital das Clínicas,
Rua Itapeva 500- 3A, São Paulo,
São Paulo 01332-000, Brazil
e-mail: mentanico@hotmail.com
Thomson syndrome, acrogeria, morphea, and
scleroderma. More commonly, EPS occurs after
chronic intake of penicillamine in patients with
Wilson’s disease.
Description
The clinical picture of EPS consists of multi-
ple keratotic papules occurring singly or in
arcuate and circinate arrangements located
more commonly on the neck (Fig. 74.1) [1, 2].
Histopathologic findings reveal transepider-
mal elimination of neutrophils and elastic
fibers from the dermis via channels in the epi-
dermis [ 1, 2].

© Springer-Verlag London 2016 373

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_74
374
Fig. 74.1 Typical lesions of elastosis perforans serpigi-
nosa on the neck of a 39-year-old male suffering from
Wilson disease, and taking penicilamine for several years
Treatment
Described therapies for EPS include isotretinoin,
tazarotene, imiquimod, topical and intralesional
corticosteroids, glycolic and salicylic acid, surgi-
cal excision, dermabrasion, electrosurgery, cello-
phane tape-stripping, and CO2, Erbium-YAG,
and pulsed dye lasers [3–5].
Cryotherapy
Cryotherapy may be useful in selected EPS cases.
Blister formation is believed to accelerate elimi-
nation of altered elastic fibers by and subsequent
re-epithelialization [2]. Some successful cases
have been reported in the literature with different
freezing techniques, with minimal scaring and no
recurrence during follow-up [2, 6, 7].
L. Samorano et al.
Cryotherapy Method (How
We Do It)
Anesthesia is seldom needed; topical EMLA
cream under occlusion for about 30–60 min before
treatment can be used. A spray tip with an aperture
of 0.022 in. (C) is recommended. The spray nozzle
is positioned approximately 1–1.5 cm above the
target lesion. One 20–30 s freezing cycle is usually
sufficient (Fig. 74.2). The open spray technique of
choice is the timed spot freeze. Thawing time is
not important for the treatment of EPS. After the
procedure, prescribe medium to high potency
analgesics, since edema and blistering can be
intense and painful (Fig. 74.3).
Success Rate
Results are usually successful when the technique
is correctly performed, with minimal scaring
(Fig. 74.4). Follow-up is necessary to evaluate the
need of a new freezing session; normally only one
to two sessions per grouped papules are required.
Fig. 74.2 Clinical aspect immediately after freezing the
larger anular lesion
74 Elastosis Perforans Serpiginosa
Fig. 74.3 Clinical aspect after 72 h: intense blistering
and edema
Fig. 74.4 Clinical aspect after 45 days. Excellent result;
only biopsy site is visible
375
References
1. Lewis KG, Bercovitch L, Dill SW, Robinson-Bostom
L. Acquired disorders of elastic tissue: part I. Increased
elastic tissue and solar elastotic syndromes. J Am
Acad Dermatol. 2004;51(1):1–21.
2. Kalkan G, Sahin M, Vahaboğlu G, Astarci M, Ekşioğlu
M. A case of elastosis perforans serpiginosa treatment
with cryotherapy. Int J Dermatol.
2012;51(12):1487–90.
3. Mehta RK, Burrows NP, Payne CM, Mendelsohn SS,
Pope FM, Rytina E. Elastosis perforans serpiginosa
and associated disorders. Clin Exp Dermatol.
2001;26(6):521–4.
4. Langeveld-Wildschut EG, Toonstra J, van Vloten WA,
Beemer FA. Familial elastosis perforans serpiginosa.
Arch Dermatol. 1993;129(2):205–7.
5. Wilkinson C, Rahimi S, Hohle R, Ramrakha-Jones
V. An erythematous papular lesion on the neck of a
young boy. Elastosis perforans serpiginosa. Pediatr
Dermatol. 2012;29(5):659–60.
6. Humphrey S, Hemmati I, Randhawa R, Crawford RI,
Hong CH. Elastosis perforans serpignosa: treatment
with liquid nitrogen cryotherapy and review of the lit-
erature. J Cutan Med Surg. 2010;14(1):38–42.
7. Tuyp EJ, McLeod WA. Elastosis perforans serpigi-
nosa: treatment with liquid nitrogen. Int J Dermatol.
1990;29(9):655–6.
 Epidermal Nevi
75
Antonios Panagiotopoulos

Abstract
Epidermal nevi are skin hamartomas. Treatment may be requested for cos-
metic reasons, foul odor, discomfort, psychologic trauma, and other symp-
toms may be reasons for patients to request treatment. Many destructive
modalities and some medications may be of value. Cryosurgery is a good
option for some.

Keywords
Epidermal nevus • Cryosurgery • Liquid nitrogen • Open spray technique

Description Epidermal nevi may involve any part of the

Epidermal nevi are hamartomas of the skin charac-
terized by hyperplasia of adnexal structures such as
the pilosebaceous unit, apocrine and eccrine
glands. They are relatively common entities; can
present at birth (1 in every 1,000 births) or later in
life, and may increase in size at puberty [1].
They may be categorized into three subtypes
by their clinical features:
Nevus verrucosus (VEN)
Inflammatory linear verruccous epidermal nevus
(ILVEN)
Icthyosis hystrix
A. Panagiotopoulos, MD
Department of Cryosurgery, Andreas Syggros,
4 I.DRAGOUMI STR, 36 Z.PIGIS,
Athens 10681, Greece
e-mail: antonispan2010@yahoo.gr
body, appearing as highly keratotic and pig-
mented papules that form well defined papillo-
matous plaques. They are generally asymptomatic.
They can be very verrucous and be widely dis-
tributed (Fig. 75.1).
Treatment Alternatives
The treatment of verrucous epidermal nevi is
very difficult. Currently, many treatments have
been described with variable therapeutic results.
Topical agents such as corticosteroids, calcipot-
riol, 5-fluouracil, podophylin, retinoids and
chemical peels have been used. Intralesional
corticosteroids, surgery, electrosurgery, derm-
abrasion, various types of lasers and photody-
namic laser have also been tried [1].

© Springer-Verlag London 2016 377

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_75
378 A. Panagiotopoulos

Fig 75.1 Verrucous epidermal nevus on the right axilla

Cryosurgery

Cryosurgery has been used to treat epidermal

nevi. Small, single lesions respond favorably to
cryosurgery in a few sessions, while widespread Fig. 75.2 Epidermal nevus on the neck. Freeze time:
10 s – 2 cycles – 2 sessions
papillomatous VEN likely require multiple ses-
sions. The former usually clear with no scaring
and minimal pigment alteration.

Methodology (How I Do It)

In general, the open spray technique can be used

with the freezing time ranging between 5 and
15 s; for small lesions, two to four sessions may
be required while for larger ones 6–12 could be
required (Figs. 75.2, 75.3, 75.4, 75.5 and 75.6).
Fox and Lapins treated several lesions of epider-
mal nevi of a child using the LN spray technique
in double freeze-thaw cycles. They reported Fig. 75.3 6 months after treatment
excellent results. No recurrences were noted in a
2 year follow-up period [2]. Panagiotopoulos
et al published a series of 11 patients with epider- spontaneously after 2 months [3]. Lapidoth et al
mal nevi treated with cryosurgery. They reported treated 71 patients with epidermal nevi, 62
cure rates above 90 %. LN spray technique was patients with cryosurgery alone. Patients with
used with freezing time between 5 and 15 s. Two small lesions required few treatments and exhib-
freeze-thaw cycles were employed and the thera- ited excellent results while those with larger
peutic results were described as excellent. Only lesions did not respond well; nine responded
in one patient with phototype IV hypopigmenta- insufficiently and were transitioned to CO2 laser
tion developed in the treated area, which resolved treatment [4].
75 Epidermal Nevi 379

Fig. 75.4 Epidermal nevus on the face before and after treatment

Conclusions
No serious side effects are observed in cryo-
surgical treatment of epidermal nevus.
Transient hypopigmentation is the most com-
mon side effect. Repigmentation occurs with
time. Recurrences can occur months or years
after treatment so patients should be informed
about this event.

Fig 75.5 Epidermal nevus on the face. Freeze time:

15 s – 2 cycles – 4 sessions References
1. Mackie RM, editor. Skin cancer. 2nd ed. London:
Martin Dunitz; 1996.
2. Fox BJ, Lapins NA. Comparison of treatment modali-
ties for epidermal nevus: a case report and review.
J Dermatol Surg Oncol. 1983;9:879–85.
3. Panagiotopoulos A, Chasapi V, Nikolaou V,
Stavropoulos PG, Kafouros K, Petridis A, Katsambas
A. Assessment of cryotherapy for the treatment of ver-
rucous epidermal naevi. Acta Derm Venereol.
2009;89:292–4.
4. Lapidoth M, Israeli H, Ben Amitai D, Halachmi
S. Treatment of verrucous epidermal nevus:experience
with 71 cases. Dermatology. 2013;226(4):342–6.

Fig 75.6 6 months after treatment

 Fibrous Papules of the Nose
76
Renata Strumia

Abstract
Fibrous papules of the nose and face occur predominantly on the nose as
1–5 mm, shiny, skin-colored, firm, dome-shaped papules. To remove them
several options are available. Curettage, shave, or ellipse excision, have
been employed. Cryotherapy with LN with cotton-tipped dipstick method
can be used with good cosmetic result.

Keywords
Fibrous papules of the nose • Cryotherapy

Introduction Description of the Disease

Fibrous papules (FP) of the nose and face are a
distinctive clinicopathologic entity that most
probably represents an inflammatory rather than
a neoplastic process, sharing some histologic fea-
tures of angiofibromas (angiofibrosis) and peri-
follicular fibromas (perifollicular fibrosis) [1].
Graham et al. [2] in a detailed article hypothe-
sized that the histogenesis and pathogenesis of
this unique tumor indicates the lesion probably
represents the residual of a cellular nevus in
which stromal elements persist because of the
anatomical location.
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara, (Former) Ferrara 44121, Italy
e-mail: restrumi@tin.it
FP on the face usually arise as single lesions;
however, occasionally multiple (i.e., normally
less than ten lesions may be present [3]. Occurring
predominantly on the nose, these lesions are gen-
erally 1–5 mm, shiny, skin-colored, firm, dome-
shaped papules.
Histologic findings in FP of the nose are usu-
ally those of fibromas or angiofibromas with
increased cellularity of the upper parts of the cutis.
Cell shape varies greatly and includes dendritic,
stellated and strap-shaped forms as well as multi-
nucleated giant cells, similar to those of juvenile
melanomatas. FP of the nose is considered a spe-
cial form of regressive nevus cells [4, 5].

© Springer-Verlag London 2016 381

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_76
382
Therapeutic Alternatives
Several options are available for the removal of
FP. Surgical procedures such as curettage, shave
excision, or elliptical excision, have been
employed with excellent cosmetic results.
Successful treatment with various lasers, includ-
ing the pulsed dye laser [6–8], CO2 laser [9] KTP
laser [10] and argon laser [9] is reported.
Cryosurgery
Cryosurgery is used in FP. A patient with fibrous
papules of the face as a part of tuberous sclerosis
was treated by cryosurgery. The definite improve-
ment attending this treatment was maintained
over an 18-month follow-up period [11].
Methodology (How I Do It)
Each FP is treated with LN using the cotton-
tipped dipstick method to produce a visible freeze
for 10 s. Patients are evaluated 4 weeks later to
decide, based on clinical response, whether fur-
ther freezing is required.
Success Rates
Usually two to three cicles are requested to
achieve a good result. Caution should be used in
treating FP in dark skin due to the possibility of
hyper-hypopigmentation.
Conclusions
Cryosurgery is a good option in the treatment
of FP of the face.
R. Strumia
References
1. Rosen LB, Suster S. Fibrous papules. A light micro-
scopic and immunohistochemical study. Am
J Dermatopathol. 1988;10:109–15.
2. Graham JH, Sanders JB, Johnson WC, Helwig
EB. Fibrous papule of the nose: a clinicopathological
study. J Invest Dermatol. 1965;45:194–203.
3. Meigel WN, Ackerman AB. Fibrous papule of the
Face. Am J Dermatopathol. 1979;1:329–40.
4. Bansal C, Stewart D, Li A, Cockerell CJ. Histologic
variants of fibrous papule. J Cutan Pathol.
2005;32:424–8.
5. Altmeyer P. Fibrous papules of the nose-a clinical and
histologic entity? Hautarzt. 1977;28:416–20.
6. Sharma VK, Khandpur S, Khanna N. An interesting
case of unilateral angiofibromas successfully treated
with pulsed dye laser. J Eur Acad Dermatol Venereol.
2004;18:641–2.
7. Paquet P, Hermans JF, Pierard GE. Effect of the
585 nm flashlamp-pumped pulsed dye laser for treat-
ment of keloids. Dermatol Surg. 2001;27:171–4.
8. Papadavid E, Markey A, Bellaney G, Walker
NP. Carbon dioxide and pulsed dye laser treatment of
angiofibromas in 29 patients with tuberous sclerosis.
Br J Dermatol. 2002;147:337–42.
9. Boixeda P, Sanchez-Miralles E, Azana JM, Arrazola
JM, Moreno R, Ledo A. CO2, argon, and pulsed dye
laser treatment of angiofibromas. J Dermatol Surg
Oncol. 1994;20:808–12.
10. Tope WD, Kageyama N. “Hot” KTP-laser treatment
of facial angiofibromata. Lasers Surg Med.
2001;29:78–81.
11. Dvir E, Hirshowitz B. The use of cryosurgery in treat-
ing the fibrous papules of tuberous sclerosis. Ann
Plast Surg. 1980;4:158–60.
 Granuloma Annulare
77
Renata Strumia

Abstract
Granuloma annulare (GA) is a benign, granulomatous disease of unknown
origin affecting patients of all ages. Localized and disseminated variants
are reported. Treatment is not often needed as the majority of these lesions
self-resolve within 2 years. Treatment may be pursued for cosmetic rea-
sons. Available options include high-dose steroid creams, PUVA, cryo-
therapy, or drugs such as niacinamide, infliximab, dapsone, and topical
calcineurin inhibitors. Patch GA lesions are more prone to regression and
the outcome of treatment is difficult to evaluate. Cryotherapy with LN is a
good option in patients with localized GA.

Keywords
Granuloma annulare • Cryotherapy

Introduction Description of the Disease

Granuloma annulare (GA) is a benign, granulo-
matous disease of unknown origin affecting
patients of all ages. Localized and disseminated
variants exist. Although GA tends to be idio-
pathic, several investigators have demonstrated in
adult patients a relationship with systemic dis-
eases and, in particular, with rheumatologic dis-
ease and diabetes mellitus.
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara, (Former) Ferrara 44121, Italy
e-mail: restrumi@tin.it
The classic clinical presentation of GA is that of
a slightly erythematous papule that tends to
expand into an annular plaque with a papular
border. There are other types of GA, which
include disseminated, subcutaneous, papular,
perforating, and linear forms. Localized GA is
characterized by erythematous, asymptomatic,
grouped papules with an enlarging annular pat-
tern favouring the distal extremities [1]. As
localized GA progresses, there is central involu-
tion, leading to the typical ring form of the
lesions. This form is typically self-limited and
resolves within 1–2 years. Disseminated GA is
characterized by widespread erythematous

© Springer-Verlag London 2016 383

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_77
384
papules, and is often chronic and difficult to
treat [1]. In a long-term survey study involving
32 patients, all patients cleared within 20 years
and none developed any other inflammatory dis-
order [2]. However, it is unclear whether these
patients had localized or disseminated GA and
what treatment was used.
The various types of GA share similar histo-
logic findings that are characteristic [3–5]. The
superficial and mid-dermis reveal foci of muci-
nous degeneration of collagen, referred to as
necrobiosis. The foci are surrounded by an infil-
trate of histiocytes, lymphocytes, and a variable
number of multinucleated giant cells. The infil-
trate has a characteristic palisading pattern
around necrobiotic foci. Occasionally there is a
neutrophilic infiltrate with nuclear dust and vas-
culitis within the necrobiotic area, and occasion-
ally the infiltrate is granulomatous, mimicking
sarcoidosis. Rarely, the necrobiosis and infiltrate
are diffuse and not well defined. This latter his-
tologic pattern has been referred to as interstitial,
infiltrative, or incomplete. Because the necrobi-
otic collagen fibers are scattered throughout the
dermis, they may be overlooked. A stain for
mucin may be helpful. Patients with the classical
annular type GA may have any of the above his-
tologic subtypes. In the perforating type, the
necrobiotic material is extruded to the skin sur-
face through an overlying perforation. In subcu-
taneous type GA the necrobiosis and
inflammation take place in the deep dermis and
subcutaneous tissue.
Therapeutic Alternatives
Treatment is often not needed as the majority of
lesions self-resolve within 2 years [6]. But it may
be pursued for cosmetic reasons. Options include
high-potency topical steroids, PUVA [7], cryo-
therapy [8], or drugs such as niacinamide, inflix-
imab, dapsone, and topical calcineurin inhibitors
[6–8]. It is not clear why some GA lesions resolve
after biopsy whereas others do not [9]. It is pos-
sible that the size of the lesion, its location, or the
length of time it has been present may be relevant
factors. Mutasim and Bridges [3] reported
R. Strumia
resolution of patch type GA within weeks to
months after biopsy in several patients, although
their patients were treated with topical corticoste-
roids. Perhaps lesions with the clinical and
microscopic features of patch GA are more prone
to regression than are those with features of a
palisaded, necrobiotic granuloma. GA responds
to physical modalities, such as psoralen ultravio-
let A, cryotherapy and pulsed dye laser [10].
There is also an interesting report of generalized
GA that spared vaccination sites [11]. These
reports suggest the possibility that forms of con-
trolled injury to the skin could sufficiently alter
the cellular and extracellular milieu as to change
the course of, and possibly clear an inflammatory
process such as GA [12]. Although the patho-
physiologic characteristics of GA are not well
understood T-cell subsets and Langerhans cells
appear to be involved.
Cryotherapy
Blume-Peytavi et al. [8] treated 31 patients with
localized GA with cryosurgery, using the contact
method. Nitrous oxide (−86 °C) or LN (−196 °C)
were used as refrigerants, and were applied with
closed probes; each lesion was treated with one
freeze-thaw cycle of 10–60 s per session; when
necessary, treatment was repeated after
20–30 days. Resolution of lesions was obtained
in all patients, and in 25 of 31 patients (80.6 %)
they resolved after a single freeze-thaw cycle.
The duration of the lesion, its location, previous
treatment with another method, and the number
of treatment sessions, did not influence the cos-
metic result. The treatment was generally well
tolerated. Blister formation occurred in all
patients.
Methodology (How I Do It)
LN is applied with the cotton-tipped dipstick
method onto the border of the lesions (Fig. 77.1).
Each lesion is treated with one freeze-thaw cycle
of 5–10 s. Blister formation may occur. If neces-
sary, treatment is repeated after 30 days.
77 Granuloma Annulare 385

Fig. 77.1 LN is applied with the cotton-tipped dipstick

method on the border of the lesions
b

Success Rates

In the study by Blume-Peytavi et al. [8] relapse

occurred in only 1 of 11 patients followed for
more than 2 years, and this occurred 16 months
after treatment. Excellent cosmetic results were
obtained in 14 of 28 patients (50 %) eligible for
evaluation and good results in 11 patients
(39.3 %). The cosmetic result obtained by cryo-
surgery with nitrous oxide was independent of
the size of the lesion, whereas in the group of
patients treated with LN a better cosmetic result Fig. 77.2 (a) GA before cryotherapy; (b) GA after
was obtained with smaller lesions (comparison of cryotherapy
lesions < or = 2.40 cm 2 with those >2.40 cm 2;
P = 0.04).

Conclusions
Patch GA are more prone to regression and the
outcome of treatment is difficult to be evalu-
ated. Cryotherapy is a good treatment in
patients with localized GA (Fig. 77.2a, b).
References
1. Smith MD, Downie JBD, Costanzo D. Granuloma
annulare. Int J Dermatol. 1997;36:326–33.
2. Dahl MV. Granuloma annulare: long-term follow-up.
Arch Dermatol. 2007;143:946–7.
386
3. Mutasim DF, Bridges AG. Patch granuloma annulare:
clinicopathologic study of 6 patients. J Am Acad
Dermatol. 2000;42:417–21.
4. Muhlbauer JE. Granuloma annulare. J Am Acad
Dermatol. 1980;3:217–30.
5. Friedman-Birnbaum R, Weltfriend S, Munichor M,
Lichtig C. A comparative histopathologic study of
generalized and localized granuloma annulare. Am
J Dermatopathol. 1989;11:144–8.
6. Barron DF, Cootauco MH, Cohen BA. Granuloma
annulare. A clinical review. Lippincotts Prim Care
Pract. 1997;1:33–9.
7. Setterfield J, Huilgol SC, Black MM. Generalised
granuloma annulare successfully treated with PUVA.
Clin Exp Dermatol. 1999;24:458–60.
8. Blume-Peytavi U, Zouboulis CC, Jacobi H, Scholz A,
Bisson S, Orfanos CE. Successful outcome of
R. Strumia
cryosurgery in patients with granuloma annulare. Br
J Dermatol. 1994;130:494–7.
9. Levin NA, Patterson JW, Yao LL, Wilson BB.
Resolution of patch-type granuloma annulare
lesions after biopsy. J Am Acad Dermatol. 2002;
46:426–9.
10. Sniezek PJ, DeBloom II JR, Arpey CJ. Treatment of
granuloma annulare with the 585 nm pulsed dye laser.
Dermatol Surg. 2005;31:1370–3.
11. Huilgol SC, Liddell K, Black MM. Generalized gran-
uloma annulare sparing vaccination sites. Clin Exp
Dermatol. 1995;20:51–3.
12. Modlin RL, Horwitz DA, Jordan RR, Gebhard JF,
Taylor CR, Rea TH. Immunopathologic demonstra-
tion of T lymphocyte subpopulations and interleukin
2 in granuloma annulare. Pediatr Dermatol. 1984;2:
26–32.
 Granuloma Faciale
78
Basil Patel, Robert A. Schwartz,
William Abramovits, and Kimberly Dawn Vincent

Abstract
Granuloma faciale (GF) is an uncommon form of chronic leukocytoclastic
vasculitis that is often treatment-resistant. A wide variety of treatment
modalities have been tested. Cryosurgery appears to be a safe, effective,
and inexpensive treatment option for this condition.

Keywords
Granuloma • Faciale • Eosinophilic • Cryotherapy

B. Patel, BS (*)
Department of Dermatology, Rutgers University
New Jersey Medical School,
185 South Orange Ave., Room H-576, Newark,
NJ 07101, USA
e-mail: patel336@njms.rutgers.edu
R.A. Schwartz, MD, MPH, DSc (Hon), FRCP (Edin)
Department of Dermatology, Rutgers University
School of Public Affairs and Administration,
Newark, NJ, USA
e-mail: roschwar@cal.berkeley.edu
W. Abramovits, MD, FAAD
Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical School,
Dallas, TX, USA
Department of Internal Medicine, Texas College of
Osteopathic Medicine, University of North Texas
Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College of
Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
Dallas, TX, USA
e-mail: DrA@dermcenter.us
K.D. Vincent, MD, FAAD
Belle Meade Dermatology, Nashville, TN, USA

© Springer-Verlag London 2016 387

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_78
388
Introduction
GF is an uncommonly occurring disease of
unknown etiology usually presenting as persistent,
discrete facial plaques, appearing inflammatory
and sub-epidermal. Multiple treatment modalities
have been reported, including topical and intrale-
sional corticosteroids, calcineurin inhibitors, cryo-
therapy, lasers, and systemic medications.
Description of Disease
GF is a rare, benign, chronic inflammatory skin
condition that typically beguins as a single
reddish-brown papule, plaque, or nodule on the
face [1]. Less commonly, multiple lesions and/or
extrafacial involvement may be present. The
pathogenesis is unknown, but the disease is
believed to be a small vessel vasculitis [2]. GF
most commonly affects middle-aged men; how-
ever, it may be found on patients of varying age
and gender [1]. The lesions are generally asymp-
tomatic but do not regress spontaneously. The
diagnosis is made by a combination of clinical
evaluation and the histopathology of a punch
biopsy. Due to the cosmetically sensitive loca-
tion of the lesions, patients often seek out
treatment.
Histology
The epidermis appears normal and is separated
by a grenz zone from a diffuse yet dense dermal
and perivascular infiltrate with eosinophils and
neutrophils indicative of leukocytoclastic vascu-
litis with fibrin deposition; histiocytes and plasma
cells may be present. Immunofluorescence iden-
tifies a granular pattern of immunoglobulins,
fibrin and complement [3].
Therapeutic Alternatives
GF has been treated with a number of different
modalities with varying levels of effectiveness.
B. Patel et al.
It is frequently resistant to treatment, so a large
variety of options have been studied [4].
Topical tacrolimus and pimecrolimus may be
effective [5, 6]. There is some evidence that
pulse-dye lasers or carbon dioxide lasers may
also be useful and causes little or no scarring
[4, 7, 8]. Intralesional corticosteroids and dap-
sone have been used effectively [9, 10]. Topical
psoralen with ultraviolet light has been used as
well [11]. Surgical excision appears to lead to
high recurrence rates and is typically not
recommended.
Cryosurgery
Cryosurgery has been used successfully for the
treatment of GF [2, 12, 13]. It is an effective,
inexpensive treatment modality with few docu-
mented side effects. The available evidence
shows that recurrence is uncommon. The main
side effect is local hypopigmentation; this typi-
cally resolves over the course of several months
[2]. Cryosurgery combined with intralesional ste-
roids has also been shown to be a useful treat-
ment modality [14]. To date, there are no
published comparison of the effectiveness of
cryosurgery alone versus combined with intrale-
sional steroids.
Methodology
Excellent results have been achieved with both
open-spray and contact cryosurgery [2]. Results
with the open-spray technique have been stud-
ied more extensively [2, 12, 13]. In one case
series, open-spray cryosurgery was performed
with one or two 20–30 s freeze-thaw cycles,
repeated after 1 month, 3 months, and 6 months
as needed [2]. In the same case series, contact
cryosurgery was also shown to be effective with
one to three 15–20 s freeze-thaw cycles.
Clinical judgment should be used based on the
size of the lesion and concern of hypopigmen-
tation. Local anesthesia is usually not required
for small lesions.
78 Granuloma Faciale
Success Rates
Case reports exist of both successful and unsuc-
cessful treatments, but the success rate appears to
be high [2, 10].
Conclusions
Although the success rate of cryosurgery for
treatment of GF is unknown, it has been shown
to be effective in selected patients. Given the
safe nature of the procedure, cryosurgery may
be used as first-line therapy. Multiple thera-
peutic alternatives also exist; ultimately, treat-
ment choices must be individualized for each
patient.
References
1. Ortonne N, Wechsler J, Bagot M, Grosshans E,
Cribier B. Granuloma faciale: a clinicopathologic
study of 66 patients. J Am Acad Dermatol. 2005;
53(6):1002–9.
2. Panagiotopoulos A, Anyfantakis V, Rallis E, Chasapi
V, Stavropoulos P, Boubouka C, et al. Assessment of
the efficacy of cryosurgery in the treatment of granu-
loma faciale. Br J Dermatol. 2006;154(2):357–60.
3. Nieboer C, Kalsbeek GL. Immunofluorescence stud-
ies in granuloma eosinophilicum faciale. J Cutan
Pathol. 1978;5(2):68–75.
389
4. Wiederkehr MS, Schwartz RA. Granuloma faciale
2013. Available from: http://emedicine.medscape.
com/article/1083474-overview.
5. Cecchi R, Pavesi M, Bartoli L, Brunetti L. Topical
tacrolimus in the treatment of granuloma faciale. Int
J Dermatol. 2010;49(12):1463–5.
6. Dourmishev L, Ouzounova-Raykova V, Broshtilova
V, Miteva L. Granuloma faciale effectively treated
with topical pimecrolimus. Acta Dermatovenerol
Croat. 2014;22(4):305–7.
7. Elston DM. Treatment of granuloma faciale with the
pulsed dye laser. Cutis. 2000;65(2):97–8.
8. Bakkour W, Madan V. Rhinophyma-like granuloma
faciale successfully treated with carbon dioxide laser.
Br J Dermatol. 2014;170(2):474–5.
9. Joshi K, Patel S, Shah PP, Parikh DJ, Bilimoria
FE. Granuloma faciale. Indian J Dermatol Venereol
Leprol. 1998;64(6):291–2.
10. Goldner R, Sina B. Granuloma faciale: the role of
dapsone and prior irradiation on the cause of the dis-
ease. Cutis. 1984;33(5):478–9. 82.
11. Hudson LD. Granuloma faciale: treatment with topi-
cal psoralen and UVA. J Am Acad Dermatol.
1983;8(4):559.
12. Zacarian SA. Cryosurgery effective for granuloma
faciale. J Dermatol Surg Oncol. 1985;11(1):11–3.
13. Maillard H, Grognard C, Toledano C, Jan V, Machet
L, Vaillant L. Granuloma faciale: efficacy of cryosur-
gery in 2 cases. Ann Dermatol Venereol. 2000;
127(1):77–9.
14. Dowlati B, Firooz A, Dowlati Y. Granuloma faciale:
successful treatment of nine cases with a combination
of cryotherapy and intralesional corticosteroid injec-
tion. Int J Dermatol. 1997;36(7):548–51.
 Granuloma Fissuratum
79
Renata Strumia

Abstract
Granuloma fissuratum (GF) is a common, however not widely recognized
lesion characterized by local thickening of the skin in response to low-
grade, chronic pressure/rubbing caused by eyeglasses. Cryosurgery
removes the lesion but it relapses if the cause is not eliminated.

Keywords
Granuloma fissuratum • Cryotherapy • Cryosurgery

Introduction poor fitting dentures. Pathology is similar to lichen

Granuloma fissuratum (GF), also known as
“Acanthoma fissuratum cutis” and “Spectacle
frame acanthoma” is a common yet not widely
recognized lesion characterized by local thicken-
ing of the skin in response to low-grade, chronic
pressure/rubbing caused by eyeglasses [1, 2].
simplex chronicus.
The differential diagnosis includes granulo-
matous dermatoses such as cutaneous sarcoid-
osis, mycobacterioses and autoimmune diseases.
It is important to rule out a basal cell carcinoma.
Therapeutic Alternatives

Description of the Disease
It commonly presents as a red, irritated nodule that
can mimmic a basal cell carcinoma. It can occur
on the top and behind the ear where eyeglass
frames rest, also inside the mouth in response to
GF usually heals within 1–6 months after correc-
tion of the glasses. Emollient and anti-inflammatory
creams are used to control symptoms of irritation/
discomfort. If the lesion does not heal on its own,
complete excision is recommended.

R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara, (Former) Ferrara 44121, Italy
e-mail: restrumi@tin.it
Cryotherapy
Cryosurgery removes the lesion but it will likely
relapse if the offending agent is not eliminated.

© Springer-Verlag London 2016 391

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_79
392 R. Strumia

Methodology (How I Do It) References

One freeze thaw cycle of 5–10 s with NL on a
cotton tipped applicator is used to remove the
lesion.
1. Sohl S, Treudler R, Gebhardt C, Harth W, Helbig D,
Simon JC. Brownish plaques on both sides of the
nose. Hautarzt. 2008;59:1008–10.
2. Dorn M, Plewig G. Acanthoma fissuratum cutis.
Hautarzt. 1981;32:145–8.

Success Rates

High if the offending agent is eliminated.

Conclusions
Cryosurgery is a valid treatment option for GF.
 Hemangiomas
80
William Abramovits and Kimberly Dawn Vincent

Abstract
Cryosurgery for hemangiomas had its golden era between 1970 and 1990.
Gilberto Castro-Ron popularized a compression technique of vascular com-
ponents during freezing, which was amazingly successful. Lasers and sys-
temic and topical drug approaches have reduced the interest in cryosurgery
for hemangiomas. The method is not dead because in many countries expen-
sive lasers and risky systemic drugs have not gained popularity over it.

Keywords
Vascular anomalies • Vascular malformation • Vascular tumors •
Cryosurgery

Introduction angiomas could benefit from a watchful wait, a

topical or systemic agent, or a surgical modality
Some hemangiomas are amenable to be properly that includes cryosurgery. The use of expert,
treated with cryosurgery. Proper selection by type proper technique is paramount for maximization
and other clinical features allows to select which of success and minimization of adverse events.

W. Abramovits, MD, FAAD (*)

Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical School,
Dallas, TX, USA
Department of Internal Medicine, Texas College of
Osteopathic Medicine, University of North Texas
Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College of
Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160, Dallas,
TX 75230, USA
e-mail: DrA@dermcenter.us
K.D. Vincent, MD, FAAD
Belle Meade Dermatology, Nashville, TN, USA

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_80
394
Hemangioma Definition
Although constantly evolving, a working classifi-
cation divides vascular anomalies into tumors
(where hemangiomas belong) and malforma-
tions. Some lesions belonging to either class are
amenable to cryosurgery, like Kaposi’s sarcoma,
pyogenic granulomas, and others discussed in
separate chapters [1].
Hemangiomas are the most common tumors
in infants. They are more common in females
and in premature babies. Hemangiomas may
have proliferation and involution phases; the
proliferation phase starts at birth and usually
lasts between 6 and 9–18 months. During the
involution phase, lesion size may be reduced
by 10 %/year until the age of 10 years, at
which time half of the affected children may
experience resolution without residual evi-
dence such as telangiectasia, atrophy or scar-
ring. Different cytokines are implicated in
each of the phases [1].
Clinically the typical hemangioma of
infancy starts as a macule, which may develop
telangiectasia and elevation, then may become
a patch or plaque of 5 cm or less; Lesions most
often occur on the face and neck, then the
torso and extremities. Some deepen into the
dermis and beyond and may have a superficial
and deep component. The bulk of the heman-
gioma may be a function of either or both
components. Thick lesions, a few decades ago
named strawberry hemangioma for their looks,
may cover large surfaces of the face and other
body parts, causing not just disfigurement but
dysfunction [2].
Some hemangiomas may be present at birth
and some may be part of a syndrome in consider-
ation to associated structural involvement such as
bone and internal organ invasion [3].
Complications such as hemorrhage from acci-
dental trauma or necrosis, platelet consumption,
pain, space occupation, obstruction and misalign-
ment of anatomic structures, and compromise of
internal organs may occur. Psychological trauma
affecting both the patient and the parents should
not be overlooked.
W. Abramovits and K.D. Vincent
Hemangioma Diagnosis
For most, the diagnosis is made clinically and
does not require more than careful observation.
Treatment may be decided on the basis of the
impairment the hemangioma may cause, for
example feeding difficulties if on the lips, or
vision obstruction and eye displacement.
For lesions suspected to be deep, especially in
the mid face, scalp or spine regions, imaging
methods including ultrasound and scans may be
required for staging and differential diagnosis.
Therapeutic Alternatives
Besides a watchful wait that should not last more
than a few weeks, involution induction therapies
include: proliferation cytokine antibodies, beta-
blockers with or without sirolimus, imiquimod,
interferon, vascular lasers and systemic, intrale-
sional and topical steroids. Cryosurgery certainly
remains a viable option as well [4–11].
Cryosurgery Methodology
The technique presented is the one used by
Gilberto Castro-Ron, MD and his many mentees,
which include one of the authors (WA). The deci-
sion to use local or systemic anesthesia depends
mostly on the expected duration and predicted dis-
comfort by the patient. Large or periorbital lesions
which would require longer treatment time and
patient inactivity are best done under general anes-
thesia, preferably by a pediatric anesthesiologist.
Small lesions that can be treated in less than a few
minutes may be done with topical, local, or no
anesthesia – with the mother feeding the baby dur-
ing or right after the procedure. I saw the latter
work surprisingly well in innumerable cases.
After explaining to the caretaker that the child
will be startled and cry due to treatment discom-
fort and frustration from being immobilized, the
cryosurgery is performed. A closed probe, which
may be already frozen or will become so during
application, is held to compress the angioma (as
80 Hemangiomas
one would a sponge), squeezing out the blood and
leaving only stroma to destroy. The freeze is done
until the entire lesion is engulfed in ice then com-
pletely thawed before attempting to detach the
probe. A second freeze-thaw cycle is not required.
The whole procedure with the right probe, one
matching the diameter of the hemangioma, ought
not last over 3 min from start to end.
Complications of Cryosurgery
for Hemangioma
The morbidity of cryosurgery is what deters most
dermatologists and plastic surgeons from perform-
ing it more often. There is no doubt that the result-
ing edema, necrosis, scab formation, (which if
picked off prematurely may cause bleeding), may
scare many not familiar with the post-operative
progression of the cryosurgical injury. Significant
bleeding requiring more than pressure may rarely
happen. Properly instructed parents will deal with
complications without much storminess.
Fear of morbidity, in a litigious environment
like the one that prevails in the United States,
deters many accomplished cryosurgeons from
providing this service.
Success Rates
There is no standardized way to statistically
interpret the results of cryosurgery for this condi-
tion because of the variability of presentations,
locations, phase of the lesion, etc. Suffice it to say
that in expert hands success is high. The end-
result is cosmetically pleasing for most.
Conclusion
In spite of recently developing therapeutic
alternatives, cryosurgery still has a role in the
management of hemangioma.
395
References
1. Grevelink SV, Mulliken JB. Vascular anomalies and
tumors of skin and subcutaneous tissues. In: Friedberg
IM, Eisen AZ, Wolf K, Austen KF, Goldsmith LA,
Katz SI, editors. Fitzpatrick’s dermatology in general
medicine. 6th ed. New York: McGraw-Hill; 2003.
p. 1002–19.
2. Luu M, Frieden IJ. Haemangioma: clinical course,
complications and management. Br J Dermatol.
2013;169(1):20–30.
3. Su L, Wang D, Fan X. Comprehensive therapy for
hemangioma presenting with Kasabach-Merritt syn-
drome in the maxillofacial region. J Oral Maxillofac
Surg. 2015;73(1):92–8.
4. Lee D, Boscolo E, Durham JT, Mulliken JB, Herman
IM, Bischoff J. Propranolol targets contractility of
infantile haemangioma-derived pericites. Br
J Dermatol. 2014;171(5):1129–37.
5. Lou Y, Peng WJ, Cao Y, Cao DS, Xie J, Li HH. The
effectiveness of propranolol in treating infantile hae-
mangiomas: a meta-analysis including 35 studies. Br
J Clin Pharmacol. 2014;78(1):44–57.
6. Xu SQ, Jia RB, Zhang W, Zhu H, Ge SF, Fan
HQ. Beta-blockers versus corticosteroids in the
treatment of infantile hemangioma: an evidence-
based systematic review. World J Pediatr. 2013;9(3):
221–9.
7. Price CJ, Lattouf C, Baum B, McLeod M, Schachner
LA, Duarte AM, Connelly EA. Propranolol vs corti-
costeroids for infantile hemangiomas: a multicenter
retrospective analysis. Arch Dermatol. 2011;147(12):
1371–6.
8. Chambers CB, Katowitz WR, Katowitz JA,
Binenbaum G. A controlled study of topical 0.25%
timolol maleate gel for the treatment of cutaneous
infantile capillary hemangiomas. Ophthal Plast
Reconstr Surg. 2012;28(2):103–6.
9. Kaune KM, Lauerer P, Kietz S, Eich C, Thoms KM,
Schön MP, Zutt M. Combination therapy of infantile
hemangiomas with pulse dye laser and Nd: YAG laser
is effective and safe. J Dtsch Dermatol Ges.
2014;12(6):473–8.
10. Musumeci ML, Schlecht K, Perrotta R, Schwartz RA,
Micali G. Management of cutaneous hemangiomas in
pediatric patients. Cutis. 2008;81(4):315–22.
11. Tronina SA, Bobrova NF, Khrinenko VP. Combined
surgical method of orbital and periorbital hemangi-
oma treatment in infants. Orbit. 2008;27(4):
249–57.
 Herpes Simplex
81
Renata Strumia

Abstract
Herpes simplex virus (HSV) infection is a painful, self-limited, often
mucocutaneous, often recurrent dermatitis, characterized by small grouped
vesicles on an erythematous base. Acyclovir famciclovir and valacyclovir
are all effective. For recurrent flares of more than six episodes per year,
suppressive treatment is warranted. Cryotherapy offers a safe, positive
approach that does not seem to act purely as a placebo. Moreover, the posi-
tive approach to treatment (we can do something), in contrast to the totally
negative approach, gives the patient an immeasurable psychologic lift.

Keywords
Herpes simplex • Cryotherapy

Introduction Description of the Disease

Herpes simplex virus (HSV) infection is a painful,
self-limited, often recurrent dermatitis, character-
ized by small grouped vesicles on an erythema-
tous base. It is often mucocutaneous. HSV type 1
is usually associated with orofacial disease, and
HSV type 2 is usually associated with genital
infection. Eighty-five percent of the population
has antibody evidence of HSV type 1 infection.
HSV type 2 infection is responsible for 20–50 %
of genital ulcerations in sexually active persons.
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara, (Former) Ferrara 44121, Italy
e-mail: restrumi@tin.it
Primary infection occurs most often in children,
exhibiting vesicles and erosions on reddened
buccal mucosa, the palate, tongue, or lips (acute
herpetic gingivostomatitis). It is occasionally
associated with fever, malaise, myalgias, and cer-
vical adenopathy. Herpes labialis appears as
grouped vesicles on red denuded skin, usually the
vermilion border of the lip; infection represents
reactivated HSV. Primary genital infection is an
erosive dermatitis (intact vesicles are rare) on the
external genitalia that occurs about 7–10 days
after exposure. Recurrent genital disease is com-
mon. Prodromal symptoms of pain, burning, or
itching can precede herpes labialis and genital
herpes infections.

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398
Therapeutic Alternatives
Acyclovir famciclovir and valacyclovir are all
effective. For often recurring infection (more
than six episodes per year), suppressive treatment
is warranted.
Cryotherapy
Home treatments for HSV include the applica-
tion of an ice cube for 1 h during the first 24 h
after lesion appears. This may make it heal more
quickly [1]. In the 1980s, anecdotical articles
were published about the effects of cryotherapy
in relapsing HSV, type 1 and 2 [2–5].
In his report, Adam [5] explained the good
result of cryotherapy in HSV lesions: “theoreti-
cally most of the herpesviruses are in the epider-
mal cells, so they are in the best location for
topical therapy”. Despite, HS is still a challeng-
ing problem, this kind of treatment was seem-
ingly abandoned and, at the best of my knowledge,
no articles appeared in the literature during the
ensuing decades.
Methodology (How I Do It)
For the last decades I have treated recurrent
herpes simplex types 1 and 2 with cryotherapy.
I see the patient within 24 h of the first evi-
dence of recurrence, at which point the her-
petic blisters are still intact. I touch the vesicles
for 5–10 s with a cotton-tipped applicator that
has been dipped in LN. This causes only mild
R. Strumia
discomfort. Over the next 2 days the blisters
dry and scab, then they usually clear within
4 days [4].
Success Rates
The duration of a recurrence is substantially
decreased, on average from 8–12 days to 3–5 days
after CT. Moreover, the frequency of recurrence
is decreased. Even if the patient has recurrences,
it is evident from the first treatment that their
length has been decreased.
Conclusions
Even if no patient had a total remission in my
experience but only a decreased frequency in
recurrences, cryotherapy offers a safe, posi-
tive approach to this disease and does not
seem to act purely as a placebo. Moreover, the
positive approach to treatment (we can do
something), in contrast to the totally negative
approach gives the patient an immeasurable
psychologic lift.
References
1. Danziger S. Ice-packs for cold-sores. Lancet.
1978;1:103.
2. Selden ST. Cryotherapy for herpes simplex infections.
Arch Dermatol. 1981;117:757–8.
3. Krashen AS. Cryotherapy of herpes labialis. CDS
Rev. 1988;81:32–5.
4. Strumìa R, Virgili A. Cryotherapy in recurrent herpes
simplex. Arch Dermatol. 1983;119:188.
5. Adam JE. Recurrent herpes simplex. Can Med Assoc
J. 1982;126:894–9.
 Post-herpetic Neuralgia
82
Jacqueline Guidry and Ted Rosen

Abstract
Herpes zoster is a very common viral infection characteristically causing
a painful eruption, especially in elderly or immunocompromised hosts.
Discomfort may precede and follow the cutaneous manifestations of the
disease. When pain continues more than 4 weeks after resolution of the
rash, it is defined as post herpetic neuralgia (PHN). The pain of PHN can
be exceedingly difficult to manage and many treatment modalities have
been studied with variable results, including: analgesics, local anesthesia,
antiepileptics, and antidepressants. Cryotherapy has been used in patients
with PHN with improvement of the pain through direct application of the
cryogen to the nerve, direct application to the skin, or indirect application
to the skin.

Keywords
Cryosurgery • Cryotherapy • Post herpetic neuralgia • Herpes zoster •
Cryocautery

Abbreviations NFT Non-freezing technique

PHN Post-herpetic neuralgia
HS Herpes simplex TCA Tri-cyclic antidepressant
HZ Herpes zoster

J. Guidry, MD
Herpes zoster (HZ) is a self-limited illness result-
Department of Internal Medicine, ing in a vesicular eruption in a dermatomal distri-
Baylor College of Medicine, Houston, TX, USA bution due to the reactivation of heretofore
T. Rosen, MD (*) dormant varicella zoster virus [1]. It is character-
Department of Dermatology, istically described as an erythematous, maculo-
Baylor College of Medicine, papular rash that rapidly evolves to grouped
1977 Butler Ave. Suite E6.200,
Houston, TX 77030, USA
vesicles [2]. The rash can be accompanied
e-mail: vampireted@aol.com by systemic symptoms (i.e. fatigue, malaise,

© Springer-Verlag London 2016 399

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_82
400
headache, fever) and almost all patients experience
pain [2]. The pain associated with HZ is neuro-
pathic and has been described as burning, tingling,
itching, boring, prickly, or knife-like [2]. The pain
often precedes the rash by hours to days and it can
continue for weeks to months after the rash has
resolved. By convention, pain persisting for more
than 4 weeks following rash resolution is classified
as post-herpetic neuralgia (PHN) [1].
HZ is a relatively common condition. It occurs
in 10–33 % of the population, with neither gen-
der nor ethnic predilection [2]. Elderly or immu-
nocompromised individuals are most likely to
develop HZ, especially HIV, post-transplant, or
chemotherapy patients [1]. The increased inci-
dence of HZ seen in elderly patients may be
related to the natural decay in cell-mediated
immunity that accompanies aging.
Description of Disease Entity
PHN occurs in 15 % of patients with HZ infec-
tion and its incidence is related to age [1]. Only
16 % of patients under 60 years of age develop
PHN after HZ infection compared to 47 % of
patients over 60 years old [1]. The mean age of
patients affected with PHN is 68 years [3].
The pain of PHN is limited to the dermatome
that was affected by the initial HZ infection [1].
PHN is reported most commonly in the thoracic
and then cephalic regions of the body, but it can
be located anywhere [1]. Although the pain is
limited in location, it can be incapacitating and
severe enough to prevent sleep. Pain can be
triggered by light touch, but sensation to pin-
prick is decreased [2, 3]. The affected skin
itself is often scarred and can be hypo- or
hyperpigmented [2].
The mechanism of PHN is poorly understood.
During active HZ infection, viral activity leads to
degeneration of cutaneous nerve fibrils [2].
Patients with PHN have been documented to
have a decreased number of myelinated fibers in
the affected nerve, which may be a consequence
of the fibril degeneration that occurs during ini-
tial HZ infection [3]. Once PHN develops, it is
usually chronic and lasts for months to years.
J. Guidry and T. Rosen
However, it does generally decrease in severity
over time. Within 6 months, 50 % of patients will
have resolution of their pain and 98 % will have
resolution by 5 years [2].
Diagnosis
HZ is a clinical diagnosis that is based on the
characteristic morphology and distribution of
lesions or a positive Tzanck smear [2]. However,
HZ cannot be differentiated from herpes simplex
(HS) based on visual examination or Tzank
smear. To ensure the diagnosis of HZ, viral cul-
ture, monoclonal antibody, or immunofluores-
cence testing must be done [2].
There are no specific diagnostic criteria for
PHN. The diagnosis is supported by dermatomal
pain in the area of a prior HZ infection that lasts
more than 4 weeks after resolution of the rash.
Therapeutic Alternatives
Though multiple treatment modalities have been
tried and studied for PHN, there is no single
method that is universally recommended or
always successful [2].
Analgesics
Analgesics, from NSAIDs to opioids, have been
used to treat PHN with variable success and are
not considered first line treatment [1].
Tricyclic Antidepressants
Tricyclic antidepressants (TCAs) are recom-
mended as first-line therapy for neuropathic
pain in general [1]. In PHN, TCAs have been
shown to be as effective as analgesics in 50 % of
patients [1]. The high rate of side effects associ-
ated with these drugs must be taken into consid-
eration. TCAs can be especially toxic in elderly
patients, who comprise the majority of PHN
patients [1].
82 Post-herpetic Neuralgia
Antiepileptic Medications
Carbamazepime has been used with controversial
success. Some studies report up to 75 % of
patients with PHN have improvement in their
pain with carbamazepime [1]. Other antiepilep-
tics that have been used to treat PHN include
lamictal, valproic acid, pregabalin, and gabapen-
tin [1]. Some authors suggest that gabapentin
should be used as first-line therapy in patients
with PHN due to a reduced side effect profile
compared to other antiepileptics [1].
Anesthetics
Local anesthetic agents (i.e. lidocaine, capsaicin
patches) have been used to treat PHN and may
work temporarily, but are complicated by a high
rate of local side effects [1]. Nerve blocks can pro-
vide relief, but only persist from several hours to a
few days, so frequent treatments are necessary [3].
Other Treatments
Intrathecal steroids, transcutaneous electrical
stimulation, and light therapy with UVB have
also been used with variable results [1].
Cryosurgery
Cryosurgery for the treatment of PHN is a rela-
tively new concept, though it has been used to
manage other neuralgias for much longer [4].
Several methods of cryotherapy for PHN have
been described in the literature, including direct
application of a cryostick onto the affected nerve
(requires surgical dissection), or cryotherapy of
the skin itself via direct or aerosolized applica-
tion of liquid nitrogen [1, 3, 4].
Indications for cryotherapy of PHN were sug-
gested by Suzuki et al.:
1. Painful region localized to relatively limited
areas of skin with hyperesthetic trigger spots
detected by tactile examination
401
2. Original pain in these areas disappears or is
profoundly relieved by local anesthesia
3. Original pain recurs a few days after lidocaine
and recurs predictably
Direct Cryotherapy on Nerve
Neuropathic pain following thoracotomies has
been treated with some success by applying a
cryoprobe directly onto the isolated nerve [5].
This technique requires dissection and exposure
of the nerve itself, which can be achieved using
local anesthesia [5]. Once exposed, the nerve is
isolated and then frozen. Success has been
obtained using two freeze cycles lasting 1 min
each, so that the cryoprobe delivers a temperature
between −60 and −80 °C to the affected nerve [5].
Direct Cryotherapy on Skin
Cryotherapy using a dry ice stick placed directly
on the skin has also been used to treat
PHN. Treatment of the skin in the area of prior
HZ infection is based on the theory that PHN is
contributed to by an increased sensitivity of the
skin [3]. The cryostick should be used on the
most sensitive sites within the HZ scar and
applied using gentle pressure for 60 s in up to two
to three areas [3]. Multiple sessions may be
required; an average of eight sessions was
reported [3]. The treated area should be covered
with sterilized gauze following the procedure [3].
A blister will form at the site of treatment,
which resolves within a few days; hypopigmenta-
tion of the treatment area may persist [3]. In
addition to blistering and the potential for dyschro-
mia and scarring, other disadvantages of direct
cryotherapy include pain from the treatment itself
and the necessity for multiple office visits [3].
Non-freezing Technique
In 2011, a new “non-freezing technique” (NFT)
was introduced. Liquid nitrogen should be
sprayed in a cloud, using a circular motion, from
402
a distance of 15 cm, across the affected cutaneous
areas [1]. This technique is intended to cool but
not freeze the skin. This modality is theorized to
serve as a cytokine immunomodulator. Optimum
administration is via a perpendicular spray utiliz-
ing a liquid nitrogen spray gun outfitted with spe-
cific attachments to create a broader jet [1]. The
spray should be directed over the entire affected
area with several, repetitive circular motions for
about 30 s [1].
Treatments with the NFT are scheduled at
weekly intervals until the pain is considered
acceptable by the patient. An average of 4.8 ses-
sions of NFT cryotherapy was required [1].
Success Expected
Direct Cryotherapy on Nerve
Results show that dissection followed by direct
cryotherapy onto the affected nerve is more suc-
cessful in non-PHN pain [5]. This technique may
cause temporary pain relief in PHN lasting for an
average of 36 days [5]. In a group of PHN patients
treated with this technique, 100 % had recurrence
of their original pain within 1 year [5].
Direct Cryotherapy on Skin
In most patients the original pain decreased or
disappeared. Ten of 14 patients had either good
of excellent relief of their pain [3]. Even if
patients that did not have complete relief of
their pain, improvement was sufficient enough
J. Guidry and T. Rosen
that they did not pursue any further treatment
[3]. However, several patients had continued
pain in new locations around the previously
treated site [3].
Non-freezing Technique
Many patients treated with the “non freezing”
technique experienced immediate improvement,
which was usually reported by patients as
decreased nocturnal awakenings due to pain,
decreased analgesic use, or longer duration of
analgesia efficacy [1]. In 75 % of cases, patients
reported excellent pain reduction with the NFT
and an additional 19 % of patients reported good
pain reduction [1]. Maximum relief was achieved
between the third and fourth treatment [1]. After
the fourth treatment, patients reported that each
subsequent treatment provided less analgesia [1].
References
1. Calandria L. Cryoanalgesia for post-herpetic neuralgia:
a new treatment. Int J Dermatol. 2011;50(6):746–50.
2. Carmichael J. Treatment of herpes zoster and posther-
petic neuralgia. Am Fam Physician. 1991;44(1):
203–10.
3. Suzuki H, Ogawa S, Nakagawa H, Kanayama T, Taj
K, Saitoh H, Ohshima Y. Cryocautery of sensitized
skin areas for the relief of pain due to post-herpetic
neuralgia. Pain. 1980;9(3):355–62.
4. Nehme AE, Warfield CA. Cryoanalgesia: freezing of
peripheral nerves. Hosp Pract (Off Ed). 1987;22(1a):
71–2, 77.
5. Barnard D, Lloyd J, Evans J. Cryoanalgesia in the
management of chronic facial pain. J Maxillofac Surg.
1981;9(2):101–2.
 Hyperkeratosis of the Nipple
and Areola
83
Christina M. Ring and Robert A. Schwartz

Abstract
Hyperkeratosis of the nipple and/or areola (HNA) is a rare and benign
condition characterized by excessive keratinatation of the nipple and/or
areola. The lesions are hyperpigmented, verrucous or filiform, with kera-
totic thickening and papillomatosis. HNA can be idiopathic or associated
with conditions, such as acanthosis nigricans, epidermal nevus, pregnancy
and cutaneous T-cell lymphoma. Cryotherapy has been shown to success-
fully treat HNA with a favorable cosmetic result.

Keywords
Hyperkeratosis • Acanthosis nigricans • Hyperkeratosis of nipple •
Hyperkeratosis of areola • Nipple • Areola • Cosmetic • Cryosurgery

Introduction cases have been reported, this condition is proba-

Hyperkeratosis of the nipple and/or areola (HNA)
is a benign condition of unknown etiology, first
described in 1923 [1–3]. While fewer than 100
C.M. Ring, BS
Department of Dermatology and Pathology, Rutgers
New Jersey Medical School, Newark, NJ, USA
e-mail: ring.christina@gmail.com
R.A. Schwartz, MD, MPH, DSc (Hon),
FRCP (Edin) (*)
Dermatology and Pathology, Rutgers New Jersey
Medical School, Rutgers University School
of Public Affairs and Administration,
185 South Orange Ave., Newark, NJ 07103, USA
e-mail: roschwar@cal.berkeley.edu
bly underreported due its benign nature [4]. HNA
is evident as hyperkeratotic, verrucous, hyperpig-
mented papules and plaques on the nipple, areola,
or both [2, 4]. HNA may be subdivided into three
categories [5]: type I is an extension of an epider-
mal nevus, tends to be unilateral and affect both
sexes; type II is associated with ichthyosis and is
typically bilateral, affecting both sexes; type III is
nevoid, or idiopathic HNA, and primarily affects
women [1]. An alternative classification groups
HNA into primary or idiopathic HNA, and sec-
ondary HNA, which is associated with various
conditions [6]: epidermal nevus, organoid nevus
[7], leiomyomas [8], verruca vulgaris [9], eryth-
rodermic ichthyosis, acanthosis nigricans [10],

© Springer-Verlag London 2016 403

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_83
404
Darier disease [11], chronic eczema, cutaneous
T-cell lymphoma [12, 13], chronic mucocutane-
ous candidiasis [14], pregnancy, males receiving
hormonal therapy for prostate cancer [1, 15] and
estrogen therapy for androgen insensitivity syn-
drome [16].
There are no incidence rates for HNA. The
disease is more common in women, who com-
prise 80 % of reported cases [2, 4]. Women gen-
erally present during the second or third decade
of life, while men with HNA have a more vari-
able age of onset [4]. Race is not a known risk
factor for HNA; it does not tend to be familial.
Mortality is not associated with primary HNA
and the morbidity is minimal, resulting primarily
from undesirable cosmetic appearance.
Pathophysiology
The pathophysiology of HNA remains unknown.
In 1978, Schwartz postulated that it may involve
a hormonal imbalance or underlying endocrinop-
athy in describing a man who developed HNA
after treatment with diethylstilbesterol (DES) for
prostate adenocarcinoma [1]. Later, a similar
case involving DES was reported, leading to the
theory that HNA may result from changing estro-
gen levels [15]. Patients who presented with
HNA in puberty or during pregnancy [4, 17, 18]
further support the role of estrogen in the devel-
opment of HNA [1]. This theory does explain the
cases of HNA in men [19] or women not under-
going hormonal changes.
Clinical Features
HNA presents as hyperkeratotic, hyperpigmented
plaques localized diffusely within the nipple and/
or areola [2]. They can be verrucous [4, 17–22]
and may show yellowish discoloration [23, 24] or
desquamation [6]. Erythema, induration, dis-
charge and pruritus may occur. In a review of 45
patients with nevoid hyperkeratosis by Kubota
et al. [21], 17 % involved the nipple, 25 %
involved the areola and 58 % of cases involved
C.M. Ring and R.A. Schwartz
both the nipple and areola. Lesions are often
present bilaterally, although unilateral hyperkera-
tosis has been described [6, 9, 17, 19]. HNA has
not been shown to interfere with normal breast
function, with the exception of one patient who
had difficulty breastfeeding [6, 21].
Histology
The epidermis shows orthokeratotic hyperkeratosis
and occasional keratotic plugging. The rete ridges
are markedly elongated, with filiform downward
acanthosis [2] and variable papillomatosis [4].
There is hyperpigmentation of the basal layer of the
epidermis without melanocytic proliferation.
Prominent surface undulation, as observed by
Schwartz [1] and Baykal et al. [2], has been sug-
gested as the primary distinction from epidermal
nevus or acanthosis nigricans. Additional findings
include mild dermal perivascular lymphocytic
infiltrate and epidermal spongiosis with microab-
scesses with normal lymphocytes [25, 26].
Differential Diagnosis
Histological and clinical features help distinguish
other disorders from HNA, which remains a diag-
nosis of exclusion [27]. The differential diagnosis
includes Paget’s disease, superficial basal cell car-
cinoma, dermatophytosis, Bowen’s disease [23],
seborrheic keratosis, Fox-Fordyce disease, hyper-
keratosis secondary to prolonged friction, and ero-
sive adenomatosis of the nipple [2]. Additional
workup such as mammography or CT may be indi-
cated if an underlying malignancy is suspected.
Therapeutic Options
As HNA is a benign and largely asymptomatic
condition, the goals of treatment are to improve
the cosmetic appearance of the nipple and areola.
A variety of treatment options have been utilized
with mostly anecdotal results. Conservative
modalities consist of topical keratolytic agents
83 Hyperkeratosis of the Nipple and Areola
such as lactic acid 12 % cream [27], salicylic
acid gel 6 % [28], topical retinoic acid [20, 29],
topical calcipotriol [30, 31], and low dose acitre-
tin [32]. Results have been variable, with reports
of recurrence following discontinuation. Non-
conservative treatment options include laser
[33], cryotherapy [17, 19, 21, 34] and surgery.
Surgical options include shave excision [35, 36],
surgical excision with skin graft reconstruction
[22, 37], radiofrequency surgery [38, 39] and
curettage [16].
Cryosurgery- Utility, Methods,
Success Rates
Cryosurgery is simple to use and effective for
hyperkeratotic cutaneous diseases such as verru-
cae and epidermal nevus [40]. There are no con-
trolled studies of cryosurgery as a treatment for
HNA; however, several case reports documented
successful resolution. In a 30-year-old woman
with unilateral HNA who failed to respond to
topical therapy, six 20-s treatments of cryo-
therapy at 3-week intervals led to excellent cos-
metic results, with no recurrence after 10 months
[17]. Similar results were noted in a 39-year-
old woman with unilateral HNA; one session
of 15-s double freeze-thaw cycles resulted in
nearly complete disappearance of lesions after
4 weeks and no recurrence at 6 months [34]. A
33-year-old Japanese man with unilateral HNA
achieved complete clearance after six 15-s treat-
ments of cryotherapy given every 2 weeks, with
no relapse after 3 months [21]. Two men had sat-
isfactory clearance after 3 and 5 treatments with
cryosurgery, respectively [19].
Conclusion
Cryosurgery has yielded favorable cosmetic
results in the treatment of HNA. It is supe-
rior to topical keratolytic agents, which
show variable success, require consistent
application and often fail to provide defini-
tive resolution. Cryosurgery is also prefera-
ble to other surgical options, which incur
greater morbidity.
405
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du mamelon. Paris Med. 1938;28:63–6.
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E, Millan F, Aliaga A. Retinoic acid treatment of nip-
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BR. Unilateral nevoid hyperkeratosis of the nipple
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the nipple and areola as a sign of malignant acanthosis
nigricans. Clin Exp Dermatol. 2005;30(6):721–2.
11. Fitzgerald DA, Lewis-Jones MS. Darier’s disease pre-
senting as isolated hyperkeratosis of the breasts. Br
J Dermatol. 1997;136(2):290.
12. Ahn SK, Chung J, Soo Lee W, Kim SC, Lee
SH. Hyperkeratosis of the nipple and areola simulta-
neously developing with cutaneous T-cell lymphoma.
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A. Hyperkeratosis of the nipple and areola in a patient
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14. Kavak A, Parlak AH, Aydogan I, Alper M.
Hyperkeratosis of the nipple and areola in a patient
with chronic mucocutaneous candidiasis. J Dermatol.
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Dermatol. 1986;122(12):1360–1.
18. Mehregan AH, Rahbari H. Hyperkeratosis of nipple
and areola. Arch Dermatol. 1977;113(12):1691–2.
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Nevoid hyperkeratosis of the areola in men: response
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the editor: unilateral nevoid hyperkeratosis of the
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Dermatol. 1994;31(6):925–44; quiz 944–926.
 Idiopathic Guttate Hypomelanosis
84
Prasad Kumarasinghe

Abstract
Idiopathic guttate hypomelanosis (IGH) is characterized by asymptomatic,
small, sharply demarcated, hypopigmented or depigmented macules. They
are more common on the limbs of elderly persons with sundamaged skin.
However, they also occur as discrete lesions, even in sunprotected areas of
skin, in young adults. Some patients are quite concerned about the cosmetic
appearance of these depigmentations. Many treatments have been described
with variable success. IGH lesions can be treated with cryotherapy effec-
tively. This is most suitable where there are only a small number of lesions.
It is not practical where there are a very large number of lesions. A short
burst of cryotherapy on the IGH lesions with a cryotherapy spray gun for
about 5 seconds is sufficient. The repigmentation can take 6–8 weeks to
develop. Ploysangam et al. [12] reported repigmentation in 90 % of treated
lesions. Some lesions may develop hyperpigmentation after treatment but
this improves with time. LN cryotherapy is fast, is very easy to perform as
an office procedure and it is relatively less expensive.

Keywords
Cryotherapy • Idiopathic guttate hypomelanosis

Disease Description measuring from 0.2 to 6 mm in diameter [1].

Idiopathic guttate hypomelanosis (IGH) usually
manifests as small, discrete, sharply demarcated,
acquired hypopigmented or depigmented lesions
P. Kumarasinghe, MBBS, MD, FAMS, FACD
Department of Dermatology, Royal Perth Hospital,
Wellington St., Perth, Western Australia 6000, Australia
e-mail: prasadkumarasinghe@yahoo.com
Rarely some lesions reach 20 mm [2]. The inci-
dence of IGH increases with age and it is com-
mon in the elderly. Once IGH lesions appear
spontaneous repigmentation does not seem to
occur. Several clinical types of IGH have been
described [1–10]. It affects all races. The com-
monest type is multiple hypopigmented or depig-
mented small discrete macules in the sun
damaged skin of older individuals (Fig. 84.1).

© Springer-Verlag London 2016 407

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_84
408
Fig. 84.1 An elderly woman with multiple hypopig-
mented IGH lesions on lower limbs on sun damaged skin
Fig. 84.2 Isolated porcelain white IGH lesion on the
volar aspect of forearm in a person with Type IV skin
Some lesions may be porcelain white, whereas
some are hypopigmented. A second type of IGH
occurs as discrete lesions irrespective of sun
damage; in exposed or non-sun exposed areas on
the trunk or limbs (Fig. 84.2). This type is par-
ticularly noticeable in darker skinned individuals.
Thirdly IGH can appear as small punctate
(0.2–1 mm) lesions [8, 9]; sometimes following
prolonged ultraviolet light therapy. Occasionally
punctate IGH lesions are seen even without a his-
tory of UV light therapy. There is yet another
type of IGH where there is a thin, macroscopi-
cally visible, pale keratinous layer over the
hypopigmented lesions [1, 10]. When the kerati-
nous layer is detached the typical appearance of
IGH becomes visible [1]. Some of the IGH
lesions appear sclerotic, particularly those that
are porcelain white. IGH lesions rarely occur on
the face [1] (Table 84.1). Chronic ultraviolet
P. Kumarasinghe
Table 84.1 Types of IGH
Multiple hypopigmented or porcelain white lesions on
sun-damaged skin
Solitary or multiple porcelain white lesions irrespective
of areas of sun damage
Relatively smaller punctate leukoderma like lesions
with or without a history of ultraviolet light treatment
Hypopigmented macules with a thin keratinous layer
on top
exposure due to sun exposure and aging are con-
tributing factors at least in the common type of
IGH on exposed areas.
Differential Diagnosis
Clinical differential diagnoses of IGH include:
vitiligo, post-inflammatory hypopigmentation,
pityriasis lichenoides chronica with secondary
hypopigmentation, rain-drop depigmentation of
chronic arsenic poisoning, dyschromic amyloi-
dosis, extra-genital lichen sclerosus et atrophi-
cus, pityriasis versicolor, depigmented macules
in patients with tuberous sclerosus, dyschromato-
sis universalis, dyschromatosis symmetrica
hereditaria, and hypopigmented macules in
patients with Darier’s disease. In most cases,
clinical diagnosis of IGH is easy due to the char-
acteristic appearance of the lesions. Wood’s lamp
examination may help identify the borders of a
lesion. If in doubt a skin scrapings test for
Malassezia furfur or a skin biopsy may be done.
Histopathology of IGH shows a reduction of
melanisation of the keratinocytes in the area [4].
There is a significant reduction,or (rarely) a total
absence of melanocytes in the lesions [4, 11, 12].
Within the lesions the melanin granules are
irregularly and focally distributed [7]. Other his-
topathological features include basket weave
hyperkeratosis, epithelial atrophy and flattening
of the retepegs [4]. Occasionally there can be
sclerotic changes in the dermal collagen.
Electron microscopy of IGH lesions show round
and less dendritic melanocytes with fewer mela-
nosomes [11, 12]. Cell cultures of melanocytes
from IGH lesions (on cell culture plates) are able
to proliferate and produce melanin as normally
84 Idiopathic Guttate Hypomelanosis
as non-lesional melanocytes. Some of the mela-
nocytes show morphological abnormalities.
Some senescence markers (e.g. p 21) are more
expressed in the lesional melanocytes compared
to non lesional melanocytes (Parsad D,
Kumarasinghe SP, Kumar R, on going study). It
is not yet clear whether the upregulation of
senescence markers of IGH melanocytes is
driven by other cells in the epidermal melanin
unit milieu.
According to some studies, it is likely that in
IGH there is an inhibitory influence on melanin
transfer and/or production due to overlying kera-
tinocytes [4, 8, 12]. Malfunctioning melanocytes
may degenerate and be removed by the body.
This theory is supported by the observation that
when small punch grafts are transplanted in vit-
iligo patients the pigment spreads outwards,
migrating even up to 5 mm around the graft, but
IGH lesions with sharply demarcated borders
resist pigment spread from surrounding normal
melanocytes. Falabella et al. demonstrated that
when a small piece of normal skin was grafted to
an area of IGH (after removing a similar sized
specimen from an IGH lesion) the whole punch
graft eventually got depigmented rather than the
IGH lesion getting pigmented from the grafted
normal skin [4]. Support for this theory also
comes from the fact that removal of the epidermis
of IGH lesions by cryotherapy, dermabrasion or
laser ablation, causes repigmentation (Fig. 84.3).
It is not clear whether dermis of the IGH lesions
Fig. 84.3 A patient who had cryotherapy 6 weeks prior
showing slight hyperigmentation of the lesion on the
right, whereas the one on the left repigmented to the
desired level
409
is exerting any influence in the melanisation of
the keratinocytes or destruction the melanocytes.
The exact cause of loss of pigment in the IGH
lesions is not yet known.
Cryotherapy
Ploysangam et al. initially described beneficial
effects of cryotherapy in IGH [12]. They did
cryotherapy for 15 s, using cryoprobes; all the
patients developed vesicles. However, we showed
in a case series that even 5-s short bursts of cryo-
therapy are adequate to bring the pigment back to
the lesions [9]. The explanation for this would be
that cryotherapy destroys the top layer of skin
(epidermis). Cryotherapy also causes tissue
inflammation in the lesional and perilesional
skin, this too may have some stimulating effect
on repigmentation. The short bursts of cryother-
apy is better, particularly in the dark skinned
patients due to possible leukoderma of the sur-
rounding skin due to excessive cryotherapy.
Furthermore it is less painful to the patients and
causes only minimal or no vesicles. Cryotherapy
is an effective low cost simple method of treat-
ment. If required cryotherapy can be repeated
after 6 weeks. However, when there are a large
number of IGH lesions none of the treatment
modalities are practically useful.
The mechanism of repigmentation following
cryotherapy is not clear. Ploysangam et al.
showed, in biopsy specimens from repigmented
lesions 6 weeks after LN treatment, more mela-
nin and more active dendritic melanocytes com-
pared to pretreatment [9, 12]. However, the total
number of melanocytes in the repigmented
lesions remained lower than in normal skin [12].
It appears that the removal of the epidermis over
the IGH lesion somehow facilitates the surround-
ing and lesional melanocytes to repigment the
site. It is not clear whether tissue inflammatory
cytokines released due to cryotherapy work syn-
ergistically in repigmentation. Considering that
some melanocytes can get destroyed during cryo-
therapy, it appears that the effect of removal of
the IGH epidermis is dominant in the facilitation
of repigmentation.
410
Success Rates
Cryotherapy does not work in all cases of
IGH. Also in some cases the pigmentation returns
but slowly the same patches lose the pigment
again. The hypopigmented lesions respond better
than the porcelain white sclerotic lesions.
Punctate lesions of <2 mm are difficult to treat
with cryotherapy.
Treatment Options
Other methods of treatment for IGH include laser
ablation using a carbon dioxide or Erbium laser,
fractional carbon dioxide laser, intralesional tri-
amcinolone injections, topical tacrolimus 0.1 %
application, topical pimecrolimus application,
topical retinoids and punch grafting with triam-
cinolone injection [1, 4, 9, 12–16].
Methodology (How I Do It)
1. Ask the patient to point out lesions that need
to be treated (it is not practical to treat hun-
dreds of lesions in one sitting)
2. Use a cryotherapy spray gun rather than cot-
ton buds, preferably use the standard nozzle
aperture sizes (e.g. 0.5–1mm). Local anesthe-
sia is not required.
3. Directly spray for approximately 5 s keeping
a distance of 0.5 cm to 1 cm between the noz-
zle and the skin of 1–1.5 cm. Cryocones are
not required. The frozen lesion should become
whitish due to ice crystal formation. Most
treated lesions and the immediate surrounding
rim of skin will become slightly erythema-
tous, transiently. Usually, vesicles do not
appear after treatment, however a few may
occur. After a few days the top layer peels off.
4. During the initial few treatments a timer (e.g.
5 s) may be used, however it is not necessary
for an experienced operator.
5. No dressings or specific care is needed. If ves-
icles occur, they are best left alone. Even if the
vesicle roof comes off due to friction, the
P. Kumarasinghe
superficial erosions heal without any
problems.
6. Repigmentation takes 6–8 weeks to fully
develop. A new set of IGH lesions may be treated
at each visit. If required, any lesions that have not
repigmented adequately may be retreated.
Complications
Cryotherapy for IGH is a very simple procedure,
usually without complications. The mild pain of
freezing IGH lesions is well tolerated. Very rarely
vesicles may become secondarily infected.
Occasionally haemorrhagic vesicles can develop.
Scarring does not occur unless frozen exces-
sively. Rarely there can be secondary leukoderma
in the surrounding skin. Some lesions may
become hyperpigmented but this gets less pro-
nounced with time.
Conclusions
Cryotherapy is effective in IGH. The proce-
dure is simple, brief, easy to perform without
anesthesia and relatively inexpensive. Some
lesions may not respond to cryotherapy. Some
may improve but later gradually lose pigment
in the same area.
References
1. Westerhof W, Njoo D, Menke HE. Miscellaneous
hypomelanoses: depigmentation. In: Nordlund JJ,
Boissy RE, Hearing VJ, King RA, Oetting WS,
Ortonne JP, editors. The pigmentary system. 2nd
ed. Oxford: Blackwell Publishing; 2006.
p. 726–9.
2. Shah AS, Supapannachart, Nordlund JJ. Acquired
hypomelanootic disorders. In: Levine N, editor.
Pigmentation and pigmentary disorders. Boca Raton:
CRC Press; 1993. p. 351–2.
3. Cummings KI, Cottel WI. Idiopathic guttate hypomel-
anosis. Arch Dermatol. 1966;93:184–6.
4. Falabella R, Escobar C, Giraldo N, et al. On the
pathogenesis of idiopathic guttate hypomelanosis.
J Am Acad Dermatol. 1987;16:35–44.
5. Ortonne JP. Pigmentary changes of the ageing skin.
Br J Dermatol. 1990;35:21–8.
6. Ortonne JP, Perrot H. Idiopathic guttate hypomelano-
sis. Arch Dermatol. 1980;116:664–8.
84 Idiopathic Guttate Hypomelanosis
7. Wallace ML, Grichnik JM, Prieto VG, Shea
CR. Numbers and differentiation status of melano-
cytes in idiopathic guttate hypomelanosis. J Cutan
Pathol. 1998;25:375–9.
8. Kumarasinghe SP. Current concepts on idiopathic
guttate hypomelanosis. Pigment Cell Melanoma Res.
2009;22:360.
9. Kumarasinghe SP. 3–5 second cryotherapy is effec-
tive in idiopathic guttate hypomelanosis. J Dermatol.
2004;31:437–9.
10. Kim SK, Park JY, Hann SK, et al. Hypopigmented kera-
tosis: is it a hyperkeratotic variant of idiopathic guttate
hypomelanosis? Clin Exp Dermatol. 2013;38:526–9.
11. Weedon D, editor. Skin pathology. 2nd ed. London:
Churchill Livingstone. 2002. p. 326.
12. Ploysangam TS, Dee Ananlap S, Suvanprakorn.
Treatment of idiopathic guttate hypomelanosis with
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liquid nitrogen: light and electron microscopic stud-
ies. J Am Acad Dermatol. 1990;23:681–4.
13. Hexel DM. Treatment of idiopathic guttate hypomela-
nosis by localized dermabrasion. Dermatol Surg.
1999;25:917–8.
14. Asawanonda P, Sutthipon T, Preiawai N. Pimecrolimus
for idiopathic guttate hypomelanosis. J Drugs
Dermatol. 2010;9:238–9.
15. Pagnoni A, Kligman AM, Sadiq I, Stoudemayer
T. Hypopigmented macules of photodamaged skin
and their treatment with topical isotretinoin. Act
Derm Venereol. 1999;79:305–10.
16. Shin J, Kim M, Park SH, Oh SH. The effect of frac-
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 Cryosurgical Treatment of Keloids
and Hypertrophic Scars
85
Christos C. Zouboulis, Yaron Har-Shai,
and Constantin E. Orfanos

Abstract
The treatment of keloids and hypertrophic scars with cryosurgery has been
found effective and safe in several studies during the last 15 years. Its
major advantage over other therapeutic modalities is the rare occurrence
of recurrences. This chapter describes the cryobiological background, the
cellular and structural effects of cryosurgery on scars and the clinical
results of the method as monotherapy, in combination with intralesional
corticosteroids, as adjuvant treatment with or without intralesional corti-
costeroids after surgical debulkment, as intralesional cryosurgery and as
cryopeeling. The cryosurgical equipment as well as the treatment tech-
niques and practical procedures are presented extensively. Possible com-
plications and contraindications are finally reported.

Keywords
Cryosurgery • Cryotherapy • Keloids • Hypertrophic scars • Cryobiology •
Equipment • Corticosteroids • Intralesional cryosurgery • Techniques •
Adverse effects • Contraindications

Introduction

C.C. Zouboulis, PhD, MD (*)
Departments of Dermatology, Venereology,
Allergology and Immunology, Dessau Medical
Center, Auenweg 38, Dessau 06847, Germany
e-mail: christos.zouboulis@klinikum-dessau.de
Y. Har-Shai, MD
Department of Plastic Surgery, The lady Davis
Carmel Medical Center, Linn Medical Center,
Haifa, Israel
C.E. Orfanos, MD, Emeritus
The Free University of Berlin, Berlin, Germany
Cryosurgery – the well aimed and controlled
destruction of diseased tissue by application of
cold – is an effective and efficient method for
treating various skin diseases [1–4]. The tech-
nique has several advantages (Table 85.1) and,
especially, in the treatment of keloids and hyper-
trophic scars, it provides good therapeutic and
cosmetic results with a few contraindications and
low incidence of complications [5–7]. The thera-
peutic properties of freezing on tissues have also

© Springer-Verlag London 2016 413

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_85
414 C.C. Zouboulis et al.

been successfully used in the treatment of super- Cryobiology

ficial atrophic acne scars [8, 9].
The first physician who used cold to treat a The biological changes that occur in cryosurgery
dermatological disease was Carl Gerhardt, have been studied in vitro and in vivo and are
German dermatologist from Jena [10]. In 1885, caused by reduction of tissue temperature and
he published on the treatment of cutaneous consequent freezing [1, 18–22]. Tissue injury is
tuberculosis with cold. Gerhardt had built a induced by direct physical effects of cell freezing
system, in which the lesions were covered with and by the vascular stasis that develops in the tis-
ice bladders 3 h twice a day. Four patients con- sue after thawing. The cryoreaction is, therefore,
siderably improved after a 2- to 4-week treat- characterized by the physical and the vascular
ment [11]. In 1899, A. Campell White, phases. A postulated third phase of cryoreaction,
American dermatologist from New York, used the immunologic phase, is still under investiga-
for the first time liquefied air to treat various tion. The factors affecting the effects of freezing
skin disorders, such as verrucae vulgares, naevi, on tissue and their optimal parameters for the
precancerous lesions and tumors [12]. In 1905, treatment of keloids and hypertrophic scars are
M. Juliusberg, a Berliner dermatologist, intro- shown in Table 85.2.
duced the term “cryotherapy” for the treatment
of skin lesions with cold. He applied the first
cryospray, a small balloon filled with carbon Physical Phase of Cryoreaction
dioxide released in spurts [13]. Modern cryo- (Reviewed in refs. [1, 19, 23])
surgery was born at the 1960s after liquid nitro-
gen became available [14] and closed-circuit Tissue Freezing: Homogenous
devices working with liquid nitrogen, freon gas and Heterogenous Nucleation
and nitrogen protoxide have been developed by Very rapid freezing (100–260 °C/min) leads to
the American neurosurgeons Irving S. Cooper intracellular ice formation giving rise to cellular
and A.S. Lee and their Italian colleagues death due to an irreversible destruction of the cells
V.A. Fasano et al. [15–17]. Nowadays, numer- known as homogenous nucleation [24]. Damage
ous sophisticated devices have been developed to cell organelles, such as mitochondria and endo-
and commercialized, not only to preserve and plasmic reticulum, has been postulated to be
deliver cryogens, but also to monitor the tem- caused by intracellular ice formation. Ice-crystal
peratures in and underneath the treated lesions
allowing a controlled and reliable cryosurgery
Table 85.2 Factors affecting the effects of freezing in
of the diseased skin. tissue
Optimum parameters for the
treatment of keloids and
Table 85.1 Advantages of cryosurgery hypertrophic scars
Safe and relatively Excellent cosmetic results Speed of tissue Moderate speed (up to 100 °C/
simple technique freezing min)
Out-patient Low rates of complications Speed of thawing Slow speed (10 °C/min,
procedure spontaneous rewarming)
Short duration of Few contraindications Intra-/extracellular Heterogenous and homogenous
treatment osmotic phenomena nucleation
Low cost High healing rates also in Probe tip temperature −85 °C to −190 °C
“difficult” areas Tissue temperature −20 °C to −25 °C
Repeatable as No general anesthesia required – Duration of freezing 30 s
often as needed local anesthesia optional Repetition of No
Protects important tissue structures freeze-thaw cycles
Applicable in old, non-operable Vascular reaction Yes
patients and in pregnancy Immunologic reaction Probable
85 Cryosurgical Treatment of Keloids and Hypertrophic Scars
size is important, since the larger the crystals are,
the greater damage is induced. Very rapid freez-
ing speeds are required in the treatment of malig-
nant skin tumors where cryosurgery has to be
lethal. In the treatment of benign skin tumors,
such as keloids and hypertrophic scars, moderate
freezing speeds (up to 100 °C/min) can also be
applied. Moderate freezing speeds lead to differ-
ential freezing in the different parts of the tissue
consequently resulting in extracellular ice forma-
tion, hypertonic and sensitization damage. These
phenomena can also induce an irreversible
destruction of the cells are known as heteroge-
neous nucleation. Extracellular ice formation
alone is not sufficient to kill cells since disruption
of cell membranes barely occurs despite the vol-
ume changes in the extra- and intracellular com-
partments. However, the temperature changes
occurring in tissue by moderate freezing speeds
are rapid enough to induce additional intracellular
ice formation. When extracellular ice is formed,
changing osmotic gradients between cells and
extracellular fluid are produced which lead to a
passage of electrolytes out of the cells, giving a
decrease in cell volume. When a certain concen-
tration of essential intracellular molecules is
reached they also pass out of the cell causing irre-
versible cell damage (hypertonic damage).
However, gross cell damage can be observed even
if the necessary hypertonic conditions are not
achieved. This leads to the assumption that this
“sensitization” damage is the result of phospho-
lipids disruption in cell membranes.
Slow freezing speeds only lead to extracellu-
lar ice formation and together with the addition
of cryoprotective agents, such as dimethyl sul-
phoxide, in order to prevent hypertonic damage,
they are used in cryoconservation of cells and
tissues.
Tissue Thawing
A slow thawing speed (10 °C/min) induces vol-
ume changes in the extra- and intracellular com-
partments leading to an increase of the
intracellular water content [24]. Rapid electrolyte
transfer has been incriminated as the cause of
damage to cell proteins and enzyme systems.
Reverse osmotic gradients during thawing may
415
give rise to “sensitization” damage. In addition,
intracellular recrystallization of ice is responsible
for tissue destruction. The latter process is as
important as the initial freezing in causing cell
death. Adequate freezing has been performed
when the thawing time is 1.5 times the freezing
time or longer.
Tissue Temperature
Freezing takes place in the tissue at −0.6 °C but this
not the lethal temperature. Various cell populations
present a differing ability to tolerate cold [25–27].
Melanocytes are the most sensitive skin cells to low
temperatures, they die at −4 °C to −7 °C. Sebaceous
glands and hair follicles are also rather sensitive to
cold; already temperatures lower than −20 °C are
for them lethal. Keratinocytes die at about −20 °C
to −30 °C, while fibroblasts are rather resistant to
cold dying at −30 °C to −35 °C. Therefore, it is dif-
ficult to achieve optimum cooling rates capable of
killing all cells during cryosurery. Theoretically,
formation of ice crystals in tissue and, therefore,
tissue freezing, starts from temperatures lower that
−21.8 °C, which is the eutectic temperature of
sodium chloride solutions [19]. In rapidly dividing
cells their water content is directly proportional to
the mitotic index, hence they are more likely to be
damaged. A probe tip temperature lower than
−180 °C and a tissue temperature at least as low as
−50 °C have been shown essential to kill all target
cells [26, 28, 29]. These parameters are required in
cryosurgery of malignant skin tumors; an optimal
cryosurgery of benign skin lesions, such as keloids
and hypertrophic scars, only requires tissue tem-
peratures of −20 °C to −25 °C [1].
Duration of Freezing
Cell death rates have been shown in vitro to
increase not only with lower temperatures but
also with longer freezing times [18, 24]. However,
the effect of freezing on cell viability reaches a
maximum at about 100 s followed by a plateau in
cell death rates with time.
Repetition of Freeze-Thaw Cycles
The importance of more than one freeze-thaw
cycles in causing increased rates of cell death has
been demonstrated in several in vitro and animal
416
studies [18]. Electron microscopic studies of nor-
mal skin showed damage to all cell structures
after a second freeze-thaw cycle [30]. Repeated
freezing-thawing cycles are essential in the treat-
ment of cutaneous tumors [29, 31] but are not
required in the treatment of keloids and hypertro-
phic scars [5].
Vascular Phase of Cryoreaction
Cryogenic injury leads to vascular stasis and
inevitable tissue anoxemia resulting to ischaemic
necrosis. Ischemia produces cell damage in addi-
tion to that due to intra- and extracellular ice for-
mation [22–24, 32]. Microscopic examination of
injured tissue in animals has shown that edema,
focal capillary damage, hemorrhages and iso-
lated microthrombi begin to occur after 2 h and
that by 5–8 h focal or segmental necrosis of blood
vessels is present. Thrombosis of terminal arter-
ies leading to gangrene appears between 1 and
7 days, but only when injury is severe. Even after
mild cold injuries, the initial circulatory impair-
ment is irreversible, thus implicating delayed
progressive thrombosis as the main factor pro-
ducing tissue loss [33, 34]. Thrombosis in 65 %
of the capillaries and 35–40 % of the arterioles
and venoles already occurs at tissue temperatures
of 11–3 °C, while thrombosis of all vessels is
detectable at −15 °C to −20 °C in tissue [35, 36].
In an attempt to explain exudation which
occurs after cryosurgery, ultrastructure studies of
endothelial cells have shown that cell damage in
the first hour after freezing and thawing includes
rupture of cell membranes, thinning and later
condensation of ground substance and swelling
of rough endoplasmic reticulum and mitochon-
dria [37].
Immunological Phase of Cryoreaction
The possibility of an immunologic response
after cryosurgical treatment was first raised
when circulating antibodies were observed
directed against prostatic or adrenal tissue that
had been treated by cryosurgery in the rabbit
C.C. Zouboulis et al.
[38, 39]. Clinically, regression of tumor masses
beyond the region treated by cryosurgery or even
in distant metastases has been observed [40–42].
It has been demonstrated in both the rabbit and
the man that antigens are released by cell lysis
following freezing. Antibody response is
directed against tissue antigens rather than tumor
antigens [43]. In the last years, further confirma-
tion of immunologic response after cryosurgery
has been provided. Natural killer cell cytotoxic-
ity was found enhanced following cryosurgery
of normal liver and liver tumors in animals [44,
45]. Parallel studies in patients with benign
tumors in the lungs and bronchial, pulmonary,
breast, hepatic and prostate cancer in operative
intervention and combined cryosurgical treat-
ment showed a stimulating effect of cryodestruc-
tion of malignant tumors with their subsequent
spontaneous thawing on the content of large
granule-containing lymphocytes and natural
killer activity [46–49]. An interesting study was
performed in rats with incompletely or com-
pletely frozen liver carcinoma. In the incom-
pletely frozen group, the survival days
significantly prolonged as compared with con-
trols. Phytohemagglutinin blast formation and
CD4 positivity exhibited high levels at 8 weeks
after cryosurgery. In the completely frozen
group, survival time was not prolonged and three
cases of early death were observed. Moreover,
CD4 positivity significantly decreased at 3 days
and CD8 positivity significantly increased at
2 weeks after cryosurgery. These results lead to
the conclusion that immunologic response after
cryosurgery for liver carcinoma may be, indeed,
induced by changes in tumor cell immunity [45].
Langerhans cell activity after cutaneous cryosur-
gery was found enhanced in another study [50].
Finally, in an experimental study, the concentra-
tion of ascites fibrosarcoma tumor cell mem-
brane proteins increased in frozen tumor cells
compared to the native cells. In addition, they
further increased with the number of freeze-thaw
cycles applied. The cell surface protein pattern
which was heterogeneous before freezing
became more homogeneous following freezing
due to depolymerization and breaking of higher-
molecular-weight components [51].
85 Cryosurgical Treatment of Keloids and Hypertrophic Scars
Cryosurgery in the Treatment
of Keloids and Hypertrophic Scars
Keloids and hypertrophic scars are benign
cutaneous lesions produced by uncontrolled
synthesis and deposition of dermal collagen as
a result of abnormal wound healing. They usu-
ally follow injury to the skin of predisposed
individuals but can also occur spontaneously.
The chest, the shoulders, the head-neck area
and the upper back are the most susceptible
regions of the body [52–54]. While keloids
have a strong tendency to grow beyond the
confines of the previous wound, hypertrophic
scars remain within the borders of the original
dermal trauma [55, 56]. In contrast to hypertro-
phic scars, keloids do not regress with time and
do not provoke scar contractures. Keloids con-
tain large, thick collagen fibers composed of
numerous fibrils closely packed together. In
contrast, hypertrophic scars exhibit modular
structures in which fibroblastic cells, small
vessels, and fine, randomly organized collagen
fibers are present [56].
The primary cell in keloids has shown to be
the myofibroblast with prominent rough endo-
plasmic reticulum and bundles of myofilaments
with focal densities in the cytoplasm [56–59].
Enhanced secretory activity was reflected in the
prominence of the Golgi apparatus and the fre-
quent presence of intracellular collagen within
the tubular membranes [59]. Proliferating der-
mal fibroblasts in the periphery of the keloid tis-
sue have been shown; their numbers were
increased in comparison with hypertrophic scars
and normal skin [60, 61]. In contrast, no prolifer-
ating cells were found in the central region of the
keloid [61]. Metalloproteinase abnormalities and
a decreased rate of metalloproteinases/tissue
inhibitors of metalloproteinases were observed
in keloids [62, 63]. Northern blot analysis of
total RNA obtained from keloids with high
growth tendency in vivo and immunohistochem-
istry of keloids and hypertrophic scars showed a
marked induction of the small proteoglycan big-
lycan and collagen-α1 (I) expression in compari-
son with normal skin [64, 65]. In another study,
increased levels of α1 (I)- and α1 (III)-collagen
417
mRNA were observed in fibroblasts from the
edge and outside of hypertrophic scar tissue,
while normal levels were noted in fibroblasts
from the centre of this tissue. In addition,
decreased levels of collagenase mRNA were
found in the hypertrophic scar fibroblasts, sug-
gesting that decreased expression of collagenase
in hypertrophic scar fibroblasts may be one pos-
sible cause for the excessive accumulation of
collagen in the skin lesions of hypertrophic scars
[66]. On the other hand, increased collagen syn-
thesis by normal collagen degradation has been
found in keloid fibroblasts in vitro [67]. Tenascin,
a large extracellular matrix glycoprotein, was
shown to be strongly expressed in keloids demar-
cating their borders in tissue [68, 69].
Significantly increased levels of tenascin expres-
sion were also found in keloidal fibroblasts in
comparison to normal cells in vitro. Like in vivo,
normal and keloidal fibroblasts have been shown
to exhibit similar basal rates of fibrin matrix gel
contraction in vitro, while fibroblasts from
hypertrophic scars exhibited a consistently
higher basal rate of fibrin matrix gel contraction
than other fibroblasts [70]. Furthermore, only
nodules of hypertrophic scars contained
α-smooth muscle actin-expressing myofibro-
blasts when compared to keloid and normal skin
tissue [56]. The presence in hypertrophic scar
myofibroblasts of α-smooth muscle actin, the
actin isoform typical of vascular smooth muscle
cells, may represent an important element in the
pathogenesis of increased contraction in hyper-
trophic scars.
Patients wish treatment mainly for cosmetic
reasons; pruritus, pain and restriction of move-
ment by lesions close to joints are often addi-
tional ones. A variety of therapeutic regimens
have been used with unsatisfactory final results
because these lesions, especially keloids, are
notoriously recurrent [52–55, 71]. Cryosurgery
was found effective and safe in keloids and
hypertrophic scars, in several studies during the
last years [72]. Due to its major advantage of
rarely occurring recurrences the technique, as
monotherapy or in combinations, has been estab-
lished as the treatment of choice for keloids and
hypertrophic scars.
418
Effects of Freezing on the Connective
Tissue
An advantage of cryosurgery often cited is that of
minimum scarring. The collagen fibre network of
the dermis has been shown to remain largely
undamaged by the standard cryosurgical proce-
dures performed by clinicians [27]. Using the
young domestic pig as model and two 1-min
freeze-thaw cycles no alteration in the periodicity
of fibrillar cross-banding as well as no fracturing
or distortion of collagen fibrils were found. In
another study on rats, wound contraction after
freeze injury was minimal in contrast to burn
damage in which contracture was the rule [73].
Effects of Freezing on Keloidal
Fibroblasts
Fibroblasts are rather resistant to freezing [27, 69]
and cryosurgery was shown to increase their prolif-
eration in vivo [21] and in vitro [69]. Suspended
fibroblast cultures established from keloids and
normal skin samples incubated in sterile cryotubes
were frozen in precooled ethanol (−75 °C) and con-
sequently seeded on culture dishes. The prolifera-
tion of keloidal fibroblasts significantly increased
immediately after cryotherapy in vitro in four of six
cultures tested. After subcultivation, persistence of
significantly increased proliferation was deter-
mined in three of four cultures. On the other hand,
the proliferation of normal fibroblasts decreased in
three of six cultures immediately after cryotherapy
but returned to higher rates after subcultivation.
These data correspond to the increase in the num-
ber of dermal fibroblasts observed 3 weeks after
cryosurgery of the young domestic pig skin [21].
Furthermore, cryosurgery induced a significant
reduction of collagen I synthesis in two of four cul-
tures examined after been frozen in comparison to
non-frozen cultures, while increased synthesis of
collagen IV was found in two of four cultures [69].
No uniform changes of collagen III and fibronectin
synthesis were detected. After subcultivation,
increased collagen IV synthesis of keloidal fibro-
blasts persisted in two of two cultures, while the
synthesis of collagen I was no more supressed.
C.C. Zouboulis et al.
Collagens I and III represented more than 90 % of
the total collagen amount produced by keloidal
fibroblasts in vitro. Normal fibroblasts showed no
uniform changes of collagen and fibronectin syn-
thesis either immediately after cryotherapy or after
subcultivation. It is likely that cryotherapy exhibits
a temporary inhibitory effect on the synthetic activ-
ity of keloidal fibroblasts, while it does not affect
the activity of normal cells.
Structural Changes in Keloids
and Hypertrophic Scars
after Cryosurgery
Significant skin thickening was found to occur
3 weeks after cryosurgery of pig skin which was
compatible to an increase in the number of fibro-
blasts, followed by significant thinning at 6 months,
probably due to the chronic ischemia induced by
cryosurgery [21]. In man, neovascularization, regu-
lar linear arrangement of collagen bundles,
increased fibroblasts in a stroma running parallel to
the skin surface and mononuclear cells mostly
arranged at the perivascular area were found in
clinically responding lesions after cryosurgery [5].
In a prospective, randomised study with 40 patients
with keloids comparing the clinical and histologi-
cal effects of cryosurgery as a single regimen or
combined with intralesional steroids increased
vessel number and lumen dilatation in both groups
and a reduction of the number and the length of
rete ridges in the monotherapy group were
the major structural changes observed [74].
Immunhistologically, enhancement and diffusion
of tenascin expression in the whole treated dermal
region and depletion of IFNγ expression, indicat-
ing immune regulation, were found [69]. These
histological and immunohistological studies indi-
cate that cryosurgery can induce changes in keloids
that are compatible with a rejuvenation of the scars.
Clinical Results
Cryosurgery was initially applied in the treatment
of keloids and hypertrophic scars as a weak cryo-
therapy regimen prior to intralesional corticosteroids
85 Cryosurgical Treatment of Keloids and Hypertrophic Scars 419

in order to induce tissue edema and to facilitate
intralesional injections [75]. Cryosurgery as a ther-
apeutic monotherapy regimen was first used by
Shepherd and Dawber in 1982: They have treated
17 patients with keloids with a single cryosurgical
session achieving 80 % improvement of the lesions,
however, they observed a high recurrence rate of
33 % [76]. With the exception of case or technical
reports [77–79], further monotherapy studies have
been probably delayed by the rather disappointing
recurrence rate, until Mende [80] as well as
Zouboulis and Orfanos [81] have shown that
repeated cryosurgical sessions can exhibit a benefi-
cial effect on keloids and hypertrophic scars and
also prevent relapses.
Cryosurgery was shown to exhibit significantly
better results than intralesional triamcinolone
(5 mg/lesion) in a randomized study with 11
patients with multiple acne keloids, especially in
early, vascular lesions [82]. It is nowadays
regarded as an established treatment for keloids
and hypertrophic scars [83], possibly being the
treatment of choice [1, 4]. Following techniques
are established or currently under evaluation.
Cryosurgery as Monotherapy
In 241 of 356 patients with keloids (68 %) and in
72 of 89 patients with hypertrophic scars (81 %) a
higher than 50 % improvement or complete regres-
sion has been observed (five studies; Table 85.3)
[5–7, 74, 80]. Acne keloids also showed a 73 %
improvement or complete regression in 16 patients
treated [84]. To achieve these results 1 to more
than 20 sessions of an average of 30 s each applied

Table 85.3 Cryosurgery of keloids and hypertrophic scars: clinical results

Cryosurgery as monotherapy
Number of patients Significant to complete remission % Recurrences
Keloids
Mende [80] 7 5 71 –
Zouboulis et al. [90] 55 28 51 –
Rusciani et al. [6] 40 34 85 –
Ernst and Hundeiker (1994) 234 158 68 9
Zouridaki et al. [74] 20 16 80 –
Total 356 241 68 % 9 2%
Hypertrophic scars
Zouboulis et al. [5] 38 29 76 –
Ernst and Hundeiker (1994) 51 43 84 2
Total 89 72 81 % 2 2%
Cryosurgery combined with intralesional corticosteroids
Number of patients Significant to complete remission % Recurrences
Keloids
Hirshowitz et al. [85] 58 41 71 9
Ernst and Hundeiker (1994) 56 38 68 2
Zouridaki et al. [74] 20 19 95 –
Banfalvi et al. [86] 25 21 84 –
Total 159 119 75 % 11 7%
Intralesional cryosurgery
Number of patients % of volume reduction after a single treatment Recurrences
Keloids
Open cryoneedle
Zouboulis et al. [94] 10 30.1 (3 sessions) 2
Closed cryoneedle (CryoShape)
Har-Shai et al. [96] 10 51.4 ± 3.2 - (18-month
follow-up)
420
Table 85.4 Variables affecting the outcome of cryosur-
gery in keloids and hypertrophic scars
Factors influencing the outcome of cryosurgery in
keloids and hypertrophic scars
Diagnosis Hypertrophic scars respond
significantly better than keloids
Number of Improved responses were detected in
sessions subjects treated with 3 or more
sessions when compared to subjects
treated once or twice
Age of the Lesions younger than 2 years
lesion responded better than older ones
Factors which do not influence the outcome of
cryosurgery in keloids and hypertrophic scars
Age of the patient
Sex of the patient
Size of the lesion
Localization of the lesion
Pretreatment
once monthly using the contact method of treat-
ment have been required. Progression or recur-
rences were rare (2 %). The number of sessions,
the diagnosis and the duration of lesions signifi-
cantly correlated with the result of the treatment.
The age and the sex of the patient, the size and the
localization of lesions and pre-treatment with
another method did not influence the outcome of
cryosurgical treatments (Table 85.4) [5]. The cryo-
surgical treatment was generally well tolerated and
only minor complications occurred. About one
third of the patients treated complained for mild
local pain which has been easily managed, if nec-
essary. 12–100 % of the subjects experienced
lesional hypopigmentation and 1–8 % skin atro-
phy. The complications were dependent on the
duration of freezing and the number of freeze-
thaw cycles applied [5, 6, 80].
Cryosurgery Combined
with Intralesional Corticosteroids
Initially performed in 1982 by Hirshowitz et al.
[85] with the impressive result of 71 % complete
remission in 58 patients with keloids, the combi-
nation of cryosurgery prior or following intrale-
sional corticosteroids exhibited significant
regression of keloids in 78 of 101 patients (77 %)
treated in three further studies (Table 85.3) [7, 74,
86]. Cryosurgery performed prior to corticosteroid
C.C. Zouboulis et al.
treatment induces tissue edema and facilitates
intralesional injections. However, the combined
therapy was not superior (90 % higher than 50 %
reduction of lesional volume) than monotherapy
(83 % higher than 50 % reduction of lesional vol-
ume) in a randomized trial with 40 patients with
keloids [74].
Surgical Debulkment Prior
to Cryosurgery With or
without Intralesional Corticosteroids
Lesions refractory to cryosurgery or cryosurgery
combined with intralesional corticosteroids can
be surgically removed and postsurgical cryopre-
vention with or without intralesional corticoste-
roids could be applied in order to avoid
recurrences. This regimen is unavoidable in large
keloids although recurrences are not rare, despite
the promising initial result [87–90]. Intramarginal
excision is advisable because it is followed by a
lower recurrence rate when compared to
extramarginal excision [91]. Removal of the
lesion by surgery or carbon dioxide laser present
similar recurrence rates [92], however, carbon
dioxide laser provides a high degree of hemosta-
sis and avoidance of sutures.
Intralesional Cryosurgery
Intralesional cryosurgery using cryoneedles was
initially described by Weshahy [93] for the treat-
ment of epidermal and dermal skin lesions.
Intralesional cryosurgery was introduced in the
treatment of keloids in the last 10 years [1, 4, 72,
94–99]. This technique exhibits an increased effi-
cacy in the treatment of hypertrophic scars and
keloids when compared with the contact tech-
nique due to the enhanced freezing area of deep
scar tissue. In addition, fewer treatment sessions
are required and less hypopigmentation is evident
following the intralesional cryosurgery method.
While the response rate of the open tip intral-
esional cryosurgery was low [94], a total average
of 51.4 % scar volume reduction was achieved
following one session of intralesional cryosurgery
treatment with a newly developed sealed intrale-
sional cryoneedle (CryoShape, Etgar Group
International, Kfar Saba, Israel) [96]. Furthermore,
in helical and lobular ear hypertrophic scars and
85 Cryosurgical Treatment of Keloids and Hypertrophic Scars 421

keloids an average volume reduction of

67.4 ± 23 % 6 months after a single session of
intralesional cryosurgery was achieved [97].
Moreover, a significant alleviation of objective
signs (hardness and color) and subjective clinical
symptoms (pain/tenderness and itchiness/discom-
fort) were documented [97]. The non-responsive
rate was less than 3 %. No worsening of the scars
was evident [98] and hypopigmentation was mini-
mal [99]. The histomorphometric analysis dem-
onstrated rejuvenation of the treated scars, i.e.,
parallelization, and a more organized architecture
of the collagen fibers when compared to the pre-
treated scars [97].

