Clinical Ophthalmic Oncology Eyelid and Conjunctival Tumors - Jacob Pe'Er Arun D. Singh 3ed 2019

Clinical Ophthalmic
Oncology
Eyelid and Conjunctival Tumors
Jacob Pe’er
Arun D. Singh
Bertil E. Damato
Editors
Third Edition
123
Clinical Ophthalmic Oncology
Jacob Pe’er • Arun D. Singh
Bertil E. Damato
Editors
Clinical Ophthalmic
Oncology
Eyelid and Conjunctival Tumors
Third Edition
Editors
Jacob Pe’er Arun D. Singh
Ocular Onocology Service and Department of Ophthalmic Oncology,
Ophthalmic Pathology Laboratory Cole Eye Institute, Cleveland Clinic
Department of Ophthalmology Cleveland, OH
Hadassah - Hebrew University Medical USA
Center
Jerusalem
Israel
Bertil E. Damato
Nuffield Department of Clinical
Neurosciences, University of Oxford,
Oxford
UK
ISBN 978-3-030-06045-9 ISBN 978-3-030-06046-6 (eBook)

https://doi.org/10.1007/978-3-030-06046-6
Library of Congress Control Number: 2019933401
© Springer Nature Switzerland AG 2019

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Preface
Ophthalmic tumors are rare and diverse so that their diagnosis can be quite
complex. Treatment usually requires special expertise and equipment and, in
many instances, is controversial. The field is advancing rapidly, because of
accelerating progress in tumor biology, pharmacology, and instrumentation.
Increasingly, the care of patients with an ocular or adnexal tumor is provided
by a multidisciplinary team, consisting of ocular oncologists, general oncolo-
gists, radiotherapists, pathologists, psychologists, and other specialists.
For all these reasons, we felt that there was a need for the new edition of
the textbook providing a balanced view of current clinical practice. Although
each section of Clinical Ophthalmic Oncology, 3rd Edition now represents a
standalone volume, each chapter has a similar layout with boxes that high-
light the key features, tables that provide comparison, and flow diagrams that
outline therapeutic approaches.
The enormous task of editing a multi-author, multivolume textbook could
not have been possible without the support and guidance by the staff at
Springer: Caitlin Prim, Melanie Zerah, ArulRonika Pathinathan, and Karthik
Rajasekar. Michael D. Sova kept the pressure to meet the production
deadlines.
It is our sincere hope that our efforts will meet high expectation of the
readers.
Jerusalem, Israel Jacob Pe’er, MD

Oxford, UK Bertil E. Damato, MD, PhD, FRCOphth
Cleveland, OH, USA Arun D. Singh, MD
v
Acknowledgments
To my wife, Edith, and my children, Liron, Neta, and Doron, for years of sup-
port and patience.
Jacob Pe’er, MD
To my family, Frankanne, Erika, Stephen, and Anna.
Bertil E. Damato, MD, PhD, FRCOphth
To my parents who educated me beyond their means, my wife, Annapurna,
and my children, Nakul and Rahul, who make all my efforts worthwhile.
Arun D. Singh, MD
vii
Contents
1 Eyelid Tumors: Examination Techniques�� 1

Catherine J. Hwang and Julian D. Perry
2 Eyelid Tumors: Classification and Differential Diagnosis�� 7
Jacob Pe’er and Shahar Frenkel
3 Benign Eyelid Squamous and Melanocytic Tumors�� 15
Lynn Schoenfield and Arun D. Singh
4 Basal Cell Carcinoma�� 33
Mordechai Rosner and Ido Didi Fabian
5 Squamous Cell Carcinoma�� 45
6 Sebaceous Gland Carcinoma�� 53
7 Eyelid Tumors: Cutaneous Melanoma�� 63
Jacob Pe’er and Robert Folberg
8 Adnexal Tumors �� 71
Martina C. Herwig-Carl and Karin U. Loeffler
9 Stromal Tumors�� 83
Geeta K. Vemuganti and Santosh G. Honavar
10 Surgical Techniques �� 97
Andrew J. Rong, Jennifer I. Hui, and David T. Tse
11 Systemic Associations�� 113
Matteo Scaramuzzi, Lucy T. Xu, Arun D. Singh,
and Elias I. Traboulsi
12 Conjunctival and Corneal Tumors:
Examination Techniques �� 131
Classification and Differential Diagnosis�� 137
ix
x Contents

Benign Epidermal and Melanocytic Tumors�� 143
Ocular Surface Squamous Neoplasia �� 159
Jacob Pe’er, Shahar Frenkel, and Arun D. Singh
Primary Acquired Melanosis�� 185
17 Conjunctival and Corneal Tumors: Melanoma�� 197
18 Conjunctival Stromal Tumors�� 209
19 Caruncle Tumors�� 235
Hans E. Grossniklaus, Daniel R. Capiz-Correa,
and Jill R. Wells
20 Pharmacotherapy for Conjunctival Malignancies�� 245
Ghada Al Bayyat, Dan Arreaza-Kaufman, Anat Galor,
Jacob Pe’er, and Carol L. Karp
21 Sentinel Lymph Node Biopsy for
Eyelid and Conjunctival Malignancies�� 261
Oded Sagiv and Bita Esmaeli
22 Surgical Techniques �� 279
Anat Galor, Bennie H. Jeng, Arun D. Singh,
and Carol L. Karp
23 Radiation Therapy: Conjunctival and
Eyelid Tumors�� 287
Christopher Fleming, Shlomo Koyfman,
and Arun D. Singh
Systemic Associations�� 295
Index�� 307
Contributors
Ghada Al Bayyat, MD Department of Ophthalmology, Bascom Palmer Eye

Institute, Miami, FL, USA
Dan Arreaza, MD Department of Ophthalmology, Bascom Palmer Eye
Daniel R. Capiz-Correa, MD Department of Orbit and Oculoplastic,
Fundacion Hospital Nuestra Senora de la Luz, I.A.P., Mexico City, Mexico
Bertil E. Damato, MD, PhD, FRCOphth Nuffield Department of Clinical
Neurosciences, University of Oxford, Oxford, UK
Bita Esmaeli, MD, MA Department of Plastic Surgery, Orbital Oncology
and Ophthalmic Plastic Surgery, The University of Texas MD Anderson
Cancer Center, Houston, TX, USA
Ido Didi Fabian, MD Department of Ophthalmology, Ocular Oncology
Center, Goldschleger Eye Institute, Sheba Medical Center, Sackler School of
Medicine, Tel Aviv University, Tel Aviv, Israel
Christopher Fleming, MD Department of Radiation Oncology, Taussig
Cancer Center, Cleveland Clinic, Cleveland, OH, USA
Robert Folberg, MD Oakland University William Beaumont School of
Medicine, Rochester, MI, USA
Shahar Frenkel, MD, PhD Ocular Oncology Service and Ophthalmic
Pathology Laboratory, Department of Ophthalmology, Hadassah - Hebrew
University Medical Center, Jerusalem, Israel
Anat Galor, MD Department of Ophthalmology, Bascom Palmer Eye
Hans E. Grossniklaus, MD MBA Department of Ophthalmology, Emory
University School of Medicine/Emory Eye Center, Atlanta, GA, USA
Martina C. Herwig-Carl, MD, FEBO Department of Ophthalmology,
University Clinic Bonn, Bonn, NRW, Germany
xi
xii Contributors
Santosh G. Honavar, MD, FACS Department of Ophthalmic Plastic

Surgery and Ocular Oncology, Centre for Sight, Hyderabad, Telangana, India
Jennifer I. Hui, MD Oculofacial Plastic Surgery, The Eyelid Institute, Palm
Desert, CA, USA
Catherine J. Hwang, MD Division of Orbital and Oculofacial Plastic
Surgery, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA
Bennie H. Jeng, MD Department of Ophthalmology and Visual Sciences,
University of Maryland School of Medicine, Baltimore, MD, USA
Carol L. Karp, MD Department of Ophthalmology, Bascom Palmer Eye
Shlomo Koyfman, MD Department of Radiation Oncology, Taussig Cancer
Center, Cleveland Clinic, Cleveland, OH, USA
Karin U. Loeffler, MD Department of Ophthalmology, Division of
Ophthalmic Pathology, University Clinic Bonn, Bonn, NRW, Germany
Jacob Pe’er, MD Ocular Oncology Service and Ophthalmic Pathology
Laboratory, Department of Ophthalmology, Hadassah - Hebrew University
Medical Center, Jerusalem, Israel
Julian D. Perry, MD Division of Orbital and Oculofacial Plastic Surgery,
Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA
Andrew J. Rong, MD Department of Oculofacial Plastic Surgery, Bascom
Palmer Eye Institute, Miami, FL, USA
Mordechai Rosner, MD Department of Ophthalmology, Eye Histopathology
Laboratory, Goldschleger Eye Institute, Sheba Medical Center, Sackler
Faculty of Medicine, Tel Aviv university, Tel Aviv, Israel
Oded Sagiv, MD Department of Plastic Surgery, Orbital Oncology and
Ophthalmic Plastic Surgery, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA
Matteo Scaramuzzi, MD Department of Pediatric Ophthalmology and
Strabismus, Center for Genetic Eye Diseases, Cole Eye Institute (i-32),
Cleveland Clinic, Cleveland, OH, USA
Lynn Schoenfield, MD Department of Pathology, Ohio State University
Wexner Medical Center, Columbus, OH, USA
Arun D. Singh, MD Department of Ophthalmic Oncology, Cole Eye
Institute, Cleveland Clinic, Cleveland, OH, USA
Elias I. Traboulsi, MD Department of Pediatric Ophthalmology and
Strabismus, Center for Genetic Eye Diseases, Cole Eye Institute (i-32),
Contributors xiii
David T. Tse, MD Department of Oculofacial Plastic Surgery, Bascom

Palmer Eye Institute, Miami, FL, USA
Geeta K. Vemuganti, MD, DNB School of Medical Sciences, University of
Hyderabad, Hyderabad, Telangana, India
Jill R. Wells, MD Department of Ophthalmology, Emory University School
of Medicine/Emory Eye Center, Atlanta, GA, USA
Lucy T. Xu, MD Department of Ophthalmic Oncology, Cole Eye Institute,
Eyelid Tumors: Examination
Techniques
1
Catherine J. Hwang and Julian D. Perry
Introduction Presenting Symptoms
Neoplasia may develop within any eyelid struc- Eyelid neoplasia present with a limited spec-
ture. Examination of the eyelid is thought to be trum of symptoms (Box 1.1). Most often,
relatively straightforward, given its anterior loca- patients notice an abnormal eyelid appearance
tion and the ability to visualize its anterior and or asymmetry compared to the contralateral
posterior surfaces. However, examination includ- eyelid. The eyelid may harbor a distinct lesion,
ing structure and function is critical to determine displaying elevation, ulceration, crusting,
the layers of the eyelid involved and if there bleeding, altered pigmentation, telangiectasia,
might be extension posteriorly into the orbit or or other visible cutaneous or conjunctival
medially into the lacrimal system. The examina- changes. The patient may complain of loss of
tion of an eyelid tumor determines the need for eyelashes or an irregularity along the eyelid
any ancillary tests and the surgical plan. margin.
History Box 1.1 Symptoms of Eyelid Neoplasia
The history begins with a description of the

• Sensory: tenderness, itching, visual
symptoms: severity, onset, and rate of progres-
changes
sion. A targeted review of systems reveals addi-
• Motor: ptosis, lagophthalmos
tional clues to the etiology.
• Structural: visible or palpable lesion,
change in symmetry
The authors of the chapter would like to thank Dr. Bryan
R. Costin for his contribution towards previous edition of
• Functional: keratopathy or tearing
this chapter. • Secondary: pigmentation,
C. J. Hwang (*) · J. D. Perry lymphadenopathy
Division of Orbital and Oculofacial Plastic Surgery,
Cole Eye Institute, Cleveland Clinic,
Cleveland, OH, USA
e-mail: hwangc2@ccf.org
© Springer Nature Switzerland AG 2019 1

J. Pe’er et al. (eds.), Clinical Ophthalmic Oncology, https://doi.org/10.1007/978-3-030-06046-6_1
2 C. J. Hwang and J. D. Perry
Eyelid neoplasia may produce symptoms of Celtic or Scandinavian descent with blonde
that occur with or without visible structural or red hair, blue eyes, and fair skin carry a
changes. Sensory symptoms such as pain, ten- greater risk for cutaneous malignancy [1, 2].
derness, itching, or vision symptoms due to The history should also include immunosup-
keratopathy, induced astigmatism, or obstruc- pression, tobacco use, prior radiotherapy, sun
tion of vision may develop. Motor symptoms, exposure, and similar growths elsewhere on the
such as blepharoptosis or lagophthalmos, may skin.
develop owing to involvement of the eyelid
retractors and protractors or indirectly from a
mass effect. Functional symptoms develop Examination
from mechanical keratoconjunctivitis, expo-
sure keratopathy, or decreased lacrimal The physical examination of an adult with sus-
outflow. pected eyelid neoplasia does not end with direct
visualization of the lesion. It should include a
comprehensive inspection of the eyelid, ocular
Rate of Onset adnexa and orbit, eye, and other cutaneous lesions
described in the history. Underlying conditions
Rapidity and progression help characterize the that may make reconstruction more challenging
pathology. Most symptoms from eyelid tumors should be noted, including prominent globe, mid-
develop over weeks to months, but associated face ptosis, hypoplastic orbital rim, lack of cuta-
hemorrhage, infection, and inflammation may be neous or tissue redundancy, previous scarring
acute. Both benign (e.g., angiomas, papillomas) from cutaneous malignancy repair or other sur-
and malignant (e.g., cutaneous malignancies, gery, asymmetry, lymph node enlargement, lag-
metastases) eyelid tumors can produce hemor- ophthalmos, trichiasis, dry eye syndrome, and
rhage. Any eyelid tumor that blocks lacrimal blepharitis.
outflow or causes diminished cutaneous integrity
can result in infection. Eyelid tumors may also
be associated with a significant inflammatory Eyelid Examination
reactions.
The patient should point out smaller lesions to
the examiner using a hand mirror. The entire
Past Medical History face should be evaluated to note Fitzpatrick skin
type and any other cutaneous lesions. The eyelid
Because the majority of eyelid neoplasms are examination should describe the appearance of
epidermal in origin, the past medical history the lesion, any associated anatomical deformi-
should focus on risk factors for epidermal ties, and the results of palpation. The dimen-
malignancy. Information should be obtained sions should be measured using a ruler or slit
regarding family history of cutaneous malig- lamp beam. The eyelid examination should
nancy, skin type, freckle density, eye color, hair focus particularly on signs of malignancy,
color, and prior history of skin cancer. Patients including telangiectasia, nodularity, pearly
1 Eyelid Tumors: Examination Techniques 3
a b
Fig. 1.1 Photograph of lower eyelid shows a benign eyelid nodule without loss of lashes (a) and loss of eyelid tissue
with cilia loss secondary to a malignant tumor (b)
translucency, ulceration, bleeding, crusting, Function of the eyelid including levator excur-
irregularity of the eyelid margin, meibomian sion, orbicularis function, lagophthalmos, and lid
gland effacement, misdirection of lashes or tri- lag in downgaze should be measured and noted.
chiasis, and loss of cilia (Fig.1.1; Box 1.2). Horizontal eyelid laxity, blepharoptosis, cutane-
Palpation results should describe the mobility of ous insufficiency, and other preexisting eyelid
the lesion, as well as any fluctuance or associ- malpositions, scarring, and conditions should be
ated tenderness. Color changes and irregulari- noted, as they may challenge repair and will
ties should be noted. affect the reconstruction design. In addition,
patients that relate these preoperative conditions
to eyelid tumor surgery in the follow-up period
can be reminded of the preoperative findings.
Box 1.2 Signs of Malignant Eyelid Tumor
• Telangiectasia Ocular Adnexal Examination

• Nodularity, pearly translucency
• Ulceration, bleeding, crusting, margin Eyelid tumors may spread directly to the lacrimal
notch gland, orbit, or lacrimal outflow apparatus.
• Misdirection of lashes or trichiasis Conversely, primary tumors of these areas may
• Loss of cilia occasionally present with only eyelid signs and
• Effacement of meibomian gland orifice symptoms. The structure and function of the orbit
and ocular adnexal tissues in proximity to the
4 C. J. Hwang and J. D. Perry
lesion should be evaluated. The examiner should biopsy. Marking the lesion and taking a photograph
palpate for preauricular, submandibular, cervical is helpful in localization if further procedures or
and supraclavicular adenopathy. Cranial nerves V monitoring are needed.
and VII should be tested carefully to assess for
involvement and possible perineural spread of an
eyelid malignancy. Dermatoscopy
Dermatoscopy is an in vivo noninvasive tech-

Eye Examination nique that may improve the clinical accuracy in
diagnosing melanoma and other pigmented skin
The ocular examination should focus on detecting lesions [3]. Optical coherence tomography
findings caused by, or associated with, the eyelid (OCT) may represent a new and promising tech-
lesion. Slit lamp biomicroscopy may reveal signs nique for noninvasive investigation of skin
of mechanical or exposure keratoconjunctivitis, tumors [4]. This modality may not only distin-
or it may reveal signs of conjunctival spread of guish tumor tissue from normal tissue but may
sebaceous cell carcinoma or cutaneous malig- also visualize the epidermis, the dermoepidermal
nancy. During the evaluation of a pigmented eye- junction, and the dermis, as well as hair follicles,
lid lesion, the sclera and episclera should be blood vessels, and sweat glands [5]. Although
observed for pigmentary changes as well. Direct noninvasive techniques may improve diagnostic
intraocular extension of eyelid tumors is extremely accuracy, the clinical diagnosis of eyelid tumors
rare, but fundoscopy may reveal signs of ocular or remains imperfect, and biopsy still represents the
orbital involvement (choroidal folds, venous con- gold standard.
gestion) in suspected cases.
Biopsy
Diagnostic Evaluation
Based on clinical examination, the clinician is
ncillary Laboratory and Imaging
A accurate in diagnoses in a high percent of patients
Studies anywhere from 83.7% to 96.9% [6, 7]. When the
lesion is clinically misdiagnosed, it is often thought
History and physical examination of a suspected the lesion is benign but in fact histologically
eyelid tumor occasionally dictates ancillary testing. malignant. Malignant lesions can be clinically
In cases of suspected eyelid granulomas, inflam- misdiagnosed as benign, especially when they are
matory labs may be indicated such as antinuclear small and have nondescript surface features,
cytoplasmic antibodies (p-ANCA/c-ANCA) and thereby emphasizing the need for a confirmatory
angiotensin-converting enzyme (ACE) to rule out histology via incisional or excisional biopsy [6, 7].
more specific causes of inflammation. If the exam- The goal of biopsy is to determine the patho-
ination reveals associated orbital or lacrimal out- logic nature of the lesion, while minimizing
flow signs, computed tomography (CT) or adverse functional and cosmetic consequences.
magnetic resonance imaging (MRI) may help to Tumor location and the presumptive clinical
determine the extent of the lesion. Schirmer test- diagnosis largely dictate the approach and tech-
ing could be considered to document underlying nique. Shave biopsy or excisional biopsy can be
dry eye disease. Lacrimal probing and irrigation performed of lesions to determine pathology.
should be performed for peri-punctal lesions, for Biopsy-proven epidermal malignancies
lesions in proximity to the nasolacrimal drainage require margin-controlled excision and repair,
system, and for patients with preexisting epiphora. with either frozen section control of Moh’s
Photodocumenation of the lesion and periorbita micrographic surgery. Melanoma, sebaceous
should also be performed, especially prior to cell carcinoma, and Merkel cell carcinoma
1 Eyelid Tumors: Examination Techniques 5
require excision with wide margins. Some tion results can direct the patient discussion to
tumors, such as capillary hemangioma, may illuminate surgical risks and realities.
resolve spontaneously or require nonsurgical
treatment (Chap. 10).
Conclusion
Treatment Planning A systematic approach to the evaluation of sus-

pected eyelid neoplasia allows the clinician to
Information gathered from the history and eye- diagnose and treat these tumors efficiently and
lid examination determines the initial surgical effectively. Current clinical diagnostic techniques
plan for biopsy. This information also deter- remain inaccurate, and the threshold for biopsy
mines whether any special studies on the should remain quite low. In the future, we hope
biopsy specimen are required. Any testing spe- less invasive diagnostic and therapeutic techniques
cific for the suspected diagnosis should be will be available, as well as for improved preven-
communicated to the pathologist in advance. tive options and better early detection to limit the
For example, if sebaceous carcinoma is sus- morbidity of these common tumors.
pected, then the specimen usually is sent fresh
for Oil Red O staining; however, it can be eval-
uated with immunohistochemistry on paraffin References
section with adipophilin and androgen receptor
depending on the pathologist’s preference [8]. 1. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis
of risk factors for cutaneous melanoma: III. Family
If suspicion for lymphoproliferative disease history, actinic damage and phenotypic factors. Eur J
exists, a fresh specimen for immunohistochem- Cancer. 2005;41:2040–59.
istry and cytology may be indicated. Such fore- 2. Cook BE, Bartley GB. Epidemiologic characteristics
sight may avoid inconclusive biopsy results, and clinical course of patients with malignant eyelid
tumors in an incidence cohort in Olmsted County.
the need for an additional tissue biopsy, and Minn Ophthalmol. 1999;106:746–50.
lost time. 3. Lallas A, Apalla Z, Chaidemenos G. New trends in
A detailed eyelid examination may also dermatoscopy to minimize the risk of missing mela-
increase the efficiency of any anticipated sur- noma. J Skin Cancer. 2012;2012:820474. https://doi.
org/10.1155/2012/820474. Epub 2012 Oct 8.
gery by determining the probable extent of 4. Khandwala M, Penmetsa BR, Dey S, et al. Imaging of
tumor burden. For instance, if examination periocular basal cell carcinoma using en face optical
points to a larger, possibly infiltrating lesion coherence tomography: a pilot study. Br J Ophthalmol.
rather than a smaller, localized process, the 2010;94:1332–6.
5. Gambichler T, Jaedicke V, Terras S. Optical coherence
examination may dictate map biopsies to deter- tomography in dermatology: technical and clinical
mine the extent of the lesion. Conversely, if aspects. Arch Dermatol Res. 2011;303:457–73.
examination shows a small, discreet lesion, 6. Kersten BC, Ewing-Chow D, Kulwin DR, et al.
then it may call for excisional biopsy to mini- Accuracy of clinical diagnosis of cutaneous eyelid
lesions. Ophthalmology. 1997;104:479–84.
mize the number of surgical interventions. 7. Margo CE. Eyelid tumors: accuracy of clinical diag-
Shave biopy is also widely used and allows for nosis. Am J Ophthalmol. 1999;128:635–6.
examination of the tissue without significant 8. Schmitz EJ, Herwig-Carl MC, Holz RG, et al.
disruption. The downside of shave biopsy is Sebaceous gland carcinoma of the ocular adnex – vari-
ability in clinical and histological appearance with anal-
evaluation of the pathology at the depth of the ysis of immunohistochemical staining patterns. Graefes
lesion is sometimes inadequate. The examina- Arch Clin Exp Ophthalmol. 2017;255(11):2277–85.
Eyelid Tumors: Classification
and Differential Diagnosis
2
Introduction Eyelid Skin
In spite of being a small organ, the eyelids con- The eyelid skin, especially the lower eyelid, is
tain numerous histological elements that can be among the most sunlight-exposed anatomical
the origin of several types of benign or malignant structures. The eye and the eyelids are one of the
tumors. In this chapter, we review the basic anat- most observed parts of the face, and therefore,
omy of the eyelid, outline a clinically relevant eyelid tumors are usually diagnosed at an early
classification of eyelid tumors, and briefly dis- stage. The eyelid skin is the thinnest in the body
cuss their differential diagnosis. and lacks subcutaneous fat, but otherwise con-
tains all other skin structures. In the pretarsal
part, the skin and orbicularis oculi muscle are
Anatomical Features normally firmly attached to the tarsal plate,
whereas in the preseptal part, they are more
The eyelids are composed of four layers: skin and loosely attached. The skin epithelium is keratin-
subcutaneous tissue, striated muscle (orbicularis ized stratified squamous epithelium, the origin of
oculi), tarsus, and conjunctiva [1]. The rest of the all types of benign and malignant epidermal
orbital entrance, which clinically may be consid- tumors. Melanocytes are spread in the basal layer
ered as part of the eyelids, is covered, behind the of the epithelium and may give rise to melano-
skin and the orbicularis muscle, by the orbital cytic cutaneous lesions. The dermis contains also
septum that holds back the orbital fat. fibrous tissue, blood and lymphatic vessels, and
nerves that can give rise to many types of fibrous
tissue tumors, fibrohistiocytic tumors, vascular
tumors, and neural tumors.
Adnexal Glands
J. Pe’er (*) · S. Frenkel The eyelids are rich in glandular tissue that may
Ocular Oncology Service and Ophthalmic Pathology be the origin of various glandular tumors.
Laboratory, Department of Ophthalmology,
Eccrine gland tumors may arise from the sweat
Hadassah - Hebrew University Medical Center,
Jerusalem, Israel glands of the eyelid skin as well as from the
e-mail: peer@hadassah.org.il accessory lacrimal glands of Krause and