Cryopeeling
The freezing peel (cryopeeling) is a full face,
superficial cryosurgical treatment for atrophic
acne scarring especially useful in patients with
mild to moderate circinate scars [100]. Results
are similar to those obtained with chemical peel-
ing but not as good as those obtained with derm-
abrasion. Repeated sessions, sometimes over
2–3 years, are required for obtaining optimum
results [9].

Fig. 85.1 Cotton-tipped applicator using a large swab

(right) and “hard tail” dip-stick (left) before cutting the
Cryosurgical Equipment distal part of the tail
and Treatment Techniques

Simple Cryosurgical Units:
The Cotton-Tipped Applicator
and the “Hard Tail” Dip-Stick
The simplest cryosurgical modality, still in cur-
rent use, is the cotton-tipped applicator method,
which applies small or large swabs soaked in LN
[14] (Fig. 85.1). Both instruments lack the capac-
ity of active freezing and, therefore, can only
induce a slow freezing speed, this limits their
application in the treatment of keloids and hyper-
trophic scars. In addition, large swabs create
large frozen surfaces, generally overriding the
limits of the area intended for treatment in small
lesions, while small swabs have a limited reser-
voir capacity. A modification of the classic
cotton-tipped applicator is the “hard tail”
dip-stick which has been devised in an attempt to
avoid these disadvantages [101]. The “hard tail”
dip-stick is made out of a standard large cotton-
tipped applicator (Fig. 85.1). At its end, a tiny
amount of cotton is pinched between the index
finger and thumb and strongly twisted in order to
obtain the so-called “hard tail”. The distal part of
the tail is cut down so that the total tail does not
exceed 5 mm. This dip-stick is soaked in
LN. Since a large swab is used, a large amount of
LN is absorbed by the cotton reservoir. Only the
tail of the swab is put in contact with the lesion.
LN is slowly released at the pointed end of the
swab, producing an accurate freezing effect. The
degree of hardness of the tail is a factor that must
be stressed. If this is not hard enough, the tail
cannot easily remain in contact with the lesion
and is useless. Therefore, one should not pull a
tiny amount of cotton but only pinch it before
422 C.C. Zouboulis et al.

twisting it strongly. When application with the

hard tail begins, some drops of LN may run. This
can be avoided by shaking the swab once or twice
in the air before the application. The method is
sufficient to treat epithelial benign lesions but
does not induce temperatures low enough for suf-
ficient cryosurgery of dermal benign lesions,
such as keloids and hypertrophic scars. However,
it can be used as an alternative technique at
lacking of other cryosurgical devices or in very
small scar lesions (smaller than 5 mm).

The Modern Cryosurgical Unit

Nowadays, there are many commercially avail-

able, well-functioning cryosurgical units with
variable design, function and performance
characteristics [102, 103]. Sufficient cold for
cryosugery can be produced by direct or indi-
rect application of a solid or liquid cryogen
stored at low temperatures, by lowering the
pressure of a gas (Joule-Thompson effect),
electromechanically or simply by refrigera-
tion. The devices are mainly characterized by
the applied cryogen and the way of cryogen
application to the skin (Table 85.5). A cryosur-
gical unit consists of five main components: a
liquid dewar/gas cylinder, the cryogen, a pres-
sure gauge, a cryogun with tubing and assorted
cryoprobe/spray tips.
The Liquid Dewar/Gas Cylinder
Dewars and gas cylinders are of widely varying
size (Fig. 85.2). The efficiency of cryosurgery
Table 85.5 Classification of cryosurgical devices
According to the cryogen used
Liquid nitrogen units (probe tip temperature −170 °C
to −190 °C)
Nitrous oxide units (probe tip temperature −65 °C to
−85 °C)
Units using a Peltier thermoelectric element (probe
tip temperature −32 °C to −40 °C)
According to the way of cryogen application
Devices using the contact technique
Devices using the spray technique
Devices for intralesional cryosurgery
Fig. 85.2 Liquid dewar (lower part) of a cryosurgery unit
using liquid nitrogen as cryogen. The upper part of the
device includes the activation trigger which needs to be
pressed during the freeze, the regulator vent, the cryo-
probe stem and the cryogun stem
using nitrous oxide is dependent on maintaining
adequate gas pressure within the cylinder.
Internal gas pressure decreases during freezing
and must regenerate at room temperature between
freezes to maintain adequate pressure. Most units
incorporate regulators to reduce or control tip
pressures for economy and safety. The regulators
provide a constant performance at various cylin-
der pressure levels.
The Cryogen
The most common cryogen is nowadays LN,
which can generate low target tissue tempera-
tures because of its boiling point of
−195.8 °C. It is considered the cryogen of
choice for dermatological cryosurgery and the
only cryogen advocated for treatment of malig-
nant skin lesions. Nitrous oxide, a non-inflam-
mable gas with a boiling point of −89.5 °C, is a
85 Cryosurgical Treatment of Keloids and Hypertrophic Scars 423

sufficient cryogen for the treatment of benign a

skin lesions.

The Gas Pressure Gauge

Nitrous oxide cryosurgical units feature a gas
pressure gauge located between the cylinder
and the cryogun (Fig. 85.3). The gauge indi-
cates the pressure within the cylinder and is
divided into three pressure zones. The high
zone of the gauge reflects excessive cylinder
pressure (a safety hazard) and the low gas pres-
sure results in inefficient and probably inade-
quate freezing. The middle zone indicates
adequate freezing.

The Cryogun
The cryogun consists of a hand grip, activation
trigger, cryogun stem and the cryoprobe stem. In
some units, the on/off switch for the gas valve is
located on the cryogun (Fig. 85.2), in other it
consists of a pedal (Figs. 85.3 and 85.4). In the
majority of the units, depressing the trigger initi-
ates the freeze (Figs. 85.3, 85.4, and 85.5), in a
few others it defrosts the probe tip. Some triggers
feature a locked position setting so that the trig-
ger needs not to be depressed during the freeze
(Fig. 85.4).

Cryoprobe and Spray Tips

b
Cryoprobe tips must be made of a good thermal
conducting metal, such as silver, gold or copper.
Interchangeable tips are available in various
shapes and sizes to enable maximum contact of
the tip with the tissue and avoid freezing of
healthy areas (Figs. 85.5, 85.6, and 85.7). Some
cryosurgical units feature pyrometers, which indi-
cate the actual temperature of the cryoprobe tip.
By applying the spray technique, spray tips with
different aperture sizes are used (Fig. 85.8).
Fig. 85.3 (a) Nitrous oxide cryosurgery unit with a 10 l
Intralesional cryosurgery has initially engaged gas cylinder, the on/off switch (pedal) and the cryogun
single use, 20-gauge or larger needles instead of supplied with a pyrometer recording the actual tempera-
tips [72, 94] (Fig. 85.9). Har-Shai et al. [96, 97] ture of the cryoprobe tip. In (b) a gas pressure gauge, a
recently refined the technique by developing a pressure indicator and an incorporated chronometer can
be seen. The temperature is registered on an indicator
novel, FDA and CE approved, intralesional cryo-
needle (CryoShape, Etgar Group International,
Kfar Saba, Israel) (Fig. 85.10). This probe con- sealed, distal tip. The proximal end of the cryo-
sists of an elongated double-lumen uninsulated probe is connected via an elongation tube to a
needle with a safety vent and a sharp-cutting, cryogen source.
424
Fig. 85.4 Large liquid nitrogen hospital cryosurgery unit
with a 10 l liquid dewar (inside the body of the device),
the on/off switch (pedal) with a locked position setting,
the cryogun supplied with a pyrometer recording the
actual temperature of the cryoprobe tip and an incorpo-
rated chronometer. The unit includes a rapid rewarming
device (for quick detachment of the cryoprobe) and a
heating device (for tissue coagulation or hemostasis)
Fig. 85.5 Cryoprobe tips in
different shapes for a liquid
nitrogen device. All
cryoprobes possess exhaust
valves with exhaust silicone
tubings
C.C. Zouboulis et al.
Classification of Cryosurgical Devices
According to the Cryogen Used
Liquid Nitrogen Units
LN units are open systems that can be used for both
cryoprobe and spray applications. They develop a
probe tip temperature −170 °C to −190 °C and,
therefore, a rapid freezing speed of over 100 °C/min.
Hand-held simple units with a liquid dewar capacity
of 250 ml to 1 l (Figs. 85.7 and 85.8) as well as large
instruments with sophisticated temperature controls
and a capacity of up to 10 l (Fig. 85.4) are available.
Most units are not pressurized until the spray is
desired. LN requires a storage container [103].
Nitrous Oxide Units
Nitrous oxide units are closed systems that oper-
ate by the Joule-Thomson effect [104] (Fig. 85.3).
They can be practically only used for cryoprobe
applications. Refrigeration results from the expan-
sion of the gas through a small opening (adiabatic
principle). Pressurized nitrous oxide advances
down the narrow cryogun stem [high-pressure
cryoprobe [19]]. When it reaches the hollow cryo-
probe tip, the gas rapidly expands, lowering it to a
temperature below freezing. The temperature of
the nitrous oxide cryoprobe drops to −65 °C to
−85 °C and, therefore, a moderate freezing speed
of less than 100 °C/min is developed.
85 Cryosurgical Treatment of Keloids and Hypertrophic Scars
Fig. 85.6 Cryoprobe tips in
different shapes for a nitrous
oxide device
Fig. 85.7 A cryoprobe tip for
a liquid nitrogen device is
going to be fixed in the
cryoprobe stem
High-pressure devices have several advantages
over liquid nitrogen probes [19] (Table 85.6).
Units Using a Peltier Thermoelectric
Element
Units using a Peltier effect cooler [19] are closed
systems only used for cryoprobe applications
(Fig. 85.11). They develop a probe tip tempera-
ture of −32 °C to −40 °C by a thermoelectric pro-
cedure, and, therefore, they do not involve the use
of a cryogen. The low freezing speed makes them
only sufficient in the treatment of superficial
benign epithelial lesions and in cosmetic derma-
tology; they are insufficient in the treatment of
keloids and hypertrophic scars.
Classification of Therapeutic
Techniques According to the Way
of Cryogen Application
The methodology of cryosurgery has nowadays
been sophisticated and the techniques
425
standardized. There are nowadays three different
techniques to be used for the treatment of keloids
and hypertrophic scars.
The Contact Technique
The contact method uses metallic probes; these
function after the principle of temperature
exchange (Fig. 85.12). These probes are circu-
lated by a gas cryogen. As the tip removes heat
from the tissue, the tissue gradually cools. The
size, material, composition and temperature of
the probe tip determine its tissue cooling capac-
ity. Other factors, such as tissue moistness, extent
of tissue contact, the duration of freeze and pres-
sure exerted on the probe, affect heat diffusion.
When the cryosurgical unit is activated and the
probe is placed in firm contact with the tissue, an
area of frozen tissue or iceball may be observed
extending radially from the cryoprobe tip
(Fig. 85.13). The interface between the iceball
and unfrozen tissue represents the 0 °C isotherm,
which is the line of connection points represent-
ing 0 °C at the given time. The longer the duration
426
of the freeze, the further the iceball radiates from
the cryoprobe tip margin [18]. The distance
between the tip margin and the 0 °C isotherm
Fig. 85.8 Small liquid nitrogen cryosurgery unit with a
spray tip instead of cryosurgery probe
a b
Fig. 85.9 Small liquid nitrogen cryosurgery unit for intralesional cryosurgery with a single use 20-gauge needle (a)
and a flexible, long metallic cryoprobe stem luer-locked to the needle (b)
C.C. Zouboulis et al.
represents the lateral spread of freeze. The depth
of the 0 °C isotherm from the tip indicates the
depth of freeze. Although variable, the lateral
spread of freeze approximates the depth of freeze
by a ratio of 1:1.3 [105]. The volume of tissue
located between the −22 °C isotherm and the
probe tip is called the lethal zone. Cells within
this zone undergo cryonecrosis [19]. Those cells
located in the warmer region between the −22 °C
isotherm and the 0 °C isotherm generally survive
the freeze. This important zone represents the
recovery zone (Fig. 85.14). Although the depth
of freeze is time related, as the duration of freeze
extends towards 100 s the lethal zone flats. The
contact method is the method of choice in the
treatment of keloids and hypertrophic scars, since
it provides controllable as well as reproducible
results. The results can be additionally modulated
by cryoprobe pressure can induce vessel
contraction.
The Spray Technique
The spray technique uses an open freezing sys-
tem with freeze secure vents (Fig. 85.15). It
directly emits a fine spray of a cryogen at the tar-
get area. It is particularly useful for irregular
lesions and lesions with a curved surface. For
large lesions to be treated in one session, a paint-
brush or spiral pattern of spray can be used [106].
The sprayed cryogen is emitted from a distance
of 1–2 cm from the target site and at 90-degree
angle to it. The depth of the freeze may be judged
85 Cryosurgical Treatment of Keloids and Hypertrophic Scars
Fig. 85.10 The novel, FDA and CE approved, intrale-
sional cryoneedle (CryoShape, Etgar Group International,
Kfar Saba, Israel). This probe consists of an elongated
double-lumen uninsulated needle with a safety vent and a
sharp-cutting, sealed, distal tip, which enhances the pen-
etration of the often hard, rubbery, and dense hypertrophic
Table 85.6 Advantages and disadvantages of high-pressure and liquid nitrogen devices
High-pressure devices (nitrous oxide)
Advantages
Relatively inexpensive and robust
The working fluid is supplied at room temperature –
highly insulated supply lines are not required
They operate efficiently without a pre-cool – the
cooling expansion occurs within the tip itself
Disadvantages
Freezing at moderate speed only
Moderately low temperature at cryo-probe tip
Available for contact technique only
Fig. 85.11 A contact cryosurgical unit using a Peltier
thermoelectric element
by the lateral spread of freezing on the surface; it
is about half the radius of the surface area [107]
(Fig. 85.16). Intermittent spraying of LN is desir-
able since it results to a more uniform temperature
in the iceball and greater depth, while it limits
lateral spread. The depth of freeze can only reach
10 mm [107] and, therefore, it is not the appropri-
427
scars and keloids. The proximal end of the cryoprobe is
connected via an elongation tube to a cryogen source. By
forcing liquid nitrogen to circulate through the needle, an
ice ball around the cryoneedle developed causing the
abutted scar tissue to be completely frozen while the gen-
erated gas is dispersed to the atmosphere
Liquid nitrogen devices
Disadvantages
More expensive due to the quick evaporation of liquid
nitrogen and the requirement of a storage dewar
Insulated supply lines are required
The cooling expansion occurs within the whole device
Advantages
Freezing at rapid speed
Very low temperature at cryoprobe tip
Available for both contact and spray techniques
Fig. 85.12 The contact method uses metallic probes cir-
culated by a gas refrigerant which function after the prin-
ciple of temperature exchange. The size, material,
composition and temperature of the probe tip determine
its tissue cooling capacity
ate technique for voluminous keloids and hyper-
trophic scars. There are two variants of the
spraying procedure, the described open-spray
technique and the confined-spray technique. The
latter directs the spray into cones [103], individu-
428
Fig. 85.13 Contact freezing technique: when the cryo-
surgical unit is activated and the probe is placed in firm
contact with the tissue, an area of frozen tissue or ice-
ball may be observed extending radially from the cryo-
probe tip
α=lateral spead of freeze
β=depth of freeze
Cryoprobe tip
α
Epidermis
β=1.3α
Lethal zone
-22°C isotherm
Recovery zone 0°C isotherm
Fig. 85.14 Iceball induced by a cryoprobe tip. The inter-
face between the ice ball and unfrozen tissue represents
the 0 °C isotherm. The longer the duration of the freeze,
the further the iceball radiates from the cryoprobe tip mar-
gin. The distance between the tip margin and the 0 °C iso-
therm represents the lateral spead of freeze. The depth of
the 0 °C isotherm from the tip indicates the depth of
freeze. Although variable, the lateral spread of freeze
approximates the depth of freeze by a ratio of 1:1.3. The
volume of tissue located between the −22 °C isotherm and
the probe tip is called the lethal zone. Cells within this
zone undergo cryonecrosis. Those cells cituated in the
warmer region between the −22 °C isotherm and the 0 °C
isotherm generally survive the freeze. This area represents
the recovery zone
ally prepared plastic moulages [108] or other
materials open at both ends and one end is placed
on the skin. The confined-spray technique
restricts the spray to the lesion and avoids wide
freezing of the healthy peripheral tissue, how-
ever, it makes impossible the clinical evaluation
of the depth of freeze (Fig. 85.16).
C.C. Zouboulis et al.
Fig. 85.15 The confined-spray technique. The liquid
nitrogen spray is directed into a plastic moulage with an
opening size fitting to the size of the lesion to be treated.
The confined-spray technique restricts the spray to the
lesion and avoids wide freezing of the healthy peripheral
tissue (Reprinted from Zouboulis [1]. With permission
from Karger)
α=radius of iceball
β=depth of freeze
Spray
α
Epidermis
β=0.5α
Lethal zone
-22°C isotherm
Recovery zone 0°C isotherm
Fig. 85.16 Iceball induced by a cryogen spray. The
interface between the iceball and unfrozen tissue
represents the 0 °C isotherm. The longer the duration of
the freeze, the larger the radius of the iceball becomes.
The maximum depth of the 0 °C isotherm from the skin
surface indicates the depth of freeze. Although variable,
the lateral spread of freeze approximates half the radius of
the iceball. The volume of tissue located between the
−22 °C isotherm and the skin surface is called the lethal
zone. Cells within this zone undergo cryonecrosis. Those
cells cituated in the warmer region between the −22 °C
isotherm and the 0 °C isotherm generally survive the
freeze. This area represents the recovery zone
Intralesional Cryosurgery
The inability of skin surface cryosurgery to freeze
beyond 20 mm in depth [109] has led Weshahy to
develop a method for applying cryosurgery in
depth [93]. One or more needles had to be
85 Cryosurgical Treatment of Keloids and Hypertrophic Scars
Fig. 85.17 The
intralesional
cryosurgery technique.
Liquid nitrogen N2
circulates through the
needle and forms an
iceball around the
cryoneedle causing the
abutted scar tissue to be
completely frozen while
the generated gas is
dispersed to the
atmosphere
-0°C isotherm
Fig. 85.18 Iceball induced
by the intralesional
cryoneedle. An ice cylinder is
formed around the embedded
part of the needle in the
deeper tissue. This is visible
through the skin and gradually
spreads from the depth
towards the surface
introduced into the skin from one point, run
through the deeper tissues of the lesion and
appear at the surface on the opposite border [93,
95]. A sprayed cryogen was then passed through
the needle by inserting the spray tip of the cryo-
surgical device into the head piece of the needle.
The cryogen travelled through the lumen exiting
to the atmosphere from the other end of the
needle.
The instrumentation of intralesional cryosur-
gery for the treatment of keloids and hypertro-
phic scars was further improved by Zouboulis
et al. [72, 94] through the application of a device
constituted of a small liquid nitrogen dewar
engaging a single use, 20-gauge needle instead of
a tip to spray liquid nitrogen through connected
by a flexible, long metallic cryoprobe stem
(Fig. 85.9). The cryoprobe stem was luer-locked
to the needle. The shape of the cryoprobe stem
was variable so that the dewar can stay upright
429
Epidermis
Recovery zone
-22°C isotherm
Freezing Iceball
zone
-22°C isotherm
Recovery zone 0°C isotherm
-22°C isotherm
Recovery zone Cryoneedle
during freezing. The shape of the needle could
also be changed in order to form a hook.
However, the results obtained by using open-
ended hypodermal cryoneedles were suboptimal
resulting in the necessity of up to ten sessions for
scar flattening. In 2003, Har-Shai et al. [96, 97]
refined the technique by developing the CryoShape
intralesional cryoneedle (CryoShape, Etgar Group
International, Kfar Saba, Israel) (Figs. 85.10 and
85.17). A sharp-cutting, sealed, distal tip enhances
the penetration of the often hard, rubbery, and dense
hypertrophic scars and keloids. The proximal end of
the cryoprobe is connected via an elongation tube to
a cryogen source. By forcing liquid nitrogen to cir-
culate through the needle, an ice ball around the
cryoneedle develops causing the abutted scar tissue
to be completely frozen while the generated gas is
dispersed to the atmosphere (Fig. 85.18).
An ice cylinder is formed around the embed-
ded part of the needle within the deeper tissues.
430
Fig. 85.19 Pyrometer-thermocouple apparatus with
three thermocouples mounted in needles of different
width and length
The distance of extension of freezing can be clin-
ically estimated by the degree of extension of the
whitish ice balls formed around the points of con-
tact between the skin surface and the visible por-
tions of the needle. Compression of the lesions is
accomplished by pooling the visible parts of the
needle up. Main advantages of intralesional cryo-
surgery are minimal surface destruction and min-
imal induction of skin depigmentation compared
to the contact and spray techniques [98, 99, 110,
111], which can be further reduced in the future
by using peripherally insulated needles.
Methods of Monitoring Tissue
Temperature
Although the depth of tissue to be frozen should be
exactly monitored in cryosurgery of malignant skin
tumors [103], in the treatment of keloids and hyper-
trophic scars monitoring of freeze depth is optional.
The progress of freezing can be clinically judged by
the duration of freezing, the thawing of the lesion
and the measurement of the lateral spread of freeze
(contact technique) or radius of iceball. To supple-
ment clinical estimation the tissue temperature can
be monitored with a pyrometer-thermocouple appa-
ratus using thermocouples mounted in 25- to
30-gauge needles [112] (Fig. 85.19). The thermo-
couples are inserted into the skin so that the tip lies
beneath or lateral to the lesion. Other monitoring
techniques are the measurement of the electrical
impedance in frozen tissue [97, 113] (Fig. 85.20),
ultrasound [114, 115] and infrared thermometry
C.C. Zouboulis et al.
Fig. 85.20 NiCr-Ni thermocouples (temperature drift of
0.01 %) which are connected to a GTH 1160 digital quick
response thermometer
[116]. Further improvement could provided by
devices combining an ultrasound microtransducer
to the nitrous oxide cryoprobe at the center of the
probe tip permitting ultrasonographic monitoring of
the tissue during freezing [117].
Practical Procedures
In following the practical procedures for the
cryosurgical treatment of keloids and hypertro-
phic scars are described step-by-step. Although
the techniques seem rather simple the physician
using cryosurgery has to be a certified dermatolo-
gist in order to securely diagnose the disease and
have knowledge of the skin and subcutaneous tis-
sues. In addition, the physician should have had
training in cryosurgery. Prior to treatment follow-
ing general measures have to be taken:
1. The patient has to be informed about the proce-
dure, the reported results of the technique and the
personal experience of the cryosurgeon as well as
the complications which may occur. In sensitive
patients lidocaine-prilocaine 1:1 crème [118] has
to be prescribed and be occlusively applied by
the patient on the lesion(s) to be treated 1 h prior
cryosurgery. Instead of long explanations about
the technique which may confuse the patient a
simplified information, a letter about cryosurgery
can be prepared and distributed to the patients
during waiting their treatment (Fig. 85.21).
85 Cryosurgical Treatment of Keloids and Hypertrophic Scars 431

Fig. 85.21 A simplified information letter about cryosur-
gery used in the Departments of Dermatology,
Venereology, Allergology and Immunology, Dessau
Medical Center, which informs the patient about the tech-
nique, its advantages, possible complications and advice
the patient what he has to do to help the physician to give
him optimal care. The letter is distributed to the patient
either when he decides for cryosurgery and books an
appointment or during waiting his treatment
432 C.C. Zouboulis et al.

Fig. 85.21 (continued)

85 Cryosurgical Treatment of Keloids and Hypertrophic Scars
Fig. 85.22 Desinfection of the lesion to be treated using
a sterile gauze soaked in ethanol solution
2. The cryoprobe tips have to be desinfected
after every treatment either by soaking them in
ethanol solution or by dry sterilization.
3. Gloves have to be worn during the
procedures.
4. The lesion to be treated has to be desinfected
using sterile gauze soaked in ethanol solution
(Fig. 85.22).
Contact Technique
1. The cryoprobe tip has to be chosen so that it
fits to the size of the lesion in order to avoid
freezing of the peripheral healthy tissue
(Fig. 85.23). The size of probe tips have to be
similar or even better a little smaller than the
size of the lesion taken into consideration that
an iceball is formed during freezing which
spreads laterally to the lesion.
433
Fig. 85.23 Choice of the adequate cryoprobe tip for the
different areas of the lesion to be treated so that it fits to
the size of the lesion or, even better, it is a little smaller
than the size of the lesion
2. When using a liquid nitrogen hand unit with
silicone exhaust tubing, the tubing has to be
frozen at a position away from the patient and
the physician, otherwise the tubing will flail
and finally freeze to a position that may dis-
turb the treatment (Fig. 85.24).
3. The time of freezing for each lesion or a part
of it has to be controlled. For keloids and
hypertrophic scars a single freeze-thaw ses-
sion of 20–60 s has to be used, depending on
the volume of the lesion (Fig. 85.25).
4. Large scars can be treated with specially
formed cryoprobes, like a flat linear probe for
a linear scar [77] (Fig. 85.5), or by classical
small probes in order to induce significant
pressure and vasoconstriction on fragments of
the lesion (Fig. 85.26).
5. As mentioned above, the optimal use of the
technique allows exact freezing of the lesion
434
Fig. 85.24 Direction of the silicone exhaust tubing and
the liquid nitrogen away from the patient and the physi-
cian during treatment in order to avoid unwanted freeze
without any freezing of the peripheral healthy
tissue (Fig. 85.27).
6. If there is no intervention after cryosurgery,
the physical course of the cryoreaction is:
(a) Peripheral erythema, occurring immedi-
ately to 30 min after cryosurgery
(Fig. 85.28).
(b) Edema of the lesion, occurring between
a few minutes and some hours after
treatment (Fig. 85.29).
(c) Bulla formation, usually presenting
between 1 and 3 days after treatment
(Fig. 85.30).
(d) Exudation, lasting between a few to
14 days after cryosurgery.
(e) Mummification, whereas a serum crust
is built from the second to the fourth post
treatment week.
(f) Healing, with a flat slightly atrophic
scar.
C.C. Zouboulis et al.
Fig. 85.25 Control of freezing time is performed by a
chronometer incorporated to the device or by a hand-
operated chronometer
7. In order to minimize erythema and edema
occurring after cryosurgery a mild, non-
atrophogenic steroid cream (e.g. hydrocor-
tisone aceponate, hydrocortisone buteprate,
hydrocortisone-17-butyrate, methylpred-
nisolone aceponate, prednicarbate) has to
be applied on the lesion immediately after
treatment, especially in areas that are prone
to react with strong edema (e.g. facial
area).
8. The patient is requested to visit again the phy-
sician when the bulla is formed so that the
physician or his assistant could aspirate the
serum content with a sterile fine needle (e.g.
26-gouge). The bulla roof has to left on the
lesion as a natural protection film (Fig. 85.31).
The bulla has to be desinfected using a sterile
gauze soaked in ethanol solution before been
aspirated.
9. The patient gets prescribed a desinfection-drying
solution (e.g. chlorhexidine 1 % solution, triclo-
san solution) or a lotion (e.g. chlorhexidine 1 %
in lotio alba aquosa) to be used once daily on the
lesion.
85 Cryosurgical Treatment of Keloids and Hypertrophic Scars
Fig. 85.26 Treatment of large keloid by a small cryo-
probe tip in order to induce significant pressure and vaso-
contraction on the lesion. Treatment is performed by
repeated freezes on consequent fragments of the lesion
10. A new appointment is given to the patient for
evaluating the result and performing the next
session of treatment 4 weeks later. The treat-
ment has to be repeated once monthly, if
required. A total of three or more sessions sig-
nificantly increase the response rates and mini-
mize recurrences.
The clinical results to be obtained by the
technique are shown in Figs. 85.32, 85.33,
85.34, 85.35, 85.36, 85.37, 85.38, 85.39,
85.40, 85.41, and 85.42.
Spray Technique
The spray technique is not advisable for the treat-
ment of keloids and hypertrophic scars. However,
the physician who prefers to apply this technique
435
Fig. 85.27 An example of optimal cryosurgery: exact
freezing of the lesion without any freezing of the periph-
eral healthy tissue
because of his overall experience has to use the
confined-spray technique (Fig. 85.15) following
a procedure similar to the one described for the
contact technique. Following additional mea-
sures have to be taken:
1. The spray has to be emitted from a distance of
1–2 cm from the target site and at 90-degree
angle to it.
2. A single freeze-thaw session of 20–60 s has to
be used, depending on the volume of the
lesion. If the open-spray technique is applied
two freeze-thaw sessions of 20–30 s are
required in order to limit the ice ball radius
and to obtain results similar to the ones
obtained by the contact method.
3. Point-spraying exhibits better results in
keloids and hypertrophic scars than a paint
brush or spiral pattern of spray.
436
Fig. 85.28 Peripheral erythema immediately after
cryosurgery. Erythema is present already during thawing
of the lesion
Cryosurgery Combined
with Intralesional Corticosteroids
Lesions, mostly keloids, being refractory or min-
imally responding to cryosurgery performed as
monotherapy after at least six sessions, may
improve by a combination of cryosurgery and
intralesional steroids. Intralesional betametha-
sone or triamcinolone (up to 2 mg/cm2 lesional
surface) are injected through a luer-locked
26-gouge needle 30–60 min after cryosurgical
treatment, performed as described above. This
delay is required in order to allow the lesions to
enter the edematous phase of cryoreaction, this
makes intralesional injections easier and leads
the fluid into the area of minor resistance, which
is in that case the lesion due to the edema.
C.C. Zouboulis et al.
Fig. 85.29 Lesional edema presenting a few minutes
after cryosurgical treatment
If intralesional injections would be performed
prior to cryosurgery or as monotherapy, the lesion
would show resistant to accept the fluid volume
leading to a concentration of the fluid at the
healthy periphery of the lesion and finally to the
well-known perilesional atrophy after intrale-
sional corticosteroid injections in keloids. In
addition, the corticosteroid concentration of up to
2 mg/cm2 lesional surface has also been defined
in order to avoid perilesional atrophy. On the
other hand, corticosteroid injections in keloids
are painful, and, therefore, a better acceptance is
occurring if the injections are performed in
edematous tissue. In patients, who despite this
improved procedure continue to feel pain during
the corticosteroid injection, a mixture of
corticosteroid-lidocaine 1 % 1:1 can be injected.
Results of the technique are shown in Fig. 85.43.
85 Cryosurgical Treatment of Keloids and Hypertrophic Scars 437

and avoids sutures. The carbon dioxide laser

setting is 11 W, 2 mm beam diameter, and
continuous discharge, energy 350 W/cm2.
Cryoprevention (20–30 s at −86 °C or
−196 °C) has to be performed on the resultanting
fresh scar after healing, repeated every 4 weeks
for at least 6 months. If intralesional corticoste-
roids are additionally applied, the first injection
has to be made intraoperatively, followed by
injections once monthly combined with
cryosurgery according to the procedure described
above. Results can be seen in Fig. 85.45.

Intralesional Cryosurgery

1. The lesion is desinfected and translesional

Fig. 85.30 Bulla formation presenting between 3 days
after cryosurgical treatment
Surgical Debulkment Prior
to Cryosurgery
Cryosurgery of large voluminous keloids is a dif-
ficult task. These lesions are better to be surgi-
cally removed and postsurgical cryoprevention,
with or without intralesional corticosteroids,
could be applied in order to decrease the recur-
rence rate. However, recurrences are unavoidable.
Before surgery is performed following facts have
to be taken into consideration:
(a) Intramarginal excision is advisable because
it is followed by a lower recurrence rate when
compared to extramarginal excision
(Fig. 85.44).
(b) Removal of the lesion by the carbon dioxide
laser provides a high degree of hemostasis
anesthesia is performed by lidocaine 1 %
solution.
2. The lesion is grasped between the index and
thumb and the cryoneedle is inserted into the
core of the scar at the one border of the lesion
to penetrate and exit on the surface of the
opposite distal edge of the scar, thus maxi-
mizing the volume of scar tissue to be
frozen.
3. The cryoneedle has to be directed towards
the longest dimension of the scar.
4. The proximal part of the cryoneedle is con-
nected to the liquid nitrogen dewar via an
elongation tube (Figs. 85.9 and 85.10).
5. Compression of the lesion is accomplished
by pulling the visible parts of the cryoneedle
up with the help of the connected cryosurgi-
cal device.
6. The cryogun is activated and LN is passed
through the needle lumen, the generated gas
is dispersed by the freeze secure vent to the
atmosphere. At the beginning of freezing
two iceballs are formed at the sites of contact
between the visible portions of the needle
and the skin.
7. These circles increase in diameter by con-
tinuation of freezing. In addition, an ice cyl-
inder is formed around the embedded part of
the needle in the deeper tissue. This is visible
438 C.C. Zouboulis et al.

a b

c d

Fig. 85.31 After desinfecting the lesion the serum content is aspirated with a sterile 26-gouge needle (a, b). The pro-
cedure is completed without destructing the bulla roof (c), which is left on the lesion as a natural protection film (d)

a b

Fig. 85.32 Keloid at

the chest of a patient
before (a) and 2 months
after a single session of
cryosurgery with
nitrous oxide, 30 s,
contact technique (b).
A reduction of the
lesional volume of
more than 50 % can be
observed
85 Cryosurgical Treatment of Keloids and Hypertrophic Scars 439

a b

Fig. 85.33 Two-year-old post acne keloids at the right technique (Reprinted from Zouboulis et al. [5]. With per-
cheek of a patient before (a) and 8 months after (b) the last mission from American Medical Association)
of seven sessions with liquid nitrogen, 30 s/lesion, contact

a b

Fig. 85.34 The left cheek of the same patient before (a) and 8 months after (b) the last of seven sessions with liquid
nitrogen, 30 s/lesion, contact technique

a b

Fig. 85.35 Large acne keloids at the right shoulder of an 18-year-old male patient before (a) and 2 months after 12
sessions with nitrous oxide, 40–60 s/lesion, contact technique (b)
440 C.C. Zouboulis et al.

a b

Fig. 85.36 Detail from Fig. 85.35. Impressive improvement of the keloids (a; from ref. [81]) 2 months after 12 ses-
sions with nitrous oxide, 40–60 s/lesion, contact technique (b)

a b

Fig. 85.37 Huge keloids after chemical burn with sulph- sessions initially with liquid nitrogen (four sessions) and
uric acid and contraction of the right elbow joint in a finally with nitrous oxide (five sessions), 30 s/lesion, con-
21-year-old male patient before (a) and 1 year after nine tact technique (b). Elbow mobility is again complete

through the skin and gradually spreads
towards the surface.
8. The procedure ends when the whole lesion and
an additional margin of 5 mm get frozen, inde-
pendently of the duration of freeze. The needle
is left to thaw and is pooled out of the lesion.
9. Since some bleeding may occur after thaw-
ing a sterile firm dressing has to be applied.
10. Postsurgical care is similar to those described
above.
11. The treatment can be repeated every
6 months. One to three sessions can lead to
optimum results.
Results of the technique are shown in Figs. 85.46,
85.47, 85.48, and 85.49.
85 Cryosurgical Treatment of Keloids and Hypertrophic Scars 441

a b

Fig. 85.38 Acne scars at the chest of a 22-year-old female patient before (a) and 1 month after the last of nine sessions
with nitrous oxide, 30 s/lesion, contact technique (b)

Cryopeeling 6. A nitrous oxide cryosurgical device (contact

1. Selection of patients has to be performed:
dark white skin patients, patients who deny
to avoid sunbathing 1 month before treat-
ment, during the treatment period and
2 months after treatment, patients taking
drugs inducing hyperpigmentation and
patients who want to experience immediate
results have to be excluded.
2. During the treatment the patient is lying into
a reclining armchair and the physician is sit-
ting at the top of patient’s head.
3. No sedation or premedication is required.
4. Goggles can used to cover patient’s eyes.
5. The facial skin is cleaned with gauze soaked
in ethanol solution. Ethanol is left to evapo-
rate before starting the treatment.
method) with a round cryoprobe tip of 2 cm
diameter are used for cryopeeling.
7. Cryopeeling is horizontally started from the
middle of the forehead towards either
direction and continues according to the plan
shown in Fig. 85.50. The cryoprobe tip is
slowly moved over the skin in order to leave
a fine ice film on it.
8. The skin is stretched and held tight to ensure
even application of the ice film.
9. Individual deeper scars are treated for a lon-
ger period of time to increase depth of
cryosurgery.
10. The whole facial skin surface has to be
treated in order to limit borderline postin-
flammatory hyperpigmentation, which is one
of the disquieting side effects.
442 C.C. Zouboulis et al.

a b

Fig. 85.39 Two-year-old hypertrophic scar before (a) from Zouboulis et al. [5]. With permission from American
and 2 months after the last of four sessions with liquid Medical Association)
nitrogen (b), 30 s/lesion, contact technique (Reprinted

a b

Fig. 85.40 (a) Six-month-old 22 cm long hypertrophic scar on the anterior base of neck following thyroidectomy.
(b) 6 months following the last five sessions with contact cryosurgery technique, 30 seconds, with liquid nitrogen
85 Cryosurgical Treatment of Keloids and Hypertrophic Scars 443

a b

Fig. 85.41 Two-year-old hypertrophic scars before (a) and 10 months after the last of six sessions initially with liquid
nitrogen (two sessions) and finally with nitrous oxide (four sessions), 30 s/lesion, contact technique (b)

a b

Fig. 85.42 Five-month-old hypertrophic scars before (a; mentation is observed due to cryosurgery; interestingly
from ref. [81]) and 1 year after three sessions with nitrous the second lesion on the physiologically pigmented skin
oxide, 30 s/lesion, contact technique (b). In the lesion on of the shoulder is not hypopigmented
the hyperpigmented skin of the arm long-term hypopig-
444
a b
Fig. 85.43 Hypertrophic scar (a) treated with three ses-
sions of combined cryosurgery (liquid nitrogen, 30 s, con-
tact technique) and intralesional corticosteroid injections
(betamethasone, 2 mg/cm2 lesional surface). Good clinical
a b
Fig. 85.44 Intramarginal removal of huge keloids (a)
with the carbon dioxide laser and intraoperative applica-
tion of intralesional corticosteroid injections into the scars
11. The skin reacts with erythema and light edema
presenting immediately after cryopeeling and
lasting up to 24 h.
12. A mild, non-atrophogenic steroid cream (e.g.
hydrocortisone aceponate, hydrocortisone
buteprate, hydrocortisone-17-butyrate, meth-
ylprednisolone aceponate, prednicarbate) can
be applied on the lesion immediately after
treatment in order to reduce erythematous
reaction.
13. After 2–3 days a fine scaling of the superfi-
cial epidermis is observed.
C.C. Zouboulis et al.
result but also a characteristic skin atrophy expanding
over the borders of the initial scar is seen as a side-effect
of the applied corticosteroid (b)
followed by three sessions of cryoprevention (liquid nitro-
gen, 30 s/lesion, contact technique) (b)
14. Treatment has to be repeated once monthly
during the winter period of the year (October
to April at the north hemisphere, six sessions
per year) and can last 2–3 years.
15. A sunscreen has to be wared during the
intermission between two sessions of
treatment.
A more aggressive cryopeeling procedure
has been described by Graham [8] and
Chiarello [100] using liquid nitrogen spray for
5–30 s on 8 cm2 facial skin fragments by the
85 Cryosurgical Treatment of Keloids and Hypertrophic Scars
a paint brush technique. This technique leads to
b local necrosis and formation of milia have been
Fig. 85.45 Huge keloid at the neck before (a) and after
intramarginal excision with the carbon dioxide laser in
general anesthesia and intraoperative intralesional corti-
costeroid injections followed by 12 sessions of cryopre-
vention (liquid nitrogen, 30 s/lesion, contact technique)
and intralesional corticosteroids (triamcinolone, 2 mg/cm2
lesional surface; b)
445
long-lasting erythema. According to our opin-
ion cryopeeling has to be a mild technique,
since dermabrasion with or without punch
excision and punch elevation is more adequate
and to better controlled in the treatment of
deeper atrophic scars.
Complications
and Contraindications
From the various temporary or permanent compli-
cations described after cryosurgery [2, 8, 83] local
pain during and/or shortly after treatment and
lesional hypopigmentation and/or peripheral
hyperpigmentation (Fig. 85.42) are the major side
effects occurring in the treatment of keloids and
hypertrophic scars. Here is the intralesional cryo-
surgery advantageous, since the initial hypopig-
mentation resolves in most of the cases with time,
even in black skin patients [98] (Fig. 85.49). Large
local edema, wound infection, local hypoesthesia,
reported in single patients [5]. Delayed wound
healing is an additional side effect mostly occur-
ring after the combined cryosurgery with intrale-
sional corticosteroids regimen [74]. There are a
few absolute contraindications including cold-
inducible urticaria, cryoglobulinemia, cryofibrino-
genemia and Raynaud’s disease [4]. As relative
contraindications are reported collagen diseases,
lesions at the extremities of old patients and black
skin because of the long-term depigmentation
occurring due to melanocyte death.
Intralesionalc cryosurgery induces mild pain
or discomfort during and after the procedure,
which can easily be managed. Local edema and
epidermolysis, followed by a relatively short re-
epitheliazation period, are evident.
446 C.C. Zouboulis et al.

a b

Fig. 85.46 Marked flattening of a recalcitrant keloid at the chest area of an elder male patients before (a) and after four
sessions of intralesional cryosurgery with the initial open needle technique (b)

a b c

Fig. 85.47 Intralesional cryosurgery with the closed
cryopobe: (a) A preoperative view of a 6-year-old pedun-
culated keloid due to piercing, with a volume of 1.9 cm3
on the posterior aspect of the left lobule which has been
treated unsuccessfully by intralesional corticosteroid
injections. (b) Intraoperative intralesional cryosurgery of
the keloid. (c) 18 months after a single intralesional cryo-
surgery the keloid has completely disappeared with no
recurrence (Reprinted from Har-Shai et al. [97]. With per-
mission from John Wiley & Sons)
85 Cryosurgical Treatment of Keloids and Hypertrophic Scars 447

a b

Fig. 85.48 Huge earlobe keloid in a 12 year-old boy before (a) and 4 months after a single intralesional cryosurgery
session (b)

a b

Fig. 85.49 Huge keloid at the right chest area of a black skin patient (a). (b) Strong hypopigmentation after intrale-
sional cryosurgery and secondary wound healing. (c) Complete repigmentation of the lesion a few months later
448
Fig. 85.50 Cryopeeling starts from the forehead and
ends at the chin. The cryoprobe tip is slowly moved from
the middle of the face towards the periphery at either
direction in order to leave a fine ice film on the skin. The
skin is stretched and held tight to ensure even application
of the ice film. The treatment is applied to the entire facial
area
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 Intralesional Cryosurgery
for the Treatment of Hypertrophic
86
Scars and Keloids

Yaron Har-Shai and Christos C. Zouboulis

Abstract
This chapter is aimed to describe in a comprehensive way the intralesional
cryosurgery method to treat hypertrophic scars and keloid by a novel cryo-
needle. This needle cryoprobe which is inserted into the core of the hyper-
trophic scar and keloid is connected to a canister of liquid nitrogen, which
causes the cryoprobe to freeze thereby freezing the abutting scar tissue
from the inside out.
This chapter describes in detail the cryobiological and scientific back-
ground of the technology which includes the thermal history, cellular and
structural effect, histomorphometric studies and skin pigmentation
changes of treated scars. Practical clinical tips for a successful clinical
application of the technology are presented which include the treatment
technique, intralesional cryosurgery for auricular keloids, pain control
regimen, the “tilt” maneuver and the “click” maneuver, adverse effects and
contraindications. Patient satisfaction and clinical results are evaluated
and presented by pre- and post-clinical photos of the treated scars.
The intralesional cryosurgery technology is a new, evidence-based and
fundamental adjunctive wound healing therapy which is responsible for
the rejuvenation of post-cryosurgery hypertrophic scar and keloid by cre-
ating a normal wound healing environment.

Keywords
Intralesional cryosurgery • Cryoneedle probe • Hypertrophic scar • Keloid •
Liquid nitrogen • Equipment • Pain control regimen • Adverse effects •
Contraindication

Y. Har-Shai, MD (*)
Plastic and Reconstructive Surgery Departments,
Carmel and Linn Medical Centers, Haifa, Israel
The Bruce Rappaport Faculty of Medicine,
Technion- Israel Institue of Technology, Haifa, Israel
e-mail: yaron07@yahoo.com
Laboratory for Biogerontology, Dermato-
C.C. Zouboulis, MD Pharmacology and Dermato-Endocrinology, Charité
Departments of Dermatology, Venereology, Universitaetsmedizin Berlin, Campus Benjamin
Allergology and Immunology, Dessau Medical Franklin, Berlin, Germany
Center, Dessau, Germany e-mail: christos.zouboulis@klinikum-dessau.de

© Springer-Verlag London 2016 453

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_86
454
Introduction
Background
Several studies during the last two decades have
proved cryosurgery to be an effective and safe
therapeutic regimen in hypertrophic scars and
keloids [1]. Because of its major advantage of a
low relapse rate, the technique, either as mono-
therapy or in combination, has been established
as the treatment of choice for keloids and hyper-
trophic scars.
Cryosurgery as a monotherapy was first used
by Shepherd and Dawber in [2]: they treated 17
patients with keloids with a single contact cryo-
surgical session achieving 80 % improvement of
the lesions; however, they observed a high recur-
rence rate of 33 %. With the exception of case or
technical reports, further monotherapy studies
have probably been delayed by this rather disap-
pointing recurrence rate, until Mende [3, 4], as
well as Zouboulis and Orfanos [5–9] have shown
that repeated contact cryosurgical sessions can
exhibit a beneficial effect on keloids and hyper-
trophic scars and additionally prevent relapses. In
the meantime, 72 of 89 patients with hypertro-
phic scars (81 %) and 241 of 356 patients with
keloids (68 %) documented in several studies
have shown more than 50 % improvement or
complete regression after cryosurgery [10].
However, 1–20 treatment sessions were
required to achieve these results using the con-
tact cryosurgery method. Thus, the need for
new, more potent and quickly effective cryosur-
gical methods and instrumentation has been
recognized.
Intralesional Cryosurgery
Intralesional cryosurgery using cryoneedles was
initially described by Weshahy [11] for the treat-
ment of epidermal and dermal skin lesions. A first
intralesional cryosurgery method for the treat-
ment of keloids was introduced by Zouboulis [7]
[also in Zouboulis et al. [8, 12]] and Gupta and
Kumar [13] and was improved and further devel-
oped by Har-Shai et al. [14–17]. This technique
exhibits an increased efficacy in the treatment of
Y. Har-Shai and C.C. Zouboulis
hypertrophic scars and keloids when compared
with the contact method, due to the enhanced
freezing area of deeply located scar tissue. In
addition, fewer cryosurgical sessions are required
and less hypopigmentation is evident following
the application of intralesional cryosurgery.
Intralesional Cryoneedle
Weshahy [11] was the first to describe a cryonee-
dle probe which consisted of a curved hypoder-
mal needle which was inserted underneath the
skin lesion/tumor. Zouboulis et al. [8, 12] further
developed this method by freezing hypertrophic
scars and keloids using a hypodermal needle
(long G20). Later, Gupta and Kumar [13] have
published their experience with intralesional
approach by employing simultaneously several
hypodermal needles (G21) to treat hypertrophic
scars and keloids. The results which have been
obtained using these open-ended and thin hypo-
dermal cryoneedles demonstrated suboptimal
results which necessitated up to 10 cryosurgical
sessions for scar flattening. In 2003, Har-Shai
et al have refined the technique by developing a
novel intralesional cryoneedle (CryoShape, FDA
and CE approved, Etgar Group International
LTd., Kfar Saba) (Fig. 86.1). This probe consists
of an elongated double-lumen un-insulated nee-
dle with a safety vent and a sharp-cutting, sealed,
distal tip which enhances the penetration of the
often hard, rubbery, and dense hypertrophic scars
and keloids. The proximal end of the cryoprobe is
connected via an elongation tube to a cryogen
source. By forcing liquid nitrogen to circulate
through the needle, an ice ball around the cryo-
needle developed causing the abutted scar tissue
to be completely frozen while the generated gas
is dispersed to the atmosphere.
Experimental Studies
Thermal History
Four phases, which compose the thermal history,
are measured during cryosurgery freezing process
(Fig. 86.2).
86 Intralesional Cryosurgery for the Treatment of Hypertrophic Scars and Keloids
Fig. 86.1 Upper – The CryoShape cryoprobe. Middle – The
intralesional cryosurgery system composed of the CryoShape
cryoprobe connected to the cryogun. Lower – Intraoperative
view of the intralesional cryosurgery technique employing the
CryoShape for the treatment of a sternal keloid. The exposed
parts of the cryoneedle are protected by sterile gauzes to pre-
vent possible cryo-injury to the surrounding skin
Fig. 86.2 Schematic representation of the thermal history
measurements during the cryosurgery process (contact/
intralesional), which include four phases: Cooling rate
455
1. Cooling rate – the ratio between the initial
room temperature and the lowest freezing
temperature reached in the time interval
[T1-T2]/ [t2-t1].
2. End temperature – the lowest temperature
reached during freezing [T5].
3. Hold time – the time in which the freezing pro-
cess retained its lowest temperature [t3-t2].
4. Thawing rate – the ratio between the time
elapsed since the cessation of the freezing
process and the tissue temperature difference
(up to 0 °C) [T4–T3]/[t4–t3].
To evaluate the possible mechanisms of injury
during intralesional cryosurgery, the four thermal
history phases of an isolated intralesional cryo-
needle and in an ex-vivo fresh swine gluteus
muscle has been reported by Har-Shai et al. [15].
The data gathered were compared with a standard
contact cryoprobe (1 cm diameter), which is in
common use for the treatment of hypertrophic
scars and keloids.
The thermal history of the isolated intrale-
sional cryoprobe showed a fast cooling rate
(200 °C/min). The end temperature was shown to
be −196 °C, The thawing rate was equally fast.
The surface cryoprobe also exhibited a fast cool-
ing rate (160 °C/min), i.e. the probe temperature
was −136 °C. The thawing rate, however, was
slow (40 °C/min), since no active rewarming of
the lesions was administered. The ex vivo studies
[T1-T2]/[t2-t1], End temperature [T5], Hold time
[t3-t2] and Thawing rate [T4-T3]/[t4-t3]
456
in the swine muscle revealed a completely differ-
ent thermal behavior. The intralesional cryoprobe
showed a much slower cooling rate (20 °C/min)
with an end temperature of −30 °C. However, the
thawing rate was faster (35 °C/min). The contact
probe showed fast cooling and thawing rates
(80 °C/min) with an end temperature of −100 °C.
Skin Pigmentation Changes
of Treated Scars
Gage et al. [18] have executed a controlled freez-
ing injury using the contact method on the skin of
adult mongrel dogs. The tested end temperatures
were between 0 and –40 °C. Biopsies of the vari-
ous treated sites were obtained and evaluated by
light and electron microscopy. The results of this
study revealed that in the freezing range from 0 to
−4 °C viable melanocytes with melanin were
identified. In the range between –4 and –7 °C,
lysis of pigment granules or enzymatic melanin
digestion within melanocytes and keratinocytes
were noticed in the deeper layer of the frozen epi-
thelium. Between the ranges of –7 to –30 °C, no
melanocytes or melanin were demonstrated. The
authors concluded that selective destruction of
melanocytes could be achieved in the tempera-
ture range from –4 to –20 °C, while repigmenta-
tion was clearly temperature-dependent and did
not occur at temperatures colder than –30 °C.
On the basis of the ex vivo work and bearing in
mind the results demonstrated by Gage et al.
[18], a clinical study has been executed by
Table 86.1 Upper – Summary of the time
measurements of the four phases of the
thermal history recorded on the scar surface
during contact and intralesional cryosurgery
(Mean value ± STD, ** t-test (2-tailed)).
Lower – Summary of the post cryosurgery
scar surface hypopigmentation following the
contact and intralesional cryosurgery
techniques. Score 2 represents treated scar
skin color with hypopigmentation without
pigment islets (Witney –Mann test,
(p < 0.0001)
Y. Har-Shai and C.C. Zouboulis
Har-Shai et al. [15] to evaluate the skin surface
thermal history of the two methods (intralesional
vs. contact) and its effect on the melanocytes
viability and the possible etiology of post cryo-
surgical skin hypopigmentation.
Assessment of hypopigmentation was exe-
cuted 6 months after the treatment, by comparing
skin pigmentation on the keloid surface with the
healthy surrounding skin in a scale from 0 to 2:
0-Treated skin color without significant pigment
changes
1-Treated skin color with hypopigmentation and
pigment islets
2-Treated skin color with hypopigmentation
without pigment islets
The comparison of the surface thermal histories
of the two cryosurgery techniques revealed a signif-
icant difference (Table 86.1). Intralesional cryosur-
gery had significantly slower cooling (6.09 ± 4.56 °C/
min) and thawing (13.47 ± 9.04 °C/min) rates when
compared with the cooling (54.52 ± 32.17 °C/min)
and thawing (89.00 ± 86.42 °C/min) rates of the
contact method (p < 0.000001). The end tempera-
ture of the contact technique (−46.77 ± 14.74 °C)
was significantly cooler when compared with that
of the intralesional method (−15.55 ± 6.77 °C)
(p < 0.000001). There was a trend for the hold time
of intralesional cryosurgery (82.67 ± 138.03 s) to
be longer than the hold time of the contact method
(16.86 ± 23.49 s) (p < 0.059). The results revealed
a significant difference in skin pigmentation
between the two cryosurgical methods. In 91.7 %
86 Intralesional Cryosurgery for the Treatment of Hypertrophic Scars and Keloids
Fig. 86.3 A clinical case demonstrating the sequence in
pigmentation changes following the intralesional cryosur-
gery method executed on a keloid located on the right
axilla on a darked skin patient. Upper Left – pre operative
view. Upper Right – 1 week post cryosurgery demonstrat-
of the keloids treated by the contact technique
a significant hypopigmentation (score 1 and 2)
was noticed while the skin surface of the keloids
treated by the intralesional method did not exhibit
marked hypopigmentation (i.e. 0 % score 1 and 2)
(p < 0.0001) (Table 86.1, Fig. 86.3 ).
Therefore it has been assumed that the end tem-
perature during intralesional cryosurgery and the
moderate cooling and thawing rates, which are
measured on the keloid skin surface, are more
“friendly” for melanocyte survival. Thus, intrale-
sional cryosurgery destroys the core of the keloid,
while at the surface, cells including melanocytes are
much less affected and therefore less hypopigmen-
tation is evident (Table 86.1, Figs. 86.3 and 86.27).
Histomorphometrical Studies
Har-Shai et al. [14, 15] have studied the histo-
morphometrical changes occurring in the scar tis-
sue following intralesional cryosurgery. Biopsies
for histomorphometrical evaluation were taken
457
ing a blister. Lower Left – 3 weeks following cryo-
treatment, the blister has drained and hypopigmentation is
evident. Lower Right – Almost no hypopigmentation is
evident 6 months following cryo-treatment
from the pre-treated scar, and then 1 month and 3
months following the cryosurgical session.
Deparaffinized tissue sections were histochemi-
cally stained by Picrosirius red and examined by
polarization microscopy [19, 20]. Images were
captured by a three-chip (RGB) video camera
(Sony, Japan) and digitized with the aid of a
frame grabber and an IBM compatible PC,
equipped with a 17 in., high-resolution screen.
Computerized morphometrical analysis of col-
lagen fibers was then performed, using the Image
Pro Plus 4.5 software (MediaCybernetics, USA).
The orientation index (ORX) of the collagen fibers
in the HSK before and after cryosurgery, was eval-
uated using the Fast Fourier Transformation (FFT)
algorithm. The larger the index value, the greater
the degree of collagen fiber orientation in the scar.
The histomorphometric results have demon-
strated that the orientation index was significantly
higher in the post-treated scar (2.06 ± 0.7) as com-
pared to the untreated keloid (1.40 ± 0.2, p = 0.044).
Hence, the architectural pattern of the collagen is
more organized in the treated scar, i.e., the parallel
458
organization of the collagen fibers in the treated
scar is similar to that in the normal dermis, in con-
trast to the disorientation of the collagenous net-
work viewed in the non-treated scar.
Method of Treatment
Treatment Technique
With the patient lying at a supine position, the
skin surface of the scar is cleansed with disinfect-
ing solution and draped. The area of penetration
into the scar and the underlying subcutaneous tis-
sue is anesthetized locally, by a translesional
approach, with Bupivacaine hydrochloride ½ %
(marcaine) (Fig. 86.4). Thereafter, the sterile
cryoprobe is forced into the long axis of the scar
in a forward rotary movement, which is parallel
to the skin surface. The cryoneedle is inserted
into the core of the scar which is approximately
the mid height of the scar. The scar itself is
grasped between the index and thumb of the other
Fig. 86.4 A schematic diagram and a clinical photo (Right Upper) demonstrating the translesional technique to achieve
local anesthesia prior to inserting the cryoneedle probe into the scar
Y. Har-Shai and C.C. Zouboulis
hand, until the sharp tip of the needle penetrated
the opposite distal edge of the scar, thus maxi-
mizing the volume of scar tissue to be frozen.
Attention is taken to prevent any penetration of
the cryoneedle into uninvolved healthy surround-
ing skin. Sterile gauzes are placed under the
proximal and distal parts of the cryoprobe and
care is taken to assure that the vent nostril is posi-
tioned away from the patient to prevent acciden-
tal freezing of adjacent skin or tissue (Fig. 86.1,
bottom).
The proximal part of the probe is connected
via an elongation tube to the cryogun (CryoPro
Maxi 500 cc, Cortex Technology, Hadsund),
which is filled with liquid nitrogen to 3/4 of the
cryogen volume and about 30 min beforehand in
order to allow a sufficient pressure to build-up
inside it (about 0.7 ATM/ 10 psi). It is advisable
to label on the cryogen the filling time with liquid
nitrogen in order to make sure that 30 min have
elapsed prior to the cryo-treatment (Fig. 86.5)
and prevent confusion and possible malfunc-
tion. A full pressurized cryogen can operate
86 Intralesional Cryosurgery for the Treatment of Hypertrophic Scars and Keloids
Fig. 86.5 Upper – Following penetration of the cryo-
needle in to the scar and connection to the cryogun, the
cryogun is grasped and located in a higher position than
the scar to facilitate a downward flow of liquid nitrogen.
Lower – The filling time of the cryogen with liquid nitro-
gen is labeled on the bottle in order to make sure that
30 min have elapsed to build up the working pressure
prior to the cryo-treatment
continuously for 1 h, thus 2–3 medium size
keloids can be treated without the need to refill.
The cryogun is grasped or placed on a steady
surface which is located higher than the scar to
facilitate the liquid nitrogen flow (Fig. 86.5) with
459
no direct contact with the patient body. By activat-
ing the cryogun trigger, the pressure valve is
opened and the cryogen enters the cryoneedle,
thereby freezing the scar. A forced steam of the
liquid nitrogen gas flows out from the vent nostril
during the entire freezing process. The strength of
the steam flow, which is observed by the naked eye
during the entire freezing procedure, indicated an
appropriate working pressure. Two ice balls appear
shortly at the two cryoprobe penetration sites and
with time they gradually spread towards each
other until a complete freezing of the scar is
achieved clinically (Figs. 86.6 and 86.7). Following
the complete freezing of the scar which is evident
clinically, regardless of the duration of the cryo-
surgery process (without the necessity of time tak-
ing), the cryogun trigger is released to stop the
freezing process and the cryoneedle is left to thaw
for 1–2 min and is then withdrawn in a reverse
rotary movement. The length of the intralesional
cryosurgery process depends upon the scar vol-
ume and ranges between 5 min and 2½ h. After a
complete thawing of the scar is clinically noticed,
slight bleeding from the penetration points of the
needle requires the application of a sterile dress-
ing. The patients were instructed to wash daily the
treated scar and to apply an antibiotic ointment
until full healing was accomplished.
In cases were the scar was longer than the
cryoneedle length or very wide, two or three par-
allel needles or successive insertions of the same
needle were necessary to freeze the entire keloid
in one session (Fig. 86.8).
Intralesional Cryosurgery
for Auricular Keloids
In the medical literature some authors [21, 22]
warn of potential cartilage cryonecrosis when
freezing auricular keloids. On the other hand,
Faber [23] suggested that ear cartilage damage is
rare because stromal tissue, such as cartilage,
connective tissue and bone, is less cold-sensitive
than cellular elements. Reinforcement to the lat-
ter findings was demonstrated by Burge et al.
[24] who have shown experimentally and clini-
cally, that auricular cartilage cryonecrosis is a
460
Fig. 86.6 Sequential steps of the intralesional cryosur-
gery procedure. Left – following penetration of the cryo-
needle into the keloid on the posterior aspect of the lobule,
two ice balls are formed at the two penetration points of
the scar. The ice cylinder that forms around the embedded
dose-related phenomenon and is uncommon with
the freezing times used in clinical practice i.e.,
maximum of 30-s double freeze-thaw cycles.
Since the intralesional cryosurgery treatment
can reach up to 2½ h, the prevention of cryoin-
jury to the auricular cartilage (mainly helix and
antihelix) during the cryotreatment process
should be considered. Therefore, warm gauzes
(up to 30–40 °C) are placed opposite to the
treated scar, thus restricting the advancement of
the ice ball to create a full thickness freezing of
the cartilage (Fig. 86.9).
Y. Har-Shai and C.C. Zouboulis
part of the needle is not visible. Middle – gradual spread
of the two ice balls towards each other. Right – complete
freezing of the scar is achieved. No time taking is neces-
sary during the intralesional cryosurgery treatment
Pain Control Regimen
The application of liquid nitrogen to the skin
induces inflammation and pain [25]. De Souza
et al. [25] have elaborated in an experimental
model the cause of pain during application of
cryosurgery to the skin. It has been found that
pain is a result of two mechanisms. The first is
the inflammatory pain which is caused by media-
tors such as kinins and substance C, which stimu-
late the free terminal of the neural cells (C fibers)
to conduct a direct and rapid pain signal to the
86 Intralesional Cryosurgery for the Treatment of Hypertrophic Scars and Keloids
Fig. 86.7 Sequential steps of the intralesional cryosur-
gery procedure. Upper Left – Pre – operative view of a
large keloid of the left lobule following piercing. Two sur-
gical excisions have been executed with complete recur-
rence of the keloid. Upper Middle – following penetration
of the cryoneedle into the keloid on the posterior aspect of
the lobule, two ice balls are formed at the two penetration
points of the scar. Upper Right – complete freezing of the
scar is achieved. Left Bottom – Pre-operative view of a
brain. The second is the mechanical nociceptor
hypersensitivity which is produced by the cyto-
kines which are released by defense cells which
may intense the pain via the arachidonic acid/
cyclo-pxygenase products, sympathomimetic
amines, TNF- α, IL -1 and IL-8.
The pain experienced by the patient can be a
limiting factor in the effective use of skin
cryosurgery [26]. It has been demonstrated by
Gupta et al. [27] that the severity of pain during
skin cryosurgery ranged between 29.1 and
55.9 mm on the visual analogue scale (VAS)
while the pain score in the group which has
been pre-treated with topical eutectic lidocaine/
prilocaine cream 5 % (EMLA) was found to be
between 22.5 and 47 mm.
Cryosurgery has been reported to be beneficial
for the relief of pain due to post herpetic neuralgia
[28]. This can be explained by the sensitivity of
myelin and axons to cold, while the neural con-
nective tissue sheaths (perineurium and epineu-
rium) have survived apparently unchanged which
correlates to a second degree nerve injury [29].
461
large keloid on the left lobule following piercing. The
freezing process is terminated in order to prevent injury to
the helix cartilage and lobule tissue (the freezing demar-
cation border is evident). Mid Bottom – 3 weeks following
treatment scar necrosis is evident. Right Bottom – 6
months following intralesional cryosurgery the lobular
keloid is reduced significantly without distortion of the
lobule and with almost no hypopigmentation
Any score above 3 mm is considered an
uncomfortable annoying pain.
Therefore, profound attention has been taken
to minimize the pain and discomfort during and
after the intralesional cryosurgery treatment. It
has been found by the authors (unpublished data)
that severe pain (level of 6–8 mm in the VAS pain
scale of 1–10 mm) was reported immediately
after contact cryosurgery which was still present,
in a some reduced form (4–6 mm), following 4 h
post treatment. Therefore, a pain control protocol
has been developed which has showed an effec-
tive reduction in pain and discomfort during and
following the procedure [16, 17]. It accounts of
taking a pain reliever tablet 1 h prior to cryo-
treatment. Thereafter, a translesional approach
for local anesthesia with ½ % Buvicaine, in which
a 23G hypodermal needle is inserted perpendicu-
lar and through the entire thickness of the scar
tissue in order to infiltrate the subcutaneous fat
tissue beneath the scar, is executed (Fig. 86.4).
This method enables to infiltrate easily in to the
loose subcutaneous fatty tissue, thus causing a
462
Fig. 86.8 Upper – In cases that few scars are schedules
for cryosurgery, two cryoneedles can be inserted in paral-
lel in order to facilitate the treatment. Lower – Following
the intralesional cryotreatment, frost is developing on the
cryoneedle plastic housing. Gloved are advocated in order
to grasp the housing in order to prevent a frost bite
significant reduction in pain when compared with
the intralesional anesthesia which generates
increased pain due to the limited availability of
the often dense and hard scar tissue to expand.
Furthermore, no injury to the surrounding normal
skin is caused thus preventing possible develop-
ment of abnormal scarring. Immediately follow-
ing treatment and 1 h later pain reliever tablets
are taken (Fig. 86.10). The level of pain reported
by the patients [30] using this regimen had been
reduced significantly i.e. 1.94 mm during the
cryotreatment, 1.69 mm immediately after the
treatment and 2.38 mm 4 h post cryosurgery
(Figs. 86.11 and 86.12).
The “Tilt” Maneuvers
It has been found that during the freezing process
the working pressure inside the cryogun is almost
Y. Har-Shai and C.C. Zouboulis
Fig. 86.9 Top – intralesional cryosurgery for the treat-
ment of a posterior helical keloid. Bottom – warm gauzes
are placed opposite to the treated scar (anterior aspect of
the auricle) in order to prevent cryoinjury to the auricular
cartilage
steady, i.e. about 10 psi (0.7 ATM) which creates
a flow of 10 l/min. A filled cryogun enables freez-
ing for 1 h. It is possible to augment the freezing
process by tilting the cryogun in 30°. In such a
maneuver, the cross section between the liquid
nitrogen and gas inside the cryogun enlarges thus
causing a 10 % increase of pressure. This maneu-
ver fastens the freezing time and shortens the
treatment duration (Fig. 86.13).
The “Click” Maneuvers
During the freezing process the intralesional cryo-
needle, which is composed of stainless steel, is
adherent to the abutting frozen scar tissue around
it. As so, it is impossible to withdraw the cryo-
needle during the freezing process. Following
the complete freezing of the scar, the cryoneedle
86 Intralesional Cryosurgery for the Treatment of Hypertrophic Scars and Keloids
Fig. 86.10 A diagrammatic demonstration of the pain
control protocol which has proved to be an effective regi-
men in the reduction of pain and discomfort during and
Fig. 86.11 Upper – Ice ball induced by the contact cryo-
probe. The interface between the ice ball and unfrozen tis-
sue represents the 0 °C isotherm. The volume of tissue
located between the –22 °C isotherm and contact probe is
the lethal zone in which cells undergo cryonecrosis. Cells
situated in the warmer region between –22 °C isotherm and
the 0 °C isotherm (recovery zone) generally survive the
freeze. The melanocytes are located within the lethal zone.
Intralesional n=24
6
5.2
5
4
2.9
3 2.62
1.83
2 1.42
1
0
During Immediately after
Fig. 86.12 Summary of the mean pain scores using the
visual analogue scale (VAS), during, immediately follow-
ing treatment and 4 h post- intralesional and contact cryo-
surgery employing the pain control protocol. The pain
463
following the intralesional cryosurgery procedure. It con-
sists of pain relieving tablets together with the transle-
sional local anesthesia approach
Bottom – Ice ball induced by the intralesional cryoneedle.
The interface between the ice ball and unfrozen tissue rep-
resents the 0 °C isotherm. The volume of tissue located
between the –22 °C isotherm and contact probe is the lethal
zone in which cells undergo cryonecrosis. Cells situated in
the warmer region between –22 °C isotherm and the 0 °C
isotherm (recovery zone) generally survive the freeze. The
melanocytes are located within the recovery zone
Contact n=26 Control=100
4.1
3.54 3.58
After 4 hours
scores are significantly reduced in both cryo-treatment
modalities with improved pain control in the intralesional
method (Mann-Whitney Test)
464
Fig. 86.13 The “Tilt Maneuver”. By tilting the cryogen
by 30°, the pressure inside the cryogen is elevated by
approximately 10 %. The Cryogun is filled with Liquid
Nitrogen to 3/4 of its volume in order to enable the cre-
ation of gas i.e., the working pressure (10 psi). The cross
is left to thaw for 1–2 min. Since the cryoneedle
possesses high thermal conductivity, this thawing
time is relatively short, but some ice connections
still remain between the scar tissue and needle.
Therefore, after complete thawing of the needle is
evident (water drops appear on the exposed parts of
the needle) the cryoneedle is turned to the right for
about 90° in which a “click” is heard which indi-
cated that the ice connections are released and the
cryoneedle can be easily withdrawn (Fig. 86.14).
Clinical Results
It has been reported by Har-Shai et al. [14,
15, 31] that a total average of 51.4 % of scar vol-
ume reduction was achieved following one ses-
sion of intralesional cryosurgery treatment
(average preoperative hypertrophic scar/keloid
Y. Har-Shai and C.C. Zouboulis
section between the liquid nitrogen and gas inside the
cryogun enlarges by the “tilt maneuver” from a circle
(red) to an ellipse (red and yellow), thus causing an
increase in pressure. This maneuver fastens the freezing
time and shortens the treatment duration
scar volume = 1.82 cm3 ± 0.33; average post-
treatment volume = 0.95 cm3 ± 0.21; p < 0.0022).
Furthermore, the average volume reduction of ear
(helical and lobular) hypertrophic scars and
keloids was 67.4 ± 23 % (p < 0.005). The average
preoperative ear hypertrophic scar/keloid vol-
ume = 2.89 ± 0.69 cm3 (range 1–6 cm3) was sig-
nificantly reduced to = 1.17 ± 0.46 cm3 (range
0–4 cm3) (Figs. 86.15, 86.16, 86.17, 86.18, 86.19,
86.20, 86.21, 86.22, 86.23, 86.24, and 86.25).
Six months after a single session of intrale-
sional cryosurgery, a significant alleviation of
objective (hardness and color) and subjective
clinical symptoms (pain/tenderness and itchiness/
discomfort) were documented. The histomorpho-
metric analysis demonstrated rejuvenation of the
treated scars, i.e., parallelization, and a more
organized architecture of the collagen fibers
when compared to the pre-treated scars.
86 Intralesional Cryosurgery for the Treatment of Hypertrophic Scars and Keloids
Fig. 86.14 Left – After complete thawing of the needle is
evident (water drops appear on the exposed parts of the
needle) the cryoneedle is turned for about 90° (Right) in
Fig. 86.15 Top – Preoperative view of keloid scars on the
left cheek following Acne. Bottom – Post operative view
18 months following a single session of intralesional
cryosurgery demonstrates a complete flattening of the scar
with no hypopigmentation
Patient Satisfaction
In order to evaluate the patient degree of concern
and deformity from their keloid or hypertrophic
scars prior and after the intralesional cryosurgery
treatment, a modified “Gorney Gram” scale,
which had been designed and employed by Har-
Shai et al [16, 17], was applied.
465
which a “click” is heard which indicated that the ice con-
nections are released and the cryoneedle can be easily
withdrawn
The patients who were enrolled in this study
had undergone aesthetic surgery and have devel-
oped hypertrophic scars and keloids. In the origi-
nal “Gorney Gram scale” [32], the deformity is
judged by the surgeon while the degree of con-
cern is scored by the patient. In this modified
scale, each patient was asked to score two param-
eters, i.e. concern and deformity as follows:
Each patient was asked to describe in words
and thereafter to score his/her concern from the
scar (in a scale from 1 to 5) prior and follow-
ing the treatment (higher score represents least
satisfaction).
For the second parameter, each patient was
asked to describe in words and thereafter to
score the magnitude of his/her scar deformity
(in a scale from 1 to 5) prior and following
the treatment (higher score represents severe
deformity).
Median follow-up was 10 months (range
4–96).
Concern score at the end of the follow-up
was significantly lower than before intralesional
cryosurgery (p = 0.001) and the median (range) of
change in the concern score was: −4 (−4 to −2),
thus, 6 (55 %) had 4 points decrease; 2 (18 %)
had 3 points decrease and 3 (27 %) had 2 points
decrease.
Deformity score at the end of the follow-up was
significantly lower than before cryosurgery
(p = 0.001), and the median (range) of change in
466 Y. Har-Shai and C.C. Zouboulis

Fig. 86.16 Left – Preoperative view of a lobular keloid months following a single session of intralesional cryo-
following piercing with a complete recurrence following surgery demonstrates a complete involution of the scar
two surgical excisions. Right – Post operative view 18 with no hypopigmentation

Fig. 86.17 Left – Preoperative view of two keloid scars cryosurgery demonstrates a complete flattening of the scar
on the left helix following piercing. Right – Post operative with no hypopigmentation. No cartilage deformation is
view 18 months following two sessions of intralesional evident
86 Intralesional Cryosurgery for the Treatment of Hypertrophic Scars and Keloids
Fig. 86.18 Left – Preoperative view of two abutting
keloids on the right posterior auricular sulcus following
surgery. Middle – Post operative view 6 months following
the first session of intralesional cryosurgery. Almost 81 %
Fig. 86.19 Left – Preoperative view of a giant keloid on
the left posterior auricular sulcus following surgery. Post
operative view 3 months (Middle) and 24 months (Right)
deformity score was: −4 (−4 to −1), thus, 6 (55 %)
had 4 points decrease; 2 (18 %) had 3 points
decrease, 2 (18 %) had 2 points decrease and 1
(9 %) had one point decrease (Figs. 86.21, 86.26).
The obtained results demonstrate a significant
and relative quick reduction in dissatisfaction
among individuals suffering from unsightly and
bothering scars.
467
of the volume of the scars is reduced. Right – Post opera-
tive view 18 months following the second session of intra-
lesional cryosurgery demonstrating a complete flattening
of the scars with almost no hypopigmentation
following a single session of intralesional cryosurgery.
Complete flattening of the scar is demonstrates with no
hypopigmentation
The intralesional cryosurgery technique
enables the plastic surgeon, dermatologist or
dermato-surgeon to have the proper and effective
instrument to reduce, in a relative short time, the
dissatisfaction of those patients who developed
hypertrophic scars and keloids following aes-
thetic surgery. Thus, the patient confidence in the
plastic surgeon is maintained which creates a
468 Y. Har-Shai and C.C. Zouboulis

Fig. 86.20 Left – Preoperative view of a keloid scar on following a single session of intralesional cryosurgery
the posterior auricular sulcus and occipital area following demonstrates a complete involution of the scar with no
cervico-facial lift. (Deformity score – 5 and concern hypopigmentation. (Deformity score – 1 and concern
score – 5). Right – Post operative view 18 months score – 1)

Fig. 86.21 Upper Left – Preoperative view of a large ster- days following cryotreatment a draining blister is evident.
nal keloid following acne. Upper Right – Complete intral- Lower Right – 3½ and a half years following intralesional
esional freezing of the scar is achieved. Lower Left – 17 cryosurgery the keloid is flat with no hypopigmentation
86 Intralesional Cryosurgery for the Treatment of Hypertrophic Scars and Keloids
Fig. 86.22 Left – Preoperative view of a keloid on the left
back following a traumatic laceration. Right – Post opera-
tive view 18 months following two sessions of intralesional
cryosurgery demonstrating a complete involution of the
scar with no hypopigmentation
Fig. 86.23 Left – Keloid scar on the posterior aspect of the
helix following Otoplasty (deformity score – 5 and concern
score – 5). Right – 10 months following a single session of
469
positive attitude for a successful solution for
those challenging scars (Fig. 86.26).
Side Effects and Contraindications
Mild pain or discomfort during and after the pro-
cedure was easily managed (see pain relief proto-
col). Significant local edema and epidermolysis,
followed by a relatively short re-epitheliazation
period depending on the pre-treatment scar
volume, were evident. Very rare local hypo-/
hyperesthesia were documented, with no impact
on the quality of life of the patient.
During the 18-month follow-up period there
was no evidence of bleeding, infection or other
adverse effects. The non-response rate was less
than 3 %. No worsening of the scars was evident
and hypopigmentation was minimal.
The absolute contraindications are: cold-
inducible urticaria, cryoglubulinemia, cryofibri-
nogenemia and Raynaud’d Disease. The relative
intralesional cryosurgery the scar is flat and asymptomatic
(deformity score – 1 and concern score – 1)
470 Y. Har-Shai and C.C. Zouboulis

contraindications are: collagen diseases and Discussion

wound healing problems, pregnancy and scars
which are adjacent to vital organs should be It has been noticed that hypertrophic scars and
treated with caution. If the total tissue to be keloids of black/darker colored skin exhibits less
frozen accedes is more than 7 % of total body depigmentation following intralesional cryosur-
weight, hypothermia might occur. gery when compared with the contact method
[15]. These findings may encourage the use of
intralesional cryosurgery for dark-skinned indi-
viduals [33, 34] suffering from such scars or fol-
Pre-treatment Post-treatment
lowing aesthetic surgery, thus minimizing the
3 2.9
2.8 depigmentation problem (Figs. 86.3 and 86.22;
2.51 2.4
2.5 Table 86.1).
2.1
2 The trend for a longer hold time demonstrated
1.45 during the intralesional cryosurgery process
1.5
when compared with the contact method, which
1 0.75
0.55 is solely related to the scar volume i.e. a larger
0.5 scar volume needs a longer freezing/hold time,
0 may explain the superior efficacy of the intral-
Itching/ Pain/
discomfort tenderness
Hardness Redness esional technique in the treatment of keloids
[15–17, 31]. Lower temperatures are present
Fig. 86.24 Significant alleviation of objective parame- around the needle, which increase the freezing
ters (hardness and redness) and subjective complaints
area of the core of the keloid tissue, which is
(pain/tenderness; itchiness/discomfort) following a single
intralesional cryotherapy in the scale 0–3 (a low score is abutting the cryoneedle, causing cryonecrosis.
better) The long hold time, which was found signifi-

Ears - 67 %

Back &
shoulders -60 %
Chest - 50 %

Fig. 86.25 The average percentage of scar volume reduction following a single intralesional cryosurgery treatment
which is achieved in the ears, back and shoulders and chest
86 Intralesional Cryosurgery for the Treatment of Hypertrophic Scars and Keloids 471

6 Pre Post flattening. Reinforcement to this assumption is

5 found in Gage et al. [36] work, which evaluated
the effect of varying freezing and thawing rates
4
in experimental cryosurgery. It was found that
3 a long hold time and slow thawing rate would
2 maximize tissue destruction, especially in cancer
1 cryosurgery.
It has been reported by Massalha and Shitzer
0
OT OT OT OT FL FL FL GYN RM BR MS [37] in an experimental study, that the freezing
process was retarded in an area in which a heat
6 Pre Post source was situated simulating a blood vessel.
5
The ambient body temperature of the body might
act as such a heat source thus preventing the
4
injury of vital deep organs or implants under-
3 neath the cryo-process.
2 The absence of infection following the intrale-
1 sional cryosurgery might be explained by an
immune response involving interplay of humoral
0
and cellular factors, which occur locally and
OT OT OT OT FL FL FL GYN RM BR MS
systemically. Following cryosurgery, a very rapid
Fig. 86.26 Pre-and Post- intralesional cryosurgery response of neutrophils to injury as well as activity
patient’s concern (Upper) and deformity (Lower) scores of natural killer cells is demonstrated. It was
(1–5, a higher score represents severe concern/deformity)
evaluated at the end of the follow-up which its median
reported that Langerhans cell activity has been
period was 10 months. OT otoplasty, FL cervico-facial enhanced after cryosurgery in mouse skin. In cryo-
lift, GYN gynecomastic, RM reduction mammoplasty, BR surgery of human keloids, tenascin-C, which is a
brachioplasy, MS mastopexy. * follow-up of 5 months member of the cell-adhesion proteins, which is
produced by the fibroblasts, interacts with integrins,
cantly longer when compared with the contact collagens, proteoglycans and fibronectin, has an
method, allows time for solute effects, ice crys- important role in the process of wound healing and
tal formation and recrystallization (Table 86.1). possible cryoimmunology. It was found that tenas-
Furthermore, in a long duration of freezing, cin-C, which was initially restricted to the diseased
the biochemical changes and the growth of ice tissue [38], following cryosurgery, became diffuse
crystals are enhanced, increasing the rate of cell in the whole treated dermal region and conse-
death [35]. Therefore, the intralesional technique quently decreased [39, 40]. In addition, the release
is more effective than the contact method. On the of the intracellular contents of the destroyed cells,
other hand, the contact method causes a severe including heat shock proteins, could activate neigh-
superficial cryodestruction harming mainly the boring neutrophils to produce proinflammatory
epidermis, including the melanocytes, and upper cytokines which would activate macrophages and
dermis. Although, the lethal zone was not inves- T cells. Therefore, it is speculated that the cryosur-
tigated in this study, during the intralesional or gery insult creates an immunological response
contact cryosurgical treatment, previous ex vivo which plays a significant role in the prevention of
studies [15] have demonstrated the creation possible wound infection [41].
of an ice ball around the cryoneedle at an end The low recurrence rates demonstrated fol-
temperature, which was lethal for the fibro- lowing intralesional cryosurgery (<3 %) could be
blasts i.e. −30 °C (Table 86.1). Therefore, sig- explained by the long term suppression effect of
nificantly less cryosurgical sessions (mainly 1–2 the cryo-treatment on the abnormal fibroblasts
cryo-treatments) are required to obtain keloid [38], or the destruction of all pathological
472
Fig. 86.27 A clinical case demonstrating the sequence in
pigmentation changes following the intralesional cryosur-
gery method executed on a keloid located on the anterior-
medial aspect of the left forearm of a fairly dark skin
patient. Left, upper – pre-treatment view, Right Upper –
Intraoperative view of the keloid demonstrating complete
fibroblasts in the scar by cryosurgery which are
replaced by the recruitment of the neighboring
normal fibroblasts, which produce normal
collagen [14, 15]. Therefore, if a second cryo-
session in indicated, it is recommended to wait
for at least 4–6 months prior to the next cryo-
treatment in order to enable the scar to complete
its humoral and cellular events and reach its final
volume and appearance, including pigmentation.
This simple to operate intralesional cryo-
surgery technology can be applied, as an office
Y. Har-Shai and C.C. Zouboulis
freezing. Left Middle – 1 week following cryo-treatment.
A blister is evident. Right Middle – 2 months following
treatment demonstrating severe hypopigmentation and the
appearance of few pigment islets. Bottom – Almost com-
plete recovery of pigmentation 5 months following
cryo-treatment
procedure, to every shape or contour of hyper-
trophic scar and keloid with a sufficient volume
into which the cryoneedle can be introduced.
In addition, it is safe to use, causes significant
less hypopigmentation, is not time consuming,
requires less cryogen fluid, necessitates less post-
operative care of the wound, possesses a short
learning curve and can easily be added to a pre-
existing cryosurgical cryogun or unit.
The final goal of the treatment of hypertro-
phic scars and keloids is a complete and entire
86 Intralesional Cryosurgery for the Treatment of Hypertrophic Scars and Keloids
flattening of the scar in addition to significant
reduction of objective and subjective clinical
complaints. Therefore, if some residual scar
volume is remaining after intralesional cryo-
surgery, it can be further dealt with a repeated
intralesional cryosurgery session, only if there is
sufficient scar volume to be penetrated or apply-
ing other appropriate therapies such as surface
contact cryosurgery, silicone sheets, intralesional
corticosteroids, pressure garments etc.
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4. Rusciani L, Rossi G, Bono R. Use of cryotherapy
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Behandlung Von Hypertropten Narben Und Keloiden.
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16. Har-Shai Y. Chapter II-10.1: Intralesional cryo-
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26. Fikrle T, Pizinger K. Cryosurgery in the treatment of
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27. Gupta AK, Koren G, Shear N. A double-blind, ran-
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prior to cryotherapy of wart in children and adults.
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28. Suzuki H, Ogawa S, Nakagawa H, Kanayama T, Tai
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29. Sonnex TS, Jones RL, Weddell AG, Dawber
RPR. Long term effect of cryosurgery on cutaneous
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Har-Shai Y. Pain evaluation and control during and
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the involution of recalcitrant auricular keloids: a new
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Dermatol. 2001;116:664–71.
 Cutaneous Larva Migrans
87
Stefano Veraldi, Ermira Çuka, and Fabrizio Vaira

Abstract
Cutaneous larva migrans (CLM) is an infestation caused by penetration
and migration in the epidermis of larvae of nematodes. Ancylostoma bra-
ziliense and Ancylostoma caninum are the species most frequently
involved. CLM is characterized by slightly raised and erythematous tracks,
very often accompanied by pruritus. CLM can sometimes heal spontane-
ously; on the other hand, a clinical variety characterized by a very long
clinical course has been described. Most used therapies are cryotherapy,
topical thiabendazole and oral albendazole and ivermectin.