8 J. Pe’er and S. Frenkel
Wolfring. The glands of Moll can give rise to the possible tumors that can originate from this
apocrine tumors. The sebaceous glands of Zeiss tissue are described elsewhere (Chap. 12).
and the meibomian gland are the origin of seba-
ceous gland tumors.
Eyelid Margin
Orbicularis Oculi The eyelid margin is a flat area on the edge of

each eyelid. The anatomical structures that are
The entire orbital entrance is covered by the orbi- seen in the margin from the skin backwards are
cularis oculi—a striated muscle that is divided the eyelashes and their lash follicles, the gray line
into pretarsal and preseptal zones which are part which consists of the tips of the pretarsal orbicu-
of the eyelids and are involved in the eyelid laris muscle (the muscle of Riolan), the meibo-
movements and the orbital zone that is located mian gland orifices, and the mucocutaneous
over the external orbital bones. junction just posterior to them.
Tarsus Vascular System
The tarsi are firm plates composed of dense con- The venous and lymphatic drainage is important
nective tissues that serve as the skeleton of the in understanding the routes of possible eyelid
eyelids. The upper tarsal plates are much larger tumor metastases. The eyelid has extensive vas-
than the lower ones. The meibomian glands, large cularity that comes from two main sources— the
sebaceous glands, are embedded in the connec- internal carotid and external carotid arteries—
tive tissue of the tarsal plates. The superior tarsal with anastomoses between these two systems.
muscle (Muller’s muscle), a smooth muscle, is The venous drainage is into the angular vein
attached to the upper margin of the tarsus. A par- medially, superficial temporal vein laterally, and
allel muscle does not exist in the inferior tarsus, the orbital veins, anterior facial vein, and the
but the aponeurosis of the inferior rectus muscle pterygoid plexus posteriorly. The lymphatic
attaches to the inferior edge of the inferior tarsus. drainage of the medial portions of the eyelids is
The upper and lower orbital septum, a thin sheet into the submandibular lymph nodes and of the
of fibrous tissue, arises from the periosteum in lateral portions into the superficial preauricular
the orbital rim and fuses with the levator aponeu- nodes and then into the deeper cervical nodes.
rosis superiorly and the lower margin of the lower
tarsus inferiorly. All these histological structures
can give rise to rare fibrous, striated, and smooth Nerve Supply
muscular and glandular tumors. The orbital fat
behind the septum and the fat under the orbital The sensory nerve supply to the eyelids is from
part of the orbicularis oculi can be the origin of the fifth cranial nerve, and the motor nerve sup-
rare lipomatous tumors. ply to the striated muscles is from the third and
seventh cranial nerves and to the smooth muscles
from sympathetic nerves.
Palpebral Conjunctiva
The posterior eyelid surface is lined by the con- Classification of Eyelid Tumors
junctiva—a translucent mucous membrane that is
composed of epithelium and subepithelial Tumors of the eyelid may be classified, like
stroma—the substantia propria. The anatomical tumors in other organs, according to their tissue
and histological features of the conjunctiva and or cell of origin and as benign or malignant. In
2 Eyelid Tumors: Classification and Differential Diagnosis 9
most groups of tumors, unique histological sub- and other stromal tumors (Tables 2.5 and 2.6) are
types behave differently in spite of being of the less frequent. Lymphoid tumors, hamartomas and
same cell of origin. choristomas, and inflammatory and infectious
The classification of eyelid tumors that lesions that simulate neoplasms are listed in
appears in this section is based primarily on the Table 2.7.
second edition of the World Health Organization
(WHO) International Histological Classification
of Tumors (Table 2.1) [2]. The epithelial tumor Differential Diagnosis
classification has been modified and divided into
groups according to the tumor cell of origin. Various characteristics of the tumor and the
Some tumors that are missing from the WHO list patient’s general health are important in making
have been added from other sources [3–5]. the correct diagnosis. The important features
The vast majority of the eyelid tumors, benign that should be noted in examining the eyelid
and malignant, are of cutaneous origin, mostly tumor are the tumor location (upper or lower
epidermal. These tumors are divided into non- eyelid, inner or outer canthus); is it on the eyelid
melanocytic and melanocytic tumors (Table 2.2). margin; the eyelid layer involved (skin, subcuta-
Benign epithelial proliferations, basal cell carci- neous tissue, or palpebral conjunctiva); is the
noma, cystic structures, and melanocytic nevi tumor solid or cystic; tumor size; the color of
represent about 85% of all eyelid tumors [6, 7]. the lesion (pigmented or non-pigmented); skin
The squamous cell carcinoma and the melanoma color (red, pink, yellow, white, or blue); the
are relatively rare [7]. Tumors arising from tumor consistency (hard, soft, or rubbery); its
adnexal structures (Table 2.3), fibrous tissue, surface (smooth, irregular, papillary, ulcerated,
fibrohistiocytic and muscular tumors (Table 2.4), umbilicated, cratered, or keratinized); its shape
(flat or raised, pedunculated, papillary); is the
tumor thin or thick; is the tumor solitary or are
Table 2.1 Major types of eyelid tumors
there several or multiple tumors; is there loss of
Category Subtypes eyelashes; the patient’s race, age, and gender; is
Epidermal Non-melanocytic tumors the tumor movable with the skin or is it fixed to
tumors Melanocytic tumors
the subcutaneous layers; the existence of sys-
Adnexal tumors Sebaceous gland tumors
Sweat gland tumors temic diseases such as genetic diseases (e.g.,
Lacrimal gland tumors neurofibromatosis) or systemic malignancies;
Hair follicle tumors and the existence of diseases or malignancies in
Cystic lesions the surrounding structures (the eyeball, con-
Stromal tumors Fibrous tissue tumors junctiva, orbit, lacrimal drainage system, and
Fibrohistiocytic tumors neighboring skin).
Lipomatous tumors
Certain features of the tumor are suggestive
Smooth muscle tumors
Skeletal muscle tumors
of malignancy [5]. Development of a new lesion
Vascular tumors or changes in size, shape, color, or surface
Perivascular tumors appearance of an existing lesion is suspicious
Neural tumors for malignant conversion. Poorly defined bor-
Lymphoid, plasmacytic, and ders, palpable induration beyond visible bound-
leukemic tumors
aries, loss of fine cutaneous rhytids,
Cartilage and bone tumors
hypervascularity, ulceration, and destruction of
Hamartoma and choristoma
Palpebral conjunctival tumors the normal eyelid architecture are all worri-
Secondary tumors some. Lesions that are not freely mobile due to
Metastatic tumors invasion of underlying structures and those
Inflammatory and infectious lesions that simulate associated with regional lymphadenopathy,
neoplasms hypesthesia, paresthesia or pain, indicating
Table 2.2 Classification of epidermal tumors of the eyelid

Category Subtypes
Non-melanocytic Benign Squamous cell papilloma
Seborrheic keratosis
Inverted follicular keratosis
Reactive hyperplasia (pseudoepitheliomatous hyperplasia)
Premalignant Actinic (solar) keratosis
Intraepithelial neoplasia
Sebaceous nevus (of Jadassohn)
Xeroderma pigmentosum
Malignant Basal cell carcinoma
Squamous cell carcinoma
Mucoepidermoid carcinoma
Keratoacanthoma
Melanocytic Epithelial pigmentation Ephelis or freckles
Lentigo simplex
Solar lentigo
Benign Junctional nevus
Intradermal nevus
Compound nevus
Spitz nevus
Balloon cell nevus
Blue nevus
Cellular blue nevus
Oculodermal nevus of Ota
Premalignant Congenital dysplastic nevus
Lentigo maligna (melanotic freckle of Hutchinson)
Malignant Melanoma arising from nevi
Melanoma arising in lentigo maligna
Melanoma arising de novo
Table 2.3 Classification of adnexal and cystic tumors of the eyelid

Category Subtypes
Sebaceous gland tumors Benign Sebaceous gland hyperplasia
Sebaceous gland adenoma
Malignant Sebaceous gland carcinoma
Sweat gland and lacrimal gland tumors Benign Syringoma
Papillary syringadenoma
Eccrine spiradenoma
Eccrine acrospiroma
Pleomorphic adenoma (benign mixed tumor)
Eccrine cylindroma
Apocrine adenoma
Other benign tumors
Malignant Sweat gland (eccrine) adenocarcinoma
Mucinous sweat gland adenocarcinoma
Apocrine gland adenocarcinoma
Adenoid cystic carcinoma
Porocarcinoma
Hair follicle tumors Benign Trichoepithelioma
Trichofolliculoma/trichoadenoma
Trichilemmoma
Pilomatrixoma (calcifying epithelioma of Malherbe)
Malignant Carcinoma of hair follicles
Table 2.3 (continued)

Category Subtypes
Other cystic lesions Benign Epidermal inclusion cyst
Sebaceous cyst
Retention cyst
Eccrine hidrocystoma
Apocrine hidrocystoma
Trichilemmal cyst
Other benign cystic lesion
Table 2.4 Classification of fibrous, fibrous histiocytic, Table 2.5 Classification of vascular and perivascular
and muscular tumors of the eyelid tumors of the eyelid
Origin Type Tumor Category Subtypes
Fibrous Benign Fibroma Vascular Benign Nevus flammeus (port wine
Keloid stain)
Nodular fasciitis Papillary endothelial
Proliferative fasciitis hyperplasia
Fibromatosis Capillary hemangioma
Malignant Fibrosarcoma Cavernous hemangioma
Congenital fibrosarcoma Venous hemangioma
Fibrous Benign Xanthelasma Epithelioid hemangioma
histiocytic Xanthoma (angiolymphoid hyperplasia)
Dermatofibroma Arteriovenous malformation
Xanthogranuloma Lymphangioma
Fibrous histiocytoma Malignant Angiosarcoma
Juvenile xanthogranuloma Lymphangiosarcoma
Necrotic xanthogranuloma Kaposi’s sarcoma
Reticulohistiocytoma Perivascular Benign Hemangiopericytoma
Intermediate Atypical fibroxanthoma Glomus tumor
Dermatofibrosarcoma Malignant Malignant
protuberans hemangiopericytoma
Angiomatoid fibrous Malignant glomus tumor
histiocytoma
Malignant Malignant fibrous Table 2.6 Classification of neural, lipomatous, cartilage,
histiocytoma and bone tumors of the eyelid
Malignant giant cell
fibrous histiocytoma Category Subtypes
Malignant fibroxanthoma Neural Benign Traumatic neuroma
Smooth Benign Leiomyoma Neurofibroma
muscle Angiomyoma Plexiform neurofibroma
Malignant Leiomyosarcoma Schwannoma
Skeletal Benign Rhabdomyoma (neurilemoma)
muscle Malignant Rhabdomyosarcoma Others, e.g., neuroglial
choristoma
Malignant Malignant peripheral nerve
sheath tumor
lymphatic or perineural spread are also suspi-
Merkel cell tumor
cious for malignancy. Lesions associated with Lipomatous Benign Lipoma
chronic inflammation that respond partially or Others, e.g., hibernoma
temporarily to topical corticosteroids or antibi- Malignant Lilposarcoma
otics also may harbor malignancies. However, Cartilage and Benign Chondroma
one should keep in mind that on the one hand bone Osteoma
malignant tumors can appear without any worri- Malignant Chondrosarcoma
Mesenchymal
some signs, while totally benign tumors can chondrosarcoma
express some of the abovementioned features. Osteosarcoma
Table 2.7 Classification of lymphoid tumors, hamarto- can be sessile (Table 2.2). Congenital nevi u sually
mas, choristomas, and inflammatory and infectious
appear at birth and acquired nevi between the
lesions that simulate neoplasms
ages of 5 and 10 years. Nevi should be differenti-
Category Subtypes
ated on the one hand from flat epithelial pigmen-
Lymphoid Benign lymphoid
hyperplasia tation such as ephelis or freckles and, on the other
Lymphoma hand, from the flat premalignant lentigo maligna
Plasmacytoma or from malignant melanoma that is relatively
Leukemic infiltration rare in the eyelids.
Hamartomas and Dermoid cyst
choristomas Phakomatous
choristoma
Ectopic lacrimal gland Adnexal and Cystic Tumors
Inflammatory and infectious Chalazion
lesions Pyogenic granuloma The eyelid adnexa include many different glands
Verruca vulgaris that are the origin of various benign and malig-
Molluscum contagiosum nant tumors (Table 2.3). These include cystic
Others lesions such as eccrine and apocrine hidrocys-
Others e.g., myxoma
toma that are totally benign and may be transpar-
ent or have a distinct color like the blue apocrine
hidrocystoma. On the other hand, there are very
Epidermal Non-melanocytic Tumors malignant solid sebaceous gland carcinomas that
may resemble chalazion but unlike chalazion
The most common benign epithelial tumor is the cause loss of eyelashes.
squamous papilloma that is often sessile or
pedunculated with papillary shape and keratin-
ized surface (Table 2.2). Squamous papillomata Stromal Tumors
may be multiple. Other epithelial tumors, includ-
ing the premalignant actinic keratosis or small The stromal eyelid tumors usually have a smooth
squamous cell carcinoma may look similar. Basal surface, being under the skin (Tables 2.4, 2.5, and
cell carcinoma comprises over 90% of all malig- 2.6). The tumor elevation may have normal skin
nant eyelid tumors [7]. Its common location is the color, but many of the tumors will have a distinct
lower eyelid and medial canthus; it is usually firm color. Xanthomatous lesions are usually yellow.
and often has an ulcerated center. Other ulcerated Most hemangiomas, diffuse or localized, are red.
eyelid tumors, such as keratoacanthoma or the Subcutaneous varix is soft and blue, and Kaposi’s
more rare papillary syringadenoma, should be sarcoma is blue or red. Merkel cell tumor is red
differentiated from BCC. Features of keratoacan- or violaceous. Eyelid lymphoma can be mani-
thoma, such as rapid growth and possible sponta- fested as a smooth, firm subcutaneous nodule.
neous regression, can help in its diagnosis. Sometimes also subcutaneous tumors can be ses-
Staging of carcinomas of the eyelid skin and sile or even ulcerated, so such phenomena, which
adnexa can be found in the AJCC Cancer Staging are usually seen in epidermal tumors, should not
Manual [8]. exclude them.
Epidermal Melanocytic Tumors Inflammatory and Infective

Simulating Conditions
The most common pigmented eyelid lesions are
the nevi, which are usually flat or mildly elevated In the differential diagnosis of eyelid tumors, we
and can appear anywhere in the eyelid in any should include lesions that simulate tumors
size, and when appearing on the eyelid margin (Table 2.7). The most common simulating lesions
are inflammatory lesions such as chalazion or pyo- 2. Campbell RJ, Sobin LH. Tumours of the eyelid.
In: Histological typing of tumours of the eye and
genic granuloma (a misnomer for granulation tis- its adnexa, World Health Organization international
sue) or infectious viral lesions such as molluscum histological classification of tumors. 2nd ed. Berlin:
contagiosum or verruca vulgaris that is clinically Springer; 1998. p. 3–9.
and histologically similar to squamous papilloma. 3. Shields JA, Shields CL. Atlas of eyelid and conjunc-
tival tumors. Philadelphia: Lippincott Williams &
Many dermatological diseases such as amyloido- Wilkins; 1999. p. 3–189.
sis and malakoplakia or connective tissue disease 4. Hassan AS, Nelson CC. Benign eyelid tumors and
and systemic metabolic diseases such as hema- skin diseases. Int Ophthalmol Clin. 2002;42:135–49.
chromatosis may, sometimes, simulate eyelid 5. Soparkar CN, Patrinely JR. Eyelid cancers. Curr Opin
Ophthalmol. 1998;9:49–53.
tumors and should be differentiated from them. 6. Kersten RC, Ewing-Chow D, Kulwin DR, et al.
Accuracy of clinical diagnosis of cutaneous eyelid
lesions. Ophthalmology. 1997;104:479–84.
7. Cook BE, Bartley GB. Epidemiologic characteristics
References and clinical course of patients with malignant eyelid
tumors in an incidence cohort in Olmsted County.
1. Bedrossian EH. Chapter 5: Embryology and anatomy of Minn Ophthalmol. 1999;106:746–50.
the eyelid. In: Tasman W, Jaeger EA, editors. Duane’s 8. Esmaeli B, Dutton JJ, Graue GF, et al. Chapter 64:
foundation of clinical ophthalmology, ocular anat- Eyelid carcinoma. In: Amin MB, et al., editors. AJCC
omy, embryology and teratology, vol. 1. Philadelphia: Cancer staging manuel. 8th ed. New York: Springer;
Lippincott Williams & Wilkins; 2004. p. 1–24. 2017. p. 779–85.
Benign Eyelid Squamous
and Melanocytic Tumors
3
Lynn Schoenfield and Arun D. Singh
Introduction of the skin, but they may also include conjuncti-

val tumors as well. Some of these tumors repre-
The eyelid consists of six layers with epidermis sent manifestations of systemic disease (Chap.
externally and palpebral conjunctiva internally. 11). A classification of the epidermal eyelid
Between these two (from outer to inner) are der- tumors is presented in Table 3.1. Only the
mis, loose subcutaneous layer, orbicularis mus- description of the most common and frequently
cle, and tarsal plate. The epithelium consists of observed benign tumors, along with their corre-
squamous cells and melanocytes primarily with sponding premalignant lesions and tumor-like
smaller numbers of Langerhans cells and Merkel nonneoplastic lesions, is included in this chapter.
cells. The presence of Langerhans cells is impor-
tant to recognize, as they, like melanocytes, are
positive for the immunohistochemical stain S100. Squamous (Non-melanocytic)
Benign tumors of the eyelid include a variety of Tumors
nonpigmented and pigmented epidermal tumors,
which arise from squamous and melanocytic Squamous Cell Papilloma
cells, respectively, adnexal tumors (Chap. 4),
stromal tumors (Chap. 5), and benign lymphoid Squamous papillomas are the most common
proliferations. Important to note is that not all benign tumors typically occurring in middle-
clinically pigmented lesions are melanocytic, aged or older adults. The clinical appearance is
since squamous cell proliferations can include that of a pedunculated or sessile nodular growth
scattered melanocytes or melanin pigment, thus with a variably convoluted surface with or with-
giving a pigmented appearance to a lesion. The out hyperkeratosis. They are often multiple, pres-
benign epidermal tumors of the eyelid are similar ent at the lid margin, and are skin-colored
to those observed in the other sun-exposed areas (Fig. 3.1a) [1].
Microscopically a papilloma consists of benign
squamous hyperplastic (acanthotic) epithelium
L. Schoenfield (*) with variable hyperkeratosis or parakeratosis
Department of Pathology, Ohio State University
overlying an expanded fingerlike fibrovascular
Wexner Medical Center, Columbus, OH, USA
e-mail: lynn.schoenfield@osumc.edu core, which creates the exophytic nodule. They
sometimes have overlapping features with sebor-
A. D. Singh
Department of Ophthalmic Oncology, rheic keratosis (Fig. 3.1b). If symptomatic, surgi-
Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA cal excision may be performed.

16 L. Schoenfield and A. D. Singh
Table 3.1 Classification of epidermal tumors of the eyelid, excluding adnexal tumors
Types Subtypes
Non- Benign Squamous cell papilloma
melanocytic Seborrheic keratosis
Molluscum contagiosum
Reactive hyperplasia (pseudoepitheliomatous
hyperplasia)
Potentially premalignant Actinic (solar) keratosis
Intraepithelial neoplasia
Sebaceous nevus (of Jadassohn)
Malignant Basal cell carcinoma
Melanocytic Benign epithelial pigmentation or Ephelis or freckles
hypermelanosis Lentigo simplex
Solar lentigo
Benign Junctional nevus
Intradermal nevus
Compound nevus
Spitz nevus
Balloon cell nevus
Blue nevus and cellular blue nevus
Oculodermal nevus of Ota
Seborrheic keratosis
Potentially premalignant Congenital dysplastic nevus
Lentigo maligna (melanotic freckle of Hutchinson)
Malignant Melanoma arising from nevi
Melanoma arising in lentigo maligna
a b
Fig. 3.1 Squamous papilloma. Clinical appearance. (a) ing a fibrovascular core ((b) hematoxylin and eosin;
Polypoid lesion consisting of benign squamous epithe- original magnification 4×)
lium with variable acanthosis and hyperkeratosis overly-
Seborrheic Keratosis also been referred to as basal cell papilloma, seb-

orrheic wart, and senile verruca. The clinical
Seborrheic keratoses are commonly acquired appearance varies considerably in terms of size
skin lesions which can occur on the eyelid affect- (few millimeters to several centimeters) and
ing middle-aged and elderly patients. They have degree of pigmentation making it sometimes
3 Benign Eyelid Squamous and Melanocytic Tumors 17
a b
Fig. 3.2 Seborrheic keratosis. Upper eyelid involvement tissue and composed of sheets of basaloid cells with
in a 75-year-old man. (a) Retiform (network-like) pattern keratin-filled horn pseudocysts ((b) hematoxylin and
of squamous epithelium surrounding islands of connective eosin; original magnification 10×)
d ifficult to differentiate clinically from nevi, pig- ant of seborrheic keratosis or verruca vulgaris. It
mented basal cell carcinomas, and melanoma [1]. is commonly seen on the face, particularly the
They are sharply demarcated warty plaques or cheeks, upper lip, and less often, eyelid [4–7]. It
dome-shaped growths with a greasy and cerebri- usually occurs in older men and ranges in size
form surface, which may become friable with from 0.3 to 1.0 cm. Usually a solitary lesion of
inflamed eczema-like features (Fig. 3.2). recent onset (less than 3 months), it may be nodu-
Seborrheic keratoses are divided into several lar, papillomatous, or cystic in appearance.
histological types according to the predominant Inverted follicular keratosis may recur following
histologic features: acanthotic, hyperkeratotic, incomplete excision and thus be easily mistaken
adenoid (reticulated), clonal, and irritated for squamous cell carcinoma [7].
(Fig. 3.2).The most common type is the acan- Histopathologically, there are four main growth
thotic, in which there is a proliferation of squa- patterns: papillomatous, keratoacanthoma- like,
mous basaloid cells protruding above the skin solid nodular form, or cystic type. Usually it con-
surface, which is punctuated by horn pseudocysts. sists of an endophytic proliferation of squamous
Typically, the basal plane of the lesion is in align- epithelium with squamous eddies, hyperkerato-
ment with the surrounding uninvolved squamous sis, parakeratosis, acantholysis, generally little if
epithelium. Hyperpigmentation can occur, which any melanin pigment, and dermal chronic inflam-
is due to transfer of melanin to the keratinocytes. mation. There may be increased mitoses and
When a patient experiences a sudden appearance apoptosis (Fig. 3.3) [6, 7]. Complete excision
of a seborrheic keratosis or an increase in the num- should be performed to prevent recurrence.
ber or size of these lesions, this may be associated
with an internal malignancy and is referred to as
the Leser-Trelat sign [2, 3]. Even in lesions that are Molluscum Contagiosum
large, the growth pattern is superficial with growth
predominantly above the epidermal surface. Molluscum contagiosum is an on neoplastic
Therefore, deep excision is unnecessary; and these skin infection caused by a virus from the pox
lesions are often removed by shave biopsy. virus group. This entity occurs frequently in
children but may also occur in adults anywhere
on the body except the palms and soles. It
Inverted Follicular Keratosis appears as papules that are white- or flesh-col-
ored measuring 2–5 mm, often with a central
Inverted follicular keratosis is a somewhat con- dimple or plug containing cheesy or waxy
troversial entity, as some consider it to be a vari- material (Fig. 3.4).
Fig. 3.3 Inverted follicular keratosis.