Keywords
Albendazole • Ancylostoma sp. • Cryotherapy • Cutaneous larva migrans •
Ivermectin • Thiabendazole

Introduction

Cutaneous larva migrans (CLM) is an infestation

S. Veraldi, MD, PhD (*) • E. Çuka, MD
Department of Pathophysiology and Transplantation,
Universita’ Degli Studi di Milano,
IRCCS FOUNDATION, Ca’ Granda Ospedale
Maggiore Policlinico, Via Pace 9,
Milan 20122, Italy
e-mail: stefano.veraldi@unimi.it
F. Vaira, MD
Dermatology Unit, Department of Medical,
Surgical Diagnostic and Pediatric Science,
University of Pavia, Fondazione IRCCS Policlinico
San Matteo, Pavia, Italy
caused by penetration and migration in the
epidermis of larvae of nematodes. Ancylostoma
braziliense and Ancylostoma caninum are the
species most frequently involved [1, 2]. Natural
reservoirs for these ancylostomas are dogs and
cats.
CLM is characterized clinically by slightly
raised and erythematous tracks: they may be sin-
gle or multiple, linear or, more often, serpiginous,
ramified and intertwined. The length of tracks is
extremely variable (sometimes many cm); the
width ranges from 2 to 4 mm. Tracks are very
often accompanied by pruritus. The feet, ankles,

© Springer-Verlag London 2016 475

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_87
476
Fig. 87.1 Multiple tracks of CLM on the plantar surface
legs, knees, buttocks, abdomen and back are most
frequently involved (Fig. 87.1) [1, 2]. CLM may
be a self-limiting infestation: usually, its duration
ranges from 2 to 8 weeks [3]. However, a rare
variety of CLM (“chronic” or “persistent” CLM),
characterized by a typical clinical presentation
but long duration (from 5 to 14 months) has been
described [4].
Treatment
The therapy of CLM is currently based on cryo-
therapy, [5] topical drugs (thiabendazole [6] and
albendazole [7]) and oral drugs (thiabendazole,
[8] albendazole [9] and ivermectin [10]). The use
of ethyl chloride [11] and oral diethylcarbam-
azine, [12] stibanose, [13] chloroquine diphos-
phate, [14] gamma-esachlorcycloexan, [15]
fluoromebendazole [16] and mebendazole [17]
has been abandoned. Topical thiabendazole has
been used at different concentrations (from 10 %
to 50 %), once-thrice/day, for 3–15 days. It is an
effective and safe drug. It may be considered in
children with CLM [6]. Literature data on topical
albendazole are limited to a small number of
patients, in whom it was used at a concentration
of 10 %, as lotion or ointment [7]. Oral thiaben-
dazole can be effective in the therapy of
CLM. However, the daily dosage (20, 25 or
50 mg/kg/day?) and the length of the therapy (1,
3 or 4 days?) have not yet established.
Furthermore, side effects (nausea, abdominal
S. Veraldi et al.
pain, vomiting, headache, dizziness, hematuria)
are rather common [8]. Thiabendazole is terato-
genic in mice and rats [18]. Oral albendazole is
used at the dosage of 400 mg/day for 1–7 days.
Regimens of 1, 3 or 5 days are often followed by
partial remission or recurrences of the infesta-
tion. A 1-week course allows for a complete
remission in almost all patients. Side effects
(nausea, abdominal pain, Herxheimer-like reac-
tion, alopecia, Stevens-Johnson syndrome) are
rare, mild in severity and self-healing [9].
Albendazole is teratogenic in mice [19]. Oral
ivermectin is effective for the therapy of
CLM. This drug can be used as a single dose,
although two to three courses are sometimes nec-
essary. In several countries, ivermectin is on the
market only for use in veterinary medicine [10].
Ivermectin is teratogenic in rats [20].
Cryotherapy Methodology
(How I Do It)
Cryotherapy may be taken into consideration in
single and small lesions [5]. A previous (30–
60 min) topical anaesthesia with lidocaine cream
or lidocaine and prilocaine cream may be neces-
sary. Three applications of 10 s each of liquid
nitrogen are usually adequate. These applications
may be made by means of a glass bar with a cotton
pad at the top or the Cry-Ac®. All visible lesions
must be treated. Furthermore, 0.5–1 cm perile-
sional skin beyond the border of the visible lesion
must be treated: this because the larva is often
located beyond the visible end of the track [21].
Results
According to literature data, cryotherapy is often
ineffective; [1, 2] in addition, it can induce the
development of blisters, erosions, ulcers and
scars [21] (Fig. 87.2). In our personal clinical
experience, based on approximately 200 patients
with CLM, no response or relapse occur in 35 %
of patients. Relapse usually occurs 10–25 days
after the cryotherapy. It is therefore necessary a
follow up of at least 1 month.
87 Cutaneous Larva Migrans
Fig. 87.2 Large bullous lesion following cryotherapy
Conclusions
Even though official therapeutic guidelines
for CLM do not exist, we would recommend
cryotherapy or topical thiabendazole only for
single and small lesions, and 1 week oral
albendazole or ivermectin for widespread and/
or chronic lesions.
References
1. Davies HD, Sakuls P, Keystone JS. Creeping eruption.
A review of clinical presentation and management of
60 cases presenting to a tropical disease unit. Arch
Dermatol. 1993;129:588–91.
2. Jelinek T, Maiwald H, Nothdurft HD, Löscher T.
Cutaneous larva migrans in travelers: synopsis of his-
tories, symptoms, and treatment of 98 patients. Clin
Infect Dis. 1994;19:1062–6.
3. Veraldi S, Parducci BA, Pontini P. Therapy of cutane-
ous larva migrans in pregnancy. G Ital Dermatol
Venereol 2016 (in press).
4. Veraldi S, Persico MC, Francia C, Schianchi R.
Chronic hookworm-related cutaneous larva migrans.
Int J Infect Dis. 2013;17:e277–9.
477
5. Tagliapietra G, Cavalieri F, Bruni L. Su due casi di
dermatite da larva migrans guariti con crioterapia
(neve carbonica). Chron Derm. 1987;18:237–40.
6. Katz R, Hood RW. The use of topical thiabendazole in
dimethylsulfoxide for creeping eruption: preliminary
report. J Invest Dermatol. 1966;46:309–10.
7. Sugathan P. Massive infestation of cutaneous larva
migrans. Dermatol Online J. 2002;8:21.
8. Stone OJ, Mullins JF, Willis CJ. Inhibition of nema-
tode development with thiabendazole. J Invest
Dermatol. 1964;43:437.
9. Coulaud JP, Binet D, Voyer C, Samson C, Moreau G,
Rossignol JF. Traitement du syndrome de larva
migrans cutanée “larbish” par l’albendazole. A pro-
pos de 18 observations. Bull Soc Pathol Exot.
1982;75:534–7.
10. Caumes E, Datry A, Paris L, Danis M, Gentilini M,
Gaxotte P. Efficacy of ivermectin in the therapy of
cutaneous larva migrans. Arch Dermatol. 1992;128:
994–5.
11. Fuller CE. A common source outbreak of cutaneous
larva migrans. Public Health Rep. 1966;81:186–90.
12. Loewenthal LJ. Treatment of sandworm disease with
hetrazan. S Afr Med J. 1950;24:999–1000.
13. Wilson JF. The treatment of larva migrans with stiba-
nose. South Med J. 1952;45:127–30.
14. Burks Jr JW, Kingery FAJ. Treatment of creeping
eruption with chloroquine diphosphate: a preliminary
report. South Med J. 1956;49:1290–2.
15. Huber HP. Epidemieartiges Auftreten von creeping
disease. Dermatologica. 1972;145:88–91.
16. Jacquemin JL. Résistance au thiabendazole et efficacité
du fluoromebendazole. Nouv Press Med. 1980;9:1779.
17. Hart PLV. Mebendazole and cutaneous larva migrans.
N Z Med J. 1990;103:408.
18. Ogata A, Ando H, Kubo Y, Hiraga K. Teratogenicity
of thiabendazole in ICR mice. Food Chem Toxicol.
1984;22:509–20.
19. Teruel M, D’Ercole J, Catalano R. Evaluation of
potential embryo toxicity of albendazole sulphoxide
in CF1 mice. Biocell. 2011;35:29–33.
20. el-Ashmawy IM, el-Nahas AF, Bayad AE. Teratogenic
and cytogenetic effects of ivermectin and its interac-
tion with P-glycoprotein inhibitor. Res Vet Sci.
2011;90:116–23.
21. Caumes E. Treatment of cutaneous larva migrans.
Clin Infect Dis. 2000;30:811–4.
 Hidradenitis Suppurativa
88
Calogero Pagliarello, Giuseppe Fabrizi,
Claudio Feliciani, and Sergio di Nuzzo

Abstract
Treatment of hidradenitis suppurativa is challenging. Medical treatments
are often disappointing whereas surgical techniques, even if effective,
involve considerable discomfort and are therefore reserved for severe dis-
ease. We introduce the cryoinsufflation as new supplementary weapon in
the dermatologist arsenal.

Keywords
Hidradenitis suppurativa • Acne inversa • Cryoinsufflation • Cryotherapy •
Velpeau disease • Verneuil disease

Introduction Disease Description

Hidradenitis suppurativa (HS) is a chronic, HS (OMIM 142690, Velpeau’s disease, Verneuil’s

inflammatory skin disease characterized by pain-
ful, deep lesions in the apocrine gland–bearing
areas of the body, most commonly the axillary
and inguinal folds. Diagnosis is often delayed;
therefore the disease usually progresses causing a
permanent anatomical skin distortion. At that
point it is very difficult to obtain a satisfactory
remission with only medical treatment. Aggressive
surgery is required if the condition is not diag-
nosed early and managed appropriately.
C. Pagliarello, MD, PhD (*) • G. Fabrizi, MD, PhD
C. Feliciani, MD, PhD • S. di Nuzzo, MD, PhD
Department of Clinical and Experimental Medicine,
University of Parma, Ospedale Maggiore,
Via Gramsci 14, Parma 43100, Italy
e-mail: calogero.pagliarello@libero.it
disease, acne inversa, apocrine acne, apocrinitis,
hidradenitis axillaries, fox-den disease, pyoder-
mia sinifica fistulans) is a scarring and persistent
inflammatory disorder of the terminal hair folli-
cles of apocrine gland-bearing skin in adults. The
condition is a disorder of follicular occlusion; it
involves follicular hyperkeratosis (possibly due
to hormonal imbalance) followed by rupture of
the follicular epithelium at its weakest point, bac-
terial infection with inflammation and perifollic-
ulitis, and finally formation of sinus tracts
between abscesses under the skin. In some
people, HS makes up one part of follicular occlu-
sion syndrome, when it is associated with acne
conglobata, dissecting cellulitis and pilonidal
sinus.

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_88
480
There are many supposed causes: in some fami-
lies, HS follows an autosomal dominant inheritance
pattern. Mutations have recently been reported in
Presenilin-1 (PSEN1), Presenilin Enhancer-2
(PSENEN), and Nicastrin (NCSTN), encoding
three of four proteins integral to γ-secretase [1].
Some authors have shown that the piloseba-
ceous junction in HS skin is almost devoid of a
PAS-positive basement membrane, making it
fragile; friction, shearing forces, and pressure,
lead to rupture and leakage of ductal contents
from the weakened folliculosebaceous unit, thus
causing an inflammatory reaction mediated
mainly by innate immunity [2]. Clearly, a combi-
nation of alterations can coexist. Women are
affected three times as often as men; the condi-
tion most commonly occurs between 20 and
40 years, and coincides with the post-pubertal
increase in androgen levels; onset rarely occurs
before puberty or after menopause.
HS usually produces painful and chronically
recurring, deep-seated follicular papules and pus-
tules that may enlarge to become nodules, form
abscesses that discharge foul-smelling pus, and
lead to scars and skin distortion. The tendency of
the process to cause tunnels ultimately leads to
inter-connected sinuses; attempts to heal them
causes scarring.
Two severity score systems are in common
use: Hurley Stages and Sartorius Hidradenitis
Suppurativa Score [3].
Recognition that HS is heterogeneous may
help clinicians formulate treatment strategies. It
is advisable to take into account information (in
bold) with a significant impact on treatment
(strategy suggested in parentheses):
1. Age, gender, body mass index, menstrual
irregularities (oral contraceptives), family
history of HS, dementia, smoking status.
2. Disease history: age at onset, long disease
duration (treat aggressively).
3. Associated conditions:
(a) Acne conglobata (isotretinoin) and dis-
secting cellulitis of the scalp
(b) Inflammatory bowel disease, pyoderma
gangrenosum (immunosuppressive drugs)
(c) Polycystic ovary syndrome (metformin)
C. Pagliarello et al.
4. Affected regions: axillae, groin, gluteal, infra-
mammary, posterior neck/ears, trunk, limbs,
other
5. Lesion types: hypertrophic scars, comedones,
epidermal cysts, follicular papules/folliculitis,
sinus tracts (surgery)
6. Disease severity: Physician reported: Hurley,
modified Hidradenitis Suppurativa Score
(Sartorius score) Patient reported: validated
quality of life measure
7. Response to treatment: topical, systemic, sur-
gical, other
Therapeutic Alternatives
Clinical trials in HS face the lack of an accepted
uniform HS severity score. Therapeutic strategy
point to correcting modifiable risk factors (smok-
ing, overweight), reduce sweating, friction, epila-
tion trauma. Topical clindamycin and dapsone
are usually effective in mild HS. Treatments
occasionally reported as effective include oral
turmeric (curcuma longa) and zinc gluconate for
its antiandrogen properties.
For early stages HS oral antibiotics are required
(rifampin with either oral clindamycin or minocy-
cline). Other treatments include: fluoroquinolones
with metronidazole and rifampin, oral dapsone,
acitretin, hormone blockers (oral contraceptive
pills, spironolactone, finasteride). Cases at severe
HS stages often require oral prednisone or immu-
nosuppressive drugs such as cyclosporine, adalim-
umab, infliximab or biologics currently undergoing
clinical research. Recurrence of HS occurred fre-
quently during therapy or within a couple of
months after cessation of biological therapy [4].
Isotretinoin, etanercept, lymecycline, sulfasala-
zine, methotrexate, metformin, colchicine, laser,
photodynamic therapy (also intralesionally) are
less favored. Intralesional corticosteroids produce
symptomatic relief and perhaps, if done at regular
intervals, improves HS more permanently [5].
Combinations are often required to achieve a satis-
factory clinical remission and for avoiding drugs
side effects.
Notably, because the mean time until defi-
nite diagnosis is 7 years, patients usually
88 Hidradenitis Suppurativa
develop permanent anatomical skin distortion,
conferring to the lesion the aspect of a fox den.
The earlier the medical treatment starts the less
significant the extent of sinuses and fistula will
be, with a higher chance of definite cure or of
prolonged remission. Complete resection of
affected tissue by wide excision is currently
regarded as the only effective management for
severe HS, but this is a very demanding solu-
tion with a long downtime. Less invasive sur-
gery techniques have been proposed, such as
deroofing [6] and Skin-Tissue-sparing Excision
with Electrosurgical Peeling (STEEP), which
regrettably requires general anesthesia [7].
Dermatologists are therefore in need of an
effective outpatient solution for treating
patients refractory to medical treatment who
nevertheless don’t want to undergo extensive
surgery.
Cryosurgery
In the past cryomassage have been empirically
used in Europe as antinflammatory treatment
and to promote purulent discharge from acne
lesion and inflamed infundibular cysts. There are
just a few reports of cryotherapy for HS treat-
ment. Cryotherapy with spray technique has
been described as a potential treatment for HS
[8], although most patients experience signifi-
cant pain during and after treatment. Significantly,
8 of 10 patients reported post-treatment ulcer-
ation, infection, or both. We modified intrale-
sional cryosurgery by using a 21 g olive tipped
cannula to inject liquid nitrogen directly into HS
tracts. We took advantage of the distinctive fea-
ture of compressed gas to easily fill the full
extent of HS lesions and their multiple sinus
tracts. Moreover, this method allows for trans-
ferring the maximum intensity of cold directly to
the tissues. For mild inflamed HS lesions at fixed
body locations, IC may be performed in the
office with good long-term results. We intro-
duced cryoinsufflation as a useful adjunctive
therapy that can be safely combined with all
other treatments even when systemic treatment
should be avoided [9].
481
Methodology (How I Do It)
We prescribe 2 months course of systemic antibio-
thic (rifampicin 300 mg/twice a day plus mynoci-
cline 100 mg/day) to clear all sinuses from pus in
order to support a good outflow of LN. Abscesses
and sinus tracts were filled with LN using 21 g
olive tipped cannula mounted on a cryosurgical
unit (CRY-AC, Brymill Cryogenic Systems Ltd.,
UK) equipped with the CRY-AC Malleable
Extension and Luerlok Adaptor for CRY-AC. The
blunt cannula tip prevents any further trauma to
the follicular unit (Fig. 88.1a). Without using
excessive force, the physician slowly inserts the tip
of the cannula into a sinus (Fig. 88.1b) then sprays
LN into the fistula track or pseudocyst. As the LN
enters the infected sinuses, it boils and vaporizes;
because of the large expansion ratio of liquid to
gas, it quickly disperses into all communicating
pockets, and is expressed like a geyser (Fig. 88.1c).
This usually requires no topical or infiltrative
anesthesia. Manual ability to incannulate sinuses
is of paramount importance. If the sinuses are too
small for olive tipped cannula a 21-gauge needle
could be sometimes carefully used (Fig. 88.2). As
for any subcutaneous infiltration caution is needed
inserting the needle to avoid possible complica-
tions such as bleeding from the penetration point,
hematoma formation, air embolism or delayed
infection caused by poor placement of the needle.
None of these complications were observed in our
patients. Injecting outside the sinuses can easily
produce a subcutaneous emphysema that usually
requires no treatment. The dermatologist can set
the number, duration, and intervals between insuf-
flations for each site, bearing in mind that the aim
of the treatment is washing out the sinuses with a
large amount of LN while avoiding the formation
of noticeable iceballs. On the other hand pulsing
each spray to avoid an overexpansion of the treat-
ment site helps in preventing excessive pain and
vagal reaction as well as painful bullous lesion or
delayed necrosis at the insertion point of the can-
nula. Acetaminophen taken for the first 24 h fully
relieved any possible delayed discomfort; a vagal
reaction with nausea, sweating, and weakness was
the only worrisome side effect experienced by our
patients.
482
a b
Fig. 88.1 (a) Luerlok adaptor allows to easly fit any nee-
dle. We prefer to apply a blunt 21gage olive tipped can-
nula. (b) The cannula is gently inserted into a pseudocyst
and slowly pulled back till it firmly occlude its outlet.
Then LN is injected pulsing the spray to expand the pseu-
Fig. 88.2 A 21gauge needle can be very cautiously used
instead of blunt cannula: in case of more advanced disease
when no sinus openings can be easily cannulated or if
despite a standard antibiotic course solid pus collection
prevent a satisfactory flowing of liquid nitrogen
C. Pagliarello et al.
docyst. (c) In the resting phase of pulsed cryoinsufflation
the pseudocyst collapses and the LN pours out. The pro-
cess should be repeated as much as patient tolerate it,
pulsing each spray to carefully avoid forming an iceball at
the insertion point
Success Rates
Clinical trials about cryoinsufflation are currently
ongoing at our institution. The technique is easy
to perform; a brief training is required to succeed
in reliably obtaining LN flow into HS lesions;
this depends on manual ability and it can be
improved. If effectively administered prelimi-
nary results suggest a high (about 70 %) remis-
sion rate for early Hurley stages HS with a mean
of 6 monthly application. When combined with
systemic antibiotics or acitretin it helps in pre-
venting disease recurrence for more advanced
disease and session are usually repeated till
lesions clearance. For very extensive disease this
88 Hidradenitis Suppurativa
endpoint requires many sessions a fact that obvi-
ously represents a drawback from the point of
view of the patient.
Conclusions
Cryoinsufflation helps in reducing recurrence
rates, produce high patient satisfaction with
relatively short healing times and favourable
cosmetic outcomes without contractures. It is
a useful treatment option when systemic ther-
apies should be avoided.
References
1. Pink AE, Simpson MA, Desai N, Trembath RC,
Barker JN. γ-secretase mutations in hidradenitis sup-
purativa: new insights into disease pathogenesis.
J Invest Dermatol. 2013;133:601–7.
2. Danby FW, Jemec GBE, Marsch WC, von Laffert M.
Preliminary findings suggest hidradenitis suppurativa
may be due to defective follicular support. Br J Dermatol.
2013;168:1034–9.
483
3. Sartorius K, Lapins T, Emtestam L, Jemec G.
Suggestions for uniform outcome variables when
reporting treatment effects in hidradenitis suppurativa.
Br J Dermatol. 2003;149:211–3.
4. Blok JL, van Hattem S, Jonkman MF, Horváth B.
Systemic therapy with immunosuppressive agents and
retinoids in hidradenitis suppurativa: a systematic
review. Br J Dermatol. 2013;168:243–52.
5. Scheinfeld N. Hidradenitis suppurativa: a practical
review of possible medical treatments based on over
350 hidradenitis patients. Dermatol Online J. 2013;19:1.
6. Boer J, et al. Deroofing: a tissue-saving surgical tech-
nique for the treatment of mild to moderate hidradenitis
suppurativa lesions. J Am Acad Dermatol. 2010;
63:475–80.
7. Blok JL, Spoo JR, Leeman FW, Jonkman MF, Horváth
B. Skin-Tissue-sparing Excision with Electrosurgical
Peeling (STEEP): a surgical treatment option for severe
hidradenitis suppurativa Hurley stage II/III. J Eur Acad
Dermatol Venereol. 2015;29:379–82.
8. Bong JL, Shalders K, Saihan E. Treatment of persis-
tent painful nodules of hidradenitis suppurativa with
cryotherapy. Clin Exp Dermatol. 2003;28:241–4.
9. Pagliarello C, Fabrizi G, Feliciani C, Di Nuzzo S.
Cryoinsufflation for Hurley stage II hidradenitis sup-
purativa: a useful treatment option when systemic
therapies should be avoided. JAMA Dermatol. 2014;
150:765–6.
 Leishmaniasis
89
Antonio Rondón Lugo

Abstract
Leishmaniasis is a chronic disease produced by Leishmania parasites. It
can compromise the skin and oropharyngeal tissues, and it constitutes a
serious worldwide Public Health problem. Even though it is not a direct
cause of mortality, it can be the motive of temporal, and even permanent,
corporal physical disability. Leishmaniasis can occur at any age. Reservoirs
are mostly rodents and several mosquito species have been identified as
vectors. Vectors and reservoirs can vary at different areas and countries.
The etiologic agent is a parasite that can belong to one of several species,
which produce different host responses.

Keywords
Leishmaniasis • Cryosurgery • Antimonials • Trypanosomatida • Vectors

Introduction occur at any age. Reservoirs are mostly rodents

Leishmaniasis is a chronic disease produced by
Leishmania parasites. It can compromise the skin
and oropharyngeal tissues, and it constitutes a
serious worldwide Public Health problem. Even
though it is not a direct cause of mortality, it can
be the motive of temporal, and even permanent,
corporal physical disability. Leishmaniasis can
and several mosquito species have been identi-
fied as vectors. Vectors and reservoirs can vary at
different areas and countries. The etiologic agent
is a parasite that can belong to one of several spe-
cies, which produce different host responses.
Leishmania Taxonomy

A.R. Lugo, MD FAMILY: Trypanosomatida

Instituto de Biomedicina,
Universidad Central de Venezuela, Calle Venezuela,
Quinta Natilse, Terrazas Club Hipico, Caracas,
Miranda 1080, Venezuela
e-mail: rondonlugo@hotmail.com;
http://www.antoniorondonlugo.com
GENUS: Leishmania – Viannia
SUBGENUS Leishmania: L. donovani, L. major,
L. tropica, L. aethiopica, L. mexicana
SUB-GENUS Viannia: L. brasiliensis, L. guya-
nensis, L. naiffi, L. lansoni

© Springer-Verlag London 2016 485

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_89
486
Description of the Disease
The immunological status of the host influences
the development of the varied clinical conditions
produced by Leishmania, so does the number of
mosquito bites, nutritional status, location of
lesions, and environmental conditions.
There is a spectrum of host responses: At one
end are patients with an adequate immunological
response towards the parasite develop Localized
Cutaneous Leishmaniasis (LCL), also known as
Immunocompetent Cutaneous Leishmaniasis.
This type of the disease is characterized by one
or several skin lesions, which generally are
ulcers of various sizes that begin as a small pap-
ule that grows slowly and tends to develop a cen-
tral ulcer; these lesions very often can acquire
secondary bacterial infections, produce satellite
lesions, and visible and palpable regional lym-
phatic pathways. LCL can simulate sporothri-
chosis, chromomycosis, pyoderma, basal cell
carcinoma or squamous carcinoma, chronic
cutaneous lupus, etc. LCL patients have a good
immunological status and respond well to rou-
tine treatments and even heal spontaneously
(5–10 %). At the other end of the spectrum are
patients (1 %) who do not show a response to
Leishmania antigens and present the type of dis-
ease known as Diffuse Cutaneous Leishmaniasis
(DCL), or Anergic Cutaneous Leishmaniasis. In
the Americas, DCL is produced by Leishmania
belonging to the subgenus Leishmania; it gener-
ally does not produce ulcers, and mucosal lesions
are very rare. The disease begins with a papule
or nodule, followed by multiple papulo-nodular
lesions distributed all over the body; occasion-
ally, the distribution of new lesions suggests
hematogenous dissemination. DCL patients are
generally resistant to routine therapies.
In-between these two extremes, we find what has
been considered as an intermediate or borderline
area of the disease, constituted by those patients
who present relapsing, verrucous lesions with a
long evolution, and with histopathological and
immunologic characteristics which differ from
the localized and diffuse types [1–4]. The histo-
pathologic study is important both for diagnosis
and as an indicator of the parasite-host response
(Figs. 89.1, 89.2, and 89.3).
A.R. Lugo
Treatment
Treatment should be initiated once the diagnosis
has been established. If there is secondary bacte-
rial infection, it is convenient to control it with
local antiseptics or local or systemic antibiotics.
Specific treatment includes antimonials such as
meglumine antimoniate (Glucantime) and
sodium stibogluconate (Pentostam) as first line
treatments, they are generally administered intra-
muscularly; intravenous and intralesional path-
ways have also been used. These drugs produce
many side effects that should be monitored, and
are expensive and difficult to obtain in some
countries. Alternatives include amphotericine B,
liposomal amphotericine, pentamidine, miltefos-
ine, ketoconazole, terbinafine, itraconazole,
hyperthermia, cryotherapy, interleukines, inter-
feron, CO2 laser, and immunotherapy. In cases
caused by L. tropica topical paromomycyne,
DDS, trimetoprim, trimetoprim + sulpha, rifam-
picine, nifurtimox, nitridazole, have produced
varying results [5–7].
Cryosurgery
Cryotherapy has been used in one or two sessions
with good results. Gilberto Castro Ron, MD,
[personal communication, 1991–2001] used
cryosurgery in some of the patients that we
referred to him from the Instituto de Biomedicina
in Caracas, Venezuela, with good results; this
series was not published. We selected cases
where the use of antimonials was contraindi-
cated: pregnant women, elderly, or persons with
cardiac compromise. We also included patients
with verrucous lesions or very hypertrophic
lesions since with cryosurgery to decrease the
size of the lesion and even cure it seemed possi-
ble (Fig. 89.4).
According to emails from Eugenio Pimentel,
MD, in December 2013, verrucous leishmaniasis
cases was successfully treated with glucantime
and cryosurgery at the Hospital Das Clinicas in
Sao Paulo, Brazil many years ago. Soto et al. [8],
carried out a study in patients with Bolivian
leishmaniasis. Patients were assigned randomly
to one of three arms: (1) intralesional Sb
89 Leishmaniasis 487

Fig. 89.1 Leishmaniasis. LEISHMANIASIS LIFE CYCLE:

Clinical spectrum

Procyclic Promastigote in the digestive tract of

the vector insect

Metacyclic Promastigote in prosbosis of the

vector insect.

Amastigote in phagolisosome of host

macrophages

Fig. 89.2 Verrucous chronic forms of leishmaniasis Fig. 89.3 Verrucous chronic forms of leishmaniasis

(N-methylglucamine – Glucantime ®, Rhodia days 1 and 14. In the cryotherapy group LN was
Laboratories, France) 650 μg/mm2 of the area of sprayed using a CryAc™ device /Brymill) for
the lesion on days 1, 3 and 5; (2) cryotherapy on 5–20 s or until the lesion and 1–2 mm of
488
Fig. 89.4 Photograph: on
the right, Gilberto Castro
Ron, great driving force of
cryosurgery at a
worldwide level; on the
left, Rondón Lugo
surrounding normal tissue appeared frozen; and
(3) placebo cream, applied daily for 20 days. The
cure rate with the antimonial injection was 70 %
(21/30); with cryotherapy 20 % (4/20); and with
placebo 17 % (5/30). Milika et al. [9] treated a
23 years old patient with a 9-months evolution
2 cm in diameter, lupoid type leishmaniasis
lesion on the face. She was first given meglumine
antimony (60 mg/Kg) intramuscularly with no
improvement at 14 days. She was then treated
with ketoconazole 200 mg/day for 1 month with
no improvement. Four months later, intramuscu-
lar antimony produced only slight improvement.
The lesion was very unsightly so cryotherapy
was tried using hand-held unit (Cry-ac®, Brymill
C.A.) with a 1 mm nozzle to spray LN at a dis-
tance of 2 cm between the nozzle and the lesion
for 10–15 s, until the freeze reached a few milli-
meters into the surrounding healthy skin; this was
repeated every other week until the entire lesion
healed. This occurred after six sessions, with
very good cosmetic results. The patient was fol-
lowed for a year during which it showed no signs
of recurrence. Panagiopoulus et al. [10] in Greece
treated 77 patients with cryotherapy in two
10–30 s cycles at 3-week intervals between; all
were cured, with good cosmetic results, there
were no relapses. In Yemen, Al-Qubati et al. [11]
mention that since the chemotherapy recom-
mended for leishmaniasis is expensive and has
A.R. Lugo
untoward side effects, a simple solution at eco-
nomically underdeveloped areas, would be to
apply carbon dioxide slush. Cryotherapy with
carbon dioxide slush had been used successfully
by one of them (YAQ) over the previous 5 years.
Since 2005 he had been treating cutaneous leish-
maniasis locally with carbon dioxide slush
obtained at a local soft drink factory. The slush
was applied directly over the lesion exerting a
slight pressure for 1 min, then the lesion was left
to thaw and the slush re-applied for another min-
ute. Sometimes a translucent blister appeared
which lasted around a week before spontane-
ously reabsorbing. One hundred eighty-three
patients (76 women and 107 men) were treated
this way between 2007 and 2009 at the private
clinic of the author mentioned above; only 12
relapsed or re-infected and, therefore retired later.
Twenty patients presented recurrent or persistent
lesions when they were examined a month later
and were re-treated in the same way. Of these 20,
18 were completely cured 1 month later, 2 had
over 5 persistent lesions, which required addi-
tional treatments, both patients were cured. Those
that required additional treatments were the ones
who had the larger or more numerous lesions.
Most were satisfied with the results, although 30
complained of hypopigmentation at the site of
the lesions after cured. Ranthilaka et al. [12] eval-
uated the efficacy and safety of cotton-tip LN
89 Leishmaniasis
cryotherapy in patients with cutaneous leishman-
iasis due to L donovani. They treated 121 lesions
on 65 patients, for 15–20 s, twice a week for
1–3 weeks, then monthly until cure. Patients
were followed for 6 months after clinical cure.
91.7 % of the patients were cured within 6–59
sessions. With one to four cryosessions, papules
smaller than 1 cm cured rapidly (90.5 %), as
compared with the larger sized papules (64.28 %).
Cure rates of head lesions were high (84.61 %),
as well as those in upper limbs (83.6 %), lower
limbs (71.42 %) and trunk (66.66 %), Local pain
was short, and there were ulcerations in 33 % of
the patients, depigmentation in 46 % and recur-
rence in 43 %.
Conclusions
Leishmaniasis is a disease produced by para-
sites, mainly characterized by ulcerated
lesions. It can be localized at any site of the
body. Its first line treatment is chemotherapy
with antimonials. Cryosurgery can be helpful
10. Panagiotopoulos A, Stavropoulos P, Hasapi V,
mainly in patients with hypertrophic lesions or
when the use of antimonials is non advisable.
11. Al-Qubati Y, Janniger EJ, Schwartz R. Cutaneous
References
12. Ranthilaka R, Hema S, Weerakoon HS, Anthilaka R,
1. Rondón Lugo AJ, Convit J. Spectrum of American
cutaneous leishmaniasis dermatology in five conti-
nents. Berlin: Springler Verlag; 1988. p. 789–92.
489
2. Convit J, Pinardi ME, Rondón AJ. Diffuse cutaneous
leishmaniasis: a disease due to an immunological
defect of the host. Trans R Soc Trop Med Hyg.
1972;66:603–10.
3. Castes M, Agnelli A, Rondón AJ. Mechanism associ-
ated with immunoregulation in human American cutane-
ous leishmaniasis. Clin Exp Immunol. 1984;57:279–86.
4. Modlin EL, Tapia FJ, Bloom BR, Gallinoto ME,
Castes M, Rondon AJ. In situ characterization of the
cellular immune response in American cutaneous
leishmaniasis. Clin Exp Immunol. 1985;60:241–8.
5. Rondón Lugo AJ, Reyes O, Ulrich M, Tapia F.
Leishmaniasis Cutáneo Mucosa. Derm Venereol.
1985;23:11–24.
6. Convit J, Rondón Lugo A, Ulrich M, Castellanos PL,
et al. Immunotherapy versus chemotherapy in local-
ized cutaneous leishmaniasis. Lancet. 1987;30:401–5.
7. Convit J, Castellanos PL, Ulrich M, Castes M,
Rondón Lugo AJ. Immunotherapy of localized, inter-
mediate and diffuse forms of American cutaneous
leishmaniasis. J Infect Dis. 1989;160:104–15.
8. Soto J, Rojas E, Guzman M, et al. Intralesional anti-
mony for single lesions of Bolivian cutaneous leish-
maniasis. Clin Infect Dis. 2013;56(9):1255–60.
9. Mlika RB, Hammami H, Sioud A. Treatment of cuta-
neous leishmaniasis with cryosurgery. Dermatol Ther.
2011;24:378–9.
Papakonstantinou A-M, Petridis A, Katsambas A. Int
J Dermatol. 2005;44:749–52.
leishmaniasis: cryosurgery using carbon dioxide slush
in a resource-poor country. Int J Dermatol. 2012;
51(10):1217–20.
Ranawaka RR, Hema S. Liquid nitrogen cryotherapy
on Leishmania donovani cutaneous leishmaniasis.
J Dermatol Treat. 2011;22:241–5.
 Lentigo and Solar Lentigines
90
Leon Neumann

Abstract
Lentigo simplex and solar lentigines, although a minor cosmetic problem,
have become an important concern among aging people, since the life
span has increased substantially in the last 50 or more years, people keep
active socially for much longer. These skin lesions can be easily removed
by a number of dermatological procedures, among them cryosurgery.
Traditionally, cryosurgery has been carried out by the use of LN. The
problem is that extreme cold (−196 °C) may be too aggressive for the
treatment of superficial dark spots, like lentigo and lentigines. For that
reason we employ nitrous oxide, a cryogen with a much less freezing
potential (boiling point −89.5 °C) for their treatment. Nitrous oxide is a
relatively cheap gas since there is no insensible loss like with LN. It has
less potential for blistering and causes less pain. It can be adjusted for
treating small lesions, either in the form of a spray or with probes. We have
found that cryosurgery with nitrous oxide to be the best treatment option
for lentigos and lentigines.

Keywords
Lentigo • Solar lentigines • Cryosurgery • Nitrous oxide

Description

Solar lentigines are also known as actinic lentigi-

L. Neumann, MD
Department of Dermatology, ABC Hospital,
Homero 109-1203, Colonia Polanco, Mexico City,
DF 11570, Mexico
e-mail: dermocirugia18@yahoo.com.mx
nes, liver spots, age spots and sun spots. They are
macular hyperpigmented lesions ranging in size
from a few millimeters to more than a centimeter
in diameter. They appear on the exposed surfaces
of fair-skinned people, long exposed to the sun.
They tend to be multiple with individual lesions
gradually increasing in size to larger macules or

© Springer-Verlag London 2016 491

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_90
492
patches. The potential negative social impact of
this condition should not be disregarded in view
of the fact that lesions appear on highly visible
parts of the body, such as the face, neck, hands
and forearms. These lesions can also be regarded
as the first signs of the photoaging process, which
can also have a significant impact on patients.
Lentigines darken significantly after exposure to
sun light [1].
The incidence increases with age, affecting
more than 90 % of white persons older than
50 years of age.
Lentigo is a hyperpigmented spot, which may
appear at any age, are usually darker and larger
than freckles [1].
Histopathology
A few minutes after freezing there is vasodilata-
tion. After 24 h a subepidermal blister forms with
epithelial necrosis. The blister may contain
countless erythrocytes and dense lymphocytic
infiltrate. On the third day, many thrombi and
extravasated erythrocytes and lymphocytic infil-
trate can be observed. A week later there is a
superficial ulcer. After the third week there is
reepithelialization, elongation of the rete pro-
cesses and thickening of collagen fibers [2].
Differential Diagnosis
They should be distinguished from ephelides,
pigmented actinic keratosis, flat seborrheic kera-
tosis, melanocytic nevus, pigmented basal cell
carcinomas, lentigo maligna and malignant mela-
noma. These can be differentiated based on clini-
cal appearance [3, 4].
Treatment
There have been many procedures that have been
tried in the treatment of solar lentigines. Among
them we can mention retinoic acid cream, TCA
(trichloroacetic acid) glycolic acid or lactic acid
peels, lasers. There have been many procedures
L. Neumann
that have been tried in the treatment of solar len-
tigines. Among them we can mention retinoic
acid cream, TCA, glycolic acid or lactic acid
peels, lasers (Erbium-YAG, Alexandrite, Ruby,
Argon, etc.) topical depigmenting agents
(Hydroquinone), dermabrasion, intense pulsed
light, etc. [5] which may indicate that there is no
perfect treatment for dermabrasion, intense
pulsed light, etc. [5] which may indicate that
there is no perfect treatment for that problem.
Nevertheless, cryosurgery has been one of the
preferred methods, either using liquid nitrogen,
solid carbon dioxide (dry ice) or nitrous oxide.
Our experience for the last 35 years has been
with nitrous oxide which we will discuss in
depth.
The Cryogen
Nitrous oxide, commonly known as laughing gas,
nitrous, nitro, or NOS is a chemical compound
with the formula N2O. It is an oxide of nitrogen.
At room temperature, it is a colourless, non-
flammable gas, with a slightly sweet odour and
taste. It has a boiling point of −89.5 °C.
It is no- flammable but will support combus-
tion. It is used in surgery and dentistry for its
anaesthetic and analgesic effects. It is known as
“laughing gas” due to the euphoric effects of
inhaling it, a property that has led to its recre-
ational use as a dissociative anaesthetic. It is also
used as an oxidizer in rocketry and in motor rac-
ing to increase the power output of engines. At
elevated temperatures, nitrous oxide is a power-
ful oxidizer similar to molecular oxygen [6].
The gas was first synthesised by an English
natural philosopher and chemist Joseph Priestley
in 1772, who called it phlogisticated nitrous air.
Priestley published his discovery in the book
Experiments and Observations on Different
Kinds of Air (1775), where he described how to
produce the preparation of “nitrous air dimin-
ished”, by heating iron filings dampened with
nitric acid.
The first time nitrous oxide was used as an
anaesthetic drug in the treatment of a patient was
when dentist Horace Wells, with assistance by
90 Lentigo and Solar Lentigines
Gardner Quincy Colton and John Mankey Riggs,
demonstrated insensitivity to pain from a dental
extraction on 11 December 1844 [7]. Today,
nitrous oxide is used in dentistry as an anxiolytic,
as an adjunct to local anesthesia, it is also used in
medicine for its cryogenic properties, namely in
Gynecology it has been used for a long time as a
treatment of benign and premalignant lesions of
the cervix.
In Ophtalmology it has been used to treat large
or recurrent intraepithelial carcinomas of the
conjunctive or cornea [8].
In Dermatology, nitrous oxide or liquid nitro-
gen were used for the treatment of Granuloma
Annulare in 31 patients. The closed probe technic
was used in all cases. Resolution was obtained in
all cases, but relapse occurred in only 1 of 11
patients who were followed for more than 2 years.
The authors conclude that cryosurgery is effec-
tive and safe in the treatment of localized
Granuloma annulare. They propose that Nitrous
Oxide with a simple freeze-thaw cycle of 20 s is
the optimal therapeutic regime [9].
Cryosurgery with N2O has been used success-
fully for the treatment of gingival melanin pig-
mentation in a 21 year old, dark- skinned female
from India who has had the pigmentation since
birth. She was followed up for 30 months with no
signs of recurrence [10].
Nitrous oxide has also been used for the man-
agement of hemangiomas of the oral cavity. In
these cases, continued use of the treatment
modality is indicated [11].
Other authors have reported on the use of
Cryosurgery with Nitrous oxide, in the treatment
of solar lentigines. Zouboulis Ch.C. et al. treated
six patients with large solar lentigo lesions.
The lesions were treated once and full remission
was achieved with excellent cosmetic result.
There were no recurrences after 10 months
follow up [12].
Advantages of Cryosurgery
Cryosurgery is a much preferred alternative to
surgical excision of many skin lesions for the fol-
lowing reasons:
493
1. Freezing produces minimal pain.
2. Results in little to no scar formation.
3. Takes less time than conventional surgery.
4. No need for local anesthesia in the majority
of cases.
5. Preoperative skin preparation (sterile tech-
nique) is not required.
6. No significant post-procedure care is
required.
7. Postoperative infection is rare.
8. After freezing patients may bathe, swim, etc.
9. Cryosurgery is cost effective.
10. Multiple lesions can be done in one office
visit.
Disadvantages of Cryosurgery
1. Freezing will destroy some pigmented cells.
The final scar may be lighter that surrounding
skin.
2. Healed cryolesiones that are exposed to the
sun, may require extra sun protection.
3. Cryosurgery is not recommended in hair-
bearing areas. Even briefly freezing treat-
ments can destroy hair follicles [13].
Contraindications for Cryosurgery
Absolute
1. Blood dyscrasias of unknown origin.
2. Cold intolerance
3. Reynaud’s disease
4. Cold urticarial
5. Cryoglobulinemia
6. Lesions in which tissue pathology is
required
7. Lesions in areas of compromised circulation.
8. Sclerosing Basal Cell Carcionomas (BCC) or
recurrent BCC or Squamous Cell Carcinomas
located in high risk areas like the temple or
nasolabial folds.
Relative
1. Keloid tendency
2. Collagen vascular disease
494 L. Neumann

3. Dark-skinned individuals due to the high risk

of developing cosmetically unacceptable pro-
tracted hypopigmentation.
4. Lesions over the nasolabial fold, eyelid mar-
gins, ala nasi and hair bearing areas (high risk
of developing alopecia, especially cicatricial
alopecia)
5. Patients with sensory loss at lesional sites.
6. Pyoderma gangrenosum [14]

Methodology (How I Do It)

We have been using an old Cryosurgical equip-

ment made by Ohio Medical Products, called
Ohio 850 Cryosurgical Unit (it is no longer avail-
able) which consists of a mobile (on wheels) unit Fig. 90.1 Ohio cryosurgical unit
with a 3.5 L N2O gas tank (E cylinder) mounted
with the exhaust valve upside down. The unit has
an on- off button which allows the exit of the gas
through a flexible hose and a handpiece. This
control button permits the outflow of the gas in a
smaller or larger quantity. If desired the machine
can be used with contact probes which come in
three different shapes. A thermocouple is never
used for benign lesions [15]. There are on the
market other brands of cryosurgical apparatus
that work on nitrous oxide (Fig. 90.1).
Preoperative anesthesia is hardly, if ever used
for benign lesions. Improvement rather than cure
may be the primary objective [15].
The procedure is very easy. It should not take
more than 5 min to treat both hands. After sign-
ing the consent form and having explained to the
patient what the procedure is about, the areas to
be treated are marked with an indelible pen
(Sharpie) in a squared fashion (Fig. 90.2). The
idea behind this design is to freeze square by
square in order not to miss any brown spot and
also not to duplicate the freezing of the areas
already done. The advantage of using this type of
marker is that the drawing can easily be removed
with an alcohol soaked cotton ball, after finishing Fig. 90.2 Wallach WA 100B
the treatment.
We start freezing square by square with the so on until we finish the whole area to be treated.
spray mode of the apparatus, moving the hand- Depending on the patient’s reaction we either
piece very quickly across each square. Once we move to treat the other hand or we make a break
finish the first square, we move to the next one and for a few minutes until the stinging or burning
90 Lentigo and Solar Lentigines 495

Fig. 90.3 Square design of the areas to be frozen Fig. 90.4 Solar lentigines before treatment

sensation go down. We may use this break to give

the patient a pain tablet if he so desires and start
with camomile compresses. After this short break
of 10–15 min, we can continue with the treatment
of the other hand. It is advisable to wait a few min-
utes after the freezing has been completed, to
check if a wheal has been formed on each of the
dark spots, which will indicate that the freezing
was sufficient Once we finish, as it has been said,
we remove the ink marks on both hands with an
alcohol moistened cotton ball.
The patient is instructed to continue with the Fig. 90.5 Solar lentigines, 1 week after freezing
camomile wet compresses several times during
the day on the first couple of days and then as
often as the patient feels it is needed. We may pre-
scribe a NSAI (non steroidal anti-inflammatory)
medication for the first 48–72 h and the recom-
mendation to avoid activities with the hands that
may injure the loose skin.
Some blisters may form on the evening of the
treatment day or during the next day. Patients
should be warned about this happening and reas-
sured that this will not affect the outcome of the
treatment.
Patient are asked to return in a couple of weeks Fig. 90.6 Solar lentigines, 1 month after freezing
to check and reassure them that everything is
OK. The usual picture at 2 weeks is that the hands At this moment the topical steroid is used only at
are still covered with dry scabs, although some night and the sunscreen several times during the
may have already gone. The skin will look ery- daylight hours (Figs. 90.5, 90.6, 90.7, and 90.8).
thematous and at this moment I ask the patient to It is also recommended that the patient wears
use a mid potency topical steroid (class IV or V), gloves while driving. The patient should under-
twice a day and a high potency topical sunscreen stand that the freezing of the solar lentigines is
with zinc oxide (Figs. 90.3 and 90.4). not a vaccine to prevent recurrences, so whatever
At 4 weeks there should be no more scabs and measures are taken to delay the reappearance of
the redness should have gone down significantly. the dark spots should be encouraged.
496
Fig. 90.7 Solar lentigines, 5 months after freezing
Fig. 90.8 Solar lentigines, 6 months after freezing
Fig. 90.9 Solar lentigines: 15 months after freezing
A few examples of the outcome of Cryosurgery
on solar lentigines and solar lentigo are shown in
Figs. 90.9, 90.10, 90.11, 90.12, 90.13, 90.14,
90.15, 90.16, 90.17, 90.18, 90.19, 90.20, 90.21,
90.22, 90.23, 90.24, 90.25, 90.26, 90.27, 90.28,
90.29, 90.30, 90.31, and 90.32.
L. Neumann
Fig. 90.10 Solar lentigines in a male patient before
treatment
Fig. 90.11 Solar lentigines, 1 month after treatment
Fig. 90.12 Solar lentigines in a female patient, before
treatment
Advantages of the Nitrous Oxide Unit
1. The gas is easily obtained.
2. Easily stored
3. Possesses a long “shelf live”
90 Lentigo and Solar Lentigines
Fig. 90.13 Solar lentigines, 3 weeks after treatment
Fig. 90.14 Solar lentigines on a female chest, before
treatment
Fig. 90.15 Solar lentigines, 2 weeks after treatment
4. Requires no electrical connections; can be
used safely in the operating room and moves
easily within the office
5. Entire cryoprobe assembly can be cleaned
with germicidal soap solution or alcohol
prior to each use.
497
Fig. 90.16 Solar lentigines before treatment
Fig. 90.17 Solar lentigines, 1 week after freezing of the
left hand
Fig. 90.18 Solar lentigines, 11 days after freezing of the
left hand
6. Fine spray emitted is excellent for treating
small lesions.
7. Spray and probe capabilities provided.
8. Refrigerant available within a few seconds in
form of spray or at the probe tip.
498
Fig. 90.19 Solar lentigines, 1 month after freezing of the
left hand
Fig. 90.20 Solar lentigines, 6 weeks after freezing both
hands
Fig. 90.21 Solar lentigo, before treatment
9. Being a much less cold cryogen (−89 °C)
than liquid nitrogen, produces fewer side-
effects such as blisters, pain, inflammation,
postinflammatory pigmentary changes, and
atrophic scars [15].
10. Relatively inexpensive.
L. Neumann
Fig. 90.22 Solar lentigo, 45 days after treatment
Fig. 90.23 Solar lentigo, before treatment
Fig. 90.24 Solar lentigo, close up of same lesion
Disadvantages of Nitrous Oxide
1. Inadequate cryogen for the treatment of
malignancies below the epidermis. Zacarian
clearly demonstrated on dog skin, that the
freezing obtained with nitrous oxide after 30 s
90 Lentigo and Solar Lentigines
Fig. 90.25 Solar lentigo, 4 days after freezing
Fig. 90.26 Solar lentigo, close up of same lesion
Fig. 90.27 Solar lentigo, 1 month after treatment
of the spray application reached −8 °C at a
depth of 2 mm, but at a depth of 5 mm there
was no freezing at all. At the end of 60 s of
freezing the temperatures obtained for nitrous
oxide became stabilized at both 2 and 5 mm of
skin depth and despite prolonging the freeze
period, no appreciable drop in temperature
499
Fig. 90.28 Solar lentigo, 1 month after treatment, close
up
Fig. 90.29 Solar lentigo in a male patient, before treatment
Fig. 90.30 Solar lentigo, 18 months after treatment
was observed. The conclusion of such an
experiment was that only superficial benign
lesions could be adequately treated with
nitrous oxide or carbon dioxide [16].
2. Cone-shaped mound of frost develops during
spraying which may pop off onto the patient’s
500
Fig. 90.31 Solar lentigo, before treatment
Fig. 90.32 Solar lentigo, 19 months after treatment
(notice the scar from a punch biopsy)
skin. Due to the nature of this cryogen while
spraying, the liquid forms small crystals of
solid nitrous oxide, which either pile up on the
treated site like a white “snow cone” or fly off
in all directions, with the secondary hazard of
freezing areas outside of the target zone [17].
3. Frequent malfunctioning of the on-off control
valve has been reported, after several months
or weeks of use [18]. In our unit, however, we
have only changed the valve on four occasions
in the last 35 years.
Complications of Cryosurgery
It is fair to say that by far, fewer complications
are seen in cryosurgical therapy of benign lesions.
Freezing is so fast and the actual time involved
so short that pain, postoperative infections and
edema are only infrequently encountered [19].
Complications of Cryosurgery can be divided
in acute complications, subacute and protracted.
L. Neumann
Acute Complications
1. Local pain especially in the periungual area,
temple, plantar areas, eyelids, lips, mucous
membranes. Tingling and numbness, espe-
cially on the fingers.
2. Edema, especially on the eyelids, lips, labia
and prepuce. More in infants and the elderly.
3. Blister formation; occasionally hemorrhagic.
4. Syncope (vasovagal reaction) in anxious patients.
5. Headache (migraine type) after the treatment
on the head and neck area.
Subacute Complications
1. Hemorrhagic necrosis.
2. Wound infection due to the use of infected
cryoprobes or redipping cotton swabs into the
cryogen.
3. Delayed wound healing after freezing over the
extremities.
4. Temporary scar hypertrophy
5. Subcutaneous emphysema due to insufflation
of the underlying tissue on spraying over bro-
ken skin.
Protracted Complications
Common
1. Hypopigmentation, especially in dark-skinned
individuals, which can be minimized br freez-
ing for less than 30 s. Atrophic scars, when
freezing time is more than 30 s.
2. Local hypoesthesia due to nerve damage,
especially in areas where the nerves lie super-
ficially, such as the sides of the fingers, angle
of the jaw, postauricular area, sides of tongue
and ulnar fossa of elbow.
3. Milia formation
4. Cicatricial alopecia which can be minimized
by freezing for less than 30 s.
Uncommon
1. Cartilage damage
2. Traumatic neuroma
3. Pyogenic granuloma
4. Fibroxanthoma [14]
90 Lentigo and Solar Lentigines
Hazards on the Use of Nitrous Oxide
In the last decade a warning has been issued by
the Centers for Disease Control and Human
Services on the use of Nitrous oxide. They men-
tion that if the exhaust gas from the N2O machine
is not properly vented, concentrations of the gas
in air can reach several thousand parts per mil-
lion, during a cryosurgical procedure; and
depending on the room ventilation’s rate, levels
may remain elevated for long periods of time fol-
lowing the procedure. Exposure to N2O should be
minimized to prevent short term behavioral and
long term reproductive health effects [19].
This should be taken into consideration, in order
to use an office area with excellent ventilation.
Conclusions
1. Cryotherapy is one of the most widely used
techniques to remove solar lentigines, particu-
larly in Western Europe and the United States.
2. The technique can be used with a number
of cryogens, including carbon dioxide,
nitrous oxide and liquid nitrogen.
3. The most commonly used agent is liquid
nitrogen, either applied with a cotton swab
or more commonly with a small hand held
spray unit.
4. The principle of the treatment in solar len-
tigines is tissue injury by cell freezing.
5. Melanocytes are especially vulnerable to cold
injury and can be destroyed by temperatures
of −4 to −7 °C
6. A single freeze-thaw cycle is usually suffi-
cient to treat solar lentigines [17]
7. The boiling temperature of nitrous oxide
(−89.5 °C) as compared to the one of liquid
nitrogen – (−196 °C) makes a lot of differ-
ence in the outcome of the procedure: less
risk of big bullae, less risk of pigmentary
sequelae (hypo or hyperpigmentation), less
pain, less risk of atrophic scars.
References
1. Arndt KA, Bowers KE. Hyperpigmentation and hypopig-
mentation. In: Manual of dermatologic therapeutics. 6th
ed. Lippincot Williams & Wilkins; 2002. p. 118.
501
2. Zolano Orozco M, Garcia Silva C, Hernandez-Torres
M. Histopathologic events of crylesion: an atlas. In:
Pasquali P, editor. Cryosurgery: a practical manual.
Berlin: Springer; 2015. p. 293–9.
3. Sauer GC, Hall JC. Manual of skin diseases. 7 ed.
Lippincot-Raven; 1996. p. 349.
4. Taylor SC. Photoaging and pigmentary changes of the
skin. In: Burgess CM, editor. Cosmetic dermatology.
Berlin: Springer; 2005. p. 29–50.
5. Ortonne JP, et al. Treatment of solar lentigines. Suppl
JAAD. 2006;54(5):S262–71.
6. Tarendash AS. Let’s review: chemistry, the physical
setting, Barron’s Educational Series. 3rd ed. New York:
Hauppauge; 2003. p. 44.
7. Erving HW. The discoverer of anesthesia, Dr. Horace
Wells of Hartford. Yale J Biol Med. 1933;5(5):
421–30.
8. Divine RD, Anderson RL. Nitrous oxide has been
used for the treatment of large or recurrent
intraepithelial carcinomas of the conjunctiva or cor-
nea. Arch Ophtalmol. 1983;101(5):782–6.
9. Blume-Peytovi V, et al. Successful outcome of cryo-
surgery in patients with granuloma annulare. Br
J Dermatol. 1994;130(4):494–7.
10. Ahmed SK, et al. Cryosurgical treatment of gingi-
val melanin pigmentation. A 30 month followed
up. Case Rep Clin Adv Periodontics. 2012;2(2):
73–8.
11. Gongloff RK. Treatment of intraoral hemangiomas
with nitrous oxide cryosurgery. Oral Surg Oral Med
Oral Pathol. 1983;56(1):20–4.
12. Zouboulis CC, et al. Treatment of solar lentigo with
cryosurgery. Acta Derm Venereol. 1999;79(6):
489–90.
13. Dawber R, Colver G, Jackson A. Cutaneous cryosur-
gery. Principles and clinical practice. London: Martin
Dunitz Ltd; 1992. p. 139–53.
14. Sharma KV, Khandpur S. Guidelines for cryosurgery.
Indian J Dermatol Venereol Lepr. 2009;75(8):
90–100.
15. Neumann L. Treatment of pigmented lesions by
cryosurgery. In: Dyall-Smith D, Marks R, edi-
tors. Dermatology at the millennium. The pro-
ceedings of the 19th world congress of
dermatology. The Parthenon Publishing Group;
l999. p. 567–9.
16. Zacarian SA. Cryosurgery of tumors of the skin and
oral cavity. Springfield: Charles C. Thomas Publisher;
1973. p. 7–10.
17. Torre D. Cryosurgical instrumentation. In: Zacarian
SA, editor. Cryosurgical advances in dermatology and
tumors of the head and neck. Springfield: Charles C.
Thomas Publisher; 1977. p. 38–54.
18. Graham G. Nitrous oxide units. In: Lubritz RR, edi-
tor. Manual of dermatologic cryosurgery. New
Orleans: Rudolph Ellender Medical Foundation;
1975. p. 25–6.
19. US Dept. of Health & Human Services. Center for
Diseases Control and Prevention. Publication No.
99–105. Jan 1999.
 Lichen Planus
91
Heather M. Holahan and Robert A. Schwartz

Abstract
Lichen planus (LP) is a papulosquamous eruption occurring on the scalp,
skin, mucous membranes, and nails. Classically, LP is evident as purple,
polygonal-shaped, pruritic papules. Oral LP (OLP) often affects the buccal
mucosa and tongue, where it may produce painful erosions and a sensation
of burning. A role for cryotherapy as treatment in OLP occurs when
plaques are hypertrophic, patient compliance is difficult, and other agents
have fail or are contraindicated. In addition, cryotherapy may provide
expedited relief of pain and a burning sensation if either is concerning.
Recent data suggests cryosurgery is as effective in OLP as triamcinolone,
a first line agent.

Keywords
Lichen • Planus • Keratosis • Pilaris • Oral disease

Description of Disease

LP is a papulosquamous eruption occurring on

H.M. Holahan, MD
Department of Dermatology,
Rutgers-New Jersey Medical School,
Newark, NJ, USA
R.A. Schwartz, MPH, DSc (Hon), FRCP (Edin) (*)
Dermatology and Pathology,
Rutgers University New Jersey Medical School,
Rutgers University School of Public Affairs
and Administration, 185 South Orange Ave.,
Newark, NJ 07103, USA
e-mail: roschwar@cal.berkeley.edu
the scalp, skin, mucous membranes, and nails.
More than one area may be involved simultane-
ously or successively. Classically, LP is evident
as purple, polygonal-shaped, pruritic papules
[1–4] (Fig. 91.1). The cutaneous presentation
includes purple plaques that are approximately
3–15 mm in diameter with Wickham striae visi-
ble on the papular surface (Fig. 91.2). Lesions
may develop in areas of prior trauma, termed the
Koebner phenomenon [1–3]. Cutaneous LP in
the pediatric population can display many mor-
phological variants including linear, hypertrophic,

© Springer-Verlag London 2016 503

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_91
504
Fig. 91.1 Cutaneous lichen planus characterized by pur-
ple, polygonal-shaped papules on the skin
Fig. 91.2 Hypertrophic lichen planus plaque, violaceous
to brown in color, polygonal-shaped on the lateral
forearm
H.M. Holahan and R.A. Schwartz
Fig. 91.3 Erosive oral lichen planus on the upper gingival
mucosa
annular, follicular, actinic, and vesiculobullous,
and pemphigoid-like [1].
LP frequently occurs on the buccal mucosa
(Fig. 91.3) and tongue, but can present on the lar-
ynx, esophagus, tonsils, conjunctivae, bladder,
vulva, anus and vagina [1, 3]. Lesions erupting in
the oral cavity can cause painful erosions and a
sensation of burning [1]. Clinical findings are
seen as a white, reticulated network composed of
patches or plaques overlying a violaceous back-
drop [1, 2]. Pediatric LP rarely involves the oral
cavity with an incidence of <1 % of all cases. LP
that occurs in the hair follicles is named lichen
planopilaris (LPP); areas of tenderness, pruritus,
hyperkeratosis and scarring alopecia can occur if
treatment is not employed [1, 5].
Cutaneous LP usually resolves within
6 months to 1 year without medical intervention,
but may persist for months or years, particularly
on the lower extremities.
Therapeutic Alternatives
Treatment is initiated in order to shorten disease
duration and to ameliorate pruritus [2]. First and
second line treatment includes topical and oral
corticosteroids, respectively [1–4]. Systemic
retinoids such as acitretin, UVB phototherapy,
as well as photodynamic therapy with UVA and
psoralen, have been effective in refractory dis-
ease [1, 2, 6]. OLP tends to be more chronic
and recurrent. First line therapy includes topi-
cal corticosteroids, with immunosuppressive
91 Lichen Planus
agents used as second line treatment in adults.
LPP is treated with topical steroids and intral-
esional steroid injections as first line treatments
[1, 2, 5].
Cryotherapy (How We Do It)
The oral cavity is a welcoming environment for
cryotherapy, as it is both moist and humid [7].
OLP may benefit from cryosurgery when lesions
are hypertrophic, patient compliance with
medication administration is difficult, first and
second line agents fail, and when topical or oral
steroids are contraindicated [8–11]. An advan-
tage of cryotherapy is expedited relief of the pain
and burning sensation, as topical and oral ste-
roids can take more time to impart an effect [12].
A recent, randomized, controlled study compared
the efficacy of cryotherapy with nitrous oxide gas
against topical triamcinolone acetonide 0.1 %
ointment in the treatment of oral lichen planus;
the results demonstrated that cryotherapy was as
effective as topical triamcinolone, and required
less patient compliance and follow-up [12].
Conclusions
Cryotherapy is an appropriate alternative to
some first and second line therapies for the
different forms of LP.
505
References
1. Sharma A, Białynicki-Birula R, Schwartz RA,
Janniger CK. Lichen planus: an update and review.
Cutis. 2012;90(1):17–23.
2. Le Cleach L, Chosidow O. Clinical practice. Lichen
planus. N Engl J Med. 2012;366(8):723–32.
3. Lai YC, Weng Y, Schwartz RA. Lichen planus and
dyslipidemia: A systematic review and meta-analysis
of observational studies. Int J Dermatol (in press).
4. Snyder RA, Schwartz RA, Schneider JS, Elias
PM. Intermittent megadose corticosteroid therapy for
generalized lichen planus. J Am Acad Dermatol.
1982;6:1089–90.
5. Zegarska B, Kallas D, Schwartz RA, Czajkewski R,
Uchanska G, Placek W. Graham-Little syndrome. Acta
Dermatovenerol Alp Panonica Adriat. 2010;19:39–42.
6. Mostafa D, Tarakji B. Photodynamic therapy in the
treatment of oral lichen planus. J Clin Med Res.
2015;7:393–9.
7. Shepherd J, Dawber RPR. The historical and scientific
basis of cryosurgery. Clin Exp Dermatol. 1982;7:925–44.
8. Loitz GA, O’Leary JP. Erosive lichen planus of the
tongue treated by cryosurgery. J Oral Maxillofac
Surg. 1986;44:580–2.
9. Bekke JP, Baart JA. Six years’ experience with cryo-
surgery in the oral cavity. Int J Oral Surg. 1979;8:
251–70.
10. Yeh CJ. Simple cryosurgical treatment for oral
lesions. Int J Oral Maxillofac Surg. 2000;29:212–6.
11. Ishida CE, Silva MR. Pharmacology and therapeutics:
cryosurgery in oral lesions. Int J Derm. 1998;37:283–5.
12. Amanat D, Ebrahimi H, Zahedani MZ, Zeini N,
Pourshahidi S, Ranjbar Z. Comparing the effects of
cryotherapy with nitrous oxide gas versus topical cor-
ticosteroids in the treatment of oral lichen planus.
Indian J Dent Res. 2014;25:711–6.
 Lichen Sclerosus et Atrophicus
92
Hee Jin Kim and Robert A. Schwartz

Abstract
Lichen sclerosus et atrophicus (LSA) is a chronic inflammatory derma-
tosis that has a predilection for the anogenital region. Vulval and peri-
anal lesions present as white papules or plaques. There may be
associated pallor, atrophy, hyperkeratosis, or scarring. Extragenital
lesions involve the upper trunk, axillae, buttocks, and lateral thighs.
LSA is associated with vulval and penile squamous cell carcinoma
(SCC). Cryosurgery has been used with success in the symptomatic
treatment of LSA.

Keywords
Lichen • Sclerosus • Atrophicus • Vulval • Perianal

Introduction planus [1]. Terminologies historically used to

LSA is a chronic inflammatory cutaneous dis-
ease that usually occurs in the anogenital area
[1–3]. In the nineteenth century, Hallopeau and
Darier first described LSA as a variant of lichen
H.J. Kim, MD
Department of Dermatology,
Rutgers University New Jersey Medical School,
Newark, NY, USA
R.A. Schwartz, MD, MPH, DSc (Hon),
FRCP (Edin) (*)
Dermatology and Pathology, Rutgers University New
Jersey Medical School, Rutgers University School of
Public Affairs and Administration,
185 South Orange Ave., Newark, NJ 07103, USA
e-mail: roschwar@cal.berkeley.edu
describe LSA include lichen planus sclerosus et
atrophicus, lichen planus morphoeicus, white
spot disease, and kraurosis vulvae [2, 3]. In
1987, the International Society for the Study of
Vulvovaginal Disease removed “et atrophicus”
from LSA and defined lichen sclerosus (LS) as a
non-neoplastic disease of the vulval skin and
mucosa [2]. Prevalence of LS ranges from 1 in
300 to 1 in 1000 [4]. It is more common in
whites. The female-to-male ratio is between 6:1
and 10:1 [3, 5]. In females, LS is predominant in
pre-menarche girls and post-menopausal
women. In males, it peaks between the ages of
30 and 50 [2]. Around 5% of cases develop a
malignancy in the area, with the majority being
SCC [2].

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_92
508
Description of the Disease
The cause of LS is not well understood. As high
as 34 % of patients with LS have associated auto-
immune disease such as alopecia areata, vitiligo,
thyroid dysfunction, and pernicious anemia [2].
There is a positive association between familial
LS and human leukocyte antigens (HLA) class II
antigen DQ7 [6]. Some describe a positive asso-
ciation between Borrelia and LS, while others
report no significant linkage [7]. LS may develop
after local trauma or irritation in genetically pre-
disposed individuals. Keobner phenomenon can
occur in LS.
LS has an unpredictable course that can be
aggressive or relatively asymptomatic for a pro-
longed period [5]. Clinical features differ between
females and males. In females, approximately
83–98 % of cases occur in the anogential area
and 15–20 % involve extragenital areas [8].
Females present with soreness and itching of the
vulvar and perianal areas, dysuria, and dyspareu-
nia. Dermatologic exam reveals a “figure eight”
pattern of thinned and atrophic skin changes
around the vulva and anus. There may be associ-
ated pallor, atrophy, hyperkeratosis, or scarring
that leads to textural changes [2, 5]. Other com-
mon findings are telangiectasia and purpura [2].
Fissures and tears that develop on the site of the
lesion, followed by scarring, may result in the
fusion of the labia minora and the narrowing of
the introitus. These changes are often confused
with sexual abuse in young girls [5]. Extragenital
lesions of LS occur on the inner thighs, neck,
shoulder, wrists, and submammary regions.
Lesions on nails and oral mucosa manifest as
pale macules or plaques without itching [5].
In males, LS occurs on the glans and foreskin,
typically sparing the perianal area. In 522 males
with LS, 57% had lesions on the glans and fore-
skin [6]. Male patients present with soreness,
itching, burning, phimosis, painful erections,
poor urinary stream, and difficulty retracting the
foreskin.[2, 5, 9] Cutaneous signs of LS were
present in 30 % of boys with congenital phimosis
and in 60 % of boys with acquired phimosis [10].
Early dermatologic manifestation of LS is
described as grayish white discoloration on either
H.J. Kim and R.A. Schwartz
the glans or prepuce. Fragile skin at the site of the
lesion may result in fissuring and chronic irrita-
tion [5]. Urethral involvement is more common
in males, presenting with obstructive symptoms
and dermatologic signs of minor mucosal skin
lesions with fissuring or ulceration [5].
Extragenital involvement is rare in males [2].
Histologic features of LS are the same in both
genders. Lesions demonstrate atrophy of the epi-
dermis with flattening of the rete ridges, hyper-
keratosis of the epithelium, homogenization of
the collagen, inflammatory changes in the der-
mis, and hydropic changes of the basal cells [2,
5] These changes contribute to the clinical
appearance of LS as shiny white lesions and
increase the risk of developing a malignancy in
the area [1, 5]. Chronic inflammatory changes
induced by oxidative stress from DNA damage
increase the risk of cutaneous cancer in patients
with LS [1]. Females with LS have an estimated
4–7 % risk of developing SCC [11]. Over 60% of
women with vulvar SCC had evidence of LS
[12]. Males with LS have an increased incidence
of penile SCC and HPV [5]. Over half of men
with penile SCC had evidence of LS. [13]. Both
clinical examination and skin biopsy should be
performed to diagnose LS and rule out any co-
existing malignancy.
Therapeutic Alternatives
There are three goals for the treatment of LS:
1. Alleviate symptoms
2. Prevent structural changes
3. Prevent malignant transformations
All patients diagnosed with LS, even those
without symptoms, need to be treated. Steroid
ointments are used to stop chronic inflammatory
process and prevent further progression of disease
[14]. Clobetasol propionate cream (0.05 %) twice
daily for 2–3 months with gradual tapering has
been used with success [15]. Triamcinolone injec-
tions are recommended for patients who respond
poorly to steroid ointments [16]. Topical andro-
gens are less used in female patients with genital
92 Lichen Sclerosus et Atrophicus
LS, because of potential side effects such as clito-
ral hypertrophy [5]. Other treatments for vulvar
and extragenital LS include stanazolol, hydroxy-
chlorquine, postassium para-aminobenzoate and
calcitriol [17–20]. When medical management
fails to control LS, surgical treatment is indicated.
Female patients may require dissection of a bur-
ied clitoris, division of fused labia, or enlargement
of narrowed introitus. Male patients may require
meatomoy or circumcision [5].
Cryosurgery-Utility, Methods,
and Success Rates
Cryosurgery has been used with success in cases
of LS that do not respond to medical treatment.
LS with marked hyperkeratosis or acanthosis on
histological examination responds poorly to ste-
roid treatment, but do well with cryosurgery [21].
To relieve pruritus in the entire genital area, one
can freeze the whole vulva under general anes-
thesia. A nitrous oxide cryoprobe is cooled to
−80 °C and applied to plaques of LS for 1 min.
Side effects of cryosurgery include blistering
without marked discomfort, scarring, and depig-
mentation. Scars associated with cryosurgery are
relatively flat and superior in appearance to those
associated with radiotherapy [21, 22].
In 12 patients with vulval LS, 75 % reported
significant relief in vulvar pruritus after cryo-
surgery. Four patients required a repeat treat-
ment with cryosurgery and five patients
experienced relapse within 3 years post-
treatment. Cryosurgery has been shown to be
effective against atrophic leukoplakic lesions
that accompany LS and SCC. Leukoplakia was
found in 50–75 % of patients with SCC. August
and Milward [22] reported post-operative clear-
ance of leukoplakia in 65 % of patients treated
with cryosurgery. Recurrence of leukoplakia
was low with 80 % of patients remaining clear
at 3 years.
A combined therapy of cryosurgery and intra-
lesional steroid injections has also been used
with success in the treatment of LS. In a study of
22 patients with LS, 14 experienced relapse after
cryosurgery. Lesions of those who experienced
509
relapse had significantly higher level of sclerosis,
thicker epidermis, and more inflammatory cells,
all of which suggest a late stage in disease
(p = 0.04). Despite relapse of LS, these patients
experienced significant improvement in pruritus
than those who did not receive cryosurgery
(p = 0.001) [23]. Therefore, early diagnosis of LS
is important for successful treatment of the
disease.
Conclusion
Cryosurgery has a limited role in the treatment
of LS. Cryosurgery should be considered in
cases of LS that fail to respond to medical
therapy. Cryosurgery offers advantages over
other therapies in the treatment of severe pru-
ritus and leukoplakia.
References
1. Murphy R. Lichen sclerosus. Dermatol Clin. 2010;
28(4):707–15.
2. Tasker GL, Wojnarowska F. Lichen sclerosus. Clin
Exp Dermatol. 2003;28(2):128–33.
3. Montgomery H, Hill WR. Lichen sclerosus et atrophi-
cus. Arch Derm Syphilol. 1940;42(5):755–79.
4. Sherman V, McPherson T, Baldo M, Salim A, Gao
XH, Wojnarowska F. The high rate of familial lichen
sclerosus suggests a genetic contribution: an observa-
tional cohort study. J Eur Acad Dermatol Venereol.
2010;24(9):1031–4.
5. Pugliese JM, Morey AF, Peterson AC. Lichen sclero-
sus: review of the literature and current recommenda-
tions for management. J Urol. 2007;178(6):2268–76.
6. Marren P, Yell J, Charnock FM. The association
between lichen sclerosus and antigens of the HLA
system. Br J Dermatol. 1995;132:197–203.
7. Dillon WI, Saed GM, Fivenson DP. Borrelia burgdor-
feri DNA is undetectable by polymerase chain reac-
tion in skin lesions of morphea, scleroderma, or lichen
sclerosus et atrophicus of patients from North
America. J Am Acad Dermatol. 1995;33:617–20.
8. Meyrick Thomas RH, Ridley CM, McGibbon DH,
Black MM. Lichen sclerosus et atrophicus and auto-
immunity – a study of 350 women. Br J Dermatol.
1988;118:41–6.
9. Micali G, Nasca MR, Innocenzi D, Schwartz RA. Penile
cancer. J Am Acad Dermatol. 2006;54(3):369–91.
10. Mattioli G, Repetto P, Carlini C, et al. Lichen sclero-
sus et atrophicus in children with phimosis and hypo-
spadias. Pediatr Surg Int. 2002;18:273–5.
11. Requena L, Kutzner H, Escalonilla P, Ortiz S, Schaller
J, Rohwedder A. Cutaneous reactions at sites of her-
510
pes zoster scars: an expanded spectrum. Br J Dermatol.
1998;138:161.
12. Leibowitch M, Neill S, Pelisse M, Moyal-Baracco
M. The epithelial changes associated with squamous
cell carcinoma of the vulva: a review of the clinical,
histological and viral findings in 78 women. Br
J Obstet Gynaecol. 1990;97:1135.
13. Powell J, Robson A, Cranston D, Wojnarowska F,
Turner R. High incidence of lichen sclerosus in
patients with squamous cell carcinoma of the penis.
Br J Dermatol. 2001;145:85.
14. Kiss A, Csontai A, Pirot L, Nyirady P, Merksz M,
Kiraly L. The response of balanitis xerotica obliterans
to local steroid application compared with placebo in
children. J Urol. 2001;165:219.
15. Val I, Almeida G. An overview of lichen sclerosus.
Clin Obstet Gynecol. 2005;48:808.
16. Miller RA. The Koebner phenomenon. Int J Dermatol.
1982;21:192.
17. Parsad D, Saini R. Oral stanozolol in lichen sclerosus
et atrophicus. J Am Acad Dermatol. 1998;38:278.
H.J. Kim and R.A. Schwartz
18. Wakelin SH, James MP. Extensive lichen sclerosus et
atrophicus with bullae and ulceration—improvement
with hydroxychloroquine. Clin Exp Dermatol. 1994;
19:332.
19. Penneys NS. Treatment of lichen sclerosus with
potassium para-aminobenzoate. J Am Acad Dermatol.
1984;10:1039.
20. Ronger S, Viallard AM, Meunier-Mure F, Chouvet B,
Balme B, Thomas L. Oral calcitriol: a new therapeutic
agent in cutaneous lichen sclerosis. J Drugs Dermatol.
2003;2:23.
21. Neill SM, Ridley CM. Management of anogenital
lichen sclerosus. Clin Exp Dermatol. 2001;26:637–43.
22. August PJ, Milward TM. Cryosurgery in the treatment
of lichen sclerosus et atrophicus of the vulva. Br
J Dermatol. 1980;103:667–70.
23. Stucker M, Grape J, Bechara FG, Hoffmann K,
Altmeyer P. The outcome after cryosurgery and intra-
lesional steroid injection in vulvar lichen sclerosus
corresponds to peroperative histopathological find-
ings. Dermatology. 2005;210(3):218–22.
 Lichen Simplex Chronicus
93
Renata Strumia

Abstract
Treatment of LSC is difficult and recurrences are frequent. Freezing cuta-
neous nerves leads to hypoesthesia, an effect utilized in cryotherapy of
LSC.

Keywords
Lichen simplex chronicus • Cryotherapy

Introduction pigment also occur, most notably in darker-

Lichen simplex chronicus (LSC) is a localized itch
with circumscribed thickening (lichenification) of
the overlying skin. Although LSC may be found on
any body surface, the typical sites are the forearms,
the nuchal area, the scrotum, and the shins. The
skin sites overlap with some common brachiora-
dial pruritus sites, suggesting that in some cases of
LSC a local neuropathy could be a cause [1].
Description of the Disease
The typical presentation of LSC is a circum-
scribed, lichenified, pruritic plaque. Scales and
excoriations are often present. Changes in
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara (Former), Ferrara, Italy
e-mail: restrumi@tin.it
skinned individuals [2]. Hypo- and hyperpigmen-
tation have been described; the most common
finding is a dusky violaceous or brown hyperpig-
mentation. Lesions of LSC can appear anywhere
on the body. The vulva, scrotum, and anus can
also be affected [2]. Patients can present with a
single lesion or have multiple sites of involve-
ment [3]. LSC usually arises on normal-appear-
ing skin but can also occur superimposed on
areas of diseased skin, such as atopic dermatitis,
psoriasis, and tinea corporis.
LSC is essentially a clinical diagnosis. The dif-
ferential includes lichen planus, psoriasis, tinea cor-
poris, contact dermatitis (irritant or allergic), and
cutaneous T-cell lymphoma. These entities can usu-
ally be differentiated from LSC on the basis of mor-
phology and distribution. A skin biopsy might be
beneficial in selected cases in which the diagnosis is
uncertain. Histopathologic findings include epider-
mal hyperplasia with acanthosis and dermal fibro-
sis, with vertical streaking of collagen bundles [4].

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DOI 10.1007/978-1-4471-6765-5_93
512
Therapeutic Alternatives
Treatment of LSC is difficult and recurrences
occur frequently. Interruption of the incessant
itch-scratch cycle, which characterizes this con-
dition, is of paramount importance. Patients
should be advised to stop rubbing and scratching
involved areas. When feeling the urge to scratch,
applying an ice cube or cold pack until the itch
subsides can be beneficial. Sedating antihista-
mines can also be helpful to prevent nocturnal
pruritus, which can be quite severe. In addition,
lifestyle modification to reduce stress and anxiety
should be encouraged, as psychological distress
is a frequent trigger of pruritus in these patients.
Referral to psychiatry might be required in severe
or recalcitrant cases [3].
Topical corticosteroids are the treatment of
choice for LSC. High-potency agents such as
betamethasone dipropionate and clobetasol pro-
pionate are very effective; however, because of
the risk of steroid induced atrophy with long-
term use, these agents are generally reserved for
initial management. For chronic lesions, low-to-
medium potency agents under occlusion may be
preferred. Menthol (0.2–0.5 %), camphor (0.2–
0.5 %), or tar (coal-tar solution; 5–10 %) can be
compounded into steroid ointments for enhanced
effect. Occlusive dressings are beneficial. Other
topical therapies less commonly employed for
LSC include tacrolimus ointment 0.1 % and topi-
cal capsaicin cream [5]. For persistent lesions,
intralesional injections of a corticosteroid, such
as triamcinolone acetonide, can be employed.
Although highly effective, this modality should
be used with caution, as the risk of atrophy and
depigmentation is greater than with topical corti-
costeroids [6].
Cryosurgery
In the literature there are only a few reports about
this topic, mainly in textbooks [7]. Freezing cuta-
neous nerves leads to hypoesthesia, an effect
R. Strumia
utilized in cryotherapy of LSC. Cryotherapy is
typically performed with LN using either a
cotton-tipped applicator or hand held spray deliv-
ery device. Complications include blister forma-
tion, hemorrhage and pigmentation abnormalities,
more evident in the pigmented plaques of LSC.
Methodology (How I Do It)
The duration of freezing should be about 15 s;
sessions can be repeated after 1–2 months, if
requested. Topical anaesthesia with a cream
relieves the pain.
Success Rates
In my experience, even after one session, when
the healing begins, the patient experiences a
remarkable decrease in itching.
Conclusions
Cryotherapy can be a useful therapeutic alter-
native for LSC.
References
1. Cohen AD, Andrews ID, Medvedovsky E, Peleg R,
Vardy. Similarities between neuropathic pruritus sites
and lichen simplex chronicus sites. IMAJ. 2014;16:
88–90.
2. Lynch PJ. Lichen simplex chronicus (atopic/neuroder-
matitis) of the anogenital region. Dermatol Ther.
2004;17:8–19.
3. Jones RO. Lichen simplex chronicus. Clin Podiatr
Med Surg. 1996;13:47–54.
4. Phelps RG, Miller MK, Singh F. The varieties of
“eczema”: clinicopathological correlation. Clin
Dermatol. 2003;21:95–100.
5. Tupker RA, Coenraads PJ, van der Meer JB. Treatment
of prurigo nodularis, chronic prurigo and neuroderma-
titis circumscripta with topical capsaicin. Acta Derm
Venereol. 1992;72:463.
6. Prajapati V, Barankin B. Dermacase. Lichen simplex
chronicus. Can Fam Physician. 2008;54:1391–3.
7. Nouri K. Complications in dermatologic surgery.
Philadelphia: Mosby Elsevier; 2008. p. 131.
 Lupus, Discoid
94
Martina Brandner and Angelika Klein-Theyer

Abstract
Discoid lupus erythematosus (DLE) is a chronic, scarring, photosensitive
skin inflammation representing the benign type of the lupus erythematosus
spectrum. Potent topical steroids and antimalarials are the mainstay of
treatment. Case reports and case series of cryotherapy in DLE lesions
document improving of itching, erythema, scaling, scarring and pain with
a minor chance of relapse. Pain in the thaw period, hypo-pigmented mild
scaring, loss of eyelashes, and persistent telangiectasias are reported side
effects. In cases of DLE lesions that are resistant to local or systemic ther-
apies, cryotherapy should be considered as alternative local treatment
modality in DLE.

Keywords
Discoid lupus erythematosus • Therapy resistant • Cryotherapy

Introduction trauma, and in rare cases infections or drugs, trig-

Discoid lupus erythematosus (DLE) is a chronic
skin inflammation representing the benign type
of the lupus erythematosus spectrum. Localized
and generalized variants are reported, both with
and without systemic manifestations of
LE. Besides a genetic predisposition, exogenous
factors such as UV radiation, cold, mechanical
ger skin involvement. It occurs frequently in the
third to fifth decade of life, especially in women
(female/male ratio of 3:1) [1, 2]. In addition to
drug therapy, some properly selected patients
may benefit from cryosurgery.
Description of the Disease

Typical lesions occur in localized form with

M. Brandner, MD (*) • A. Klein-Theyer, MD
Department of Ophthalmology,
Medical University Graz, Auenbruggerplatz 4,
Graz 8036, Austria
e-mail: martina.brandner@medunigraz.at
sharply demarcated, erythemato-keratotic, atro-
phic and scarring lesions on the face and scalp, or
in the generalized form, additionally on the
region below the neck. Predominantly

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_94
514
light-exposed areas, such as the nose, cheeks,
forehead and ears, as well as eyebrows, eyelids
and lips are affected.
The first morphological manifestation of DLE
presents as small, well-defined, disc-shaped,
sharply demarcated, slightly elevated erythema
with an adherent rough scale often attached to the
hair follicles (“carpet-tack” phenomenon).
Histopathology of active lesions typically shows
hyperkeratosis of the epidermis, dilated follicular
orifices filled with compact keratin, mononuclear
periadnexal and perivascular cell infiltrates and
mucinosis of the dermis.
Intermediate lesions develop central atrophy
with loss of normal skin texture, which can be
surrounded by residual active lesions as ring-like
arcuate or polycyclic scaly erythema. Old lesions
present as large, sharply demarcated, depig-
mented, alopecic, flat, thin scars. Telangiectasia
and pigmentary changes such as hyper- and
hypopigmentation are common [1, 2].
Therapeutic Alternatives
Isolated lesions normally respond to local corti-
costeroids (fluorinated or non-fluorinated of var-
ied potency). In case of indurated and chronically
scaling lesions occlusive corticosteroid therapy
or intralesional injections may be necessary [2–
4]. Systemic antimalarials constitute first-line
systemic therapy of DLE; the most commonly
used being chloroquine and hydroxychloroquine.
Both have shown to be useful. Systemic side
effects include antimalarial retinopathy, pruritus,
erythema, exfoliative dermatitis, cutaneous pig-
mentation and neuromyopathy [2, 4]. Patients in
whom systemic antimalarials fail to clear the
cutaneous lesions may benefit from systemic cor-
ticosteroids. For a faster resolution at the begin-
ning of the treatment Fabbri et al. advice the
combination of prednisone and an antimalarial
for 2 or 3 weeks [2]. Cortés-Hernández et al.
reported a case series of 60 patients with refrac-
tory cutaneous lupus erythematosus who
responded to low dose thalidomide. Complete
remission occurred in 85 %, but clinical relapse
happened frequently and usually 5 months after
M. Brandner and A. Klein-Theyer
withdrawal or reduction of therapy. Nevertheless,
the report emphasizes that benefits need to be
balanced against the potential serious adverse
effects such as teratogenicity and neuropathy [5].
Methotrexate, a competitive inhibitor of dihydro-
folate reductase, shows anti-inflammatory and
antiproliferative effects and has been reported
effective against DLE lesions refractive to steroid
and antimalarial drugs [6]. Other therapeutic
alternatives include dapsone, gold, topical calci-
neurin blockers, interferon-alpha-2a, anti-tumor
necrosis factor agents, rituximab, cyclosporine,
azathioprine, mycophenolate mofetil and efali-
zumab [3, 7, 8].
Several other studies also reported good
responses to physical modalities of such as pulse
dye laser [9], cryotherapy [10–12], and photody-
namic therapy [13].
Cryotherapy
Cryotherapy for DLE is described only in a few
reports [10–12]. Molin et al. [10] reported cryosur-
gery in DLE performed with LN via open spray
for up to 20 s and a halo thawing time over 40 s or,
as an alternative for the most hyperkeratotic
lesions, application of LN on a cotton swab with
mild pressure for equivalent freezing and thawing
time. Wollina et al. [11] described cryotherapy in
20 cutaneous lesions in 4 of 6 patients that had
previously undergone systemic treatment; cryo-
therapy was performed in two freeze-thaw cycles
of LN open sprayed for 10–60 s sessions. The
follow-up period was 17 months. Blister formation
occurred in all patients 2 days after the treatment
and healed with a hypo-pigmented scar after
2 weeks. Koch et al. [12] applied LN to a DLE
lesion of the lower eyelid, resistant to topical and
systemic therapy for years. Treatment was well
tolerated and resulted in a complete regression.
Methodology (How I Do It)
LN is applied with a non-contact spray applicator
of 0.8 mm in diameter. Each lesion is treated with
one freeze-thaw cycle of 20 s per session. The
94 Lupus, Discoid
Fig. 94.1 Scaly and crusted lid margin
Fig. 94.2 Complete remission after cryotherapy
treatment is repeated after 14 days (Figs. 94.1
and 94.2).
Success Rates
Molin et al. [10] reported complete healing in a
single case of DLE, leaving slightly hypo-
pigmented soft scars, with no tendency of relapse
during a follow-up period of 10 years. Wollina
et al. [11] in their study described that relapse
occurred in only 2 of the 20 lesions which were
followed for 17 months. All patients improved
regarding itching, erythema, scaling, scarring and
pain. Persistent telangiectasia was reported, as an
unwanted side-effect. Koch et al. [12] reported a
515
longstanding discoid lupus erythematosus lesion
resistant to topical and systemic therapy for
years, improving by cryotherapy with no relapse
in the follow-up period of 6 months.
Conclusions
Case reports and case series of cryotherapy in
DLE lesions document improving of itching,
erythema, scaling, scarring and pain, with a
minor chance of relapse. Pain in the thaw
period, hypopigmented mild scaring, loss of
eyelashes, and persistent telangiectasias are
reported side- effects. Cryotherapy should be
considered as alternative local treatment
modality in DLE.
References
1. Kuhn A, Sontheimer RD, Ruzicka T. Clinical mani-
festation of cutaneous lupus erythematosus. In:
Kuhn A, Lehmann P, Ruzicka T, editors. Cutaneous
lupus erythematosus. Berlin: Springer; 2005.
p. 59–93.
2. Fabbri P, Cardinali C, Giomi B, Caproni M. Cutaneous
lupus erythematosus: diagnosis and management. Am
J Clin Dermatol. 2003;4(7):449–65.
3. Jessop S, Whitelaw DA, Delamere FM. Drugs for dis-
coid lupus erythematosus. Cochrane Database Syst
Rev. 2009;7(4):CD002954.
4. Panjwani S. Early diagnosis and treatment of discoid
lupus erythematosus. J Am Board Fam Med. 2009;
22(2):206–13.
5. Cortés-Hernández J, Torres-Salido M, Castro-Marrero
J, Vilardell-Tarres M. Thalidomide in the treatment of
refractory cutaneous lupus erythematosus: prognostic
factors of clinical outcome. Br J Dermatol. 2012;
166(3):616–23.
6. Goldstein E, Carey W. Discoid lupus erythematosus :
successful treatment with oral methotrexate. Arch
Dermatol. 1994;130(7):938–9.
7. Goyal S, Nousari HC. Treatment of resistant discoid
lupus erythematosus of the palms and soles with
mycophenolate mofetil. J Am Acad Dermatol. 2001;
45(1):142–4.
8. Booken N, Schumann T, Fuchslocher M, Goerdt S,
Goebeler M. Successful therapy of discoid lupus ery-
thematosus with efalizumab. Hautarzt. 2010;61(3):
246–9.
9. Ekbäck MP, Troilius A. Laser therapy for refractory
discoid lupus erythematosus when everything else has
failed. J Cosmet Laser Ther. 2013;15(5):260–5.
10. Molin L, Tarstedt M. Discoid lupus erythematosus
treated with cryotherapy. J Dermatolog Treat. 2003;14(3):
182–3.
516
11. Wollina U, Prifert K. Cryogenic contact therapy of
cutaneous lesions of lupus erythematosus. Dermatol
Monatsschr. 1990;176(2–3):105–9.
12. Koch M, Horwath-Winter J, Aberer E, Salmhofer
W, Klein A. Cryotherapy in discoid lupus erythe-
matosus (DLE). Ophthalmologe. 2008;105(4):
381–3.
M. Brandner and A. Klein-Theyer
13. Fernández-Guarino M, Pérez-García B, Harto A,
Jaén P. Discoid lupus erythematosus: good
response to treatment with photodynamic therapy.
J Eur Acad Dermatol Venereol. 2008;22(9):
1142–3.
 Lymphangioma Circumscriptum
95
Jessica Alexis Savas and Gloria F. Graham

Abstract
Lymphangioma circumscriptum (LC) is a rare, superficial cutaneous lym-
phatic malformation. Lesions of LC may be present at birth or acquired
later in life. Despite the time of onset, lesions of LC are clinically charac-
terized by clusters of thin-walled, translucent vesicles, likened to “frog-
spawn” on the skin. First described by Whimster in 1970, the
pathophysiology of LC has been attributed to deep lymphatic cisterns that
transmit pressure to superficial lymphatics causing saccular dilatations in
the overlying epidermis, resulting in vesicles on the skin. Management is
difficult due to high recurrence rates, regardless of the treatment modality
chosen. Superficially destructive modalities, including cryosurgery, are
useful adjuncts to treatment. Although surgical excision offers the only
definitive cure, cryotherapy is a less-invasive option that offers symptom-
atic relief with a tolerable side effect profile and an acceptable cosmetic
result.

Keywords
Lymphangioma circumscriptum • Lymphangiectasis • Microcystic lym-
phatic malformation • Lymphatic malformation • Cutaneous lymphangi-
oma • Cryotherapy • Cryosurgery

Introduction

J.A. Savas, BS, MD Cutaneous lymphangiomas are relatively uncom-

Department of Dermatology and Cutaneous Surgery,
University of Miami Miller School of Medicine,
Miami, FL, USA
G.F. Graham, MD (*)
Department of Dermatology, Wake Forest University
School of Medicine, Winston Salem, NC, USA
e-mail: ggfgraham@aol.com
mon lymphatic malformations, accounting for
only 4 % of all vascular tumors [1]. Lymphangioma
circumscriptum (LC) is a rare form of superficial
cutaneous lymphangioma, it may be congenital
or acquired. Acquired cases are often seen several
years after an exogenous insult, such as radiation

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_95
518
therapy [2]. Lesions of LC may appear anywhere,
but most commonly involve the thigh, buttocks,
groin or axilla. There is no true gender predilec-
tion, however women tend to present for treat-
ment more often than men, likely due to cosmetic
selection [3]. Clinically, lesions of LC are charac-
terized by clusters of small, thin-walled, translu-
cent vesicles giving them the classic appearance
of “frog-spawn on the skin” [1]. Some lesions
exhibit overlying hyperkeratosis, resulting in a
verrucous or wart-like appearance [4].
Lymphangioma circumscriptum may also pos-
sess a significant vascular or hemorrhagic com-
ponent, producing a variation in lesion color from
pink to red, to black, depending on the ratio of
blood to lymph within the vesicles.
Description of the Disease
In 1970, Whimster hypothesized that the patho-
genesis underlying LC is the result of an ectopic
system of muscular-lined lymphatic cisterns
located deep within the dermis, subcutis, and on
occasion, muscle. Pulsatile contractions of the
muscular coat lining these cisterns transmit pres-
sure through dilated endothelial-lined lymphatics
into the papillary dermis causing cystic dilatation
in the overlying superficial lymphatic vessels. It is
these saccular dilatations within the dermal papilla
that create the clinical appearance of vesicles [5].
Lymphangioma circumscriptum is generally a
benign process; however reports of lymphangio-
sarcoma and squamous cell carcinoma arising
within long-standing lesions of LC have been
reported [6, 7]. Furthermore, drainage of lym-
phatic fluid from ruptured vesicles, recurrent bouts
of cellulitis, and a distressing aesthetic appearance
may all be “quality-of-life-threatening,” thus
prompting patients to seek treatment.
Therapeutic Alternatives
Complete surgical excision of the deep lymphatic
cisterns offers the only definitive cure; however,
the risk of nerve damage, scarring, and cosmetic
disfigurement make a conservative approach the
J.A. Savas and G.F. Graham
more palatable option in some cases. These less
invasive alternatives include superficially
destructive modalities such as electrocautery,
sclerotherapy, topical imiquimod, radiofrequency
ablation, ablative and non-ablative laser devices,
as well as cryotherapy [8–16]. Most of these
options are largely palliative and recurrence of
the lesions is generally the rule.
Cryosurgery
The lesions of LC are benign hamartomatous
proliferations of lymphatic tissue and thus render
themselves vulnerable to the destructive power of
freezing with LN. Low cost, ready availability,
low risk of infection and simple post-procedural
care are all added advantages of cryosurgery over
surgical resection. Furthermore, most complica-
tions of cyrotherapy are mild and well tolerated.
Most commonly these include pain at the treated
site, edema, blister formation, and post-
inflammatory pigment alteration.
Methodology (How I Do It)
No general consensus exists regarding the opti-
mal parameters for the use of cryotherapy for the
treatment of LC. Vesicles of LC range in size
from 2 to 5 mm in diameter and are themselves
relatively superficial. It is important to remember
that the therapeutic goal of cryosurgery is the
destruction of the superficial component of the
lesions in an effort to provide symptomatic relief.
Cryosurgery does not address the deeper compo-
nent of the lesions. That being said, a timed spot
freeze technique, with or without the use of an
open cone shield, and a freeze time between 20
and 30 s is generally sufficient for the formation
of an ice ball that will accomplish tissue destruc-
tion within a 2 cm radius.
Having treated several cases of LC I (GG)
have had success using this particular technique.
A few representative cases include a patient with
Fitzpatrick skin type V with LC involving the left
breast, extending into the axilla. I used a freeze
time of 20 s and was able to eradicate most of the
95 Lymphangioma Circumscriptum
Fig. 95.1 Hypopigmentation following crysurgery of
multiple vesicles
lesions over several treatment sessions.
Hypopigmentation occurred in the treated areas
and several areas of recurrence required retreat-
ment (Fig. 95.1). Given the extensive area of
involvement of this particular case, cryosurgery
offered a non-invasive, temporary solution with
an overall satisfactory result. Using the same
parameters, I treated a male patient with lesions
of LC on the foot complicated by lymphatic
drainage. This patient achieved improvement of
his symptoms but not permanent eradication. I
have also encountered the limitations of cryosur-
gery for LC. One particular case of congenital
LC in a young female involving the abdomen and
right thigh was both extensive in size and charac-
terized clinically by marked fibrosis. This patient
would likely not benefit form monotherapy with
cryosurgery and therefore was referred to plastic
surgery for more definitive treatment.
Success Rates
The successful use of cryotherapy for the treat-
ment of LC has been reported in the literature
with conflicting results. Tasdelen et al. reported a
case of acquired LC of the breast treated with a
combination of electrocautery and cryotherapy.
Some vesicles were drained and cauterized while
519
others were treated with two applications of liquid
nitrogen for 20 s each. At 8 weeks, the wound had
re-epithelialized and they noted no evidence of
recurrence at 4-month follow-up [17]. Similarly,
Fatani and colleagues treated verrucous lesions of
LC, originally thought to be genital condyloma,
with multiple sessions of cryotherapy with good
results [18]. Conversely, Darmstadt treated a case
of perianal LC in a pediatric patient with cryo-
therapy with no reported improvement [19]. Cases
of acquired LC secondary to Crohn’s with peri-
neal or vulvar involvement have also been treated
with liquid nitrogen resulting in short-term
improvement with eventual recurrence requiring
further intervention [20].
Conclusions
Given the rarity of the condition, LC does not
lend itself to large, randomized-controlled
trials and therefore the majority of informa-
tion available is based on small case series
and case reports. Despite this limitation, from
both evidence-based knowledge and anec-
dotal reports, it is generally concluded that
cryosurgery may be a useful adjunct to other
treatment modalities or as a mitigating mea-
sure for symptomatic control. Complete
remission through the use of cryotherapy
alone is unlikely and not recommended unless
both patient and physician understand that
multiple sessions will be required for future
recurrences.
References
1. Patel GA, Schwartz RA. Cutaneous lymphangioma cir-
cumscriptum: frog spawn on the skin. Int J Dermatol.
2009;48:1290–5.
2. Jappe U, Zimmermann T, Kahle B, et al.
Lymphangioma circumscriptum of the vulva follow-
ing surgical and radiological therapy of cervical can-
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3. Peachey RD, Lim CC, Whimster IW. Lymphangioma
of skin. A review of 65 cases. Br J Dermatol. 1970;83:
519–27.
4. Erkilic S, Kocer NE, Mutaf M. Giant lymphangioma
circumscriptum mimicking wart in a 13-year-old girl.
J Dermatol. 2006;33:501–3.
5. Whimster IW. The pathology of lymphangioma cir-
cumscriptum. Br J Dermatol. 1976;94:473–86.
520
6. King DT, Duffy DM, Hirose FM, et al.
Lymphangiosarcoma arising from lymphangioma cir-
cumscriptum. Arch Dermatol. 1979;115:969–72.
7. Wilson GR, Cox NH, McLean NR, et al. Squamous
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8. AlGhamdi KM, Mubki TF. Treatment of lymphangi-
oma circumscriptum with sclerotherapy: an ignored
effective remedy. J Cosmet Dermatol. 2011;10:156–8.
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in 64 patients with lymphangioma. J Pediatr Surg.
1994;29:784–5.
10. Bikowski JB, Dumont AM. Lymphangioma circum-
scriptum: treatment with hypertonic saline sclerother-
apy. J Am Acad Dermatol. 2005;53:442–4.
11. Lapidoth M, Ackerman L, Amitai DB, et al. Treatment
of lymphangioma circumscriptum with combined
radiofrequency current and 900 nm diode laser.
Dermatol Surg: Off Publ Am Soc Dermatol Surg.
2006;32:790–4.
12. Niti K, Manish P. Microcystic lymphatic malforma-
tion (lymphangioma circumscriptum) treated using a
minimally invasive technique of radiofrequency abla-
tion and sclerotherapy. Dermatol Surg: Off Publ Am
Soc Dermatol Surg. 2010;36:1711–7.
13. Harashima T, Hossain M, Walverde DA, et al.
Treatment of lymphangioma with Nd:YAG laser
J.A. Savas and G.F. Graham
irradiation: a case report. J Clin Laser Med Surg.
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14. Lai CH, Hanson SG, Mallory SB. Lymphangioma cir-
cumscriptum treated with pulsed dye laser. Pediatr
Dermatol. 2001;18:509–10.
15. Tsilika K, Bahadoran P, Passeron T. Superficial
lymphangioma treated with fractional ablative laser: a
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16. Wang JY, Liu LF, Mao XH. Treatment of lymphangi-
oma circumscriptum with topical imiquimod 5%
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18. Fatani MI, Bitar M, Al Afif KA, Baltow B, Baghadi S.
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19. Darmstadt GL. Perianal lymphangioma circumscrip-
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20. Handfield-Jones SE, Prendiville WJ, Norman S. Vulval
lymphangiectasia. Genitourin Med. 1989;65:335–7.
 Lymphocytoma Cutis
96
Hee Jin Kim, Brian W. Lee, and Robert A. Schwartz

Abstract
Lymphocytoma cutis is a subtype of cutaneous pseudolymphoma involv-
ing the face, chest, and upper extremities. It clinically presents as skin-
colored to dark-red papules, nodules, or infiltrative plaques similar in
appearance to cutaneous malignant lymphoma. Histologic features help
differentiate lymphocytoma cutis from cutaneous malignant lymphoma.
The cause of lymphocytoma cutis is typically indeterminate. Cryosurgery
is an acceptable treatment of choice for patients whose lymphocytoma
cutis fails to respond to known trigger avoidance, and other topical or sys-
temic drugs as well as radiation therapy.

Keywords
Lymphocytoma • Pseudolymphoma • B-cell • Borrelia

Introduction [1]. In 1891, Kaposi first described cutaneous

Lymphocytoma cutis (Spiegler–Fendt sarcoid) is
a variant of cutaneous pseudolymphoma, a
dermatologic process that results in a benign
reactive accumulation of T- or B-cells in the skin
H.J. Kim, MD • B.W. Lee, MD
Department of Dermatology, Rutgers University
New Jersey Medical School, Newark, NY, USA
R.A. Schwartz, MD, MPH, DSc (Hon),
FRCP (Edin) (*)
Dermatology and Pathology, Rutgers University
New Jersey Medical School, Rutgers University
School of Public Affairs and Administration,
185 South Orange Ave., Newark, NJ 07103, USA
e-mail: roschwar@cal.berkeley.edu
pseudolymphoma as sarcomatosis cutis and in
1923, Biberstein coined the term lymphocytoma
cutis [2, 3]. Cutaneous pseudolymphomas are
divided into two subtypes: cutaneous T-cell pseu-
dolymphoma (CTPL) and cutaneous B-cell pseu-
dolymphoma (CBPL) [1]. Lymphocytoma cutis
is more commonly associated with B-cell pre-
dominant CBPL. This dermatologic condition is
more prevalent in males than females with a ratio
of 2:1 and in whites than blacks with a ratio of
9:1 [2, 3]. It develops early in adult life with a
median age of onset at 34 years [3]. There is a
wide spectrum of triggers associated with lym-
phocytoma cutis, but the cause is unknown most
of the time. It is important to differentiate

© Springer-Verlag London 2016 521

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_96
522
lymphocytoma cutis from cutaneous malignant
lymphoma and to be sure it is not a component of
Lyme boreliosis (Lyme disease) [1].
Description of the Disease
The cause of lymphocytoma cutis is typically
unknown, but common etiologies are drugs, for-
eign agents, infections, photosensitivity, and
idiopathic causes [1, 4]. Drugs that cause lympho-
cytoma cutis include anticonvulsants, antipsy-
chotics, antihypertensives, angiotensin-converting
enzyme inhibitors, beta-blockers, calcium chan-
nel blockers, diuretics, cytotoxics, antibiotics,
anxiolytics, antihistamines, antiarrhythmics, and
lipid-lowering agents [1]. Foreign agents that
stimulate the manifestation of lymphocytoma
cutis include tattoo pigment, insect bites, injection
of arthropod venom, and gold pierced earrings
[1]. Pseudolymphomatous reaction to tattoo dyes
predominantly occurs on black and red areas of
the tattoo. More patients with black or red tattoos
experience local swelling, itching, pain, and red-
ness than those with blue or green tattoos [5–7].
Lymphocytoma cutis has been reported following
excision arthroplasty [8]. Infectious causes
include B. burgdorferi, varicella-zoster, and HIV
[1]. Borrelia burgdorferi infection stimulates
lymphoid tissues in the skin, which results in
perivascular lymphocytic infiltrates and B-cell
pseudolymphomas [9, 10]. This cutaneous mani-
festation is present in 0.6–1.3 % of patients diag-
nosed with Lyme disease [11–13]. Cutaneous
borreliosis rarely mimics the appearance of cuta-
neous T-cell lymphoma [14].
The clinical presentation of lymphocytoma
cutis varies from papules, nodules, to infiltrative
plaques that are similar in appearance to cutane-
ous malignant lymphoma [15]. Lymphocytoma
cutis is characterized as skin-colored to dark-red
dermal and subcutaneous nodules or plaques that
mimic cutaneous B-cell lymphoma [1]. It is fre-
quently found on the face, chest, and upper
extremities [4]. A localized form of lymphocy-
toma cutis is described as a single asymptomatic
nodule that is soft, doughy, or firm in texture and
can measure up to 4 cm in diameter. A clustered
H.J. Kim et al.
form is characterized as miliary papules that are
only a couple of millimeters each in diameter.
These lesions are skin-colored, red, red-brown, or
red-purple and do not have associated ulceration
or scales [1, 14]. Borrelial lymphocytoma cutis
presents as blue to red-colored plaques or nodules
that measure up to 5 cm in diameter at the site of
a tick bite, near the periphery of erythema chroni-
cum migrans [1]. It may manifest as a concen-
trated collection of multiple nodules with regional
lymphadenopathy. Anatomic sites with low tem-
perature, such as the ear lobe, nipple, areola, nose,
and the scrotal area, are involved. More than half
of the patients with borrelial lymphocytoma cutis
have an increased number of serum antibodies to
B. burgdorferi [1, 3].
Lymphocytoma cutis is difficult to differenti-
ate from cutaneous lymphoma on clinical
grounds alone due to the similarity in their pre-
sentations. However, lymphocytoma cutis usu-
ally takes the form of a single papule or nodule
on the face or neck, whereas cutaneous lym-
phoma is larger and darker with associated ulcer-
ation [3, 4]. The course of disease differentiates
these two in that lymphocytoma cutis tends to
regress without treatment, whereas cutaneous
lymphoma tends to worsen with extracutaneous
involvement. Histologic features also help dif-
ferentiate lymphocytoma cutis from cutaneous
lymphoma. B-cell predominant pseudolym-
phoma is composed of nodular or diffuse lym-
phocytic infiltrates and a variable amount of
histiocytes, eosinophils, and plasma cells [1, 3,
4]. Lymphocytoma cutis usually involves the
superficial papillary dermis while sparing the
epidermis, and may extend into the subcutane-
ous layer of fat. Other histologic features of lym-
phocytoma cutis include acanthosis, superficial
location, mixed cellular infiltrate, vasculature
proliferation, germinal centers, and debris of
degenerate lymphoid cells [1].
Therapeutic Alternatives
Cutaneous pseudolymphoma is usually of inde-
terminate cause, which makes it difficult to iden-
tify and remove the causative agent. Some lesions
96 Lymphocytoma Cutis
regress completely without treatment, but others
recur and persist. Treatments used for localized
lymphocytoma cutis include topical or intrale-
sional corticosteroids, cryosurgery, interferon
alfa, laser, local radiation and surgical excision.
For widespread lesions, antimalarials, photoche-
motherapy, or cytotoxic agents have been used
with success [1, 3]. Careful follow-up is recom-
mended for recurrent cases because they have an
increased tendency to become malignant. Topical
tacrolimus was effective in reducing lymphocytic
infiltrates in two patients with lymphocytoma
cutis, even though the response time was slow
(>4 months) [16].
Lymphocytoma cutis with a known cause is
treated appropriately by removing the causative
agent. In an anticonvulsant-induced lymphocy-
toma cutis, the cutaneous presentation regresse
spontaneously over a period of 3–4 weeks with
discontinuation of the drug. In an early borrelial
lymphocytoma cutis, antibiotics are used, such as
penicillin 1 g orally three times daily or doxycy-
cline 100 mg orally twice daily for a 2-week
course [17]. One pediatric patient with atypical
presentation of Borrelia-associated lymphocytoma
cutis on right eyebrow was successfully treated
with cefuroxime for 3 weeks (250 mg/day) [18].
Patients with untreated borrelial lymphocy-
toma cutis of several months duration may
require a longer course of antibiotics. In a tattoo
dye-induced pseudolymphoma, fractional resur-
facing and laser treatments have been used with
success [19]. Argon laser not only alleviates
symptoms of lymphocytoma cutis, but also
improves cosmetic appearance [20].
Subcutaneous injection of interferon-alpha is
effective in treating cutaneous pseudolymphoma
[21, 22]. Intralesional triamcinolone acetate
40 mg/ml every 10–15 days was effective in a
patient who responded poorly to PUVA [23].
Surgical excision was found to be curative in
some cases. In drug-induced lymphocytoma
cutis, no recurrence of excised lesions has been
reported following discontinuation of the caus-
ative agent. External radiation therapy has been
used with success as an additive treatment in
patients with incomplete regression of lympho-
cytoma cutis [19].
523
Cryosurgery (How We Do It)
Cryosurgery has been used with success in the
treatment of lymphocytoma cutis. In a study of five
patients with lymphocytoma cutis, each lesion was
treated with liquid nitrogen using a single cycle of
15–20 s. Complete resolution was documented
within 3–6 weeks [24]. Patients treated with cryo-
surgery should be monitored for dyschromia [25].
Conclusion
Cryosurgery may be an acceptable therapeu-
tic alternative for patients whose lymphocy-
toma cutis fails to respond to other
therapeutic options.
References
1. Ploysangam T, Breneman DL, Mutasim DF.
Cutaneous pseudolymphomas. J Am Acad Dermatol.
1998;38(6): 877–98.
2. Bluefarb SM, editor. Cutaneous manifestations of
the benign inflammatory reticuloses. Lymphocytoma
cutis. Springfield: Thomas CC; 1960. p. 131–99.
3. Burg G, Kempf W, Dummer R. Cutaneous lymphoma,
leukemia and related disorders. In: Schwartz RA, edi-
tor. Skin cancer: recognition and management. 2nd
ed. Oxford: Blackwell; 2008. p. 238–66.
4. Rijlaarsdam JU, Willemze R. Cutaneous pseudo-
lymphomas: classification and differential diagnosis.
Semin Dermatol. 1994;13:187–96.
5. Blumental G, Okun MR, Ponitch JA. Pseudolym-
phomatous reaction to tattoos. J Am Acad Dermatol.
1982;6:485–8.
6. Cristaudo A, Forte G, Bocca B, Petrucci F, Muscardin
L, Trento E, Di Carlo A. Permanent tattoos: evidence of
pseudolymphoma in three patients and metal composi-
tion of the dyes. Eur J Dermatol. 2012;22(6):776–80.
7. Carlsen KH, Serup J. Photosensitivity and photo-
dynamic events in black, red, and blue tattoos are
common: a “Beach Study”. J Eur Acad Dermatol
Venereol. 2014;28:231–7.
8. Mehta V, Balachandran C, Hameed S. Lymphocytoma
cutis following excision arthroplasty. Indian J Dermatol.
2011;56:104–6.
9. Goodlad JR, Davidson MM, Hollowood K, Batstone
P, Ho-Yen DO. Borrelia burgdorferi-associated cuta-
neous marginal zone lymphoma: a clinicopathological
study of two cases illustrating the temporal progres-
sion of B. burgdorferi-associated B-cell proliferation
in the skin. Histopathology. 2000;37:501–8.
10. Chodynicka B, Flisiak I, Okrasinska K, Andrezejewska
A, Schwartz RA. Lymphocytoma cutis: cases linked with
Lyme disease. Cutis. 2000;66(4):243–6.
524
11. Stanek G, Wewalka G, Groh V, et al. Differences
between Lyme disease and European arthropod-borne
borrelia infections. Lancet. 1985;1:401.
12. Bhate C, Schwartz RA. Lyme disease: update and per-
spective. Part I. J Am Acad Dermatol. 2011;64:619–36.
13. Bhate C, Schwartz RA. Lyme disease: update and per-
spective. Part II. J Am Acad Dermatol. 2011;64:639–53.
14. Kempf W, Kazakov DV, Hubscher E, Gugerli O,
Gerbig AW, Schmid R, Palmedo G, Kutzner H.
Cutaneous borreliosis associated with T-cell predomi-
nant infiltrates: a diagnostic challenge. J Am Acad
Dermatol. 2015;72:683–9.
15. Bergman R. Pseudolymphoma and cutaneous lym-
phoma: facts and controversies. Clin Dermatol.
2010;28(5):568–74.
16. El-Dars LD. Lymphocytoma cutis treated with topi-
cal tacrolimus. Clin Exp Dermatol. 2005;30:305–7.
17. Asbrink E, Hovmark A. Lyme borreliosis. In:
Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM,
Austen KF, editors. Dermatology in general medicine.
4th ed. New York: McGraw-Hill; 1993. p. 2410–20.
18. Amschler K, Schön MP, Mempel M, Zutt M. Atypical
location of lymphocytoma cutis in a child. Pediatr
Dermatol. 2013;30(5):628–9.
H.J. Kim et al.
19. Lucinda TS, Hazel OH, Joyce LS, Hon CS. Successful
treatment of tattoo-induced pseudolymphoma with
sequential ablative fractional resurfacing followed by
Q-switched Nd: YAG 532nm laser. J Cutan Aesthet
Surg. 2013;6(4):226–8.
20. Wheeland RG. Role of the argon laser in treatment
of lymphocytoma cutis. J Am Acad Dermatol. 1985;
14(2):267–72.
21. Singletary H, Selim MA, Olsen E. Subcutaneous
interferon alfa for the treatment of cutaneous psudo-
lymphoma. Arch Dermatol. 2012;148(5):572–4.
22. Tomar S, Stoll HL, Grassi MA, Cheney R. Treatment
of cutaneous pseudolymphoma with interferon alfa-
2b. J Am Acad Dermatol. 2009;60(1):172–4.
23. de Oliveira EVL, Badiale GB, Moraes MM.
Lymphocytoma cutis-case report. An Bras Dermatol.
2013;88(6):128–31.
24. Kuflik AS, Schwartz RA. Lymphocytoma cutis:
a series of five patients successfully treated with
cryosurgery. J Am Acad Dermatol. 1992;26(3 Pt 2):
449–52.
25. Barikbin B, Lofti S, Rahimi H, Asadi-Kani Z, Yousefi
M. Cutaneous pseudolymphoma of the breast. Iran
J Dermatol. 2012;15(1):18–21.
 Molluscum Contagiosum
97
Chante Karimkhani, Lindsay N. Boyers,
Ryan Gamble, and Robert P. Dellavalle

Abstract
Molluscum contagiosum virus causes a benign and self-limited infection with
a classic umbilicated papular manifestation in children, sexually active adults,
and immunocompromised individuals. While several classes of therapy are
available including physical therapy, chemical destructive therapy, chemical
non-destructive therapy, immune modulators, and antiviral therapy, cryosur-
gery offers the advantage of high-eradication rates and is a relatively quick
office procedure. It can be performed in several freeze-thaw cycles, each with
10–20 second long bursts of liquid nitrogen spray. Adverse effects include mild
pain with application, blister and scar formation, and hypopigmentation. Along
with various effective chemical treatments, cryosurgery should be considered a
first-line therapy for the treatment and eradication of MCV infection.

Keywords
Molluscum contagiosum virus • Cryosurgery • Viral skin infection •
Physical therapy • Hypopigmentation

Abbreviations
C. Karimkhani, MD (*) HIV Human immunodeficiency virus
University Hospitals Case Medical Center, 408 W St.
Clair Avenue, apt 317, Cleveland, OH 44113, USA KOH Potassium hydroxide
e-mail: ck2525@columbia.edu LN Liquid nitrogen
L.N. Boyers, MD MCV Molluscum contagiosum virus
Yale-Waterbury Department of Internal Medicine,
Waterbury, CT, USA
R. Gamble, MD Introduction
Department of Dermatology, University of Colorado,
Aurora, CO, USA
Molluscum contagiosum is a common and benign
R.P. Dellavalle, MD, PhD, MSPH
Department of Dermatology, Veteran Affairs viral skin condition that often affects children,
Medical Center, Denver, CO, USA sexually-active adults, and immunocompromised

© Springer-Verlag London 2016 525

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_97
526
individuals [1]. Following the eradication of
small pox, molluscum contagiosum virus (MCV)
has become the predominant poxvirus affecting
humans in the modern-day [2]. The virus has a
predilection for the epidermal layer of human skin
and does not cross the basement membrane, thus
evading immune surveillance mechanisms in the
dermis and underlying structures [3]. Resolution
or eradication of the superficial epidermal lesions
is considered a complete cure, although subse-
quent primary re-infection is a possibility.
Description of the Disease
MCV manifests as small (3–5 mm in diameter),
waxy, pink to white, hemispherical papules with
central umbilication (Fig. 97.1). While most
lesions occur on the extremities, approximately
50 % of infected individuals have lesions in
multiple anatomic regions [4]. A thorough skin
exam should be performed to ensure additional
areas of infection are not overlooked. The
lesions can appear in groups or as single papules
that are typically painless. Squeezing or trauma
to the lesion classically produces a creamy,
grey-white exudate that is easily spread by shav-
ing and scratching. Immunocompetent hosts
typically have <20 lesions, although the virus
can present with >100 lesions [1]. MCV is
believed to infect the epidermis via a breach in
Fig. 97.1 Cluster of molluscum contagiosum papules,
demonstrating characteristic waxy pink color and central
umbilication
C. Karimkhani et al.
the skin barrier resulting in a localized eczema-
tous reaction with associated pruritus that facili-
tates viral spread by auto-inoculation. Clinical
identification of the characteristic umbilicated
papules is usually sufficient for diagnosis,
although dermatoscopy and histopathology can
aid in the diagnosis. Henderson-Paterson bod-
ies, also referred to as “molluscum bodies,” may
be identified on cytological smears of the central
liqid-rich core, representing a cytoplasmic sac
containing many viral particles [5].
The natural history of the disease usu-
ally results in spontaneous regression; with
untreated clearance of lesions in 6–9 months
[6]. MCV in the genital area is classified as a
sexually transmitted disease and should raise
suspicion for abuse when observed in children.
Immunocompromised states, such as Human
immunodefficiency virus (HIV) infection and
drug-induced immunosuppression, result in a
more severe and intense MCV infection. The
cell-mediated immune system is critical for reso-
lution of MCV infection, demonstrated by a high
prevalence of this infection in 5–18 % of HIV
infected patients [7]. Improvement of immune
status, such as with highly-active antiretroviral
therapy, is the only treatment necessary for MCV
associated with immunodeficiency states [8].
Therapeutic Alternatives
Given the benign and self-limited nature of MCV
infection, the benefits of viral eradication must be
weighed against potential treatment adverse
effects. In addition, coexisting complications
such as inflammation, pruritus, dermatitis, and
secondary bacterial infection, may need to be
resolved prior to MCV treatment. Several classes
of therapy are available including physical ther-
apy, chemical destructive therapy, chemical non-
destructive therapy, immune modulators, and
antiviral therapy [1]. Phenol 10 % and trichloro-
acetic acid 100 % are commonly utilized options
for chemical destructive therapy, while canthari-
din 0.9 %, podophyllotoxin 0.3–0.5 % cream,
salicylic acid gel 12 %, benzoyl peroxide 10 %
cream, retinoic acid 0.5 % cream, and potassium
97 Molluscum Contagiosum
hydroxide (KOH) aqueous solution 5–10 % serve
as examples of chemical non-destructive therapy
[1]. Chemical treatments or no intervention at all
may be more appropriate for young children who
may not tolerate the physical treatments [6].
Cyrosurgery (liquid nitrogren (LN) spray), curet-
tage, pulsed dye 585 nm laser, photodynamic
therapy, and electron beam therapy constitute the
range of physical therapies used for MCV treat-
ment [1].
Cryosurgery
Advantages of cryosurgery include short prepa-
ration time, low maintenance costs, low risk of
infection, and minimal post-procedure wound
care. In addition, cryosurgery is a fast and conve-
nient office procedure. A survey of 300 pediatric
dermatologists revealed that 67 % of respondents
utilize cryotherapy for the treatment of MCV [9].
Methodology (How I Do It)
Various spray patterns of LN include direct spray,
paintbrush, and rotary or spiral spray [10]. The
spray gun is triggered until an ice field encom-
passes the lesion and desired margin (typically
1–2 mm is an adequate margin). A short duration
of up to 10–20 seconds until the surface of the
umbilicated molluscum papule turns white is
usually adequate to freeze through the epidermis
while maintaining the underlying non-infected
dermis intact. After allowing the lesion to com-
pletely thaw for several minutes, an additional
freeze-thaw cycle may be required for lesion
eradication. Potential adverse effects associated
with cryotherapy include pain with the applica-
tion, blister formation, scarring, atrophy, and
post-treatment hypopigmentation [11].
Success Rates
Few studies have sufficiently investigated the
efficacy of cryosurgery compared to other treat-
ment modalities. A prospective, randomized,
527
comparative, observer-blinded study compared
imiquimod to cryotherapy in 74 children aged
2–12 years with visually diagnosed MCV [12].
Specifically, patients received imiquimod 5 %
cream applied topically 5 days per week until
cure or up to 16 weeks or received cryotherapy
with liquid nitrogren sprayed for 10–20 s using
two freeze-thaw cycles to each lesion repeated
weekly until cure or up to 16 weeks. Cryotherapy
resulted in complete clearance of infection in
70.3 % of patients at 3 weeks, and all patients at
6, 12, and 16 weeks [12]. These clearance rates
were significantly greater than those for imiqui-
mod at 3 and 6 weeks (p = 0.001 for both 3 and
6 weeks) but not at 12 or 16 weeks (p = 0.3 for
both 12 and 16 weeks). A recent commentary has
revealed that a major review proclaiming imiqui-
mod’s effectiveness neglected to report results of
several large, randomized but unpublished stud-
ies in which imiquimod was demonstrated to be
ineffective for treatment of MCV as well as novel
safety concerns [13]. Thus, cryosurgery is of
even greater importance as a first-line therapeutic
strategy.
Another open-label randomized clinical trial
investigated KOH 10 % solution applied twice
daily until lesion resolution compared to cryo-
therapy performed weekly for 4 weeks [14]. At
4 weeks, 93.3 % of patients treated with cryo-
therapy had complete resolution compared to
86.6 % of those treated with KOH, although
these results were not statistically significant
(p > 0.05) [14].
Conclusions
MCV causes a benign and self-limited infec-
tion with a classic umbilicated papular mani-
festation. Patient selection and adverse effects
are necessary considerations when determin-
ing the most appropriate treatment modality.
Cryosurgery offers the advantage of high-
eradication rates and is a relatively quick
office procedure. It can be performed in sev-
eral freeze-thaw cycles, each with 10–20 s
long bursts of liquid nitrogen spray. The edi-
tors of this textbook recommend even shorter
LN bursts. Adverse effects include mild pain
with application, blister and scar formation,
528
and hypopigmentation. Along with various
effective chemical treatments, cryosurgery
should be considered a first-line therapy for
treatment and eradication of MCV infection.
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sum virus infection. Lancet Infect Dis. 2013;13(10):
877–88.
2. Smith KJ, Skleton H. Molluscum contagiosum: recent
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sum in patients with human immunodeficiency virus
infection. A review of twenty-seven patients. J Am
Acad Dermatol. 1992;27(4):583–8.
8. Calista D, Boschini A, Landi G. Resolution of dis-
seminated molluscum contagiosum with Highly
Active Anti-Retroviral Therapy (HAART) in patients
with AIDS. Eur J Dermatol. 1999;9(3):211–3.
9. Coloe J, Morrell DS. Cantharidin use among pediatric
dermatologists in the treatment of molluscum conta-
giosum. Pediatr Dermatol. 2009;26(4):405–8.
10. Pasquali P. Cryosurgery. In: Nouri K, editor.
Dermatologic surgery: step by step. Oxford: Wiley-
Blackwell; 2012.
11. Elton RF. Complications of cutaneous cryosurgery.
J Am Acad Dermatol. 1983;8(4):513–9.
12. Al-Mutairi N, Al-Doukhi A, Al-Faraq S, Al-Haddad A.
Comparative study on the efficacy, safety, and accept-
ability of imiquimod 5% cream versus cryotherapy for
molluscum contagiosum in children. Pediatr Dermatol.
2010;27(4):388–94.
13. Katz K. Imiquimod is not an effective drug for mol-
luscum contagiosum. Lancet Infect Dis. 2014;14(5):
372–3.
14. Handjani F, Behazin E, Sadati MS. Comparison of
10% potassium hydroxide solution versus cryother-
apy in the treatment of molluscum contagiosum: an
open randomized clinical trial. J Dermatol Treat.
2014;25(3):249–50.
 Milia en Plaque
98
Giuseppe Noto

Abstract
Milia en plaque (MP) is an uncommon skin condition, usually occurring in
periauricular distribution, due to confluence of whitish smooth milia with
formation of typical plaques. Lesions are usually asymptomatic, but in a
minority of cases a slight sensation of burning or itching has been referred.
Histologically MP is formed by laminated keratin-filled small cysts pre-
senting at their periphery a few layer of flattened basaloid cells. Diagnosis
is usually a clinical one; differential diagnosis can include milia secondary
to a blistering disease, milia secondary to topically applied perfumes, or
due to topical drugs, as corticosteroids or 5-fluorouracil, or oral drugs as
benoxaprofen, milia after radiotherapy or mechanical traumas as well as
other pathological skin conditions like familial or naevoid comedo sin-
drome, Favre-Racouchout disease, lichen planus tumidus folliculans. Oral
minocycline or etretinate, topical tretinoin, electrodesiccation, CO2 laser,
all have been proposed to treat MP, but oral therapy in some instances could
be judged excessive, while topical retinoids can give rise to heavy inflam-
mation and electrodesiccation and laser can lead to poor aesthetic results. A
32-year-old woman who presented with primary MP with bilateral retroau-
ricolar localization was treated with cryosurgery, a single freeze-thaw cycle
of 75 s. In about 8 weeks complete healing was observed in both areas.
After 2 years of follow-up no recurrence was observed with no pigmentary
side effects and a very good aesthetic results. Open spray cryosurgery can
be suggested as first choice treatment for MP, this method appearing a safe,
effective, well-tolerated, time-sparing and not expensive therapy.

Keywords
Milia • Milia en plaque • Periauricular • Cryosurgery

G. Noto, MD
Unit of Dermatology, Department of Oncology,
La Maddalena, Via San Lorenzo, 312,
Palermo 90146, Italy
e-mail: notoderm@libero.it

© Springer-Verlag London 2016 529

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_98
530
Introduction
Milia en plaque (MP) is an uncommon skin
condition due to confluence of whitish smooth
milia with formation of typical plaques, sometimes
presenting with a slight underlying erythema [1].
MP usually occurs in periauricular distribution;
involved sites are posterior and anterior areas of the
ear as well as ear lobes. Less commonly, MP can be
observed in periocular areas. Lesions are usually
asymptomatic, but in a minority of cases a slight
sensation of burning or itching has been referred. A
linear facial pattern has been described [2] as well
as some pediatric cases [3].
Histologically MP is formed by laminated
keratin-filled small cysts presenting at their
periphery a few layer of flattened basaloid cells
and in the centre of the cystic structures occa-
sional tricholemmal keratinization; an uncom-
mon rosacea-like pattern, with granulomatous
inflammation, has been described [4].
The diagnosis is usually a clinical one; differ-
ential diagnosis can include milia secondary to a
blistering disease, milia secondary to topically
applied perfumes, or due to topical drugs, as cor-
ticosteroids or 5-fluorouracil, or oral drugs as
benoxaprofen, milia after radiotherapy or
mechanical traumas as well as other pathological
skin conditions like familial or naevoid comedo
sindrome, Favre-Racouchout disease, lichen pla-
nus tumidus folliculans [4, 5].
Treatment Alternatives
A number of treatments other than cryosurgery
have been proposed for MP, namely, oral minocy-
cline [4], oral etretinate [6], topical tretinoin [7,
8], electrodesiccation [9], CO2 laser [10]. Oral
therapy in some instances could be judged exces-
sive, while topical retinoids can give rise to heavy
inflammation [5] and electrodesiccation and laser
can lead to poor aesthetic results.
Cryosurgery
I treated a 32-year-old woman who presented
with primary MP with bilateral retroauricolar
localization [11]. Plaques were due to confluence
G. Noto
of many crowded white smooth small milia, with
a pale pinkish background and well-defined bor-
ders, slowly growing during the previous 3 years.
Histology confirmed the diagnosis of MP. No
trauma, burns, use of cosmetics or any other topi-
cal substance was referred. Both areas were
treated with open spray with LN for one single
freeze-thaw cycle of 75 s, without local anesthe-
sia. Topical antibiotic cream was applied once
daily until complete re-epithelization, which
occurred after 3 weeks. In about 8 weeks com-
plete healing was observed in both areas. After
2 years of follow-up no recurrence was observed
with no pigmentary side effects and a very good
aesthetic result.
Conclusion
We suggest open spray cryosurgery as first
choice treatment for MP, this method appear-
ing a safe, effective, well-tolerated, time-spar-
ing and not expensive therapy for MP.
References
1. Wong SS, Goh CL. Milia en plaque. Clin Exp
Dermatol. 1999;24:183–5.
2. Lee SH, Kim SC. Linear milia en plaque on the cen-
tral face: an acquired skin rash following Blaschko
lines? J Dermatol. 2012;39:936–7.
3. Cota C, Sinagra J, Donati P, Amantea A. Milia en
plaque: three new pediatric cases. Pediatr Dermatol.
2009;26:717–20.
4. Keohane SG, Beveridge GW, Benton EC, Cox
NH. Milia en plaque: a new site and novel treatment.
Clin Exp Dermatol. 1996;21:58–60.
5. Losada-Campa A, De La Torre-Fraga C, Cruces-
Prado M. Milia en plaque. Br J Dermatol. 1996;134:
970–2.
6. Ishiura N, Komine M, Kadono T, et al. A case of milia
en plaque successfully treated with oral etretinate. Br
J Dermatol. 2007;157:1287–9.
7. Hubler WR, Randolph AH, Kelleher RM. Milia en
plaque. Cutis. 1978;22:67–70.
8. Samlaska CP, Benson PM. Milia en plaque. J Am
Acad Dermatol. 1989;21:311–3.
9. Lee DW, Choi SW, Cho BK. Milia en plaque. J Am
Acad Dermatol. 1994;31:107.
10. Pozo JD, Castineiras I, Fernandez-Jorge B. Variants
of milia successfully treated with CO(2) laser
vaporization. J Cosmet Laser Ther. 2010;12:
191–4.
11. Noto G, Dawber R. Milia en plaque: treatment with
open spray cryosurgery. Acta Derm Venereol
(Stockh). 2001;81:370–1.
 Digital Mucoid Cysts
99
Alba G. Quiñones

Abstract
Digital mucoid cysts (DMC) are usually singular and translucent nodules
located on the dorsal distal phalange and the proximal nail fold of the fin-
gers. They are classified as ganglion and myxomatous type. The first
responds to herniation of the joint space due to degenerative changes. The
second is related to focal mucinosis despite abnormal production by fibro-
blasts. DMC are predominantly asymptomatic, but some patients ask for
treatment because of pain or for aesthetic reasons. Cryosurgery is an
excellent option for the treatment of DMC because of its high curative rate
and satisfactory cosmetic outcome.

Keywords
Digital mucoid cysts • Cryosurgery

Introduction are considered hernations of tendon sheets. Joint

Digital mucoid cysts (DMC) (ganglion, synovial,
myxoid, and mucous cysts) are common benign
tumors located on the distal interphalangeal (DIP)
joints of the fingers, but rarely on the toes [1, 2].
DMCs are classified as ganglion and mucinosis
types. Ganglion types arise from degenerative
changes in the DIP joints, such as orteoarthitis,
Heberden’s nodes, and osteophyte formations and
spaces allow the collection of acid hyaluronic from
joint fluid. Ganglion and synovial cysts have con-
necting stalks between them and the joints. The
myxomatous type is represented by focal mucino-
sis, which is associated with excessive amounts of
hyaluronic acid resulting from metabolic disorders
in the fibroblast, are independent from joints and
involve the proximal nail fold [2–7].

Description of the Disease

A.G. Quiñones, MD
Dermatology Treatment and Research Center,
DMC are usually chronic, rarely involuting,
5310 Harvest Hill Rd., Suite 160, Dallas,
TX 75230, USA solitary, fluctuant, and small nodules (<15 mm
e-mail: albagquinones@gmail.com in diameter.) They are translucent or

© Springer-Verlag London 2016 531

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_99
532 A.G. Quiñones

flesh-colored, and usually located between the Cryosurgery/Methodology

dorsal DIP joint and the proximal nail fold.
They are more common on the dominant hand,
and on middle aged to elderly women [7, 8].
Some patients report linear nail plate dystro-
phies such as grooves and furrows; they are
most often asymptomatic, however, when the
nail matrix is involved, DMC may cause tender-
ness, discharge, and infection [2, 8, 10]. Trauma
has been considered a prone factor in patients
under 40 years old [7].
Histologically, ganglion cysts have a pedicle
leading to joint space and the cyst is framed by an
epithelial lining. As opposed to myxomatous
cysts, which have a cavity full of mucin sur-
rounded by collagen fibers, without an epithelial
cell wall; this characterizes them as pseudo cysts
[1, 2, 7].
Clinical diagnosis is often easy, not requiring
complimentary images when the cyst is located
on the nail fold. Drape et al. [11] reported the
usefulness of magnetic resonance imaging on
those cysts placed in the nail beds for diagnostic
and treatment purposes. Differential diagnoses
include xanthomas, knuckle pads, epidermoid
cysts, and tender leiomyomas between
others [2].
(How I Do It)
Cryosurgery has been an effective alternative treat-
ment for DMC because of its high cure rate and
the excellent cosmetic results it produces [10].
Two techniques have been performed: intermittent
LN spray, and round closed probe. It is recom-
mended to unroof and drain the lesion prior to per-
forming the techniques for a more successful
result [8]. Open spray technique must be applied
producing a 2 mm halo surrounding the edges of
the cyst. Freeze time is about 15–30 s and thaw
time is about 60–90 s [4, 9]. A double freeze-thaw
technique is superior to a single freeze [16]
(Figs. 99.1 and 99.2). Strumia advises a double
freeze thaw cycle, but just for 5 s with an open
spray or cotton type applicator [15]. Additionally,
Sonnex and Dawber propose including the cyst

Therapeutic Alternatives

Although most DMC are asymptomatic, some

patients may seek treatment because of pain or Fig. 99.1 Periungual myxoid cyst
aesthetic reasons. Treatment modalities include
simple and radical surgery, cryosurgery, laser,
lesional esteroids injections, multiple needle
puncturing, or injection of sclerosing agents
[1, 3, 12–14]. Radical surgery has the highest
cure rate in synovial ganglions, because it
removes osteo, pedicle and stalk components.
However, complications such as loss of motion,
infection, scar, persitence or postoperative nail
deformity, along with pain, swelling or joint
stiffness are reported to occurr [4, 12]. The
other modalities have a variable low cure rate.
Cryosurgery has the leading success cure rate
for DMC [8, 13]. Fig. 99.2 Proper freezing – may require two cycles
99 Digital Mucoid Cysts
base, and as far proximal as the transverse groove
overlying the distal interphalangeal joint, because
of the possibility of the presence of a stalk [16].
However, Bardach reported success with a single
cycle [8]. For the cryoprobe technique the tip
should be of the same size of the cyst, and the
freeze time of 20–30 s, as reported.
Success Rates
Kuflik didn’t find a different recurrence rate with
either technique. Notching of the nail fold was
reported as complication [10]. Healing is
complete in 4–6 weeks after either technique.
The follow-up period ranges from approximately
15 to 36 months. Successful re-treatment is pos-
sible if needed. Cure rates of above 80 % have
been reported [4, 10].
Conclusions
Cryosurgery is an excellent option treatment
for DMCs due to its high cure rate, recovery is
rapid and cosmetic result satisfactory. Another
advantage is that the procedure may be done
in the office.
References
1. Kim JH, Park JH, Jee H, OH SH. Successful treatment
of recurrent digital mucoid cysts using a 1,444-nm
neodymium-doped yttrium aluminum garnet laser.
Dermatol Surg. 2011;37:1528–30.
2. Hernández-Lugo AM, Domínguez-Cherit J, Vega-
Memije ME. Digital mucoid cyst: the ganglion type.
Int J Dermatol. 1999;38:533–5.
533
3. Armijo M. Mucoid cysts of the fingers. Differential
diagnosis, ultrastructure, and surgical treatment.
J Dermatol Surg Oncol. 1981;7(4):317–22.
4. Böhler-Sommeregger K, Kutschera-Hienert G.
Cryosurgical management of myxoid cysts. J Dermatol
Surg Oncol. 1988;140:1405–8.
5. Salasche SJ. Myxoid cysts of the proximal nail fold: a
surgical approach. J Dermatol Surg Oncol. 1984;10(1):
35–9.
6. Johnson WC, Helwig EB. Cutaneous focal mucinosis.
A clinicopathological and histochemical study. Arch
Dermatol. 1966;93(1):13–20.
7. Zuber TJ. Office management of digital mucous cysts.
Am Fam Physician. 2001;64(12):1987–91.
8. Bardach HG. Managing digital mucoid cysts by cryo-
surgery with liquid nitrogen: preliminary report.
J Dermatol Surg Oncol. 1983;9(6):455–8.
9. Dawber RP, Sonnex T, Leonard J, Ralfs I. Myxoid
cysts of the finger: treatment by liquid nitrogen
spray cryosurgery. Clin Exp Dermatol. 1983;8(2):
153–7.
10. Kuflik EG. Specific indications for cryosurgery of the
nail unit. Myxoid cysts and periungual verrucae.
J Dermatol Surg Oncol. 1992;18(8):702–6.
11. Drapé JL, Idy-Peretti I, Goettmann S, Salon A,
Abimelec P, Guérin-Surville H, Bittoun J. MR
imaging of digital mucoid cysts. Radiology. 1996;
200(2):531–6.
12. Rizzo M, Beckenbaugh RD. Treatment of mucous
cysts of the fingers: review of 134 cases with mini-
mum 2-year follow-up evaluation. J Hand Surg Am.
2003;28(3):519–24.
13. Audebert C. Treatment of mucoid cysts of fingers and
toes by injection of sclerosant. Clin Exp Dermatol.
1986;11(5):510–3.
14. Audebert C. Treatment of mucoid cysts of fingers and
toes by injection of sclerosant. Dermatol Clin. 1989;
7(1):179–81.
15. Strumia R. Cisti mucoide. In: La crioterapia in
dermatología.1st ed. Italy: Ed Business Enterprise;
2006. p. 178–80.
16. Sonnex TS, Dawber RP. Cryosurgery for digital
mucoid cysts. J Dermatol Surg Oncol. 1983;9(9):714.
 Nevus Sebaceus
100
Marc Zachary Handler and Robert A. Schwartz

Abstract
Nevus sebaceus is a congenital hamartoma known for the potential to
develop secondary neoplasms at and after puberty. Clinically, nevus seba-
ceus presents as a solitary yellow-orange nodule of the scalp which
becomes more prominent at puberty as sebaceous and apocrine structures
develop. Resulting from concern of secondary tumor development within
the nevus sebaceus, many clinicians chose to surgically excise it. Although
scarring will likely occur, destruction of the nevus sebaceus with cryosur-
gery is an alternative to excision with a scalpel.

Keywords
Sebaceous • Hamartoma

Introduction Removal of the hamartoma has been traditionally

Nevus sebaceus is a well-circumscribed congeni-
tal hamartoma of both adnexal and epithelial
structures. Development results from a post-
zygotic mutation in the Kristen rat sarcoma viral
oncogene homolog (KRAS) and Harvey rate
sarcoma viral oncogene homolog (HRAS) [1, 2].
M.Z. Handler, MD
Department of Dermatology, Rutgers University
New Jersey Medical School, Newark, NJ, USA
R.A. Schwartz, MD, MPH, DSc (Hon),
FRCP (Edin) (*)
Dermatology and Pathology, Rutgers University New
Jersey Medical School, Rutgers University School of
Public Affairs and Administration,
185 South Orange Ave., Newark, NJ 07103, USA
e-mail: roschwar@cal.berkeley.edu
© Springer-Verlag London 2016
W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_100
performed to prevent secondary development of a
malignant neoplasm within it. Current, recom-
mendations include excision during adolescence
or watchful waiting, as >97 % of secondary
tumor developments are benign [3]. Increased
understanding of the activating Ras mutations in
nevus sebaceus may lead to developments that
target proliferation signaling.
Disease Description
Nevus sebaceus, an organoid nevus, is a type of
cutaneous hamartoma, present at birth in
0.5–1.0 % of newborns, [4] and composed of
overgrown sebaceous glands, hair follicles,
535
536
apocrine glands and connective tissue in the
epidermis. This usually solitary hamartoma may
become first evident as a yellowish, hairless patch
on the scalp that becomes verrucous during
puberty due to pilosebaceous-apocrine develop-
ment [3]. Up to 22.5 % of nevus sebaceus develop
secondary tumors [3, 4]. Of those, the majority are
benign, the most frequent being syringocystade-
noma papilliferum and trichoblastoma; malignant
tumor development is <3 % [2, 3].
Therapeutic Alternatives
Excision remains the standard method of removal
for nevus sebaceus. For cosmetically sensitive
areas, such as the face, photodynamic therapy
may be attempted [5] using 5-aminolevulinic
acid and intense pulsed light, but may be unsuc-
cessful [6]. Successful results have been achieved
with laser, utilizing ablative CO2 laser with or
without erbium: YAG laser [7–9].
Cryosurgery
Cryosurgery can be utilized in selected patients to
destroy a nevus sebaceous and, at least in theory,
prevent secondary tumor development. Although
>97 % of all secondary growths within a nevus
sebaceus are benign, the biggest concern has been
that of malignant tumor growth. Because of this,
similar to excision, destruction must remove the
entire lesion. The use of cryosurgery for destruc-
tion is aided by the simple anatomy of the scalp.
Destruction requires a vigorous freeze due to the
thickness of the scalp and a patch of scarring alope-
cia will likely result. However, even with complete
destruction there is a low risk of non-melanocytic
skin cancer recurrence on the scalp [10].
Methodology (How We Do It)
Treatment with an open spray technique is
employed with a goal lesion temperature of
-50 °C to -60 °C and lateral spread of 0.5–1.0 cm
M.Z. Handler and R.A. Schwartz
[10]. This is performed under local anesthesia in
a triple freeze/thaw cycle performed on a single
visit. In addition to expectant alopecia, patients
should be counseled to expect site edema, exu-
date, sloughing and headache that will begin after
treatment.
Conclusions
For selected patients and using aggressive
techniques cryosurgery to destroy tumors
developing within a sebaceous nevus or the
hamartoma itself, should result in successful
outcomes.
References
1. Patel P, Malik K, Khachemoune A. Sebaceus and
Becker’s nevus: overview of their presentation, patho-
genesis, associations, and treatment. Am J Clin
Dermatol. 2015;16(3):197–204.
2. Aslam A, Salam A, Griffiths CE, McGrath JA. Naevus
sebaceus: a mosaic RASopathy. Clin Exp Dermatol.
2014;39(1):1–6.
3. Idriss MH, Elston DM. Secondary neoplasms associ-
ated with nevus sebaceus of Jadassohn: a study of
707 cases. J Am Acad Dermatol. 2014;70(2):
332–7.
4. Munoz-Perez MA, Garcia-Hernandez MJ, Rios JJ,
Camacho F. Sebaceus naevi: a clinicopathologic
study. J Eur Acad Dermatol Venereol: JEADV. 2002;
16(4):319–24.
5. In SI, Lee JY, Kim YC. Topical photodynamic therapy
for nevus sebaceous on the face. Eur J Dermatol: EJD.
2010;20(5):590–2.
6. Kim HS, Jun JH, Lee JY. Photodynamic therapy of
facial nevus sebaceous. Photodermatol Photoimmunol
Photomed. 2010;26(2):98–100.
7. Chung BY, Han SS, Kim BW, Chang SE, Lee MW.
Effective treatment of congenital melanocytic
nevus and nevus sebaceous using the pinhole
method with the erbium-doped yttrium alumin-
ium garnet laser. Ann Dermatol. 2014;26(5):
651–3.
8. Lee HE, Park SB, Lee JH, Im M. Nevus sebaceous
treated with fractional carbon dioxide laser followed
by pulsed dye laser. Indian J Dermatol Venereol
Leprol. 2014;80(5):478–80.
9. Ashinoff R. Linear nevus sebaceus of Jadassohn
treated with the carbon dioxide laser. Pediatr
Dermatol. 1993;10(2):189–91.
10. Kuflik EG, Gage AA. Cryosurgical treatment for skin
cancer. New York: Igaku-Shoin; 1990.
 Orf
101
Jorge Ocampo-Candiani and Kristian Eichelmann

Abstract
Orf is caused by a parapox virus that infects mainly sheep and goats and is
often known as ecthyma contagiosum. Transmission is caused by direct
contact and lesions favor the hands. The original papular lesion goes
through several stages following a self limited course. Mild fever with
malaise and associated lymphadenopathy can occur. Cryosurgery is and
effective, cheap method with minimal complications when done properly.

Keywords
Orf • Parapox • Cryosurgery

Introduction Disease Description

Orf is caused by a parapox virus that infects
mainly sheep and goats; it is also known as
ecthyma contagiosum, contagious pustular der-
matitis or sore mouth disease. Transmission
occurs by direct contact, making farmers, butch-
ers, veterinarians, and sheepsherders at-risk
occupations [1, 2].
Lesions favor the hands or other sites that can be
in direct contact with infected animals. The dis-
ease has a short incubation period (5 days) and is
followed by a papule (one or several) which pro-
gresses through several clinical stages; maculo-
papular, targetoid, weeping nodule, regenerative,
papilomatosis and regression with dry crust [3].
Mild fever with malaise and associated lymph-
adenopathy can occur. Orf is a self-limited dis-
ease, resolving between 3 and 6 weeks [2, 3].

Diagnosis
J. Ocampo-Candiani, MD (*) • K. Eichelmann, MD
Department of Dermatology, University Hospital
“José E. González”, Francisco I. Madero y History alone and the clinical picture are enough
Gonzalitos s/n Col. Mitras Centro, Monterrey, to make a diagnosis. Histologic findings depend
Nuevo León 64460, Mexico upon the clinical stage the lesion is going through.
e-mail: jocampo2000@yahoo.com.mx

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_101
538 J. Ocampo-Candiani and K. Eichelmann

Epidermal necrosis, vacuolated keratinocytes, Methodology (How I Do It)

mixed dermal infiltrates, fingerlike proyections
into the dermis and eosinophilic inclusion bodies
can be seen. Electron microscopy or real-time
PCR are confirmatory, if clinical doubt persists.
Treatment
Cryosurgery is and effective, cheap method, with
minimal complications when done properly. We
prefer the open spray technique (two cycles). A
3 mm freezing halo is more than enough to treat
this benign lesion.

Multiple treatments have been described such Cure Rates

as surgery, antibiotics, cryosurgery and imiqui-
mod [4]. Complete clearance is reported at 15 days with-
out scarring [3] (Fig. 101.1).

a b

d e

Fig. 101.1 (a) Typical Orf nodule. (b) Histopathological findings, vacuolated keratinocytes, mixed dermal infiltrates.
(c) Freezing halo. (d) Hemorrhagic bullae 5 days after cryosurgery. (e) Resolution after 3 weeks of cryosurgery
101 Orf 539

References 3. Ocampo Candiani J, González Soto R, Welsh Lozano

O. Orf nodule: treatment with cryosurgery. J Am
Acad Dermatol. 1993;29(2 Pt 1):256–7.
1. Pérez-Camarero ER, Jiménez C, Garikano M, Martí J,
4. Sarma DP, Cox M, Walter P, Crisler W, Huerter C. A
Berruete ML, Antón E. Orf nodule. Enferm Infecc
man with an umbilicated papule of the hand: what is
Microbiol Clin. 2000;18(8):421.
your diagnosis? Case Rep Med. 2010;2010:524021.
2. Dellamonica P, Bernard E, Ortonne JP, Defontaine
doi:10.1155/2010/524021. Epub 2010 May 31.
A. The Orf nodule. Dermatol Online J. 2011;17(4):9.
 Pearly Penile Papules
102
Jorge Ocampo-Candiani and Kristian Eichelmann

Abstract
Pearly penile papules are benign lesions located circumferentially on the
corona and sulcus of the gland. Cryosurgery is a simple, effective and safe
method with low morbility and no complications that can be used to treat
this benign lesions.

Keywords
Pearly penile papules • Cryosurgery

Introduction the looks of the lesions drive patients to request

Pearly penile papules are benign lesions classi-
fied among the cutaneous angiofibromas based
on their histologic findings. Clinically they are
pearly papules located circumferentially on the
corona and sulcus of the glans in single or multi-
ple rows [1].
from biopsies to treatments. Histological exami-
nation reveals findings similar other cutaneous
angiofibromas such as dense connective tissue,
acanthosis and a vascular network [1].
Therapy

Usually a through explanation of its benign nature

Diagnosis
Although the trained dermatologist will rarely
misdiagnose them, they are frequently mistaken
for condyloma acuminata [2]. Aprehension over
comforts most patients but some insist upon a med-
ical solution. Cryosurgery has been used as well as
some other more destructive techniques such as
electrofulguration or laser vaporization [3–5].

Cryosurgery
J. Ocampo-Candiani, MD (*) • K. Eichelmann, MD
Department of Dermatology, University Hospital
“José E. González”, Francisco I. Madero y Cryosurgery is a simple, effective and safe
Gonzalitos s/n Col. Mitras Centro, Monterrey, method with low morbility that can be used to
Nuevo León 64460, Mexico treat these benign lesions.
e-mail: jocampo2000@yahoo.com.mx

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_102
542 J. Ocampo-Candiani and K. Eichelmann

Methodology (How I Do It) Success Rates

We prefer an open spray technique with two Normally a second treatment is needed
15–20 s freeze-thaw cycles. No anesthesia is usu- 1–2 months after the first intervention
ally required but when in need topical formula- (Fig. 102.1).
tions may be adequate.

a b

c d e

Fig. 102.1 (a, b) Typical pearly papules of the penis. (c, d) Technique used. (e) 1 month after treatment showing excel-
lent results
102 Pearly Penile Papules 543

References 3. Ocampo-Candiani J, Cueva-Rodriguez JA. Cryosurgical

treatment of pearly penile papules. J Am Acad Dermatol.
1996;35(3 Pt 1):486–7.
1. Agrawal SK, Bhattacharya SN, Singh N. Pearly
4. Porter WM, Bunker CB. Treatment of pearly penile
penile papules: a review. Int J Dermatol.
papules with cryotherapy. Br J Dermatol.
2004;43(3):199–201.
2000;142(4):847–8. No abstract available.
2. Watanabe T, Yoshida Y, Yamamoto O. Differential
5. Rokhsar CK, Ilyas H. Fractional resurfacing for
diagnosis of pearly penile papules and penile condy-
the treatment of pearly penile papules. Dermatol
loma acuminatum by dermoscopy. Eur J Dermatol.
Surg. 2008;34(10):1420–2. doi:10.1111/j.1524-
2010;20(3):414–5. doi:10.1684/ejd.2010.0944. Epub
4725.2008.34300.x; discussion 1422. Epub 2008 Jul 22.
2010 Feb 22.
 Porokeratosis of Mibelli
103
Selçuk Özyurt and Tuárul Dereli

Abstract
Porokeratosis of Mibelli is a rare, chronic disorder of epidermal keratiniza-
tion characterized by hyperkeratotic papules or plaques surrounded by a
“Great Wall of China”-like elevated border. This is formed by the histo-
pathologic feature: “cornoid lamella”. Other than the classical form
described by Mibelli in 1893, there are at least five clinical variants of the
disease. Pororkeratosis may be inherited as an autosomal dominant disorder,
but most cases appear to be sporadic. Although the pathogenesis of the dis-
ease is still unclear, the lesions are thought to result from an expanding
mutant clone of keratinocytes that form the cornoid lamella. In genetically
predisposed individuals triggering factors like UV exposure or immunosup-
pression may induce porokeratosis formation. Chronic lesions of porokera-
tosis are benign, however some risk of malignant transformation have been
reported. Treatment of each patient should be evaluated on an individual
basis. Different treatment modalities have been reported for porokeratosis
but most of them are anecdotal case reports or series with limited number of
subjects. As a general acceptance, cryosurgery is the first line therapy for
porokeratosis. Open spray technique with LN is the choice of treatment.
After anesthesia hyperkeratotic borders of the porokeratosis should be
removed with a scalpel blade otherwise they will produce an insulating
effect. The entire lesion should be frozen for about 30 s until a palpable ice-
ball is formed. Appropriate treatment of porokeratosis of Mibelli should also
destroy the lesional dermis as there are some reasonable findings suggesting

S. Özyurt, MD (*)
Department of Dermatology, Izmir Atatürk Education
and Research Hospital,
Bostanli Mahallesi, 1738 SOKAK 135/1, İzmir
35540, Turkey
e-mail: ozyurtselcuk@yahoo.com
T. Dereli, PhD, MD
Department of Dermatology, Ege University,
İzmir, Turkey

© Springer-Verlag London 2016 545

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_103
546 S. Özyurt and T. Dereli

a dermal component contributing to the pathogenesis. Healing generally

completes in 4–6 weeks and slight atrophy and pigmentary changes may be
observed. Cryosurgery is the choice of treatment of Porokeratosis of Mibelli
because of its simplicity, high cure rates, low cost, short treatment duration
and few complications.

Keywords
Porokeratosis of mibelli • Cryosurgery • Cornoid lamella • Open spray •
Epidermal keratinization

Introduction

Porokeratosis of Mibelli is a rare, chronic

disorder of epidermal keratinization charac-
terized by hyperkeratotic papules or plaques
surrounded by a “Great Wall of China”-like
elevated border, which gives the lesions an
annular appearance (Figs. 103.1 and 103.2).
A sine qua non histopathologic feature, the
“cornoid lamella” corresponds to the raised
hyperkeratotic border of the lesions. The clas-
sical form of the disease was first described
by Mibelli in 1893 and since then at least
five other clinical variants have been defined:
Disseminated superficial porokeratosis, linear
porokeratosis, disseminated superficial actinic
porokeratosis, porokeratosis palmaris et plan-
taris disseminata, and punctate porokeratosis.
Pororkeratosis may be inherited as an autoso-
mal dominant disorder, but most cases appear
to be sporadic. Although the pathogenesis
of the disease is still unclear, the lesions are
thought to result from an expanding mutant
clone of keratinocytes that form the cornoid
lamella [1]. Findings of abnormal DNA ploidy
and chromosomal abnormalities in lesional
keratinocytes support this mutant clone the-
ory [2]. In genetically predisposed individu-
als triggering factors like UV exposure or
immunosuppression may induce porokeratosis
formation. Fig. 103.1 Porokeratosis of Mibelli on ala nasi
103 Porokeratosis of Mibelli
Fig. 103.2 Porokeratosis of Mibelli.
Hyperkeratotic plaques surrounded by a
“Great Wall of China”-like elevated border
Diagnosis
The classic lesion of Porokeratosis of Mibelli
usually starts in the childhood as a brown or skin
colored keratotic papule. As it enlarges over
years, the center becomes atrophic, hipo or
hyperpigmented, and the borders take the thread-
like elevated hyperkeratotic annular appearance.
The lesions persist indefinitely. These chronic
lesions are benign; other than punctate porokera-
tosis, all clinical forms of porokeratosis are
reported as associated with some risk of malig-
nant transformation. Large, longstanding, or lin-
ear lesions, and those that present in elderly or
immunocompromised patients, have the greatest
risk of malignant transformation. Malignancy
incidence has been reported to occur in between
7 % and 11 % of affected individuals. Squamous
cell carcinoma is the most frequently reported
carcinoma followed by Bowen disease and basal
cell carcinoma [3, 4].
Treatment
As porokeratotic lesions are progressive and they
carry malignant potential treatment is necessary.
Pruritus, burning-like sensation, and cosmetic
concerns, motivate patients to search for treat-
ment. Each patient should be evaluated on an
individual basis. Sometimes even discontinuation
of an immunosuppressive drug may lead to the
resolution of lesions [5].
Treatment should include avoidance from UV
and X-ray irradiance. For each patient, type of
547
the porokeratosis, extend of the disease and like-
lihood of the malignant transformation should be
evaluated. Different treatment modalities have
been reported for porokeratosis but most of them
are anecdotal case reports or series with limited
number of subjects. Topical 5-Fluorouracil [6],
imiquimod [7], Vitamin D3 analogs [8], systemic
[9] and topical [10] retinoids, CO2 laser [11], Nd:
YAG laser [12], pulsed dye laser [13], ruby laser
[14], fractional photothermolysis [15], photody-
namic therapy [16], dermabrasion [17], diclofe-
nac gel [18], surgical excision and topical
corticosteroids have been reported with variable
degrees of success. But, as a general acceptance,
cryosurgery is the first line therapy for
porokeratosis.
Cryosurgery Methodology (How
I Do It)
Open spray technique with LN is the choice of
treatment. A handheld unit is used to emit the
cryogen directly on to the surface of the lesion.
For each lesion, anesthesia via preoperative infil-
tration with 2 % prilocaine or 1–2 % lidocaine is
recommended, as the hyperkeratotic borders of
the porokeratosis should be removed with a scal-
pel blade until a conic shaped canaliculus of
1–2 mm depth results; otherwise the border will
produce an insulating effect. After hemostasis,
the entire lesion should be frozen for about 30 s
until a palpable ice-ball is formed. A 2–3 mm
halo of freeze around the lesion is usually ade-
quate. For larger lesions the spray tip may be
548
moved slowly along the visible border for a more
complete freezing. Large lesions may be treated
in sections over several sessions. In a series of
eight patients with 20 lesions treated as described
above a success rate of 90 % was reported.
Eighteen of the lesions resolved after one treat-
ment, one more session was required for the other
two lesions [19].
Although porokeratosis is thought to be the
result of proliferation of abnormal clone of kera-
tinocytes in the epidermis, there are some reason-
able findings suggesting a dermal component
contributing to the pathogenesis. There is a
chronic inflammatory infiltrate and findings of
degenerative fibroblasts especially beneath the
cornoid lamella in the superficial dermis.
Porokeratosis usually recur after treatment
modalities destroying only the epidermal compo-
nent of the lesions. Therefore the appropriate
treatment of porokeratosis of Mibelli should also
destroy the lesional dermis, which will inevitably
cause some degree of scarring. Following cryo-
therapy, edema and blister formation occur in
almost every patient usually within first 24 h of
the treatment. Healing is generally completed in
4–6 weeks and slight atrophy and pigmentary
changes may be observed.
Conclusions
Cryosurgery is the choice of treatment of
Porokeratosis of Mibelli because of its sim-
plicity, high cure rates, low cost, short treat-
ment duration and few complications.
References
1. Reed RJ, Leone P. Porokeratosis-a mutant clonal ker-
atosis of the epidermis. I. Histogenesis. Arch
Dermatol. 1970;101:340–7.
2. Otsuka F, Chi HI, Shima A. Cytological demonstra-
tion of abnormal DNA ploidy in the epidermis of
porokeratosis. Arch Dermatol Res. 1988;230:61–3.
3. Maubec E, Duvillard P, Margulis A, Bachollet B,
Degois G, Avril MF. Common skin cancers in poro-
keratosis. Br J Dermatol. 2005;152:1389–91.
S. Özyurt and T. Dereli
4. Sasson M, Krain AD. Porokeratosis and cutaneous
malignancy. A review. Dermatol Surg. 1996;22:339–42.
5. Tsambaos D, Spiliopoulos T. Disseminated superfi-
cial porokeratosis: complete remission subsequent to
discontinuation of immunosuppression. J Am Acad
Dermatol. 1993;28:651–2.
6. McDonald SG, Peterka ES. Porokeratosis (Mibelli):
treatment with topical 5-fluorouracil. J Am Acad
Dermatol. 1983;8:107–10.
7. Agarwal S, Berth-Jones J. Porokeratosis of Mibelli:
successful treatment with 5 % imiquimod cream. Br
J Dermatol. 2002;146:338–9.
8. Harrison PV, Stollery N. Disseminated superficial
actinic porokeratosis responding to calcipotriol. Clin
Exp Dermatol. 1994;19:95.
9. Garg T, Ramchander Varghese B, Barara M, Nangia A.
Generalized linear porokeratosis: a rare entity with
excellent response to acitretin. Dermatol Online J.
2011;17:3.
10. Agrawal SK, Gandhi V, Madan V, Bhattacharya
SN. Topical tretinoin in Indian male with zosteriform
porokeratosis. Int J Dermatol. 2003;42:919–20.
11. Rabbin PE, Baldwin HE. Treatment of porokeratosis
of Mibelli with CO2 laser vaporization versus surgical
excision with split-thickness skin graft. J Dermatol
Surg Oncol. 1993;19:199–202.
12. Liu HT. Treatment of lichen amyloidosis (LA) and
disseminated superficial porokeratosis (DSP) with
frequency-doubled Q-switched Nd:YAG laser.
Dermatol Surg. 2000;26:958–62.
13. Alster TS, Nanni CA. Successful treatment of poro-
keratosis with 585 nm pulsed dye laser irradiation.
Cutis. 1999;63:265–6.
14. Lolis MS, Marmur ES. Treatment of disseminated
superficial actinic porokeratosis (DSAP) with the
Q-switched ruby laser. J Cosmet Laser Ther.
2008;10:124–7.
15. Chrastil B, Glaich AS, Goldberg LH, Friedman
PM. Fractional photothermolysis: a novel treatment
for disseminated superficial actinic porokeratosis.
Arch Dermatol. 2007;143:1450–2.
16. Cavicchini S, Tourlaki A. Successful treatment of dis-
seminated superficial actinic porokeratosis with
methyl aminolevulinate-photodynamic therapy.
J Dermatol Treat. 2006;17:190–1.
17. Spencer JM, Katz BE. Successful treatment of poro-
keratosis of Mibelli with diamond fraise abrasion.
Arch Dermatol. 1992;128:1187–8.
18. Marks S, Varma R, Cantrell W, Chen SC, Gold M,
Muellenhoff M, Elewski B. Diclofenac sodium 3 %
gel as a potential treatment for disseminated superfi-
cial actinic porokeratosis. J Eur Acad Dermatol
Venereol. 2009;23:42–5.
19. Dereli T, Ozyurt S, Ozturk G. Porokeratosis of
Mibelli: successful treatment with cryosurgery.
J Dermatol. 2004;31:223–7.
 Porokeratosis, Linear
104
Renata Strumia

Abstract
Linear porokeratosis is a rare variant of porokeratosis. The lesions of LPK
are grouped and arranged along the lines of Blaschko. Treatment is
requested for cosmetic reasons and to prevent malignant transformation.
Topical agents, such as keratolytics, 5-fluorouracil, corticosteroids, reti-
noids, and calcipotriol, has shown variable degrees of success. Surgical
modalities, such as curettage, excision, cryosurgery, and electrodesicca-
tion, have been utilized, with recurrence after superficial procedures.
Segmental cryosurgery allows for a good cosmetic result with no recur-
rences for many years.

Keywords
Linear porokeratosis • Cryosurgery

Introduction two or more forms of porokeratosis in a single

Linear porokeratosis (LPK) is the rarest variant
of porokeratosis. The lesions of LPK are grouped
and arranged along the lines of Blaschko [1].
They can present at childhood or can develop in
adult life [2]. A few congenital occurrences have
been sporadically reported [3]. It has an autoso-
mal dominant mode of inheritance and affects
men twice as often as women. The coexistence of
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara (Former), Ferrara, Italy
e-mail: restrumi@tin.it
individual has been rarely reported.
Description of the Disease
Two forms of LPK exist. In the more common
localized form of the disease, lesions are unilat-
eral, confined to an extremity, and frequently dis-
tally; in this way it resembles linear verrucous
epidermal nevus. LPK is clinically characterized
by sharply demarcated annular lesions with dis-
tinct keratotic edges (histologically correspond-
ing to the presence of cornoid lamella). In the
rare generalized form, lesions are multiple, affect
several extremities, and involve the trunk. Lesions

© Springer-Verlag London 2016 549

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_104
550
appear as grouped annular keratotic papules that
may coalesce into larger plaques with central
atrophy and raised peripheral borders [4, 5].
When the trunk is involved, lesions often have a
zosteriform pattern. In the classical textbooks,
LPK is strictly unilateral, however, a few general-
ized LPK cases that are bilateral have been
reported in [6].
Malignant degeneration has been observed in
all clinical variants of porokeratosis [7, 8].
Malignancies include Bowen’s disease, squa-
mous cell carcinoma, and, rarely, basal cell carci-
noma. This risk of cancer development does not
occur to the same degree in all types of porokera-
tosis. Allelic loss in linear porokeratosis may
explain its higher susceptibility to malignancy.
Overexpression of tumor suppressor gene p53
has been shown in LPK. The highest risk of
malignant degeneration is in large, long-standing,
or linear lesions. Monitoring is important for the
detection of early malignant transformation.
Porokeratosis is considered a chronic, pro-
gressive disease. No laboratory analyses are nec-
essary in diagnosing this condition, though
screening for HIV, renal failure, or other causes
of immunosuppression may be advisable when a
patient has a sudden eruption of porokeratosis.
Histology
The hallmark of porokeratosis is the cornoid
lamella, a thin column of parakeratotic cells that
corresponds to the hyperkeratotic border.
Underlying the cornoid lamella, the granular
layer is thinned or absent and keratinocytes are
edematous with spongiosis. A dermal lympho-
cytic infiltrate may also be evident.
Therapeutic Alternatives
The treatment of LPK with topical agents, such
as keratolytics, 5-fluorouracil, corticosteroids,
retinoids, and calcipotriol, has shown variable
R. Strumia
degrees of success [9–11]. Surgical modalities,
such as curettage, excision, cryotherapy, and
electrodesiccation have been utilized, with
recurrences after superficial procedures. The
successful use of carbon dioxide laser and
dermabrasion without recurrence or scarring
has been reported. Photodynamic therapy has
been reported. Widespread lesions of porokera-
tosis present a problem in management. Topical
and surgical modalities are impractical.
Systemic retinoids have been advocated not
only as a method of clearance but also as a pro-
phylactic measure against the development of
malignant changes.
Treatment plans should be selected based on
the size, number, and location of the lesions and
the patient’s desires.
Cryotherapy
Cryotherapy with LN (using either a spray gun,
or cotton bud sticks) has been reported using a
single 20 s freeze thaw cycle for each treatment
[12]. Treatment is well tolerated, and requires no
local anaesthesia. Treated areas heal leaving atro-
phic scarring with loss of hair follicles, but never-
theless with an improvement in the cosmetic
appearance.
Methodology (How I Do It)
Segmental cryosurgery is the best technique to
treat LPK segments in separate sessions. This
technique allows to evaluate the atrophic scarring
and to stop the treatment if necessary and is less
painful for the patient. Cryotherapy with LN
using either a spray equipment or cotton bud
sticks is performed using a single 20 s freeze
thaw cycle for each treatment. This is repeated on
a 3–6-monthly basis at first and then yearly,
depending the patient desire. Topical corticoste-
roid cream is applied after cryotherapy to mini-
mize discomfort.
104 Porokeratosis, Linear
Success Rates
Segmental cryosurgery achieves good cosmetic
results with no recurrences for many years.
Conclusions
Results with cryotherapy have been considered
disappointing in the past, with high recurrence
rates seen in addition to significant scarring;
not so with the methodology described here
[13]. We propose that cryotherapy be consi-
dered as an inexpensive, effective treatment
option for LPK.
References
1. Cho E, Lee YB, Park HJ, Cho BK. Coexistence of con-
genital linear porokeratosis and disseminated superficial
porokeratosis. Australas J Dermatol. 2012;53:e30–1.
2. Suh DH, Lee HS, Kim SD, et al. Coexistence of dis-
seminated superficial porokeratosis in childhood with
congenital linear porokeratosis. Pediatr Dermatol.
2000;17:466–8787.
3. Fisher CA, LeBoit PE, Frieden IJ. Linear porokerato-
sis presenting as erosions in the newborn period.
Pediatr Dermatol. 1995;12:318–22.
551
4. Lee KS, Kim MN, Hong CK, et al. Coexistence of
porokeratosis of Mibelli with linear porokeratosis.
Ann Dermatol. 1999;11:169–73.
5. Agrawal SN, Pawar PC, Dhillan PV. Linear porokera-
tosis: an unusual presentation. Indian J Dermatol.
2014;59:318.
6. Dervis E, Demirkesen C. Generalized linear poroker-
atosis. Int J Dermatol. 2006;45:1077–9.
7. Otsuka F, Shima A, Ishibashi Y. Porokeratosis as a
premalignant condition of the skin. Cytologic demon-
stration of abnormal DNA ploidy in cells of the epi-
dermis. Cancer. 1989;63:891–6.
8. Magee JW, McCalmont TH, LeBoit PE. Overexpression
of p53 tumor suppressor protein in porokeratosis. Arch
Dermatol. 1994;130:187–90.
9. Gu CY, Zhang CF, Chen LJ, Xiang LH, Zheng ZZ.
Clinical analysis and etiology of porokeratosis. Exp
Ther Med. 2014;8:737–41.
10. Schamroth JM, Zlotogorski A, Gilead L. Porokeratosis
of Mibelli. Overview and review of the literature.
Acta Derm Venereol. 1997;77:207–13.
11. Skupsky H, Skupsky J, Goldenberg G. Disseminated
superficial actinic porokeratosis: a treatment review.
J Dermatol Treat. 2012;23:52–6.
12. Bhushan M, Craven NM, Beck MH, Chalmers RJG.
Linear porokeratosis of Mibelli: successful treat-
ment with cryotherapy. Br J Dermatol. 1999;
141:389.
13. Eyre WG, Carson WE. Linear porokeratosis of
Mibelli. Arch Dermatol. 1972;105:426–9.
 Cryosurgery for Disseminated
Superficial Actinic Porokeratosis
105
Vijay Vanchinathan and Robert A. Schwartz

Abstract
Disseminated Actinic Porokeratosis is an epidermal keratinization disor-
der of erythematous patches and plaques with well-demarcated raised bor-
ders, usually on the legs and forearms, in response to ultraviolet radiation.
Topical retinoids, florouracil, and imiquimod have been used with limited
success. Cryosurgery produces good responses for individual lesions.

Keywords
Porokeratosis • Disseminated • Superficial • Actinic • DSAP • Cryosurgery

Introduction can be both safe and successful, offering an

Porokeratosis is an uncommon disorder of epi-
dermal keratinization with several clinical vari-
ants, including disseminated superficial actinic
porokeratosis (DSAP). Although cryosurgery is
a known effective treatment modality for soli-
tary porokeratotic lesions, its use in the dissemi-
nated form is less appreciated. When performed
appropriately, one-time cryosurgery of DSAP
V. Vanchinathan, MD (*)
Department of Dermatology, Rutgers University New
Jersey Medical School, University Hospital,
185 South Orange Ave., Medical Science Building
H-576, Newark, NJ 07103-2757, USA
e-mail: vijayv37@gmail.com
R.A. Schwartz, MD, MPH, DSc (Hon), FRCP (Edin)
Department of Dermatology, Rutgers University
School of Public Affairs and Administration,
Newark, NJ, USA
alternative to the frequent use of topical or sys-
temic medications.
Disease Description and Histology
Porokeratosis is an epidermal keratinization dis-
ease classically characterized by a flesh-colored
to erythematous plaque with a well-demarcated,
raised border and an atrophic center. The lesions
are readily diagnosed on histologic examination
by the presence of cornoid lamellae, which are
columns of parakeratosis directly overlying an
epidermis devoid of granular cells with apoptotic
keratinocytes in the basal layer [1, 2]. Six differ-
ent variants of porokeratosis have been described
in the literature: porokeratosis of Mibelli, dis-
seminated superficial porokeratosis, disseminated
superifical actinic porokeratosis, linear

© Springer-Verlag London 2016 553

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_105
554
porokeratosis, punctate porokeratosis, and poro-
keratosis palmaris et plantaris disseminata [3].
Disseminated pororkeratosis is an autosomal
dominant disease, although it has been reported
to occur sporadically following immunosuppres-
sion [2, 4]. Disseminated superficial actinic poro-
keratosis (DSAP), as the name suggests, occurs
in response to ultraviolet radiation exposure and
typically presents on the lower legs and forearms,
but spares the face [4, 5]. DSAP is the most com-
mon porokeratosis subtype and has been linked
to chromosomes 1, 12, 15, and 18 [1]. The main-
stay of treatment is prevention of new lesion
development with sunscreen and sun-protective
clothing [4].
Therapeutic Alternatives
A number of different therapies for porokeratosis
have been employed, all with varying degrees of
success. These include topical 5-fluorouracil,
tretinoin, and imiquimod, oral isotretinoin, PDT,
PUVA, CO2 laser ablation, surgical excision, and
combinations of the above [1, 4, 6]. The treat-
ment of choice should target the underlying
mutated keratinocytes to prevent recurrence.
Patients with DSAP should be advised to avoid
ultraviolet radiation exposure that could trigger
new flares [1, 4].
Cryosurgery
Liquid nitrogen (LN) has long been used as
a treatment modality for porokeratosis, par-
ticularly porokeratosis of Mibelli [6, 7]. Labial
porokeratosis and linear porokeratosis have
been successfully managed with cryosurgery as
well [8, 9]. The fact that keratinocytes are more
resistant to freezing than melanocytes, how-
ever, means that porokeratotic plaques require
more aggressive treatment than their pigmented
counterparts [10]. Exact therapy regimens vary
according to the severity and location of the
lesion and provider preference, but may range
V. Vanchinathan and R.A. Schwartz
from 20 to 30 s in total freeze time or freeze-
thaw time. Individual plaque keratotic borders
may be gently pared down with an 11 blade prior
to freezing and soothed with clobetasol cream
after [6, 9].
Comparative evaluations of the effectiveness
of LN application for the treatment of DSAP are
limited. One study examined topical imiquimod,
PDT, and direct cryosurgery on different fields of
DSAP on the same patient, with seven patients
total. The authors applied a contact cryosurgical
unit to each individual lesion for 20 s at −32 °C
and repeated the treatment at follow-up, if neces-
sary [4].
Methodology (How We Do It)
We prefer treating DSAP with an open spray
application of LN with concurrent perilesional
temperature monitoring to ensure freezing at an
estimated temperature of −30 °C or lower. Open
spray application offers wide coverage for larger
lesions and quick treatment of multiple lesions
from one to the next. Care should be taken, how-
ever, to ensure that each patient’s skin reacts to
the cryosurgery appropriately with few compli-
cations. We therefore recommend spot treating
one to three plaques in a discrete area to evaluate
for potential side effects such as scarring and
hypo or hyperpigmentation. Upon successful
treatment, patients should be advised on proper
wound care, the need for follow-up evaluations,
and the importance of regular sun-protective and
sun-avoidant practices to limit recurrence.
Success Rates
In one study, cryosurgery was found to be the
more effective than both topical imiquimod and
PDT. Topical imiquimod did not reduce the num-
ber of lesions in any patient treated; two-thirds of
patients saw no improvement after PDT. Eighty
to one hundred percent of all lesions cleared
completely by 4 weeks post-cryosurgery; any
105 Cryosurgery for Disseminated Superficial Actinic Porokeratosis
remaining ones resolved after a second treatment
course [4].
Conclusions
DSAP is an epidermal keratinization disorder
exacerbated by ultraviolet radiation exposure
that responds well to cryosurgery. Factors
such as large lesion size and extensive body
surface area should not hinder the clinician
from using this simple and potent treatment
modality. Further research needs to be con-
ducted to better quantify its effectiveness rela-
tive to other therapies.
References
1. Kuflik EG, Kuflik JH. Cryosurgery. In: Bolognia JL,
Jorizzo JL, Schaffer JV, editors. Dermatology. 3rd ed.
Philadelphia: Elsevier Saunders; 2012. p. 2283–9.
2. Knoell KA, Patterson JW, Wilson BB. Sudden onset
of disseminated porokeratosis of Mibelli in a renal
transplant patient. J Am Acad Dermatol.
1999;41:830–2.
555
3. Suárez-Amor O, Pereiro-Ferreirós M, Ginarte M,
Peteiro C, Toribio J. Coexistence of linear porokeratosis
and disseminated superficial actinic porokeratosis: a
type 2 segmental manifestation. Acta Derm Venereol.
2006;17:363–4.
4. Schmook T, Kraft J, Ulrich C, Stockfleth E. Disseminated
superficial actinic porokeratosis: report of 7 patients suc-
cessfully treated with cryotherapy. J Am Acad Dermatol.
2005;52:195.
5. Wiltz H, Schwartz RA, Lambert WC. Disseminated
superficial actinic porokeratosis: appearance after
suntan parlor exposure. Photodermatol.
1987;4(1):47–8.
6. Dereli T, Ozyurt S, Ozturk G. Porokeratosis of
Mibelli: successful treatment with cryosurgery.
J Dermatol. 2004;31(3):223–7.
7. Chowdhury MM, Inaloz HS, Holt PJ. A scaly macule
on the bridge of the nose of a 15-year-old boy. Pediatr
Dermatol. 2000;17(2):149–50.
8. Bel PH, Jimenez OS, Bröker GS, Barona CG. Labial
porokeratosis. Am J Dermatopathol.
2010;32(6):638–9.
9. Bhushan M, Craven NM, Beck MH, Chalmers
RJG. Linear porokeratosis of Mibelli: successful
treatment with cryotherapy. Br J Dermatol.
1999;141(2):389.
10. Kuflik EG. Cryosurgery updated. J Am Acad
Dermatol. 1994;31(6):925–44; quiz 944–6.
 Cryosurgery for Psoriasis
106
Mohammad-Ali Yazdani Abyaneh, Robert Griffith,
Leyre Falto-Aizpurua, and Keyvan Nouri

Abstract
Psoriasis is a chronic inflammatory disease affecting the skin with various
treatment options. Cryosurgery has been studied in only a limited number
of case series for the treatment of small plaque psoriasis with variable
results. Findings from these studies suggest cryosurgery can improve the
induration, erythema, and scaling of small psoriatic plaques with one or
just a few treatments. Furthermore, these studies suggest that cryosurgery
is a safe treatment modality with hypopigmentation as the only major
adverse effect. However, further studies are necessary to clarify the role of
cryosurgery in the armamentarium of psoriasis therapy.

Keywords
Psoriasis • Psoriatic • Plaque • Cryosurgery • Cryotherapy • Liquid
nitrogen

Introduction individualized in light of the patient’s history

Psoriasis is a chronic inflammatory disease
affecting the skin with variable response to dif-
ferent treatment modalities among patients. A
host of therapies, including topical medica-
tions, phototherapy, and systemic agents are
available; however, treatment should always be
M.-A.Y. Abyaneh, BS • R. Griffith, MD
L. Falto-Aizpurua, MD • K. Nouri, MD (*)
Department of Dermatology and Cutaneous Surgery,
University of Miami Miller School of Medicine,
1475 NW 12th Ave., Suite 2099H, Miami,
FL 33136, USA
e-mail: knouri@med.miami.edu
and preferences. Cryosurgery has been studied
in four small case series for the treatment of
small plaques in patients with chronic plaque
type psoriasis. These studies have reported effi-
cacy in improving lesion induration, erythema,
and scaling, with residual hypopigmentation as
the only major adverse effect. It is speculated
that physical destruction as well as a reverse
Koebner phenomenon may underlie this
response. Cryosurgery offers a safe, cheap, and
potentially effective means of treating localized
small papules and plaques but appropriate
patient selection (i.e., by treating a few small
lesions to test response in individual patients) is

© Springer-Verlag London 2016 557

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_106
558
important. Further studies are needed to verify
these findings and to elucidate the role of cryo-
surgery in the treatment of psoriasis.
Description of the Disease
Psoriasis is an inflammatory, multi-systemic,
chronic disease with both genetic and environ-
mental contributions to its pathogenesis and
progression [1, 2]. An estimated 2 % of the pop-
ulation suffers from the disease [3]. While it is
most prominently characterized as a chronic
inflammatory disease of the skin, patients may
also suffer from psoriatic arthritis and other
comorbidities including cardiovascular disease,
inflammatory bowel disease, and metabolic syn-
drome [1]. Psoriasis carries a significant psy-
chosocial burden (i.e., reduced income and
employment) and impairs the quality of life of
patients [4, 5].
Psoriasis classically presents as erythema-
tous papules and plaques with silvery scale that
may be associated with pruritus and pain. The
thickness of the lesions is owed to acanthosis
due to keratinocytic hyperplasia and inflamma-
tory infiltrates, whereas the redness of lesions is
owed to a greater number of tortuous capillaries
and thinned epithelium between the elongated
rete pegs [2].
Psoriasis is classified based on its clinical
morphology into one of five groups. The most
common type is plaque psoriasis, accounting
for 80–90 % of cases. However, the majority
of patients overlap among the clinical mor-
phologies. Clinical findings may range from a
few localized plaques to lesions all over the
body. The distribution commonly involves the
extensor surface of the limbs (elbows and
knees) as well as the scalp, trunk, and but-
tocks. Inverse or flexural psoriasis, while
much less common, can involve the flexural
regions of the skin instead. About 80 % of
patients have mild to moderate disease; the
other 20 % have involvement of more than 5 %
of their body surface area or involvement of
important body areas like the face, hands, feet,
and genitals [1].
M.-A.Y. Abyaneh et al.
Therapeutic Alternatives
The choice of treatment for psoriasis should take
a number of factors into account: the area and
severity of lesions, the disease impact on a
patient’s quality of life, response to previous
therapies, as well as contraindications for indi-
vidual patients.
Limited disease may be managed with topical
therapies such as vitamin D3 analogues and cor-
ticosteroids or targeted phototherapy. More
extensive disease may require phototherapy
(ultraviolet B or psoralen with ultraviolet A),
classic systemic agents such as methotrexate,
cyclosporine, retinoids, or newer targeted
immune modulators (etanercept, infliximab,
adalimumab, ustekinumab). The presence of con-
current psoriatic arthritis may favor use of meth-
otrexate or tumor necrosis factor alpha inhibitors
[1, 6].
Lack of efficacy, patient inconvenience, and
safety concerns limit the use of many conven-
tional treatment options. As such, newer thera-
peutic modalities are continously sought to
improve the care of patients with psoriasis.
Cryosurgery
Four small case series have evaluated the use of
cryosurgery for the treatment of small plaque
psoriasis in patients from 6 to 81 years of age
(Table 106.1). Scoggins was the first to report his
findings in 1987 in an uncontrolled series [7]. He
stated that patients should be selected for this
treatment modality if they can tolerate the imme-
diate freezing and the subsequent blister forma-
tion. In fact, in the initial phase of his study, he
reported that among 31 treated plaques, complete
resolution resulted in 67 % of lesions where bulla
formation was noted but only 29 % of lesions that
were not associated with bulla formation after
cryosurgery. He subsequently postulated that
freezing should be sufficient to induce formation
of bulla and went on to treat 191 additional
lesions (with bulla formation). All three subse-
quent case series reported formation of vesicles
or bulla after treatment in all patients.
106 Cryosurgery for Psoriasis 559

Table 106.1 Studies on the use of cryosurgery for small plaque psoriasis
Shamsadini et al.
Scoggins (1987) Nouri et al. (1997) El-Taweel et al. (1999) (2005)
Study design Case series Case series (intra-individual Case series (intra-individual Case series
(uncontrolled) control, with control) (intra-individual
randomization) control)
# of subjects 35 (17 M, 19 F) 9 50 (25 M, 25 F) 63 (32 M, 31 F)
(sex)
# of lesions Treated: 222 Treated: 9 Treated: 50 Treated: 217
Control: 9 Control: 50 Control: 192
Lesion 0.2–14 cm 0–5 cm 1–5 cm 1.5–12 cm
diameters
Age range 22–74 35–81 13–67 6–67
Treatment 1 treatment 1 treatment Weekly treatment until Every other day
regimen “observable improvement” for 2 weeks
Freezing time 5–20 s 5–15 s 9–15 s 9–15 s
Last 1–11 months after 12 weeks after treatment Not reported End of treatment
follow-up treatment period (2 weeks)
Outcome NA 4 point scale assessing 4 point scale assessing 3 point scale
measured induration, erythema, induration, erythema, assessing
scaling scaling induration,
erythema, scaling
Complete 67–80 % of lesions 56 % of lesions 62 % of lesions 6.4 % of patients
resolution
with treatment
Complete No controls Mean severity score was not Not reported 4.7 % of patients
resolution in significantly decreased in
controls control lesions
Adverse Varying degrees of Hypopigmentation and Hypopigmentation (only Only one
effects hypo- or atrophy at treatment site in with complete resolution). superimposed
hyperpigmentation 3 of 5 patients who had More common in younger infection
complete resolution. Mild patients, smaller lesions,
secondary infection in 1 and with fewer and shorter
patient, requiring oral duration sessions (P < 0.001)
antibiotic

Lesions treated in the four studies ranged from
0 to 14 cm in size. Patients were subjected to
treatment once [7, 8], once weekly until observ-
able improvement [9], or every other day for
2 weeks [10]. Three studies reported using a scale
for evaluating treatment outcomes (complete res-
olution) that assesed the induration, erythema,
and scaling of the treated lesions [8–10].
The most commonly reported adverse effect
from treatment was hypopigmentation, which
was exclusively found in patients who achieved
complete resolution of their lesions. Two patients
in all studies developed a secondary infection.
There are conflicting reports regarding which
patients and lesions have better improvement;
El-Taweel et al. reported better improvement in
younger patients and smaller lesions [9] while
Shamsadini et al. reports better improvement in
older patients and larger lesions [10]. After
cryosurgery, healing usually occurs in about
2 weeks [7].
Methodology
All studies treating small plaque psoriasis with
cryosurgery have used liquid nitrogen spray
(Scoggins also used a cotton applicator).
Freezing times with the spray range from 5 to
20 s depending on the size and thickness of
lesions. Scoggins reported longer treatment time
with a cotton applicator, and a thaw time of
560
1–2 min. It is important to note that longer freez-
ing time (sufficient for bulla formation) results
in both a greater chance of plaque resolution and
adverse effects following treatment. Freezing
too deeply should be avoided especially in darkly
pigmented individuals and in cosmetically sensi-
tive areas [7, 8].
Treatment should start with small lesions. If
the patient tolerates the treatment well, then
larger lesions can be treated at subsequent
encounters. To minimize the risk of recurrence,
the treatment site should be frozen homogene-
rously and completely. Moreover, re-treatment of
residual or recurrent papules may be considered
in order to achieve a desirable outcome [7, 8].
Secondary infections may be avoided with
the application of topical antibiotics. While
one study applied twice daily fucidin cream
for 1 week after each treatment [9], another
applied mupirocin cream after each session of
treatment [10].
Success Rates
The aforementioned studies have reported vary-
ing degrees of success using cryosurgery for
reducing induration, erythema, and scaling in
patients with chronic plaque psoriasis. In lesions
that were treated sufficiently to result in bulla for-
mation, Scoggins initially reported complete res-
olution rates of 67–80 % after a single treatment;
the study also reported that 77 % of 13 residual
lesions completely responded after 1–3 addi-
tional treatments [7]. Nouri et al. reported com-
plete resolution in 56 % of their subjects after one
treatment; an additional 22 % of subjects had
75–80 % resolution [8]. El-Taweel et al. had
complete resolution in 62 % of treated lesions
(the number of total treatments varied) [9].
Shamsadini et al. reported much lower rates of
complete resolution in a right vs. left comparative
study. Only 6.4 % of patients had complete reso-
lution on their treated sites vs. 4.7 % of patients
who had complete resolution of untreated control
sites [10]. Unlike the other three studies,
Shamsadini et al. did not report the percent of
M.-A.Y. Abyaneh et al.
plaques with complete resolution. Instead they
reported the percent of patients (who may each
have had multiple plaques) who had complete
resolution. This may partially account for the dis-
crepancy in the results from this study in com-
parison to the other previous studies.
Conclusions
A number of mechanisms may account for the
response of psoriatic lesions to cryosurgery.
One possibility is normal re-epithelialization
following the physical destruction of elon-
gated papillae. Cryosurgery may reduce the
germinative cell base and halt further hyperp-
roliferation of keratinocytes [11]. A reverse
Koebner phenomenon following injury may
also account for resolution of lesions in select
patients [12]. Because it is inexpensive, quick,
and easy to perform, cryosurgery is an attrac-
tive possibility for the treatment of psoriasis.
The prospect of significant clinical response
in small lesions with just one or a few treat-
ments is also very convenient for patients.
However, studies with a larger sample size,
controls with other standard topical therapies,
randomization, and long term follow-up are
necessary to make a more clear determination
of the role for cryosurgery in the armamen-
tarium for psoriasis therapy.
References
1. Menter A, Gottlieb A, Feldman SR, et al. Guidelines
of care for the management of psoriasis and psoriatic
arthritis: section 1. Overview of psoriasis and guide-
lines of care for the treatment of psoriasis with biolog-
ics. J Am Acad Dermatol. 2008;58:826–50.
2. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl
J Med. 2009;361:496–509.
3. Christophers E. Psoriasis – epidemiology and clinical
spectrum. Clin Exp Dermatol. 2001;26:314–20.
4. Horn EJ, Fox KM, Patel V, Chiou CF, Dann F,
Lebwohl M. Association of patient- reported psoriasis
severity with income and employment. J Am Acad
Dermatol. 2007;57:963–71.
5. Gelfand JM, Feldman SR, Stern RS, Thomas J,
Rolstad T, Margolis DJ. Determinants of quality of
life in patients with psoriasis: a study from the US
population. J Am Acad Dermatol. 2004;51:704–8.
106 Cryosurgery for Psoriasis
6. Kerkhof PCM, Nestle FO. Psoriasis. In: Bolognia JL,
Jorizzo JL, Schaffer JV, editors. Dermatology. 3rd ed.
London: Mosby; 2012. p. 135–56.
7. Scoggins RB. Cryotherapy for psoriasis. Arch
Dermatol. 1987;123:427–8.
8. Nouri K, Chartier TK, Eaglstein WH, Taylor JR.
Cryotherapy for psoriasis. Arch Dermatol.
1997;133:1608–9.
9. El-Taweel AEZ, Kotb M, El-Wahab AA, Kamal A,
Ali AA. Cryotherapy in psoriasis. Gulf J Dermatol.
1999;2:46–8.
561
10. Shamsadini S, Varesvazirian M, Shamsadini A.
Cryotherapy as a treatment for psoriasis. Dermatol
Online J. 2005;11:21.
11. Stone OJ. The elongated dermal papillae of psoriasis.
Int J Dermatol. 1990;29:187–9.
12. Eyre RW, Krueger GG. Response to injury of skin
involved and uninvolved with psoriasis, and its rela-
tion to disease activity: Koebner and ‘reverse’
Koebner reactions. Br J Dermatol. 1982;106:153–9.
 Prurigo Nodularis
107
Renata Strumia

Abstract
Prurigo nodularis (PN) is a chronic skin disorder of unknown aetiology
characterized by intensely pruritic and excoriated nodules, mainly located
symmetrically on the bilateral extensor extremities, the number of which
may vary from a few to hundreds. The treatment of PN is often frustrating.
Topical antipruritics, localized phototherapy and photochemotherapy, sys-
temic corticosteroids and cyclosporine have been employed. PN has been
treated successfully with blistering cryotherapy. When scarring begins, the
patient experiences a remarkable decrease in itching.