Note endophytic growth pattern with
overlying hyperkeratosis and
parakeratosis. Flattened concentric
epidermal cells within acanthotic areas
are called squamous eddies (hematoxylin
and eosin; original magnification 10×)
a b
c d
Fig. 3.4 Molluscum contagiosum. Clinical appearance. is well-demarcated, white, sessile lesion located on the
(a) Epidermal crater filled with keratinocytes containing grey line. (d) A molluscum contagiosum virus under elec-
molluscum bodies (intracytoplasmic inclusions). ((b) tron microscopy. (c, d): (Reprinted from Rosner and Zloto
hematoxylin and eosin; original 40× magnification). (c) [8]. With permission from John Wiley & Sons)
The clinical presentation of a conglomerated lesion which
Molluscum contagiosum is characterized by ing dermis is usually inflamed but without

downward growth of hyperplastic epidermis, desmoplasia, unless the lesion is involuting.
sometimes forming multiple lobules. The kerati- Deeper sections are recommended in order to
nocytes contain large eosinophilic intracytoplas- rule out the possibility of typical infiltrating
mic inclusion bodies (“molluscum bodies”), squamous cell carcinoma, which may be focal in
which enlarge as they reach the surface and an otherwise classic picture of keratoacanthoma
become more basophilic (Fig. 3.4). The central (thus the term “keratoacanthoma-like squamous
crater consists of disintegrating cells discharging cell carcinoma”) [12]. Complete excision should
the molluscum bodies and keratin [8]. These be performed.
lesions usually resolve over months to years in
patients with intact immune systems. However,
removal of individual lesions can be done surgi- Reactive Hyperplasia
cally or by scraping, decoring, freezing, or elec- (Pseudoepitheliomatous
trosurgery. Medications used for warts may also Hyperplasia)
be used, and cantharidin (“beetle juice”) is the
most common solution used. Tretinoin cream is Squamous epithelial hyperplasia occurs as a
an alternative. reaction to trauma, surgical wound, cryotherapy,
burn, radiation, ulcers, or fungal infection [13]. It
can also occur in association with tumors such as
Keratoacanthoma granular cell tumor and melanocytic lesions. It is
not a tumor but rather a reactive process that may
Keratoacanthoma has a complicated history and clinically be seen as a tumor.
has been classified both as benign and malignant Histopathology can be challenging as well. An
(self-healing squamous cell carcinoma or squa- elevated nodular or ulcerative lesion resembling
mous cell carcinoma, keratoacanthoma-type). basal or squamous cell carcinoma. There may be
The latter is favored in many countries. However, an ulcer.
in some literature, it has been noted to sometimes There is squamous hyperplasia with elon-
spontaneously regress and thus considered to be a gated, irregular, and sometimes anastomosing
benign lesion [9–12]. Typically a keratoacan- rete pegs (rete ridges) which may resemble inva-
thoma is a solitary-, pink-, or flesh-colored, dome- sive tongues or nest of squamous carcinoma.
shaped nodule with a central keratin crater, arising Cellular nests may be contain neutrophilic micro-
on sun-exposed skin of an elderly individual. abscesses, especially when associated with infec-
There may be rapid growth to 1 or 2 cm over the tion (Fig. 3.5) [14]. The epithelium shows normal
course of 2–10 weeks. This is followed by a sta- maturation without true dysplasia; however, there
tionary period of similar duration and then involu- may be cytologic atypia and even mitoses, further
tion over the course of 8–50 weeks or more. complicating the distinction from carcinoma.
The histologic features needed for a confident Complete excision is recommended when clini-
diagnosis require assessment of the entire lesion, cally suspicious.
so as not to miss an infiltrating squamous cell
carcinoma at the base. The tumor is cup- or
crater-shaped and consists of centrally proliferat- utaneous Horn or Nonspecific
C
ing well-differentiated squamous cells with Keratosis
strongly eosinophilic cytoplasm that enlarge in
the center of the tumor nests. Often there is a cen- These are nondiagnostic descriptive terms for
tral keratin plug, and there may be neutrophilic any hyperkeratotic lesion (benign or malignant)
abscesses in the epithelium. At the periphery, the and thus do not imply by themselves predilection
epithelium forms symmetrical “lips” or “but- for malignant behavior. A protruding keratotic
tresses” which overhang the crater. The underly- lesion is the presentation (Fig. 3.6). This lesion is
the lesion [15]. Treatment should be determined

by the histopathology if possible. If the lesion is
clinically suspicious for malignancy, excision is
recommended.
Sebaceous Nevus (of Jadassohn)
Sebaceous nevus syndrome (of Jadassohn), an

uncommon congenital lesion, is part of the epi-
dermal nevus syndrome and characterized by
cutaneous sebaceous nevi and extracutaneous
manifestations. It is a benign hamartoma com-
Fig. 3.5 Reactive hyperplasia (pseudoepitheliomatous
hyperplasia). Epidermal (squamous) hyperplasia with posed of large sebaceous glands, heterotopic apo-
elongated and sometimes anastomosing rete ridges, nor- crine glands, defective hair follicles, acanthosis,
mal maturation of epithelium, and variable hyperkerato- and papillomatosis. These lesions evolve with
sis. Note the absence of atypia in this case (hematoxylin time. They are most commonly found on the head
and eosin; original magnification 20×)
and neck region and appear as irregular linear
lesions with alopecia (Fig. 3.7). In spite of their
being benign, there is an increased risk in adult-
hood for the development of secondary benign
(such as syringocystadenoma papilliferum) or
malignant skin tumors (most commonly basal
cell carcinoma) within the area of these nevi
[17–19].
Actinic (Solar) Keratosis
Actinic or solar keratosis is most frequently a

Fig. 3.6 Cutaneous horn is a clinically descriptive, non- result of chronic and cumulative exposure of the
diagnostic term for a nonspecific keratosis epidermal cells of the skin to ultraviolet radiation
(UV-B) in the form of sunlight, causing muta-
associated with a variety of benign or malignant tions to the p53 gene [20]. Fair-skinned older
lesions. In a study of 48 cases [6] involving the patients and those with a history of excessive sun
eyelids, 77.1% were associated with found to be exposure are typically affected. However, there is
benign on histopathology, 14.6% were premalig- also an increased incidence in renal transplant
nant, and 8.3% were malignant skin tumors. The patients, and thus immunosuppression is a risk
most common associated lesions were seborrheic factor [21]. There are a variety of clinical presen-
keratosis, actinic keratosis, basal cell carcinoma, tations, usually characterized by multiple,
and squamous cell carcinoma [15, 16]. erythematous, scaly lesions with either discrete
There are no specific histopathologic features or diffuse borders [21]. They feel like sandpaper
other than hyperkeratosis, with or without para- and may be plaque-like on palpation. Actinic
keratosis. The keratosis (or horn) by itself is not keratosis has historically been considered a pre-
diagnostic, but rather the features of the squa- cursor to squamous cell carcinoma, and most
mous epithelium giving rise to the keratosis are now consider it to represent squamous cell carci-
the defining factors as to the biologic behavior of noma in situ or keratinocyte intraepithelial neo-
a plasia. In a study wherein histopathologic

evaluation of 165 cases of resected squamous cell
carcinoma was undertaken, 82.4% of cases had
concomitant actinic keratosis close to the carci-
noma [22]. However, it is not clear what the rate
of conversion of an actinic keratosis to squamous
cell carcinoma is; and studies have given a wide
range of estimates [23].
Histopathology generally shows hyperkeratosis
and parakeratosis with varying degrees of squa-
mous dysplasia, characterized by loss of epithelial
cell polarity, cytologic atypia, and dysmaturation.
The parakeratosis is usually focal and overlies areas
b of underlying loss of the granular layer of the epi-
dermis. Solar elastosis of varying degrees is present
in the dermis, along with a mild chronic inflamma-
tory infiltrate (Fig. 3.8). Subtypes include hypertro-
phic (characterized by acanthotic epithelium with
irregular psoriasiform hyperplasia), proliferative
(characterized by fingerlike projections into the der-
mis), atrophic (atrophic or thin epithelium), acan-
tholytic (characterized by prominent dyscohesion
of the basal cells), and lichenoid (when there is a
dense band-like mononuclear cell infiltrate in the
upper dermis). The hyperkeratotic or parakeratotic
crust may be so thickened as to form a keratotic
horn. With severe full thickness dysplasia, the dif-
ferential is with Bowen’s disease (Fig. 3.9).
c Management is close observation and excision of
Fig. 3.7 External photo showing tan-colored linear nasal

lesion (a); Low magnification (b, 4×) and higher magnifi-
cation (c, 10×) histopathology of a benign epidermal
lesion with presence of acanthosis and hyperkeratosis in Fig. 3.8 Actinic (solar) keratosis. Note dysmaturation of
association with enlarged gland lobules consistent with the squamous epithelium, mitoses, loss of granular layer,
nevus sebaceous. (Reprinted from Echegaray et al. [18]. and parakeratotic crust (hematoxylin and eosin; original
With permission from Taylor & Francis) magnification 20×)
1–2 mm in diameter. Pigmentation is usually uni-

form. They are the precursors of junctional nevi
and are clinically indistinguishable from them.
Similar appearing multiple lesions of the perioral
skin, buccal mucosa, and sometimes eyelid may
be associated with the autosomal dominant
Peutz-Jeghers syndrome of mucocutaneous pig-
mentation and intestinal polyposis (Chap. 11),
Carney syndrome, LEOPARD syndrome, and
xeroderma pigmentosum [27].
Histology shows hyperpigmentation of the
basal layer with increased number of melano-
cytes, often with regular elongation of the rete
Fig. 3.9 Squamous intraepithelial neoplasia. Marked
squamous dysplasia (Bowen’s disease, also considered a ridges. The papillary dermis may contain a lym-
type of squamous carcinoma in situ); also note suggestion phohistiocytic infiltrate and melanophages. If the
of early or superficial invasion (hematoxylin and eosin; melanocytic hyperplasia evolves to form early
original magnification 10×) junctional nests (with or without an intradermal
component), the lesion is referred to as a lentigi-
more suspicious lesions. Multiple lesions can be nous nevus.
treated with topical chemotherapeutic agents or
cryotherapy. A meta-analysis of published studies
indicates that 3% diclofenac in 2.5% hyaluronan gel Solar (Senile) Lentigo
is effective in treatment of actinic kertatosis [24].
Topical gel must not be applied to the eyelids as it is The lesions of solar lentigo are light to dark
not approved for ophthalmic use [25]. brown, slowly expanding macules that develop
in chronically sun-exposed areas of the skin,
including the eyelids. They occur in middle-
elanocytic Benign Epidermal
M aged to elderly adults and are considered a hall-
Tumors mark of aged skin. Presenting as small macules
3–5 mm in diameter, the lesions may gradually
Freckles or Ephelides grow to several centimeters in diameter. They
sometimes evolve into the reticulated (adenoid)
Freckles are flat brown skin macules measuring form of seborrheic keratosis and thus develop a
1–2 mm that appear in childhood. Freckles char- thickened and warty surface. Differentiation
acteristically occur in fair-skinned individuals from lentigo maligna and lentigo malignant
and darken with sunlight exposure and fade in melanoma may be necessary, requiring histo-
winters in the absence of sunlight exposure. In pathologic examination. Solar lentigo lesions
contrast, solar lentigines do not fade with cessa- respond to treatment with topical 0.1% treti-
tion of sunlight exposure [26]. The epidermal noin, 2% hydroxyanisole, laser therapy, and
structure is not altered. There is increased mela- cryotherapy.
nin pigment in the basal layers without an
increase in melanocytes. The delineation of the
lesion with the surrounding skin is distinct. Melanocytic Nevus
A melanocytic nevus is considered as a hamar-

Lentigo Simplex toma or a benign tumor of neural crest-derived
melanocytes [28]. An eyelid nevus, as in other
The lesion of lentigo simplex is flat, brown to areas of the skin, can be acquired (usually) or
black sharply circumscribed macule measuring congenital.
[30]. Despite evidence supporting origin of

melanoma in small congenital nevi, it is rare in
children [30].
Congenital nevi may be junctional, com-
pound, or intradermal; and they show different
patterns depending on the age of the individual.
In neonates they are usually junctional and show
prominent melanocytic hyperplasia in the epider-
mis and adnexal epithelium. If biopsied during
the first year of life, the histologic picture is that
of larger nevus cells in the epidermis and just
below it with an intervening uninvolved dermal
space and small nevus cells in the reticular der-
mis. Congenital nevi after the postnatal period
have a tendency to involve the lower dermis and
Fig. 3.10 Congenital nevus of the eyelid surrounding the
subcutaneous tissue with single-file permeation
puncta
of dermal collagen bundles and perineural, peri-
follicular, and perivascular distribution of nevus
Congenital Nevus cells. There are differences of opinion as to
Congenital nevi are present in about 1% of new- whether or not these features are pathognomonic
borns (Fig. 3.10) [29, 30]. Congenital nevi may and sufficient to distinguish from acquired nevi.
be single or multiple with sharp borders and are Like most other melanocytic nevi, except for blue
usually larger than acquired nevi. They may be nevi and Spitz nevi, congenital nevi commonly
light in color in neonates and relatively hairless, show BRAF mutation [29, 31]. Surgical excision
and they tend to become darker with papular or is recommended for giant congenital nevi because
nodular change which may be verrucous or cere- they are disfiguring and potentially malignant.
briform with age. With age, darkly pigmented
hairs may develop. Congenital nevi have been Neurocutaneous Melanosis
reported to be associated with several develop- Neurocutaneous melanosis (NCM) is a rare asso-
mental abnormalities, including scoliosis, spina ciation of multiple and large congenital cutane-
bifida, clubfoot, elephantiasis, and cranial bone ous nevi and meningeal melanosis or melanoma
hypertrophy, as well as syndromes such as neuro- [32, 33].
cutaneous melanocytosis and neurofibromatosis
type I [30]. Split Nevus (Kissing Nevus, Divided Nevus)
Congenital nevi are classified by their largest A variant of congenital compound nevus involv-
diameter as small (<1.5 cm), medium (1.5– ing both upper and lower eyelids is the kissing
19.9 cm), and large or giant congenital melano- nevus, which can be associated with significant
cytic nevi (>20 cm). However other classifications cosmetic and functional defect of the eyelids
are based on ease of removal, location, and rela- (Fig. 3.11). Such a contiguous involvement sug-
tionship to other anatomic structures, comparison gests that the nevus develops between 9th and
to the size of the patient’s palm, and surface area 20th week of gestation when the eyelids are
of the body involved. Proportionate expansion fused. There have been reports citing potential
over time is also important in classification [30]. for malignant transformation, but a review of 23
The risk of malignant transformation varies sig- articles (149 cases) revealed no documented
nificantly with the size of the lesion. Lifetime cases of this occurring. Most were of medium
risk of developing melanoma in patients with size. Surgical repair involves excision, and
giant congenital nevi has been reported to range numerous methods of reconstruction have been
from about 2–31%, mostly in the 5–6% range utilized [34, 35].
ing with a differential including scar, dermatofi-

broma, neurofibroma, and desmoplastic
melanoma, and intermediate or hard to classify
lesions are often given terms such as atypical or
metastasizing nevi, terms which by definition
should be avoided [40]. Surgical excision is rec-
ommended for cosmesis or to establish a defini-
tive diagnosis.
Histologically, the common blue nevus is
composed of dendritic (elongated and finely
branching) melanocytes confined to the mid- and
upper dermis. Melanophages are also present.
The cellular blue nevus consists of both dendritic
melanocytes and a second population of islands
of epithelioid and plump spindle-shaped melano-
Fig. 3.11 Split nevus. A sharply demarcated, brown dis-
coloration, involving the upper and lower eyelids in a cytes. Blue nevi do not show BRAF and NRAS
16-year-old Asian female. Nevomelanocytes migrate from mutations as found in conventional melanocytic
the neural crest to the skin after the tenth week in utero but nevi. They do show frequent somatic mutations
before 24 weeks when splitting of eyelids occurs. (83%) in GNAQ, a gene also frequently impli-
Concomitant conjunctival nevus is also present
cated in uveal melanoma [41, 42].
Blue Nevus Nevus of Ota

The blue nevus arises from dermal dendritic The nevus of Ota (oculodermal melanocytosis)
melanocytes that have been arrested in the dermis occurs as a diffuse or speckled bluish or brown
before reaching the epidermis (Fig. 3.12) [33]. discoloration of the eyelids and periorbital skin
Within the spectrum of types of blue nevi, differ- and episclera due to a proliferation of dermal
ent clinicopathologic variants are identified: melanocytes. The temple, forehead, malar region,
common blue nevus and cellular blue nevus sclera, and mucosa of the nose and mouth may
(localized variants), and oculodermal melanocy- also be involved (Chap. 14). These regions cor-
tosis (diffuse variant) [36, 37]. Epithelioid blue respond to the ophthalmic and maxillary divi-
nevus is a multicentric familial form that is part sions of the trigeminal nerve. Associated
of the Carney complex together with cardiac melanocytosis of structures such as uvea, orbit,
myxoma, endocrine tumors, schwannoma, and and ipsilateral meninges may be present but not
other abnormalities [38]. The blue nevus appears readily apparent. Nevus of Ota may appear at
as an atypical small dark lesion, the blue color birth or may develop during the first year of life
due to the deep location of the melanocytes with or during adolescence. It tends to follow the dis-
absorption of larger wavelengths of light as it tribution of the first and second divisions of the
passes through the dermis (Tyndall phenome- trigeminal nerve. It may rarely be bilateral.
non).Such eyelid changes can extend to involve Histopathologically, nevus of Ota is character-
adjacent conjunctiva (Chap. 14), orbit, and intra- ized by excess scattered dendritic and plump
cranial cavity. polyhedral melanocytes in the dermis.
The relationship between blue nevus, blue Nevus of Ota carries a small risk of develop-
nevus that has undergone malignant transforma- ment of a uveal melanoma [43]. Possibility of
tion, and melanoma is fraught with classification malignant transformation of the cutaneous com-
controversies [39]. Difficulties arise because ponent is even more remote [44, 45]. Periodic
some metastatic melanomas can resemble blue observation including dilated fundus examination
nevi, spindled sclerotic lesions may be challeng- is the recommended treatment.
a b
c d
e f
Fig. 3.12 (a) Eyelid margin blue nevus. A 93-year-old zone in the center of most of the cells. Note the absence of
Caucasian woman had an irregular, flat, black lesion both inflammatory cells and a prominent vascularity in the
(arrow) measuring 3 × 4 mm at the left upper eyelid muco- background stroma (hematoxylin-eosin, X400). (e) Ki-67
cutaneous junction. (b) A full-thickness perpendicular sec- immunostaining for cells in the S-phase signifying active
tion of the eyelid contains a loose population of pigmented DNA replication demonstrate positive nuclear staining
cells mostly located in the dermis (arrows) that has failed among the basal germinal cells of the epithelium (EP). The
to produce any appreciable eyelid thickening. There are no arrows point out central clear zones corresponding to non-
intraepithelial junctional nests. The tarsus (T), Meibomian staining melanocytic nuclei in the connective tissue
glands (MG), and orbicularis striated muscle fibers (OR) (immunoperoxidase reaction, diaminobenzidine chromo-
are overall noninvolved by the tumor cells. The crossed gen, X200). (f) Microphthalmia-associated transcription
arrow indicates a cilium (hematoxylin-eosin, X25). (c) The factor immunostains the nuclei of scattered dendritic mela-
cells in the dermis are a mixture of elongated and polygo- nocytes (arrows) within the epithelium (EP) with trail-off
nal melanocytes. The arrow highlights a small fascicle of on the left within the conjunctiva. There are no visible
nonpigmented cells, depicted to greater advantage in the nuclei among the dendritic dermal melanocytes constitut-
inset. This feature was regarded as a terminal nerve twig ing the tumor, because the immunoproduct of the posi-
with mild Schwann cell hyperplasia. OR, orbicularis mus- tively staining nuclei merges imperceptibly with the
cle fibers devoid of infiltrating cells (hematoxylin-eosin, melanin within the surrounding cytoplasm (immunoper-
X200). (d) Spindled and rounded pigmented cells are oxidase reaction, diaminobenzidine chromogen, X200).
intermixed. Despite the density of the cytoplasmic pig- (Reprinted from Kirzhner et al. [37]. With permission from
mentation, a central round nucleus is discernible as a clear Wolters Kluwer Health, Inc.)
Acquired Nevus clear cytoplasm and variable melanin. Typically the