Keywords
Prurigo nodularis • Cryotherapy

Introduction Description

Prurigo nodularis of Hyde (PN) is a chronic
skin disorder of unknown aetiology character-
ized by intensely pruritic excoriated nodules,
mainly located symmetrically and bilaterally
on the extensor aspect of the extremities, the
number of nodules may vary from a few to
hundreds [1].
The lesions are firm, hyperkeratotic pruritic nod-
ules with symmetrical distribution, and predomi-
nance on the extensor surface of arms and legs.
PN occurs mainly in adults, especially middle-
aged women.
Histology

PN is characterized by hypertrophy and prolifer-

R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara (Former), Ferrara, Italy
e-mail: restrumi@tin.it
ation of dermal nerves, in the epidermis of skin
nodules there are increased numbers of Merkel
cells. The dermis shows a non-specific inflamma-
tory infiltrate including lymphocytes, mast cells,
histiocytes and occasionally eosinophils. There is

© Springer-Verlag London 2016 563

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_107
564
a proliferation of fibroblasts and it is possible to
find a subepidermal deposition of fibrin. PN rep-
resents a primary dermatological condition or a
dermatological manifestation of repeated trau-
matic manipulation secondary to chronic pruri-
tus. One must consider underlying causes of
pruritus, which may include psychiatric disorders
and internal disease. Given its chronicity and
relapsing nature, treatment of PN can be chal-
lenging. Interruption of the itch-scratch cycle is
difficult; long-term prognosis remains guarded.
Therapeutic Alternatives
The first-line agents used in the treatment of PN
are topical antipruritics including emollients,
menthol, capsaicin cream, topical corticosteroids
and occlusion with bandaging. Oral antihista-
mines, sedatives and antidepressants are an alter-
native treatment. Occasionally a short period of
systemic therapy with corticosteroids may be
indicated. The improvement with corticosteroids
is variable, and corticosteroids are sometimes not
helpful. Intralesional corticosteroid (usually tri-
amcinolone acetonide) treatment is commonly
used in resistant cases of limited extent [2].
Second-line agents include localized photo-
therapy and photochemotherapy [3, 4], cryother-
apy [5], and topical vitamin D3 [6]. UV light
treatment using UV-B or UV-A plus psoralen may
be beneficial for severe pruritus. Monochromatic
308-nm light therapy may be helpful for recalci-
trant lesions, although this modality may be more
useful in atopic dermatitis. UV-A has also been
reported to benefit lichen simplex chronicus and
prurigo nodularis.
Third-line agents include cyclosporine, of
which the use is limited by side effects that include
hypertension, renal damage, and relapse of disease
after cessation of treatment [7]. In 1975, Sheskin
[8] was the first to treat prurigo nodularis with tha-
lidomide. In 1961 thalidomide was withdrawn
from the world market on discovery of its terato-
genic effect, rare congenital abnormalities such as
phocomelia in infants born to women who used
thalidomide during pregnancy. During the past
few decades, thalidomide has been reintroduced
R. Strumia
for use in a variety of refractory dermatologic con-
ditions and other disorders thought to have an
autoimmune or inflammatory basis, such as lupus
erythematosus, aphthous stomatitis, pyoderma
gangrenosum, Behçet’s syndrome, actinic prurigo,
Kaposi sarcoma, Crohn’s disease, multiple
myeloma and prurigo nodularis [9]. In 1973
Mattos [10] and in 1984 Wilkelmann et al. [11]
observed that in patients with prurigo nodularis
thalidomide administration induced the resolution
of the pruritus within weeks and an involution of
the nodular lesions in several months. The authors
suggest that a long-term benefit may be obtained
in about 6 months and state that a 200-mg daily
dose is adequate for treatment. The mechanism of
action of thalidomide is through its central seda-
tive effect, causing a reduction in peripheral stim-
uli perception, such as pruritus. However
thalidomide may also have a direct peripheral
action on the proliferated neural tissue in the
lesions. The rapid improvement of pruritus may
possibly be attributed to the immunomodulatory
and anti-inflammatory properties of its anti- TNF-a
action, or by a decrease in the perception of periph-
eral stimuli, such as pruritus [12]. For steroid unre-
sponsive patients or those with lesions on thin
skin, a few case reports and small studies have
shown efficacy of the topical immunomodulators
tacrolimus and pimecrolimus [13]. Anecdotally,
gabapentin has been reported to benefit prurigo
nodularis [14]. Sedation is the main problem with
this generic medication.
Cryosurgery
There is a scarcity of literature concerning the use
of liquid nitrogen cryotherapy in the treatment of
PN [15, 16]. PN has been treated successfully with
blistering cryotherapy. Cryotherapy results in
smooth macule formation and affords extended
relief of pruritus. Graham listed cryotherapy as a
useful therapeutic agent in PN, but did not discuss
the duration of the freezing, if bullae were pro-
duced, or how many freeze-thaw cycles were
applied. Waldinger et al. obtained significant
results only when bullae were produced. The num-
ber of simultaneously treated nodules and the
107 Prurigo Nodularis
duration of cryotherapy for individual nodules
must be determined case by case. If numerous
nodules are treated on the same extremity and at
the same time, edema and resulting pain may be
considerable and of long duration. Furthermore,
black-skinned patients must be aware of possible
residual hypopigmentation following this thera-
peutic method. The initial eradication of the nod-
ules with cryotherapy is due to the production of a
blister with subsequent healing. The continued
absence of pruritus after cryotherapy may be due
to the resolution of the lesions, or it may be the
result of sensorial nerve damage. Stoll et al.
obtained good results in treatment of PN with the
combined use of cryosurgery and intralesional ste-
roids plus lidocaine at 1 %. Keratoacanthoma
developed from one nodule of prurigo nodularis
that had been treated with cryotherapy for
3 months. The authors hypothesized that irritations
of cryotherapy in addition to repeated mechanical
traumas of scratching might have played a role in
the formation of this tumor [17].
Methodology (How I Do It)
The duration of freezing should be 10–30 s,
depending the size of the nodules. Two to three
cycles of freezing should be performed in the
same session because cryotherapy works well
only if blistering is achieved. All the nodules
should be treated in the same session, except
when the lesions are too numerous. At least three
to four freeze-thaw cycles are requested to
achieve a good result. Topical anaesthesia with a
cream relieves the pain.
Success Rates
In my experience, even after one session, when
scarring begins, the patient experiences a remark-
able decrease in itching.
Conclusions
Cryotherapy can be a useful therapeutic alter-
native for prurigo nodularis.
565
References
1. Vaidya DC, Schwartz RA. Prurigo nodularis: a benign
dermatosis derived from a persistent pruritus. Acta
Dermatovenerol Croat. 2008;16:38–44.
2. Lee MR, Shumack S. Prurigo nodularis: a review.
Australas J Dermatol. 2005;46:211–8.
3. Bruni E, Caccialanza M, Piccinno R. Phototherapy of
generalized prurigo nodularis. Clin Exp Dermatol.
2010;35:549–50.
4. Hammes S, Hermann J, Roos S, Ockenfels HM. UVB
308-nm excimer light and bath PUVA: combination
therapy is very effective in the treatment of prurigo
nodularis. JEADV. 2011;25:799–803.
5. Graham GF. Cryosurgery in treatment of acne and
specific cutaneous neoplasia. In: Zacarian SA, editor.
Cryosurgical advances in dermatology and tumors of
the head and neck. Springfield: Charles C Thomas;
1977. p. 74–97.
6. Wong SS, Goh CL. Double-blind, right/left compari-
son of calcipotriol ointment and betamethasone oint-
ment in the treatment of prurigo nodularis. Arch
Dermatol. 2000;136:807–8.
7. Siepmann D, Luger TA, Ständer S. Antipruritic effect of
cyclosporine microemulsion in prurigo nodularis: results
of a case series. J Dtsch Dermatol. 2008;6:941–6.
8. Sheskin J. Treatment of prurigo nodularis Hyde using
thalidomide. Hautarzt. 1975;26:215–7.
9. Taefehnorooz H, Truchetet F, Barbaud A, Schmutz
J-L, Bursztejn A-C. Efficacy of thalidomide in the
treatment of prurigo nodularis. Acta Derm Venereol.
2011;91(3):344.
10. Mattos O. Prurigo nodular de Hyde tratado com talid-
omida. Bol Div Nac Lepra. 1973;32:71–7.
11. Winkelmann RK, Connolly SM, Doyle JA, Gonçalves
AP. Thalidomide treatment of prurigo nodularis. Acta
Derm Venereol (Stockh). 1984;64:412–7.
12. Orlando A, Renna S, Cottone M. Prurigo nodularis of
Hyde treated with low-dose thalidomide. Eur Rev
Med Pharmacol Sci. 2009;13:141–5.
13. Ständer S, Schürmeyer-Horst F, Luger TA, Weisshaar
E. Treatment of pruritic diseases with topical calcineu-
rin inhibitors. Ther Clin Risk Manag. 2006;2:213–8.
14. Mazza M, Guerriero G, Marano G, Janiri L, Bria P,
Mazza S. Treatment of prurigo nodularis with prega-
balin. J Clin Pharm Ther. 2013;38:16–8.
15. Waldinger TP, Wong RC, Taylor WB, Voorhees
JJ. Cryotherapy improves prurigo nodularis. Arch
Dermatol. 1984;120:1598–600.
16. Stoll DM, Fields JP, King LE. Treatment of prurigo
nodularis: use of cryosurgery and intralesional steroids
plus lidocaine. J Dermatol Surg Oncol. 1983;9:922–4.
17. Okuyama R, Takahashi K, Ohi T, Tagami
H. Keratoacanthoma developing in prurigo nodularis
treated with cryotherapy. Dermatology. 1997;194:290–2.
 Cryosurgery for Pruritus Ani
108
Parmvir Singh and Robert A. Schwartz

Abstract
Pruritus ani is a male predominant disorder of perianal itching that is asso-
ciated with an itch-scratch cycle leading to lichenification. It can be caused
by infection, medications, irritation, systemic disease, and colorectal/anal
disease. Dermatologic diseases associated with pruritus ani include psori-
asis, seborrheic keratosis, atopic dermatitis, contact dermatitis, lichen
sclerosus, lichen simplex chronicus, Paget’s disease, and Bowen’s disease.
The primary treatment for pruritus ani is maintenance of anal hygiene.
Steroid creams, capsaicin, tacrolimus, and injectable methylene blue have
been used with mixed success. Cryosurgery disrupts nerve endings, caus-
ing cessation of the itch-scratch cycle. Only 1 out of 18 patients had recur-
rence after cryosurgery. Cryosurgery is an effective option for pruritus ani
due to its cost-effectiveness and low morbidity.

Keywords
Pruritus • Ani • Primary • Secondary

Introduction male to female ratio [1, 2]. It is most common in

Pruritus ani is a dermatological condition of peri-
anal itching and burning [1]. It has an incidence
of 1–5 % of the general population, with a 4:1
P. Singh, MD (*)
Department of Dermatology, University Hospital,
185 South Orange Ave., Newark, NJ 07103, USA
e-mail: parmvirsingh90@gmail.com
R.A. Schwartz, MD, MPH, DSc (Hon), FRCP (Edin)
Department of Dermatology, Rutgers University
School of Public Affairs and Administration,
Newark, NJ, USA
the fourth to sixth decades of life [1]. Pruritus ani
can be either primary, idiopathic (50–90 %) or
secondary, the most common (50–90 %) being
idiopathic. The hallmark of the condition is a
self-perpetuating “itch-scratch” cycle, leading to
lichenification [2, 3]. Most patients self treat for
an average of 12 months before seeking physician
care. Primary pruritus ani has been staged from
stage 0 to stage 3 [1]. Stage 0 is normal skin,
stage 1 is red and inflamed, stage 2 is lichenified,
stage 3 is lichenified with coarse ridges or
ulcerations.

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Description of the Disease
Clinical features and the histology of the disease
relate to its cause. Secondary etiologies of pru-
ritus ani include infectious, medications, topical
irritants, dermatologic disease, systemic dis-
ease, local irritants, and colorectal or anal causes
[1, 4]. Infectious causes include bacterial, viral,
fungal and parasitic infections [1]. Pinworm is
particularly common among children and insti-
tutionalized adults [2]. Medications that cause
pruritus ani include colchicine, neomycin, and
quinidine. Dermatologic causes include psoria-
sis, seborrheic dermatitis, hidradenitis suppura-
tiva, lichen planus, lichen simplex chronicus,
lichen sclerosus et atrophicus, contact dermati-
tis, atopic dermatitis, and local malignancy [1,
2, 4]. Systemic causes include diabetes mellitus,
leukemia, lymphoma, thyroid disease, inflam-
matory bowel disease, anemia, uremia and
obstructive hepatic disease [1, 2, 5]. Colorectal
and anal causes include hemorrhoids, rectal pro-
lapse, fistulas, fissures and diarrhea [1]. Patch
testing may occasionally be of value to deter-
mine secondary etiology [6].
Dermatologic conditions responsible for pruri-
tus ani may not show their classic appearance in
the perianal region [1]. Many of the conditions
that cause pruritus ani fall under the category of
chronic secondarily lichenified plaques [3].
Psoriasis typically appears as scaly plaques. In the
perianal region, psoriasis may be less well demar-
cated, less erythematous, and less scaly.
Seborrheic dermatitis may produce moist ery-
thema in the perineum. Atopic dermatitis may be
evident as dry, scaly patches. In the perianal
region, soaps are known to be a common trigger
of atopic dermatitis. Contact dermatitis may be
evident as erythematous vesicles. Lichen sclero-
sus may be evident as darkly pigmented, shiny,
flat-topped papules with Wickham striae. Lichen
sclerosus et atrophicus is a female predominant
condition that begins in the vulva and extends
posteriorly as white patches around the anus.
Lichen simplex chronicus is a common cause of
perianal lichenification. Perianal Paget’s disease
and Bowen’s disease can be first evident with pru-
ritus ani. A typical presentation of extramammary
P. Singh and R.A. Schwartz
Paget’s disease is a patient in the seventh decade
of life with an erythematous, eczematous plaque
in the perianal region [1].
Therapeutic Alternatives
Management of pruritus ani can be challenging
[1]. Non-specific pruritus is troublesome [7]. The
most important treatment for primary pruritus ani
is maintenance of anal hygiene [1, 2, 6]. Patient
education is of the utmost importance [2].
Avoidance of irritants, avoidance of trauma,
avoidance of moisture, and maintenance of regu-
lar bowel movements are crucial [1]. Generally,
steroids such as 1 % hydrocortisone cream are
used [1, 2, 4, 6, 7]. Steroids cause temporary
relief, but also lead to atrophy [1, 2, 7]. Capsaicin,
may be effective for idiopathic pruritus ani [1, 2].
Injectable methylene blue, by destruction of
nerve endings, may also be useful in idiopathic
pruritus ani [1]. Topical 0.1 % tacrolimus was
found to be effective in 68 % of cases of idio-
pathic pruritus ani [8]. A sedating anti-histamine
can be used to reduce scratching at night [2, 4].
Psoriasis can be treated with 1 % hydrocorti-
sone cream [1]. Seborrheic dermatitis may
respond to 1 % hydrocortisone or miconazole
topically applied. Contact dermatitis can be
treated by avoiding irritants, taking sitz baths,
keeping skin dry, and applying 1 % hydrocorti-
sone cream. Lichen planus is usually self-limiting
and resolves in 8–12 months, but severe symp-
toms may require topical or systemic corticoste-
roid therapy. Lichen sclerosus et atrophicus is
treated with a potent corticosteroid, followed by
a less potent one. First line treatment of lichen
simplex chronicus is topical steroids, but other
options include oral antihistamines, doxepin
creams, capsaicin creams,, and topical tacrolimus.
Treatment of Paget’s disease is usually surgical.
Cryosurgery
Cryosurgery may work by temporarily disrupting
nerve fibers so as to interrupt the “itch-scratch”
cycle. In a study of 18 patients, a single session of
108 Cryosurgery for Pruritus Ani
LN spray was an effective treatment for chronic
pruritus ani [7]. With the patient in the lateral
modified Sims position, the entire lesion was
sprayed with LN for 2 or 3 s. The depth of the
freeze was no more than 1 mm in order to avoid
scarring; following complete thaw, this was
repeated as needed. Patients that experienced an
unpleasant burning sensation were given a topical
anesthetic cream. No aftercare was required.
Drainage lasted for about 5 days. It took 2 weeks
to achieve complete healing in all patients; no
scarring was evident.
Cryosurgery has been used for some second-
ary causes of pruritus ani as well. In a study of
over 21,000 patients with symptomatic hemor-
rhoids at the Rudd Clinic in Toronto, cryosur-
gery followed by plication ligation was found to
be a suitable and cost effective procedure [9].
The combination procedure reduces the dis-
charge, edema, and bleeding associated with
cryosurgery alone and the failure rate of plica-
tion alone. Cryotherapy has been used with a
85.5 % recurrence-free success in treatment of
anal fissures [10].
Success Rates
Only 1 patient out of 18 with idiopathic pruritus
ani had a recurrence 2 months after cryotherapy.
Following the procedure, all patients reported
569
occasionally experiencing a momentary, minor
itch. Only one patient reported that he would not
have the procedure if faced with the same decision
again [7].
Conclusions
Cryosurgery is a therapeutic option for pruri-
tus ani.
References
1. Markell KW, Billingham RP. Pruritus ani: etiology and
management. Surg Clin N Am. 2010;90(1):125–35.
2. Fargo MV, Latimer KM. Evaluation and management
of common anorectal conditions. Am Fam Physician.
2012;85(6):624–30.
3. Vaidya DC, Schwartz RA. Prurigo nodularis: a benign
dermatosis derived from a perpetual itch. Acta
Dermatovenerol Croat. 2008;16:37–43.
4. Klecz RJ, Schwartz RA. Pruritus. Am Fam Physician.
1992;45:2681–6.
5. Urbonas A, Szepietowski J, Schwartz RA. Uremic
pruritus: an update. Am J Nephrol. 2001;21:343–50.
6. Dasan S, Neill SM, Donaldson DR, Scott HJ. Treatment
of persistent pruritus ani in a combined colorectal and
dermatological clinic. Br J Surg. 1999;86:1337–40.
7. Detrano SJ. Cryotherapy for chronic nonspecific pru-
ritus ani. J Dermatol Surg Oncol. 1984;10(6):483–4.
8. Suys E. Randomized study of topical tacrolimus oint-
ment as possible treatment for resistant idiopathic pru-
ritus ani. J Am Acad Dermatol. 2012;66(2):327–8.
9. Rudd W. Ligation and cryosurgery of all hemorrhoids:
an office procedure. Int Surg. 1989;74:148–51.
10. Krasznay P. Ambulatory cryotherapy of anal fissures.
Orv Hetil. 1991;132(32):1761–2.
 Pyogenic Granuloma
109
Renata Strumia

Abstract
Pyogenic Granuloma (PG) is a relatively common benign acquired, prolif-
erative vascular lesion of the skin and mucosa whose exact cause is
unknown. Treatment methods include excision, curettage, sclerotherapy,
chemical and electrical cauterization, radiotherapy, and the use of lasers.
Cryotherapy causes resolution of PG without significant scarring. The
endothelial cells may be more vulnerable to cryotherapy than collagen
fibres. Cryotherapy is a simple, easy to perform, cheap, and safe treatment
that could be one of the first-line therapeutic modalities used in treatment
of PG.

Keywords
Pyogenic granuloma • Cryotherapy

Introduction become pedunculated. The surface frequently

PG is a relatively common benign acquired, pro-
liferative vascular lesion of the skin and mucosa
whose exact cause is unknown.
Description of the Disease
PG usually appears as a solitary red papule. The
lesion grows rapidly for a few weeks and may
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara (Former), Ferrara, Italy
e-mail: restrumi@tin.it
erodes, leading to bleeding. It develops most often
on the head, neck, extremities, and upper trunk. It
is defined histologically by a collarette of epider-
mis enclosing lobules of proliferating capillaries in
an oedematous matrix. Some lobules may extend
into the deep dermis [1]. Spontaneous involution
of lesions is uncommon but has been reported [1].
PG often arises in pregnancy (or rarely with oral
contraceptive usage), particularly on the gingiva or
elsewhere in the oral mucosa, and then is termed
the “pregnancy tumor.” Other PG variants that
have been well documented include the dissemi-
nated, subcutaneous, intravenous, and medication-
induced (for example, retinoid, antiretroviral, and
oncologic agent) subtypes.

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Therapeutic Alternatives
Many different treatments have been used for PG
with variable success rates. Treatment methods
include excision, curettage, sclerotherapy, chem-
ical and electrical cauterization, radiotherapy,
and the use of lasers [2–8]. Treatment failure and
local recurrence of the lesion is a problem with
all treatment methods.
Cryotherapy
Cryotherapy is an easy to perform treatment that
has been used in the treatment of PG and other
vascular lesions without significant side-effects
[9]. Pregnancy-associated PG of the lip has been
successfully treated using cryotherapy [10]. A
case of PG arising in port-wine stain after cryo-
therapy was reported [11] PG following treat-
ment of verruca vulgaris with cryotherapy and
Duoplant has been described [12].
Methodology (How I Do It)
A cotton-tipped applicator is used to apply LN to
the centre of the lesion. A swab is made for each
lesion with a tip size about 70 % of the lesion
diameter. Freezing is continued until a 1- to 2-mm
rim of normal tissue surrounding the lesion was
frozen. I do not apply further cryogen when this
1- to 2-mm zone is reached and use two freeze-
thaw cycles. I do not use any anaesthesia before
procedure. After performing the procedure, the
patient is instructed to return to the clinic if there
is any problem such as uncontrollable bleeding, or
redness or swelling beyond the margin of the
lesion. The patient is followed up every 3 weeks
until the disappearance of the lesion. At each fol-
low-up visit, if there is any major complication,
the treatment is discontinued. If the lesion is still
present, the treatment is repeated. If the lesion is
still present after five treatment sessions, it is con-
sidered a treatment failure.
R. Strumia
Success Rates
In a series of 135 patients, treatment resulted in
complete disappearance of the PG after one to four
sessions of two freeze-thaw cycles each (mean 1.58
treatments) [9]. Ghodsi et al. [13] evaluated and
compared prospectively the results of cryotherapy
and curettage in patients with PG. This study
showed that both cryotherapy and curettage are safe
and effective but cryotherapy may require more
treatments.
Curettage has the advantage of fewer treatment
sessions required to achieve resolution, better cos-
metic results, and the ability to obtain histological
confirmation of the diagnosis. However, the find-
ings must be carefully interpreted because the
results of cryotherapy, curettage and electrosur-
gery are both operator and device dependent.
Conclusions
Cryotherapy causes resolution of PG without
significant scarring. The endothelial cells may
be more vulnerable to cryotherapy than colla-
gen fibres [14]. Cryotherapy is a simple, easy to
perform, cheap, and safe treatment that could be
one of the first-line therapeutic modalities used
in treatment of PG. It is much easier than exci-
sion and curettage and cheaper than laser. If
there is any doubt about the diagnosis, it should
be confirmed by histologic examination.
References
1.Patrice SJ, Wiss K, Mulliken JB. Pyogenic granuloma
(lobular capillary hemangioma): a clinicopathologic
study of 178 cases. Pediatr Dermatol. 1991;8:267–76.
2.Witthaut J, Steffens K, Koob E. Reliable treatment of
pyogenic granuloma of the hand. J Hand Surg (BR).
1994;19:791–3.
3.Gunduz K, Shields CL, Shields JA, Zhao DY. Plaque
radiation therapy for recurrent conjunctival pyogenic
granuloma. Arch Ophthalmol. 1998;116:538–9.
4.Hamilton R, Nicholas G, Royster HP. Recurrent pyo-
genic granuloma – favorable response to radiation
therapy. Plast Reconstr Surg. 1968;41:145–8.
5. Gonzalez S, Vibhagool C, Falo Jr LD, Momtaz KT,
Grevelink J, Gonzalez E. Treatment of pyogenic
109 Pyogenic Granuloma
granulomas with the 585 nm pulsed dye laser. J Am
Acad Dermatol. 1996;35:428–31.
6. Quitkin HM, Rosenwasser MP, Strauch RJ. The efficacy
of silver nitrate cauterization for pyogenic granuloma of
the hand. J Hand Surg (Am). 2003;28:435–8.
7. Raulin C, Greve B, Hammes S. The combined contin-
uouswave/pulsed carbon dioxide laser for treatment of
pyogenic granuloma. Arch Dermatol. 2002;138:33–7.
8. Matsumoto K, Nakanishi H, Seike T, Koizumi Y, Mihara
K, Kubo Y. Treatment of pyogenic granuloma with a
sclerosing agent. Dermatol Surg. 2001;27:521–3.
9. Mirshams M, Daneshpazhooh M, Mirshekari A, Taheri
A, Mansoori P, Hekmat S. Cryotherapy in the treatment
of pyogenic granuloma. JEADV. 2006;20:788–90.
573
10. Cohen PR. Pregnancy-associated pyogenic granu-
loma of the lip: successful management using cryo-
therapy. J Gt Houst Dent Soc. 1996;67:18–9.
11. Aghaei S. Pyogenic granuloma arising in port-wine
stain after cryotherapy. Dermatol Online J. 2003;9:16.
12. Kolbusz RV, O’Donoghue MN. Pyogenic granuloma
following treatment of verruca vulgaris with cryother-
apy and Duoplant. Cutis. 1991;47:204.
13. Ghodsi SZ, Raziei M, Taheri A, Karami M, Mansoori
P, Farnaghi F. Comparison of cryotherapy and curet-
tage for the treatment of pyogenic granuloma: a ran-
domized trial. Br J Dermatol. 2006;154:671–5.
14. Thai KE, Sinclair RD. Cryosurgery of benign skin
lesions. Australas J Dermatol. 1999;40:175–84.
 Rhinophyma
110
Renata Strumia

Abstract
Rhinophyma, an end stage of acne rosacea, is characterized by a slow
progressive enlargement of the nasal skin due to a proliferation of seba-
ceous glands and fibrous tissue. Cryosurgery provides a quick, simple,
inexpensive method of destroying tissue. If used correctly, it does appear
to provide an alternative method of performing decortication that does not
require operating facilities or hospital admission yet produce excellent
cosmetic results without scarring.

Keywords
Rhinophyma • Cryotherapy

Introduction purple discoloration and a nodular appearance.

Rhinophyma is an end stage of acne rosacea that
occurs almost exclusively in men. It is characterized
by a slow progressive enlargement of the nasal skin
due to a proliferation of sebaceous glands and fibrous
tissue. Rhinophyma cannot resolve spontaneously,
Histopathology of rhinophyma includes prominent
sebaceous gland hyperplasia; sebaceous ducts are
dilated and filled with keratin material and sebum.
There may be dermal fibroplasia and an increase in
connective tissue. Rhinophyma is a disfiguring
hypertrophy of the skin of the tip of the nose associ-
ated with much social embarrassment.

Description of the Disease

Clinically, the lower two-thirds of the nose becomes
enlarged and hypervascular, developing a reddish-
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara (Former), Ferrara, Italy
e-mail: restrumi@tin.it
Therapeutic Alternatives
These may be medical or surgical. It can be suc-
cessfully treated with various resurfacing tech-
niques, including erbium or carbon dioxide
lasers, electrosurgery, dermabrasion and cryosur-
gery. Surgery basically consists of the removal of
hyperplastic tissue followed by the repair of any

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DOI 10.1007/978-1-4471-6765-5_110
576
resulting defects. This involves a prolonged,
often two-stage procedure requiring hospital
admission, with the inherent expense. The gen-
eral disadvantage of surgical techniques include:
high level of operator expertise, length of proce-
dure (particularly if a two stage operation is
required), total cost, and risks of general anaes-
thetic if this is necessary.
Superficial decortication [1], the most popular
method at present, entails the destruction of tis-
sue down to a level where part of the piloseba-
ceous apparatus remains intact, supposedly to
serve as a source of epithelium. The simplest
method of achieving this is with a scalpel or even
an unmodified standard injector-blade razor but
profuse bleeding can be a major problem.
Dermabrasion also suffers this disadvantage. A
cutting electric current has the advantage of pro-
ducing immediate haemostasis, which increases
speed and accuracy of the operation, but derm-
abrasion is often then required for fine sculptur-
ing and for removal of burn wounds in preparation
for grafting or re-epithelialization.
Cryosurgery
Benefits of cryosurgery using LN include mini-
mal bleeding, little pain requiring no anesthesia,
and no damage to the nasal cartilage [2, 3]. The
patient sees improvement after each visit, making
him motivated to return for more treatments.
Patients require no anesthesia and experience
basic postoperative pain relief with aspirin or a
nonsedating narcotic. The visit time is between 5
and 10 min, making the follow-ups acceptable to
the patient and simple for the treating physician.
Disadvantages associated with cryosurgery are
pigmentary changes, scarring, and decreased
control for depth and contour of the nose but with
repeated office visits, the depth and contour can
be adjusted with each subsequent visit. Patients
with fair skin types have less risk of pigmentary
R. Strumia
changes associated with this treatment, as there
was none reported with this patient and in prior
publications. Kempiak et al. used cryosurgery in
combination with low dose spironolactone, an
aldosterone agonist with anti-androgen proper-
ties; thus, able to decrease the rate of sebum
excretion and pore size [4].
Methodology (How I Do It)
I perform two to three 15–20 s freeze–thaw
cycles at each session (Fig. 110.1a, b). Each cycle
is performed freezing one side of the nose using
the paintbrush method and freezing the other half
immediately thereafter. The cycles are separated
by 1 min. Each session is repeated every
2–4 weeks. To protect the patient’s eyes from LN
splatter, I have him wear plastic sunglass covers.
The patient feels a moderate level of pain during
and up to 7 days after the procedure. Blisters and
crusts due to freezing are treated with compress
and mild antiseptic dressing.
Success Rates
There have been no reports of recurrence of rhi-
nophyma in patients treated with cryosurgery
(Fig. 110.1c).
Conclusions
Cryosurgery provides a quick, simple, inex-
pensive method of destroying tissue. If used
correctly, it appears to provide a good alterna-
tive to decortication that does not require
operating facilities or hospital admission yet
producing excellent cosmetic results without
scarring. Furthermore, there have been no
reports of recurrence of rhinophyma in
patients treated with cryosurgery. Patients
with fair skin types have less risk of pigmen-
tary changes associated with this treatment.
110 Rhinophyma 577

a b

Fig. 110.1 (a) Rhinophyma; (b) cryotherapy; (c) after one session (1 month)

2. Nolan JO. Cryosurgical treatment of rhinophyma.

References
1. Husein-Elahmed H, Armijo-Lozano R. Management
of severe rhinophyma with sculpting surgical decor-
tication. Aesthetic Plast Surg. 2013;37(3):572–5.
Case report. Plast Reconstr Surg. 1973;52:437–8.
3. Sonnex TS, Dawber RP. Rhinophyma-treatment by
liquid nitrogen spray cryosurgery. Clin Exp Dermatol.
1986;11:284–8.
4. Kempiak SJ, Lee PW, Pelle MT. Rhinophyma treated
with cryosurgery. Dermatol Surg. 2009;35:543–5.
 Rosacea
111
Renata Strumia

Abstract
Rosacea is a chronic inflammatory cutaneous disorder, primarily affecting
the central face. It occurs in both men and women, although at higher
prevalence in the latter. Men with the condition are more likely to develop
phymatous changes. Cryotherapy with LN is effective in erythemato-
telangiectatic rosacea. Massage with LN is the best technique. The cotton-
tipped dipstick or the probe are applied on the lesion with a rotary or spiral
pattern and the paintbrush method until the skin becomes white.

Keywords
Rosacea • Cryotherapy • Cryosurgery

Introduction lated, including, for vascular abnormalities: der-

Rosacea is a chronic inflammatory cutaneous dis-
order, primarily affecting the central face (cheeks,
chin, nose and central forehead). It occurs in both
men and women, although it is more prevalent in
women than in men. Men with the condition are
more likely to develop phymatous changes [1, 2].
Caucasians of Celtic origin appear to be particu-
larly susceptible, whilst it is less common in dark
skinned individuals. At present, a detailed under-
standing of the pathophysiology remains elusive.
Potential pathogenetic roles have been postu-
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara (Former), Ferrara, Italy
e-mail: restrumi@tin.it
mal matrix degeneration, microorganisms such
as Demodex folliculorum and Helicobacter
pylori, and environmental factors. A number of
predisposing factors and stimuli, the so-called
‘trigger’ factors, are recognized which result in
initial manifestations or exacerbations of rosacea
including heat, alcohol, sunlight, stress, menstru-
ation, certain medications or foods [3].
Description of the Disease
The most important finding is persistent ery-
thema of the central portion of the face lasting for
at least 3 months. There is a marked tendency to
spare the periocular skin. Flushing, papules, pus-
tules, and telangiectases on the convex surfaces

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DOI 10.1007/978-1-4471-6765-5_111
580
are supportive characteristic findings, but not
necessary for diagnosis. Secondary features
include burning or stinging, edema, plaques, a
dry appearance, ocular manifestations, peripheral
locations, and phymatous changes. When pres-
ent, the relative abundance of these associated
findings will dictate the subtype of disease the
patient manifests.
Differential Diagnosis
This can be challenging, as symptoms such as
flushing, flaking or sensitive skin and facial
edema are shared with other conditions. Rosacea
may occur in combination with, or needs to be
distinguished from, seborrhoeic dermatitis (SD),
acne vulgaris and perioral dermatitis.
Therapeutic Alternatives
Rosacea is treatable rather than curable; it is
characterized by an unpredictable pattern of
exacerbations and remissions on a background of
highly sensitive skin. Key goals of treatment are
to alleviate symptoms and improve appearance,
delay or prevent development of the more
advanced stages of the condition and to sustain
remission [4].
Topical agents provide the mainstay of treat-
ment for many patients with rosacea. The pri-
mary drugs for the topical treatment of rosacea
are azelaic acid, metronidazole and sodium
sulfacetamide-sulphur. Their efficacy has been
validated by multiple studies. Orally, tetracycline
(tetracycline hydrochloride) and its second-
generation derivatives doxycycline and minocy-
cline have for years been the mainstay in the
systemic treatment. Oral antibiotics were used
assuming that rosacea was caused by microbial
infection. Although this has now been proven not
to be the case, the benefits observed with antibi-
otic treatment have led to its continued use.
R. Strumia
Cryotherapy
Despite that cold may be an etiological factor for
flare-ups, at the beginning of the last century, car-
bonic dioxide snow was considered the treatment
of choice for the rosacea presenting with minor
folliculitis and fine telangiectasias [5, 6].
Cryotherapy causes transient vasodilatation
locally followed by vasoconstriction with oblit-
eration of some of the superficial vessels.
Methodology (How I Do It)
Cryo-massage with LN is the best technique.
The cotton-tipped dipstick or the probe are
applied on the lesion with a rotary or spiral pat-
tern and the paintbrush method until the skin
becomes white. Shortly after this the skin
becomes bright red; his is accompanied by a
mild feeling of burning. By the next day most
signs of the immediate effects of treatment
should be gone but there may be some blistering,
especially after the first treatment when the sen-
sitivity of the skin is not known; there is less
likelihood of blistering after subsequent applica-
tions. The total length of treatment is variable
and must be individualized in terms of time and
pressure. I usually perform four to eight sessions
with intervals of 2–3 weeks. I avoid treating in
the summer.
Success Rates
A progressive improvement in the redness of the
skin is achieved after four to six sessions. More
sessions are requested to achieve the regression
of telangiectasias.
Conclusions
General and local therapy must be used in
rosacea. Cryotherapy is a particularly useful
ancillary method.
111 Rosacea 581

References 3. Kligman AM. A personal critique on the state of knowl-

edge of rosacea. Dermatology. 2004;208:191–7.
4. van Zuuren EJ, Gupta AK, Gover MD, Graber M,
1. Elewski BE, Draelos Z, Dréno B, Jansen T, Layton A,
Hollis S. Systematic review of rosacea treatments.
Picardo M. Rosacea – global diversity and optimized
J Am Acad Dermatol. 2007;56:107–15.
outcome: proposed international consensus from the
5. Marin A. A few remarks about the treatment of rhino-
Rosacea International Expert Group. JEADV. 2011;25:
phymathe. Can Med Assoc J. 1948;58:70–1.
188–200.
6. Cohen EL. Cryotherapy for rosacea. Postgrad Med J.
2. Berg M, Liden S. An epidemiological study of rosa-
1948;24:656–9.
cea. Acta Derm Venereol. 1989;69:419–23.
 Cutaneous Sarcoidosis
112
Ann M. John, Brian W. Lee, and Robert A. Schwartz

Abstract
Sarcoidosis is a chronic, multisystem disorder with potentially debilitating
clinical manifestations. Cutaneous sarcoidosis occasionally causes a vast
distribution of papules and plaques on the extremities. A more specific
form, lupus pernio, involves the head, neck, nasolabial folds, and peri-
ocular regions. Treatment is based on case reports, expert opinion, and
clinical experience. Cryotherapy has been used in cutaneous and other
forms of sarcoidosis; it is most appropriate for nodules less than 3 cm in
diameter. Complications include scarring, alopecia, and dyschromia at the
site of cryotherapy.

Keywords
Cryosurgery • Sarcoidosis • Lupus pernio • Darier-Roussy subcutaneous
nodules • Erythema nodosum

Introduction

Sarcoidosis is a chronic, multisystem disorder

A.M. John, MD
Department of Dermatology, Rutgers New Jersey
Medical School, Newark, NJ, USA
B.W. Lee, MD
Department of Dermatology, Rutgers New Jersey
Medical School, Newark, NJ, USA
R.A. Schwartz, MD, MPH, DSc (Hon), FRCP (Edin) (*)
Dermatology and Pathology, Rutgers University New
Jersey Medical School, Rutgers University School
of Public Affairs and Administration,
185 South Orange Ave., Newark, NJ 07103, USA
e-mail: roschwar@cal.berkeley.edu
that may have an array of clinical manifesta-
tions. With a gradual onset and unpredictable
course, sarcoidosis may involve multiple organs,
including the lungs, liver, spleen, muscles,
eyes, heart, brain, and skin [1, 2]. Since the first
description in 1868 by Sir Jonathan Hudson,
this disorder has been the subject of consider-
able study [3]. Genetic, environmental, and
immunologic factors predispose patients to
developing it. Age of presentation is bimodal,
with a peak of incidence between the third and
fourth decade of life and then at ages 65–69 [4].

© Springer-Verlag London 2016 583

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_112
584
Diagnosis is based on thorough clinical, physi-
cal and radiological examination and is con-
firmed by histolopathology showing the classic
non-necrotizing granuloma. Additional studies
are sometimes performed to exclude infectious
and foreign body processes. Treatment options
are many and differ based on classification into
acute episode, chronic disease, and refractory
disease. One option for treatment of cutaneous
sarcoidosis is cryotherapy.
Description of Disease
As a multisystem disease, sarcoidosis has many
clinical presentations. Fever, fatigue, and weight
loss can occur in one-third of patients [2]. The
lungs are the most commonly involved organ,
causing dyspnea, cough, and wheezing. Chest
radiography and pulmonary function tests should
be regularly performed to assess pulmonary
involvement [5]. Ocular manifestations include
uveitis, conjunctivitis, lacrimal gland enlarge-
ment, and optic neuritis. Treatment is pivotal to
prevent permanent visual loss or impairment [6].
Neurologic involvement causes cranial nerve pal-
sies, meningitis, psychiatric symptoms, seizures,
and hormonal dysfunction. The base of the brain
is most commonly affected [7]. Hepatic involve-
ment may be documented by elevated alkaline
phosphatase and aminotransferases and can
rarely lead to liver failure [8]. Kidney involve-
ment may result in elevated calcium in both the
blood and urine and consequent nephrolithiasis
[9]. Cardiac involvement causes palpitations, car-
diomyopathy, left ventricular dysfunction, and
arrhythmias [10]. Musculoskeletal involvement
presents as arthritis and arthralgias. Hematologic
manifestations include lymphopenia and hyper-
gammaglobulinemia [5].
Cutaneous manifestations are present in
25–30 % of patients with sarcoidosis [2]. Specific
lesions are characterized by non-necrotizing
granulomas, whereas nonspecific lesions are a
result of systemic inflammation [11]. Papules
and plaques may be located on the head, around
the eyes, on the neck, and in the nasolabial folds
[3, 12, 13]. Papular sarcoidosis is associated
A.M. John et al.
with a good prognosis and little scarring upon
resolution of lesions. The maculopapular form
also has a good prognosis, although it is more
commonly associated with acute organ involve-
ment causing lymphadenopathy, arthritis, uve-
itis, and parotid gland enlargement [14]. Lupus
pernio presents with indurated plaques with
telangiectasia, causing a perinasal, mid-facial,
laryngeal, and pharyngeal mucosal involvement.
The lesions may coalesce to form disfiguring
plaques on the nose and cheeks and can lead to
nasal septum perforation [15]. Darier-Roussy
nodules, which represent the subcutaneous form,
are deep lesions located on the trunk and extrem-
ities. When present on the lower extremities,
these are distinguished from erythema nodosum
by the lack of tenderness to palpation. The scar
form of sarcoidosis results from granulomatous
infiltration of surgical scars, tattoos, skin pierc-
ings, and other cutaneous trauma. Less common
forms include the psoriasiform, annular, lichen-
oid, photodistributed, verrucous, ichthyosiform,
lymphedematous, tumoral, atrophic, ulcerative,
hypopigmented, erythrodermic, angiolupoid, sar-
coidal alopecia, polymorphous, mucosal, and nail
forms [14]. Erythema nodosum, a non-specific
reaction pattern, is seen in 17 % of patients and
characterized by erythematous, tender, subcuta-
neous nodules on the shins. Histopathology dem-
onstrates a septal panniculitis [2, 3, 16–19].
The classic histological feature of sarcoidosis
is a non-caseating granuloma, composed of epi-
thelioid cells, a modified macrophage with
Langerhans-type, and multinucleated giant cells
in the center. Sparse lymphocytes are located at
the periphery. Fibrinoid necrosis may be seen [3,
20]. While the granulomatous changes may
resolve, the disease can progress to fibrosis, caus-
ing irreversible tissue damage [14].
Etiology is unclear, with genetic, immuno-
logic, infectious, and environmental factors
playing a role. Genetic involvement is implied
by the increased incidence in siblings and first-
degree relatives [6]. Mutations in the genes
for TNF-alpha, interferon, interleukin, and
HLA subtypes have been implicated [21, 22].
Environmental and infectious factors that can
lead to or be associated with sarcoidosis include
112 Cutaneous Sarcoidosis
Insecticides and pesticides, mildew, mold,
pine pollen, combustible wood, heavy metals
(aluminum, zirconium, talc, beryllium), peanut
dust, hair sprays, mineral oil, clay consump-
tion, phenylbutazone, sulfonamide, methotrex-
ate, Mycobacteria, Propionobacterium acnes,
Borrelia spp., mycoplasma, mumps, influenza,
Nocardia, and mycosis fungoides [2, 3, 23–25].
Alternative Therapeutics
Treatment for cutaneous sarcoidosis is based on
retrospective studies and expert opinion, rather
than clinical trials. Wanat et al. [2] classified the
options into: topical, immune-modulators, immu-
nosuppressive agents, and biologic agents.
Topical steroids commonly used are clobeta-
sol and halobetasol [26, 27]. Intralesional ste-
roids, such as triamcinolone, can also be injected
into lesions [28, 29]. Topical tacrolimus is suited
for cutaneous lesions on the face due to a lower
side-effect profile than steroids [30, 31].
Photodynamic therapy, including pulsed-dye
lasers and carbon dioxide lasers, have been used
with success. Pulsed-dye lasers have been effec-
tive in lupus pernio but cessation of the photody-
namic therapy led to recurrence [32–36].
Ultraviolet A phototherapy is another option for
local disease [37].
Immuno-modulating agents include doxycy-
cline, tetracycline, and minocycline. These anti-
biotics provide an anti-inflammatory effect in
cutaneous sarcoidosis. Minocycline is the first-
line in this class of drugs [38, 39]. Antimalarials,
including chloroquine and hydroxychloroquine,
have also been used as monotherapy or in combi-
nation with other drugs [40, 41]. Phosphodiesterase
type 4 inhibitors, including pentoxifylline and
apremilast, may also be effective [42, 43].
Immunosuppressive agents usually require
close monitoring and have toxic side effects.
Oral corticosteroids, such as prednisone, have a
quick onset of action and can be tapered down
after acute flares have passed. Other therapies are
usually started concomitantly to facilitate taper-
ing. Length of treatment differs base on the type
of lesion; erythema nodosum requires a much
585
shorter length of treatment compared to lupus
pernio. Abrupt withdrawal of corticosteroids can
lead to an acute flare. Therefore, careful taper-
ing is necessary [2, 3, 44–46]. Methotrexate is
another effective drug, although side effects of
gastrointestinal intolerance, hepatic dysfunction,
leukopenia, and oral ulcerations often diminish
compliance. Methotrexate has a delayed action
of onset of up to 3–6 months [47]. Cutaneous
sarcoidosis may be treated effectively with intra-
lesional 5-fluorouracil [48]. Thalidomide has
shown limited success; peripheral neuropathy,
sedation, nausea, and deep venous thrombosis
limit its use [49–51]. Azothioprine and myco-
phenolate may have efficacy in cutaneous sar-
coidosis [52, 53]. Leflunomide is synergistic with
methotrexate for treating cutaneous lesions [3].
IL-17 inhibitors, statins, and nicotine should
be studied more thoroughly before determining
their efficacy in sarcoidosis [2]. Tumor necrosis
factor inhibitors, including infliximab and adali-
mumab, have been effective in lupus pernio and
recalcitrant lesions. However, these drugs can
paradoxically cause sarcoidosis flares and may
reactivate tuberculosis, histoplasmosis, coccid-
iodomycosis, and listeriosis [54, 55]. Radiation
has also been utilized with some efficacy [56].
Cryosurgery-Utility, Methods,
and Success Rates
Cryosurgery in sarcoidosis is usually reserved for
disfiguring and relatively localized lesions. Of
note, treatment of one lesion may result in resolu-
tion of other ones, suggesting that an anti-inflam-
matory response exists against other lesions [57,
58]. Cryotherapy is most effective on plaques of
less than 3 cm in diameter, although it can also be
used as an adjunctive therapy to surgical resec-
tion or debulking for larger ones. Side effects of
cryotherapy include hypopigmentation, blister-
ing, delayed healing, and infection at the site of
the lesion [58–61].
Cryotherapy may be employed for conjuncti-
val nodules secondary to sarcoidosis. In a
55-year old woman, cryotherapy was applied
using the double-freeze method. LN was applied
586
for 1–2 s with thawing of 5–10 s between freezes.
The conjunctiva did not demonstrate any scar-
ring or pigmentation issues and had not experi-
enced recurrent nodules within 6 months [62].
Uveitis associated with ocular sarcoidosis has
also been treated successfully with cryotherapy.
However, retinal detachment is associated with
cryotherapy [63, 64].
Conclusion
In sarcoidosis, cryotherapy is useful for small
nodules without substantial depth and requires
several freeze-thaw cycles. Cryotherapy
should also be explored as an adjunctive ther-
apy for larger lesions. Its use in other forms of
sarcoidosis, primarily ocular, has shown
promising results. If a nodule or plaque of sar-
coid is of an appropriate size and relatively
disfiguring, cryotherapy may be considered.
Studies evaluating concomitant use of
other therapies with cryotherapy for possible
synergistic clinical effect might be beneficial.
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 Seborrheic Keratosis
113
Kimberly Dawn Vincent and William Abramovits

Abstract
Seborrheic keratosis is a benign keratinocytic proliferation of unknown
etiology, acquiring a papillomatous morphology and varying degrees of
pigmentation. Dermatologists easily diagnose them visually. Although
usually asymptomatic and not treated for reasons other than cosmesis,
they may become irritated or infected; in such circumstances removal by a
variety of methods including cryosurgery is medically justifiable.

Keywords
Keratosis • Seborrheic • Papilloma • Condyloma • Melanoacanthoma
• Dermatosis papulosa nigra

K.D. Vincent, MD, FAAD

Belle Meade Dermatology, Nashville, TN, USA
W. Abramovits, MD, FAAD (*) Disease Description
Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA Seborrheic keratosis (SK) is a benign keratino-
Departments of Family Practice and Dermatology, cytic proliferation that may acquire a warty or
The University of Texas Southwestern Medical School, papillomarous morphology as well as a color
Dallas, TX, USA
range from light tan to, dark brown or black. The
Department of Internal Medicine, Texas College of size varies from a few millimeters to several cen-
Osteopathic Medicine, University of North Texas
timeters. Their numbers vary from just one to
Health Science Center, Fort Worth, TX, USA
hundreds, often in relation to increasing age. Per a
Department of Dermatology, University of Texas
Pub-med™ search SK, unlike many resembling
Medical Branch, Dallas, TX, USA
papillomata, are not associated with viral causes.
Texas Tech University, Health Sciences Center,
Several clinical and histopathologic variants are
Lubbock, TX, USA
described, including: common type, reticulated,
Texas A&M Health Science Center College of
flat, stucco, irritated, with squamous atypia, mela-
Medicine, Dallas, TX, USA
noacanthoma, desmoplastic [1], dermatosis papu-
Dermatology Treatment & Research Center,
losa nigra, inverted follicular keratosis, and as a
5310 Harvest Hill Road, Suite #160,
Dallas, TX 75230, USA paraneoplastic entity (the sign of Lesser-Trelat,
e-mail: DrA@dermcenter.us which is of questionable existence [2]). A variety

© Springer-Verlag London 2016 589

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_113
590 K.D. Vincent and W. Abramovits

of chemotherapeutic agents have caused SKs to

react with inflammation [3–5] or to resolve [6].
SKs spare only palms and soles; mostly they are
found on the face, trunk and lower (more than
upper) extremities; they are conspicuously infre-
quent on the buttocks. Oddly they occur fre-
quently on the external ear [7, 8]. Fibroblast
growth factor receptor 3 (FGFR3) gene mutations
may play a role in the pathogenesis of SK [9, 10].

Differential Diagnosis
Fig. 113.2 Open spray
Thin lesions may be difficult to tell apart from
lentigo maligna or superficial basal cell carci-
noma. Intermediate lesions may resemble condy-
lomata. Epidermal nevi and SKs may look alike
but the distribution may help to tell them apart.
Thick lesions may suggest squamous cell carci-
noma, viral warts and, if pigmented, basal cell
carcinoma and melanoma. The dermatoscope can
be of help in differentiating SK from melanoma
[11–13]. In vivo confocal microscopy may be of
value assessing the differential diagnosis of
lesions that resemble SKs [11, 14–16]. When in
doubt, biopsies are de rigueur (Figs. 113.1, 113.2, Fig. 113.3 Frozen halo of 2 mm
113.3, and 113.4).

Histology

SK histology consists of often basaloid, keratino-

cytic proliferations in variable proportions of
hyperkeratosis, papillomatosis and acantosis.

Fig. 113.4 Resolution at 4 months

Horn pseudocysts that connect to the surface may

be seen particularly within areas of acanthosis.
Melanin at the basal layer or throughout the
lesion accounts for varying degrees of pigmenta-
tion. Irritated lesions may show crusting, spon-
giosis, acantholysis, and even moderate atypia,
Fig. 113.1 Common type SK over a lymphocytic infiltrate [17].
113 Seborrheic Keratosis
Therapies
Although most SKs do not need to be treated for
medical reasons, those that become irritated or
infected and those causing cosmetic distress can
be treated by a variety of surgical alternatives
including: light eletrodesiccation, curettage fol-
lowed by electrodessication [18], chemical cau-
terization (with trichloroacetic acid, for example)
[19], carbon dioxide or thulium or alexandrite
and other lasers [20–22], shave removal or exci-
sion [23], and cryosurgery. Less efficient thera-
pies include topical retinoids [24] delivered in
microneedle patches [25], vitamin D3 derivatives
[26, 27], alpha hydroxyl acids such as pyruvate
[28], urea [29], proteases [30], plus a variety of
products belonging in the realm of quackery.
Cryosurgery (How I Do It)
Simplistically, SK should be one of the easiest
lesions for a dermatologist to destroy with cryo-
surgery because they are benign, so leaving a bit
behind is no medical problem. However, doing it
correctly from the start is much more cost-
effective, convenient, and rewarding. Of concern
is that hypochromic changes may occur due to
overzealous freezing; sometimes such an out-
come represents the most normal-looking area
within a damaged field of skin.
Because of the irregular surface of most SKs,
a closed probe is not the best choice, unless there
is concern for splatter to a delicate structure, like
the eye. If a closed probe is required, an interface
should be created between the surface of the SK
and the probe, a gel or ointment may minimize
the loss of thermal efficiency that would occur
with an air interface [31].
For most SKs the best way to perform cryo-
surgery is the spray method, using an open probe
of such pore diameter as to permit the most effi-
cient flow of LN to the entire thickness and diam-
eter of the lesion, creating a halo of 2 mm around
the lesion. This indicates that a temperature low
enough to destroy the entire lesion with minimal
risk to healthy surrounding skin was achieved.
This should not take over 15 s.
591
Local anesthesia is rarely required, except for
thick lesions or critically located SKs. If one or
few lesions are to be treated, intradermal infiltra-
tion with lidocaine or a similar anesthetic should
be appropriate; some prefer to use such anesthe-
tizing molecules in a variety of topical formula-
tions. We leave such selection to the operator (in
agreement with the patient). We frequently freeze
many SKs, very efficiently and effectively in one
session.
Success Rates
In one or two sessions, success rates should
approach 100 %. This compares favorably with
the rates reported for some lasers, which fall
around 60 % [22], or around 30 % for vitamin D3
derivatives applied twice a day for 3 months!
[26]. A recent, well-designed study comparing
cryosurgery to curetting and electrodiseccation
shows a 60 % preference for the former. Low
incidence of hypopigmentation, less pain, and
decreased post-operative wound care were cited
by the patients as supporting their choice [32].
Conclusions
For most patients with SKs, cryosurgery is
quite likely the treatment of choice.
Cryosurgery in combination with modalities
such as topical retinoids, vitamin D3 deriva-
tives and keratolytics, may beneficial. The
most relevant decision in the management of
SKs is the correct diagnosis; as many as 6 %
have been diagnosed erroneously by non-der-
matologists and melanomas have been missed
[28, 33, 34]. The spray method with LN is
practical and simple, but as for so many other
indications, the success of cryosurgery is
operator-dependent.
References
1. King R, Page RN, Googe PB. Desmoplastic seborrheic
keratosis. Am J Dermatopathol. 2003;25(3):210–4.
2. Noiles K, Vender R. Are all seborrheic keratoses
benign? Review of the typical lesion and its variants.
J Cutan Med Surg. 2008;12(5):203–10.
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3. Lilly E, Granter SR, Haynes HA, Ibrahimi
OA. Chemotherapy-induced inflammatory seborrheic
keratosis in a man with acute myeloid leukemia: a
variant of Leser-Trélat sign? Cutis. 2012;90(5):235–6.
4. Patton T, Zirwas M, Nieland-Fisher N, Jukic
D. Inflammation of seborrheic keratosis caused by
cytarabine: a pseudo sign of Leser-Trelat. J Drugs
Dermatol. 2004;3(5):565–6.
5. Chu CY, Yang CH, Chiu HC. Inflammation of sebor-
rheic keratoses due to docetaxel treatment. Acta Derm
Venereol. 2001;81(4):316–7.
6. Seyfer S, Duvic M. Disappearance of seborrheic kera-
toses following treatment with methotrexate. Cutis.
2013;92(1):E2–3.
7. Konishi E, Nakashima Y, Manabe T, Mazaki T, Wada
Y. Irritated seborrheic keratosis of the external ear
canal. Pathol Int. 2003;53(9):622–6.
8. Kobayashi M, Hiruma M, Suga Y, Nishimura K,
Ogawa H. A patient with a seborrheic keratosis which
caused impaired hearing by closure of the external
auditory meatus. Int J Dermatol. 2000;39(7):550–1.
9. Blomberg M, Jeppesen EM, Skovby F, Benfeldt
E. FGFR3 mutations and the skin: report of a patient
with a FGFR3 gene mutation, acanthosis nigricans,
hypochondroplasia and hyperinsulinemia and review
of the literature. Dermatology. 2010;220(4):297–305.
10. Hafner C, Vogt T, Hartmann A. FGFR3 mutations in
benign skin tumors. Cell Cycle. 2006;5(23):2723–8.
11. Aoyagi S, Hata H, Izumi K, Iitani MM, Shimizu
H. Diagnostic pitfalls of using dermoscopic features
to differentiate between malignant melanoma and pig-
mented seborrhoeic keratosis. Acta Derm Venereol.
2010;90(4):440–1.
12. Flaxman BA. The important of clinical judgement in
the evaluation of abnormal pigmented lesions. J Am
Acad Dermatol. 2008;59(4):721.
13. Thomas I, Kihiczak NI, Rothenberg J, Ahmed S,
Schwartz RA. Melanoma within the seborrheic kera-
tosis. Dermatol Surg. 2004;30(4 Pt 1):559–61.
14. Braga JC, Scope A, Klaz I, Mecca P, González S,
Rabinovitz H, Marghoob AA. The significance of the
reflectance confocal microscopy in the assessment of
solitary pink skin lesions. J Am Acad Dermatol.
2009;61(2):230–41.
15. Longo C, Zalaudek I, Moscarella E, Lallas A, Piana S,
Pellacani G, Argenziano G. Clonal seborrheic kerato-
sis: dermoscopic and confocal microscopy character-
ization. J Eur Acad Dermatol Venereol. 2013.
doi:10.1111/jdv.12261 [Epub ahead of print].
16. Ahlgrimm-Siess V, Cao T, Oliviero M, Laimer M,
Hofmann-Wellenhof R, Rabinovitz HS, Scope
A. Seborrheic keratosis: reflectance confocal micros-
copy features and correlation with dermoscopy. J Am
Acad Dermatol. 2013;69(1):120–6.
17. Rapini R. Seborrheic keratosis (SK). Pract Dermatopathol.
2005;234–6.
18. Tay YK, Tan SK. A study comparing the efficacy and
risk of adverse events using two techniques of
K.D. Vincent and W. Abramovits
electrocautery for the treatment of seborrheic kerato-
ses. Dermatol Surg. 2013;39(5):810–3.
19. Chun EY, Lee JB, Lee KH. Focal trichloroacetic acid
peel method for benign pigmented lesions in dark-
skinned patients. Dermatol Surg. 2004;30(4 pt 1):
512–6.
20. Fitzpatrick RD, Goldman MP, Ruiz-Esparza J. Laser
treatment of benign pigmented epidermal lesions
using a 300 nsecond pulse and 510 nm wavelength.
J Dermatol Surg Oncol. 1993;19(4):341–7.
21. Wang HW, Wang JB, Liu YH, Zuo YG, Jin HZ, Jiang
GT, Li HC, Ma DL. Clinical efficacy of Q-switched
Alexandrite laser for pigmentary skin diseases in
4656 patients. Zhongguo Yi Xue Ke Xue Yuan Xue
Bao. 2006;28(2):202–5.
22. Polder KD, Mithani A, Harrison A, Bruce S. Treatment
of macular seborrheic keratoses using a novel 1927-
nm fractional thulium fiber laser. Dermatol Surg.
2012;38(7 pt 1):1025–31.
23. Eads TJ, Hood AF, Chuang TY, Faust HB, Farmer
ER. The diagnostic yield of histologic examination of
seborrheic keratoses. Arch Dermatol. 1997;133(11):
1417–20.
24. Herron MD, Bowen ER, Krueger GG. Seborrheic
keratoses: a study comparing the standard cryosurgery
with topical calcipotriene, topical tazarotene, and
topical imiquimod. Int J Dermatol. 2004;43(4):
300–2.
25. Hiraishi Y, Hirobe S, Iioka H, Quan YS, Kamiyama F,
Asada H, Okada N, Nakagawa S. Development of a
novel therapeutic approach using a retinoic acid-
loaded microneedle patch for seborrheic keratosis
treatment and safety study in humans. J Control
Release. 2013;171(2):93–103.
26. Mitsuhasi Y, Kawaguchi M, Hozumi Y, Kondo
S. Topical vitamin D3 is effective in treating senile
warts possibly by inducing apoptosis. J Dermatol.
2005;32(6):420–3.
27. Mitsuhasi Y. New aspects on vitamin D3 ointment;
treatment of senile warts with topical application of
active forms of vitamin D3. Clin Calcium.
2004;14(10):141–4.
28. Caperton C, Valencia O, Romanelli E, Fulton J.
Pyruvic acid facilitates the removal of actinic kerato-
ses and seborrheic keratoses. Dermatol Surg. 2012;
38(10):1710–5.
29. Burkhart CG, Burkhart CN. Use of keratolytic agent
with occlusion for topical treatment of hyperkeratotic
seborrheic keratoses. Skinmed. 2008;7(1):15–8.
30. Fein H, Maytin EV, Mutasim DF, Bailin PL. Topical
protease therapy as a novel method of epidermal abla-
tion: preliminary report. Dermatol Surg. 2005;31(2):
139–47.
31. Abramovits W, Pruiksma R, Bose S. Ultrasound-
guided thermocouple placement for cryosurgery.
Dermatol Surg. 1996;22(9):771–3.
32. Wood L, Stucki J, Hollenbeak C, Miller J.
Effectiveness of cryosurgery vs curettage in the
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treatment of seborrheic keratoses. JAMA Dermatol. Venereol. 2014. doi:10.2340/00015555-1831

2013;149(1):108–9.
33. Ahnlide I, Nielsen K, Bjellerup M. Diagnosis of
pigmented skin tumours in a dermatological set-
ting: different aspects of the number needed to
excise as a measure of efficiency. Acta Derm
[Epub ahead of print].
34. Defazio J, Zalaudek I, Busam KJ, Cota C, Marghoob
A. Association between melanocytic neoplasms and
seborrheic keratosis: more than a coincidental colli-
sion? Dermatol Pract Concept. 2012;2(2):202a09.
 Acrochordons (Skin Tags)
114
Kimberly Dawn Vincent and William Abramovits

Abstract
One skin tag removal option is cryosurgery. Not all lesions that look like a
skin tag are one; on rare occasions it is appropriate to send a fleshy, soft,
pedunculated lesion for biopsy. Most acrochordons can be snipped, elec-
trodesiccated, or lasered.

Keywords
Acrochordons • Skin tags • Electrocautery • Laser • Snip • Forceps
• Metabolic syndrome

K.D. Vincent, MD, FAAD
Belle Meade Dermatology, Nashville, TN, USA
W. Abramovits, MD, FAAD (*)
Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical School,
Dallas, TX, USA
Department of Internal Medicine, Texas College of
Osteopathic Medicine, University of North Texas
Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College of
Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160, Dallas,
TX 75230, USA
e-mail: DrA@dermcenter.us
Disease Description
Most acrochordons are 2–6 mm papules or nod-
ules, usually pedunculated, soft, pigmented or
not (in comparison to the skin they sit on).
Occasionally they become inflamed causing dis-
comfort; this tends to happen mostly in intertrigi-
nous areas subject to friction, which strangles
their blood supply and leads to partial or com-
plete necrosis. Most are at the collar, groin and
axillary areas, and surroundings.
Skin tags may be seen in association with obe-
sity, dyslipidemia, hypertension, insulin resis-
tance and elevated high sensitivity C-reactive
protein; signs of the metabolic syndrome, which
carries increased risk of atherosclerosis and car-
diovascular disease [1]. They are common, have
a genetic tendency and affect men as frequently
as women, mostly those over the age of 50. When
skin tags are present in an unusual number and

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_114
596
atypical manner, the patient should be investi-
gated for tuberous sclerosis. [2] Acrochordon-
like lesions may be part of the Brit
Birt-Hogg-Dubé/Hornstein Knikenberg syn-
drome [3] the dysplastic nevus syndrome [4],
acromegaly, and be questionably associated with
colonic polyps.
Histology
A flattened epithelium overlies a dermis filled
with loosely arranged collagen fibers and dilated
capillaries and lymphatics. It is possible, although
extremely infrequent, to find mycosis fungoides,
basal cell carcinomas and squamous cell carcino-
mas and human papilloma viral DNA within
acrochordons.
Differential Diagnosis
A dermatoscopic pattern may be helpful in dif-
ferentiating benign skin tags from basal cell car-
cinomas [5]. Neurofibromas, melanocytic nevi
and melanomas, seborrheic keratoses, warts and
the premalignant fibroepithelial tumor of Pinkus
may look like skin tags.
Therapeutic Alternatives
Besides snip removal with an Iris scissor, destruc-
tive methods such as electrocauterization, or CO2
lasering, and even mechanical devices to flatten
and thus restrict blood supply, are available to
remove skin tags.
K.D. Vincent and W. Abramovits
Cryosurgery Technique (How We Do It)
For small skin tags, a snip or a brief touch with
the electrode of an electrocautery is sufficient,
but many patients are exquisitely sensitive to
electric currents and request an alternative; for
them cryosurgery is a welcome option, a pair of
forceps, their tips cooled in LN is a superb way
to destroy a small skin tag; the forceps tip is
dipped into the cryogen and applied to the tag
until a visible freeze is achieved; this action is
repeated until the lesion has been frozen for
over a minute. A specialized forceps with a
bulked tip and a narrow connection to the part
held between the operator fingers has been
designed (see Equipment). For larger tags we
employ the open probe method, flattening the
acrochordon with the pressure of the spray for
about 2 min; intermittent spraying may be
appropriate to keep it frozen while avoiding
damage to the surrounding skin; in fact the
freeze should not go beyond the stalk of a tag.
The patient should be told that the acrochordon
will become inflamed for a few days, then
necrotic, and finally fall off after a few weeks; a
band-aid may reduce discomfort by minimizing
friction (Fig. 114.1a, b).
Success Rates
Near 100 % success should be expected.
Sometimes a small stub remains at the site and
may be re-treated if desired. Rarely a post
inflammatory pigmentary issue will affect the
area for a few weeks, as with other destructive
procedures.
114 Acrochordons (Skin Tags)
Fig. 114.1 (a) Typical Acrochordon (b) Frozen Acrochordon
Conclusion
For lesions that undoubtedly are benign
“garden variety” skin tags, cryosurgery is a
quick, inexpensive and efficient therapy that is
easy to apply safely and successfully.
References
1. Sari R, Akman A, Alpsoy E, Balci MK. The meta-
bolic profile in patients with skin tags. Clin Exp Med.
2010;10(3):193–7.
2. Merritt 2nd JL, Davis DM, Pittelkow MR, Babovic-
Vusksanovic D. Extensive acrochordons and pancre-
atic cell tumors in tuberous sclerosis associated with
597
TSC2 mutations. Am J Med Genet A. 2006;140(15):
1669–72.
3. De La Torre, Ocampo C, Doval IG, Losada A, Cruces
MJ. Acrochordons are not a component of the Britt-
Hogg-Dubé syndrome. Am J Dermatopathol. 1999;
21(4):369–74.
4. Ellis DL, Nanney LB, King Jr LE. Increased epider-
mal growth factor receptors in seborrheic keratosis
acrochordons of patients with the dysplastic nevus
syndrome. J Am Acad Dermatol. 1990;23(6 Pt
1):1070–7.
5. Feito-Rodriguez M, Sendagorta-Cudós E, Moratinos-
Martinez M, Gonzalez-Beato MJ, de Lucas-Laguna
R, Pizarro A. Dermatoscopic characteristics of
acrochordon-like basal cell carcinomas in Gorlin-
Golz syndrome. J Am Acad Dermatol. 2009;60(5):
857–61.
 Steatocystoma Multiplex
115
Renata Strumia

Abstract
Steatocystoma multiplex (SM) is characterized by the appearance of cysts
during the first or second decade of life. These cysts become inflamed and
suppurate. Treatment options are limited; these include prolonged courses
of antibiotics, oral isotretinoin, dermabrasion, surgical excision or drain-
age, LN cryotherapy and lasers, especially nonablative devices. Limited
success has been reported with cryotherapy. Acceptable cosmetic results
were reported in a case where it was used in combination with
isotretinoin.

Keywords
Steatocystoma multiplex • Cryotherapy • Cryosurgery

Introduction such as it originating from sebaceous retention

Steatocystoma multiplex (SM) is a dermatosis
characterized by the appearance of cysts during
the first or second decade of life. In some cases,
the cysts become severely inflamed and suppu-
rate. This rare variant is known as steatocystoma
multiplex suppurativum (SMS). Most cases are
sporadic; however, familial cases with autosomal
dominant inheritance have been described [1].
The etiopathogenesis of SM remains elusive but
there are several hypotheses to explain its cause,
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara (Former), Ferrara, Italy
e-mail: restrumi@tin.it
cysts, or representing a naevoid malformation of
the pilosebaceous duct. Mutations in the keratin
17 (K17) gene (KRT17) have been repeatedly
reported for familial cases of SM [2]. K17 is a
type I keratin expressed in a number of epidermal
appendages, such as the nail bed, hair follicles
and sebaceous glands.
Description of the Disease
SM is characterized by the appearance of multiple
yellow or flesh-colored dermal cysts in adoles-
cence that may cause disfigurement, particularly
due to inflammation, formation of sinus tracts or
scarring as seen in the inflammatory variant.

© Springer-Verlag London 2016 599

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_115
600
Presentation in the form of a solitary lesion is
known as steatocystoma simplex. Classically, the
common sites involved are regions with greater
density of pilosebaceous glands, usually the trunk,
axilla, proximal extremities and chest but lesions
may occur on the scrotum, thighs and back [3].
Acral SM has been described [4] and congenital
linear SM of the nose has been reported [5]. SM is
equally common in males and females. Typical
histologic findings include multiple sebaceous
glands within cyst walls.
Therapeutic Alternatives
Treatment options are limited, with varying
degrees of success; they include prolonged
courses of antibiotics, oral isotretinoin, dermabra-
sion, surgical excision or drainage, LN cryother-
apy and lasers, especially nonablative. The most
effective method is excision, but cosmetic consid-
erations, time, overall cost, and pain must be con-
sidered, because patients tend to have many cysts.
Treatment with isotretinoin has been reported in a
small number of patients with varied results. Most
of the responsive patients had SMS. This thera-
peutic response probably reflects the anti-inflam-
matory effect of retinoids. Some authors reported
that isotretinoin exacerbated or worsened the con-
dition [6]. Others reported that isotretinoin ther-
apy had no effect on non-inflamed lesions. Lasers
have been utilized in the treatment of SM. One
patient experienced substantial clearance of
lesions after two treatments using the diode laser
to target the superficial sebaceous glands and the
fractionated erbium-doped fiber laser to target the
cystic component in the dermis [7].
Cryosurgery
Cryotherapy has been reported showing limited
success. Cryotherapy in combination with oral
isotretinoin for non-inflamed lesions had accept-
able cosmetic results in one report [8].
R. Strumia
Methodology (How I Do It)
LN using the spray technique or the cotton-tipped
dipstick method is applied for 10 s until ice forms
on each lesion. In almost all lesions, a single
treatment is required leaving acceptable
scarring.
Success Rates
In small non-inflamed cysts cryotherapy allows
to obtain good cosmetic results with acceptable
depigmentation and scarring.
Conclusions
Cryotherapy may be used alone but, combina-
tions with other therapies, such as oral isotret-
inoin, may achieve better results.
References
1. Hashimoto K, Fisher BK, Lever EF. Steatocystoma
multiplex case reports and electron microscopic stud-
ies. Hautarzt. 1964;15:299–305.
2. Covello SP, Smith FJ, Sillevis Smitt JH, et al. Keratin
17 mutations cause either steatocystoma multiplex or
pachyonychia congenita type 2. Br J Dermatol.
1998;139:475–80.
3. Naik NS. Steatocystoma multiplex. Dermatol Online
J. 2000;6:10.
4. Rollins T, Levin RM, Heymann WR. Acral steatocys-
toma multiplex. J Am Acad Dermatol. 2000;
43:396–9.
5. Park YM, Cho SH, Kang H. Congenital linear steato-
cystoma multiplex of the nose. Pediatr Dermatol.
2000;17:136–8.
6. Rosen BL, Brodkin RH. Isotretinoin in the treatment
of steatocystoma multiplex: a possible adverse reac-
tion. Cutis. 1986;37:115–20.
7. Moody MN, Landau JM, Goldberg LH, Friedman PM.
1,450-nm diode laser in combination with the 1550-
nm fractionated erbium-doped fiber laser for the treat-
ment of steatocystoma multiplex: a case report.
Dermatol Surg. 2012;38:1104–6.
8. Apaydin R, Bilen N, Bayramgürler D, Başdaş F,
Harova G, Dökmeci S. Steatocystoma multiplex sup-
purativum: oral isotretinoin treatment combined with
cryotherapy. Australas J Dermatol. 2000;41:98–100.
 Syringoma
116
Renata Strumia

Abstract
Syringoma (SG) is a benign eccrine sweat gland tumor, usually presenting
as multiple skin colored papules on face, neck, and trunk with a female
predominance. Patients with vulvar SG may complain of severe itching.
Multiple and widespread facial lesions can cause cosmetic problems for
the affected individuals. The traditional methods of treating SG are repre-
sented by cryotherapy, electrodesiccation, surgical excision or CO2 laser
treatment. Cryotherapy should be considered in the treatment of SG, expe-
cially in multiple lesions of the vulva to control pruritus.

Keywords
Syringoma • Cryoteraphy • Cryosurgery

Introduction family member [4]. It is likely autosomal domi-

Syringoma (SG) is a benign eccrine sweat gland
tumor, usually presenting as multiple skin col-
ored papules on face, neck, and trunk with a
female predominance [1]. A rare variant is vulvar
SG without extragenital involvement [2]. SG of
the penis is rare and usually presents as multiple
lesions on the dorsal and lateral aspects of the
shaft [3]. SG, particularly in some individuals
with eruptive onset, may occur in more than one
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara (Former), Ferrara, Italy
e-mail: restrumi@tin.it
nantly inherited.
Description of the Disease
Clinically, SGs appear as small yellowish or skin-
colored papules often located on the periorbital
area. The pathogenesis of eruptive SG is contro-
versial; it has been suggested that it represents a
reactive eccrine gland ductal proliferation fol-
lowing a cutaneous inflammatory condition.
Histologically, SGs are symmetrical, well cir-
cumscribed, confined to the upper dermis, and
usually have no connection with the overlying
epidermis. The tumours consist of proliferation of
epithelial cells, and are arranged in nests, cords or

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_116
602
tubules, in which some display a “comma” or
“tadpole” shape. The tubules are lined by single or
double layers of bland, monomorphous, cuboidal
epithelial cells with small normochromic nuclei,
and small to moderate amount of pale eosino-
philic cytoplasm. In some tumours, the neoplastic
cells predominantly exhibit abundant clear cyto-
plasm (clear cell SG). A PAS positive eosinophilic
material is often present within the tubular lumina.
SG should be distinguished from the extremely
rare malignant counterparts, syringoid eccrine
carcinoma and microcystic adnexal carcinoma.
Patients with vulvar SG may complain of
severe itching [5, 6]. Vulvar SG should be in the
differential diagnosis of pruritus vulva and vulvar
papular lesions, such as Fox-Fordyce disease,
epidermal cysts, milias, senile angiomas, condy-
loma acuminata, steatocystoma multiplex, vulvar
idiopathic calcinosis, lymphangioma circum-
scriptum, and lichen simplex chronicus.
The eruptive and clear cell variants of SG
were mostly reported to be associated with diabe-
tes mellitus but the presentation of nonclear cell
variant of localized SG on the vulvar region asso-
ciated with diabetes mellitus has been reported.
The endocrinological abnormalities underlying
diabetes mellitus may predispose the develop-
ment of vulvar SG and probably contribute to
more itching and changing in morphology
[7–11].
Therapeutic Alternatives
Although SG represents a benign tumor of skin
appendage, multiple and diffuse facial lesions
can cause cosmetic problems for the affected
individuals. Traditional methods of treating SG
include cryotherapy, electrodesiccation, surgical
excision, and CO2 laser. However, these methods
pose problems such as postinflammatory hyper-
pigmentation and scar formation occasionally
occur. Like cryotherapy, electrodesiccation also
has a disadvantage due to the high possibility of
hyperpigmentation and scar formation, since it is
invasive to the surrounding tissues. Surgical exci-
sion is also an easy method to remove lesions
R. Strumia
with a high certainty of results, but it is not so
well suited for cases where the population of pap-
ules is large or a large papule has formed; his is
due to the fact that the scar after surgery may
stand out more than the papule before surgery.
The CO2 laser has been used for the treatment of
SG because of minimal thermal damage to the
surrounding tissue, but there is also a problem
that hyperpigmentation and scar formation occa-
sionally occur, such as with cryotherapy and
electrodesiccation. Combination of CO2 laser and
trichloroacetic acid has been reported in the treat-
ment of SG [12]. Fractional photothermolysis,
more recently introduced for the treatment of SG,
seems to achieve good results [13].
Treatment of vulvar syringomas with pruritus
is challenging. Antihistamines and topical ste-
roids may be ineffective in some cases.
Electrodessication, excision, laser, or cryother-
apy may provide favorable cosmetic results and
regression of pruritus.
Cryosurgery
It is the easiest method among all those reported
in the treatment of SG but often requires several
treatments on the same area increasing the risk of
hyperpigmentation expecially in dark skin.
Methodology (How I Do It)
Cryosurgery should be used only in fair skin. LN
should be applied for 2–3 s to each lesion; a
pointed closed probe may be particularly suited
when working on the eye area. Repeat sessions
can be done at 1–2 months. In multiple lesions of
the vulva cryotherapy allows a good control of
pruritus.
Success Rates
Scarring, recurrence and postinflammatory hyper-
pigmentation can be serious troubles, especially
for oriental people receiving various sessions of
116 Syringoma
cryotherapy. In fair skin, one session of cryother-
apy allows to make the lesions less visible.
Conclusions
Cryotherapy should be considered in the treat-
ment of SG, expecially in multiple lesions of
the vulva to control pruritus.
References
1. Jamalipour M, Heidarpour M, Rajabi P. Generalized
eruptive syringomas. Indian J Dermatol. 2009;54:65–7.
2. Dereli T, Turk BG, Kazandi AC. Syringomas of the
vulva. Int J Gynecol Obstet. 2007;99:65–6.
3. Cohen PR, Tschen JA, Rapini RP. Penile syringoma:
reports and review of patients with syringoma located
on the penis. J Clin Aesthet Dermatol. 2013;6:
38–42.
4. Lau J, Haber RM. Familial eruptive syringomas: case
report and review of the literature. J Cutan Med Surg.
2013;17:84–8.
5. Young Jr AW, Herman EW, Tovell HMM. Syringoma
of the vulva: incidence, diagnosis, and cause of pruri-
tus. Obstet Gynecol. 1980;55:515–8.
603
6. Kavala M, Can B, Zindanci I, et al. Vulvar pruritus
caused by syringoma of the vulva. Int J Dermatol.
2008;47:831–2.
7. Wallace ML, Smoller BR. Progesterone receptor posi-
tivity supports hormonal control of syringomas.
J Cutan Pathol. 1995;22:442–5.
8. Yorganci A, Kale A, Dunder I, Ensari A, Sertcelik
A. Vulvar syringoma showing progesterone receptor
positivity. Br J Obstet Gynaecol. 2000;107:292–4.
9. Huang Y, Chuang Y, Kuo T, Yang L, Hong H. Vulvar
syringoma: a clinicopathologic and immunohisto-
logic study of 18 patients and results of treatment.
J Am Acad Dermatol. 2003;48:735–9.
10. Timpanidis PC, Lakhani SR, Groves RW. Progesterone
receptor-positive eruptive syringoma associated with
diabetes. J Am Acad Dermatol. 2003;48:S103–4.
11. Akoglu G, Ibiloglu I, Durmazlar N. Vulvar nonclear
cell syringoma associated with pruritus and diabetes
mellitus. Case Rep Dermatol Med. 2013;418794.
doi:10.1155/2013/418794. Epub 2013 Aug 28.
12. Akita H, Takasu E, Washimi Y, Sugaya N, Nakazawa
Y, Matsunaga K. A new treatment for syringoma.
Combination of carbon dioxide laser and trichloro-
acetic acid. Dermatol Surg. 1998;24:1370–4.
13. Akita H, Takasu E, Washimi Y, Sugaya N, Nakazawa
Y, Matsunaga K. Syringoma of the face treated with
fractional photothermolysis. J Cosmet Laser Ther.
2009;11:216–9.
 Sebaceous Gland Hyperplasia
117
Rivka C. Stone and Robert A. Schwartz

Abstract
Sebaceous gland hyperplasia refers to hypertrophic enlargement of the
sebaceous glands. Though benign, its predilection for cosmetically sensi-
tive areas such as the face make efficacious treatment options desirable.
While multiple therapeutic modalities are available, sebaceous hyperpla-
sia can be treated quickly and successfully with cryosurgery.

Keywords
Sebaceous gland hyperplasia • Cryoprobe technique • Cosmesis

Introduction Description of the Disease

Sebaceous gland hyperplasia (SH), a benign
enlargement of sebaceous glands, commonly of
the face, that can be a cause for cosmetic concern.
Successful therapeutic modalities include cryo-
surgery, excision, electrodessication, chemical or
mechanical dermabrasion, laser treatment, and
topical and/or oral retinoids. Treatment may be
complicated by scarring and dyspigmentation.
R.C. Stone, MD, PhD
Department of Dermatology, Rutgers-New Jersey
Medical School, Newark, NJ, USA
R.A. Schwartz, MD, MPH, DSc (Hon), FRCP (Edin) (*)
Dermatology, Pathology, Medicine and Pediatrics,
Rutgers University New Jersey Medical School,
Rutgers University School of Public Affairs and
Administration,
185 South Orange Ave, Newark, NJ 07103, USA
e-mail: roschwar@cal.berkeley.edu
SH refers to localized hypertrophy of the seba-
ceous glands. It manifests clinically as a 2–6 mm
soft smooth tan or yellow-hued papule, often with
a central umbilication. It is most commonly
located in facial areas (including nose, forehead,
and cheeks), but also may appear in other areas
with high concentration of sebaceous glands such
as the chest and anogenital skin [1]. Lesions may
be single or grouped, and may display an annular
or linear configuration. They may require distinc-
tion from a basal cell carcinoma and sebaceous
neoplasms of the Muir-Torre syndrome [2]. On
dermoscopy, white-yellow aggregations, often
with a peripheral rim of non-arborizing blood ves-
sels, are seen [3]. Prevalence of sebaceous hyper-
plasia increases with age [1]. Transplant recipients,
particularly those undergoing immunosuppressive
treatment with cyclosporine, may develop more

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_117
606
clinically severe cases [4–6]. Treatment is gener-
ally employed for cosmetic purposes, as sebaceous
hyperplasia has no known potential for malignant
transformation [1].
Therapeutic Alternatives
SH may be treated by low-voltage intralesional
electrodessication, such as by needle-based
hyfrecation [7]. Excision is effective, but is not
as commonly employed due to cosmetic con-
cerns. Chemical abrasion with trichloroacetic
or bichloracetic acid is also an efficacious
option [8]. Successful treatment of sebaceous
hyperplasia with photodynamic therapy utiliz-
ing photosensitizing 5-aminolevulinic acid has
been reported as well [9]. Another option is
topical tretinoin cream applied to affected
areas, but a treatment course of many months
may be required to achieve lesion resolution.
Low-dose systemic isotretinoin is effective as
well [10–12], but is typically reserved for
severe cases due to its adverse effects profile.
Finally, several laser treatments have demon-
strated efficacy in treating sebaceous hyperpla-
sia, including pulsed-dye, carbon dioxide, and
argon laser therapies [13–15].
Cryosurgery
Cryosurgery treatment of sebaceous hyperplasia
is quick, efficacious, and requires minimal fol-
low-up care [16]. A probe-based technique is typi-
cally employed to target individual lesions [17].
While no standardized protocol exists, one rec-
ommended regimen is cryoprobe treatment of
each individual lesion for a 10-s freeze time, per-
formed monthly for three consecutive months
[16]. A sharply pointed conical probe a 1 mm
diameter, flat tipped closed probe are marketed;
these are also called molluscum probes after one
of its other uses. A cotton tipped bud may also be
used [17]. Darker-skinned patients are at increased
risk for cryotherapy-induced pigmentary altera-
R.C. Stone and R.A. Schwartz
tions and may prefer alternative treatment
modalities.
Conclusions
Though benign, SH should be distinguished
from sebaceous neoplasms of the Muir-Torre
syndrome [18]. SH can cause considerable
cosmetic concern. can be a cause for great
cosmetic concern. Safe treatment with cryo-
surgery can be employed to achieve satisfac-
tory lesion resolution.
References
1. Eisen DB, Michael DJ. Sebaceous lesions and their
associated syndromes: part I. J Am Acad Dermatol.
2009;61(4):549–60; quiz 561–2.
2. Schwartz RA, Torre DP. The Muir-Torre syndrome: a
25-year retrospect. J Am Acad Dermatol.
1995;33(1):90–104.
3. Kim NH, Zell DS, Kolm I, Oliviero M, Rabinovitz
HS. The dermoscopic differential diagnosis of yellow
lobularlike structures. Arch Dermatol. 2008;144(7):962.
4. Boschnakow A, May T, Assaf C, Tebbe B, Zouboulis
CC. Ciclosporin A-induced sebaceous gland hyper-
plasia. Br J Dermatol. 2003;149(1):198–200.
5. de Berker DA, Taylor AE, Quinn AG, Simpson
NB. Sebaceous hyperplasia in organ transplant recipi-
ents: shared aspects of hyperplastic and dysplastic
processes? J Am Acad Dermatol. 1996;35(5 Pt
1):696–9.
6. Salim A, Reece SM, Smith AG, et al. Sebaceous hyper-
plasia and skin cancer in patients undergoing renal
transplant. J Am Acad Dermatol. 2006;55(5):878–81.
7. Bader RS, Scarborough DA. Surgical pearl: intrale-
sional electrodesiccation of sebaceous hyperplasia.
J Am Acad Dermatol. 2000;42(1 Pt 1):127–8.
8. Rosian R, Goslen JB, Brodell RT. The treatment of
benign sebaceous hyperplasia with the topical appli-
cation of bichloracetic acid. J Dermatol Surg Oncol.
1991;17(11):876–9.
9. Richey DF. Aminolevulinic acid photodynamic ther-
apy for sebaceous gland hyperplasia. Dermatol Clin.
2007;25(1):59–65.
10. Wang W, Qiu Y, Zhou G, Pei Z, Zhang F. Premature
sebaceous hyperplasia with satisfactory response to
oral isotretinoin. Indian J Dermatol Venereol Leprol.
2016;82(1):113.
11. McDonald SK, Goh MS, Chong AH. Successful treat-
ment of cyclosporine-induced sebaceous hyperplasia
with oral isotretinoin in two renal transplant recipi-
ents. Australas J Dermatol. 2011;52(3):227–30.
117 Sebaceous Gland Hyperplasia
12. Noh S, Shin JU, Jung JY, Lee JH. A case of sebaceous
hyperplasia maintained on low-dose isotretinoin after
carbon dioxide laser treatment. Int J Dermatol.
2014;53(2):e151–3.
13. Aghassi D, Gonzalez E, Anderson RR, Rajadhyaksha
M, Gonzalez S. Elucidating the pulsed-dye laser treat-
ment of sebaceous hyperplasia in vivo with real-time
confocal scanning laser microscopy. J Am Acad
Dermatol. 2000;43(1 Pt 1):49–53.
14. No D, McClaren M, Chotzen V, Kilmer SL. Sebaceous
hyperplasia treated with a 1450-nm diode laser.
Dermatol Surg. 2004;30(3):382–4.
607
15. Wat H, Wu DC, Rao J, Goldman MP. Application of
intense pulsed light in the treatment of dermatologic
disease: a systematic review. Dermatol Surg.
2014;40(4):359–77.
16. Andrews MD. Cryosurgery for common skin condi-
tions. Am Fam Physician. 2004;69(10):2365–72.
17. Wheeland RG, Wiley MD. Q-tip cryosurgery for the
treatment of senile sebaceous hyperplasia. J Dermatol
Surg Oncol. 1987;13(7):729–30.
18. John A, Schwartz RA: Muir-Torre syndrome: an
update and approach to diagnosis and management. J
Am Acad Dermatol (in press).
 Cryosurgery for Tattoo Removal
118
Christina M. Ring and Philip J. Cohen

Abstract
Tattoos are an ancient form of body adornment that has persisted to mod-
ern times. Approximately 20 % of Americans have at least one tattoo, and
many seek to remove tattoos later in life. Surgical, chemical, and thermal
modalities are commonly used to remove tattoos. Laser treatments have
emerged as a more efficacious approach, while cryosurgery stands as a
marginal treatment option.

Keywords
Tattoo • Tattoo pigment • Tattoo removal • Cryosurgery • Efficacy

Introduction reported to have later regretted acquiring their

Tattoos are one of mankind’s most ancient art
forms, dating to at least the Stone Age (12,000
BCE). Tattoo removal is also ancient, evident in
Egyptian mummies from 4,000 BCE [1]. In 543
CE, the Greek physician Aetius described sal-
abrasion for tattoo removal [2, 3]. In the United
States, approximately one in five adults possess
at least one tattoo [4]. Of these, 17 % were
tattoo, with most choosing to remove their tattoo
[5]. Other reasons for tattoo removal include
allergic reactions to the dyes, seeking to replace
an old tattoo with a new one, and concealing old
tattoos on occasion of seeking new employment
[2, 6].
Histology, Morphology
and Physiology of Tattoos

Tattooing involves the placement of a dye into the

C.M. Ring, BS (*)
Department of Dermatology and Pathology, Rutgers
New Jersey Medical School, Newark, NJ, USA
e-mail: ring.christina@gmail.com
P.J. Cohen, MD
Department of Dermatology, VA New Jersey Health
Care System, Rutgers New Jersey Medical School,
Newark/East Orange, NJ, USA
dermis using a small needle [2]. The injected pig-
ment elicits a foreign body reaction that recruits
phagocytic cells, which engulf the pigment [3].
Ink taken up by keratinocytes is eliminated within
the first month through normal sloughing of the
epidermis. Within 3 months, dermal ink particles

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_118
610
phagocytosed by macrophages are found beneath
a layer of fibrosis that remains as evidence of the
earlier granulation tissue [7]. Over time, tattoos
may acquire a faded, blurred quality, reflecting
migration of ink-containing phagocytes, which
may eventually find their way to regional lymph
nodes [7]. Tattoos can also be remarkable dura-
ble, perpetuated through the ongoing engulfment
of aging ink-laden phagocytes by still newer
phagocytes.
Cryosurgery: Utility, Methods
and Success Rates
A variety of factors make tattoo removal chal-
lenging. “Homemade” tattoos are often applied
unevenly. Certain pigments, especially dark blue
and black, are especially difficult to eradicate [6].
Tattoo removal may employ mechanical, thermal
or chemical techniques [2]. Mechanical methods
include salabrasion, dermabrasion and surgical
excision [8]. Thermal methods include lasers,
with the Q-switched laser recognized as the gold
standard for tattoo removal [2]. Chemical meth-
ods include tannic acid and silver nitrate, although
this approach is marred by unpredictable results,
prolonged healing time, pain, scarring, skin dis-
coloration, and ink retention [9].
Cryotherapy may be viewed as mechanical,
thermal, and chemical, all at the same time.
Application of liquid nitrogen to the tattoo causes
immediate freezing. Cell membrane damage and
cell necrosis occur during the thawing process,
the duration of which determines the extent of
destruction. A rapid thaw results in less destruc-
tion and scarring. Side effects include pain, blis-
tering and permanent scarring [9–12].
Two small studies (N = 15, N = 4) attempted to
assess the efficacy of cryotherapy in tattoo
removal. In a study on “homemade” tattoos in 15
patients, a single 30-s freeze-thaw cycle yielded
unsatisfactory results for 4 patients, while two
30-s freeze-thaw cycles, given at 3 minute inter-
vals, was efficacious for 9 patients (60 %) but
yielded unsatisfactory results for 6 patients [13].
Five of these 6 patients were retreated 2 months
later, with 2 showing satisfactory results. Overall,
C.M. Ring and P.J. Cohen
11 of 15 patients (nearly 75 %) had a satisfactory
outcome after a varied number of treatments. A
study of four patients demonstrated good results
in three cases [14]. Overall, there is a paucity of
research on the efficacy of cryosurgery for tattoo
removal.
Conclusion
Cryosurgery for tattoo removal yields incon-
sistent results, with side effects including
hypopigmentation, scarring and prolonged
healing [9]. While this modality has largely
been superseded by laser therapy, it represents
an inexpensive, widely available alternative
that may be effective in some patients [10].
References
1. Adatto MA, Halachmi S, Lapidoth M. Tattoo removal.
Curr Probl Dermatol. 2011;42:97–110.
2. Burris K, Kim K. Tattoo removal. Clin Dermatol.
2007;25(4):388–92.
3. Aguirre C. Tattoos and skin health. 2015. http://www.
dermalinstitute.com/us/library/78_article_Tattoos_
and_Skin_Health.html.
4. Braverman S. One in five U.S. adults now has a tattoo.
Harris Polls. 2012.
5. Tattoo Statistics – Statistic Brain. 2015. http://www.
statisticbrain.com/tattoo-statistics/.
6. Unwanted tattoos. 2015. https://www.asds.net/
TattooRemovalInformation.aspx.
7. Kilmer S, Fitzpatrick R, Goldman M. Tattoo lasers. 2013.
http://emedicine.medscape.com/article/1121212-
overview.
8. Goldstein N, Penoff J, Price N, et al. VIII. Techniques
of removal of tattoos. J Dermatol Surg Oncol.
1979;5(11):901–10.
9. Kirby W, Chen CL, Desai A, Desai T. Causes and rec-
ommendations for unanticipated ink retention follow-
ing tattoo removal treatment. J Clin Aesthet Dermatol.
2013;6(7):27–31.
10. Thai KE, Sinclair RD. Cryosurgery of benign skin
lesions. Australas J Dermatol. 1999;40(4):175–84.
quiz 185–176.
11. Kuflik EG. Cryosurgery updated. J Am Acad
Dermatol. 1994;31(6):925–44.
12. Guan H, Zhao Z, He F, et al. The effects of different
thawing temperatures on morphology and collagen
metabolism of -20 degrees C dealt normal human
fibroblast. Cryobiology. 2007;55(1):52–9.
13. Colver GB, Dawber RP. Tattoo removal using a liquid
nitrogen cryospray. Clin Exp Dermatol. 1984;9(4):364–6.
14. Dvir E, Hirshowitz B. Tattoo removal by cryosurgery.
Plast Reconstr Surg. 1980;66(3):373–9.
 Tick Removal with Liquid Nitrogen
119
Mira Pavlovic

Abstract
The use of LN to freeze and remove the tick attached to the skin has been
recently reported. The dose of LN to be delivered depends on the tick size.
Cotton-tipped dipstick or LN spray equipment may be used. An applica-
tion for around 15–20 s is sufficient to freeze a tick, rapid contraction of
its body and a complete and immediate detachment of the parasite from
the skin. This is an effective, painless, non-invasive, safe, “one shot” sim-
ple method of tick removal, especially convenient in case of multiple tick
bites in endemic areas.

Keywords
Tick removal techniques

Introduction most specific clinical manifestation and a defin-

Ticks are important vectors of different disease
pathogens such as spirochetes, rickettsiae and
viruses [1]. The most widespread human tick
borne disease is Lyme disease, caused by a spiro-
chete Borrelia burgdorferi and transmitted by
Ixodes ricinus in Europe and neighboring parts of
North Africa, and Ixodes Scapularis and Ixodes
Pacificus on the west coast of North America.
Erythema chronicum migrans, developing around
tick bite, is the first, the most common and the
M. Pavlovic, MD
Department of Dermatology, Hospital Tenon,
4, rue de la Chine, Paris 75020, France
e-mail: dr.pavlovic-ganascia@dermatologie.pro
ing criterion for Lyme disease [2].
Different methods have been employed to pre-
vent tick bite; these include education, applying
repellants on the skin or wearing protective or
permethrin-impregnated clothing [1]. As no
method is fully effective, tick bites occur fre-
quently, especially in endemic areas.
The risk of transmission of Borrelia or other
tick borne diseases significantly increases after
24 h of tick attachment (the time needed for
Borrelia to migrate from the tick’s gut to the sali-
vary glands and subsequently to human blood)
[3], even if shorter time for transmission has been
reported in laboratory conditions [4]. Therefore,
it is usually recommended that a tick be immedi-
ately and completely removed as soon as possible

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_119
612 M. Pavlovic

and ideally within 24 h. The removal should

include the whole tick with the mouth-part and
the cement the tick has secreted to secure its
attachment to the skin. Ideally, the tick removal
procedure should not allow for infective body flu-
ids to escape through the tick head into the wound
site; touching the tick during the removal attempt
is believed to irritate the tick and cause it to force
more liquid into the wound [5].
Many physical methods of tick removal have
been reported [6, 7]; those aiming at suffocating
the tick, such as applications of gasoline, petro-
leum jelly or alcohol have revealed to be useless Fig. 119.1 Tick attached to the skin
as ticks have a low respiratory rate [8]. A spe-
cially designed tick removal tools appear to
remove the attached tick with more success; sur-
gical removal with fine curved forceps to avoid
squeezing the body of the tick seems to be the
preferred one [9]. However, there is limited evi-
dence that any of these methods allow for com-
plete and timely tick removal [2]. Trials with
antimicrobial agents administered to decrease B.
burgdorferi transmission after tick bite gave con-
flicting results [10–13] and antibiotic prophylaxis
is generally not recommended [14].
Cryotherapy has been used to treat different
skin lesions for approximately one century [15].
Surprisingly, the use of liquid nitrogen to freeze Fig. 119.2 Freezing the tick with liquid nitrogen
and remove the tick attached to the skin has been
reported only recently [16], even if oral sources
report the use of this technique in European
countries where ticks are hyper endemic.
The dose of LN to deliver depends on the tick
size. Whatever the tool used to apply liquid nitrogen
(cotton-tipped dipstick or liquid nitrogen spray
equipment), an application for around 15–20 s is
sufficient to cause a complete freezing of a tick,
rapid contraction of its body and a complete and
immediate detachment of the parasite from the skin
(Figs. 119.1, 119.2, 119.3, and 119.4).
We highly encourage this technique, as
according to our experience, it is an effective,
Fig. 119.3 Frozen tick
“one shot” simple method of tick removal, espe-
cially convenient in case of multiple tick bites in In some countries there are different cryother-
endemic areas. The method is very simple, abso- apy home kits available over the counter that
lutely effective, painless, non-invasive, safe and patients may use to treat warts. Even if one might
rapid and very easy to apply at least in settings be tempted to try such a device to remove a tick,
equipped with liquid nitrogen. there is currently no information if it is effective
119 Tick Removal with Liquid Nitrogen
Fig. 119.4 Tick completely detached including mouth
part
and without danger; insufficient efficacy and skin
burns have been reported by patients who
attempted to remove their own warts. In addition,
patients who experienced a tick bite have to be
adequately examined, treated and followed up in
case of signs and symptoms of erythema chroni-
cum migrans or another tick borne disease.
Therefore, we recommend that tick removal by
LN be performed by a physician or an experi-
enced nurse whenever possible and not by
patients themselves.
References
1. Due C, Fox W, Pietzch M, Logan JG. Tick bite pre-
vention and tick removal. BMJ. 2013;347:f7123.
2. Roupakias S, Mitsakou P, Nimer AA. Tick removal.
J Prev Med Hyg. 2011;52(1):40–4.
613
3. Radolf JD, Caimano MJ, Stevenson B, Hu LT. Of
ticks, mice and men: understanding the dual-host life-
style of Lyme disease spirochaetes. Nat Rev Micro.
2012;10:87–99.
4. Crippa M, Rais O, Gern L. Investigations on the mode
and dynamics of transmission and infectivity of
Borrelia burgdorferi Sensu Stricto and Borrelia afzelli
in Ixodes ricinus ticks. Vector Borne Zoonotic Dis.
2002;2:3–9.
5. McGrath M, Buchan-Hepburn G. Tick bite – a case
study. Aust Fam Physician. 2012;41(3):125–6.
6. Fingerle V, Wilske B. Ticks, tick bites and how best
to remove the tick. MMW Fortschr Med. 2006;
148(25):30–2.
7. Gammons M, Salam G. Tick removal. Am Fam
Physician. 2002;66(4):643–5.
8. De Boer R, Van den Bogaard AE. Removal of attached
nymphs and adults of Ixodes ricinus (Acari: Ixodidae).
J Med Entomol. 1993;30:748–52.
9. Roupakias S, Mitsakou P, Al Nimer A. Surgical tick
removal. Wilderness Environ Med. 2012;23(1):97–9.
10. Costello CM, Steere AC, Pinkerton RE, Feder HM. A
prospective study of tick bites in an endemic area for
Lyme disease. J Infect Dis. 1989;159:136–9.
11. Agre F, Schwartz R. The value of early treatment of
deer tick bites for the prevention of Lyme disease. Am
J Dis Child. 1993;147:945–7.
12. Shapiro ED, Gerber MA, Holabird ND, et al. A con-
trolled trial of antimicrobial prophylaxis for Lyme
disease after deer-tick bites. N Engl J Med.
1992;327:1769–73.
13. Nadelman RB, Nowakowski J, Fish D, et al.
Prophylaxis with single-dose docycycline for the pre-
vention of Lyme disease after an Ixodes Scapularis
tick bite. N Engl J Med. 2001;345:79–84.
14. Aberer E. What should one do in case of a tick bite?
Curr Probl Dermatol. 2009;37:155–66.
15. Andrews MD. Cryosurgery for common skin condi-
tions. Am Fam Physician. 2004;69(10):2365–72.
16. Pavlovic M, Alakeel A, Frances C. Tick removal with
liquid nitrogen. JAMA Dermatol. 2013;149(5):633.
 The Tuberous Sclerosis Complex
120
Carmelo Schepis

Abstract
Tuberous Sclerosis Complex (TCS) is a neurocutaneous syndrome affect-
ing the skin, central nervous system, heart, kidney, lung and other sites of
the human body. The onset of facial angiofibromas (FA) is at about 5 years
old and becomes more evident later. After puberty, FA lesions grow and
may bleed, often causing discomfort. The primary treatments for FA
include: lasers, dermabrassion, electrosurgery, podophyllin, photody-
namic therapy followed by pulsed dye laser and topical rapamycin. An
advantage of cryosurgery is that it can be performed without anesthesia.
Cryosurgery is rarely documented as a treatment for FA in general. We
treated four female patients affected by TSC and FA with cryosurgery. All
patients improved after a series of treatments. In our experience, cryosur-
gery is effective, efficient, relatively inexpensive and easy to perform.
Furthermore, according to the patient’s clinical evolution, it can be repeat-
able from time to time.

Keywords
Tuberous Sclerosis Complex • Facial angiofibromas • Treatment • Liquid
nitrogen • Cryosurgery

Introduction

Tuberous Sclerosis Complex (TSC) is a neurocu-

C. Schepis, MD
Unit of Dermatology, Oasi Institute for Research on
Mental Retardation and Brain Aging,
Via Conte Ruggero, 73, Troina, Sicily 94018, Italy
e-mail: cschepis@oasi.en.it
© Springer-Verlag London 2016
W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_120
taneous syndrome affecting the skin, central ner-
vous system, heart, kidneys, lungs and other sites
of the human body. It is an autosomal dominant
genetic condition related to two tumor suppressor
genes located on chromosome 9 or chromosome
16 [1]. Cutaneous manifestations of TSC are
considered to be part of the major features required
for its diagnosis [1].
615
616 C. Schepis

Description of the Disease Methodology (How Do I Do It)

Among skin features, facial angiofibromas (FA)
develop at approximately the age of 5 years and
become more evident later in life. At first, FA are
small pink or red papules, usually located on the
cheeks, nasolabial folds, nose and chin. After
puberty they grow, may bleed, and often cause
discomfort for patients and their parents. For this
reason, various modalities of treatment have been
adopted
Thin nozzles are used to emit an open spray of
LN and the application is repeated after several
minutes. In our recent experience, we found it
easy to tolerate without local anesthesia, or just
using topical formulations of lidocaine, or
regional nerve blocks, as its administration pro-
duces only an initial mild pain that disappears in
a few minutes [8].

Success Rates
Therapeutic Alternatives
We recently treated four young TSC females
Laser [2] dermabrassion, electrosurgery, photo- for FA (Fig. 120.1a, b). All patients easily tol-
dynamic therapy followed by pulsed dye laser erated the intervention and only reported a
[3]; recently tincture of podophyllin [4] and topi- mild burning sensation during the application.
cal rapamycin [5] have been proposed as treat- A mild erythema over the treated area may per-
ment. These destructive procedures, done sist for up to 1 h. Patients improved signifi-
repeatedly, can have acceptable cosmetic results. cantly after a series of treatments and reported
All surgical methods need previous local anes- feeling satisfied with the results of the therapy
thesia, consisting of regional nerve block or (Fig. 120.2a, b).
EMLA application under occlusion over the
affected area. Sometimes, general anesthesia
may be required. Lately occasional experiences a
have suggested the use of a topical drug, rapamy-
cin (sirolimus) [5], which would act on the vascu-
lar component of angiofibromas.
Rapamycin inhibits mTOR (mammalian tar-
get of rapamycin) a well documented protein in
the pathogenesis of TSC. Oral rapamycin’s abil-
ity to induce regression of visceral TSC-related
tumors is well-established and its use is preva-
lently dedicated to treatment of Subependymal
Giant Cell Astrocytoma (SEGA).

b
Cryosurgery

Only cryosurgery, among the different surgical

techniques mentioned above, can be used with-
out anesthesia. Cryosurgery is only anecdotally
cited in the treatment of FA in patients with
TSC, and is rarely documented for FA in gen-
eral [6]. On the other hand, it is widely used in
dermatology to destroy several types of benign Fig. 120.1 (a) A young female affected by TSC at the
lesions [7]. beginning of treatment; (b). Detail of the nose area
120 The Tuberous Sclerosis Complex
a In select patients, such as the four in this report,
b therapy followed by immediate pulsed dye laser.
Fig. 120.2 (a) The same patient after six sessions of
cryosurgery with LN; (b) Detail of the nose area
617
Conclusions
cryosurgery will not require hospitalization or
day surgery. In our experience, cryosurgery is
efficient, cost-effective, easy to administer,
convenient and can be used repeatedly, accord-
ing to the clinical evolution [8]. Its side effects
are minimal and predictable; moreover it can
be used in conjunction with other available
treatments, such as lasers, in case of need.
References
1. Schwartz RA, Fernández G, Kotulska K, Józwiak
S. Tuberous sclerosis complex: advances in diagnosis,
genetics, and management. J Am Acad Dermatol.
2007;57:189–202.
2. Kaufman AJ, Grekin RC, Geisse JK, Frieden
IJ. Treatment of adenoma sebaceum with the copper
vapour laser. J Am Acad Dermatol. 1995;33:770–4.
3. Weinberger CH, Endrizzi B, Hook KP, Lee
P. Treatment of Angiofibromas of Tuberous Sclerosis
with 5-Aminolevulinic acid blue light photodynamic
Dermatol Surg. 2009;35:1849–51.
4. Türkmen M, Ertam I, Ünal I, Dereli T. Facial angiofi-
bromas of Tuberous Sclerosis: successful treatment
with podophyllin. JEADV. 2009;23:713–4.
5. Haemel AK, O’Brian AL, Teng JM. A novel approach
to facial angiofibromas in tuberous sclerosis. Arch
Dermatol. 2010;146(7):715–8.
6. Dvir E, Hirshowitz B. The use of cryosurgery in treat-
ing the fibrous papules of Tuberous Sclerosis. Ann
Plast Surg. 1980;4:158–60.
7. Thai KE, Sinclair RD. Cryosurgery of benign skin
lesions. Australas J Dermatol. 1999;40:175–86.
8. Schepis C, Siragusa M. Cryosurgery: an easy and
cheap therapy for facial angiofibromas in tuberous
sclerosis. Eur J Dermatol. 2010;20:506–7.
 Venous Lakes
121
Renata Strumia

Abstract
Venous lakes are commonly acquired, benign vascular ectasias that have a
predilection of forming on sun-exposed areas such as the lip and head and
neck region of elderly patients.

Keywords
Venous lake • Cryotherapy

Introduction to 1 cm in diameter. VL usually are well demar-

Venous lakes (VL) are commonly acquired,
benign vascular ectasias that have a predilection
of forming on sun exposed areas such as the lip
and head and neck region of elderly patients [1].
Description of the Disease
The typical presentation is a slow-growing
asymptomatic lesion. Patients with VL may
report that the papule has been present for
several years prior to presentation. Recurrent
bleeding after minor trauma may be reported.
Physical examination usually reveals a soft,
compressible, dark-blue or violaceous papule up
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara (Former), Ferrara, Italy
e-mail: restrumi@tin.it
cated, with a smooth surface. Compression
often causes a emptying of the blood content.
VL typically are distributed on the sun-exposed
surfaces of the face and neck, especially on the
helix and antihelix of the ear and the posterior
aspect of the pinna. Another common site of
involvement is the vermilion border of the lower
lip. Sometimes, several lesions are found on the
same person, and the surrounding skin reveals
actinic damage. Two main theories regarding
the development of venous lakes have been pro-
posed. The first involves injury to the vascular
adventitia and the dermal elastic tissue due to
long-term solar damage permitting dilatation of
superficial venous structures. The second theory
involves the involvement of vascular thrombosis
in the development of venous lakes. Thrombosis
is commonly present in lesions of this type;
however, whether it is a primary or a second-
ary event in their development is unclear. Bean
and Walsh [1] reported that 95 % of VL were

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_121
620
observed in males. The disproportionate male
distribution may be related to occupational sun
exposure, hair length, and hairstyles. Women
comprised the majority of treated patients in a
large study of laser therapy for venous lakes;
however, this may be related to increased con-
cern among women regarding cosmetic appear-
ance rather than with true incidence. The average
age of presentation for VL has been reported to
be 65 years.
Histologically a VL is an ectasia of one or
several interconnecting channels arising within
deteriorations in the three-dimensional network
of connective tissue of the vascular adventia and
dermis. Typically, no smooth muscle or elastic
tissue is found in the vessel wall. Evidence of
solar elastosis and other aspects of photodamage
can be found in adjacent tissue dermis [1, 2].
VL are important because of their mimicry of
malignant lesions, such as melanoma and pig-
mented basal cell carcinoma.
Therapeutic Alternatives
Cryosurgery [3], electrodesiccation [4], excision
[2], infrared coagulation [4], and CO2 and argon
lasers have all been used with variable success
relating to the depth of the lesion [5–8]. Longer
wavelength lasers are often employed to address
depth and improve success at the cost of comfort.
Treatment usually is performed for cosmetic rea-
sons or to alleviate recurrent bleeding.
Cryotherapy
Cryotherapy for VL may be performed with
the cotton-tipped dipstick dipped into LN or
with probes, because a pression on the lesion is
requested to achieve the best result. Pyogenic
granuloma as a complication of cryosurgery for
venous lake is reported [9].
R. Strumia
Methodology (How I Do It)
I use the cotton-tipped dipstick with one freeze-
thaw cycle of 5–10 s per session. Blister forma-
tion may occur. If necessary, treatment is repeated
after 30 days. There is no bleeding. Pain is well
tolerated.
Success Rates
The success rate is high. The most common com-
plication is a change in pigmentation.
Conclusions
Cryotherapy can be used as first line therapy
in VL.
References
1. Bean WB, Walsh JR. Venous lakes. AMA Arch Derm.
1956;74:459–63.
2. Astner S, Anderson R. Treating vascular lesions.
Derm Ther. 2005;18:267–81.
3. Suhonen R, Kuflik EG. Venous lakes treated by liquid
nitrogen cryosurgery. Br J Dermatol. 1997;137:1018–9.
4. Ah-Weng A, Natarajan S, Velangi S, Langtry JA. Venous
lakes of the vermillion lip treated by infrared coagulation.
Br J Oral Maxillofac Surg. 2004;42:251–3.
5. Apfelberg DB, Maser MR, Lash H, Flores J. Expanded
role of the argon laser in plastic surgery. J Dermatol
Surg Oncol. 1983;9:145–51.
6. Del Pozo J, Pena C, Garcia Silva J, Goday JJ, et al.
Venous lakes: a report of 32 cases treated by car-
bon dioxide laser vaporization. Dermatol Surg.
2003;29:308–10.
7. Cheung ST, Lanigan SW. Evaluation of the treatment
of venous lakes with the 595-nm pulsed dye laser: a
case series. Clin Exp Dermatol. 2007;32:148–50.
8. Roncero M, Canueto J, Blanco S, Unamuno P, Boixeda
P. Multi wavelength laser treatment of venous lakes.
Dermatol Surg. 2009;35:1942–6.
9. Cecchi R, Giomi A. Pyogenic granuloma as a compli-
cation of cryosurgery for venous lake. Br J Dermatol.
1999;140:373–4.
 Cryosurgery of Common Warts
122
Noah Scheinfeld

Abstract
Common warts occur commonly and although they may be mostly a banal
problem, they may cause functional and quality of life issues for patients.
Cryosurgery is a very effective modality in the treatment of most warts.
LN spray is the most efficient means to deliver the LN onto a wart. Paring
increases the efficiency of wart cryosurgery.

Keywords
Wart • Verruca vulgaris • Palmar • Plantar • Periungual • Salicylic
acid • Paring

Introduction treatment of warts [3]. Warts are estimated to

Non-genital cutaneous warts are among the most
common problem dermatologists treat and one of
the most common dermatological complaints that
primary care doctors note. Common, plantar, fili-
form or flat warts (non-genital cutaneous warts)
are cutaneous manifestations of the human papil-
lomavirus [1]. Common warts also known as ver-
rucae vulgaris most commonly occur on the
hands and feet. In 1974 warts accounted for 8 %
of dermatology visits [2]. Of 22,000,000 derma-
tology visits in 1995, 3,900,000 were for the
N. Scheinfeld, MD, JD
Department of Dermatology-Weil Cornel
Medical College, New York Hospital,
New York, NY, USA
e-mail: nss1scheinfeld@gmail.com
occur in up to 10 % of children and young adults.
The range of greatest incidence is between 12
and 16 years of age. The peak incidence is at
13 years of age in females and 14.5 years of age
in males [4]. This chapter will deal with cryosur-
gery for the treatment of warts.
Warts are not just a cosmetic problem. Ciconte
[5] studied 85 people aged 2–76 years with 250
common and plantar warts were followed pro-
spectively for 9 months. Eight (19.5 %) said the
treatment resulted in the development of scars. A
quality-of-life assessment related to their current
warts revealed that 81.2 % were moderately to
extremely embarrassed by them; 70.5 % were
moderately to extremely concerned about nega-
tive appraisal by others for having them; 24.7 %
said that it was moderately to extremely difficult
to play sport because of their warts. Moderate to

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_122
622
severe discomfort from their warts occurred in
51.7 % of people and 35.4 % said they had mod-
erate to severe pain. Bacelieri [1] noted that (1)
warts typically continue to increase in size and
distribution and may become more resistant to
treatment over time; (2) children with treatment-
resistant warts potentially may be reservoirs for
HPV transmission; (3) warts can be painful
depending on their location (e.g., soles of the feet
and near the nails); (4) warts can be viewed as
socially unacceptable when located on visible
areas (e.g., hands and face).
Cryosurgery Methodology
(How I Do It)
Cryosurgery utilizing LN applied with a cryostat
gun can be used on all types of wart on all patients
who will tolerate it. The LN exits the unit at
−196 °C and hits the skin at −70 °C. The tem-
perature needed to destroy warts is −40 °C. The
skin is at about 38 °C; the penetration of freezing
declines geometrically within it. Before the
development of the cryostat unit dermatologist
used solid carbon dioxide, which is only at
−70 °C and much harder to manipulate, hence
over-the-counter freezing treatment units are tend
not to be good enough to effectively treat warts.
Scarring and pigment alterations can occur
with cryosurgery, although this happens rarely on
the hands and feet. Most dermatologists utilize
LN delivery units to apply it. Some people use a
large cotton wool bud to apply LN; one study
noted equal effectiveness when LN was applied
with a cotton wool bud or by means of a spray
[6]. It appears to be that the freeze that the bud
induces does not produce optimal so I only use it
in patients who want it or who have a very low
pain tolerance. Patients should be informed that
the spray method delivers more LN to the skin
than a bud; hence it is more painful. Hemorrhagic
bullae and blisters on the hand or foot can occur
after cryotherapy.
When freezing wart it is optimal to apply the
LN for over 10 s at a session because a study has
shown that a 10 s application is more effective
N. Scheinfeld
than shorter ones [7]. Most dermatologists apply
LN onto warts for two freeze thaw cycles. This
has a basis for plantar but not for hand warts; a
study noted that a double freeze-thaw cycle con-
fers little or no advantage over a single freeze in
the treatment of hand warts, although it may be
considerably more effective for plantar warts [8].
More rapid cures may be achieved by more fre-
quent treatments according to some studies;
Brourke [8] concluded that the percentage cure is
related to the number of treatments, independent
of the intervals between them.
A useful adjunct to cryosurgery is to pare the
warts before freezing them, this increases the
number of infected cells lysed. Possible reasons
for not paring warts include that the procedure is
time-consuming and requires a scalpel, which
some patients find frightening, and that it may
induce bleeding. The most important thing that I
do that other physicians do not is to pare warts
before freezing. Two freeze-thaw cycles and par-
ing before freezing in one study improved the
cure rate for plantar warts but not hand warts
[9–11]. Sometimes repeated freezing is not
needed; one study suggests that, a single applica-
tion generally sufficed for hand warts [10]. A ret-
rospective randomized trial of cryosurgery for
common warts showed that weekly sessions pro-
duced more rapid cures, but the overall cure rate
depended on number of treatments [11]. There
still might be a basis for paring thick hand warts
but evidence based literature on this is lacking. It
seems optimal to me to pare the warts down just
to the point that bleeding occurs because this tells
me the epidermis is gone, and the human papil-
loma virus lives in the epidermis. There are no
nerve endings in the epidermis so, if the blade
stays there, paring does not induce pain. Paring is
sometimes problematic as patients may bleed
profusely and it can take 5 or 10 min to stop,
which concerns them, agitates the nursing staff,
and leads to prolonged unplanned utilization of
an examination room. Also, sometimes the der-
mis is cut into and this can be painful. Injecting
anesthesia before paring in also painful so there
is no way to forestall all possibility of pain if par-
ing is performed.
122 Cryosurgery of Common Warts 623

Salicylic Acid Combined

with Cryosurgery

Good evidence supports use of salicylic acid in

combination with cryotherapy [1]. The Cochrane
review [12] identifies topical therapy with sali-
cylic acid as safe and effective and that no clear
evidence exists to prove that other therapies have
an advantage in regard to cure rates or adverse
effects; pooled data from six randomized clinical
trials demonstrated a cure rate of 75 % in those
treated with salicylic acid compared with 48 % in
Fig. 122.2 Plantar shows wart after treatment with cryo-
the control group. Sterling noted that salicylic therapy with decrease in size of the wart
acid is the first-line therapy for flat warts on the
face, plantar warts, and flat and common warts on
the hands [13]. With Verruca Freeze™/70 % sali-
cylic acid the success rate was higher than with
all other methods [14]. Provided are images that
related to use of cyrotherapy with salicyclice acid
with cryosurgery (see Figs. 122.1, 122.2, and
122.3). Periungual warts present a challenge to
use of cryotherapy as part of the wart is covered
by the nail plate [15]. In this case combination
modalities such as candida antigen and paring the
nail should be considered. Some suggest that for
periungual warts keratolytic agents are the best
first-line approach. Surgical treatments include
Fig. 122.3 Plantar wart after three rounds of cyrotherapy
cryosurgery, excision, electrosurgery, infrared of salicyclic acid daily 17 % liquid over night under occlu-
coagulation, localized heating with a radio- sion and rubbed down with a pomace stone in the
frequency heat generator and laser therapy, espe- morning;-the wart is much smaller after combination
cryotherapy and salicyclic acid
cially the Er: YAG laser, which has an excellent
safety profile [16].
Conclusion
No treatment works for all warts on all patients,
but many options are available and, with time
and patience, in immuno-competent patients
most warts (periungual and subungual excepted)
will respond to treatment. Combinations with
salicylic acid, imquimod, tazarotene can
increase cure rates. Contraindications to cryo-
surgery include cryofibrinogenemia, cryoglobu-
linemia, Raynaud disease, agammaglobulinemia,
and multiple myeloma [17]. Mallet finger can
be a complication of LN cryosurgery for ver-
ruca vulgaris [18]. Over-the-counter freezing
Fig. 122.1 Shows a plantar wart before treatment with
kits do not get cold enough as to destroy watrs
cyrotherapy or salicyclic acid and patient should be discouraged from using
624
them [19]. For the best results warts should be
frozen for 10 s at a time [20]. Cryosurgery is an
effective wart treatment but patients and physi-
cians should not expect that a single session,
even with paring, will cure all particularly those
on the hands and feet.
References
1. Bacelieri R, Johnson SM. Cutaneous warts: an
evidence-based approach to therapy. Am Fam
Physician. 2005;72(4):647–52.
2. Stern RS, Johnson ML, DeLozier J. Utilization of
physician services for dermatologic complaints. The
United States, 1974. Arch Dermatol. 1977;113(8):
1062–6.
3. Thompson TT, Feldman SR, Fleischer Jr AB. Only
33% of visits for skin disease in the US in 1995 were
to dermatologists: is decreasing the number of derma-
tologists the appropriate response? Dermatol Online
J. 1998;4(1):3.
4. Plasencia JM. Cutaneous warts: diagnosis and treat-
ment. Prim Care. 2000;27:423–34.
5. Ciconte A, Campbell J, Tabrizi S, Garland S, Marks R.
Warts are not merely blemishes on the skin: a study on
the morbidity associated with having viral cutaneous
warts. Australas J Dermatol. 2003;44(3):169–73.
6. Ahmed I, Agarwal S, Ilchyshyn A, Charles-Holmes S,
Berth-Jones J. Liquid nitrogen cryotherapy of com-
mon warts: cryo-spray vs. cotton wool bud. Br
J Dermatol. 2001;144(5):1006–9; Connolly M, Bazmi
K, O’Connell M, Lyons JF, Bourke JF. Cryotherapy of
viral warts: a sustained 10-s freeze is more effective
than the traditional method. Br J Dermatol.
2001;145(4):554–7.
7. Massing AM, Epstein WL. Natural history of warts. A
two-year study. Arch Dermatol. 1963;87:306–10; van
Brederode RL, Engel ED. Combined cryotherapy/70%
N. Scheinfeld
salicylic acid treatment for plantar verrucae. J Foot
Ankle Surg. 2001;40(1):36–41.
8. Bourke JF, Berth-Jones J, Hutchinson PE. Cryotherapy
of common viral warts at intervals of 1, 2 and 3 weeks.
Br J Dermatol. 1995;132(3):433–6.
9. Berth-Jones J, Hutchinson PE. Modern treatment of
warts: cure rates at 3 and 6 months. Br J Dermatol.
1992;127:262–5.
10. Berth-Jones J, Bourke J, Eglitis H, et al. Value of a
second freeze-thaw cycle in cryotherapy of common
warts. Br J Dermatol. 1994;131:883–6.
11. Wetmore SJ. Cryosurgery for common skin lesions.
Treatment in family physicians’ offices. Can Fam
Physician. 1999;45:964–74.
12. Gibbs S, Harvey I, Sterling JC, Stark R. Local treat-
ments for cutaneous warts. Cochrane Database Syst
Rev. 2003;3:CD001781.
13. Sterling JC, Handfield-Jones S, Hudson PM. Guidelines
for the management of cutaneous warts. Br J Dermatol.
2001;144:4–11.
14. van Brederode RL, Engel ED. Combined cryother-
apy/70% salicylic acid treatment for plantar verrucae.
J Foot Ankle Surg. 2001;40(1):36–41.
15. Herschthal J, McLeod MP, Zaiac M. Management of
ungual warts. Dermatol Ther. 2012;25(6):545–50.
16. Tosti A, Piraccini BM. Warts of the nail unit: surgical
and nonsurgical approaches. Dermatol Surg. 2001;
27(3):235–9.
17. Zimmerman EE, Crawford P. Cutaneous cryosurgery.
Am Fam Physician. 2012;86(12):1118–24.
18. Al-Qattan MM, Al-Arfaj N. Mallet finger as a compli-
cation of liquid nitrogen cryosurgery for verruca vul-
garis. J Hand Surg Eur Vol. 2009;34(4):546–8.
19. Burkhart CG, Pchalek I, Adler M, Burkhart CN. An
in vitro study comparing temperatures of over-the-
counter wart preparations with liquid nitrogen. J Am
Acad Dermatol. 2007;57(6):1019–20.
20. Connolly M, Bazmi K, O’Connell M, Lyons JF,
Bourke JF. Cryotherapy of viral warts: a sustained
10-s freeze is more effective than the traditional
method. Br J Dermatol. 2001;145(4):554–7.
 Cryosurgery for Verruca Palmaris
123
Nancy S. Handler, Marc Zachary Handler,
and Robert A. Schwartz

Abstract
Verruca palmaris is a common presentation resulting from HPV infection
of keratinocytes of the palms. If the virus is not suppressed, replication of
the epithelium occurs, creating a keratotic papilloma of the palm.
Cryosurgery is the first line treatment for verruca palmaris, resulting in
destruction of the verruca’s vascular supply and stimulation of the immune
system. Optimal technique involves targeted destruction of the wart with
no greater than 2–3 mm of collateral destruction of healthy adjacent
tissue.

Keywords
Verruca • Wart • HPV • Human papilloma virus (HPV) • Verruca palmaris •
Imiquimod • Podophyllotoxin

Introduction (HPV); subsequent cell proliferation produces a

Verruca vulgaris, also known as a viral wart, is a
common disorder with a prevalence in children
between 2 and 20 % [1]. It results from epithelial
cell infection by the human papilloma virus
N.S. Handler, MD • M.Z. Handler, MD
Department of Dermatology, Rutgers University
New Jersey Medical School, Newark, NJ, USA
R.A. Schwartz, MD, MPH, DSc (Hon),
FRCP (Edin) (*)
Dermatology and Pathology, Rutgers University New
Jersey Medical School, Rutgers University School of
Public Affairs and Administration, Newark, NJ, USA
e-mail: roschwar@cal.berkeley.edu
thickened, warty papule on the skin. Although
the majority resolve without treatment, disap-
pearance may take years, and the wart’s pres-
ence may cause functional impairment on areas
such as the volar surface of the hand. Many
products have been used to treat warts, some as
home therapies, others requiring in-office appli-
cation. Although none is definitive, there are
multiple options for the treatment of warts of
the palm. These include topical keratolytics,
lasers, topical immunotherapy, oral cimetidine,
electodestruction, intralesional injection and
cryotherapy. The latter is often the treatment of
choice.

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_123
626
Disease Description
Viral warts are more common in children than in
adults [2]. Although the prevalence of appear-
ance on the hand is unknown, the location is
commonly affected. The infection resulting from
HPV entering via a skin break [3], is usually con-
trolled by the immune system. Should the latter
not clear it, viral replication will occur, resulting
in proliferation of epithelium. If the virus is sup-
pressed by the immune system, it will remain
dormant and no wart will result [4]. Warts resis-
tant to therapy may be due to a cell mediated
immune deficiency to HPV. Warts of the hand
may represent an occupational disease in butch-
ers and other meat handlers, who tend to have an
infection with HPV-7 [5]. Certain oncogenic
strains of HPV may be associated with skin can-
cer, particularly in an unusual genetic disorder
called epidermodysplasia verruciformis, which
particularly affects the hands and feet [6].
Persistent palmar warts may represent or have
evolved into a verrucous carcinoma [7, 8].
Therapeutic Alternatives
Up to 66 % of warts of the palm resolve without
external intervention within 2 years and 80 %
within 4 years [9]. Many patients with verrucas
palmaris have symptomatic, functional or cos-
metic concerns that require therapy. Topical
imiquimod 5 % has demonstrated efficacy similar
to cryosurgery when used daily, 5 days per week,
for 3 months. A combination treatment with 15 %
salicylic acid solution and imiquimod 5 %, daily,
5 days per week for 3 months may be slightly
more effective than cryosurgery alone [10].
Podophyllotoxin, a patient-applied topical, is
effective but may produce site reactions [11].
Formic acid ointment may lead to a third degree
chemical burn if applied to the volar surface of the
hand under occlusion [3]. Occlusion with duct
tape demonstrated benefit with 2 weeks of appli-
cation, as rapidly in 2 months, in 85 % of patients
[12]. Lasers resolve verrucas of the hands, with-
out destruction of dermatoglyphs, in approxi-
mately 50 % of patients treated with low-energy
N.S. Handler et al.
1064 Nd: YAG laser monthly for 3 months [13,
14]. Intralesional therapy with such antigens as
candida [15], purified protein derivative, or the
mumps, measles, rubella vaccine have shown effi-
cacy when injected directly into a wart; [16] this
is believed to be a result of activation of humoral
and cellular immunity targeting infected host cells
[17]. Cimetidine, a histamine H2-receptor antago-
nist, in doses from 25 to 40 mg/kg per day, has
been used to treat warts; some studies demon-
strate slightly better efficacy than a control while
others find no efficacy [18–20].
Cryosurgery
Cryosurgery is a safe, effective treatment for ver-
ruca vulgaris of the hand. Cryosurgery, has
increased efficacy compared to topical salicylic
acid [21]. Cryosurgery results in destruction of
tissue, and the vascular supply to the wart; at the
same time it stimulates the immune system; in
this way causing the resolution of verruca.
Application of LN can be via spray, touching the
surface with a probe, molded carbon dioxide, or
an applicator such as a cotton swab; melamine
foam sponges in lieu of the cotton swab provide
faster wart reduction and requires fewer follow
up treatments [22]. Injection of local anesthetic
to the wart prior to cryosurgery results in signifi-
cant decrease in the pain felt by the patient [23].
Cryosurgery has been trialed with adjuvant topi-
cal 5-fluorouracil but no additional benefit was
seen compared to LN monotherapy [24].
Methodology (How We Do It)
The open spray and the dipstick method are the
techniques most commonly employed in the treat-
ment of verruca palmaris. With the open spray the
end-point of treatment should be a 2–3 mm halo
of ice around the wart in a single cycle of freez-
ing, which may take 20–30 s [25, 26].
With the dipstick method, LN is applied with
a saturated cotton-tipped applicator dipped into a
LN filled cup and the applicator is then placed on
the wart, creating a 2–3 mm radius of a frosted
123 Cryosurgery for Verruca Palmaris
halo. This may take 20–60 s of repeated dipping
and placing.
As a split develops between the epidermis and
dermis, the patient should anticipate a blister to
form within the day, and be reassured this is a
sign of successful treatment. The blister, if pain-
ful, may be drained, leaving the epidermis
remaining as a physiologic bandage with antici-
pated resolution within 3-weeks [25]. No scar-
ring should occur with use of cryosurgery [27].
Conclusion
For patients requiring resolution of verruca pal-
maris, cryosurgery remains a recommended,
safe, and efficacious first-line treatment.
References
1. Kilkenny M, Marks R. The descriptive epidemiology
of warts in the community. Australas J Dermatol.
1996;37:80–6.
2. Lynch MD, Cliffe J, Morris-Jones R. Management of
cutaneous viral warts. BMJ. 2014;348:g3339.
3. Balague N, Vostrel P, Beaulieu JY, van Aaken J. Third
degree formic acid chemical burn in the treatment of a
hand wart: a case report and review of the literature.
Springerplus. 2014;3:408.
4. Cryotherapy systems for wart removal: a review of the
clinical effectiveness, cost-effectiveness, and guide-
lines. Ottawa (ON). Canadian Agency for Drugs and
Technologies in Health; 2014 Jun. CADTH Rapid
Response Reports.
5. Matsukura T, Mitsuishi T, Sugase M, Kawashima
M. Human papillomavirus type 7-associated condy-
loma. Dermatology. 2010;221:5–8.
6. Majewski S, Jablonska S. Current views on the role of
human papillomaviruses in cutaneous oncogenesis.
Int J Dermatol. 2006;45:192–6.
7. Schwartz RA. Verrucous carcinoma of the skin and
mucosa. J Am Acad Dermatol. 1995;32:1–21; quiz 2–4.
8. Gertler R, Werber KD. Management of verrucous car-
cinoma of the hand: a case report. Int J Dermatol.
2009;48:1233–5.
9. Kuwabara AM, Rainer BM, Basdag H, Cohen BA.
Children with warts: a retrospective study in an outpa-
tient setting. Pediatr Dermatol. 2015;32:679–83.
10. Stefanaki C, Lagogiani I, Kouris A, Kontochristopoulos
G, Antoniou C, Katsarou A. Cryotherapy versus
imiquimod 5% cream combined with a keratolytic
lotion in cutaneous warts in children: a randomized
study. J Dermatol Treat. 2016;27:80–2.
11. Kwok CS, Gibbs S, Bennett C, Holland R, Abbott R.
Topical treatments for cutaneous warts. Cochrane
Database Syst Rev. 2012;9:CD001781.
627
12. Focht 3rd DR, Spicer C, Fairchok MP. The efficacy of
duct tape vs cryotherapy in the treatment of verruca
vulgaris (the common wart). Arch Pediatr Adolesc
Med. 2002;156:971–4.
13. Goldberg DJ, Beckford AN, Mourin A. Verruca vul-
garis: novel treatment with a 1064 nm Nd:YAG laser.
J Cosmet Laser Ther. 2015;17:116–9.
14. Kimura U, Takeuchi K, Kinoshita A, Takamori K,
Suga Y. Long-pulsed 1064-nm neodymium: yttrium-
aluminum-garnet laser treatment for refractory warts
on hands and feet. J Dermatol. 2014;41:252–7.
15. Johnson SM, Roberson PK, Horn TD. Intralesional
injection of mumps or Candida skin test antigens: a
novel immunotherapy for warts. Arch Dermatol.
2001;137:451–5.
16. Shaheen MA, Salem SA, Fouad DA, Abd El-Fatah
AA. Intralesional tuberculin (PPD) versus measles,
mumps, rubella (MMR) vaccine in treatment of mul-
tiple warts: a comparative clinical and immunological
study. Dermatol Ther. 2015;28:194–200.
17. Zamanian A, Mobasher P, Jazi GA. Efficacy of
intralesional injection of mumps-measles-rubella
vaccine in patients with wart. Adv Biomed Res.
2014;3:107.
18. Bauman C, Francis JS, Vanderhooft S, Sybert VP.
Cimetidine therapy for multiple viral warts in chil-
dren. J Am Acad Dermatol. 1996;35:271–2.
19. Yilmaz E, Alpsoy E, Basaran E. Cimetidine therapy
for warts: a placebo-controlled, double-blind study.
J Am Acad Dermatol. 1996;34:1005–7.
20. Rogers CJ, Gibney MD, Siegfried EC, Harrison BR,
Glaser DA. Cimetidine therapy for recalcitrant warts
in adults: is it any better than placebo? J Am Acad
Dermatol. 1999;41:123–7.
21. Bruggink SC, Gussekloo J, Berger MY, Zaaijer K,
Assendelft WJ, de Waal MW, et al. Cryotherapy with
liquid nitrogen versus topical salicylic acid applica-
tion for cutaneous warts in primary care: randomized
controlled trial. CMAJ. 2010;182:1624–30.
22. Na CH, Park HP, Song IG, Choi H, Kim MS, Shin BS.
A comparison of therapeutic efficacy of a melamine
foam sponge and conventional cotton wool bud in the
cryotherapy of viral warts: a paired comparison study.
Pediatr Dermatol. 2012;29:555–9.
23. Buckley D. Evaluation of local anaesthetic infiltration
for cryosurgery of hand warts: a prospective compara-
tive study. Ir J Med Sci. 2015. [Epub ahead of print].
24. Luk NM, Tang WY, Tang NL, Chan SW, Wong JK,
Hon KL, et al. Topical 5-fluorouracil has no additional
benefit in treating common warts with cryotherapy: a
single-centre, double-blind, randomized, placebo-
controlled trial. Clin Exp Dermatol. 2006;31:394–7.
25. Kuflik EKJ. Cryosurgery. In: Bolognia JJ, Jorizzo J,
Schaffer JV, editors. Dermatology. Philadelphia:
Saunders; 2012.
26. Prasad AJ. Targeted cryotherapy using disposable
biopsy punches. J Cutan Aesthet Surg. 2014;7:
118–20.
27. Kuflik EG. Cryosurgical treatment of periungual
warts. J Dermatol Surg Oncol. 1984;10:673–6.
 Verruca Plana (Flat Viral Warts)
124
Renata Strumia

Abstract
Flat viral warts (FVWs) are circumscribed papules with hyperkeratotic
surfaces that can occur singly or in groups. No single therapy has been
proven effective at achieving complete remission in every patient. As a
result, many different approaches to wart therapy exist. Cryotherapy is a
good option in the treatment of FVW of the face.

Keywords
Verruca plana • Flat viral warts • Cryotherapy • Cryosurgery

Introduction area, or back of the hands, and primarily affect

Flat viral warts (FVWs) are circumscribed papules
with hyperkeratotic surfaces that can occur singly or
in groups. In these types of warts, the human papil-
loma virus (HPV) has been shown to infect the koilo-
cytes. Although no viral subtype is absolute, typically
the infection is with HPV types 3, 10, 28, and 41.
Description of the Disease
These papillomata are small in size (1–5 mm),
flat, or slightly elevated. FVWs typically present
as skin-colored or light brownish, flat-topped
papules or thin papillomas on the face, beard
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara (Former), Ferrara, Italy
e-mail: restrumi@tin.it
© Springer-Verlag London 2016
W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_124
children and young adults.
Their evolution is variable, and although two
thirds of cases regress spontaneously in the
course of 2 years due to immunological mecha-
nisms, they occasionally are long lasting. FVWs
can greatly affect a patient’s quality of life, and
their persistence and/or recurrence can cause
frustration. Moderate-to-extreme discomfort is
reported in 51.7 % of patients, and social or lei-
sure activities are affected to a moderate-to-
extreme degree in 38.8 % of patients [1–3].
Therapeutic Alternatives
No single therapy has been proven effective at
achieving complete remission of FVWs in every
patient. As a result, many different approaches
exist. The following therapies have been used
with varying success: salicylic acid [2, 3], retinoic
629
630
acid [4], cantharidin [5], topical 5-aminolevulinic
acid photodynamic therapy [6], cryotherapy and
Candida antigen [7]. Good results have been
reported with topical imiquimod 5 %, with com-
plete clearance of all FVWs occurring after
3 weeks of therapy [8]; however, this treatment is
expensive. Glycolic acid has been used in the
treatment of FFWs with good results [9, 10]. It
has been suggested that alpha-hydroxy acids can
produce an authentic exfoliation and dehiscence
of the corneocytes from recently formed layers of
the stratum corneum. Alpha-hydroxy acids also
reduce the number of desmosomes and tonofila-
ments. Glycolic acid plus salicylic acid, is also
well tolerated and did not produce scars upon
withdraw of therapy in any patient [11]. Many
other treatments for FVWs are expensive and
require that parents accompany their children to
several office visits, resulting in loss of time and
work hours. Fifteen percent glycolic acid plus
2 % salicylic acid is self-administered, requires no
special care and, according to some authors, may
be considered first-line treatment for nonrecalci-
trant FVWs in children or young adults who suf-
fer cosmetic embarrassment or pain.
Destructive therapies such as surgical curettage,
cautery or caustic chemical ablation, should be
used with care for flat warts due to their tendency to
Koebnerize [2]. Patients should be informed of the
possible side effects of all treatments, such as
severe erythema, exfoliation, and postinflamma-
tory hyperpigmentation. Patients should also be
informed about the importance of sun protection.
Cryotherapy
One report [12] states that cryotherapy is recom-
mended as first-line therapy for flat and common
warts.
Methodology (How I Do It)
In multiple FVWs cryotherapy should be per-
formed with the technique of cryomassage.
The cotton-tipped dipstick or the probe are
applied on the lesions with a rotary or spiral
R. Strumia
pattern and the paintbrush method. The cotton-
wool or the probe stay in contact with the skin for
1–3 s until it goes white momentarily from freez-
ing. This technique prevents scars.
Success Rates
FVWs occasionally are long lasting despite
repeated treatment.
Conclusions
Cryotherapy is a good option in the treatment
of FVW of the face.
References
1. Massing AM, Epstein WL. Natural history of warts. A
two-year study. Arch Dermatol. 1963;87:306–10.
2. Sterling JC, Handfield-Jones S, Hudson PM, British
Association of Dermatologists. Guidelines for the
management of cutaneous warts. Br J Dermatol.
2001;144:4–11.
3. Leman JA, Benton EC. Verrucas. Guidelines for man-
agement. Am J Clin Dermatol. 2000;1:143–9.
4. Kubeyinje EP. Evaluation of the efficacy and safety of
0.05% tretinoin cream in the treatment of plane warts
in Arab children. J Dermatol Treat. 1996;7:21–2.
5. Kartal Durmazlar SP, Atacan D, Eskioglu F.
Cantharidin treatment for recalcitrant facial flat warts:
a preliminary study. J Dermatolog Treat. 2009;20:
114–9.
6. Lin MY, Xiang LH. Topical 5-aminolevulinic acid
photodynamic therapy for recalcitrant facial flat wart
in Chinese subjects. J Dermatol. 2008;35:658–61.
7. Ritter SE, Meffert J. Successful treatment of flat warts
using intralesional Candida antigen. Arch Dermatol.
2003;139:541–2.
8. Khan Durani B, Jappe U. Successful treatment of
facial plane warts with imiquimod. Br J Dermatol.
2002;147:1018.
9. Van Scott EJ, Yu RJ. Control of keratinization with
alpha hydroxy acids and related compounds. Arch
Dermatol. 1974;110:586–90.
10. Borbujo J, Olmos O, Zamora E, Diez JJ. Treatment of
verrucae plana with 15% glycolic acid. Int J Dermatol.
2000;39:236–40.
11. Rodríguez-Cerdeira C, Sánchez-Blanco E. Glycolic
acid 15% plus salicylic acid 2%. A new therapeutic
pearl for facial flat warts. J Clin Aesthet Dermatol.
2011;4:62–4.
12. Rocky Bacelieri R, Marchese Johnson S. Cutaneous
warts: an evidence-based approach to therapy. Am
Fam Physician. 2005;72:647–52.
 Verruca Filiformis (Filiform Wart)
125
Renata Strumia

Abstract
Verruca filiformis or filiform wart (FW) is a long and slender wart. It
projects from the skin’s surface and is described as a stalk with finger-like
projections. It can be treated with LN cryotherapy. A cotton-tipped
applicator or a spray is used to treat FW for 10–15 s. It is important that
visible freezing reaches the base of the lesion.

Keywords
Verruca filiformis (filiform wart) • Cryotherapy • Cryosurgery

Introduction Description of the Disease

The clinical picture of cutaneous warts differs
somewhat by specific location on the body.
Verruca filiformis also known as a digitate or fili-
form wart (FW) is most often seen on the face
with characteristic frond-like projections that
exhibit quick proliferation [1, 2].
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara (Former), Ferrara, Italy
e-mail: restrumi@tin.it
FW is a long and slender wart. It projects quite
from the skin’s surface and is described as a stalk
with finger-like projections. FW prefers to grow
on thin skin areas. Therefore, these warts are
commonly found on the eyelids, around the eyes,
around the lips, on the neck, on the arms, on the
chin, and on the nose. These benign warts are
flesh colored and grow rapidly. Any age group
can get the warts, but older children have a higher
incidence of contracting them.
FWs can itch and bleed. Because they project
away from the skin’s surface and are thin, they
may experience a lot of friction and rubbing and
can break open; abrasion leads to discomfort.
This can also lead to spreading of the wart and
possible infection. Treatment is recommended,
especially if the wart is in an area of constant rub-
bing or friction [3].

© Springer-Verlag London 2016 631

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_125
632
Therapeutic Alternatives
Different types of warts may need different site-
dependent treatments, and treatments may need
to be combined. FW is easy to treat compared to
several of the other wart types. In more sensitive
areas, such as on the eyelids or around the eyes
removal with scissors or a scalpel is preferred.
Local anesthesia is generally required [3].
Successful treatment of multiple filiform facial
warts with imiquimod 5 % cream in a patient
infected by human immunodeficiency virus has
been reported [4]. LN can be used in some skin
areas.
Cryotherapy
In FW, treatment with LN, whether applied with
a cotton-tipped applicator or sprayed with a
cryogun, can result in tissue damage (e.g., blisters)
beyond the intended target. A method providing
rapid and painless treatment for small skin fili-
form tags is to dip a hemostat, a nontoothed for-
ceps, or a needle holder into liquid nitrogen for
15 s, and then to use that instrument to gently
grasp the stalk of each FW for about 10 s. Care
is taken to not touch the surrounding skin. The
frozen tips of the instrument can treat up to
about ten lesions after being dipped in the
LN. The patient experiences only a very mild
sting. The procedure results in little or no col-
lateral damage to the skin, just a narrow rim of
erythema. Multiple lesions can be treated by
this method. No hemostasis or dressings are
R. Strumia
necessary. The frozen FW will be shed in
approximately 7–10 days [5].
Methodology (How I Do It)
I use a cotton-tipped applicator or LN spray to
treat FW for 10–15 s. It is important that visible
freezing reaches the base of the lesion.
Success Rates
In multiple FW many cycles are requested to
achieve a good result.
Conclusions
Cryosurgery is a good option in the treatment
of FW.
References
1. Stulberg DL, Hutchinson AG. Molluscum contagio-
sum and warts. Am Fam Physician. 2003;67:1233–40.
2. Stulberg DL, Hutchinson AG. Physicians need more
evidence on treatments of warts: in reply. Am Fam
Physician. 1716;68:1714.
3. Lipke MM. An armamentarium of wart treatments.
Clin Med Res. 2006;4:273–93.
4. Hagman JH, Bianchi L, Marulli GC, Soda R, Chimenti
S. Successful treatment of multiple filiform facial warts
with imiquimod 5% cream in a patient infected by
human immunodeficiency virus. Clin Exp Dermatol.
2003;28:260–1.
5. Goodheart HP. Surgical pearl: a rapid technique for
destroying small skin tags and filiform warts.
Dermatol Online J. 2003;9:34.
 Cryosurgery for Xanthomas
126
Parmvir Singh, Marc Zachary Handler,
and Robert A. Schwartz

Abstract
Xanthoma is a highly prevalent disorder of lipid deposition that manifests
as cutaneous papules, nodules, or plaques. Microscopically, lipid-laden
macrophages, known as foam cells, are seen. The different types of xan-
thoma include eruptive xanthoma, plane xanthoma, xanthoma tuberosum,
tendon xanthoma, and xanthelasma palpebrarum. The most commonly
used therapeutic method for all forms of xanthoma is surgical excision,
although dietary modification to lower serum lipid levels, particularly for
tendinous xanthoma, has been attempted. Therapeutic alternatives for xan-
thelsma palpebrarum include electrocautery, trichloroacetic acid, and car-
bon dioxide laser vaporization. Tuberous xanthoma and xanthelasma
palpebrarum have been successfully treated with cryosurgery, with low
recurrence rates. Cryosurgery should be considered due to its ease of use,
cost-effectiveness, comparable outcomes and superior cosmetic outcome.

Keywords
Xanthoma • Cryosurgery • Xanthelasma palpebrarum • Treatment • Tendinous
xanthoma • Plane xanthoma • Xanthoma tuberosum • Tendon xanthoma

P. Singh, MD (*)
Department of Dermatology, University Hospital,
Newark, NJ, USA
e-mail: parmvirsingh90@gmail.com
M.Z. Handler, MD
Department of Dermatology,
Rutgers University New Jersey Medical School,
Newark, NJ, USA
R.A. Schwartz, MD, MPH, DSc (Hon), FRCP (Edin)
Department of Dermatology, Rutgers University
School of Public Affairs and Administration,
Newark, NJ, USA
Introduction
Xanthomas are localized lipid deposits in the
skin, tendons, and subcutaneous tissue that usu-
ally occur in adults greater than 50 years old of
age. The deposits may contain triglycerides or
cholesterol esters [1]. Xanthomas occur in more
than 4 % of the population with equal prevalence
in men and women [2]. They present clinically as
yellow papules, nodules, or plaques [1]. Elevated
serum lipid content, the result of a genetic
disorder or a secondary cause, may manifest as

© Springer-Verlag London 2016 633

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_126
634
xanthomas [1, 3]. Secondary causes of elevated
serum lipid content include diabetes mellitus,
hypothyroidism, nephritic syndrome, and medi-
cations such as estrogens, retinoids, antiretroviral
therapy [1]. Xanthomas may also be evident in
normolipidemic individuals. The most common
histological finding of the disease is foamy, lipid
laden dermal macrophages referred to as foam
cells [4]. Foam cells result from phagocytosis of
extravasated lipids in the interstitial space by
receptor-mediated endocytosis. Xanthomas are
associated with increased cardiovascular risk and
decreased average life span [2].
Description of the Disease
Xanthomas may present in different forms,
including eruptive xanthoma, plane xanthoma,
xanthoma tuberosum, tendon xanthoma, and xan-
thelasma palpebrarum [3, 4]. Of these, xanthe-
lasma palpebrarum is the most common, seen as
slightly raised, yellow papules or plaques on the
eyelids [2, 5]. Eruptive xanthomas are a manifes-
tation of severe hypertriglyceridemia and hyper-
chylomicronemia and most commonly develop
on the extensor surfaces of the upper and lower
extremities, buttocks, and hands [2]. They are
first evident as erythematous, yellow, dome-
shaped papules [1, 2]. They are referred to as
“eruptive” because they occur as a sudden erup-
tion within 3 weeks of increased plasma triglyc-
erides. Eruptive xanthomas are associated with
increased risk of type two diabetes mellitus and
pancreatitis. Plane xanthomas are large plaque-
like lesions associated with paraproteinemia and
lymphoproliferative disorders such as myeloma
and monoclonal gammopathy [2, 6, 7].
Lipoproteins are proposed to form a complex
with the excess protein associated with these dis-
orders, leading to cutaneous manifestations.
Direct infiltration of the skin by malignant cells
has also been postulated. There is usually no
underlying abnormality in lipid metabolism [6].
Tendinous xanthomas are most commonly
found on the Achilles’ tendons, the extensor ten-
dons of the hands, and the elbows. They are
associated with a particularly high level of free
P. Singh et al.
and total cholesterol in the serum. Xanthoma size
is correlated with degree of hypercholesterolemia.
Patients with homozygous familial hypercholes-
terolemia present with tendinous xanthomas from
childhood, while those that are heterozygous
develop tendon xanthomas by age 20 [4].
Tuberous xanthoma is also related with familial
hypercholesterolemia [2]. The tendon increases in
size due to lipid deposition, edema, and inflam-
mation. The differential diagnosis of tendinous
xanthoma includes tendonitis, bursitis, rheuma-
toid nodules, gout tophi, and trauma [4]. Tuberous
xanthomas present as flat or elevated nodules in
the joints near the elbows, knees, hands, and feet
that can be several centimeters in size [2].
Cerebrotendinous xanthomatosis is an important
but rare neurocutaneous syndrome [8, 9].
Therapeutic Alternatives
All types of xanthomas may be treated with surgi-
cal excision [3]. Some people may experience
resolution with dietary modification and lowering
of serum lipid levels [1, 3, 7]. In the case of xan-
thelasama palpebrarum, alternative methods
include destruction by electrocautery, tricholoro-
acetic acid, and carbon dioxide laser vaporization
[3, 5]. Lesions treated with electrocautery, trichol-
oroacetic acid, and surgical excision tend to recur.
Surgery is associated with post-operative compli-
cations, particularly scarring. Carbon dioxide
laser vaporization has been associated with hyper-
trophic and atrophic scarring, pigment changes,
pain, hemorrhage, long healing times, and infec-
tion [5]. Pulsed Dye Laser, Q-switched Nd-Yag
laser and Erbium-Yag laser have been success-
fully used with good cosmetic outcomes [1].
Several studies have shown that the best treat-
ment for tendinous xanthoma is to address the
underlying disorder of lipid metabolism.
Probucol, one of the first drugs used to treat
hyperlipidemia, decreases levels of total serum
cholesterol and HDL cholesterol. Significant
regression of tendinous xanthomas was also
found with fibrates. Statins, the most commonly
used hypolipidemic drugs, lead to significant
decrease in xanthoma size by decreasing total
126 Cryosurgery for Xanthomas
cholesterol and LDL cholesterol and increasing
HDL cholesterol. Due to the presence of dyslip-
idemia, the most common cause of death in
patients with tendinous xanthoma is ischemic
heart disease secondary to atherosclerosis [4].
Cryosurgery
Cryotherapy is widely used to treat dermal and
epidermal lesions because of its therapeutic and
cosmetic outcomes. It would be expected to
destroy xanthomas due to a lack of collagen in
long established lesions. Tuberous xanthoma has
been successfully treated with cryosurgery. A
patient with multiple tuberous xanthomas on his
elbows and knees did not experience resolution
of his lesions after institution of dietary measures
for 3 months. Each of his lesions was sprayed
with LN in open spray with a single freeze-thaw
cycle of 15 s. Three to four lesions were sprayed
at each monthly session, with the patient return-
ing until all his lesions were treated [3].
Xanthelasma palpebrarum also may be treated
with liquid nitrogen cryotherapy [3, 5]. One hun-
dred patients with xanthelasma palpebrarum
were treated with a 15 s cycle of nitrous oxide
using the Basco Cryos apparatus. A single ses-
sion was conducted, with the number of freeze-
thaw cycles varying from 1 to 21, depending on
the patient [5].
Success Rates
Wright et al. [3] described mild pain, which was
controlled with aspirin. Edema, which occurred
in every patient, resolved within 3 days. Each
xanthoma developed an eschar that withered
within 2 weeks, leaving behind permanent macu-
lar hyperpigmentation. A single freeze-thaw
cycle was sufficient to completely prevent recur-
rence at 6 months.
Dewan et al. [5] reported local and radiating
post-procedure pain lasting from 2 to 6 min. All
635
patients had edema at 24–48 h and 8 % had
edema after 1 week. After 24–48 h, tense bullae
were found in 8 % of cases. After 1 week, crust-
ing was observed in all cases and infection
occurred in 3 % of patients. At 6 months, recur-
rence was observed in 26 patients with average
lesion size of 50 % of the original lesion. Another
6 % of patients had hypopigmentation in the cen-
ter of their lesion.
Conclusions
Cryosurgery should be considered due to its
low morbidity and ease of use [3]. It is effec-
tive, safe, less time consuming, less painful,
and cosmetically appropriate [5].
References
1. Zaremba J, Zaczkiewicz A, Placek W. Eruptive xan-
thomas. Adv Dermatol Allergol Postepy Dermatol
Alergol. 2013;30(6):399–402.
2. Zak A, Zeman M, Slaby A, Vecka M. Xanthomas:
clinical and pathophysiological relations. Biomed
Pap. 2014;158(2):181–8.
3. Wright AL, Colver GB, Buxton PK. Treatment of
tuberose xanthomata with liquid nitrogen cryother-
apy. Clini Exp Dermatol. 1988;13(2):121–2.
4. Tsouli SG, Kiortsis DN, Argyropoulou MI,
Mikhailidis DP, Elisaf MS. Pathogenesis, detection
and treatment of Achilles tendon xanthomas. Eur
J Clin Invest. 2005;35(4):236–44.
5. Dewan SP, Kaur A, Gupta RK. Effectivenes of cryo-
surgery in xanthelasma palpebrarum. Indian
J Dermatol Venereol Leprol. 1995;61(1):4–7.
6. Marcoval J, Moreno A, Bordas X, Gallardo F, Peyrí
J. Diffuse plane xanthoma: clinicopathologic study of
8 cases. J Am Acad Dermatol. 1998;39(3):439–42.
7. Eisendle K, Linder D, Ratzinger G, Zelger B, Philipp
W, Piza H, et al. Inflammation and lipid accumulation
in xanthoma disseminatum: therapeutic consider-
ations. J Am Acad Dermatol. 2008;58(2):S47–9.
8. Honda A, Salen G, Matsuzaki Y, Batta AK, Xu G,
Hirayama T, Tint GS, Doy M, Shefer S. Disrupted
coordinate regulation of farnesoid X receptor target
genes in a patient with cerebrotendinous xanthomato-
sis. J Lipid Res. 2005;46:287–96.
9. Salen G, Shefer S, Berginer V. Biochemical abnor-
malities in cerebrotendinous xanthomatosis. Dev
Neurosci. 1991;13:363–70.
 Part XII
Pre-malignant and Malignant
Skin Conditions
 Cryosurgery for Premalignant
and Malignant Skin Conditions
127
Parmvir Singh, Rivka C. Stone, Robert A. Schwartz,
and Giuseppe Micali

Abstract
Cryosurgery can be used to treat pre-malignant and malignant skin condi-
tions. Actinic keratosis (AK) is a pre-malignant proliferation of keratino-
cytes manifesting as erythematous, scaly papules or plaques on sun-exposed
skin. Two types of therapy are need for AK: lesion directed, to destroy
individual AK and field, to destroy perilesional, microscopic changes.
Lesion directed therapies include electrodessication and curettage, exci-
sion, and laser ablation. Field physical modalities include photodynamic
therapy (PDT), peels, and laser resurfacing. Cryosurgery, a lesion directed
therapy, is very successful and is one of the most commonly employed
treatments for AK. Bowen’s disease presents as a well-defined, hyperkera-
totic plaque; therapeutic options include PDT, curettage, topical 5-FU,
excision, laser ablation, radiotherapy and cryosurgery. Malignant lesions
treatable with cryosurgery include basal cell carcinoma (BCC) and squa-
mous cell carcinoma (SCC). Excision is the most commonly used therapy
for them. Alternatives include electrodessication and curettage, radiation,
PDT, topical 5-FU and imiquimod. Cryosurgery for BCC and SCC shows
success rates that rival excision when performed by a trained physician.

Keywords
Actinic keratosis • Bowen’s disease • Basal cell carcinoma • Squamous
cell carcinoma • Cryosurgery

P. Singh, MD R.A. Schwartz, MD, MPH, DSc (Hon), FRCP (Edin)

Department of Dermatology, Department of Dermatology, Rutgers University
University Hospital, School of Public Affairs and Administration,
Newark, NJ, USA Newark, NJ, USA
R.C. Stone, MD, PhD G. Micali, MD (*)
Department of Dermatology, Department of Dermatology, University of Catania,
Rutgers- New Jersey Medical School, Catania, Italy
Newark, NJ, USA e-mail: gimicali1@hotmail.it

© Springer-Verlag London 2016 639

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_127
640
Introduction
Cryosurgery has historically been used in the
treatment of pre-malignant and malignant skin
conditions. The pre-malignant conditions include
actinic keratosis (AK) and Bowen’s disease.
Malignant conditions include both basal cell car-
cinoma (BCC) and squamous cell carcinoma
(SCC). Topical and surgical treatment options are
also available.
Description of the Disease
AK affects an estimated 58 million people in the
United States [1]. AKs are pre-malignant prolif-
erations of atypical keratinocytes. They manifest
clinically as erythematous, scaly papules or
plaques on sun-exposed skin, most commonly in
older, fair-skinned individuals (Fig. 127.1) [1–3].
Occupational sun exposure is a major risk factor
for development of AKs [3]. They usually occur
on the face and dorsal surface of the hands [4].
AK may undergo progression to SCC [2–6]; the
risk of progression is estimated to be between 0.1
and 20 %, but 60–97 % of SCC originate from
AK [1, 5]. In addition to visible AK, subclinical
pre-neoplastic changes, termed field canceriza-
Fig. 127.1 Actinic keratoses of the face: multiple ery-
thematous, scaly patches
P. Singh et al.
tion, can be appreciated histologically in peri-
lesional skin [1, 2, 4, 7]. Dermatoscopy shows a
peculiar strawberry appearance, produced by: a
pink-to-red pseudonetwork, white-to-yellow sur-
face scales, fine, linear-wavy vessels, and hair
follicle openings filled with yellowish keratotic
plugs and/or surrounded by a white halo.
Histology identifies subclinical lesions and may
help predict future recurrence [4].
Bowen’s disease, or SCC in situ, manifests as
a well-defined, hyperkeratotic, and erythematous
plaque (Fig. 127.2) with histological evidence of
full-thickness epidermal dysplasia [8].
Dermatoscopy may show irregular glomerular
vessels and scaling [8]. The risk for progression
to SCC is 3–5 % [8].
Non-melanoma skin cancers (NMSC) include
BCC and SCC (Fig. 127.5). The BCC: SCC ratio
in the United States is 4:1 [9]. BCC is the most
common cancer in the United States with increas-
ing incidence and lifetime prevalence of 15–39 %
[10–12]. It arises from the non-keratinized cells of
the basal layer of the skin [11]. It is slow growing,
and has a mortality rate of 0.1 % [11]. It is most
common in chronically sun-exposed locations,
such as the head, neck, and upper chest [11, 12].
p53 mutation plays a role in the pathogenesis of
50 % of BCC cases [11, 13], as does aberrant acti-
vation of the Hedgehog signaling pathway [14].
Three main forms of BCC exist: superficial
(Fig. 127.3), nodular (Fig. 127.4) and scleroder-
miform. A peripheral raised border is classically
Fig. 127.2 Bowen’s disease of the forearm: well-defined,
erythematous, scaly, slightly raised plaque
127 Cryosurgery for Premalignant and Malignant Skin Conditions
Fig. 127.3 Superficial basal cell carcinoma of the trunk:
erythematous, crusted plaque with a raised peripheral
border
Fig. 127.4 Small nodular basal cell carcinoma of the
face: translucent nodule with small erosions and superfi-
cial linear vessels
observed. On dermatoscopy, BCC shows typical
tree-like vessels and/or ulcerations, leaf-like
areas, spoke-wheel areas, blue-gray globules and/
or large blue-gray ovoid nests in pigmented forms.
SCC may be superficial, nodular (Fig. 127.5) or
ulcerated. On dermatoscopy, SCC displays a
641
Fig. 127.5 Nodular invasive squamous cell carcinoma of
the trunk: ulcerated, crusted nodule
polymorphous vascular pattern (hairpin, dotted,
and/or linear irregular vessels) over a whitish
background, with centrally located scales or kera-
tin crusts. BCC has a high risk of local destruc-
tion, but a low risk of metastatic spread, SCC has
substantial metastatic potential [9].
Therapeutic Alternatives
There are two main classes of therapies for AK:
lesion directed and field directed [1]. Lesion-
directed therapy, applied to visible AKs, is best
when lesions are early and few [1, 4]. They
include electrodessication and curettage, shave
excision, and laser ablation [15]. The former is
used for large, hypertrophic lesions but often
results in scarring [1, 6]. Curettage may be used
alone or to debulk hyperkeratotic lesions to make
them more amenable to cryosurgery [1].
AK may benefit from field therapy to treat sub-
clinical damage to peri-lesional skin [1, 7]. Field
directed therapies include photodynamic therapy
(PDT), dermabrasion, peels, and laser resurfacing
[1, 3]. Topical therapeutic options include 5-fluoro-
uracil, imiquimod, ingenol mebutate and diclofe-
nac; all treat AK by provoking an inflammatory
response [3, 15, 16]. 5-FU is the drug with the best
cost-benefit ratio [7]. It interferes with DNA
synthesis [16]. 0.5 %, 1 %, 2 %, and 5 % 5-FU are
approved for the treatment of AKs [16]. Imiquimod,
a toll-like-receptor 7 immunomodulator, is approved
for AKs on the face and scalp at concentrations of
642
5 % and 3.75 % [16]. Diclofenac is a cyclooxygen-
ase inhibitor approved as a 3 % gel [16]. Ingenol
mebutate works by inducing cell death and provok-
ing inflammation [16]. Adverse effects of topical
agents are erythema, xerosis, pruritus, and irritation
[1]. 5-FU, imiquimod, diclofenac, and ingenol meb-
utate display comparable efficacies [15]. Optimally,
AK should be treated with a combination of lesion
and field-directed therapies [1].
Curettage of Bowen’s disease is well-tolerated,
with few complications, and low recurrence rate
[8]. PDT has been found to be effective for
Bowen’s disease; superior to curettage and topi-
cal 5-FU [8]. 5-FU and cryosurgery have similar
efficacies [8]. Other options for Bowen’s disease
include excision, Mohs micrographic surgery,
laser ablation, and radiotherapy [8].
Excision,with negative histologic margins, is
favored for NMSC; its cure rate being near 90 % [9].
Mohs micrographic surgery is employed for com-
plex and/or ill-defined NMSCs [17]. Non-surgical
options may be preferred in the elderly and in poor
surgical candidates, or for those desiring superior
cosmesis [16, 18]. Electrodessication and curettage
carries a higher risk of NMSC recurrence.
Non-surgical options include radiation, PDT,
and topical 5-FU and imiquimod [11, 12, 15, 16].
PDT is not as efficacious as surgery and should
be limited to treat lesions less than 1–2 mm in
thickness, in patients for whom other alternative
are contraindicated [9]. 5-FU is approved for
superficial BCC; side effects include local pruri-
tus, burning, erythema, blistering, erosions, and
occasionally necrosis [16]. Imiquimod 5 % is
approved for superficial BCC; adverse effects
include localized itching, burning, erythema, ves-
icles, and erosion [16]. Neither 5-FU nor imiqui-
mod are effective options for SCC [9]. Both are
inferior to surgical options for BCC [9]. There is
not enough evidence to support the use of topical
diclofenac or ingenol mebutate for NMSC.
Cryosurgery
Recommended cryosurgery methodology
include rapid freezing (over 100 °C per min, to
below –25 °C) and slow thawing (over 10 °C per
P. Singh et al.
min) [9]. Prolonged freeze-thaw cycles correlate
to impaired healing and exacerbate the common
adverse effects of cryosurgery, including blister-
ing, ulceration, and dyspigmentation [1, 5].
Bullae and ulcers result from damage down to
the epidermal basement membrane, a marker of
efficacious cryosurgery [1]. The risk of hypo-
chromia is proportional to the depth and duration
of the freeze cycle, since melanocytes are par-
ticularly susceptible to low temperatures [19].
Less common adverse effects include alopecia,
milia, hypertrophic scarring, and tissue distor-
tion [9].
Liquid nitrogen (LN) cryosurgery is one of the
most commonly used treatments for AK [5, 6]. It
targets clinically apparent individual lesions and
may not adequately treat subclinically affected
neighboring skin [1]. In a study of 92 patients with
5–50 AKs on the face and forearms treated with
cryosurgery and SPF 30 sunscreen, a significant
reduction in count and lesion size was observed [5].
Each lesion was treated with LN spray for 5–10 s to
a freeze margin of 1–2 mm; repeated 120 days later.
Longer freeze cycles yield better responses; in a
prospective study, clearance rate at 3 months with a
single freeze-thaw cycle was 39 % with freezing
times under 5 s and 83 % with freezing times over
20 s [19]. In a head-to-head study, cryosurgery was
found to be inferior to a combination of 0.5 % 5-FU
plus 10 % salicylic acid, displaying lower histologi-
cal clearance and increased rate of recurrence [4].
Additional studies suggest that cryosurgery com-
bined with topical therapy (0.015 % ingenol mebu-
tate [2], 0.05 % 5-FU [20], or 3.75 % imiquimod
[21]) can improve clearance rates while maintaining
an acceptable profile of adverse effects.
For Bowen’s disease, cryosurgery can be a
simple, inexpensive, outpatient treatment, pro-
viding that an adequate regimen is followed [8].
This includes a single freeze-thaw cycle of 30 s
using LN, two freeze-thaw cycles of 20 s with a
thaw period in between, or three single 20-s treat-
ments at weekly intervals. In one study of 225
BCC’s, 34 SCC’s, and 128 SCC in situ treated
with cryosurgery, recurrence rates were 2.7 %,
2.9 %, and 0.8 %, respectively [22].
NMSC most amenable to cryosurgery include
low-risk sharply demarcated BCC on the eyelids,
127 Cryosurgery for Premalignant and Malignant Skin Conditions
nose, ears, lips, dorsa of the hands, scalp, trunk
and lower legs [11, 18]. If the borders are irregu-
lar or the tumor invades deeply, cryosurgery is
not a first choice [23]. Often, debulking is
required prior to cryosurgery [23]. A number of
studies report successful cryosurgery treatment
of BCC on the eyelid [10], vulva [11], and other
delicate locations [23]. There, flat probes may be
more suitable [11]. Cryosurgery regimens for
treatment of NMSC often incorporate several
freeze-thaw cycles down to at least –50 °C,
directed at an area encompassing the lesion plus
a 3–5 mm margin [24–26]. Recurrent BCC have
been successfully treated with cryosurgery [27].
Success Rates
In several studies, pre-malignant lesion recurrence
rates are very low [10, 11, 23], 30-year cure rates of
cryosurgery-treated SCC and BCC have been
reported to be over 97 % [28–30]. Overall data
show clearance rates of 94–99 % for non-melanoma
skin cancer [9]. Wound healing and cosmetic out-
comes are generally very satisfactory.
Conclusions
Cryosurgery performed on appropriately
selected lesions by a trained professional can
effectively treat most pre-malignant and malig-
nant skin lesions [18]. Cryosurgery is quicker,
safer, and cheaper than other modalities. In com-
bination with topical therapies, cryosurgery can
effectively treat visible and subclinical lesions,
serving as an attractive and viable field therapy.
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 Actinic Keratosis
128
Leonard H. Goldberg, Diane Trieu,
and Anna Drosou

Abstract
Actinic keratoses are sun-induced in situ epidermal tumors characterized
by the proliferation of abnormal keratinocytes. Clinical lesions present as
erythematous, rough, scaly, hyperkeratotic papules or plaques on sun
exposed areas. However, a subclinical component may be present due to
invasion of tumor cells down the hair follicle, sweat duct, or at the base of
the epidermis without affecting keratinization and causing clinical change.
Lesions with an increased risk of progression to invasive squamous cell
carcinoma should be biopsied. The two main treatment approaches for
actinic keratoses are field-directed and lesion-directed therapy. Cryotherapy
is the most common form of treatment of actinic keratoses. Here, we pres-
ent the technique, application, adverse events, efficacy, limitations, and
compare cryotherapy versus other treatment modalities. Overall, cryother-
apy coupled with field-directed therapy provides the best clinical outcome
for the treatment of AKs.

Keywords
Actinic keratosis • Cryotherapy • Cryosurgery • Lesion directed therapy •
Field directed therapy • Proliferative actinic keratosis • Squamous cell
carcinoma in situ • Invasive squamous cell carcinoma

Introduction

Actinic keratoses (AKs) are sun-induced in situ

L.H. Goldberg, MD (*) • D. Trieu, MD
A. Drosou, MD
Department of Dermatology,
Derm Surgery Associates, Houston, TX, USA
e-mail: goldb1@dermsurgery.org
epidermal tumors characterized by the prolifera-
tion of abnormal keratinocytes. Clinical lesions
present as erythematous, rough, scaly, hyperkera-
totic papules or plaques on sun exposed areas
(Fig. 128.1). However, a subclinical component
may be present due to invasion of tumor cells
down the hair follicle, sweat duct, or at the base

© Springer-Verlag London 2016 645

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_128
646
of the epidermis not affecting keratinization,
causing parakeratosis/scale. The main rationale
to treat AKs is to prevent the formation of inva-
sive squamous cell carcinoma (SCC), and later
deeper invasion and metastasis.
Fig. 128.1 Actinic keratosis. AK presents as a hyper-
keratotic scaly papule on the nose
Fig. 128.2 First description of actinic keratosis, at Unna’s book “Die Histopathologie der Hautkrankheiten”, in 1894.
The name he used was “Carcinom der Seemanshaut” (sea-man’s skin)
L.H. Goldberg et al.
History
In 1894, Unna wrote a description in the chapter
“Carcinom der Seemanshaut” (“sea-man’s skin”)
in his book Die Histopathologie der
Hautkrankheiten (Fig. 128.2) [1]. In 1896,
William Auguste Dubreuilh described senile ker-
atosis as a ‘lesion of the epidermis similar to an
epithelioma with a natural tendency to degener-
ate into an epithelial cancer’. The concept of AK
being a premalignant lesion versus SCC in situ
was debated as early as the 1900s [2].
Epidemiology
AK is one of the most common dermatologic dis-
eases in the US (58 million people) [3] causing a
huge financial burden. The development of AKs
is dependent on a combination of risk factors
including cumulative sun exposure, fair skin
128 Actinic Keratosis
complexion, advancing age, early childhood sun
exposure, male gender, occupational exposure,
recreational outdoor activities, and living closer
to the equator [4]. The prevalence of AKs
amongst males ages 60–69 is 83 %, and in
females 64 % which increases with age. The inci-
dence of AKs amongst men and women over the
age of 65 during one calendar year is approxi-
mately 26 million [3, 5].
Clinical Presentation
AKs clinically present as an erythematous mac-
ule or patch with fine scales which eventually
become erythematous and or hyperkeratotic
plaque with yellow to white scale. Symptoms
include tenderness, itchiness, burning, and a
sandpaper-like texture [5]. Lesions range from
just a few millimeters up to 1 cm. Lesions greater
than 1 cm or tenderness are indications of inva-
sive SCC. Subclinical AKs have histological
change of AKs without alteration of the keratini-
zation pattern and a clinical keratosis. This may
be referred to as field cancerization. AKs typi-
cally occur on sun-exposed areas favoring the
head, bald or balding scalp, face, extensor fore-
arms, dorsal hands [6], and the lower legs espe-
cially in women.
Proliferative AK is a SCC in situ of well-
differentiated squamous cell carcinoma cells
present at the base of the epidermis. These cells
may be seen around the sweat ducts and the hair
follicles and are often invasive in the dermis.
They may be subclinical or present with red scaly
macules and plaques with a large diameter. They
tend to ulcerate [7]. This deep involvement of the
infundibular structures and lateral spread results
in poor cure rates with regular cryotherapy. In
order to appropriately treat proliferative AK and
SCCis, a wide freeze with 1 cm margins to
account for the subclinical spread of AK is
suggested.
Actinic cheilitis occurs on the sun-exposed
areas of the mucous membrane of the lower lip.
Lesions on the lip present as leukoplakia or as
areas of scaly macules, papules, and plaques
that may ulcerate. Histologically there may be
647
thickening of the epithelium and growth of
abnormal squamous cells at the base of the
epithelium.
AKs as represented by SCC in situ may prog-
ress to invasive squamous cell carcinomas
(SCCs). Signs of progression to invasion include
tenderness, ulceration, bleeding, induration,
inflammation, thickening, diameter greater than
1 cm, and erythema. Immunosuppressed patients
(organ transplant patients, myelodysplastic dis-
eases, immunosuppressive therapy) are at
increased risk for invasive SCC. The progression
rate to invasive squamous cell carcinoma has
been reported to range between 0.025 and 16 %
[8, 9]. The duration of time for AKs to develop
into invasive SCCs averaged 24.6 months [10].
The lifetime risk of a patient with AKs to develop
malignant invasion of the dermis is between 6.1
and 10.2 % [11]. Sixty to 90 % of invasive SCCs
on histologic examination have SCCis/AK in
their margins [12]. It is presumed that early
detection and treatment of AKs could signifi-
cantly reduce the number of invasive SCC, result-
ing in improved patient morbidity and reduced
medical care expenses.
Histopathology
AK is characterized by a proliferation of abnor-
mal keratinocytes at the basal layer of the epider-
mis. These epidermal keratinocytes appear larger
than normal keratinocytes with variation in size
and staining of the nuclei with multiple nuclei
and prominent nucleoli. There is usually an
increased number of mitotic figures and individ-
ual cell keratinization may be seen.
Management of AKs
A five step approach has been proposed to opti-
mize the treatment of AKs: (1) Routine dermato-
logic examinations, (2) Regular self/spousal
examination, (3) Lesion-directed therapy, (4)
Field-directed therapy, (5) Patient education with
respect to both sun protection and the need for
AK treatment [13].
648
Patients should be screened every 3–6 months
for the presence of AKs and invasive SCCs.
Patients with AKs that are painful, greater than
1 cm in diameter, thick, inflamed, rapidly enlarge,
bleed, or ulcerate should be biopsied to rule out
invasive SCC.
Field-directed therapy is appropriate for
patients with multiple or diffuse AK lesions [13].
Available treatment modalities include physical
treatments such as dermabrasion, chemical peels,
carbon-dioxide laser resurfacing, and photody-
namic therapy; as well as topical pharmacologic
agents including 5-FU, imiquimod, diclofenac,
and ingenol mebutate.
Lesion-directed therapies require well-defined
target lesions. These therapies include destruc-
tive procedures such as cryotherapy with LN,
shave removal, elliptical excision, laser resurfac-
ing, and electrodessication and curettage.
A combination of field-directed therapy and
lesion-directed therapy may be used as sequential
therapy. A national physician survey study in
2006 revealed that about 75 % of the diagnosed
AKs were treated with LN, 16 % with pharmaco-
therapy, and 9 % with a combination of both [14].
For the purpose of this textbook, we focus on
the treatment of AKs with cryotherapy.
Cryotherapy
Cryotherapy uses LN spray at 196 °C to freeze
and destroy the affected epidermis with the AK
lesions. The epidermis and upper dermis is fro-
zen to −5 to −20 °C, which causes death of cells
by freezing. Ice crystals form intra and extra-
cellular leading to cell death and vascular throm-
bosis [15]. Exposure to high electrolyte
concentrations in the surrounding non-frozen or
thawing fluid and recrystallization patterns dur-
ing thaw contribute to further tissue damage [16].
Slow cooling produces extracellular ice, but this
is not as damaging as rapid cooling, which pro-
duces intracellular ice formation [17].
Additionally, inflammation develops during the
first 24 h after treatment, further contributing to
the destruction of the lesion through immuno-
logical mechanisms [18].
L.H. Goldberg et al.
Cryosurgery has been the most common treat-
ment of choice for AKs for decades [19, 20]. It is
cheap, environmentally friendly, quick, effective,
easy to perform, safe, easy to tolerate for the
patient, and does not rely on patient compliance
for efficacy.
Methodology (How I Do It)
LN can be applied as an open spray, through
closed contact with a cryoprobe, or dabbed onto
the lesions with cotton swabs. Before spraying
LN we recommend local anesthesia with ½ %
lidocaine with 1/200,000 epinephrine. This allows
the patient to tolerate more freezing for a longer
duration. It may not be necessary for thinner
AKs, but is a valuable option for patients with a
low pain threshold.
The open spray technique is the most common
method for the treatment of AKs (Fig. 128.3).
The LN spray gun is positioned 1–1.5 cm away
from the skin and targets the center of the lesion.
The LN is sprayed until an ice ball develops over
and around the lesion with a 1–2 mm margin. The
spraying continues until the desired freeze of the
epidermis is completed. Depending on the size
and thickness of the lesion the freezing may be
prolonged until the entire dermis is frozen. Freeze
time is defined as the time from the formation of
an ice-ball to the beginning of thawing [21]. If
more than one freeze-thaw cycle is desired, suf-
ficient time should be provided to allow for com-
plete thawing before the next cycle. AKs are
generally treated with a freeze time between 5
and 20 s and one freeze-thaw cycle. Lesions
larger in diameter and hypertrophic AKs require
a longer freeze time. A surface temperature of −5
to −20 °C is sufficient to destroy the epidermis.
The length of application of the LN can only
be accurately defined by the infrared measure-
ment of surface temperature (Brymill©)
(Fig. 128.4). As a rule of thumb the ice-ball at the
surface of the skin forms at −5 °C, which is
sufficient to kill the epidermis. For a deeper
freeze, the dermis must be frozen as can be
judged by the button sign—hold the dermis
between two fingers, it is hard like a button and
128 Actinic Keratosis 649

a b

c d

e f

Fig. 128.3 Cryotherapy for actinic keratosis. (a) ice ball during freezing. (d) Ice ball remains for several
Injection with local anesthetic. (b) Initial stage of freez- seconds after LN. (e) Partial thawing of the lesion. (f)
ing. A small ice ball starts forming. (c) Fully developed Complete thawing of the lesion

presumably frozen. Fat freezes at lower tempera- With the cryoprobe technique, a cryoprobe is
tures −20 °C and is relatively resistant to freezing attached to the LN spray gun and is applied
by the spray technique. directly onto the skin. Occasionally, a gel
650
a b
d e
Fig. 128.4 LN spray with an infrared sensor. (a) View of
the LN spray. (b) The liquid crystal display, which dis-
plays temperature and time. (c) The light emitted changes
based on the temperature. Originally is purple when we
interface medium can also be used [18]. Direct
contact of the cryoprobe eliminates excess scat-
tering of LN and avoids damaging surrounding
healthy skin. This is particularly useful in sensi-
tive areas such as the eyelid. However, the freeze
time is generally two to three times longer
L.H. Goldberg et al.
c
f
start freezing. (d) The infrared sensor. (e) At lower tem-
perature the light becomes green. (f) When it reaches the
target temperature the light becomes red
compared to the open spray technique. The
cryoprobe technique has not gained popularity
due to the tedious nature of applying the differ-
ent probe sizes to the varying sizes of AKs. Also,
the required probe size may not be readily
available.
128 Actinic Keratosis
The cotton swab technique can be used as an
alternative method when the dispersion of LN
spray is unwanted as around the eyes and ears. A
cotton swab is dipped into the LN poured into a
cup. The cotton swab filled with LN is then
applied to the AK and the epidermis is frozen.
The operator can control the depth of the freezing
by varying the time of application of the cotton
swab to the lesion. Overall, the cotton swab tech-
nique delivers less freezing intensity to treated
areas, so this method is most effective for thin
superficial AKs.
Applications
Spot Treatment
Cryosurgery is mostly used for spot treatment of
AKs. It is optimal for visible lesions with clearly
defined margins [20]. When the lesion is ill
defined there is a greater possibility that a part of
the lesion remains untreated, resulting in a higher
recurrence rate.
Field Treatment
Cryopeeling or extensive cryotherapy is used for
the field treatment of AKs. It may be a full-face,
cosmetic unit of the face, or extremity peel with
liquid nitrogen and requires use of local anesthe-
sia and analgesics. The face is divided into 15 seg-
ments and each segment is sprayed separately.
The segmental spraying with resting periods of
approximately 30 s allows for pain dissipation.
The redness, edema, and peeling may be followed
by blister formation, with about a 10-day recovery
time [22]. It can be used in other locations such as
the hands. The recurrence rate after cryopeeling at
12–18 months is about 12 %, which compares
favorably to other field therapy treatments [23].
Despite good therapeutic results, cryopeeling has
not appealed to dermatologists due to the long
application period and the difficult, symptomatic
required down-time. The technique is operator
dependent and may be followed by pain, blister
formation, ulceration, and hypopigmentation.
651
Combination Treatment
Combination of spot treatment cryotherapy with a
field treatment method such as PDT, 5-FU, or
imiquimod is also used as a method to reduce recur-
rences after the treatment of AKs [13, 24]. The need
for field treatment in addition to cryotherapy has
become more apparent in efforts to prevent subse-
quent recurrences or new lesion formation [13]. We
prefer cryotherapy with regular treatments with
PDT every 3–12 months. An abbreviated course of
5-FU with subsequent cryosurgery of any remain-
ing lesion has also been suggested as a method to
combine treatment of subclinical lesions and fully
developed AKs [25, 26].
Adverse Events
The side effects of cryotherapy treatment for AKs
can be immediate, during the time of the proce-
dure, shortly after, or delayed. Immediate side
effects include pain, headache [27], erythema, dis-
comfort, blistering, edema (especially on the eye-
lids and ears), and infection. The pain and
discomfort varies depending on the number of
lesions, the freezing time, and the patients’ pain
threshold [15]. Local anesthesia can/should be
used to reduce patient discomfort. Delayed adverse
events include post-inflammatory hypo or hyper-
pigmentation, and less commonly scarring [21].
Success Rates
Cryotherapy with LN is broadly accepted as a
very efficient treatment for AKs.
The therapeutic efficacy of cryotherapy treat-
ment for AKs is operator dependent and strongly
depends on the technique used, especially the
amount of time of the spray and the frequency of
the applications (number of freeze-thaw cycles).
A longer freeze time and an increased number of
freeze-thaw cycles strengthen the efficacy of the
technique.
Lubritz et al. reported a cure rate of 98.8 % in a
study published in 1982, however, newer studies
demonstrated a cure rate ranging from 39 to 100 %
[28, 29]. The great variability of the cure rate after
652
treatment with liquid nitrogen may be due to differ-
ent parameters used for freezing. In the study by
Thai et al. the response rate was 39 % with a freeze
time less than 5 s, while it was 83 % for a freeze
time greater than 20 s [29]. In a study by Goldberg
et al. where the target surface temperature was
standardized at –5 °C with an infrared thermometer
attached to the hand held LN unit named Tracker
(Brymill ©), the cure rate was found to be close to
100 % at the 6-week follow up [30].
The efficacy of cryosurgery depends greatly
on the practitioner’s experience and level of
expertise, as the technique is not well standard-
ized. However, the infrared thermometer of
Brymill achieves this goal. The treatment param-
eters include freeze time, freezing depth, time of
application, thaw time, number of freeze-thaw
cycles and can vary among different operators
[30]. Pressure in the LN tank and the size of the
nozzle affect the amount and speed of freezing
and confounding factors. Another challenge for
the standardization of cryotherapy treatment of
AKs is the variability of the histology and depth
spread down hair follicle and sweat ducts of each
individual AK. Features such as thickness, long-
standing history, recurrence, location (i.e. dor-
sum of hands) requires more aggressive treatment,
whereas thin plaques and lesions on the eyelids
or on atrophic cigarette paper-like older skin
might need less intense freezing. The LN spray
with an integrated infrared sensor (Brymill©)
measures the surface temperature of treated
lesions. This approach may reduce the variability
in the efficacy of cryotherapy, as it directly mea-
sures the end-result and surpasses many of the
other confounding factors [30].
Furthermore, treatment of AKs with cryotherapy
does not address subclinical lateral spread and does
not allow for histologic examination of the tissue.
Proliferative AK/SCCis may have a high recurrence
rate due to the adjacent subclinical spread.
Cryotherapy versus Other
Treatment Modalities
Cryotherapy is the most frequently used treat-
ment for AKs because it is easiest to use, readily
available, cheap and environmentally friendly.
L.H. Goldberg et al.
Studies evaluating new pharmaceutical treat-
ments or destructive methods compare the new
modality with cryotherapy using LN.
Krawtchenko et al. compared cryotherapy cure
rates with 5-FU and with imiquimod for AK treat-
ment [31]. The initial cure rate after the treatment
was approximately 70 % for cryosurgery vs. 96 %
for 5-FU and 85 % for imiquimod. Cryosurgery
had the higher recurrence rate 1 year later (72 % of
initially cleared lesions, vs 46 % for 5-FU and
27 % for imiquimod). Several studies have been
performed comparing methyl aminolaevulinate-
photodynamic therapy (MAL-PDT) to cryother-
apy [32–35]. Freeman et al. found superior efficacy
of two sessions of MAL-PDT vs single cycle cryo-
therapy for treatment of AKs in 204 patients (91 vs
68 %). In another intraindividual randomized con-
trolled study both treatments were found to have a
high cure rate (89 % vs 86 %) 24 weeks after treat-
ment [34]. Another prospective randomized study
of 193 patients demonstrated a superior response
rate from cryotherapy compared to MAL-PDT at
3 months (75 % vs 69 %) [33]. The cosmetic
results and patient satisfaction however was supe-
rior with PDT. Cryotherapy has also been shown
to be superior to ablative CO2 laser for the treat-
ment of isolated AKs of the scalp and face (Cure
rate at 3 months:78 % vs 72 %, no relapse at
12 months: 73 % vs 22 %) [36].
Conclusion
Cryotherapy is a valuable tool in the derma-
tologists’ armamentarium for the treatment of
AKs. It is the preferred method of treatment
for lesion-directed therapy because of effi-
cacy, ease of use, safety, tolerability, and low
cost. However, for patients with extensive
subclinical AKs the recurrence rate after cryo-
therapy is high and cryotherapy should be
combined with field-directed treatment to
ensure good long-term outcomes.
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J Am Acad Dermatol. 2000;43(1):138–50.
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3. Society for Investigative Dermatology, American
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skin diseases, 2005. Available from: http://www.
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april2005skindisease. Accessed 20 Mar 2014.
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carcinoma. J Am Acad Dermatol. 2000;42:S4–7.
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for AKs (protocol for a cochrane review). Chichester:
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6. Marks R, Ponsford MW, Selwood TS, Goodman G,
Mason G. Non-melanotic skin cancer and solar kera-
toses in Victoria. Med J Aust. 1983;2:619–22.
7. Goldberg LH, Joseph AK, Tschen JA. Proliferative
actinic keratosis. Int J Dermatol. 1994;33:341–5.
8. Marks R, Rennie G, Selwood TS. Malignant transfor-
mation of solar keratoses to squamous cell carcinoma.
Lancet. 1988;1:795–7.
9. Graham JH. Precancerous lesions of the skin. Prim
Care. 1976;2:699–716.
10. Fuchs A, Marmur E. The kinetics of skin cancer: pro-
gression of AK to squamous cell carcinoma. Dermatol
Surg. 2007;33:1099–101.
11. Dodson JM, DeSpain J, Hewett JE, Clark DP.
Malignant potential of AKs and the controversy over
treatment. Arch Dermatol. 1991;127:1029–31.
12. Ceilley RI, Jorizzo JL. Current issues in the manage-
ment of AK. J Am Acad Dermatol. 2013;68:
S28–38.
13. Lee AD, Jorizzo JL. Optimizing management of AK
and photodamaged skin: utilizing a stepwise approach.
Cutis. 2009;84:169–75.
14. Balkrishnan R, Cayce KA, Kulkarni AS, et al.
Predictors of treatment choices and associated out-
comes in AKs: results from a national phycisian sur-
vey study. J Dermatol Treat. 2006;17:162–6.
15. Poziomczyk CS, Koche B, Dornelles MA, Dornelles
SIT. Pain evaluation in the cryosurgery of AKs. An
Bras Dermatol. 2011;86(4):645–50.
16. Chapter 37: Dermatologic surgery Andrew’s disease
of the skin: clinical dermatology. 11th edn. p. 863–87.
17. Kuflik EG. Cryosurgery. In: Bolognia JL, Jorizzo JL,
Rapini RP, editors. Dermatology. New York: Elsevier;
2007.
18. Andrews MD. Cryosurgery for common skin condi-
tions. Am Fam Physician. 2004;69(10):2365–72.
19. Feldman SR, Fleischer AB, Williford PM, Jorizzo JL.
Destructive procedures are the standard of care for treat-
ment of AKs. J Am Acad Dermatol. 1999;40:43–7.
20. Jorizzo JL, Carney PS, Ko WT, Robbins P, Weinkle
SH, Werschler WP. Treatment options in the manage-
ment of AK. Cutis. 2004;74 Suppl 6:9–17.
21. Nashan D, Meiss F, Muller M. Therapeutic strategies
for AKs- a systematic review. Eur J Dermatol.
2013;23(1):14–32.
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22. Chiarello SE. Full-face cryo-(liquid nitrogen) peel.
J Dermatol Surg Oncol. 1992;18:329–32.
23. Chairello SE. Cryopeeling (extensive cryosurgery) for
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Dermatol Surg. 2000;26(8):728–32.
24. Management of AK. Drug Ther Bull 2013;7:81–4.
25. Abadir DM. Combination of topical 5-fluorouracil
with cryotherapy for treatment of AKs. J Dermatol
Surg Oncol. 1983;9(5):403–5.
26. Jorizzo J, Weiss J, Vamvakias G. One week treatment
with 0.5% fluorouracil cream prior to cryosurgery in
patients with AKs: a double blind, vehicle-controlled,
long term study. J Drugs Dermatol. 2006;5:133–9.
27. Buckhart CG, Buckhart CN. Ice cream headaches
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1116–7.
28. Lubritz RR, Smolewski SA. Cryosurgery cure rate of
AKs. J Am Acad Dermatol. 1982;7:631–2.
29. Thai KE, Fergin P, Freeman M, et al. A prospective
study of the use of cryosurgery for the treatment of
AKs. Int J Dermatol. 2004;43:687–92.
30. Goldberg LH, Kaplan B, Vergilis-Kalner I, Landau
J. Liquid nitrogen: temperature control in the treat-
ment of AK. Dermatol Surg. 2010;36(12):1956–61.
31. Krawtchenko N, Roewert-Huber J, Ulrich M, Mann I,
et al. A randomized study of topical 5% imiquimod vs
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petent patients with AKs: a comparison of clinical and
histological outcomes including 1-year follow up. Br
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32. Kaufmann R, Spelman L, Weightman W, et al.
Multicenter intraindividual randomized trial of topi-
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33. Szeimies RM, Karrer S, Radakovic-Fijan S, et al.
Photodynamic therapy using topical methyl
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34. Morton C, Campell S, Gupta G, et al. Intraindividual,
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photodynamic therapy and cryotherapy in subjects with
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35. Freeman M, Vinciullo C, Francis D, et al. A compari-
son of photodynamic therapy using topical methyl
aminolaevulinate (Metvix) with single cycle cryother-
apy in patients with AK: a prospective randomized
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36. Zane C, Facchinetti E, Rossi MT, Specchia C, Ortel B,
Calzavara-Pinton P. Cryotherapy is preferable to abla-
tive CO2 laser for the treatment of isolated actinic
keratoses of the face and scalp: a randomized clinical
trial. Br J Dermatol. 2014;170(5):1114–21.
 Bowenoid Papulosis
129
Thomas J. Jasterzbski and Robert A. Schwartz

Abstract
Bowenoid papulosis (BP) is a human papillomavirus-associated, high-grade
squamous intraepithelial lesion (HSIL) that is evident as red, brown, or flesh
colored papules that may coalesce to form small plaques. Eruptions are tradi-
tionally found in the anogenital regions of young, sexually active men and
women, but extra-genital manifestations have also been documented.
Although BP typically follows a benign, self-limited course, it carries slight
malignant potential with transformation to invasive squamous cell carcinoma
in up to 2.6 % of cases. BP may also serve as a warning for occult infection
with high risk HPV, most commonly HPV-16. Due to the histologic similar-
ity between BP and squamous cell carcinoma in-situ, it is important to clini-
cally distinguish BP from the larger well-demarcated plaques of Bowen’s
disease and erythroplasia of Queyrat.
Treatment options for BP include a variety of medical and surgical
therapies. Although cryotherapy is commonly used for BP, there are lim-
ited studies evaluating the effectiveness of different freeze-thaw regimens.
Cryosurgical techniques used in the treatment of Bowen’s disease may
serve as an appropriate model for treatment of BP due to similar histopa-
thology. When choosing a regimen, it is important to consider that the risk
of hypopigmentation increases with longer freezing times. Size, abun-
dance, and location of the BP should guide treatment, as smaller, less
numerous lesions are more amenable to cryotherapy.

T.J. Jasterzbski, MD
Department of Dermatology, Rutgers University
New Jersey Medical School, University Hospital,
Newark, NJ, USA
R.A. Schwartz, MD, MPH, DSc (Hon),
FRCP (Edin) (*)
Department of Dermatology and Pathology,
Rutgers University New Jersey Medical School,
Rutgers University School of Public Affairs and
Administration, Newark, NJ, USA
e-mail: roschwar@cal.berkeley.edu
© Springer-Verlag London 2016 655
W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_129
656
Keywords
Bowenoid papulosis • Bowen’s disease • Human papillomavirus (HPV) •
Squamous cell carcinoma (SCC) • Anogenital lesion • Cryotherapy
Introduction
Bowenoid papulosis (BP) is a human
papillomavirus-associated, high-grade squamous
intraepithelial lesion (HSIL) that is evident as
red, brown, or flesh colored papules that may
coalesce to form small plaques [1–4]. Eruptions
are traditionally found in the anogenital regions
of young, sexually active men and women, but
extra-genital manifestations have also been docu-
mented [1, 5, 6].
Description
Despite a similar clinical appearance to condy-
loma acuminata, BP is caused by oncogenic
types of HPV, predominately HPV-16, and has a
histologic pattern that resembles squamous cell
carcinoma (SCC) in-situ (CIS) [3, 7, 8]. Although
BP typically follows a benign, self-limited
course, it carries slight malignant potential with
transformation to invasive squamous cell carci-
noma in up to 2.6 % of cases [8, 9]. Furthermore,
BP may also serve as a warning for occult infec-
tion with high risk HPV [1]. For example, a
woman with BP of the vulva and a man with BP
of the penile shaft may be at increased risk for
developing cervical cancer and penile cancer,
respectively [1].
The differential diagnosis for BP includes,
but is not limited to the following: condyloma
acuminata, Bowen’s disease/erythroplasia of
Queyrat, invasive SCC, melanocytic nevi, seb-
orrheic keratosis, psoriasis, lichen planus, and
molluscum contagiousm [3, 8]. The diagnosis
of BP is confirmed by evaluation of a histologi-
cal specimen, which typically shows moderate
scattered or full-thickness intraepidermal cel-
lular dysplasia, mitotic figures, dyskeratosis,
T.J. Jasterzbski and R.A. Schwartz
and irregular acanthosis [3, 10, 11]. However,
due to the histologic similarity between BP and
CIS, it is important to clinically distinguish BP
pigmented papules from the larger well-demar-
cated plaques seen in Bowen’s disease and
erythroplasia of Queyrat. Dermatoscopy may
aid in the diagnosis of BP, with lesions exhibit-
ing peripheral brown-grey dots in a linear
arrangement [10].
Alternative Treatment [8, 11–13]
Medical:
– Fluorouracil 5 % cream
– Imiquimod 5 % cream
– Brachytherapy (superficial, selective
radiotherapy)
– Photodynamic therapy
Surgical:
– Laser resection (CO2 or Nd:YAG)
– Curretage and cautery
– Local excision
– Moh’s micrographic surgery
Cryosurgery
Although standardized cryosurgical techniques
for the treatment of bowenoid papulosis are not
well published, regimens used for the treatment
of Bowen’s disease may provide optimal benefit,
since these two conditions demonstrate similar
histopathology. When choosing a regimen, it is
important to consider that the risk of hypopig-
mentation increases with longer freezing times
[11, 14]. Furthermore, distribution, size, and
location of lesions should guide treatment, as
smaller, less numerous lesions are more amena-
ble to cryotherapy [14].
129 Bowenoid Papulosis
Methodology (How We Do It)
The following are used in the treatment of
Bowen’s disease (use as a guide)
– One 30 second freeze-thaw cycle
– Two 20 second freeze-thaw cycles with a thaw
period
– Three single 20 second treatments, each
spaced several weeks apart
Response Rates
There is limited literature regarding the effec-
tiveness of cryotherapy in the treatment of
bowenoid papulosis. A study by Hansen et al.
indicated that cryotherapy was associated with a
greater risk of Bowen’s disease reoccurrence fol-
lowing treatment (13.4 %) compared with fluo-
rouracil (9 %) and surgical excision (5.5 %) [15].
However, this study may not accurately reflect
the benefits of cryosurgery in the treatment of
bowenoid papulosis, as large BD plaques may be
more difficult to remove than smaller BP
papules.
Conclusion
BP is a rare, HPV-induced premalignant
condition that manifests as pigmented pap-
ules predominately in the anogenital region.
Despite histologic similarity to SCC in-situ,
BP typically follows a benign, self-limited
course. Treatment options include a variety
of medical and surgical therapies, which
should be tailored to the size, abundance,
and location of lesions. Although commonly
used for BP, there are limited studies evalu-
ating the effectiveness of different freeze-
thaw regimens. Cryosurgical techniques
used in the treatment of Bowen’s disease
may serve as an appropriate model for treat-
ment of BP due to similar histopathology.
One should also consider that HPV vaccina-
tion does not treat, but may be suitable pre-
vention of HPV-induced precancerous and
cancers [16, 17].
657
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a four-year retrospective review of epidemiology and
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2008;34:878–83.
16. Handler MZ, Handler NS, Majewski S, Schwartz RA.
Human papilloma virus vaccine trials and tributions.
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743–56.
17. Handler NS, Handler MZ, Majewski S, Schwartz RA.
Human papilloma virus vaccine trials and tributions.
Vaccine efficacy. J Am Acad Dermatol. 2015;
73:759–67.
 Basal Cell Carcinoma
130
Eshini Perera and Rodney Sinclair

Abstract
Nonmelanoma (NMSC) are the most common skin cancer in the Western
world. Basal cell carcinoma (BCC) account for roughly 80 % of
NMSC. BCC are slow growing and rarely aggressive. A variety of treat-
ments exist for the treatment of BCC with conventional surgical excision
being the most commonly use method. Other options include Mohs’ sur-
gery, curettage and electrodessication, laser therapies, radiotherapy and a
number of topical treatments. Cryosurgery is a potentially under-utilised
treatment option that offers the benefit of being less invasive. Cryotherapy
is not recommended for lesions that are: morphoeic; have poorly defined
margins; recurrent; on the eyelid, nasolabial fold or preauricular region;
fixed to deeper structures; have a depth greater than 3 mm. Lesions greater
than 2 cm in diameter can be treated segmentally. BCCs that are thick can
be debulked with a curette prior to treatment. Common complications
include pain, edema and blistering. When BCC lesions are selected care-
fully treatment outcomes are highly successful.