Acquired nevi develop during childhood and cells become smaller and contain less pigment in
adolescence. Mild to moderate sun exposure in the deeper dermal component of the lesion if pres-
early life induces the development of nevi [45]. ent. Junctional, compound, and intradermal nevi are
The acquired nevus appears as a small, flat, or differentiated by the location of these nests of nevus
minimally elevated lesion that is light brown in cells. There is an evolution of acquired nevi in
color (Fig. 3.13). They have a limited growth which the nevus cells are initially located only at the
phase, often during adolescence after which they dermoepidermal junction (junctional nevus)
stabilize. Acquired nevi may be located anywhere (Fig. 3.13), followed later with nests at the dermo-
on the eyelids and frequently involve the eyelid epidermal junction and dermis (compound nevus)
margin and conjunctiva. Surgical excision of (Fig. 3.14), and finally in the dermis only (intrader-
large eyelid nevi may necessitate significant tis- mal nevus) (Fig. 3.15). This progression is referred
sue loss, so frequent observation rather than rou- to as the process of nevogenesis [16]. Thus, junc-
tine excision may be warranted in many cases. tional nevi are most frequent in the first decade,
The nevus cells (melanocytes) are found in dis- compound nevus in the second decade, and the pro-
crete nests and consist of oval to cuboidal cells with portion of dermal nevi increases with age [45].
a b
Fig. 3.13 Eyelid compound nevus. Pigmented melano- atypia in the epithelium at the dermoepidermal border as
cytic nevus on the margin of the upper eyelid. (a) Compound well as nests in the dermis (left half of photograph) ((b)
nevus consisting of melanocytic nests without cytologic hematoxylin and eosin; original magnification 20×)
a b
Fig. 3.14 Junctional nevus. Flat pigmented lesion (a). Junctional nests of melanocytes (at dermoepidermal junction)
only (b) (hematoxylin and eosin; original magnification 20×)
a b
Fig. 3.15 Eyelid nevus. Nonpigmented intradermal cords, and singly with maturation (nuclei becoming
nevus of the eyelid margin. Note that surface epithelium smaller) in the deeper dermis (b) (hematoxylin and eosin;
and lashes are intact. (a) Intradermal nevus composed of original magnification 10×)
nevus cells confined to the dermis and arranged in nests,
Spitz Nevus
A distinctive type of nevus is the Spitz nevus
[46], which is usually reported only in childhood
and adolescence. They are found on the face,
trunk, or extremities; and they can rarely involve
the eyelid (Fig. 3.16) [47, 48]. These lesions are
rapidly growing red- or tan-colored lesions that
should be differentiated from pyogenic granu-
loma or hemangioma and, more importantly,
from melanoma, which is extremely uncommon
in children. They are a type of nevocellular nevus
and have been referred to in the past as spindle
cell nevus, epithelioid nevus, and benign juvenile Fig. 3.16 Spitz nevus: Recurrent eyelid margin Spitz
nevus in a 6-year-old girl
melanoma. While some point to controversy over
their biologic nature, they are generally consid-
ered benign. However, it is recognized that there and 20% are intradermal. They are composed of
may be local recurrences following incomplete either spindle or epithelioid cells, spindle cells
excision; and several cases have been associated being more common. Superficially located
with regional lymph node involvement or rarely mitotic figures tend to be few in number, and they
metastasis. These unusual cases probably are due reflect rapid clinical growth but not an indication
to the fact that distinction between some Spitz of malignancy. Atypical mitoses should not be
nevi and melanoma (Spitzoid melanoma) can be present nor should mitoses deep in the lesion [2,
difficult; and both melanomas falsely called Spitz 29]. These nevi are symmetrical, with no lateral
nevi and the reverse have occurred. Some authors extension of junctional activity beyond the intra-
invoke the term atypical Spitz nevus/tumor in dermal component. There may be aggregates of
borderline cases. While sometimes worrisome nevus cells within the epidermis (but not single
histopathological features are noted, these are not cells) in what is referred to as transepidermal
uniformly present [48]. elimination. Kamino bodies may be present at the
Histologically, Spitz nevi are usually com- dermoepidermal junction. These are eosinophilic
pound in type; however 5–10% are junctional, globules which stain with PAS and trichrome
h istochemical stains, and they are an important no melanomas. In the few melanomas that did
diagnostic feature [48]. Maturation of the nevus develop in the other studies, 0.39% were in
cells toward the base is also seen in most cases. observed lesions and 0.44% in re-excised lesions.
Minor diagnostic criteria include junctional While recognizing inherent problems in many of
cleavage (separation of the epidermis from the the studies as well as selection bias in determin-
nevus nests in the junctional zone), pseudoepithe- ing whether to observe or re-excise (such as fam-
liomatous hyperplasia, absence of pleomorphism, ily history of melanoma, large burden of HDNs,
dermal edema and telangiectasia, and giant nevus tanning bed use, or sunburns in childhood), the
cells [48]. Comparative genomic hybridization authors concluded that observation of HDNs may
(CGH) and fluorescence in situ hybridization be safe with only minimal risk of subsequent
(FISH) can be useful in difficult cases because melanoma [52].
most melanomas show chromosomal changes, as
opposed to Spitz nevi which do not typically. amilial Atypical Mole and Melanoma
F
Homozygous deletion of 9p21 (location of Syndrome (Dysplastic Nevus
CDKN2A/p16) is commonly seen in Spitzoid Syndrome)
melanomas but not Spitz nevi [48]. In general, Atypical mole or dysplastic nevus syndrome
there is genetic similarity between Spitzoid denotes a specific clinicopathologic entity that is
melanoma and conventional melanoma [49]. associated with an increased risk for the develop-
Because the clinical features of rapid onset are ment of cutaneous melanoma [53]. This syn-
alarming, excision to exclude the possibility of drome of autosomal dominant predisposition to
melanoma should be performed. cutaneous melanoma was originally described by
Clark as B-K mole syndrome [54]. FAM-M syn-
typical (Clark’s) or Dysplastic Nevus
A drome is due to mutations of the gene CDKN2A
Atypical nevi are present in the 2–18% of the on chromosome 9p21 [55]. Even so, the concept
population, and they may be associated with an of FAM-M syndrome remains controversial [36].
increased risk for malignant melanoma. In addi- The association between FAM-M syndrome and
tion to educating such patients about dangers of uveal nevi and uveal melanoma is discussed else-
sun exposure, periodic total skin examinations where [56].
starting at puberty should be recommended. The
term “dysplastic nevus” has been controversial entigo Maligna (Melanotic Freckle
L
with suggestions to not use in the clinical setting of Hutchinson)
[50]. Atypical nevi tend to be larger (≥5 mm), Lentigo maligna refers to an acquired pigmented
with ill-defined borders, and have variegated col- macule in the sun-exposed skin of middle-aged
ors (tan, brown, and pink). They may be or elderly individuals [57]. It was initially
multiple. described by Hutchinson; hence, it is also called
The characteristic features of dysplastic nevi are melanotic freckle of Hutchinson [58]. Lentigo
lentiginous hyperplasia, random cytologic atypia maligna is now considered the in situ phase (mel-
of the melanocytes, stromal response (lamellar anoma in situ) of lentigo maligna melanoma
fibroplasia of the papillary dermis), and shoulder- (invasive melanoma).
ing or peripheral extension of the junctional com- Lentigo maligna is characterized by an atypi-
ponent over the intradermal component. cal melanocytic proliferation (cells occurring sin-
Management of dysplastic nevi has been con- gly or in nests) confined to the epidermis (mostly
troversial. Options are re-excision of histologi- basilar), with features including pleomorphic and
cally dysplastic nevi (HDN) vs. observation [51]. enlarged nuclei, increased and eosinophilic cyto-
A recent review of 2673 cases published in 12 plasm, and mitotic activity.
articles was performed. Of these cases, 1535 Lentigo maligna can slowly enlarge horizon-
were observed and 1138 re-excised with follow- tally before entering a vertical growth phase and
up from 2 weeks to 30 years. Nine studies found transforming into lentigo maligna melanoma
(invasive melanoma). Overall, it is estimated that 6. Sim-Davis D, Marks R, Wilson-Jones E. The inverted
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Basal Cell Carcinoma
4
Introduction the USA, the incidence of BCC is more than 500

per 100,000, and in parts of Australia, it reaches
Basal cell carcinoma (BCC) is a malignant cutane- 2400 per 100,000 [1, 3, 4]. While increase in fre-
ous neoplasm capable of extensive tissue destruc- quency was reported during the last century, a
tion. It is often observed on the head and neck, and possible decreasing trend in the incidence rates
the eyelids are a very common location. BCC was was shown in the last decade [5, 6].
initially described as a distinct entity by Krompecher
at the beginning of the twentieth century. Some
authorities preferred the term “epithelioma” to car- Etiology
cinoma because of the tumor’s limited capacity to
metastasize [1]. While the mortality from BCC is The risk factors for periocular BCC include ultra-
low, the morbidity may be considerable. violet (UV) irradiation, local and systemic
immune dysfunction, previous ionizing radiation,
and focal trauma. It is believed that exposure to
Epidemiological Aspects UV light causes defects in immune function and
that this has a role in the pathogenesis of
BCC is the most common human malignancy and BCC. Other risk factors are fair skin color, inabil-
accounts for nearly 90% of all nonmelanoma ity to tan, and exposure to trivalent inorganic arse-
skin cancers. It is also the most common skin nic, such as from medications including arsenical
cancer of the eyelid, accounting for 86–96% of compounds [1]. Genetic or congenital diseases
all cases [2]. It seems that geographical and eth- predisposing to BCC are Gorlin–Goltz syndrome,
nic differences exist in the occurrence of BCC. In xeroderma pigmentosum, albinism, Basex–Dupré
syndrome, Muir–Torre syndrome, Rombo syn-
drome, linear basocellular hamartoma, and seba-
M. Rosner (*)
Department of Ophthalmology, Eye Histopathology ceous hamartoma of Jadassohn [3].
Laboratory, Goldschleger Eye Institute, Sheba
Medical Center, Sackler Faculty of Medicine,
Tel Aviv University, Tel Aviv, Israel
Pathogenesis
I. D. Fabian
Department of Ophthalmology,
The origin of BCC is controversial. It could arise
Ocular Oncology Center, Goldschleger Eye Institute,
Sheba Medical Center, Sackler School of Medicine, from the basal cell of the epidermis, from the
Tel Aviv University, Tel Aviv, Israel infundibular cells of the hair follicle, or from a

34 M. Rosner and I. D. Fabian
pluripotential cell. BCC does not arise from a also morpheaform or sclerotic) BCC. All the clini-
precursor lesion [1]. cal variants are usually accompanied by loss of
adnexa (hair and lashes); they are firm to palpation
and are painless unless secondarily infected [1].
Clinical Features
Approximately 95% of all BCCs occur in people Nodular

between 40 and 79 years of age, and the average
age at diagnosis for BCC of the eyelid is 60. BCC The nodular BCC begins as a small papule and
may occur in young adults and in children who slowly enlarges to an irregular, dome-shaped
have an inherited predisposition to cutaneous tumor. The epithelial surface of the tumor is usually
neoplasia. However, rarely, a solitary BCC may smooth, often described as pearly, with fine telan-
arise in an adolescent or young adult who has no giectatic vessels beneath it. Ulceration may develop
known risk factors. Men may be more afflicted and is filled with a crusty exudate (Fig. 4.1).
than women. In most cases, BCC arises as a soli-
tary lesion on hair-bearing sun-exposed skin, par-
ticularly the face. Most periocular BCCs arise on Pigmented
the lower eyelid and medial canthus and least
often near the lateral canthus. Tumors are usually The pigmented BCC is usually nodular or nodulo-
present for many months prior to diagnosis [1, 4]. ulcerative, ranging in color from light tan to deep
brown.
Symptoms and Signs

Cystic
There are several different clinical variants of
BCC, including nodular and nodulo-ulcerative, The cystic BCC may attain significant dimen-
pigmented, cystic, and infiltrating (which is called sions (Fig. 4.2).
a b
Fig. 4.1 Nodular BCC of the lower lid margin, presenting as an irregular, pearly dome-shaped tumor (a). Ulcerated
lesion with poorly defined margins (b)
4 Basal Cell Carcinoma 35
Infiltrating Histopathologic Features
The infiltrating BCC presents as an indurated, BCC is characterized by a proliferation of cells

yellowish to tan patch or plaque with occasional with oval nuclei and scant cytoplasm that form
focal ulceration and poorly defined margins infiltrative nests or strands (Fig. 4.4). The neo-
(Fig. 4.3). Patchy crusts, papules, and nodules are plastic cells are relatively uniform in appearance
scattered throughout some morpheaform tumors. and seldom display significant anaplasia or
Infiltration within the eyelid can cause deformi- mitotic figures. At the periphery of the nests, they
ties and malpositioning of the lid margin. are usually arranged in a radial pattern called
“palisading” (Fig. 4.5): although this is not diag-
nostic, in its absence, the diagnosis of BCC
should be questioned. The nests of tumor cells
characteristically retract from the stroma, creat-
ing a gap (Fig. 4.5). Initially thought to be a pro-
cessing artifact, this gap reflects defects in the
production of adhesion-like substances by tumor
cells. Necrosis is a common finding in BCC, and
the necrotic debris eventually calcifies or is
replaced by fibrous scar tissue. BCC also demon-
strates an inflammatory infiltrate of variable
intensity around the nests of tumor cells that con-
sists predominantly of lymphocytes. The junction
between the stroma of the neoplasm and normal
connective tissue is ill defined [1].
There is no universally accepted histopatho-
logic subclassification of BCC according to
Fig. 4.2 Cystic BCC of the upper lid patterns of growth and cellular differentiation.
a b
Fig. 4.3 Nodulo-ulcerative lesion of the lid margin with loss of lashes (a). External examination reveals lid retraction
with linear scars on the upper eyelid due to infiltrative BCC (b)
Fig. 4.6 An infiltrative BCC is composed mainly of elon-

gated strands of tumor cells that are several cell layers
thick, with no peripheral cellular palisading
Fig. 4.4 Histopathologically, BCC is characterized by a
proliferation of cells with oval nuclei and scant cytoplasm
that form infiltrative nests or strands
Fig. 4.7 In many cases, different growth patterns of BCC

occur in the same tumor
Fig. 4.5 At the periphery of the nests, the tumor cells are
usually arranged in a radial pattern called “palisading”
(arrow), and these are characteristically retracted from the terns occur in the same tumor (Fig. 4.7). There is
stroma, creating a gap (arrowhead) a third important histologic pattern, the superfi-
cial BCC, which is presumed to be of multicen-
The two most important growth patterns are the tric origin and with horizontal spread. Superficial
circumscribed and the infiltrative. Circumscribed BCC is described mainly on the trunk and
BCC is characterized by nests and sheets of extremities [1]. More than 20 types of cellular
tumor cells and usually corresponds clinically to differentiation or histologic patterns have been
a nodular tumor. In contrast, an infiltrative BCC described in BCC as signs of sebaceous, apo-
is composed mainly of elongated strands of crine, or eccrine gland, as well as pillar differen-
tumor cells that are several cell layers thick, with tiation in an otherwise typical BCC [1, 8].
no peripheral cellular palisading (Fig. 4.6), and However, the rare morpheaform, infiltrating and
usually corresponds to a morphemic variety. basosquamous subtypes of BCC, are more
However, in many cases, different growth pat- aggressive. The metatypical (basosquamous) car-
cinomas have an impact on prognosis. highly questionable, otherwise excisional biopsy

Basosquamous carcinoma displays various should be performed.
degrees of squamous differentiation and has been
suggested to occupy a conceptual intermediate
ground between squamous cell carcinoma and Exfoliative Cytology
BCC (Box 4.1) [1].
Exfoliative cytology has been shown to have a
high diagnostic accuracy for BCC but may be
Box 4.1 Salient Diagnostic Findings considered only occasionally, when the plan is to
treat the tumor nonsurgically [9].
• Painless, firm, nodular, or flat skin

lesion with smooth, pearly epithelium, Imaging
and subepithelial telangiectatic vessels,
accompanied by loss of adnexa. When orbital or intraocular invasion is suspected,
• Microscopic findings of infiltrative imaging is used to evaluate it. T1 contrast-enhanced
nests, sheets, or strands of cells with fat-suppressed MRI scans are the modality of
oval nuclei and scant cytoplasm, which choice for demonstrating a soft tissue mass or infil-
are arranged at the periphery of the nests tration. Computed tomographic (CT) bone win-
in a radial “palisading” pattern. dows with axial and coronal views of the orbit are
• Presence of a gap between the nests of best for demonstrating bony destruction – which,
tumor cells and the stroma. however, is uncommon in BCC patients [10].
Other Noninvasive Methods