Keywords
Cryotherapy • Nonmelanoma skin cancer • Non-melanoma • Basal cell
carcinoma • Segmental cryosurgery • Debulking

Introduction

Nonmelanoma skin cancer (NMSC) are the most

E. Perera, MBBS, BMedSci (*) common skin cancer in the fair-skin population
R. Sinclair, MBBS, MD, FACD [1]. Basal cell carcinomas (BCCs) are the most
Sinclair Dermatology, Department of Medicine, common NMSC. There are a variety of treatment
Dentistry and Health Sciences, options available for the management of BCC
University of Melbourne, East Melbourne,
VIC, Australia with surgical excision being the most commonly
e-mail: eshinip@gmail.com used method. Cryosurgery has been widely

© Springer-Verlag London 2016 659

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_130
660
available for the treatment of BCCs for the last
20 years, and is a useful alternative to the tradi-
tional surgical methods of removal [2].
Cryosurgery has a comparable outcome to con-
ventional surgical excision when lesions are care-
fully selected and the correct technique is used. It
is a less invasive method of treatment with a
lower side effect profile and it is well tolerate
without anaesthesia.
Description of the Disease
BCCs are the most common malignant neoplasm
found in human populations [1]. BCCs constitute
roughly 80 % of all non-melanoma skin cancers
[3]. The growths are derived from cells originat-
ing in the basal layer of the epidermis [1]. Skin
directly exposed to sunlight is commonly
affected, including skin on the eyelids, the inner
canthus and behind the ear.
BCC tumors have a characteristic slow pro-
gression. The slow rate of enlargement is due to
constant and frequent cell death, whereby dying
neoplastic cells undergo shrinkage and necrosis
[4]. Extensive cell death causes BCC tumors to
be contained within the area of origin [5].
Current estimations indicate that 0.0028–0.1 %
of BCCs metastasize [6–8]. Lesions infiltrate
tissues with irregular finger-like outgrowths
contiguous with the main tumor mass. The
malignancy is locally invasive and causes
significantly greater morbidity than mortality
[8]. Local tissue destruction is the main morbid-
ity that results from BCC and this can impact on
the cosmetic appearance or the functional out-
come of the location [9].
Nodular BCCs are the most common clinical
subtype [10, 11]. Nodular BCCs present as trans-
lucent or slightly erythematous papules or nod-
ules with a sharp contour, a smooth margin, and
telangiectasia. They commonly occur in sun-
exposed areas of the head and neck region.
Pigmented BCCs are hyperpigmented nodular
BCCs. These lesions exhibit increased melanisa-
tion and thus can resemble malignant melano-
mas. The pigmented BCC has histological
features which are similar to the nodular form,
but with additional melanin [12].
E. Perera and R. Sinclair
The superficial subtypes also occur com-
monly. BCCs of the superficial variety present as
well-circumscribed flat lesions with a pearly bor-
der [5]. Often there is scaling and crusting. These
lesions often occur on the trunk and can resemble
eczema [11].
Infiltrative and morpheic BCCs are more
aggressive variants and they are less common [13–
15]. Morpheic BCCs may present as a depressed
white macule or scariform lesion which has a
poorly defined border. The morpheic variety of
BCCs usually has an aggressive growth pattern.
These aggressive variants may invade extensively
prior to exhibiting any obvious clinical symptoms.
Therapeutic Alternatives
Surgical Excision
Surgical excision is the most commonly used
method of treating BCC. Complete specimens
can be sent for histological examination and to
assess the adequacy of excision. Primary exci-
sion is associated with a high rate of local control
and complete excision has a high cure rate [16].
However, conventional surgical excision may not
produce a cosmetically attractive outcome, par-
ticularly on the face.
Mohs Micrographic Surgery
Another surgical technique that allows for greater
histological control is Mohs micrographic sur-
gery. This technique – a microscopically-
controlled method of removing skin cancers – is
considered the gold standard for treatment of
NMSC [16]. It involves excision of the lesion and
a surrounding margin of tissue [16]. The tissue is
sent for histopathological examination and
another excision is undertaken if there are remain-
ing tumor cells [17]. This process is repeated until
all of the remaining abnormal cells are removed.
This treatment modality is associated with an
increased certainty of tumor eradication com-
pared with conventional excision. Traditionally,
this surgical option is performed on NMSC
lesions occurring on the face. The technique also
130 Basal Cell Carcinoma 661

allows for preservation of non-affected skin and
produces a better cosmetic outcome.
Unfortunately, the increasing cost of using
Mohs micrographic surgery means that the pro-
cedure is usually limited to areas like the face
where the cosmetic and functional outcome justi-
fies the cost.
Prior to the introduction of PDT, laser thera-
pies were used. The CO2 laser in particular, was
found to be effective using between two and four
passes of the laser. These findings were reported
in a number of individual case reports and case
series [26–28]. Since the introduction of PDT, the
use of lasers has become relatively infrequent.

Curettage and Electrodessication Cryosurgery

Skin curettes are oval or fenestrated spoons with a
sharp cutting edge, usually used combined with an
electrosurgical modality [18]. In the treatment of
NMSC, electrodessication is used by superficially
destroying affected tissue [18]. This technique
involves removing cancerous tissue with the curette
followed by lightly applying an electrical current to
the base to burn any remaining tumor cells. This
modality is relatively cheap and easy to perform.
The cure rate for primary BCCs treated with this
technique has been reported at 92.3 % [19]. A study
examining 150 curetted non melanoma skin cancers
showed that 76 % left some residual tumor tissue at
the surgical margins [20]. Risk of recurrence is
much higher with this technique and this is not the
treatment of choice for recurrent BCCs [21].
Cryosurgery is a method that involves tumor cell
destruction by freezing the affected area with
vaporizing liquid nitrogen [29]. Tumor cells are
sensitive to cryosurgery because of their high
water content and high metabolism [30]. Ice
forms both extra- and intracellularly. Intracellular
ice crystals expand and burst from inside the cell.
Like curettage, cryotherapy is simple and
inexpensive; however, it does not allow for tumor
margins to be examined under the microscope.
Table 130.1 outlines features to consider when
selecting lesions for cryosurgery.
Methodology
Instruments Required

Radiotherapy, Photodynamic, Sterile gloves

Topical and Laser Treatments Hand-held cryotherapy unit with various size tips.
Antiseptic agents
Treatments such as radiotherapy, or using radia- Curette
tion to treat abnormal cells, are reserved for Gauze and bandage
BCCs that cannot be cured with surgical manage-
ment. Often radiotherapy is used to complement
Table 130.1 Lesion selection
surgical management [22]. Topical treatments
like imiquimod (5 % concentration) that stimu- Favorable features Unfavorable features
late a cell-mediated immune response to cancer Well defined margins Poorly defined margins
cells, have been approved for treatment of BCCs, Diameter less than Diameter more than 2 cm
2 cm
with an 82 % clearance rate [23].
Depth less than 3 mm Depth more than 3 mm
Photodynamic therapy (PDT) is a technique of
Mobile Fixed to deeper structures
using light to activate a photo-sensitizer applied Primary lesions Recurrent lesions
to the skin, which causes formation of reactive Superficial or nodular Morphoeic
oxygen species that destroy tumor-affected cells Previous radiotherapy Pigmented skin
[24]. A study evaluating nodular BCC treatment to site
using PDT in comparison with surgical excision Back/helix of ear Ala nasi, eyelid, nasolabial
demonstrated a 76 % clearance rate compared fold, scalp, preauricular region
with 96 % respectively [25]. Based on data from Ref. [2]
662 E. Perera and R. Sinclair

Treatment of Lesions Less Than 2 cm after cryosurgery to prevent post-cryosurgery

morbidity. Figure 130.3 demonstrates the end
BCC lesions should have a clearly defined mar- result using this technique.
gins. Lesions that do not have a clear border or
those that are recurring should be treated using Single freeze-thaw cycle may be used, how-
surgical excision. The canister should be full so ever there is some debate as to the success rate of
that the flow of liquid nitrogen is even. For this this method [31]. A study comparing sing and
method the ‘B’ tip should be used. double freeze-thaw cycles demonstrated a 95.3 %
cure rate of facial BCC when double freeze-thaw
1. The lesion and an area of 0.5–0.75 cm of nor- cycle was used compared to 79.4 % cure rate
mal skin is clearly demarcated with a surgical [31]. Effective tissue-destruction occurs with
pen (Fig. 130.1). multiple freeze-thaw cycles.
2. Hold the spray 1 cm away from the lesion at a
90° angle.
3. Spray the center of the lesion until ice forms
over the lesion and spreads laterally to the
margin (Fig. 130.2)
4. Maintain the field size of ice formation, at the
marked margin, for a total 30 s. The time mea-
sured should begin from when ice first forms
at the marked margin. At this stage the lesion
should be frozen solid and firm on palpation.
5. The area is then thawed out for no less than 60 s.
The lesion should be palpated until the lesion
softens and the white appearance disappears.
6. Steps 2–4 are repeated.
7. The area is dressed with a potent steroid cream Fig. 130.2 Treatment of a basal carcinoma on the left
side of the nose. The frield size of ice formation should be
(used twice daily) to prevent inflammation.
held at the marked margin for 30 s (Courtesy of Gloria
Oral prednisolone can also be used for 3 days Graham, MD [45])

Fig. 130.1 A basal cell carcinoma. An area of 0.5– Fig. 130.3 Post-operative result of a basal cell carcinoma
0.75 cm should be marked around the lesion with surgical treated with cryotherapy. Note that there is very minimal
pen (Courtesy of Gloria Graham, MD [45]) scarring (Courtesy of Gloria Graham, MD [45])
130 Basal Cell Carcinoma
Treatment of Lesions That Are
Irregular, Thick or Larger than 2 cm
in Diameter
Segmental Therapy
For lesions that are larger than 2 cm or those that
are irregular a single spray to the center of the
lesion will not be adequate, as the temperatures at
the margins may not reach destructive tempera-
tures. Segmental treatment can be used for these
types of lesions:
1. Divide the lesion into multiple sections. Areas
of no more than 2 cm are recommended so
that the whole lesion can be frozen to a satis-
factory temperature.
2. Each section is treated using the same meth-
odology outlined for the treatment of lesions
less than 2 cm. Each area is treated separately
and the field of treatment may overlap.
3. Treatment may occur over two sessions, the
second session may occur after 4 weeks
4. Alternatively a portion of the lesion can be treated
in one session and remaining treatments treated in
a second section. This may help to reduce the
severity of the side effects that may occur.
Debulking
Keratin is a poor conductor of cold and as a result
thick BCC lesions do not reach satisfactory tem-
peratures sufficient for tumor cell destruction.
For BCCs which are large or thick a debulking
procedure can be performed using a sharp curette.
Recently a study examining 38 patients found
that debulking BCCs with radio frequency prior
to cryotherapy was also a useful method of deb-
ulking lesions, and provided the benefits of less
bleeding, decreased procedure time and reduced
use of surgical material. Currently, there is no lit-
erature comparing efficacy of the two debulking
methods with each other [32].
Complications
The most common side effect of cryosurgery is
pain [2]. Usually pain occurs in most patients
however the severity of pain can vary. In some
663
cases the pain can be so severe patients may have
a syncopal episode. Edema and blistering is also
a common occurrence. Symptoms are most
severe around the eyelids, lips and genitals.
Hypopigmentation is also a common side
effect. This loss of pigment is permanent. This
side effect is not usually a problem for patients
with fair skin. A feathering technique (light spray
around the margin after treatment) can be used to
disguise the contrast between the hypopigmented
and normal skin.
Success Rates
Cure rates are in the order of 92–96 % which is
comparable to conventional surgical excision [2].
Recurrence rates have varied in the literature
ranging from 0 to 8.2 % [33–43]. A recent study
in 2003 examining 12 BCCs, smaller than 1 cm,
located on the trunk and arms. The lesions were
treated with a single freeze-thaw treatment and
were excised and examined histologically. All of
the lesions examined had no histologic evidence
of the tumor after 1–2 months [43].
Cosmetic results have been shown to be better
in conventional surgical treatment compared to
cryotherapy [44]. One prospective randomized
study compared the cosmetic results of BCC
treated with cryosurgery and surgical excision.
Cosmetic outcome was evaluated by the patient,
a dermatologist, a dermatology nurse, a plastic
surgeon and a beautician. The dermatologist, sur-
geon and nurse all felt that the excision yielded a
significantly better cosmetic outcome. The
patients felt that the excision produced a better
cosmetic result, however the difference between
the ratings for both treatments was small. Lastly,
the beautician, who was unbiased, had no prefer-
ence for either procedure.
Conclusions
There are many treatment options available
for the treatment of BCC, including surgical
excision, Mohs micrographic surgery, curet-
tage and electrodessication and lasers.
Cryosurgery is one potentially under-utilised
and less invasive option for the treatment of
664
BCC. It is easy to perform in an outpatient set-
ting and offers the benefits of being a fast and
cheap procedure to perform. Studies have
shown that cryosurgery can be equally as
effective as traditional surgical options when
the correct technique is used and the lesions
are carefully chosen.
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 Squamous Cell Carcinoma
131
Gloria F. Graham and Sara Moradi Tuchayi

Abstract
Cutaneous squamous cell carcinoma (CSCC) is the second most common
nonmelanoma skin cancer in the United States, with 700,000 new cases
diagnosed yearly. Keratoacanthoma, squamous cell carcinoma in situ, pre-
cancerous lesions and CSCC will be discussed in this chapter. As more
studies report the self-healing tendency of Keratoacanthoma (KA), cryo-
surgery is used frequently unless the tumor is already beginning to regress.
Excision or shave biopsy, which can be followed by freezing for 30–60 s,
extirpates these tumors frequently. Excisional biopsy, intralesional therapy
or topical therapy and radiotherapy are other options.
Actinic keratosis (AK) is the third most common reason for consulting
a dermatologist with estimated annual risk of progression to SCC of 0.075
(Marks et al., Lancet 1(8589):795–797, 1988) to 0.6 (Criscione et al.,
Cancer 115(11):2523–2530, 2009) per lesion per year. Cryosurgery is the
most common treatment method for SCC in situ and AK. Freezing the
lesion for about 3 up to 30 s is a fast effective method. Shave excision,
curettage and laser therapy, photodynamic therapy (PDT), topical drug
therapy are other available treatment methods. Radiation therapy helps
with certain large squamous cell carcinomas. Referral to a Moh’s surgeon
should be considered for large, deep tumors with ill-defined tumors, or
those in cosmetically critical locations.
The total metastasis rate of CSCC is about 4 %. Tumor thickness, tumor
location and histological subtype are important factors affecting metasta-
sis rate. SCC of ear has a significantly higher risk of metastasis. SCC less

G.F. Graham, MD (*) • S.M. Tuchayi, MD, MPH

Department of Dermatology, Wake Forest University
School of Medicine, Winston Salem, NC, USA
e-mail: ggfgraham@aol.com

© Springer-Verlag London 2016 667

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_131
668 G.F. Graham and S.M. Tuchayi

than 2 cm in size and 3–5 mm in depth with well-defined borders is ideal

for cryosurgery.
With a high cure rate of 97–98 % and a reasonable cost cryosurgery is
an efficient convenient method for treatment of SCC with acceptable cos-
metic results.

Keywords
Squamous cell carcinoma • Keratoacanthoma • Actinic keratosis • Actinic
cheilitis • Cryosurgery • Photodynamic therapy • Radiotherapy • Mohs
microsurgery

Introduction rate. Risk of metastasis in lip carcinoma is

CSCC is the second most common nonmelanoma
skin cancer in the United States, with 700,000
new cases diagnosed yearly [1–3]. The incidence
of CSCC is increasing. Although most patients
achieve complete remission with available treat-
ment modalities, those with advanced disease
have a poor prognosis [3]. Keratoacanthoma
(KA), SCC in situ, precancerous lesions and
CSCC are discussed in this chapter.
slightly more than SCC of the free skin [8, 9], but
SCC of ear has a significantly higher risk of
metastasis mostly because of lymphatic drainage
via the parotid gland. The same happens about
temples and lateral cheek [9].
Erythroplasia of Queyrat is a carcinoma in situ
of the mucous membranes with a characteristic
tendency to bleed easily [10].
Therapeutic Alternatives

Description of the Disease Excisional biopsy and histopathological study of

As more studies report the self-healing tendency
of KA [4], therapy is in general not necessary, but
can be preventive of disfiguring atrophic scars
after healing.
Actinic keratosis (AK) is the third most com-
mon reason for consulting a dermatologist [5].
Although AK is a premalignant skin condition,
estimated annual risk of progression to SCC is
0.075 [6] to 0.6 [7] per lesion per year in different
studies. Actinic cheilitis predominantly on the
lower lip is another precancerous lesion. Bowen
disease of the skin or SCC in situ can progress to
invasive SCC, which occurs in about 10 % of
patients, therefore SCC in situ should be treated [8].
The total metastasis rate of cutaneous SCC is
about 4 %, ranging from 0 % in SCC up to 2 mm
tumor thickness to 4 % in tumors between 2 and
6 mm, and 18 % in tumor thickness of more than
6 mm. Tumor location and histological subtype
are other important factors affecting metastasis
the biopsy is the preferable therapy for KAs.
Intralesional therapy with MTX, 5-FU, bleomy-
cin or interferon-α [11], topical therapy with
imiquimod or 5-FU and radiotherapy are other
options [12]. Electrodessication and curettage
and cryosurgery are destructive techniques that
are used by those trained in those techniques.
Shave excision, curettage and laser therapy
are ablative treatment modalities for SCC in situ
and AK. Photodynamic therapy (PDT) also
shows good results and is an important therapy
form for field cancerization leading to scar-free
healing. Side effects of PDT include erythema,
and pain during irradiation. Topical drug therapy
options include 5-fluorouracil (5-FU), imiqui-
mod, diclofenac, and ingenol mebutate. For
actinic cheilitis after histopathological study, sur-
gical excision, laser therapy, vermilionectomy, or
topical therapy can be applied. In erythroplasia of
Queyrat choosing treatment method depends on
location with ablative therapy often preferred
131 Squamous Cell Carcinoma
when possible. Topical drug therapy with imiqui-
mod or 5-FU is another choice [8].
For suspected invasive SCC histopathological
study determines therapy method by estimating
the metastasis risk considering tumor size (>2 cm
diameter), tumor penetration depth (<2 mm, no
risk; >2 mm, moderate risk; >6 mm, high risk) and
also histological classification. Other critical fac-
tors are location of the tumor around the ear and
long-term immunosuppression. The therapy of
choice for low-risk tumors is excision with safety
margins of 4 mm, but high-risk tumors need to be
treated with micrographically controlled excision
(MCS) with ideal safety margins of 1 cm when
possible and never less than 6 mm [8].
For patients with a high surgical risk radiother-
apy remains an appropriate alternative therapy.
Cryosurgery
Cryosurgery is used frequently for KA unless the
tumor is already beginning to regress.
Cryosurgery is the most common treatment
method for SCC in situ and AK. Cryosurgery
side effects like hypo- or hyperpigmentation and
scarring are probable.
SCC less than 2 cm in size and 3–5 mm in
depth with well-defined borders is ideal for cryo-
surgery. Tumors overlying bone or cartilage
respond well with excellent healing. Tumors in
darker-skinned patients are best treated by other
techniques because hypopigmentation can be
expected. Highest cure rates are in smaller and
even larger, more superficial, tumors, while deeper
tumors of approximately 7–8 mm in size have
shown the highest recurrence rate in statistics that
I have kept for more than 30 years [13, 14].
Methodology (How I Do It)
Keratoacanthoma
For KA, excision or shave biopsy, which can be
followed by freezing for 30–60 s, extirpates these
tumors frequently and often with a better cos-
metic result than natural regression (Fig. 131.1).
669
Squamous Cell Carcinoma In Situ
and Actinic Keratosis
Freezing SCC in situ and AKs for about 3 up to
30 s is a fast effective method that is usually
applied without anesthesia. For precancerous
lesions a 2-mm halo of ice is the goal.
My experience of treating 563 selected squa-
mous cell carcinomas over 20 years from 1966 to
1989 has shown a total cure rate of 97.8 %.
Comparing the results of 5-year intervals indi-
cates an improvement from 91.2 % in 1966–1970
to 98.5 % in 1985–1989. The most important rea-
son might be the evolution of cryosurgical meth-
ods, especially the shift from −25 to −50 °C. Most
were treated by a double freeze-thaw cycle and
for 15 years with thermocouple monitoring. Most
required approximately 60 s of freezing to
achieve a 5–6 mm halo of ice around the frozen
tumor site [13].
An important conclusion of this data analysis
was absence of a significant relationship between
size as measured in skin surface diameter and
cure rate when dividing lesions in size groups of
≤0.5, 0.6–1.2, 1.3–2.4, and >2.4. SCC arising
from an AK may stay superficial before develop-
ing SCC [15]. Kuflik’s experience showed a simi-
lar result [15]. Both studies were in contrast with
Zacharian’s [16]. Many of his earlier cases were
treated to –25° C. as were Grahams for the first
several years.
The results from four different methods of
single and double freeze/thaw cycles with or
without curettage gave 100 % cure rate with
curettage and double freeze, followed by 97.9 %
with single freeze, 97.5 % with curettage and
freeze, and 95 % with Double freeze for
Squamous cell carcinoma [13].
Data from this study suggested that SCC of
eyelids and nose require more aggressive cryo-
surgical procedures [13] (Fig. 131.2).
We did not have anyone doing Mohs microsur-
gery until Shelly Pollock arrived at Duke in 1980s.
I sent him so many large aggressive tumors that he
came monthly to my office to do follow up of
cases and brought Ron Riefkohl, plastic surgeon
from Duke. This gave me much better choices and
patients were pleased to have this variety of
670 G.F. Graham and S.M. Tuchayi

a b

Fig. 131.1 (a) Keratoacanthoma. (b) Spray after curettage. (c) Hypopigmented atrophic scar 7 years after cryosurgery
of a large Keratoacanthoma in a patient who has had numerous ones, only on her legs

options in the only dermatology practice in
Wilson a town of 25,000 people. There were
many farmers who grew tobacco and were
exposed not only to sun from morning to night but
to arsenic used to kill budworms in tobacco. They
had punctate keratoses 1–2 mm in size on their
palms and soles. Clark et al. studied selenium in
the soil and found it to be low and this probably
accounted for more absorption of arsenic [14, 17].
SCC is well treated with shave excision, curet-
tage, and cryosurgery. Defining the border of the
lesion with a marking pen prior to infiltrating
with local anesthetic is the first step. After that
the visible portion of the tumor can be shaved and
sent for pathology. Curettage of the base of the
lesion can help define the margins after tangential
excision, and is followed by freezing. A 5-mm
halo around the tumor is desired for skin cancer.
When freezing around the ear use a cone and a
cotton pledget to protect surrounding areas and to
prevent pain and dizziness, which can occur if
LN enters the canal. The eye should be protected
by a plastic Jagher retractor or the plastic cone.
When freezing on a mucous membrane, such as
inside the lip using K-Y jelly or applying the
cryoprobe prechilled prevents inadvertently
removing mucosa when the probe is pulled away
from the tissue.
Success Rates
With a high cure rate of 97–98 % and a reason-
able cost cryosurgery is an efficient convenient
method for the treatment of SCC with acceptable
cosmetic results.
131 Squamous Cell Carcinoma 671

a b

c d

Fig. 131.2 (a) SCC of the nasal dorsum. (b) SCC of the nasal dorsum, side view. (c) Closed probe cryosurgery of SCC.
(d) View 6 months post cryosurgery (Photos courtesy of William Abramovitz, MD)

Avoid treatment of large tumors on the scalp
and those in nasolabial fold, which often have ill-
defined margins. Always caution patients that
healing may take 4–8 weeks, especially for
tumors larger than 2 cm. Some cryosurgeons pre-
fer not to treat tumors on the lower leg while oth-
ers find it a useful modality. Being in a beach
community and living on an outer bank there are
many skin cancers seen on the legs. Avoid freez-
ing in patients with severe atherosclerosis. In my
experience a promising cure rate of 90 % was
achieved when treating recurrent tumors [13]
(Figs. 131.3 and 131.4).
Conclusion
Always consider discussing available treat-
ment options with the patient. KA and precan-
cerous lesions are good candidates for
cryosurgery. In general for patients with cer-
tain size and depth range SCC, who are on
672 G.F. Graham and S.M. Tuchayi

a b

Fig. 131.3 (a) Bowen SCC-type, left leg. (b) Six months post cryosurgery

anticoagulants, or have multiple tumors, cryo- logic surgeon should be considered for large,
surgery is preferred. Radiation therapy helps deep tumors with ill-defined tumors, or those
with certain large SCC. Referral to a dermato- in cosmetically critical locations.
131 Squamous Cell Carcinoma 673

a b

c d

e f

Fig. 131.4 Elderly patient with history of severe pruritus
associated with renal disease. Multiple squamous cell car-
cinoma (SCC) and Keratoacanthoma (KA) were arising in
areas of prurigo nodularis (PN). Referred for cryosurgery
due to the multitude of lesions. Cryosurgery (CS) was
helpful with eradicating the pruritus in the PNs. Most of
his KAs and SCCs were controlled with cryosurgery. (a)
Two areas of PN were treated. (b) Hypopigmentation
from previous freezing noted. (c) CS freeze time one min-
ute for KA. (d) Extensive area of PN during freezing. (e)
Two areas of biopsy proven SCCs shown treated with CS.
(f) Two additional SCCs shown during CS and an exten-
sive hypopigmented area from previous treatments.
Patient continued to receive treatment with CS until his
demise of unrelated illness in 2014
674 G.F. Graham and S.M. Tuchayi

References 8. Manousaridis I, Leverkus M. Malignant epithelial

tumors: Part II. Therapy and prevention. J Dtsch
Dermatol Ges. 2013;11(1):9–25; quiz 6–7.
1. Kwa RE, Campana K, Moy RL. Biology of cutaneous
9. Brantsch KD, Meisner C, Schönfisch B, Trilling B,
squamous cell carcinoma. J Am Acad Dermatol.
Wehner-Caroli J, Röcken M, et al. Analysis of risk
1992;26(1):1–26.
factors determining prognosis of cutaneous squamous-
2. Johnson TM, Rowe DE, Nelson BR, Swanson
cell carcinoma: a prospective study. Lancet Oncol.
NA. Squamous cell carcinoma of the skin (excluding
2008;9(8):713–20.
lip and oral mucosa). J Am Acad Dermatol. 1992;26(3
10. Leverkus M. Malignant epithelial tumors: Part
Pt 2):467–84.
I. Pathophysiology and clinical features. J Dtsch
3. Farasat S, Yu SS, Neel VA, Nehal KS, Lardaro T,
Dermatol Ges. 2012;10(7):457–71; quiz 72.
Mihm MC, et al. A new American Joint Committee
11. Kirby JS, Miller CJ. Intralesional chemotherapy for
on Cancer staging system for cutaneous squamous
nonmelanoma skin cancer: a practical review. J Am
cell carcinoma: creation and rationale for inclusion of
Acad Dermatol. 2010;63(4):689–702.
tumor (T) characteristics. J Am Acad Dermatol.
12. Donahue B, Cooper JS, Rush S. Treatment of aggres-
2011;64(6):1051–9.
sive keratoacanthomas by radiotherapy. J Am Acad
4. Savage JA, Maize JC. Keratoacanthoma clinical
Dermatol. 1990;23(3 Pt 1):489–93.
behavior: a systematic review. Am J Dermatopathol.
13. Graham GF. Cryosurgery in the management of cutane-
2014;36(5):422–9.
ous malignancies. Clin Dermatol. 2001;19(3):
5. Salasche SJ. Epidemiology of actinic keratoses and
321–7.
squamous cell carcinoma. J Am Acad Dermatol.
14. Graham GF, Clark LC. Statistical analysis in cryosur-
2000;42(1 Pt 2):4–7.
gery of skin cancer. Clin Dermatol. 1990;8(1):101–7.
6. Marks R, Rennie G, Selwood TS. Malignant transfor-
15. Kuflik EG, Gage AA. Cryosurgical treatment for skin
mation of solar keratoses to squamous cell carcinoma.
cancer. New York: Igaku-Shoin; 1990.
Lancet. 1988;1(8589):795–7.
16. Zacarian SA. Cryosurgery for skin cancer and cutane-
7. Criscione VD, Weinstock MA, Naylor MF, Luque C,
ous disorders. St. Louis: Mosby; 1985.
Eide MJ, Bingham SF, et al. Actinic keratoses: natural
17. Clark LC, Graham GF, Crounse RG, Grimson R,
history and risk of malignant transformation in the
Hulka B, Shy CM. Plasma selenium and skin neo-
Veterans Affairs Topical Tretinoin Chemoprevention
plasms: a case-control study. Nutr Cancer. 1984;6(1):
Trial. Cancer. 2009;115(11):2523–30.
13–21.
 Verrucous Carcinoma (Oral)
132
Marcello Menta Simonsen Nico
and Silvia Vanessa Lourenço

Abstract
Verrucous carcinoma is a special form of well-differentiated squamous
cell carcinoma with specific clinical and histological features. Oral verru-
cous carcinoma is usually extensive and difficult to treat with conventional
surgical methods. Cryosurgery can be useful in selected cases and under
experienced hands. Favored methods include previous reduction of tumor
thickness using oral retinoids or methotrexate followed by massive cryo-
surgical freezing with cryochambers or closed probes.

Keywords
Verrucous carcinoma • Florid oral papillomatosis • Verrucous leucoplakia
• Cryosurgery

Introduction matosis, epithelioma cuniculatum, and carci-

Verrucous carcinoma (VC) is a special form of
well-differentiated squamous cell carcinoma
(SCC) with specific clinical and histological fea-
tures [1]. According the site involved, names
used for this tumor include Ackerman’s tumor,
Buschke-Loewenstein tumor, florid oral papillo-
M.M.S. Nico, MD (*)
Department of Dermatology, Medical School,
University of São Paulo, Brazil, Hospital das
Clínicas, São Paulo, São Paulo, Brazil
e-mail: mentanico@hotmail.com
S.V. Lourenço, DDS
Department of Pathology, Faculdade de Odontologia
da Universidade de São Paulo, São Paulo,
São Paulo, Brazil
noma cuniculatum [2]. Inadequate names such as
verrucous proliferative leucoplakia, or verrucous
hyperplasia are occasionally used [1–3], delaying
correct diagnosis and treatment.
Clinical picture of VC on the oral mucosa
consists of cauliflower-shaped exophytic lesions,
or intensely leukokeratotic plaques. The tumor
grows slowly and locally, is invasive in nature
and unlikely to metastasize. The most common
sites of oral mucosal involvement include the
buccal mucosa, followed by the mandibular alve-
olar crest, gingiva, and tongue [1]. Buccal muco-
sal lesions often spread to the labial comissure
(Figs. 132.1 and 132.2). Differential diagnoses
include viral warts, lichen simplex chronicus,
and other forms of mucosa SCC.

© Springer-Verlag London 2016 675

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_132
676
Fig. 132.1 Oral verrucous carcinoma in a 70-year-old
male
Therapeutic Alternatives
Surgery has been the first choice of treatment for
these lesions, and radiotherapy is controversial
[1, 3]. Nevertheless, lesions frequently compro-
mise extensive mucosal areas, making conven-
tional surgery very difficult.
Cryosurgery
Cryosurgery has shown excellent results in well-
selected cases under experienced hands [2]. More
aggressive forms of SCC should be ruled out
before using this method; thorough clinicopatho-
logical correlation is mandatory.
As intense hyperkeratosis may hamper deeper
freezing, a course of acitretin 0.5–1.0 mg/kg or
methotrexate 15–20 mg/week may be used for
1–2 months, in order to reduce tumor thickness
M.M.S. Nico and S.V. Lourenço
Fig. 132.2 Same patient: commissural aspect
[4] (Figs. 132.3 and 132.4). Occasionally, clinical
picture consists of a nodule surrounded by large
keratotic plaques. These nodules can be initially
shaved off.
After adequate reduction of hyperkeratosis
has been obtained, the lesion may be ready for
freezing. Freezing must be intense and profound;
remember that VC is a malignant neoplasm, and
that the entire thickness of the epithelium must be
destroyed to achieve cure.
Methodology (How I Do It)
1. Explain the procedure to the patient, since
adequate compliance during treatment is very
important. The area to be treated must be
under local anesthesia. Use lidocaine with
epinephrine.
2. If the lesion is too extensive (florid oral papil-
lomatosis), it should be mapped, and different
132 Verrucous Carcinoma (Oral)
Fig. 132.3 The patient took acitretin 40 mg/day for
30 days. Notice significant reduction of hyperkeratosis
and lesion size
areas are then treated separately. It is not man-
datory to treat all the areas in a same session.
3. Ask for the patient to breath using only his
nose during the complete freeze and thaw
cycle; this will extend thawing time.
4. Cryochambers are the best indications for
intra oral lesions, since these cause profound
and precise surgical destruction of tissue by
allowing a confined spray of liquid nitrogen to
pool continuously over deep lesions
(Fig. 132.5). The cryochamber usually heav-
ily sticks to the treated tissue after freezing;
wait until it can be easily separated from the
mucosa without harm to the patient. This usu-
ally takes about 1 min.
5. Commissural lesions are best treated with con-
ical closed probes. Use the thumb and first fin-
ger to firmly press upper and lower lips against
the probe for a closer contact (Fig. 132.6)
677
Fig. 132.4 Reduction of commissural lesion after acitre-
tin intake
6. One 20–30 s freezing cycle is usually sufficient
if thaw time exceeds 2 min; one additional
cycle may be required.
7. Small areas left untreated may be frozen with
smaller probes.
8. Prescribe high potency analgesics.
9. Results are usually successful when the tech-
nique is correctly performed (Figs. 132.7 and
132.8). Follow-up should be extended since
VC occasionally locally relapses.
Success Rates
Contra- indications to this method mainly include
other forms of SCC, and lesions located on
mucosal areas difficult to access by cryosurgery.
Again, strict clinical pathological correlation is
mandatory.
678 M.M.S. Nico and S.V. Lourenço

Fig. 132.5 Cryochamber was used in the intraoral lesion

Fig. 132.7 Clinical aspect after 3 months

Fig. 132.6 Conical probe cryosurgery. Lips have been

pressed against probe by the surgeon’s fingers, to enhance
freezing
132 Verrucous Carcinoma (Oral) 679

References
1. Alkan A, Bulut E, Gunhan O, Ozden B. Oral verru-
cous carcinoma: a study of 12 cases. Eur J Dent.
2010;4:202–7.
2. Yu CH, Lin HP, Cheng SJ, Sun A, Chen
HM. Cryotherapy for oral precancers and cancers.
J Formos Med Assoc. 2014. doi:10.1016/j.
jfma.2014.01.014. Epub ahead of print.
3. Sciubba JJ, Helman JI. Current management strate-
gies for verrucous hyperkeratosis and verrucous carci-
noma. Oral Maxillofac Surg Clin N Am.
2013;25(1):77–82.
4. Karagozoglu KH, Buter J, Leemans CR, Rietveld DH,
van den Vijfeijken S, van der Waal I. Subset of
patients with verrucous carcinoma of the oral cavity
who benefit from treatment with methotrexate. Br
J Oral Maxillofac Surg. 2012;50:513–8.

Fig. 132.8 Clinical aspect after 3 months. If residual

lesions persist, the procedure can be repeated
 Kaposi Sarcoma
133
Renata Strumia

Abstract
Kaposi sarcoma (KS) is a vascular neoplasm with four clinical variants:
classic, endemic, immunosuppression-associated, an HIV associated.
Localised KS cutaneous tumours have been successfully treated with sur-
gical excision, laser therapy, liquid nitrogen cryotherapy and radiotherapy.
Cryotherapy can be a useful therapeutic alternative for KS nodules, expe-
cially in patients with multiple lesions.

Keywords
Kaposi sarcoma • Cryotherapy • Cryosurgery

Introduction live near the equator in Africa. Symptoms of

Kaposi sarcoma (KS) is a vascular neoplasm
with four clinical variants: classic, endemic,
immunosuppression-associated, an HIV associ-
ated [1].
Classic KS affects old men of Eastern Europe
and Mediterranean countries. It presents with red-
dish-brown papules and nodules on distal extremi-
ties and has a slow progression and benign course.
Visceral and mucosal involvement is uncommon.
Endemic African KS is a fairly common form
of the disease found in young adult males who
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara (Former), Ferrara, Italy
e-mail: restrumi@tin.it
African KS can be the same as classic
KS. However, African KS can also be found in a
much more aggressive form that may spread
from the skin to the tissues and to the bone.
Another form of KS that is common in young
children in Africa does not affect the skin but
spreads through the lymph nodes to vital organs,
and quickly becomes fatal.
Immunosuppressive therapy–related KS is
found in patients who have had an organ trans-
plant. When the immune system is weakened by
immunosuppressive drugs, diseases like KS can
develop. Immunosuppressive therapy-related KS
often affects only the skin, but may also occur in
the mucous membranes or certain other organs of
the body. This type of KS is also called transplant-
related or acquired KS.

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682
AIDS-associated KS or Epidemic KS was
described during the 1980s as an aggressive dis-
ease in AIDS patients (HIV also causes a defect
in T-cell immunity). It is over 300 times more
common in AIDS patients than in renal trans-
plant recipients.
Description of the Disease
Lesions in KS may involve the skin, oral mucosa,
lymph nodes, and visceral organs. Most patients
present with cutaneous disease. Visceral disease
may occasionally precede cutaneous
manifestations.
Cutaneous lesions in KS are characterized as
follows:
• May occur at any location but typically are
concentrated on the lower extremities and the
head and neck.
• May have macular, papular, nodular, or
plaquelike appearances.
• Nearly all are palpable and nonpruritic.
• May range in size from several millimeters to
several centimeters in diameter
• May assume a brown, pink, red, or violaceous
color and could be difficult to distinguish in
dark-skinned individuals.
• Lesions may be discrete or confluent and typi-
cally appear in a linear, symmetrical distribu-
tion, following Langer lines.
• Mucous membrane involvement is common
(palate, gingiva, conjunctiva)
Gastrointestinal lesions can occur anywhere
in the gastrointestinal tract. Pulmonary lesions
may be an asymptomatic radiographic finding,
but signs and symptoms can include cough,
hemoptysis and chest pain.
Therapeutic Alternatives
Localised KS cutaneous tumours have been suc-
cessfully treated with surgical excision, laser
therapy, liquid nitrogen cryotherapy and radio-
R. Strumia
therapy. With any local modality, there is gener-
ally residual evidence of the disease process,
whether it be a scar associated with laser therapy
or cryotherapy, or residual pigmentation after
irradiation or intralesional injections.
Radiotherapy, which has been frequently
employed in the treatment of classical Kaposi’s
sarcoma, has become the most important ther-
apy in the local treatment of AIDS-related
Kaposi’s sarcoma. Whole body electron
beamtherapy, fractionated focal x-ray therapy
in doses up to 4500 cGy, and single dose treat-
ments of 800 cGy produced complete remis-
sions in 50–80 % of patients. However,
postradiation hyperpigmentation remained in
20 % of lesions and 10 % of patients had a local
recurrence. In addition, patients with HIV
infection tend to have more radiation-related
complications for any given dose than non-
HIV-infected patients. Treatment of the oral
cavity and pharynx has resulted in unexpect-
edly severe mucositis in some patients with
HIV and treatment of large volumes of skin has
led to the development of lymphoedema.
Complications of radiotherapy may take many
months to appear, and they may be aggravated
by subsequent therapies, such as doxorubicin-
containing regimens.
Other options photodynamic therapy, hyper-
thermia, infrared coagulation, cyclosporine, pac-
fitaxel, imiquimod and a variety of
chemotherapeutic regimens [1].
Cryotherapy
KS lesions are sensitive to cold killing and most
lesions only require a single 15–50 s session and
a 3 mm margin of surrounding tissue. This is a
particularly useful treatment in HIV associated
cases where the lesions are often multiple, and
may have been treated previously by radiother-
apy. Wound healing post-cryosurgery is not
impaired by previous irradiation.
The lesions that respond best are those that are
small and thin and the earlier a lesion is treated
the better [2–4].
133 Kaposi Sarcoma
Methodology (How I Do It)
The duration of freezing should be 30 s, depend-
ing the size of the nodules. Two to three cycles of
freezing should be performed in the same ses-
sion. All the nodules should be treated in the
same session, except when the lesions are too
numerous. After one freeze-thaw cycle the
lesions disappear. Topical anaesthesia with a
cream relieves the pain.
Success Rates
In my experience, even after one session, most of
the lesions disappear.
Conclusions
Cryotherapy can be a useful therapeutic alter-
native for KS nodules, especially in patients
with multiple lesions.
683
References
1. Antman K, Chang Y. Kaposi’s sarcoma. N Engl
J Med. 2000;342:1027–38.
2. Tappero JW, Berger TG, Kaplan LD, Volberding PA,
Kahn JO. Cryotherapy for cutaneous Kaposi’s sar-
coma (KS) associated with acquired immune defi-
ciency syndrome (AIDS): a phase II trial. J Acquir
Immune Defic Syndr. 1991;4:839–46.
3. Sinclair RD, Dawber PR. Cryosurgery of malignant
and premalignant diseases of the skin: a simple
approach. Australas J Derm. 1995;36:133–42.
4. Nasti G, Errante D, Santarossa S, Vaccher E, Tirelli
U. A risk and benefit assessment of treatment for
AIDS-related Kaposi’s sarcoma. Drug Saf.
1999;20:403–25.
 Keratoacanthoma
134
Renata Strumia

Abstract
Keratoacanthoma (KA) is a rapidly growing tumour that presents more
commonly in the elderly, in fair-skinned individuals and on sun-exposed
areas. There have been many treatment options for KA including complete
excision, radiation therapy, intralesional injection of chemotherapeutic
agents, oral retinoids, photodynamic therapy and, recently, 5 % imiqui-
mod cream. Cryotherapy can be an effective option for the non-operative
management of KA. Spontaneous regression of KA can be promoted by
cryotherapy. The scar is cosmetically better when involution of KA is
achieved by cryotherapy than when it spontaneously happens.

Keywords
Keratoacanthoma • Cryotherapy

Introduction sure to chemical agents, human papilloma virus

Keratoacanthoma (KA), first described in 1889
by Jonathan Hutchinson as crater-shaped ulcer
on the face, is a rapidly growing tumour that
presents more commonly in the elderly, in fair-
skinned individuals and on sun-exposed areas.
The predilection of KA for sun exposed areas
suggests ultraviolet radiation is an important aeti-
ological factor. Other possible factors in the
pathogenesis include immunosuppression, expo-
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara (Former), Ferrara, Italy
e-mail: restrumi@tin.it
infection, chronically injured skin (ulcers, burns,
sinus tracts, vaccination scars, and chronic skin
diseases and after cryotherapy for prurigo nodu-
laris and solar keratosis), and genetic
aberrations.
Description of the Disease
Keratoacanthoma is a unique entity in skin
cancer, characterized by a very rapid growth
phase, followed by gradual involution. Some
authors see it as a distinctive tumour whereas
others define it as a subtype of squamous cell
carcinoma and treat it accordingly [1–4].

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DOI 10.1007/978-1-4471-6765-5_134
686
Although the morphological features of KA
are quite distinctive, a definite distinction from
invasive SCC can only be made histologically
[5, 6].
Solitary KA is characterised by three clinical
stages [1]: a proliferative/growth phase which
lasts 2–10 weeks [2], a stationary period of sim-
ilar duration, and [3] resolution/involution phase
of up to 1 year duration [4]. There are also sev-
eral variants of keratoacanthoma which are of
clinical importance: the giant keratoacanthoma
(exceeding 3 cm in diameter), keratoacanthoma
centrifugum marginatum (characterised by pro-
gressive peripheral growth and ventral healing),
subungal KA (painful destructive KA of the
nail), mucosal KA (affecting mucous mem-
branes), and multiple keratoacanthomas (usu-
ally associated with the Ferguson Smith type,
the Grzybowski type, Muire-Torre syndrome,
and xeroderma pigmentosum) [1, 3, 4]. During
the proliferative phase, a firm hemispheric pap-
ule grows rapidly. The border of the papule is
skin coloured or slightly erythematous, and fine
telangiectatic vessels may be evident. When it
reaches its mature form, it is bud shaped or
dome shaped, with a central, umbilicated, kera-
tinous core.
Therapeutic Alternatives
Most authors believe that KA is a well-
differentiated, squamous cell carcinoma with
potential for metastasis. Therefore, it is important
to treat these tumours. There have been many
treatment options for KA including complete
excision, radiation therapy, intralesional injection
of chemotherapeutic agents, oral retinoids and
photodynamic therapy. There are a few recent
reports of successful treatment of KA with 5 %
imiquimod cream [7].
R. Strumia
Treatment Modalities
Complete surgical excision is the treatment of
choice, but complete excision can be too destruc-
tive and cosmetically or functionally unaccept-
able for tumors on cosmetically important sites.
There are many other treatment options of KA
with various outcomes, such as cryotherapy and
radiotherapy. Radiotherapy is an effective treat-
ment of KA [8] but it is inappropriate for younger
patients and is inconvenient because of the need
for multiple visits to the hospital.
Cryosurgery
One session of cryotherapy with LN is usually all
that is needed to achieve complete regression of
the lesion.
Methodology (How I Do It)
I use cryotherapy in KA not larger than 1 cm,
localized on cosmetically important sites and in
old patients. The duration of freezing should be
30 s, depending the size of the lesion. Two or
three cycles of freezing should be performed in
the same session. Topical anaesthesia with a
cream relieves the pain. Complete involution of
the lesion is usually achieved after 30–40 days. If
a complete resolution does not happen, excisional
surgery with histologic control is suggested.
Conclusions
Cryotherapy can be an effective option for the
non-operative management of KA. Spontaneous
regression of KA can be promoted by cryother-
apy. The scar is cosmetically better when invo-
lution of KA is achieved by cryotherapy than
when it spontaneously happens (Fig. 134.1).
134 Keratoacanthoma
Fig. 134.1 (left) KA of the lip, (center) cryotherapy, (right) 1 month after cryotherapy
References
1. Schwartz RA. Keratoacanthoma. J Am Acad
Dermatol. 1994;30:1–19.
2. Skidmore Jr RA, Flowers FP. Non-melanoma skin
cancer. Med Clin N Am. 1998;82:1309–23.
3. Weedon D. Tumors of the epidermis. In: Weedon D,
editor. Skin pathology. London: Churchill Livingstone;
1997. p. 657–60.
4. Weedon D. Keratoacanthoma: a personal perspective.
Curr Diagn Pathol. 2003;9:259–65.
5. Kane CL, Keehn CA, Smithberger E, Glass
LF. Histopathology of cutaneous squamous cell carci-
noma and its variants. Semin Cutan Med Surg. 2004;
23:54–61.
687
6. Hodak E, Jones RE, Ackerman AB. Solitary keratoacan-
thoma is a squamous cell carcinoma: three examples with
metastases. Am J Dermatopathol. 1993;15:332–42.
7. Hye Chan Jeon, Mira Choi, Seung Hwan Paik, Chang
Ho Ahn, Hyun Sun Park, Kwang Hyun Cho. Treatment
of keratoacanthoma with 5% imiquimod cream and
review of the previous report. Ann Dermatol.
2011;23:357–61.
8. Vergara A, Isarría MJ, Domínguez JD, Gamo R,
Rodríguez Peralto JL, Guerra A. Multiple and relaps-
ing keratoacanthomas developing at the edge of the
skin grafts site after surgery and after radiotherapy.
Dermatol Surg. 2007;33:994–6.
 Cutaneous Leiomyosarcoma
135
Ann M. John, Shilpa Agarwal,
and Robert A. Schwartz

Abstract
Cryosurgery has been employed for the treatment of leiomyosarcoma. The
gold standard of treatment is excision with wide margins and sufficient
depth. Cryosurgery is sometimes considered as treatment for small, recur-
rent leiomyosarcomas and those in areas that are difficult to resect.
Cryosurgery may also be employed as an adjunctive therapy to surgical
resection due to the high rate of recurrence and metastasis when the leio-
myosarcoma is incompletely excised.

Keywords
Cryosurgery • Leiomyosarcoma • Cutaneous leiomyosarcoma •
Subcutaneous leiomyosarcoma • Hereditary cutaneous leiomyomatosis
with renal cell cancer

Introduction

Cutaneous leiomyosarcoma (CLM) is a rare

A.M. John, MD
Department of Dermatology, Rutgers New Jersey
Medical School, Newark, NJ, USA
S. Agarwal, MD
Department of Dermatology, Rutgers New Jersey
Medical School, Newark, NJ, USA
R.A. Schwartz, MD, MPH, DSc (Hon),
FRCP (Edin) (*)
Department of Dermatology, Rutgers University New
Jersey Medical School, Rutgers University School of
Public Affairs and Administration,
Newark, NJ, USA
e-mail: roschwar@cal.berkeley.edu
smooth muscle cancer, first described in 1959 [1].
It represents 2–3 % of all superficial soft-tissue
sarcomas [2]. Tumors originating in the superficial
dermis are known as primary CLMs and arise
from the arrector pili muscles. Tumors originating
in the deep soft tissue are known as the subcutane-
ous form (sub-CLM), and arise from vascular
smooth muscle of subcutaneous adipose tissue.
Primary CLM tends to behave less aggressively,
although diagnosis and treatment is similar for
both. Low incidence and atypical clinical presen-
tation of CLM commonly lead to misdiagnosis.
Recurrence, metastasis, and mortality are high

© Springer-Verlag London 2016 689

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_135
690
with untreated CLM, particularly the subcutane-
ous form [3, 4]. As such, wide local excision is the
preferred treatment modality. Cryosurgery is an
option usually reserved most commonly for recur-
rent CLM, CLM in areas that are difficult to
resect, and as an adjunct to surgical resection.
Description of the Disease
Both CLM and sub-CLM are first evident as a
solitary, slowly growing, often painful or pruritic
nodule. Primary CLM is located on hair-bearing
surfaces and is associated with ulceration and
underlying skin discoloration. Sub-CLM usually
presents as a mobile mass with the overlying skin
resembling an indurated plaque with brown or red
discoloration. While both forms are most com-
monly located on the proximal extremities, they
can be found anywhere on the body, including the
face, neck, trunk, genitals, areola, gluteal region,
wall of large blood vessels, and ectopic areola
[5–12]. They are usually 0.3–3 cm in diameter.
Paresthesia, bleeding, pruritus, and burning sen-
sation are associated symptoms [2–4, 13].
The diagnosis is confirmed by histological
and immunohistochemical examination that
demonstrates smooth muscle cells in irregular
bundles with dense cellularity and active cell
division. Malignant cells are often located at
the tumor’s periphery; these smooth muscle
cells can be well-differentiated or poorly-dif-
ferentiated. If well-differentiated, there are
interlacing bundles of elongated or spindled
cells with well-oriented myofibrils in the cyto-
plasm and elongated, cigar-shaped nuclei. If
poorly-differentiated, cells display nuclear
atypia and there is disorganized myofibrils or
the complete absence of myofibrils [3, 4, 14].
Other rare histological variants include epithe-
lioid, granular cell, desmoplastic, inflamma-
tory, and myxoid leiomyosarcoma. On
immunohistochemistry, the tumor expresses
smooth muscle actin, with some reports of
100 % sensitivity [1, 15]. Other markers include
vimentin, desmin, S-100, and ki-67 [1, 3, 4].
Immunohistochemical examination is espe-
cially important in poorly-differentiated forms
A.M. John et al.
to distinguish CLM from other diagnoses,
including schwannoma, lipoma, neurofibroma,
dermatofibroma, leiomyoma, fibroacanthoma,
melanoma, malignant fibrous histiocytoma,
spindle cell synovial sarcoma, pyogenic granu-
loma, angiosarcoma, rhabdomyoma, spindle
cell carcinoma, squamous cell carcinoma, and
basal cell carcinoma [1, 4, 16].
Primary CLM occurs during the fifth to sev-
enth decades of life with a male predominance.
Sub-CLM occurs in patients aged 50–80 years
with an equal male to female incidence ratio [3,
4]. Etiological factors implicated in the develop-
ment of CLM include ionizing irradiation, sun-
light, trauma, burn scars or scars due to infectious
causes, use of topical chemicals, lupus vulgaris,
contusions, inoculation site, tick bite, and venous
stasis [1, 6, 11, 17, 18]. Rates of recurrence are
approximately 50–60 %, even in small tumors
[3].
Rates of metastasis, usually hematogenous,
are 30–60 % in sub-CLM and 5 % in primary
CLM. The scalp and lung are the two most com-
mon sites of metastases [3, 4, 19, 20]. Worse
tumor prognosis is correlated with tumor size
>5 cm, high mitotic rate, presence of necrosis,
vascular invasion, increased tumor depth with
fascial involvement, higher grade of tumors,
increased DNA ploidy, high Ki-67 proliferative
index, and acral distribution. It has been proposed
that the greater tumor size of sub-CLM compared
to primary CLM explains its more aggressive
nature. Better prognosis is associated with longer
disease-free intervals between initial diagnosis
and metastasis [19–23].
Two other forms of CLM include the familial
and metastatic forms. Hereditary cutaneous leio-
myomatosis with renal cell cancer (HLRCC) is
an autosomal dominant disorder. Patients with
this condition are predisposed to benign leiomyo-
mas of the skin and uterus and are at risk for
aggressive renal cell carcinoma. Females usually
require hysterectomies due to the development of
large, symptomatic leiomyomas. Renal involve-
ment presents as a unilateral solitary mass with
high metastatic potential. HLRCC has been
linked to germ line mutations in the fumarate
hydratase gene, whose gene product is involved
135 Cutaneous Leiomyosarcoma
in the citric acid cycle. The majority of affected
families are of Eastern European descent [24,
25].
The metastatic form, particularly from uterine
leiomyosarcoma, is extremely rare, with few
cases described. It presents as a subcutaneous
nodule or cyst [26]. Scalp metastases have been
reported in four patients. First, in 1917, Gardner
described a deceased patient with evident metas-
tases to the lungs, liver, pancreas, and bone in
addition to the scalp [27]. Other reports describe
cutaneous metastases in addition to metastases to
other sites [28–30]. The theory for metastasis via
hematogenous spread is through Batson’s plex-
uses, which are inner vertebral venous plexuses
with thin walls and low pressure. The low pres-
sure allows the bypass of other venous systems,
forming a vascular pathway from the pelvis to the
head and neck [26, 31, 32].
Therapeutic Alternatives
Excision with negative margins is the gold stan-
dard of treatment for both CLM and
sub-CLM. The size of the margin of safety is not
well-established, although margin status has been
reported as the most important predictor of recur-
rence. Excision with positive or narrow margins
(<0.2 cm) results in higher rates of recurrence
and metastasis and increased mortality. Excision
with 1 cm margins is the primary method of treat-
ment of CLM. Some studies suggest a 3–5 cm
margin with depth of excision including the sub-
cutaneous tissue and fascia. Lymph node dissec-
tion is not necessary unless there is evidence of
concomitant lymph node disease [13].
Mohs micrographic surgery is an option that
may have comparable or even better results than
excision. More studies need to be performed to
validate the efficacy of this treatment. Rates of
recurrence have been reported between 0–14 %
in small case series. Follow up in these cases
demonstrated no recurrence between 4 months
and 4 years [33–35].
Adjunctive therapy includes radiation, chemo-
therapy, and super-voltage cobalt therapy. The
utility of adjunctive therapy is largely derived
691
from anecdotal experience and reserved for cases
of recurrence or metastasis. Indications for
administration of radiation or chemotherapy
include larger and deeper tissue involvement on
initial diagnosis, positive margins following
resection, and limited options for resection due to
location. Recurrence is common with adjuvant
therapy and often requires resection. Few studies
have shown the efficacy of radiation therapy, and
other studies suggest re-excision in the case of
positive margins or recurrence.
Cryosurgery: Utility, Methods,
and Success
Cryosurgery as a treatment of leiomyosarcoma
is not well established, primarily because tumor
resection with negative margins is most protec-
tive against recurrence and metastasis. The few
reports of its use are discussed here. Three
methods have been utilized in soft tissue
sarcomas: cryoablation, intraoperative resection
with cryosurgery, and palliative cryosurgery.
Cryoablation is most suitable for small, localized
tumors. Intraoperative resection with cryosur-
gery relies on cryosurgery to obliterate remain-
ing malignant tissue. Palliative cryosurgery is
reserved for non-resectable tumors to de-bulk
the tumor in preparation for the use of chemo-
therapy and radiotherapy [36]. The process is
performed with liquid nitrogen (LN) to engage
in a freeze-thaw cycle. The probe is placed using
radiologic scanning for internal tumors. Freeze-
thaw cycles are monitored with MRI in visceral
tumors and microscopy in cutaneous tumors.
Risks include freezing of non-targeted areas,
damage to structures in close proximity to the
lesion, bleeding, and infection [37].
Montes et al. [38] reported the successful use
of cryosurgery in two elderly patients with pri-
mary CLM on the scalp, who had no signs of
recurrence 2 years after treatment. Treatment was
performed for 5 min and repeated every 2 weeks
for a total of three to six treatments. Both tumors
achieved gradual shrinking and eventually com-
plete involution. Early on in the treatment, eosin-
ophils and erythrocytes accumulated followed by
692
lymphocytes and plasma cells. Capillary
angiogenesis and newly formed connective tissue
fibers were evident in later stages of healing.
Montes et al. [38] also noted the efficacy of cryo-
therapy in equine sarcoid, which has several clin-
ical and histological similarities to CLM. In
patients with HLRCC, cryotherapy has been used
successfully for small and isolated lesions. In
addition, these lesions are often tightly packed,
unsightly, or painful. Surgical excision is not the
recommended treatment of choice for patients
with HLRCC [25, 26].
In other types of leiomyosarcoma, cryosur-
gery has shown some success. It was employed to
destroy a pelvic nodule representing metastasis
from a primary uterine leiomyosarcoma utilizing
the double freeze-thaw cryoablation protocol.
After 8 months of follow-up, a patient remained
disease free. Moreover, there was a positive cos-
metic outcome with no complications. Other
advantages were of decreased morbidity and
mortality with cryosurgery compared to wide
excision [39]. Another study utilized cryoabla-
tion for hepatic metastases with low rate of recur-
rence and complications [40].
Conclusion
Cutaneous leiomyosarcoma is a rare smooth
muscle cancer that can affect people of any
age on any part of the body. Diagnosis is
established by histopathological and immuno-
histochemical examination. Gold standard of
treatment is excision with wide margins and
depth into the subcutaneous tissue or fascia.
Cryosurgery may be beneficial for selected
patients; it may be used for lesions that are
recurrent or in areas where it is difficult to
resect, such as the scalp. It may also be used as
an adjunctive therapy to wide excision.
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 Lentigo Maligna and Lentigo
Maligna Melanoma
136
Raymond Cornelison

Abstract
Lentigo maligna is a subtype of melanoma that may progress to Lentigo
maligna melanoma as it becomes invasive. Age and sun exposure are risk
factors. Excisional surgery and Mohs micrographic surgery are the tradi-
tional choices of treatment. Grenz rays may be a reasonable therapy.
Cryosurgery appears to be a valid option as melanocytes are particularly
susceptible to be destroyed by low temperatures; a combination of this
method plus imiquimod has been reported as successful.

Keywords
Lentigo, lentigo maligna, lentigo maligna melanoma • Imiquimod, grenz
rays, cryosurgery

Introduction These occupational risk factor are related to

Lentigo maligna is a subtype of melanoma that
develops almost exclusively on actinically dam-
aged skin. The most common areas of occurrence
are the face and neck but it can occur on the
extremities, scalp and trunk. Lentigo maligna
was first described by Sir John Hutchinson in
1890 (Hutchinson’s melanotic freckle). Lentigo
maligna occurs mostly in elderly individuals with
light skin but it can occur in all skin types. Risk
factors include ultra violet light exposure, history
of severe sunburn and occupational risk factors.
R. Cornelison, MD
OKC Dermatology Associates,
Oklahoma City, OK, USA
e-mail: cornelison.r@gmail.com
occupations with significant sun exposure. The
incidence of lentigo maligna developing into len-
tigo maligna melanoma is approximately 5–10 %.
The incidence of melanoma is highest in Australia
and lentigo maligna accounts for 10–15 % of
melanomas in that country. Lentigo maligna can
be present for years before invasion occurs. Many
cases never exhibit an invasive phase.
Description
The next chapter overlaps with this one; an excel-
lent description of lentigo maligna and lentigo
maligna melanoma makes being repetitive
unnecessary.

© Springer-Verlag London 2016 695

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_136
696
Treatment Options for Lentigo
Maligna and Lentigo Maligna
Melanoma
The traditional method of treatment of lentigo
maligna and lentigo maligna melanoma has been
surgical excision. The recurrence rate with a
5 mm margin of excision is 8–20 %. The recur-
rence rate with mohs micrographic surgery is
4–5 % [1].
Cryosurgery
The method of treatment for lentigo maligna that
seems most appropriate is that of, under local
anesthesia, two freeze-thaw cycles using LN
spray to a 1 cm halo of freeze sustained for
30–60 s (Figs. 136.1 and 136.2). This, in combi-
nation with imiquimod 5 % cream, should pro-
vide the best results. Because melanocytes are
clearly identifiable with the in vivo confocal
microscope, the likelihood of preoperatively
increasing the precision for detecting the extent
of local disease, as well as the presence of resid-
ual disease immediately post-operatively, and of
early recurrence, it is likely that success rates
with cryosurgery will increase.
Success Rates
Cryosurgical treatment has been described in
multiple studies and has had varying results with
regard to efficacy. One stud had 18 patients with
clinical and histopathological diagnosis of len-
tigo maligna treated with cryosurgery. The mean
age was 60 years and 11 of the patients were
R. Cornelison
male. They were chosen for cryosurgery because
the lesion posed a surgical challenge or the
patient was not a good surgical candidate. Two
freeze-thaw cycles under local anesthetic was
used. The lesions resolved clinically in all cases
with no recurrence or metasteses detected during
the mean follow up of 75.5 months [2]. Another
study of cryosurgery of lentigo maligna reported
12 cases treated successfully between 1984 and
1990. The average follow-up period was
51.4 months, and the recurrence rate was 8.3 %
[3]. Collins reported eleven patients treated with
cryotherapy, ten with lentigo maligna and one
with lentigo maligna melanoma. The lesions
cleared in all except in one with lentigo maligna.
There were recurrences in four patients and three
of those patients cleared with further treatment
[4].
Over the years other modalities have been
used to treat lentigo maligna and this include
grenz ray. Eighty-eight percent of 593 patients
with lentigo maligna and early lentigo maligna
melanoma showed complete clearance [5].
Multiple studies have reported use of 5 %
imiquimod as the sole treatment agent or in com-
bination with or modalities [6].
Summary
The most common treatment of lentigo maligna
and lentigo maligna melanoma is excision with
adequate margins. Cryosurgery is an effective
and practical therapeutic alternate of lentigo
maligna in selected cases, especially in those
patients who are not candidates for surgical exci-
sion. Cryosurgery cannot be recommended for
the treatment of lentigo maligna melanoma.
136 Lentigo Maligna and Lentigo Maligna Melanoma 697

a b

c
d

Fig. 136.1 (a, b) Lentigo Maligna. (c) 1 week post cryo. (d) 2 weeks post cryo. (e) Post cryo (Photos courtesy of Gloria
Graham, MD [7])
698 R. Cornelison

Fig. 136.1 (continued)

a b

Fig. 136.2 (a, b) Lentigo maligna: Divide into smaller segments. (c, d) Lentigo Maligna. Cryosurgery: Double freeze
thaw cycle, 1 min + to – 40° C. (e) Hypopigmentation after Cryosurgery (Photos courtesy of Gloria Graham, MD [7])
136 Lentigo Maligna and Lentigo Maligna Melanoma 699

c d

Fig. 136.2 (continued)

700 R. Cornelison

References 4. Collins P, et al. Cryotherapy for lentigo maligna. Clin

Exp Dermatol. 1991;16(6):433–5.
5. Hedblad MA, Mallbris L. Grenz ray treatment of len-
1. Mckenna JK, et al. Lentigo maligna/lentigo maligna
tigo maligna and early lentigo maligna melanoma.
melanoma: current state of diagnosis and treatment.
JAAD. 2012;67(1):60–8.
Dermatol Surg. 2006;32(4):493–504.
6. Naylor MF, et al. Treatment of lentigo maligna with
2. de Moraes AM, et al. Cryosurgical treatment of len-
topical imiquimod. Br J Dermatol. 2003;149 suppl
tigo maligna. J Dtsch Dermatol Ges. 2007;5(6):
66:66–70.
477–80.
7. Graham GF. Cryosurgery for benign, premalignant, and
3. Böhler-Sommeregger K, et al. Cryosurgery of lentigo
malignant lesions. In: Wheeland RG, editors. Cutaneous
maligna. Plast Reconstr Surg. 1992;90(3):436–40; dis-
Surgery. Philadelphia: WB Saunders; 1994. p. 853.
cussion 441–4.
 Malignant Melanoma
137
Pedro Redondo

Abstract
Melanoma is one of the most aggressive forms of human cancer. The
increase of its incidence over the past 15 years is greater than that for any
other malignancy. Melanoma serves as a ‘model’ tumor for understanding
immunity to cancer. Currently cryotherapy is not an accepted treatment for
primary cutaneous melanoma except in the case of lentigo maligna, a pre-
cursor of lentigo maligna melanoma and choroidal melanoma. It is also
considered a suitable palliative treatment for in-transit metastases and for
locally advanced unresectable disease.
In addition to its cytoablative properties, multiple studies have shown
that cryosurgery has the ability to stimulate an immune response by the
tumor antigens produced by tissue necrosis. Tumor cryoablations release
large amounts of tumor antigens in the form of necrotic tumor cells and
cellular debris, and enhance migration of dendritic cells from the tumor
site to the draining lymph nodes There are several immunotherapy
approaches that can be combined with cryoablation to devise a cryoim-
munotherapeutic strategy with potential to affect the progression of meta-
static melanoma. If the cryoablation of cutaneous melanoma associated
with topical imiquimod can induce an antitumor immune response capable
of reducing both local and distant recurrence, then this approach may be
even superior to surgical excision. Further studies are warranted to assess
the potential of this combination for treating “some” primary melanoma.

Keywords
Cryosurgery • Cryoimmunotherapy • Immunotherapy • Melanoma •
Lentigo maligna • Imiquimod • Dormant metastases

P. Redondo, MD, PhD

Department of Dermatology, University Clinic
of Navarra, Pamplona, Navarra, Spain
e-mail: predondo@unav.es

© Springer-Verlag London 2016 701

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_137
702
Introduction
Melanoma is one of the most aggressive forms of
human cancer. The increase in incidence of cuta-
neous malignant melanoma over the past 15 years
is greater than that for any other malignancy.
Melanoma tumor-associated antigens were
among the first cancer antigens to be identified
and classified. In addition, melanoma regression
has been associated with vitiligo, visibly con-
firming an active role of the immune system in
this type of cancer and spontaneous regression of
primary melanomas has also been observed in
some cases. For these reasons melanoma serves
as a ‘model’ tumor for understanding immunity
to cancer. Expression of tumor-associated anti-
gens by melanoma cells makes the disease a
promising candidate for immunotherapy [1] The
potential for immunotherapy in melanoma has
been demonstrated by improved outcomes among
patients with stage III melanoma receiving
interferon-α2b [2] and patients with metastatic
melanoma receiving the anti-cytotoxic
T-lymphocyte antigen 4 (CTLA-4) antibody ipili-
mumab alone or in combination with a gp100
peptide vaccine or dacarbazine [3], as well as by
durable complete responses with high-dose inter-
leukin-2 [4] and high response rates after adop-
tive T cell transfer therapies [5].
At the same time, tumor cells are weakly
immunogenic and even produce factors that sup-
press cellular immunity. The mechanisms used
by melanoma cells to escape from immunologic
responses during elicitation and/or effector
phases are complex [6]. The principal mecha-
nisms identified are self-tolerance to melanoma
antigens, down-regulation of class II major histo-
compatibility complex molecules, the expression
of Fas-L and HLA-G molecules, and cytokine
production by malignant melanoma cells.
Cryosurgery of Melanoma
Currently cryotherapy is not an accepted treat-
ment for primary cutaneous melanoma except in
the case of lentigo maligna, a precursor of lentigo
maligna melanoma and choroidal melanoma. It is
P. Redondo
also considered a suitable palliative treatment for
in-transit metastases and for locally advanced
unresectable disease (Fig. 137.1).
Lentigo Maligna
Lentigo maligna (LM), also discussed in the pre-
vious chapter, is characterized as an irregularly-
pigmented macule or patch with an indistinct
border and slow growth on sun-exposed areas in
older Caucasians, and is generally not associated
with precursor melanocytic nevi. Histologically,
LM is characterized by the presence of atypical
melanocytes in the basal layer of the epidermis,
often extending into the deep adnexal epithelium.
When these melanocytes invade the dermis, the
tumor becomes a lentigo maligna melanoma
(LMM), which is a potentially metastatic and
fatal tumor. LMM represents one of the four main
subtypes of melanoma, and comprises an esti-
mated 4–15 % of all melanoma cases. Available
treatments for LM include conventional surgery,
micrographic surgery, cryosurgery, radiation
therapy, laser therapy, dermoabrasion, electroco-
agulation and curettage [7]. Conventional or
micrographic surgery is the most effective treat-
ment for this lesion. Cryosurgery is one alterna-
tive approach that has produced good results. It
can be useful in managing LM or LMM when
conventional or micrographic surgery is not eas-
ily employed [8–10].
Cryosurgery
Several studies have shown that melanocytes are
highly sensitive to low temperatures. At between
−4 and −7 °C melanocytes are selectively
destroyed whereas keratinocytes are first dam-
aged at −20 °C [9, 11, 12]. For this reason, cryo-
surgery aims at the total destruction of the LM, as
well as the atypical melanocytes so frequently
found around such lesions. The biggest problem
associated with treating LM with cryosurgery is
that the complete tumor is not available for histo-
pathologic examination. Another problem is that
the exact percentage of LM cases that progress to
137 Malignant Melanoma 703

a b

c d

Fig. 137.1 (a) Patient refused excisional surgery for this (c) Lesion a few seconds after frozen to a 8 mm halo using
superficial spreading melanoma of 0.75 mm depth and LN with spray technique. (d) Post-op at 1 year; no ade-
was referred for cryosurgery. (b) Close-up of the lesion. nopathies. Patient treated by Dr. Abramovits
704 P. Redondo

LMM is unknown [13] and different estimates

vary widely. An epidemiologic analysis by
Weinstock and Sober [14] reported an approxi-
mate 5 % lifetime risk of LMM in patients diag-
nosed with LM at age 45. However, in two series
of 85 LM excisions, more than 50 % contained
occult invasive melanoma foci [15] and, in a
more recent report of 92 consecutive cases, 16 %
of LM lesions undergoing staged excisions har-
bored unexpected foci of invasion [16].

Methodology (How I Do It)

The standard approach is to employ two freeze-

thaw cycles with temperatures in the freeze
cycle reaching between −20 and −50 °C and
with the thaw period lasting approximately
twice as long as the freezing period [12]. The
recommended safety margin is 5 mm for LM
and 1 cm for LMM [17, 18]. Kuflik et al. [12]
and Robinson [17] recommend larger margins,
Fig. 137.2 LMM treated with cryotherapy. Achromic
especially in the case of lesions with undefined
areas and other slightly pigmented areas can be observed
borders: 5 mm in the case of lesions of up to where it is difficult to clinically differentiate between
2 cm; 1 cm for lesions of 2–3 cm; and 1.5 cm for tumor persistence and pigmentary abnormalities second-
lesions >3 cm. This addresses the concern that ary to the treatment
the real margins of LM (or at least the presence
of atypical melanocytes) very often extends with visual assessment of cure following cryosur-
beyond the clinically pigmented area [19]. gery is that the treated areas often feature varying
Breuninger et al. showed that outgrowths 5 mm degrees of dyspigmentation (Fig. 137.2). It is
beyond the clinical tumor border occurred in therefore sometimes difficult to determine if the
54 % of all LMM. For this reason, a cryosurgi- lesion has been cured or if the patient continues
cal margin of 10 mm is theoretically most to have residual disease. In line with this, amela-
appropriate to ensure good safety [18]. notic malignant melanoma following cryosur-
gery for atypical LM has been reported in two
patients [22].
Success Rates

The rate of recurrence reported in the literature is Metastatic Melanoma

controversial. In one study of 30 patients, the
3-year recurrence rate was 6.6 % [12]. However,
other studies have reported a 5-year recurrence
rate of 34 % [20]. These data probably reflect a
wide variety of approaches to therapy with differ-
ent margins and freezing parameters [9, 21]. The
usual complications of cryosurgery include infec-
tions, atrophy, hypopigmentation, hyperpigmen-
tation, and irregular scars [10, 11]. One problem
Cryosurgery has been proposed for the treatment
of head and neck melanoma, mostly for mucosal
melanoma in anatomically critical sites as well as
for palliation in high-risk surgical patients or
those with unresectable disease [23, 24].
Cryosurgery represents a good palliative proce-
dure for inoperable or recurrent melanoma due to
the peculiar features of this neoplasm which
137 Malignant Melanoma
makes it particularly freeze-sensitive, as the tech-
nique selectively destroys the neoplastic tissue.
In these cases, an adequate pressure with the
probe on the tissue is required in order to reduce
the amount of blood flow within the lesion.
Moreover, repeated freezing cycles are required
mostly in extensive lesions. In any case, the cryo-
surgical treatment should be aggressive, in order
to produce an “ice-ball” including at least 5 mm
of apparently normal tissue surrounding the pri-
mary tumor site [25].
Breitbart published his early findings in 1990,
when he treated 67 melanoma patients with cryo-
surgery [26]. Although he proposed the use of
palliative cryosurgery for metastatic melanoma,
the patients included in his main study had pri-
mary cutaneous melanomas. Grotmann et al.
treated 30 metastatic melanoma patients with
palliative cryosurgery, with an average time of
disease remission of 36 months [27]. They found
that cryosurgery significantly improved the qual-
ity of life of their patients, with a possible immu-
nologic stimulus but provided little evidence to
support this.
True local recurrence is defined as the reap-
pearance of melanoma in or contiguous to an
excision scar or graft and where an in situ compo-
nent is present [28]. Satellitosis has been defined
as cutaneous disease within 5 cm of the primary
tumor [29], although in previous AJCC classifi-
cations satellite nodules were defined as lesions
within 2 cm of the scar [30]. Previously the pres-
ence of satellite nodules defined a melanoma as
stage II (T4) disease, equivalent to a thick (more
than 4 mm) melanoma. In-transit disease indi-
cates non-nodal, cutaneous or subcutaneous dis-
ease between the primary site and the regional
lymph nodes. Satellitosis and in-transit disease
are manifestations of the same biological process
and have the same prognostic significance.
In-transit metastases almost certainly result from
lymphatic dissemination of melanoma cells to
tissues between the primary melanoma site and
the draining regional lymph nodes. In-transit dis-
ease and regional lymph node metastases are
both grouped as stage III disease in the current
melanoma staging system. In-transit metastases
are a manifestation of melanoma at an advanced
705
stage, with an associated 5-year survival rate of
25 % and almost no 10-year survivors.
Surgical excision is generally proposed as the
treatment of choice for isolated loco-regional
skin recurrences. When the number, size or dis-
tribution of metastases becomes a surgical chal-
lenge, current convention seems to suggest either
perfusional/infusional techniques when disease
is limited to an area that can be isolated (nor-
mally a limb) or otherwise the use of local abla-
tive techniques, including intralesional injection,
electrochemotherapy, laser ablation, cryotherapy,
and irradiation [31]. As in-transit disease is at an
advanced stage, the choice of local treatment
does not affect survival, which is dictated by the
development of distant metastatic disease. Local
treatments should therefore be viewed as pallia-
tive. The real value of cryotherapy is in the man-
agement of multiple small volume in-transit
metastases that are too numerous to be treated by
simple surgical excision (Fig. 137.3). The dis-
tinct lack of published outcome data in the last
20 years suggests that in the treatment of meta-
static melanoma, cryosurgery may have fallen
out of favor, even among the earlier proponents
of the method.
In any case, the practical advantages of cryo-
therapy are as follows:
– It is a relatively simple procedure
– It is an outpatient or day-case procedure
– Side-effects of treatment are minimal and
wound care is easily managed
– It can be applied precisely with minimal col-
lateral damage.
– There is no contraindication to re-treatment at
previous sites.
– Lesions disappear rapidly following
treatment.
– Good cosmesis at treatment sites is achieved.
– Local recurrences at treated sites are rare.
In addition to its cytoablative properties, mul-
tiple studies have shown that cryosurgery has the
ability to stimulate an immune response by the
tumor antigens produced by tissue necrosis, as
demonstrated by the increase in circulating spe-
cific antineoplastic antibodies.
706
a b
Fig. 137.3 A 67-year old woman with stage III mela-
noma. Three in-transit metastases treated with cryother-
apy (a three-cycle 30-s freeze/thaw regimen) and
imiquimod (once a day for 10 days). Appearance at 24 h
On the other hand, it seems clear from the lit-
erature that local ablative therapies have a worth-
while role in the management of regionally
metastatic melanoma. Numerous authors have
published evidence for the role of CO2 laser
treatment. Almost all of the studies using these
local tissue necrosing techniques report instances
of unexpected and unexplained beneficial effects
including very low levels of recurrences at treated
sites and unexpected complete remissions.
Choroidal Melanoma
Cryosurgery has also been used to a limited
degree in the treatment of choroidal melanomas.
Several authors have evaluated cryosurgery in
small series of patients with medium-sized and
large melanomas, but exudative retinal detach-
ment and incomplete tumor destruction nega-
tively affected treatment [32, 33]. Cryotherapy
may be useful as a primary treatment for small,
growing choroidal melanomas or as an adjunct
for treating recurrences of melanomas treated
primarily with radioactive plaque [34].
P. Redondo
(a), 8 days (b) and 21 days (c) post-treatment. Cryosurgery
associated with topical imiquimod induced reactivation of
localized vitiligo in her face (not shown)
Cryoablation
Ice crystal formation during cryosurgery leads to
mechanical damage of the plasma membrane and
intracellular constituents; the withdrawal of
water from the extracellular system by freezing
creates a hyperosmotic environment, inducing
cell dehydration and shrinking; cell metabolism
progressively fails and lipid-protein complexes
within the cell membranes are denatured [35].
These direct effects of freezing result in necrosis.
The cryoreaction is characterized by physical and
vascular phases. Endrich et al. [36] demonstrated
increased permeability in capillaries, postcapil-
lary and collecting venules in normal tissue of the
dorsal skinfold chamber of the hamster after
cooling.
In immunocompetent models the acute phase
of inflammation is followed by intense edema as
well as a perivascular and interstitial lymphocytic
infiltrate [37]. The importance of secondary
inflammation following cryotherapy is supported
by the findings of Doolin et al. [38] who
demonstrated in vitro that the presence of
137 Malignant Melanoma
leucocytes and apoptosis. Apoptosis was
observed in the periphery of the tumor and leuco-
cytes accumulated mainly at the margin of the
tumor in normal tissue 24 h after cryotherapy.
Thus, tissue destruction by cryotherapy is not
only induced by direct necrosis and microvascu-
lar stasis, but also by the inflammatory infiltrate
and subsequent apoptosis [39].
Cryoimmunomodulation
Induction or stimulation of a tumor-specific
immune reaction after cryosurgery in humans has
been reported in recent years [40–42]. Previously
the production of antibodies as a consequence of
freezing treatment was reported in animal models
[43, 44]. Today it is accepted that cryosurgery-
induced necrosis is a useful model to analyze the
interaction among necrosis, inflammation, and
the generation of an immune response [45].
Necrosis can activate antigen-presenting cells
and initiate an immune response [45]. Several
case reports mention a reduction of metastatic
disease after cryoablation of the primary tumor.
Joosten et al. [46] demonstrated in a colon 26-B
tumor model that cryoablation of tumor tissue
has a significant inhibitory effect on secondary
tumor growth. Compared to excision, cryoabla-
tion of a primary tumor in the thigh clearly inhib-
ited tumor growth of a secondary tumor in the
flank. Cryotherapy of normal tissue did not result
in any growth inhibition of secondary tumor. In
conclusion, besides local destruction of the pri-
mary tumor, it has been claimed that cryoablation
is sometimes able to induce systemic antitumor
immune responses.
Cryotherapy Associated
with Immunotherapy
Tumor cryoablations release large amounts of
tumor antigens in the form of necrotic tumor cells
and cellular debris, and enhance the migration of
dendritic cells (DCs) from the tumor site to the
draining lymph nodes [45, 47]. Cryoablation
induces both a tumor-specific T-cell response in
the tumor draining lymph nodes and an increased
707
systemic natural killer (NK) cell activity, which
correlates with rejection of tumors on rechal-
lenge. This immunologic response is clearly lim-
ited and it may be necessary to augment it by
adding an adjuvant [48]. Local administration of
immature DCs in combination with the immune
adjuvant (CpG-oligodeoxynucleotides, ODN)
potentiates the immune response induced by
cryoablation [49]. A recent paper has shown the
systemic antitumor immune effect of tumor cryo-
surgery combined with subsequent in situ injec-
tion of autologous unmodified immature DCs
[50]. There are several immunotherapy
approaches that can be combined with cryoabla-
tion to devise a cryoimmunotherapeutic strategy
with potential to affect the progression of meta-
static disease [51]. According to other reports, it
is useful to either administer a blocking mono-
clonal antibody against cytotoxic T-lymphocyte-
associated antigen 4 [52], the toll-like receptor
(TLR) 9-ligand CpG-ODN [53], or an immuno-
therapy with IL-2 and GM-CSF [54] at the time
of local tumor destruction.
The TLR proteins initiate the DC maturation
process upon recognition of conserved pathogen-
associated molecular patterns, such as lipopoly-
saccharides or unmethylated CpG-ODN. Recently
it has been showed that a combination treatment
of cryoablation plus TLR-9 stimulation via CpG-
ODN is far more effective in the eradication of
local and systemic tumors than either treatment
modality alone [53]. In a murine model cryoabla-
tion of cutaneous melanoma associated with topi-
cal imiquimod (TLR-7 agonist) induces an
antitumor immune response capable of reducing
both local and distant recurrence. Thus, our group
demonstrated that local cryosurgery of B16/oval-
bumin (OVA)-derived subcutaneous tumor nod-
ules leads to curative destruction of the lesions. If
imiquimod is repeatedly applied to the cryo-
treated lesion, a conspicuous, leukocyte-rich
inflammatory infiltrate appears during the days
following treatment. Mice treated by cryosurgery
plus imiquimod rejected rechallenges of B16/
OVA in 90 % of the cases, whereas cryosurgery
alone failed to prevent tumor grafting in 70 % of
cases (Fig. 137.4). Addition of imiquimod to
cryosurgery results in increases in the cellular
immune response against tumor antigens as
708 P. Redondo

a b

c d

e f

Fig. 137.4 Mice were injected subcutaneously in the
middle of the left flank with 3 × 105 B16/OVA cells (a).
Cryosurgery was performed using an intermittent liquid
nitrogen spray (2–3 cm from the tumor at a 90° angle) A
three-cycle 30-s freeze/thaw regimen was performed to
ensure maximum tumor cell death (b). Immediately after
cryosurgery, during 10 days, mice received topical treat-
ment with imiquimod (c). Fifteen days after cryosurgery,
mice were challenged by subcutaneous injection on the
contralateral flank with 3 × 104 B16/OVA cells. The effect
of cryosurgery of the primary tumor on the growth rate of
the second tumor in the right flank was determined and
compared with excisional treatment (left mouse, d).
Cryosurgery of B16/OVA (left flank) resulted in a clear
delay in the outgrowth of B16/OVA tumor cells (right
flank) and in a low level of protection (25–30 % of the
mice) (middle mouse, d). The combination of cryosurgery
and imiquimod treatment (left flank) resulted in protection
against such a lethal dose (right flank) in 80–90 % of the
mice (right mouse, d). Topical imiquimod treatment with-
out cryosurgery was not sufficient to eradicate either the
primary tumor or a tumor rechallenge. Massive chemo-
taxis and B16F10 tumor cell destruction in a mouse
treated with the combination of cryosurgery and imiqui-
mod, showing an intense neutrophil infiltrate (e, original
magnification ×100). Detail of (e) (f, original magnifica-
tion ×400)
137 Malignant Melanoma
measured by in vitro IFN-g production and T-cell
proliferation in response to OVA. These
approaches may be even superior to surgical
excision, although further studies are warranted
to assess the potential of this combination for
treating melanoma [55].
The combination of cryotherapy with
DC-activated cytokine-induced killer cells is a
good treatment in metastatic hepatocellular can-
cer, metastatic non-small cell lung cancer and
osteosarcoma [56–58].
The Future
Just as I began this chapter by stating that cryo-
therapy is not indicated for the treatment of pri-
mary melanoma, I would not like to finish without
casting some doubt on the opposing hypothesis. I
am referring to those large tumors, diagnosed late
by the physician, those with which the patient has
lived for many years and in which systemic
spread may have already occurred at the time of
diagnosis. Occasionally, we have the clinical
experience, or at least intuition, that radical resec-
tion of these tumors leads to a rapid spread of the
metastases. The probability that cancer patients
develop metastatic disease is reduced after surgi-
cal removal of the primary tumor [59]. However,
in some patients surgical removal of the primary
tumor is followed by accelerated growth of pre-
existing metastases in secondary organ sites [59].
The hypothesis states that a primary tumor can
inhibit neovascularization of a dormant metasta-
sis by generating angiogenesis inhibitors.
Metastasis suppression by the primary tumor
may be mediated by angiogenesis inhibitors such
as thrombospondin-1 [60], angiostatin [61] and
transforming growth factor-b1. Other authors
have used a spontaneous mouse model of mela-
noma to investigate tumor cell dissemination and
immune control of metastatic outgrowth. They
have demonstrated that maintenance of dormancy
in visceral organs required CD8+ T cells and that
depletion of these cells significantly accelerated
visceral tumor outgrowth [62]. Clinical interest
in the in situ destruction of melanoma has
resurfaced [49–52] and methods to enhance the
709
immunogenicity of tumor cells might improve
the clinical efficacy of cryosurgery. If the cryoab-
lation of cutaneous melanoma associated with
topical imiquimod can induce an antitumor
immune response capable of reducing both local
and distant recurrence, then this approach may be
even superior to surgical excision.
Our experience and that of other colleagues,
with isolated cases reported at scientific meet-
ings, suggests disease control and a more satis-
factory a priori progression are achieved when
cryotherapy is combined with imiquimod in the
treatment of in-transit melanoma as compared to
other surgical or locally destructive therapies. For
the moment these preliminary results lend sup-
port to the hypothesis although further studies are
warranted to assess the potential of this combina-
tion for treating “some” primary melanomas.
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 Leukoplakia
138
Marcia Ramos-e-Silva, Cleide Eiko Ishida,
and Stella Ramos-e-Silva

Abstract
Leukoplakia is a common lesion seen on the oral mucosa. There are many
predisposing factors and it may evolve into a neoplasia. We describe the
use of cryosurgery for the treatment of this pre-malignant lesion on the
oral cavity, which can be a very efficient procedure for leukoplakia.

Keywords
Leukoplakia • Mouth • Benign • Cryosurgery • Cryotherapy

Introduction a marker of oropharyngeal cancer [2]. The 5-year

Lesions in the oral mucosa have been increas-
ingly found because oral health is receiving more
and more attention. Among them are oral cancers
and pre-cancerous lesions, such as leukoplakia.
Oral cancer has an annual incidence greater than
300,000 cases and squamous cell carcinoma is
the most common malignant tumor of the oral
cavity [1]. Precancerous lesions are even more
frequent and when not properly treated can
evolve into malignant lesions. Leukoplakia is the
most common of them and is present in 60 % of
patients with squamous cell carcinoma. It is also
M. Ramos-e-Silva, MD, PhD (*) • C.E. Ishida, MD
S. Ramos-e-Silva, MD, PhD
Sector of Dermatology and Post-Graduation Course,
Federal University of Rio de Janeiro,
Rio de Janeiro, Brazil
e-mail: ramos.e.silva@dermato.med.br
survival rate of oral cancers in advanced stages is
approximately 20 %. The most appropriate con-
servative treatment for each patient is the best
way to prevent the further malignization of pre-
cancerous lesions and one of the best strategies to
eradicate oral cancers [3].
Disease Description
The term leukoplakia as clinical entity is the
result of the effort of an international group of
experts who met in Uppsala in 1994 to review
leukoplakia definition and classification on the
basis of previously published work and new sci-
entific acquisitions. The World Health
Organization (WHO) defines it as “a white patch
or plaque that cannot be characterized clinically
or histologically as any other disease” [4]
(Fig. 138.1).

© Springer-Verlag London 2016 713

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_138
714
Fig. 138.1 Leukoplakia on the tongue
Leukoplakia is a clinical term used when any
other white oral lesion has been excluded by
means of clinical examination and histological
assessment; [5] it is regarded as a premalignant
or precancerous condition strongly associated
with the use of tobacco and alcohol [6]. In daily
practice, diagnosis can be made by including the
observation that the lesion cannot be removed by
simple scraping, procedure that permits its dis-
tinction from pseudomembranous candidiasis.
Leukoplakia are mostly asymptomatic; the
major problem that clinicians face in their man-
agement is its tendency to progress into squa-
mous cell carcinoma. The rate of malignant
transformation varies from almost 0 % to about
20 % in one to 30 years [5–8] and it is consid-
ered to be “a morphologically altered tissue in
which cancer is more likely to occur than in its
apparently normal counterpart” [9]. The diagno-
sis of leukoplakia should be ruled out if an
etiologic factor is established, except in the case
of smoking. Candida, human papillomavirus
(HPV) and, Epstein Barr virus (EBV) have been
identified as cofactors that may affect the prog-
nosis of established leukoplakia. Tobacco is a
carcinogen considered one of the most important
risk factors for the development of cancers of
head and neck. In smokers with oral leukoplakia,
it is necessary to differentiate between nicotine
stomatitis or “smoker’s mouth” and leukoplakia.
A typical clinical feature is a fingerprint pattern-
like or pumice-like, in which fine whitish streaks
M. Ramos-e-Silva et al.
on the surface resemble a fingerprint; histology
reveals a “Christmas tree”, “castle”, or v-shaped
pattern of keratinization [4]. There is much
debate about whether Candida species are impli-
cated in the etiology and/or progression of leu-
koplakia. Fungal superinfection is considered a
significant risk factor for oncogenesis.
Elimination of the fungus leads to transforma-
tion of leukoplakia from a non-homogeneous
high-risk variant into a homogeneous low risk,
but the eradication of the infection does not
resolve the lesion. Whether HPV acts as a caus-
ative agent for the development of leukoplakia
or is simply a superinfection is debatable. There
is a well-established link between HPV-16 and
HPV-18 and squamous cell carcinoma of the
cervix. This association in the oral region is still
controversial. HPV-16 is a risk factor for malig-
nant change in leukoplakia regardless of the
harmful effects that tobacco smoke and alcohol
can have on the oral mucosa [4].
Oral leukoplakia can take different forms
according to the clinical pattern, distribution or
spread of the lesion and location within the oral
cavity; it may appear as a homogeneous or non-
homogeneous white plaque that usually has
sharply demarcated borders. Preferred sites are
the floor of the mouth, tongue on its lateral and
ventral surfaces, and soft palate [4, 6]. The
homogenous pattern refers to lesions with a
regular, smooth whitish surface and well-
defined edges. The nonhomogenous pattern
includes leukoplakias that are associated with
an erythematous component (erythroleukopla-
kia) or a nodular, erosive, ulcerated, or verru-
cous exophytic component (oral verrucous
hyperplasia) [4].
Erythroplakia is an intraoral lesion similar to
erythroplasia de Queyrat, a condition of the glans
of the penis. It is defined as a red patch that does
not represent any other recognizable condition
usually with a flat or slightly elevated, velvety,
rather than sharply circumscribed plaque. The
lesions are often asymptomatic. They may be
clinically indistinguishable from inflammatory
conditions. Sites of involvement are similar to
those of oral leukoplakia [6].
138 Leukoplakia
Oral leukoplakias with epithelial dysplasia
are much more likely to undergo malignant
transformation, and many studies have sug-
gested that the risk of cancer incidence may
increase with the severity of dysplastic
changes [5 ]. The distribution or expansion of
leukoplakia in the oral cavity is a prognostic
factor for long-term malignant transforma-
tion. The focal leukoplakia is associated with
good long-term prognosis while disseminated
forms may indicate a worse prognosis. The
homogeneous pattern shows a low risk of
long-term malignant transformation (5 %).
Leukoplakias with homogeneous pattern or
located on the floor of the mouth and the ven-
trolateral region of the tongue are associated
with an increased risk of malignancy, with an
average progressing rate of 43 %. The fact
that these areas are more exposed to carcino-
gens from the salivary secretions and the epi-
thelium in these areas is more permeable,
justify this claim, as indicated by experimen-
tal studies of the oral mucosa [4 ]. Malignant
transformation rates of oral leukoplakia
lesions have been reported to be 1–7 % for
homogeneous thick leukoplakia, 4–15 % for
granular or verruciform leukoplakia, and
18–47 % for erythroleukoplakia [10 ]. It is
important to consider that lesions larger than
20 mm, rapid growth, history of squamous
cell carcinoma, and regular consumption of
alcohol or cigarettes are factors of poor
prognosis.
Histology
Approximately 90 % of oral leukoplakia lesions
show hyperkeratosis and/or epithelial hyperpla-
sia, 5 % epithelial dysplasia or carcinoma in situ,
and another 5 % invasive carcinoma [3]. Biopsies
of erythroleukoplakias usually shows more
advanced dysplastic change compared to leuko-
plakia [6]. There is no definitive clinical or
microscopic reliable method to identify which
lesion will undergo malignant transformation.
Measurement of DNA content (ploidy) has been
715
proposed as a predictive factor. Although promis-
ing, the results of these studies need further
investigation before they can be made clinically
applicable [5].
Treatment Alternatives
There is no consensus regarding the most appro-
priate treatment for oral leukoplakia. Among
many options, elimination of risk factors (smok-
ing, alcohol) is a preventative measure applicable
to all patients [1]. Nonsurgical therapeutic
options reportedly successful include vitamin A,
retinoids, beta-carotene, vitamin E, bleomycin,
alpha-tocopherol. Lodi et al. showed evidence
that vitamin A and beta carotene may clinically
resolve the oral lesions [5], homogeneous leuko-
plakias and smaller lesions responding better
than non-homogeneous and larger lesions, and
that retinoic acid may prevent histological dete-
rioration, based on a small number of patients [5,
11]. A Cochrane review concluded that interven-
tions with topical bleomycin, systemic retinoids,
and systemic lycopene may help resolve the dys-
plasia, but the supporting evidence is inadequate
given the lack of long-term studies [12]. A disad-
vantage of systemic retinoids is toxicity needing
dose reduction or temporary abstinence. Adverse
reactions comprise cheilitis, facial erythema, dry-
ness and peeling of the skin, conjunctivitis, pho-
tophobia and hypertriglyceridemia [13]. Many
subjects receiving treatments have lesions that
will never progress to cancer; thus proposed
treatments should have minimal adverse effects.
This is not the case for high doses of retinoids
[5].
The invasive therapeutic modalities, ablative
procedures, include cryosurgery, application of
carbon dioxide laser light, and surgical resection,
are the only options with an acceptable level of
evidence for local short-term control of leukopla-
kia [14]. Excision is the traditionally recom-
mended treatment for oral leukoplakia with or
without dysplasia; CO2 laser surgery can be used
either by excision of the lesion and part of the
underlying tissue, or by evaporation of the surface
716
epithelium; cryosurgery locally destroys lesional
tissues by in situ freezing and it is an effective
and alternative treatment modality for a variety of
other oral mucosal lesions. It has several advan-
tages including bloodless treatment, a very low
incidence of secondary infections, and a relative
lack of scarring and pain.
Cryosurgery Methodology
(How We Do It)
Both the open spray technique and the closed one
by direct contact of the cryoprobe onto the
lesional surface may be used. Closed-system
cryosurgery offers a greater degree of tempera-
ture control and is usually a better option for
lesions located inside the mouth because the LN
vapors released with the spray technique obstruct
the proper visualization of the lesion to treat
(Fig. 138.2a, b). Open-system cryosurgery
involves directly applying the cryogen to the
lesion with the spray apparatus; this is best suited
for the treatment of medium and large oral lesions
with either a smooth or rough surface, located on
the anterior region of the mouth. Cryo cones may
help reducing splatter. The application with a cot-
ton swab is useful only for benign and superficial
lesions [3]. Swabs of different diameters can be
used depending on the size of the lesion. The site
needs to be air-dried before treatment to prevent
the cotton from sticking to the oral mucosa. The
cotton swab is dipped into LN for at least 5 s and
a b
Fig. 138.2 (a) Leukoplakia on the tongue. (b) Leukoplakia on the tongue during cryosurgery
M. Ramos-e-Silva et al.
applied to the lesion with pressure for 20 s to
form an ice ball and then allowed to thaw for
another 20 s; the number of freeze-thaw cycles
depends on the area and type of the lesion [15].
Cryosurgery for leukoplakia requires a deeper
destruction of the tissues, needing rapid freezing,
slow defrosting, 3–4 mm margin, and two to
three freezing/thawing cycles for mucosa and
semimucosa lesions, which should be previously
biopsied. During the treatment procedure, high-
power suction to remove the saliva, vapor fog and
to improve visibility, is recommended. Most
patients can tolerate the pain induced by the treat-
ment [16]. In patients with severe pain, topical
application of 2 % xylocaine gel before the pro-
cedure is an option. If necessary, analgesics are
prescribed after cryogun cryosurgery to control
the post-cryosurgery pain [17].
Clinical responses of oral soft tissues to cryo-
surgery include tissue edema, subepithelial hem-
orrhage, blister formation, necrosis, sloughing,
and repair. The degree of tissue destruction and
the rate of tissue regeneration after cryosurgery
are slightly different and depend on the size and
location of the lesion and the cryosurgery system
used. In general, hyperemia, edema, or erythema
appears immediately or within a few hours after
cryosurgery. Local swelling and blistering devel-
ops and increases for 1 or 2 days, followed by
superficial necrosis and an ulceration covered by
a layer of whitish or yellowish necrotic pseudo-
membrane. The whitish or yellowish slough
separates from the underlying tissue within the
138 Leukoplakia
first week leaving a clean, granulating surface
that is partially covered by the epithelium.
Epithelialization is complete after 1–4 weeks
with no or very little scar formation [3]. Delayed
healing can happen mainly in patients that com-
plain of severe pain after cryogun treatment.
Analgesics like acetaminophen can be prescribed
after the procedure to control the post-cryosurgery
pain if necessary [17]. Patients should be seen
once a month for 3 months; once every 2 months
for the next 4 months, and then once every
3 months thereafter. If the oral lesion recurs, it
may be treated with the same cryogun cryosur-
gery protocol until complete regression of the
lesion had been achieved [17, 18].
Conclusions
Cryosurgery is an appropriate treatment for
oral leukoplakia.
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 Lymphoma
139
Patricia L. Myskowski

Abstract
Cryosurgery of cutaneous lymphoma is rarely used, but is a potentially
helpful locally destructive method in selected patients with this malig-
nancy. Patients with primary cutaneous T- cell lymphoma (mycosis fun-
goides, Sezary syndrome) or disseminated lymphomas of any kind would
not be candidates for this treatment approach. The closest precedent for
the use of cryosurgery in skin lymphomas may be found in the treatment
of conjunctival lymphomas. Cryosurgery for cutaneous lymphoma is
appropriate for only a small subset of patients with cutaneous lymphomas,
specifically those with low-grade primary cutaneous B cell lymphomas
(i.e. primary cutaneous marginal zone lymphoma and primary cutaneous
follicle cell lymphoma). Appropriate patients for cryosurgery of skin lym-
phomas should also have light skin and multiple small skin lesions. In
addition, for these selected patients, surgery or radiation therapy would
too time-consuming, expensive and/or would have unacceptable cosmetic
results. Cryosurgery should be added to the armamentarium of skin-
directed therapies [surgery, radiation therapy, intralesional injection of
corticosteroids or biologic agents] for the treatment of indolent primary
cutaneous B cell lymphomas.

Keywords
Cryotherapy • Cryosurgery • Lymphoma • Primary cutaneous B cell lym-
phoma • Primary cutaneous follicle center lymphoma • Primary cutaneous
marginal zone lymphoma

Disease Description
P.L. Myskowski, MD
Department of Dermatology, Weill Cornell
Cryosurgery of skin lymphomas is a relatively
Medical College, Memorial Sloan-Kettering
Cancer Center, New York, NY, USA new addition to the treatment of these neoplasms
e-mail: myskowsp@mskcc.org [1, 2]. Skin lymphomas occur in two clinical

© Springer-Verlag London 2016 719

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_139
720
settings: primary cutaneous lymphomas, and sec-
ondary cutaneous lymphomas occurring in the
setting of disseminated disease [2, 3].
Therapy
Only primary cutaneous lymphomas are appro-
priate targets for cryosurgery, as disseminated
lymphomas with skin involvement are usually
managed with systemic anti-neoplastic therapy
with or without radiotherapy [4].
When considering the use of cryotherapy for
primary cutaneous lymphoma, one must first con-
sider the type of lymphoma. While an in-depth
discussion of the different types of primary cuta-
neous lymphoma is beyond the scope of this
paper, in general, primary cutaneous lymphoma
may be divided into two groups: T-cell lympho-
mas and B-cell lymphomas [4]. In the largest
study of the incidence of cutaneous lymphomas in
the United States, of 3,884 cases identified
through the National Cancer Institute’s SEER
program, 71 % were cutaneous T-cell lymphomas
and 29 % were primary cutaneous B cell lympho-
mas [5]. Approximately 1,500 new cases of cuta-
neous T cell lymphoma are diagnosed annually
[6], of which 70 % of cases are mycosis fungoides
(MF) or Sezary syndrome. The skin lesions of MF
are usually flat, broad, multiple and centimeters in
diameter in most patients, and are therefore not
appropriate targets for cryosurgery. Papular
lesions are not typical of MF [7]. Larger lesions
(i.e. tumors) are best managed by radiation ther-
apy and/or systemic anti-cancer agents. Similarly,
there is no place for cryosurgery for the general-
ized erythroderma of Sezary syndrome. Finally,
MF often affects people with dark skin [Fitzpatrick
Type IV or above], for whom the post-treatment
hypopigmentation of cryosurgery to MF lesions
would be cosmetically unacceptable [7, 8].
Primary cutaneous B cell lymphoma (PCBCL)
represents an even more rare type of primary skin
lymphoma, with only a few hundred new cases
diagnosed in the United States annually [3, 5].
PCBCL is generally divided into aggressive (pri-
mary cutaneous large B cell lymphoma, leg-type)
and indolent (primary cutaneous follicle center
P.L. Myskowski
lymphoma [PCFCL] and primary cutaneous
marginal zone lymphoma [PCMZL]) forms.
Primary cutaneous large B-cell lymphoma, leg-
type is an aggressive malignancy, usually starting
with tumors, often multifocal, on the legs of
elderly women; it is most often treated with radi-
ation therapy and/or systemic chemotherapy/
rituximab from the beginning [2, 3].
Only the indolent forms of PCBCL are usually
managed with local therapy [2]. Both PCMZL
and PCFCL are typically found in middle-aged to
older men more than women, and are far more
more common in Caucasian individuals than in
other races [3]. In the indolent forms of PCBCL
the over-all 5-year survival approaches 95–100 %.
Lesions of PCFCL—the more common of the
two indolent forms—usually present as pink to
purplish-red papules, nodules or plaques on the
head. For PCFCL and PCMZL, the treatment of
choice for single lesions is either radiation ther-
apy or surgical excision; the methods are essen-
tially equivalent, and the choice largely
determined by site and patient preference. In
PCFCL and PCMZL, of patients with a single
lesion who are treated with surgical excision,
30–50 % will recur and 20 % will develop new
lesions outside the initial anatomic site. For soli-
tary PCMZL and PCMZL treated with radiation
therapy, the local recurrence rate may be slightly
less, but recurrences outside the primary site are
similar. Thus the majority of patients with indo-
lent PCBCL will develop multiple lesions and,
while this occurrence does not generally affect
prognosis unless disseminated, PCBCL lesions
may be bothersome and of cosmetic and emo-
tional concern to patients [2].
The most relevant literature supporting the use
of cryosurgery in PCBCL may be found in the
ophthalmologic literature. Cryosurgery has been
successfully used in the treatment of various con-
junctival malignancies, including melanoma and
squamous cell carcinoma, as well as lymphoma
[9]. Lymphomas involving the ocular adnexae
represent 8 % of extranodal lymphomas, and
approximately one-quarter of these are limited to
the conjunctiva [10]. In addition, most conjuncti-
val lymphomas are low grade B cell lymphomas
as well [9]. Patients with conjunctival lymphomas
139 Lymphoma 721

are also generally older (average age of

60–66 years) [9]. Radiotherapy is often first-line
therapy for conjunctival lymphoma, with local
success rates of over 90 % [9]. Brachytherapy has
also been used, but complications occur in the
majority of patients. In conjunctival lymphoma—
just as in primary low grade CBCL—rituximab,
intralesional interferon and even observation
have been supported as therapeutic options [9].
There is limited experience on the use of cryo-
therapy as primary treatment of conjunctival
lymphoma [11] although some have advocated
its use as adjuvant therapy after surgical excision
[12]. There is one retrospective case series of 12
patients with 42 biopsy–proven lymphoid con-
junctival tumors—nine B-cell lymphomas two
reactive lymphocytic infiltrates, and one atypical
lymphocytic infiltrate. In contrast to our patients, Fig. 139.1 Multiple small papules of PCFCL (to left of
these individuals received local anesthesia with hair pin in photo)
0.75 % bupivacaine hydrochloride/2 % lidocaine
with epinephrine, diluted 1:1, before cryother-
apy; the lesions were then treated with a Brymill® otoscope cone (usually used for wall-mounted
cryosurgical unit, with a C or D nozzle, for com- otoscope devices) may be placed with pressure
plete thaw times of 1–2 min [11]. With this over the papule of lymphoma, and the LN spray
method, 28 lesions resolved with one treatment, directed into the cone to assure that the lesion is
11 required a second treatment to resolve, and 2 completely frozen. Lesions are treated with
required a third treatment [11]. freeze-thaw cycles of at least 20 seconds [13].
Most lesions resolve with a single treatment, but
occasionally re-treatment may be necessary.
Cryotherapy (How I Do It) Another situation in which cryosurgery is useful
is in hair-bearing areas, where the alopecia follow-
The ideal candidate for cryosurgical treatment of ing radiation therapy would be cosmetically unac-
cutaneous lymphoma has fair to light skin, so that ceptable, and surgical excision would not be
hypopigmentation following LN is cosmetically feasible. We have successfully utilized cryosurgery
acceptable. For example, we have reported the for two patients with multiple small papules of
successful use of cryotherapy in PCMZL on the PCFCL on the scalp: one man two and one woman
arm of a patient with very fair skin [1]. (Fig. 139.1); the esions have not recurred, although
Coincidentally, he had had multiple non- new ones developed in other areas of the scalp in
melanoma skin cancers and actinic keratoses, both patients, which were successfully treated in
was quite familiar with the use of cryosurgery, the same manner (Personal observation).
and tolerated the procedures well. We have used
cryosurgery in similar patients with PCMZL, Conclusions
usually papular lesions with a maximum diame- We reviewed the background and use of cryo-
ter of 6 mm., with a #22 gauge Angiocath plastic surgery in selected patients with low-grade
peripheral venous catheter, with the needle hub PCBCL. This method can provide a simple
removed, screwed to a needle adapter attached to and relatively inexpensive tool for the derma-
the spray opening of the cryosurgical canister tologist to provide local control of these
[13]. Alternatively, a disposable black plastic lesions.
722 P.L. Myskowski

References Diagnosis, clinical and histopathologic features, and

new molecular and biologic markers. J Am Acad
Dermatol. 2014;70(2):205, e1–16.
1. Kennedy-Crispin M, Myskowski PL. Cryotherapy for
8. Jawed SI, Myskowski PL, Horwitz Q, Moskowitz A,
primary cutaneous B cell lymphoma. J Am Acad
Querfeld C. Primary cutaneous T-cell lymphoma
Dermatol. 2012;67(6):e292–4.
(mycosis fungoides and Sezary syndrome): part
2. Suarez AL, Querfeld C, Horwitz S, Pulitzer M,
II. Diagnosis, clinical and histopathologic features,
Moskowitz A, Myskowski PL. Primary cutaneous B
and new molecular and biologic markers. J Am Acad
cell lymphomas: part II. Therapy and future direc-
Dermatol. 2014;70(2):223.e1–17.
tions. J Am Acad Dermatol. 2013;69(3):343.e1–11.
9. Tsai PS, Colby KA. Treatment of conjunctival lym-
3. Suarez AL, Querfeld C, Horwitz S, Pulitzer M,
phomas. Semin Ophthalmol. 2005;20:239–46.
Moskowitz A, Myskowski PL. Primary cutaneous B
10. Knowles DM, Jakobiec FA, McNally L, Burke
cell lymphomas: part I. Clinical features, diagnosis
IS. Lymphoid hyperplasia and malignant lymphoma
and classification. Therapy and future directions.
occurring in the ocular adnexa (orbit, conjunctiva, and
J Am Acad Dermatol. 2013;69(3):329.e1–13.
eyelids): a prospective multiparametric analysis of
4. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E,
108 cases during 1977–1987. Hum Pathol. 1990;21:
Swerdlow SH, et al. WHO-EORTC classification for
959–73.
cutaneous lymphomas. Blood. 2005;105:3768–85.
11. Eichler MD, Fraunfelder FT. Cryotherapy for con-
5. Bradford PT, Devesa SS, Anderson WF, et al.
junctival lymphoid tumors. Am J Ophthalmol. 1994;
Cutaneous lymphoma incidence patterns in the United
118:464–7.
States: a population based study of 3884 cases. Blood.
12. Shields CL, Shields JA, Carvalho C, Rundle P, Smith
2009;113:5064–73.
AF. Conjunctival lumphoid tumors: clinical analysis
6. Criscione VD, Weinstock MA. Incidence of cutane-
of 117 cases and relationship to systemic lymphoma.
ous T-cell lymphoma in the United States, 1973–2002.
Ophthalmology. 2001;108:979–84.
Arch Dermatol. 2007;143(7):854–9.
13. Boulier IC, Myskowski PL, Torre DP. Disposable
7. Jawed SI, Myskowski PL, Horwitz Q, Moskowitz A,
attachments in cryosurgery: a useful adjunct in the
Querfeld C. Primary cutaneous T-cell lymphoma
treatment of HIV-associated neoplasms. J Dermatol
(mycosis fungoides and Sezary syndrome): part I.
Surg Oncol. 1991;17(3):277–8.
 Chronic Radiodermatitis
140
Francesco Feletti and Renata Strumia

Abstract
Chronic radiodermatitis (CRD) is defined as a chronic inflammation of the
skin associated with exposure to ionizing radiation. It usually presents in
individuals who, because of their profession, have been repeatedly exposed
to low doses of radiation over a long period of time without appropriate
protection. Few treatments have been found which affect the natural his-
tory of this disease: topical 5-fluorouracil, antibiotic cream, topical corti-
costeroids and cryosurgery. Nevertheless, only surgery with excision and
grafting provides satisfactory treatment for extensive radionecrosis. In
selected cases, cryosurgery seems to be a safe and useful treatment for
CRD because it eliminates pain and avoids surgical procedures.

Keywords
Chronic radiodermatitis • Cryotherapy • Cryosurgery

Introduction

Chronic radiodermatitis (CRD) is defined as a

F. Feletti, MD (*)
Local Health Trust of Romagna, Department of
Diagnostic Imaging, S. Maria delle Croci Hospital,
Ausl della Romagna, Ravenna, Italy
Department of Electronics, Information and
Bioengineering Polytechnic University of Milan,
Milan, Italy
e-mail: feletti@extremesportmed.org
R. Strumia, MD
Unit of Dermatology, Department of Clinical and
Specialistic Medicine, S. Anna Hospital, University
of Ferrara (Former), Ferrara, Italy
chronic inflammation of the skin associated with
exposure to ionizing radiation. It usually presents
in individuals who, because of their profession,
have been repeatedly exposed to low doses of
radiation over a long period of time without
appropriate protection [1]. The progression and
degree of chronic radiodermatitis is determined
by the quality and intensity of the radiation. The
cumulative dose necessary to induce chronic
radiodermatitis is estimated to be greater than
10–12 Gy [2]. But repeated exposure to lower
doses may also produce lesions of this type.

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_140
724
In the last years cases of CRD have been
reported in patients who underwent diagnostic
procedures. Cardiac angiography is frequently
used in diagnostic and therapeutic coronary
procedures. A less well-known characteristic of
this technique is that it involves the highest
radiation levels in diagnostic radiology [3]. The
incidence of radiodermatitis after percutaneous
coronary interventions is rising with the
increasing number and complexity of these pro-
cedures. The main risk factor is a long duration
of fluoroscopy using the same incidence. The
skin lesions encompass a wide spectrum, rang-
ing from erythema, telangiectasia, atrophy,
hyperpigmentation and hypopigmentation to
necrosis, chronic ulceration and squamous cell
carcinoma [4].
Description of the Disease
CRD may develop very slowly or insidiously
after prolonged, chronic, usually occupational
exposure to repeated very small doses of ionizing
radiation. The affected area may be soft,
depressed and/or wrinkled, or indurated because
of marked fibrosis. CRD is also characterized by
the partial or complete loss of skin appendages.
However, the most serious problem of chronic
exposure to ionizing radiation is the development
of precancerous lesions and skin cancers such
as squamous cell carcinoma. Painful ulcers
and superficial squamous cell carcinoma are
frequently seen together in chronic X-ray
dermatitis.
Lagrot [5] has written a major work entitled
‘Radiodermatites des Mains’ where he describes
the histopathology in detail. Most damage is in
the dermis, with ‘vasculitis obliterans’ leading
to ischaemia of the connective tissue and sclero-
sis. Later, the epidermis becomes dysplastic. He
reported that the average incubation time for
cancers to develop was 25 years, and the aver-
age time until the first signs of radiodermatitis
was 11.6 years. Once keratoses developed,
malignancy was twice as common.
F. Feletti and R. Strumia
Therapeutic Alternatives
Few treatments have been found which affect
the natural history of this disease: topical
5-fluorouracil, antibiotic cream, topical
corticosteroids and cryosurgery. Nevertheless,
only surgery with excision and grafting pro-
vides satisfactory treatment for extensive radio-
necrosis. When chronic radiodermatitis appears
on the hands, surgical treatment can be more
difficult. Photodynamic therapy seems to be a
safe and useful treatment for CRD because it
eliminates pain and avoids surgical procedures
such as amputation, ensuring the preservation
of finger function [6].
Cryotherapy
Conejo-Mir et al. [7] emphasized the advantages
of cryosurgery for the treatment of professional
chronic radiodermatitis with incipient pretumoral
lesions. They performed cryosurgery on six
patients affected with professional CRD that
showed keratomas and ulcerations, using both
spray (keratomas) and a probe 0.5 cm in diameter
(ulcerations, in situ squamous cell carcinoma).
Nerve block anesthesia with mepivacaine 1 %
was used in all cases. Before the treatment, all
suspected lesions were biopsied; if invasive squa-
mous cell carcinoma was revealed in the derma-
topathological study, the patient was rejected.
Variables such as blister and necrosis formation,
pain, and achromatic, sensibility, and mobility
disorders were studied. The follow-up period was
2 years.
Immediate postoperative results showed
great pain and blistering in all cases. Residual
achromias were observed early postoperatively
in all cases, but were repigmented 1 year after
therapy in four cases (66 %). Sensory altera-
tions (hypo- and hyperthesias) were found in
four cases (66 %) 1 month after treatment,
although this complication was not observed
6 months after treatment. Finger mobility was
perfect in all cases 2 months after treatment,
140 Chronic Radiodermatitis
and there was no recurrence in any case after
2 years of follow-up.
Methodology (How I Do It)
Liquid nitrogen is applied with the cotton-tipped
dipstick method on the lesions. Each lesions is
treated with one freeze-thaw cycle of 5–10 s.
Keratomas and small ulcerations are treated.
Before the treatment, all suspected lesions are
biopsied.
Success Rates
Good success rate is achieved in up 80 % of
cases.
Conclusions
In selected cases, cryosurgery seems to be a
safe and useful treatment for CRD because it
eliminates pain and avoids surgical
procedures.
725
References
1. Muiños-Ruano L, Llaneza-Folgueras A, Rizzo-Ramos
A, Menendez-Dizy C. Eficacia de imiquimod topico al
5 % en paciente con radiodermitis cronica en las
manos. Actas Dermosifiliogr. 2012;103:441–2.
2. Sachse MM, Zimmermann J, Bahmer FA. Efficiency
of topical imiquimod 5 % cream in the management of
chronic radiation dermatitis with multiple neoplasias.
Eur J Dermatol. 2006;16:56–8.
3. Dehen L, Vilmer C, Humilière C, et al. Chronic radio-
dermatitis following cardiac catheterisation: a report
of two cases and a brief review of the literature. Heart.
1999;81:308–12.
4. Aerts A, Decraene T, van den Oord JJ, Dens J, Janssens
S, Guelinckx P, Flour M, Degreef H, Garmyn
M. Chronic radiodermatitis following percutaneous
coronary interventions: a report of two cases. J Eur
Acad Dermatol Venereol. 2003;17:340–3.
5. Lagrot F. Radiodermites des Mains. Paris: Doin,
Editeurs; 1974.
6. Escudero A, Nagore E, Sanmartin O, Botella R,
Guillen C. Chronic X-ray dermatitis treated by topical
5-aminolaevulinic acid–photodynamic therapy. Br
J Dermatol. 2002;147:394–5.
7. Conejo-Mir JS, Moreno JC, Camacho F. Cryosurgical
treatment of professional chronic radiodermatitis.
Dermatol Surg. 1997;23:483–6.
 Part XIII
Socioeconomic Issues
 Cryosurgery for Non-melanoma
Skin Cancer: A Cost Analysis
141
Howard W. Rogers

Abstract
There have been rapid increases in the number of skin cancers diagnosed
in the United States and worldwide with associated burgeoning costs.
Despite recent focus by insurers, government regulators and patients on
reducing healthcare expenditure and promoting cost-effective care, the US
utilization of Mohs micrographic surgery for the treatment of skin cancer
has increased by 466 % from 1996 to 2012, while the utilization of less
expensive destructive modalities like cryosurgery has decreased.
Understanding the relative costs and cost effectiveness of skin cancer
treatments including cryosurgery will be critical in making cost conscious,
evidence based skin cancer treatment decisions.

Keywords
Cryosurgery • Cost analysis • Cost effectiveness • Mohs surgery • Excision
• Basal cell carcinoma • Squamous cell carcinoma • Electrodessication
and curettage

Background The number of new skin cancers treated in the

Rapidly increases in the incidence of skin cancer
in the United States (US) and throughout the
world have been documented. The incidence of
non-melanoma skin cancer (NMSC) in the US
has been estimated at 3.5 million cases in 2006
with over 2.2 million affected individuals [1].
H.W. Rogers, MD, PhD
Advanced Dermatology, Norwich, CT, USA
e-mail: rogershoward@sbcglobal.net
Medicare population has increased on average
4.2 % per year from 1992 to 2006 [1]. New cases
of invasive malignant melanoma in the US have
been estimated at 70,230 cases in 2011 with
increases in annual incidence rates of 3.1 % per
year from 1992 to 2008 [2, 3]. Worldwide studies
have also recorded significant increases in both
melanoma and non-melanoma skin cancer [4–8].
The treatment of this skin cancer epidemic has
resulted in very significant associated costs espe-
cially in the US healthcare system. Skin cancer is
now the fifth most costly malignancy to treat in

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W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_141
730
the US [9, 10]. The costs of treating skin cancer
have been estimated at 5 % of the healthcare
expenditures in the US. The direct reimburse-
ments from Medicare for skin cancer treatment
procedure codes were over 633 million dollars in
2008, increasing by 137 % since 1996 [11]. As
healthcare systems struggle to reduce overall
expenditure and promote cost effective treatment,
understanding the costs of different skin cancer
treatments will be critical.
In researching the costs of a medical proce-
dure or intervention, various measures of cost
have been employed. The Current Procedural
Terminology (CPT)/Resource Based Relative
Value Scale (RBRVS) model provides a rela-
tively simple model of cost in that each compo-
nent of a medical treatment is assigned a relative
value unit (RVU) amount, and reimbursement is
based on the total number of RVU’s used [12].
The compensation for procedures in the RVU
based system is calculated based on the time and
effort to perform the procedure as well as the
associated practice expenses. This RVU based
system is the most commonly employed and eas-
ily reproduced cost model in the literature.
Another cost model evaluates the total medical
resources required for a medical treatment
including all medical supplies, personnel time,
and facility time [13]. This is a much more pre-
cise and exacting method of cost analysis, but the
calculations are cumbersome and not generaliz-
able even within a healthcare system in which
patterns of care and resource usage differ. Other
non-monetary considerations that may be as
important to the patient as cost in valuing a pro-
cedure include cosmetic outcome, convenience,
ease and length of wound healing, tumor recur-
rence, anxiety over whether the tumor will recur,
and associated pain and complications.
There are numerous surgical and non-surgical
techniques that have been studied and are widely
used in the treatment of NMSC including cryo-
surgery, electrodessication and curettage
(ED&C), traditional surgical excision, Mohs
micrographic surgery, imiquimod application,
photodynamic therapy and radiation therapy. The
cost of some of the numerous options in the treat-
ment of skin cancer has been evaluated by recent
H.W. Rogers
publications and varies substantially between
treatments [14–21]. Other important consider-
ations in the overall cost of skin cancer treatment
procedures are the choices of histologic margin
control in excisional modalities (permanent ver-
sus frozen section pathology) and the site of ser-
vice (office based, ambulatory surgical center, or
hospital based operating room). Choices in how
and where a skin cancer is treated may dramati-
cally affect the ultimate cost of the procedure.
Cryosurgery is one of the oldest and most
established therapies for NMSC [22]. The terms
cryosurgery and cryotherapy are used inter-
changeably and refer to the therapeutic technique
in which localized freezing is used to destroy dis-
eased tissue. Rapid cooling of tissues to a tem-
perature of −60 °C or lower causes ice crystals to
form, disrupting cell structure and ultimately
killing the cell [23]. During the treatment of skin
cancer, the tissue is most commonly treated with
liquid nitrogen, and a cryoprobe may be used to
monitor tissue temperature and assure suffi-
ciently deep freeze. Moreover, the treated tissue
may undergo curettage prior to freezing to better
define the tumor borders as well as to debulk the
cancer.
Many studies point to low cost as an advan-
tage of cryosurgery, but there is no published
study to specifically support this supposition
[23–25]. Resource utilization modelling has been
developed to look at the relative expenditure of
resources in traditional surgical excision and
Mohs surgical excision of facial basal cell carci-
noma [19]. However, a resource utilization model
for cryosurgery has not been developed. There
are studies that have evaluated the relative costs
of skin cancer treatments, based on insurance
reimbursement [15–18, 21]. However, the exact
definition of cost for a skin cancer treatment may
vary from study to study with some studies
including the cost of diagnostic biopsies, follow
up visits, or treatment of recurrences in the cost
of the procedure.
Given the varying techniques of cryosurgery
performance from physician to physician and
varying compensation for cryosurgery between
healthcare systems, a systematic approach to eval-
uating the cost of this procedure is needed.
141 Cryosurgery for Non-melanoma Skin Cancer: A Cost Analysis
Fortunately, in the US healthcare system, the
physical destruction of a skin cancer (termed
destruction of cutaneous malignancy or malignant
destruction) is defined by the same CPT code
regardless of the technique (cryosurgery, curet-
tage and cryosurgery, or electrodessication and
curettage.) Malignant destruction procedure
codes (CPT series 1726X, 1727X and 1728X) are
specific for the size and location of the tumor
treated. The reimbursement for larger tumors is
higher than smaller tumors, and treatment of
tumors of the head, neck, hands, feet and genitalia
are more costly than those of the trunk, arms or
legs. Although there are very limited studies, the
costs of skin cancer destructions (using ED&C as
the model system) have been evaluated and
because the CPT codes are the same, may be
extrapolated to cryosurgery. In the following dis-
cussion, the costs of ED&C and cryosurgery will
be equated.
Cost Comparison Studies
In 2009, Rogers and Coldiron [17] published a
cost comparison study of numerous treatment
modalities for non-melanoma skin cancer
(Fig. 141.1). The authors examined the costs to
treat two model skin cancer examples, a basal
cell carcinoma (BCC) of the cheek and a squa-
mous cell carcinoma (SCC) of the forearm by
electrodessication and curettage (ED&C)
destruction, imiquimod immunotherapy, Mohs
Fig. 141.1 Estimated costs of varied skin cancer treat-
ment modalities and sites of service based of published
cost comparison studies. Mohs Mohs Micrographic
Surgery, Exc. Traditional Surgical excision, Perm. forma-
lin permanent section margin control, Froz. frozen section
margin control, Office Office based surgical setting, ASC
731
surgery, traditional surgical excision with perma-
nent or frozen sections, and radiation therapy.
The costs of employing surgical facilities such as
an ambulatory surgical center or hospital operat-
ing room for excision were also evaluated.
Each skin cancer example in this study was
varied in size from 0.6 to 3.1 cm, and hypotheti-
cal treatment algorithms were planned using his-
torical rates of treatment failure, positive margins,
and recurrence. Each treatment plan was trans-
lated into CPT procedure codes and facility fees,
and dollar values were assigned based on the
2008 RBRVS values of these codes. It was
assumed that tumor recurrences would be treated
by excisional treatment like Mohs surgery and
not a repeat of the previous treatment.
Estimation of costs for each of the treatment
modalities revealed that tumor destruction (using
ED&C as a model) was the least expensive option
with average costs of $471 (BCC cheek), $392
(SCC arm). Imiquimod treatment and office-
based excision with immediate repair of the sur-
gical defect had similar total average costs of
$959 (BCC cheek), $912 (SCC arm) and $1,006
(BCC cheek) and $907 (SCC arm), respectively.
If repair of the defect was delayed until negative
surgical margins were confirmed by permanent
section, the cost of excision increased to $1,170
and $1,041. The average cost of Mohs micro-
graphic surgery was $1,263 (BCC cheek) and
$1,131 (SCC arm). Excision with frozen section
margin control in an ambulatory surgery center
resulted in costs of $2,334 (BCC cheek) and
ambulatory surgery center, OR Hospital based operating
room setting, Destruction Skin cancer destruction mod-
elled by electrodessication and curettage or cryosurgery,
Radiation Radiation therapy treatment based on 12–17
fractions, * Mixed site of service that may include some
facility based treatment
732
$2,200 (SCC arm). However, if the excision was
performed in a hospital operating room, the pro-
cedure was substantially more expensive at
$3,085 and $2,680. The cost of radiation therapy
treatment was $2,591–$3,460 for the basal cell
carcinoma of the cheek and $2,559–$3,431 for
the squamous cell carcinoma of the arm, depend-
ing on the fractional dose used.
There are some limitations to this analysis.
This study is based on the treatment of hypotheti-
cal tumors based on historical rates of recurrence
or treatment failure and not on actual patients.
Moreover, these costs include the cost of treating
recurrences. If the cost of treating the cancer
recurrence is not included in the calculation, then
the average cost of cryosurgery falls to $204
(BCC cheek) and $157 (SCC arm). Thus, the cost
is 20 % and 23 % of the cost of excision ($880 –
BCC cheek and $794 – SCC arm, both without
recurrence costs), respectively. The cost of treat-
ing a cancer recurrence is 60–67 % of the calcu-
lated cost for cryosurgery. The study calculations
assume a recurrence rate of 20 % for destruc-
tions. However, with cryosurgery recurrences
rates reported as low as 1 % or up to 39 %, the
cost of treating recurrences is difficult to calcu-
late [23–29].
In a recent study by Wilson et al., the costs of
destructions, excisions, and Mohs surgeries were
compared for all the skin cancers treated in the
Dermatology Dept. at UCSF and the San
Francisco Veterans Administration Hospital [18].
This study compared the costs to treat 936 pri-
mary NMSC in the UCSF system using 2007
RBRVS values for the procedures as performed.
Costs of follow up visits were included in the
costs but not the costs of treating recurrences or
treatment failures. The diagnosing dermatologist
determined the proper treatment and referred
patients based on clinical judgment. The research-
ers determined the costs at $463 for destruction,
$1,222 for excision, and $2,085 for Mohs
surgery.
The study by Wilson et al. has numerous criti-
cal weaknesses [30]. Most importantly, there was
significant case selection bias as treatment selec-
tion was done by the dermatologist, so more
complex cases were referred to excision and
H.W. Rogers
Mohs, skewing the costs of these procedures
higher. Moreover, multiple surgery reduction was
not applied for the Mohs surgery costs that
resulted in dramatically inflated costs attributed
to Mohs surgery. Lastly, the costs of treating
recurrences from destructions were not accounted
in the destruction category. Since recurrent
tumors were likely referred for Mohs surgery or
excision, the cost of recurrence from destructions
was actually counted as higher costs for the exci-
sional treatments.
Is Cryosurgery Cost Effective?
Cryosurgery has been shown effective in the
treatment of NMSC in numerous studies
[reviewed in 23]. It also has numerous advan-
tages over other skin cancer treatment options
especially when compared to excision.
Cryosurgery has low cost; and the equipment,
staffing and ancillary service requirements are
modest. Treatment is convenient for the patient
with only one short surgical visit required. There
is no surgical repair or sutures. Many studies
have shown good cosmetic results with cryosur-
gery [28, 31, 32]. However, some authors have
indicated that excision is preferred over cryosur-
gery, especially for facial BCC, due to effective-
ness but without consideration of cost [29]. So
the question is “Compared to excision, is cryo-
surgery cost effective?”
When reviewing studies that evaluate the rela-
tive costs of medical treatments, the distinction
between a cost comparison study and a cost
effectiveness study is critical. Cost comparison
can be defined as the evaluation of the cost of one
procedure to a different procedure(s) done under
similar circumstances and the variables that may
affect that cost. In contrast, cost effectiveness
analysis is an economic analysis that compares
the relative costs and outcomes of two or more
medical interventions. The cost effectiveness of a
medical intervention is thus defined as the ratio
of the cost of the intervention to a relevant mea-
sure of its effect [33].
In cost-effectiveness analysis, the costs
and effectiveness of competing procedures or
141 Cryosurgery for Non-melanoma Skin Cancer: A Cost Analysis
medical interventions are compared. In the sim-
plest situation, one strategy is less costly and
more effective than another, and it is clear that
the first strategy is cost effective [34]. However,
when a new medical treatment is more costly but
more effective (therefore, by extension, the old
treatment is less costly and less effective), cost-
effectiveness analysis and calculation of the cost
effectiveness (CE) ratio is used to decide which
particular intervention is cost effective. The CE
ratio is defined as the difference in cost between
two treatment strategies divided by the differ-
ence in effectiveness (Fig. 141.2) [35]. The CE
ratio represents the extra cost required by the
new strategy to result in one more unit of effec-
tiveness (one quality-adjusted life year, one can-
cer cure, one fewer complication, etc.). Another
important concept is the “threshold” amount,
defined as the value that a cost effectiveness
study or healthcare system places on one unit of
effectiveness [36]. Thus, if the threshold amount
is less than the CE ratio for the new treatment,
the new treatment is not cost effective.
Conversely, if the threshold amount is more than
the CE ratio for the new treatment, the new treat-
ment is cost effective.
From cost comparison studies, it is clear that
cryosurgery is less costly than excisional treat-
ment [17, 18]. However, it is also likely less
effective [23, 29]. Therefore, CE analysis will be
critical in determining whether excision or cryo-
surgery is more cost effective. Using Rogers and
Coldiron costs, we can determine the CER for
excision vs. cryosurgery in the treatment of facial
and non-facial NMSC [17]. For a BCC on the
cheek, the average cost of excision is $880, and
the cost of malignant destruction (cryosurgery) is
$204. Assuming a 10 % difference in effective-
ness (recurrence rate), the CER is 6,760.
Therefore, the extra cost to prevent one recur-
rence by using excision instead of cryosurgery is
costnew strategy – costcurrent practice
CE ratio =
effectnew strategy – effectcurrent practice
Fig. 141.2 Calculation of the cost-effectiveness (CE)
ratio
733
$6,760. Using the same method, the CER for an
SCC of the arm, still assuming a 10 % effective-
ness difference between treatments, will be
6,370. In both of these examples, the CER for
excision vs. cryosurgery is over seven times more
expensive than an excision. Given that threshold
levels for skin cancer treatment have been previ-
ously studied at three times the cost of the more
expensive treatment, cryosurgery is determined
to be cost effective compared to excision in both
examples [19].
This sort of bootstrap CEA has significant
limitations. Again, the costs of skin cancer treat-
ment are based on historical tumor treatment pat-
terns and recurrence rates. If the effectiveness
difference between treatments increases, the
CER will be lower. However, the difference of
effectiveness between excision and cryosurgery
would need to reach 25 % to reach the threshold
of cost effectiveness. A simple CER does not take
any of cryosurgery’s advantages over excision
into account. It also does not calculate any of
cryosurgery’s disadvantages including poten-
tially more difficult and longer wound healing,
slightly worse cosmetic result, patients’ anxiety
over whether the tumor will recur because of lack
of histologically clear margins, and the cost to
treat potentially catastrophic recurrences as peri-
neural tumor spreads under a cryosurgical scar
[27, 28, 37, 38].
Conclusion
From US cost studies, it is clear that cryosur-
gery is a highly effective treatment modality
that is initially less costly than traditional sur-
gical excision. There is also preliminary evi-
dence that cryosurgery may be more cost
effective than traditional surgical excision for
facial and non-facial NMSC. However, there
are numerous limitations to this data and its
generalization. Effectiveness measures such
as patient satisfaction, cosmetic result, wound
healing, and patient anxiety have not been
quantitated but are important considerations.
The cost of treating recurrence is also very
important in the cost of skin cancer treatment.
As recurrence rate increases, treatment of the
recurrence can be more that the initial cost of
734
the cryosurgery. With aggressive tumors and
high risk patients, the risk of recurrence and
costly catastrophic treatment failures is high.
In fact, NCCN guidelines limit the use of
destructive modalities in large and high-risk
tumors [39]. Further controlled studies will
need to be performed to better define the skin
cancers best treated by cryosurgery and its
cost effectiveness.
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11. Rogers HW, Coldiron BM. Analysis of skin cancer
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12. Overview of the RBRVS. American Medical
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15. Ravitskiy L, Brodland DG, Zitelli JA. Cost analysis:
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16. Bialy TL, Whalen J, Veledar E, Lafreniere D, Spiro J,
Chartier T, et al. Mohs micrographic surgery vs tradi-
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17. Rogers HW, Coldiron BM. A relative value unit-based
cost comparison of treatment modalities for nonmela-
noma skin cancer: effect of the loss of the Mohs mul-
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Dermatol. 2009;61(1):96–103.
18. Wilson LS, Pregenzer M, Basu R, Bertenthal D,
Torres J, Asgari M, et al. Fee comparisons of treat-
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19. Essers BA, Dirksen CD, Nieman FH, Smeets NW,
Krekels GA, Prins MH, et al. Cost-effectiveness of
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20. Mosterd K, Krekels GA, Nieman FH, Ostertag JU,
Essers BA, Dirksen CD, et al. Surgical excision
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1149–56.
21. Seidler AM, Bramlette TB, Washington CV, Szeto H,
Chen SC. Mohs versus traditional surgical excision
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22. Kuflik EG, Gage AA, Lubritz RR, Graham
GF. Millenium paper: history of dermatologic cryo-
surgery. Dermatol Surg. 2000;26(8):715–22.
23. Kokoszka A, Scheinfeld N. Evidence-based review of
the use of cryosurgery in treatment of basal cell carci-
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24. Zimmerman EE, Crawford P. Cutaneous cryosurgery.
Am Fam Physician. 2012;86(12):1118–24.
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25. Nordin P, Larkö O, Stenquist B. Five-year results of
curettage-cryosurgery of selected large primary basal
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Andersson-Engless S, Svanberg S, et al. Photodynamic
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28. Thissen MR, Nieman FH, Ideler AH, Berretty PJ,
Neumann HA. Cosmetic results of cryosurgery vs.
surgical excision for primary uncomplicated basal cell
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2000;26:759–64.
29. Kuijpers DI, Thissen MR, Berretty PJ, Ideler FH,
Nelemans PJ, Neumann MH. Surgical excision versus
curettage plus cryosurgery in the treatment of basal
cell carcinoma. Dermatol Surg. 2007;33(5):579–87.
30. Rogers HW, Coldiron BM, Dinehart SM, Hendi A,
Hruza G, Fosko SW, et al. Letter: skin cancer treat-
ment fee comparisons inaccurate. Dermatol Surg.
2012;38(12):2038–9.
31. Lindemalm-Lundstam B, Dalenbäck J. Prospective
follow-up after curettage-cryosurgery for scalp and
face skin cancers. Br J Dermatol. 2009;161(3):
568–76.
32. Nordin P, Stenquist B. Five-year results of curettage-
cryosurgery for 100 consecutive auricular non-
melanoma skin cancers. J Laryngol Otol. 2002;
116(11):893–8.
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33. Chen S, Bayoumi AM, Goldstein MK. Cost-
comparison analysis versus cost-effectiveness analy-
sis: an important difference. J Am Acad Dermatol.
1999;41(6):1050.
34. Folland S, Goodman AC, Stano M. Chapter 4:
Economic efficiency and cost-benefit analysis. In:
The economics of health and health care. 6th ed.
Boston: Prentice Hall; 2010.
35. Drummond MF, Sculpher MJ, Torrance GW, O’Brien
BJ, Stoddart GL. Methods for the economic evalua-
tion of health care programmes. 3rd ed. New York:
Oxford University Press; 2005.
36. Eichler HG, Kong SX, Gerth WC, Mavros P, Jönsson
B. Use of cost-effectiveness analysis in health-care
resource allocation decision-making: how are cost-
effectiveness thresholds expected to emerge? Value
Health. 2004;7(5):518–28.
37. Geist DE, Garcia-Moliner M, Fitzek MM, Cho H,
Rogers GS. Perineural invasion of cutaneous squa-
mous cell carcinoma and basal cell carcinoma: raising
awareness and optimizing management. Dermatol
Surg. 2008;34(12):1642–51.
38. Chren MM, Sahay AP, Bertenthal DS, Sen S,
Landefeld CS. Quality-of-life outcomes of treatments
for cutaneous basal cell carcinoma and squamous cell
carcinoma. J Invest Dermatol. 2007;127(6):1351–7.
39. NCCN Guidelines®. National Comprehensive Cancer
Network (NCCN). http://www.nccn.org/profession-
als/physician_gls/f_guidelines.asp#site. Last accessed
on 11 Mar 2015.
 A Photographic Walk in Veterinary
Cryosurgery
142
Bobby L. Limmer

Abstract
This abstract is an iconographic description of veterinary cryosurgery as
experienced by Dr. Bobby Limmer, an experienced dermatologist and
expert cryosurgeon.

Keywords
Lick • Granuloma • Carcinoma • Epulus • Canine • Bovine • Feline • Warts

During the decade of 1974–1984 I was given the
opportunity to participate in the cryosurgical
treatment of a number of problems in the field of
veterinary medicine. These opportunities arose
because of personal friendships with many vet-
erinarians around the state and I am very thankful
to these excellent doctors for giving me the
unique opportunity to learn from them and to
share my knowledge and experience with them.
These experiences gave me a great respect for
these talented doctors and provided me with
some of my most enjoyable days in medicine.
The following cases in photographic form
present only a brief and partial view of some of
the applications of cryosurgery in the field of vet-
erinary medicine.
Credits: The following Doctors of veterinary
medicine provided the cases presented and
assisted with diagnosis, pre-operative and post-
operative care of the animals.

Dr. Wallace Larson Dr. Gary Norsworthy

Dr. Larry Moore Dr. James West
Dr. Louis Radicke Dr. Don Miller
B.L. Limmer, MD Dr. James Wells Dr. Jim Roffin
Department of Dermatology, Plastic Surgery, Dr. Tom Vice Dr. Frank Moffett
University of Texas Health Science Center,
Dr. James Bielfeldt Dr. James Black
San Antonio, TX, USA
e-mail: carolelimmer@icloud.com Dr. Henry Weir

© Springer-Verlag London 2016 737

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_142
738 B.L. Limmer

Canine Lick Granuloma Canine Wart

(Figure 142.1) (Figure 142.2)

Fig. 142.1 Before (left), 1 week (center), and 10 weeks after cryosurgery (right)

Fig. 142.2 Before (left) and 4 weeks after cryosurgery (right)

142 A Photographic Walk in Veterinary Cryosurgery 739

Canine Intraoral Nodular Melanoma

(Figure 142.3)

Fig. 142.3 Before (top left), during (top right), and 3 weeks after cryosurgery (bottom)
740 B.L. Limmer

Canine Epulus

(Figure 142.4)

a b

Fig. 142.4 Before (a), during (b), 5 days (c), and 8 (d) weeks after cryosurgery
142 A Photographic Walk in Veterinary Cryosurgery 741

Canine Hemangioma

(Figure 142.5)

Fig. 142.5 Before (top left), during (top right), 5 days (bottom left), and 8 weeks after cryosurgery (bottom right)
742 B.L. Limmer

Canine Interdigital Cyst Canine Pannus

(Figure 142.6) (Figure 142.7)

c d

Fig. 142.6 Before (a), during (b), 2 (c) and 4 (d) weeks after cryosurgery

Fig. 142.7 Before (left) and 4 weeks after cryosurgery (right)

142 A Photographic Walk in Veterinary Cryosurgery 743

Feline Squamous Cell Carcinoma Feline Eosinophilic Granuloma

of Lateral Canthus and Lower
Eyelid (Figure 142.9)

(Figure 142.8)

Fig. 142.8 Before (top left), 4 (top right), 6 (bottom left), and 8 (bottom right) weeks after cryosurgery

Fig. 142.9 Before (left), during (center), and 8 weeks (right) after cryosurgery
744 B.L. Limmer

Bovine Squamous Cell Carcinoma Bovine Precancerous Keratosis

(Figure 142.10) (Figure 142.11)

Fig. 142.10 Before (left) and 8 weeks (right) after cryosurgery

Fig. 142.11 Before (left) and 16 weeks (right) after cryosurgery

142 A Photographic Walk in Veterinary Cryosurgery 745

Bovine Periocular Warts Equine Freeze Brands

(Figure 142.12) (Figure 142.13)

(Figure 142.14)

Fig. 142.12 Before (left) and 6 weeks (right) after cryosurgery

a b c d

Fig. 142.13 Fabricated copper tubing contact brand in ery regrowth of white hair at all sites; incomplete at the 30-s
shape (a). Three days after 30, 60, and 120-s applications of site (c). Close up of the 120- s freeze brand demonstrating
the brand, top to bottom respectively (b). Eight weeks after, white hair by depigmentation of the follicle (d)

Fig. 142.14 Freeze brand number 5 on the shoulder of a deer

746 B.L. Limmer

Cryosurgical Dehorning of Male

Suggested Reading
Goat Kid
Fraunfelder FT, Zacarian SA, Limmer BL, Winfield
(Figure 142.15) DL. Cryosurgery for malignancies of the eyelid.
Ophthalmology. 1980;87:461.
Fraunfelder FT, Zacarian SA, Winfield DL, Limmer
BL. Results of cryotherapy for eyelid malignancies.
Am J Ophthalmol. 1984;97:184–8.
Zacarian SA, editor. Cryosurgical advances in dermatol-
ogy and tumors of the head. Springfield: Charles
C. Thomas; 1977.

Fig. 142.15 Before (left), eschar in place 3 weeks after (center), and successful 12 weeks after (right)
 Part XIV
The Future of Cryosurgery
 The Future of Cryosurgery
143
William Abramovits

Abstract
The future of cryosurgery is intricately related to imaging technologies in
progress; particularly those for in vivo real-time use.

Keywords
Future • In-vivo • Real-time • Nano-particles • MOHS

If I have seen further it is by (nanus gigantum There is nothing to be discovered in physics now.
humeris insidentes) standing on the shoulders of All that remains is more and more precise
giants measurements
John of Salisbury in Metalogicon (1159) William Thomson (aka. Lord Kelvin) v. Albert
Issac Newton in a letter to Robert Hook (1676) Michelson?
Kareem Abdul-Jabbar (2009)
The future of dermatologic cryosurgery of
It is difficult to make predictions, especially about
skin malignancies is intricately associated to
the future
Nostradamus imaging methodology. The criticism that most
The Danish Parliament (1930) severely affects the reputation of cryosurgery is
Niels Bohr that it conveys no proof that the epithelial malig-
Yogi Berra (1991)
nancy it treats is ablated to its last cell. In this

W. Abramovits, MD, FAAD

Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
Departments of Family Practice and Dermatology,
The University of Texas Southwestern Medical School,
Dallas, TX, USA
Department of Internal Medicine, Texas College
of Osteopathic Medicine, University of North Texas
Health Science Center, Fort Worth, TX, USA
Department of Dermatology, University of Texas
Medical Branch, Dallas, TX, USA
Texas Tech University, Health Sciences Center,
Lubbock, TX, USA
Texas A&M Health Science Center College of
Medicine, Dallas, TX, USA
Dermatology Treatment & Research Center,
5310 Harvest Hill Road, Suite #160, Dallas, TX
75230, USA
e-mail: DrA@dermcenter.us

© Springer-Verlag London 2016 749

W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5_143
750
sense, it is considered inferior to excisional sur-
gery with margin and depth control, or to micro-
scopic oriented histographic surgery (MOHS);
this when in reality, in the clinic setting, properly
selected lesions, in properly selected patients, by
properly trained dermatologists, are cured with
similar efficacy, and at a fraction of the cost and
inconvenience to the patient.
Imaging methodologies that can, in vivo and
non-invasively, determine the edges at the surface
and, more importantly, the depth of skin cancers,
like confocal microscopy, should be matched to
isotherms that kill malignant cells in order to cure
skin cancer with the reliability of Mohs.
If the latter seems utopian, it is not. In the
recent scientific literature one can notice the con-
tributions that nanoparticles such as quantum
dots of iron and gold are making to imaging, and
their ability to sensitize to temperature conduc-
tivity those cells that incorporate them in simile
to labeling.
W. Abramovits
Needed is a way to freeze and observe
simultaneously and precisely, in real-time, the
progression of cryodestructive fronts until they
reach their target, hold in place for the required
amount of time, and retrieve, in ways that mini-
mizes collateral damage; that technologic pro-
cess has begun.
Of course, one could theorize that the agent
that will selectively destroy a skin cancer, whether
topically or systemically administered, is around
the corner; but then such agent will do away with
not just cryosurgery but MOHS and other what-
you-see-is-what-you-get surgical modalities. But
that is really not around the corner, yet.
The same could be said about the genetic
manipulations that would make us immune to
skin malignancies.
Until that day arrives, it behooves us to keep
working on optimizing cryosurgery.
 Index
A Apoptosis, 10–14, 30–32, 48–50, 53, 55, 149, 194,
Absolute and relative contraindications, 160, 266
Acne
excoriee, 204
inversa, 457
vulgaris, 174, 201, 320, 558
Acrochordons, 270–271, 573–575
Actinic
cheilitis, 5, 285, 339–343, 625, 646
keratosis, 5, 54, 107, 148, 151–154, 157–159, 174,
176, 177, 185–188, 204, 216, 217, 221, 222,
232, 238, 306, 312, 313, 340, 470, 618,
623–630, 646–648, 699
Adaptors, 102, 123–128, 460
Adjunctive therapy, 14, 459, 563, 564, 669, 670
Adverse effects, 245, 251, 270, 273–275, 346, 362, 492,
504, 505, 535, 537, 538, 584, 601, 620, 693
Aging, 340, 400, 408, 588
Albendazole, 454, 455
ALHE. See Angiolymphoid hyperplasia with
eosinophilia (ALHE)
Alopecia, 191, 213, 222, 233, 234, 238, 239, 267,
325–327, 454, 472, 478, 482, 486, 514, 562,
620, 699
Alopecia areata, 191, 325–327, 486
Ancylostoma sp., 453
Anesthesia, 5, 38, 148, 159, 167, 177, 205, 220, 233,
236, 239, 251, 270–273, 278, 303, 334, 336,
337, 340–343, 345, 352, 359, 374, 388, 394,
401, 410, 414, 437, 445, 459, 471, 472, 487,
508, 514, 520, 525, 554, 569, 594, 600, 610,
626, 629, 647, 654, 674, 699, 702
Angiokeratoma, 174, 329
Angiokeratoma of fordyce, 329
Angiokeratoma of mibelli, 329
Angiokertoma coporis diffusum, 329
Angiolymphoid hyperplasia, 5, 174, 300–303, 331–332
Angiolymphoid hyperplasia with eosinophilia (ALHE),
300, 331–332
Ani, 545–547
Anogenital lesion, 634
Anticoagulants, 152, 153, 237, 650
Antimonials, 464, 466, 467
© Springer-Verlag London 2016
W. Abramovits et al. (eds.), Dermatological Cryosurgery and Cryotherapy,
DOI 10.1007/978-1-4471-6765-5
195, 685
Applicators, 48, 82, 92–94, 99, 105–106, 131, 132, 179,
180, 186, 194, 196–198, 392, 398, 421–422,
490, 492, 510, 537, 550, 604, 610
Aprons, 79–80
Area, 12, 21, 41, 50, 65, 81, 91, 101, 107, 111, 113, 119,
121, 136, 137, 139, 141, 152, 165, 170, 174,
180, 186, 194, 202, 211, 216, 220, 223, 227,
236, 247, 256, 258, 266, 273, 283, 295, 306,
326, 333, 335, 339, 350, 359, 362, 367, 378,
384, 400, 408, 414, 457, 463, 471, 481, 485,
489, 492, 497, 500, 504, 508, 514, 528, 532,
563, 568, 573, 579, 580, 583, 589, 594, 597,
600, 603, 607, 609, 619, 623, 638, 648, 654,
663, 667, 673, 680, 693, 699, 702
Areola, 403–405, 500, 668
Argon, 13, 17, 18, 140, 279, 329, 382, 470, 501, 584,
598
Arteriosclerosis, 152, 154, 159, 267
Atrophicus, 408, 485–487, 546
B
Ballooning, 233, 239, 307
Basal cell carcinoma, 4, 54, 117, 153, 174, 210–213,
221, 222, 233, 234, 238, 239, 265, 266,
295–297, 306, 358, 391, 404, 464, 470, 525,
528, 568, 574, 583, 598, 618, 619, 637–642,
668, 708–710
Base, 10, 77–78, 82–84, 109, 121, 129, 166, 174, 212,
270, 271, 336, 340, 343, 368, 369, 397, 510,
538, 562, 610, 624, 625, 639, 648
B-cell, 52, 55, 499, 500, 698, 699
Behavioral approaches, 244
Benign, 4, 38, 89, 92, 94, 132, 148, 158, 164, 165, 167, 174,
179, 180, 191, 220, 222, 228, 238, 270, 271, 274,
275, 286, 295, 299, 329, 331, 339–347, 357,
361, 365, 367–369, 383, 388, 403, 404,
415–417, 422, 423, 425, 471, 472, 477, 478,
491, 496, 499, 503–505, 509, 513, 514, 516,
519, 525, 549, 567, 569, 574, 579, 580, 584, 594,
597, 609, 634, 635, 659, 668, 694
751
752
Bent, 83, 101, 102, 122, 123, 128
Benzoyl peroxide, 320, 504
Biophysics, 20–25, 27, 28, 30, 32
Bloodless technique, 159
Blunt, 105, 121, 459, 460
Body contouring, 193, 199
Borrelia, 486, 500, 501, 589
Bovine, 722
Bowenoid papulosis, 5, 174, 259, 633–635
Bowen’s disease, 5, 153, 174, 261, 404, 528, 546, 618,
620, 634, 635
Bullae, 5, 216, 223, 226–228, 236, 237, 359, 479, 516,
542, 600, 613, 620
C Cornoid lamella, 335, 524, 526, 528, 531
Callosities, 333–334
Cancer, 4, 10, 18, 30, 48, 151, 159, 164, 183, 186, 222,
233, 237, 267, 279, 306, 312, 361, 404, 416,
486, 514, 528, 604, 618, 624, 634, 637, 646,
663, 667, 680, 691, 698, 702, 707, 728
Canine, 716–720
Canister, 18, 82, 92, 123, 131–133, 185, 640, 699
Carbon dioxide (CO2), 4, 13, 17, 18, 89–94, 167,
201–205, 259, 270, 271, 321, 340, 358, 388,
410, 414, 420, 437, 444, 445, 466, 470, 477,
479, 528, 553, 563, 569, 584, 600, 604, 612,
626, 693
Carcinoma, 4, 54, 89, 117, 153, 160, 164, 174, 210, 217,
221, 226, 232, 238, 259, 266, 278, 295, 306,
340, 358, 391, 404, 416, 464, 496, 525, 528,
568, 580, 583, 598, 604, 618, 624, 634, 637,
645, 653, 663, 691, 698, 702, 708, 721
Cartilage, 150, 152, 154, 158, 211, 226, 233, 234, 239,
267, 303, 306, 307, 478, 554, 647
Cell compression, 38
Chambers, 23, 28, 102, 119–120, 124, 684
Cheilitis, 5, 285, 339–347, 625, 646, 693
Chemical peeling, 201, 204, 421
Children, 140, 245–251, 270, 326, 327, 342, 345, 350,
358, 394, 397, 454, 504, 505, 546, 599, 600,
603, 604, 607–609, 659
Chromoblastomycosis, 349–354
Chronic radiodermatitis (CRD), 701–703
Clavi, 333–334
Clear cell acanthoma, 5, 357–359
Clear cell acanthosis, 358
Closed, 13, 18, 67, 68, 82, 85, 101, 102, 113–117, 247,
272–274, 283–287, 289, 299, 340, 341, 384,
394, 414, 419, 424, 425, 446, 471, 510, 569,
580, 584, 626, 649, 655, 694
Cold induced lipolysis, 193–199
Complete thaw time, 148, 175, 699
Complex medical patients, 211
Condyloma
acuminata, 257, 259–261, 345, 519, 580, 634
acuminatum, 361–363
Cones, 85, 102, 109–111, 132, 163, 165, 166, 174, 232,
237, 427, 694
Cone spray, 165, 232, 340, 341, 343
Index
Cone technique, 299, 300
Confocal, 6, 141–143, 568, 674, 728
Conical opening, 110, 111
Contact, 4, 21, 25, 49, 67, 79, 82, 83, 91, 102, 114, 116,
123, 124, 173, 175, 180, 191, 244, 247, 248,
258, 283, 286, 299, 307, 327, 340, 343, 362,
384, 388, 420–423, 425–428, 430, 433–435,
437–445, 472, 489, 515, 532, 546, 608, 626,
628, 655, 694, 723
Contraindications, 151–155, 157–160, 169, 196–197,
211–213, 222, 246, 248, 265–267, 278, 346,
413, 414, 445–448, 471, 536, 601, 683
Cooling, 10–12, 14, 20–22, 24, 25, 27–30, 37, 40–43, 48,
50, 92, 100, 102, 131, 148, 194, 233, 321, 415,
425, 427, 626, 684, 708
Corns, 333–334, 336
Corticosteroids, 258, 313, 320, 326, 331, 347, 374, 377,
384, 388, 418–420, 436, 437, 444–446, 458,
482, 490, 492, 501, 508, 525, 528, 536, 542,
546, 563, 564, 702
CO2 slush, 204, 205
Cosmesis, 158, 238, 279, 620, 683
Cosmetic, 154, 155, 158–160, 173, 175, 188, 209, 232,
233, 238, 239, 260, 266, 267, 269–275, 297,
306, 307, 312, 332, 341, 345, 347, 365–368,
370, 382, 384, 385, 388, 395, 404, 405, 413,
414, 417, 425, 461, 466, 471, 472, 496, 501,
508, 510, 511, 525, 528, 538, 550, 554, 569,
578, 580, 583, 584, 594, 598, 599, 604, 608,
612, 613, 621, 629, 630, 638, 639, 641, 647,
648, 650, 664, 670, 698, 699, 708, 710, 711
Cost analysis, 707–712
Cost effectiveness, 154, 209, 710–712
Cotton swab, 4, 147, 163, 164, 180, 236, 270, 273, 321,
340, 342, 344, 352, 478, 479, 492, 604, 626,
629, 694
Cotton-tipped dipstick method, 180, 366, 382, 384, 385,
578, 702
Cotton-wool, 95, 99, 105, 179, 180, 191, 327, 340, 359,
600
Crospray, 320
Cross-contamination, 95, 99
Cryoablation, 9–14, 48–56, 140, 228, 238, 279, 669, 670,
684–685, 687
Cryobiology, 4, 19, 22, 23, 169, 414
Cryocautery, 399
Cryochambers, 102, 119, 120, 124, 655, 656
Cryofibrinogenemia, 154, 196, 205, 213, 267, 445, 601
Cryogen, 5, 6, 9, 10, 13, 17–18, 131, 132, 147, 163–167,
170, 179, 186, 216, 226, 270, 272–275, 296,
307, 340, 345, 414, 422–429, 470–471, 476,
478, 479, 525, 550, 574, 694
Cryogenic mixtures, 92
Cryoglobulinemia, 160, 196, 213, 223, 346, 445, 471,
601
Cryo immunology, 53–54
Cryoimmunotherapy, 685–687
Cryoinsufflation, 459–461
Cryolipolysis, 196
Index
Cryomassage, 191, 327, 459, 608
Cryomicroscopy, 23, 26
Cryopattern, 174, 175
Cryopeel, 108, 185–188, 421, 441–445, 448, 629
Cryopeeling, 185–188, 421, 441–445, 448, 629
Cryoprobe, 10–13, 30, 48, 92–93, 163, 165, 166, 173,
236, 237, 270, 278, 279, 340, 341, 366, 401,
409, 422–430, 433, 435, 441, 448, 475, 478,
487, 511, 584, 626–628, 648, 694, 708
Cryoprobe technique, 341, 366, 511, 627, 628
Cryospray, 163, 165, 166, 173, 174, 236, 321–323, 414
Cryosurgery,
Cryosurgical unit, 165, 166, 421–423, 425, 427, 428,
459, 472, 532, 699
Cryotherapy,
Crystals, 3, 10–12, 14, 18, 20, 21, 28–30, 37, 38, 40,
48–50, 194, 266, 341, 410, 414, 415, 478, 626,
628, 639, 684, 708
Cup, 71, 99, 105, 130, 167, 179, 180, 340, 604, 629
Curettage, 6, 149, 151, 153, 155, 158, 159, 170, 173,
186, 212, 238, 258, 271, 274, 295, 299, 312,
333, 334, 351, 358, 362, 367–370, 382, 405,
505, 528, 550, 569, 608, 619, 620, 626, 639,
641, 646–648, 680, 708, 709
Cutaneous larva migrans, 5, 453–455
Cutaneous leiomyosarcoma, 667–670
Cutaneous lymphangioma, 495
D 728
Darier-Roussy subcutaneous nodules, 562
Darker skin tone, 256
Debulking, 6, 9, 216, 220, 236, 237, 312, 563, 621, 641
Deep, 3, 18, 72, 109, 119, 173, 179, 185, 205, 211, 232,
233, 237, 239, 248, 249, 259, 267, 279, 286, 340,
341, 346, 350, 384, 394, 420, 457, 458, 496, 549,
562, 563, 625, 650, 655, 667, 680, 708
Delivery, 63, 72, 73, 81–87, 91, 101, 131–134, 166, 196,
202, 209, 216, 256, 270, 296, 490, 600
Delivery system, 81–87, 91, 101, 131–134, 256
Dermatofibroma, 5, 174, 176, 306, 365–366, 668
Dermatologist, 4, 10, 18, 83, 151, 169, 170, 185, 203,
279, 295, 395, 414, 430, 459, 505, 519, 564,
569, 599, 600, 629, 630, 641, 646, 699, 710,
728
Dermatosis papulosa nigra, 367–370, 567
Dewars, 65, 67–69, 72–77, 167, 422
Diagnosis, 160, 169, 238, 258, 259, 266, 271, 320, 339,
344, 350, 358, 362, 365, 368, 388, 391, 394, 400,
404, 408–409, 420, 457, 458, 464, 470, 486,
487, 489, 504, 508, 510, 515–516, 519, 525,
550, 558, 561, 564, 568, 569, 574, 580, 593, 612,
634, 653, 667–670, 674, 687, 692, 715
Diagnostic biopsy, 273, 708
Diameter, 18, 68, 105, 110, 111, 114, 142, 159, 174, 183,
221, 266, 296, 335, 341, 365, 368, 395, 407, 437,
441, 466, 469, 481, 492, 496, 500, 504, 509, 537,
550, 563, 569, 584, 597, 625, 626, 639, 641, 647,
660, 664, 668, 694, 698, 699, 702
753
Diclofenac, 186, 313, 525, 619, 620, 626, 646
Differential scanning calorimetry, 23, 25
Digital mucoid cysts, 509–511
Dimethyl ether and propane, 180–181
Dipper, 68, 71, 74, 167
Discapacitated, 255
Discoid lupus erythematosus, 491, 493
Dispensing, 18, 65, 68, 89–94
Disseminated, 53, 174, 257, 258, 383, 384, 524,
531–533, 549, 693, 698
Disseminated superficial actinic porokeratosis (DSAP),
524, 531–533
Dormant metastases, 687
DSAP. See Disseminated superficial actinic porokeratosis
(DSAP)
E
Edema, 5, 149, 154, 170, 198, 202, 203, 216, 218,
219, 225–228, 236, 239, 260, 270, 273,
274, 289, 297, 320, 321, 340, 346, 347,
352, 359, 370, 374, 375, 395, 416, 419,
420, 434, 436, 444, 445, 478, 496, 514,
526, 528, 543, 547, 558, 612, 613, 629,
641, 660, 684, 694
Efficacy, 12–14, 55, 158, 186, 205, 244, 259–261,
312–314, 326, 327, 402, 420, 466, 483, 501,
505, 535, 536, 542, 558, 563, 564, 584, 588,
591, 604, 626, 629, 630, 641, 669, 674, 687,
Elastosis perforans serpiginosa, 5, 373–375
Electrocautery, 237, 270, 496, 497, 574, 612
Electrodessication, 149, 151, 153, 155, 158, 170, 238,
271, 295, 331, 367, 369, 370, 569, 580,
583, 584, 619, 620, 626, 639, 641, 646,
708, 709
Electrodessication and curettage, 151, 155, 238, 295,
619, 620, 626, 646, 708, 709
ENT specialist, 170
Eosinophilic, 5, 30, 258, 259, 516, 580, 721
Epidermal keratinization, 524, 531, 533
Epidermal nevus, 5, 377–379, 403–405, 527
Epulus, 718
Equipment, 18, 63–65, 71, 79, 83, 89, 138, 147, 154,
163–167, 170, 174, 179, 180, 251, 266, 275,
337, 340, 344, 421–430, 472, 528, 574, 590,
710
Erythema, 5, 149, 198, 203, 216, 218, 226, 236, 258,
259, 270, 273, 274, 320, 321, 326, 327, 332,
340, 346, 404, 434, 436, 444, 445, 492, 493,
500, 508, 535, 537, 538, 546, 557, 563, 589,
591, 594, 608, 610, 620, 625, 629, 646, 693,
694, 702
Erythematous, 154, 197, 213, 222, 256, 350, 383, 397,
399, 410, 444, 453, 473, 531, 536, 546, 562,
612, 618, 619, 623, 625, 638, 664, 692
Erythroerma nodosum, 562
Erytrosis, 191
Ethnic skin, 368
754
Excision, 51, 53, 55, 151, 152, 155, 158, 170, 199, 213,
239, 259, 274, 312, 314, 331, 334, 335, 344,
358, 359, 365, 374, 382, 388, 391, 405, 420,
437, 445, 459, 471, 496, 500, 501, 513, 514,
525, 528, 532, 550, 569, 578, 580, 583, 584,
588, 598, 601, 612, 619, 620, 626, 634, 635,
637–639, 641, 646–648, 660, 664, 667, 669,
670, 674, 683, 685, 687, 693, 698, 699, 702,
708–711
Excisional surgery, 211, 329, 664, 681, 728
Extensions, 6, 23, 83, 101, 102, 122–128, 139, 186, 187,
215, 228, 307, 350–353, 403, 430, 459, 711
Eyelid, 5, 113, 114, 152, 173, 211, 213, 234, 266, 270,
295–297, 472, 478, 492, 609, 610, 612, 620,
621, 628–630, 638, 639, 641, 647, 721
F 490, 612, 694
Fabry disease, 329
Facial angiofibromas, 594
Faciale, 5, 174, 176, 306, 387–389
Fat reduction, 199
Feline, 721
Fibrous papules of the nose, 381–382
Field directed therapy, 619, 620, 625, 626
Fitzpatrick skin types I-VI, 159
Flasks, 18, 81, 83, 95–97, 180
Flat viral warts, 607–608
Florid oral papillomatosis, 653, 654
5-Fluorouracil, 151, 186, 222, 362, 508, 525, 528, 532,
604, 619, 646, 702
Fonsecaea pedrosoi cladophialopora carrionii, 351
Forceps, 129, 164, 180, 236, 337, 574, 590, 610
Freeze
front, 10, 138
injury, 20, 30, 418
substitution, 28
time, 90, 114, 136, 148, 153, 158, 164, 166, 174, 176,
210, 232, 237, 238, 284, 313, 314, 337, 341,
353, 370, 378, 379, 496, 510, 511, 532, 584,
626, 628–630, 651
Freeze-thaw, 5, 11–14, 18, 37, 38, 49, 50, 91, 148, 150,
153, 174, 179, 183, 221, 238, 258, 259, 270,
271, 273, 274, 303, 307, 329, 340–342, 344,
359, 370, 374, 378, 384, 388, 392, 395, 405,
414–416, 418, 433, 435, 471, 479, 492, 505,
508, 510, 514, 520, 528, 532, 542, 543, 550,
554, 564, 588, 598, 600, 613, 620, 621, 626,
629, 630, 635, 640, 641, 647, 661, 669, 670,
674, 676, 682, 684, 686, 694, 699, 702
Freezing model, 30
Fucosidosis, 329
Future, 13, 43, 245, 430, 497, 618, 687, 727–728
G 369, 378, 379, 382, 388, 401, 408, 420, 421,
Gas cylinders, 422, 423
Genital warts, 259, 361–363
Gloves, 79–80, 167, 433, 473, 639
Granuloma
Index
annulare, 5, 176, 188, 259, 383–385, 471
fissuratum, 174, 391–392
Grenz rays, 673, 674
H
Halo, 148, 153, 164, 165, 173–175, 179, 210, 221, 226,
232, 238, 284, 289, 303, 306, 307, 340, 366,
492, 510, 516, 525, 563, 568, 569, 604, 605,
618, 647, 648, 674, 681
Halo thaw time, 148, 153, 175, 210
Hamartoma, 5, 377, 496, 513, 514
Handicapped, 256
Helium, 17, 18, 340
Hemangioma, 4, 5, 174, 176, 201, 244, 270–275, 285,
303, 306, 339, 341, 393–395, 471, 719
Hemorrhage, 216, 227, 228, 236, 237, 343, 394, 416,
Hemorrhagic bullae, 216, 223, 227, 516, 600
Hereditary cutaneous leiomyomatosis with renal cell
cancer (HLRCC), 668–670
Herpes simplex, 5, 397–398, 400
Herpes zoster, 4, 325, 399
Hidradenitis suppurativa, 457–461, 546
Histiocytoma, 365, 668
Histology, 30, 122, 199, 203, 326, 339, 344, 388, 404,
508, 528, 531–532, 541–542, 546, 568–569,
574, 618, 630, 692, 693
History, 3–6, 9, 28, 40, 43, 136, 151, 159, 160, 196, 211,
223, 248, 258, 274, 362, 368, 408, 458, 504,
515, 535, 564, 624, 630, 651, 673, 693, 702
HIV. See Human immunodeficiency virus (HIV)
HLRCC. See Hereditary cutaneous leiomyomatosis with
renal cell cancer (HLRCC)
Holding time, 68, 69, 81, 83, 96, 167
Hormone therapy, 320
HPV. See Human papilloma virus (HPV)
Human immunodeficiency virus (HIV), 257–261, 400,
500, 504, 528, 659, 660
Human papilloma virus (HPV), 54, 180, 255, 259, 271,
340, 345, 361, 486, 599, 600, 603, 604, 607,
634, 635, 663, 692
Hyperkeratosis, 329, 333, 335, 336, 368, 403–405, 408,
457, 482, 486, 487, 492, 496, 568, 654, 655,
693
Hyperkeratosis of areola, 403–405
Hyperkeratosis of nipple, 403–405
Hyperpigmentation, 5, 204, 232, 256, 275, 365, 368–370,
404, 441, 445, 479, 489, 532, 537, 564, 580,
608, 613, 629, 647, 660, 682, 702
Hyperthermia, 313–314, 464, 660
Hypertrophic scars, 5, 121, 149, 179, 244, 306, 313,
413–448, 458
Hypopigmentation, 154, 159, 160, 188, 204, 205, 222, 232,
238, 239, 267, 273, 275, 323, 346, 352, 359,
443, 445, 447, 466, 472, 478, 492, 497, 505,
535, 537, 543, 563, 564, 569, 588, 613, 629,
634, 641, 647, 651, 676, 682, 698, 699, 702
Hysteresis, 42
Index
I Lentigo maligna melanoma, 5, 673–677
Idiopathic guttate hypomelanosis, 5, 407–410
Imiquimod, 6, 54, 151, 153, 154, 186, 238, 239,
258–260, 270, 307, 312, 313, 331, 362, 374,
394, 496, 505, 516, 525, 532, 604, 608, 610,
619, 620, 626, 629, 630, 634, 639, 646, 647,
660, 664, 674, 684–687, 708, 709
Immune response, 31, 32, 37, 48–56, 148, 149, 169, 259,
639, 683, 685, 687
Immunotherapy, 48, 50, 54–56, 255, 260, 326, 336, 464,
603, 680, 685–687, 709
Insufflation, 226–228, 237, 459, 478
Insulated, 9, 41, 83, 95–97, 99, 100, 179, 427, 430
Intervention, 40, 225, 236, 238, 239, 245–251, 279, 312,
416, 434, 482, 497, 505, 520, 604, 693, 702,
708, 710, 711
Intralesional, 48, 121, 239, 258, 271, 272, 313, 321, 326,
331, 341, 362, 374, 377, 388, 394, 410,
418–423, 426–430, 436–441, 444–447, 458,
459, 464, 482, 487, 490, 492, 501, 542, 543,
563, 584, 603, 604, 646, 660, 664, 683, 699
Intralesional cryosurgery, 419–423, 426, 428–430,
437–440, 445–447, 459
Invasive squamous cell carcinoma, 619, 624, 625, 634, 702
in vivo, 6, 14, 31, 32, 37, 138, 141, 142, 414, 417, 418,
568, 674, 728
Ischemia, 14, 30–32, 38, 40, 49, 194, 341, 416, 418
Isotherms, 6, 11, 18, 30, 137, 148, 165, 166, 185, 728
Isotretinoin, 320, 321, 374, 458, 532, 578, 584
Itraconazole, 351, 352, 464
Ivermectin, 454, 455
K 613, 629, 630, 639, 640, 655, 660, 686, 702,
Kaposi sarcoma, 257, 260, 542, 659–661
Keloids, 4, 5, 18, 121, 174, 176, 186, 244, 270, 299–300,
303, 304, 313, 413–448
Keratoacanthoma, 159, 174, 176, 306, 543, 646–648,
651, 663–665
Keratosis, 4, 5, 54, 151–155, 159, 174, 176, 186, 204,
221, 232, 259, 271, 273, 306, 312, 340, 358,
361, 404, 470, 567–569, 618, 623–630, 634,
646, 647, 663, 722
Koebner, 481, 486, 535, 538
L M
Laser, 41, 42, 83, 141, 142, 151, 154, 155, 170, 193,
258–260, 270–272, 278, 320, 326, 329, 331,
351, 358, 362, 369, 377, 378, 382, 384, 405,
409, 410, 420, 437, 444, 445, 458, 464, 492,
496, 501, 505, 508, 510, 514, 519, 525, 528,
532, 550, 578, 580, 583, 584, 588, 594, 598,
601, 604, 612, 619, 620, 626, 630, 634, 639,
646, 660, 680, 683, 684, 693
Leiomyosarcoma, 5, 667–670
Leishmaniasis, 5, 174, 306, 325, 463–467
Lentigo, 107, 176, 256, 272–273, 469–479
Lentigo maligna, 4, 5, 54, 169, 170, 174, 213, 238, 470,
568, 673–677, 680
755
Lesion, 4, 10, 18, 20, 37, 49, 82, 91, 102, 109, 113, 121,
123, 129, 131, 135, 139, 148, 153, 157, 163,
170, 174, 179, 183, 191, 201, 209, 215, 222,
226, 232, 236, 256, 258, 266, 270, 278, 284,
296, 300, 307, 311, 321, 332, 334, 335, 340,
350, 357, 362, 365, 369, 374, 381, 384, 388,
391, 394, 398, 405, 408, 419, 454, 458, 464,
476, 486, 489, 492, 496, 501, 504, 510, 514,
515, 525, 532, 535, 547, 549, 558, 563, 568,
574, 578, 580, 584, 597, 610, 613, 619, 624,
634, 638, 646, 654, 660, 664, 669, 674, 680,
692, 698
Lesion directed therapy, 619, 625, 626, 630
Leukoplakia, 4, 5, 176, 270, 340, 487, 625, 691–695
Lichen, 4, 5, 174, 233, 259, 325, 340, 343, 345, 391, 408,
481–483, 485–487, 489–490, 508, 542, 546,
562, 580, 634, 653
Lichen simplex chronicus, 233, 391, 489–490, 542, 546,
580, 653
Lick, 716
Lid, 67, 68, 72, 81, 82, 234, 267, 493
Linear porokeratosis, 524, 527, 528, 532
Lips, 5, 166, 203, 234, 258, 270, 274, 283, 339–341,
343–346, 358, 394, 397, 478, 492, 609, 621,
641, 655, 656
Liquid air, 4, 10, 17, 18, 270
Liquid nitrogen, 4, 13, 17, 18, 29, 65–69, 83, 85, 136,
159, 166, 167, 179–180, 187, 191, 204, 212,
236, 270, 273, 321, 322, 359, 365, 369, 401,
414, 422, 424–429, 433, 434, 437, 439, 440,
442–445, 454, 459, 460, 470, 471, 476, 479,
497, 501, 505, 537, 542, 555, 588–591, 610,
708
Liquid oxygen, 4, 10, 17, 18, 270
LN2, 65
LN2 generation, 65
Lupus pernio, 562, 563
Lymphangiectasis, 495
Lymphangioma circumscriptum, 495–497, 580
Lymphatic malformation, 495
Lymphocytoma, 5, 174, 499–501
Lymphoma, 267, 404, 489, 499, 500, 546, 697–699
Magnetic resonance, 6, 13, 139, 510
Melanoacanthoma, 567
Melanoma, 5, 48, 54, 55, 138, 169, 170, 174, 213, 238,
266, 267, 279, 344, 470, 568, 598, 668,
673–677, 679–687, 698, 699, 707, 717
Metabolic syndrome, 536, 573
Microcystic lymphatic malformation, 495
Microemboli, 149
Microscopic oriented histographic surgery (MOHS), 728
Microscopy, 6, 28, 321, 351, 408, 516, 568, 669
Migraines, 220, 226, 478
Milia, 5, 166, 232, 234, 238, 445, 478, 507–508, 620
Milia en plaque, 232, 507–508
756
Mohs, 122, 151, 152, 154, 170, 211–213, 238, 266, 295,
306, 307, 312, 351, 358, 620, 638–639, 641,
647, 669, 674, 708–710, 728
Mohs microsurgery, 647
Mohs surgery, 151, 154, 170, 211–213, 238, 312,
708–710
Molluscum, 5, 154, 176, 236, 244, 255, 257, 258,
503–505, 584, 634
Molluscum contagiosum, 5, 154, 176, 244, 258–259,
503–505
Molluscum contagiosum virus, 258, 504
Monitor, 12, 41, 136, 137, 140, 141, 414, 708
Monitorization, 4, 6, 137–139
Monotherapy, 159, 307, 417–420, 436, 497, 563, 604
Mouth, 4, 68, 123, 203, 204, 247–249, 284, 289, 346,
391, 515, 590, 591, 692–694
Myeloma, 223, 267, 346, 542, 601, 612
N Parapox, 515
Nanoparticles, 6, 314, 728
Needles, 6, 12, 18, 83, 101, 102, 121–122, 124, 127, 128,
135, 136, 138, 140, 148, 165, 166, 176, 198,
220, 336, 419, 420, 423, 426–430, 434,
436–438, 440, 446, 459, 460, 510, 564, 569,
584, 587, 610, 699
Neoprene, 110, 111, 166
Neurotic excoriations, 204
Nipple, 247, 248, 358, 403–405, 500
Nitrogen gas, 65, 226–228, 237
Nitrogen gas insufflation, 226–228, 237
Nitrous oxide, 13, 17, 18, 82, 89–94, 167, 340, 384, 385,
422–425, 427, 430, 438–441, 443, 470–472,
474–476, 478, 479, 483, 487, 613
Nonfreezing cold injury, 43
Noninvasive, 193, 194
Non melanoma, 159, 267, 299, 618, 621, 638, 639, 699,
707–712
Nonmelanoma skin cancer, 637, 646
Nonpharmacologic methods, 246–249
Nose, 142, 152, 170, 203, 211, 220, 232, 236, 238, 249,
260, 266, 267, 274, 279, 305–307, 326,
381–382, 492, 500, 553, 554, 557, 562, 564,
578, 583, 594, 595, 609, 621, 624, 640, 647,
655
Nozzle, 82, 83, 101, 102, 166, 321, 340, 343, 374, 410,
466, 594, 630, 699
O 489, 508, 546, 634
Open
cones, 102, 109–111, 299, 300, 496
spray, 114, 129, 165, 174, 227, 271–274, 329, 332,
340, 341, 343, 353, 359, 366, 374, 378, 388,
427, 435, 492, 508, 510, 514, 516, 523, 525,
532, 568, 594, 604, 613, 626, 628, 694
technique, 283–285, 299, 352, 353
Open spray technique, 129, 174, 271, 329, 332, 343, 359,
374, 378, 388, 427, 435, 510, 514, 516, 520,
525, 626, 628, 694
Index
Oral, 4, 5, 53, 89, 102, 121, 205, 236, 248, 250, 260, 273,
274, 283–293, 320, 331, 339–341, 343–345,
347, 454, 455, 458, 471, 481–483, 486, 508,
532, 537, 542, 546, 549, 558, 563, 578, 583,
590, 594, 603, 640, 653–657, 660, 664,
691–695
Oral mucous, 283–293
Orf, 515–516
Organizer, 99
Osteoma, 140
P
Pain management, 244–246, 248, 251
Palliative, 48, 277–279, 496, 669, 680, 682, 683
Palmar, 524, 532, 603–605
Papilloma, 95, 255, 259, 271, 339, 367–369, 377, 378,
404, 567, 568, 574, 599, 600, 603, 607, 634,
653, 654, 663, 692
Paresthesia, 226, 233, 239, 668
Paring, 333, 336, 600–602
Patient, 267
PCFCL. See Primary cutaneous follicle center lymphoma
(PCFCL)
Pearly penile papules, 5, 519–520
Pediatric dermatologist, 170, 505
Pediatric dermatology, 170, 244, 505
Pediatrician, 170
Peel, 107, 188, 204, 205, 274, 421, 629
Perianal, 121, 122, 362, 486, 497, 545, 546
Periauricular, 508
Periungual, 478, 510, 601
Personnel, 708
Pharmacological interventions, 244
Photodamage, 186–188, 204, 205, 598
Photodynamic therapy, 151, 186, 255, 258, 259, 320,
326, 331, 351, 458, 482, 492, 505, 514, 525,
528, 563, 584, 594, 608, 626, 630, 634, 639,
646, 660, 664, 702, 708
Phototherapy, 326, 482, 535, 536, 542, 563
Physical therapy, 352, 504, 505
Pilaris, 482
Plane xanthoma, 612
Plantar, 4, 91, 119, 132, 174, 180, 260, 334–337, 454,
478, 524, 532, 599–601
Plantaris, 335–337, 524, 532
Plantar verrucae, 260, 336
Planus, 4, 174, 259, 325, 340, 343, 345, 481–483, 485,
Plaque, 5, 167, 174, 176, 211, 217, 232, 260, 329, 333,
343, 350, 352, 353, 358, 377, 383, 388, 394,
403–405, 481, 482, 486, 489, 490, 500,
507–508, 524, 525, 528, 531, 532, 535–538,
546, 558, 562, 564, 611, 612, 618, 619, 623,
625, 630, 634, 635, 653, 654, 660, 668, 684,
691, 692, 698
Podophyllotoxin, 260, 504, 604
Poor candidate, 211
Porokeratosis, 5, 174, 335–337, 523–529, 531–533
Index
Porokeratosis of mibelli, 5, 174, 523–526, 531, 532
Post herpetic neuralgia, 245, 399–402
Pregnancy, 205, 255–256, 404, 414, 542, 549, 550
Primary cutaneous B cell lymphoma, 698, 699
Primary cutaneous follicle center lymphoma (PCFCL),
698, 699
Primary cutaneous marginal zone lymphoma, 698
Probes, 41, 82–84, 89, 91, 102, 113–117, 119, 123, 127,
135, 165, 166, 180, 221, 239, 273, 283, 284, 286,
299, 384, 425, 427, 433, 472, 584, 598, 621, 655
Production, 18, 38, 49, 63, 65, 187, 337, 409, 543, 680,
685, 687
Proliferative actinic keratosis, 625, 630
Protection, 10, 50, 79, 80, 111, 166, 167, 272, 283, 300,
434, 438, 471, 608, 625, 686, 701
Protectors, 84, 123–128
Prurigo nodularis, 5, 159, 174, 176, 233, 541–543, 651,
663
Pruritus, 5, 258, 259, 313, 350, 358, 365, 368, 404, 417,
453, 482, 487, 489, 490, 492, 504, 525, 536,
542, 543, 545–547, 580, 581, 620, 651, 668
Pseudoepitheliomatous hyperplasia, 5, 232, 234, 236,
238, 297
Pseudolymphoma, 499–501
Pseudotumor recidive, 232
Psoriasis, 137, 167, 176, 211, 217, 350, 358, 489,
535–538, 546, 634
Psoriatic, 326, 536, 538
Pyogenic granuloma, 174, 226, 228, 236, 238, 274, 300,
339, 340, 343, 358, 394, 478, 549–550, 598, 668
R 261, 266, 279, 306, 325, 340, 350, 471, 496,
Radiofrequency, 6, 52, 53, 55, 193, 278, 312, 405, 496
Radiotherapy, 4, 267, 331, 487, 508, 550, 620, 634, 639,
646, 647, 654, 660, 664, 669, 698, 699
Raynaud’s disease, 160, 196, 223, 346, 445
Raynaud’s syndrome, 213
Rayon, 99, 105–106
Real-time, 6, 13, 135, 137, 516, 728
Recommendations and guidelines, 246
Refrigerant, 5, 63, 64, 131, 204, 384, 427, 475
Retinoids, 6, 151, 313, 320, 331, 377, 410, 482, 508,
525, 528, 536, 549, 569, 578, 583, 612, 664,
693
Rhinophyma, 5, 274, 306, 553–555
Roller bases, 77–78
Rosacea, 154, 174, 191, 274, 508, 553, 557–558
S 271, 322, 326, 327, 329, 336, 337, 340, 341, 344,
Salicylic acid, 228, 238, 334, 374, 405, 504, 601, 604,
608, 620
Sarcoidosis, 384, 391, 561–564
SBF. See Skin blood flow (SBF)
Scars, 5, 121, 186, 203, 205, 234, 239, 244, 273–275,
297, 306, 313, 321, 334, 350, 352, 413–448,
454, 458, 476, 478, 479, 487, 492, 493, 562,
599, 608, 646, 663, 668, 682
Sclerosus, 5, 174, 408, 485–487, 546
757
Sebaceous
gland hyperplasia, 553, 583–584
hyperplasia, 5, 114, 166, 174, 271, 272, 583, 584
Seborrheic, 4, 5, 151, 154, 155, 158, 163, 167, 175, 236,
259, 271, 273, 358, 361, 404, 470, 546,
567–569, 574, 634
Secondary, 10, 11, 14, 23, 25, 31, 51, 152, 216, 219, 227,
260, 267, 314, 336, 347, 352, 403, 404, 408,
410, 447, 464, 478, 497, 504, 508, 513, 514,
537, 538, 542, 545–547, 558, 564, 597,
611–613, 682, 684, 685, 687, 694, 698
Sedation, 250, 251, 278, 441, 542, 563
Segmental cryosurgery, 183, 184, 528
Sensor, 41, 135, 136, 194, 628, 630
Sharp, 114, 115, 297, 326, 335–337, 357, 407, 409, 423,
427, 429, 472, 491, 492, 527, 584, 620, 638,
639, 641, 692
Skin
aging, 186, 187
tags, 129, 130, 164, 180, 236, 270–271, 573–575
Skin blood flow (SBF), 40–42
Snip, 574
Solar lentigines, 469–479
Solar lentigo, 191, 272–273, 471, 474, 476–478
Solid, 18, 48, 63, 91, 105, 167, 201–205, 278, 286, 292, 301,
303, 321, 340, 422, 460, 470, 478, 600, 640
Solid carbon dioxide, 167, 201–205, 321, 340, 470, 600
Special populations, 255–256
Spray, 107
Sprayer, 85, 107–108
Squamous cell carcinoma, 4, 5, 152–154, 159, 160, 174,
175, 211, 212, 217, 222, 226, 232, 233, 259,
525, 528, 568, 574, 618, 619, 624, 625, 634,
645–651, 653, 663, 664, 668, 691–693, 698,
702, 709, 710, 721, 722
Squamous cell carcinoma in situ, 233, 647–648
Stainless steel, 67, 83, 96–97, 99, 100
Stands, 68, 72, 77–78, 167
Steatocystoma multiplex, 577–578, 580
Stick, 18, 48, 105, 106, 179, 180, 401, 421–422, 528,
655
Storage, 18, 63, 65, 67–69, 73, 77, 167, 180, 202, 424,
427
Storing, 65, 68, 83
Straight, 17, 83, 85, 102, 122, 197
Subcutaneous leiomyosarcoma, 667, 668
Superficial, 3, 4, 89, 91, 94, 108, 109, 121, 148, 150, 153,
159, 170, 174, 176, 185, 188, 204, 205, 209, 216,
221, 222, 226, 228, 232–234, 236, 237, 249,
350, 384, 394, 404, 410, 414, 421, 425, 444, 470,
477, 478, 495, 496, 500, 504, 524, 526, 528,
531–533, 554, 558, 578, 618–620, 629, 634,
638, 639, 647, 667, 681, 694, 702
Swab, 4, 106, 147, 163, 164, 180, 236, 270, 273, 321,
340, 342, 344, 352, 359, 421, 422, 478, 479,
492, 550, 604, 626, 629, 694
Syncope, 220, 225, 227–228, 236, 237, 478
Syringoma, 174, 244, 579–581
758 Index

T U
Tangential shave, 648 Ultrasound, 6, 13, 136–139, 193–195, 278, 394, 430
Tattoo Urtication, 166, 216, 226, 346
pigment, 500
removal, 587–588
Techniques, 421 V
Telangiectasia, 5, 222, 306, 394, 486, 492, 493, 558, 562, Vacuum, 9, 67, 68, 81, 95–97, 194, 197, 198
638, 702 Valve, 67, 72, 81, 83, 166, 186, 423, 424, 472, 478
Temperature, 5, 6, 9, 11–14, 18, 20–27, 30, 37, 39–43, Varicella zoster, 260, 399, 500
48, 50, 79, 82–84, 90–92, 109, 129, 131, Vascular anomalies, 394
135–136, 148, 165, 167, 180, 181, 185, 194, Vascular lesion, 4, 113, 139, 154, 166, 270, 284, 286,
198, 201, 202, 204, 205, 226, 244, 270, 278, 419, 549, 550
296, 307, 313, 340, 351, 352, 401, 414, 415, Vascular malformation, 285–293, 313
422–425, 427, 430, 470, 477, 479, 500, 514, Vascular tumors, 228, 238, 329, 495
532, 563, 564, 569, 600, 626, 628, 630, 641, Vasoconstriction, 40–43, 267, 314, 433, 558
694, 708, 728 Vasovagal, 198, 220, 228, 236, 237, 478
Tendinous xanthoma, 612, 613 Vectors, 463, 589
Tendon xanthoma, 612 Velpeau disease, 457
Terbinafine, 351–353, 464 Venous lake, 5, 174, 228, 238, 270, 341, 597–598
Thawing, 5, 10, 11 Verneuil disease, 457
Therapy resistant, 493 Verruca
Thermocouples, 6, 12, 13, 41, 90, 135, 136, 138, 148, filiformis (filiform wart), 609–610
152, 165, 166, 174–176, 238, 296, 430, 472, palmaris, 603–605
563, 564, 647 plana, 176, 607–608
Thermoregulation, 40 vulgaris, 176, 223, 227, 228, 238, 550, 601, 603, 604
Thiabendazole, 454, 455 Verrucous
Tick removal techniques, 589–591 carcinoma, 604, 653–657
Timed spot freeze technique, 496 leucoplakia, 653
Tips, 78, 82–85, 90–92, 94, 101–103, 105, 106, 121, Viral skin infection, 503
123, 124, 127–129, 164, 166, 174, 236, Vismodegib, 307
284, 299, 344, 353, 422–425, 433, 574, Vulval, 485, 487
610, 639
Tissue freezing, 28–30, 233, 414–415
Tissue ice, 12 W
TNF-α, 53, 244, 313, 542, 562 Warts, 4, 91, 109, 114, 119, 132, 154, 166, 180, 181,
Tomography, 6, 13, 14, 139 226, 227, 237, 238, 244, 259, 270, 271, 336,
Transportation, 159 337, 345, 361–363, 568, 574, 590, 591,
Treatment, 594 599–604, 607–610, 653, 723
Trigger, 48–50, 82–84, 89–91, 160, 166, 194, 246, 279, Wickham, 481, 546
400, 401, 422, 423, 490, 491, 499–501, 505, Withdrawal devices, 71–76, 166, 167
524, 532, 546, 557, 564
Trypanosomatida, 463
Tuberous sclerosis complex, 593–595 X
Tubing, 18, 123–128, 135, 422, 424, 433, 434, 723 Xanthelasma palpebrarum, 612, 613
Tumor ablation, 13, 55 Xanthoma, 510, 611–613
Tylomata, 333–334 Xanthoma tuberosum, 612