The morpheaform BCC showed a high expres-
sion of Bcl-2 (an important apoptotic gene) and Pulsed ultrasound at 20 MHz has been used for
moderate levels of proliferating cell nuclear anti- the noninvasive measurement of BCC thickness
gen (a proliferation-associated marker) in a histo- in order to plan photodynamic therapy (PDT) and
logical and immunohistochemical study of eyelid to evaluate the rate of tumor regression after
BCCs [7]. It was also found that telomere length treatment. It was found that such measurements
was shortened and gene expression of Bcl-2 and can distinguish between skin, fibrosis, and tumor
Ki-67 (correlated with cell proliferation) was and can even trace recurrences of BCC prior to
increased in BCC samples compared with normal clinical findings [11].
tissues [7]. Near-infrared reflectance-mode confocal
scanning laser microscopy is a novel imaging
technique for microscopic analysis of skin lesions
Diagnostic Evaluation that may offer a sensitive and specific tool for the
noninvasive diagnosis of BCC in vivo [12, 13].
Histopathologic Examination
of Excisional or Incisional Biopsy
Differential Diagnosis
The most important diagnostic evaluation of
BCC is histopathologic examination of the The clinical and histopathologic differential
excised tissue. Incisional biopsy should be taken diagnosis is broad. Challenging examples are
only in cases where the clinical diagnosis is trichoepithelioma and desmoplastic trichoepithe-
lioma, metastatic carcinoma, sebaceous carci- culty, time, and expense of Mohs’ surgery may
noma, squamous cell carcinoma, and not be justified in all BCCs of the eyelid, it is
keratoacanthoma. However, as BCC is by far the usually reserved for deeply infiltrative tumors
most common malignant lesion of the periocular with a high risk of recurrence [1]. An intermedi-
skin, most periocular nodular or cystic skin ate technique that incorporates Mohs’ surgery
lesions should be treated as suspicious. using formalin-fixed, paraffin-embedded sections
(slow Mohs) was suggested to offer a histologi-
cally superior and cheaper alternative to standard
Treatment Mohs’ surgery [16].
The carbon dioxide laser has a few advantages
The main treatment modality for BCC is surgical over the conventional scalpel in the excision of
excision of the lesion with microscopic monitor- BCC, including the possibility of bloodless exci-
ing of its margins or Mohs’ microsurgery [1, 12]. sion of tissue in thin layers for histological exam-
The other surgical and nonsurgical modalities ination of the margins and the possibility of
include curettage and electrodessication, cryo- obviating electrocautery, which is important for
surgery, radiotherapy, chemotherapy, photody- patients taking anticoagulants or who have a car-
namic therapy, and immunotherapy. Selection of diac pacemaker [1].
the appropriate therapy depends on the patient’s Special reconstructive techniques are used to
age, anticipated life expectancy, and the location, maintain the functions of the eyelid and to
size, and pattern of growth characteristics of the achieve the best cosmetic results after surgical
tumor. However, therapies that are not surgical excision of periocular BCC (Chap. 10).
and do not include microscopic monitoring
should be avoided for BCCs when they are not
very small, when they are located in the medial Curettage and Electrodesiccation
canthus, or when the margins are clinically ill
defined. The importance of preventing sun expo- Curettage and electrodesiccation and, lately,
sure needs to be stressed to children and young vaporization of the tumor by CO2 laser are com-
adults in order to reduce the incidence of BCC in monly used techniques to treat small BCC in
the future [1]. areas remote from the eye. As the adequacy of
margins is not determined, there is always the
risk that residual tumor will escape destruction,
Surgical Excision especially near embryonic fusion planes. Also,
the amount of secondary scarring and contracture
Only by surgical excision of the tumor with safe with electrodesiccation may be cosmetically
margins it is possible to assess the adequacy of unacceptable in the periocular area [1].
extirpation. However, in cases with deep infiltra-
tion into the orbit or in proximity to the eyeball
tissues, excision with safe margins is not possi- Cryotherapy
ble, and exenteration is inevitable. A variety of
ways are used to examine the surgical margins, Cryotherapy is a tissue-sparing modality with no
and good results have been reported when frozen- control of the adequacy of tumor removal. It has
section control is used. Mohs’ micrographic sur- been suggested that cryotherapy of eyelid BCC
gery has been considered to be the most reliable with a well-defined border, including tumors
method for tumor extirpation or as reliable as larger than 10 mm and tumors in the medial can-
excision with frozen-section or permanent- thal area, has a high cure rate and is cost-effective
section control, with the lowest recurrence rate and well tolerated, with good cosmetic and func-
and best cure rate [1, 14, 15]. As the extra diffi- tional outcomes [1, 17–21].
Radiation Therapy tural damage. IMQ is an immune response modi-

fier that causes eventually production of cytokines
The role of radiation therapy in the management such as interferon-a. It was reported to be effec-
of BCC is controversial. It has been found that tive for treatment of eyelid nodular BCCs with
there is significant recurrence after radiotherapy good cosmesis and good functional results [27].
for BCC [1, 22], and such recurrences, particu-
larly those in the midface, are exceptionally dif- Vismodegib
ficult to treat successfully by any means and are Vismodegib (Erivedge) is a molecular inhibitor
at high risk ultimately to cause death [1]. of the Hedgehog signaling pathway. It was
Radiotherapy can be used as an adjuvant therapy approved by the FDA in January 2012 for the oral
to exenteration in cases with orbital invasion by therapy of metastatic and locally advanced
periocular basal cell carcinoma [10]. BCC. Oral Vismodegib has been shown to be
effective in preventing disease progression in
patients with metastatic or locally advanced BCC
Chemotherapy and Other Therapies not amenable to surgical excision or radiotherapy
[2, 28] (Fig. 4.8).
Chemotherapy is used for cases of nonresectable Although new nonsurgical procedures were
BCC, when for some reason surgery cannot be found to be promising approaches in the therapy
undertaken, or for rare cases of metastatic of BCC of the eyelids, none of them are yet an
BCC. Cisplatinum chemotherapy, used alone or acceptable alternative to surgical excision and are
in combination with doxorubicin or with pacli- reserved for research or for selected patients.
taxel, has been beneficial in case reports [1, 23].
The results of preliminary studies using retinoids
(etretinate and isotretinoin) in the management of Follow-Up
BCC have been varied [1].
As two-thirds of recurrences appear within
Interferon 3 years of treatment and 18% appear between 5
Over a decade ago, intralesional injection of and 10 years, long-term clinical follow-up is nec-
human recombinant α-interferon was used to essary [1, 3].
treat BCC, with some success [1, 24]. A new
class of immune response modifier, represented
by topical imiquimod cream, was demonstrated Prognosis
to have the potential to provide topical treatment
of BCC, either alone or in combination with reti- Prognostic Factors
noids [24, 25].
The prognosis of BCC depends mainly on the
Photodynamic Therapy size of the tumor, its anatomic location, its pat-
Photodynamic therapy (PDT) is a new, noninva- tern of infiltrative growth, and the age of the
sive procedure that produces tumor destruction, patient [1]. Large tumors and location in the
and photodynamic therapy with aminolevulinic medial canthal region are the most important
acid was found to be a promising approach in the clinical features predicting recurrence.
therapy of dermal lesions of the eyelids [10, 26]. A high risk for orbital invasion was found for
BCC of the medial and lateral canthus [1, 8]. The
Imiquimod morpheaform clinical pattern, the histologic find-
Topical treatments such as imiquimod cream ing of an infiltrative growth pattern, or metatypi-
(IMQ) have the advantage of assisting in the cal (basosquamous carcinoma) differentiation
removal of BCC without causing collateral struc- have been correlated with deep invasion and
a b
c d
Fig. 4.8 A 67-year-old woman presented with a biopsy sion of the residual infiltrating soft tissue skull base mass
proven neglected basal cell carcinoma (over 2.5 years) involving the right orbit, paranasal sinuses, facial soft tis-
involving the right side of the face with loss of orbital con- sues, and masticator space into the right anterior cranial
tents (a, b). She was started on vismodegib 150 mg daily fossa (d, e). Following discussion in a multidisciplinary
(November 2016). For another 6 months, there was grad- treatment group, surgery followed by radiation therapy is
ual reduction in the nodular and ulcerative surface of the also being considered. (Courtesy of Allison Vidimos, MD,
lesion (c), but in February 2018, patient noticed growth Dermatology, Cleveland Clinic)
over the cheek. MRI also showed slight increased exten-
greater recurrence after treatment [1]. More Staging

aggressive tumors and a higher frequency of
recurrence was found in patients under 35 years According to the applied practical review of the
of age [1]. American Joint Committee on Cancer (AJCC)
seventh edition (Box 4.2) [30], primary BCC
5 mm or less, between 5 and 20 mm in greatest
Local Spread dimension, not invading the tarsal plate or eyelid
margin with no involvement of regional lymph
The vast majority of BCC grow in a slow but nodes and no distant metastasis, were classified
relentless manner. However, localized spontane- as stage I tumors. BCC more than 20 mm in
ous regression has been documented [29]. BCC greater dimension or any tumor that invades adja-
invades along the paths of least resistance and cent ocular or orbital structures were classified as
then destroys adjacent tissues (Fig. 4.8). stage II. Stage III was when tumor complete
Destruction of bone, cartilage, and muscle is usu- resection requires enucleation, exenteration, or
ally seen only in the very late stages of the d isease. bone resection, when regional lymph node metas-
Invasion of lymphatics is common but does not tasis is evident, or when the tumor is not resect-
correlate with the rarely occurring regional metas- able due to extensive invasion of ocular, orbital,
tasis. Some BCCs follow peripheral nerves and and craniofacial structures or the brain. Stage IV
can thereby gain access to deeper tissues. Spread is the rare cases with distant metastasis. This
to the central nervous system may occur via cra- classification was found to be a practical tool for
nial nerves, the orbital fissure, and cranial foram- staging of carcinoma of the eyelids [31].
ina. Intraocular invasion by BCC is rare and
usually occurs in advanced cases with orbital Box 4.2 AJCC Cancer Staging of Carcinoma
invasion. The globe is entered through a sclera of the Eyelids
emissary canal or an old surgical wound [1].
• Stage I A – primary BCC 5 mm or less

Recurrence in greatest dimension, not invading the
tarsal plate or eyelid margin with no
The recurrence rate of treated BCC of the eyelid involvement of regional lymph nodes
averages 4.2% in the short term and 8.7% for more and no distant metastasis.
than 5 years. This varies according to the therapeu- • Stage I B – primary BCC between 5 and
tic method used. Tumors that recur tend to be more 10 mm in greatest dimension, not invad-
aggressive and difficult to manage [1, 3, 4]. ing the tarsal plate or eyelid margin with
no involvement of regional lymph nodes
and no distant metastasis.
Metastases and Mortality • Stage I C – primary BCC between 10
and 20 mm in greatest dimension, not
Metastatic BCC is extremely rare, and its rate has invading the tarsal plate or eyelid mar-
been estimated to be between 0.0028% and gin with no involvement of regional
0.01%. The most frequent sites of metastasis are lymph nodes and no distant metastasis.
the lymph nodes, lungs, bone, liver, and spleen • Stage II – primary BCC more than
[1]. Clinical features suggesting a greater proba- 20 mm in greater dimension or any
bility of metastasis include multiple recurrences, tumor that invades adjacent ocular or
an aggressive histological appearance, perineural orbital structures.
invasion, and a history of previous ionizing radia- • Stage III A – when tumor complete
tion [23]. Mortality from eyelid and medial can- resection requires enucleation, exenter-
thal BCC is rare, and all deaths recorded were ation, or bone resection.
related to intracranial extension [1].
12. Nori S, Rius-Diaz F, Cuevas J, et al. Sensitivity and

• Stage III B – when regional lymph node specificity of reflectance-mode confocal micros-
copy for in vivo diagnosis of basal cell carci-
metastasis is evident. noma: a multicenter study. J Am Acad Dermatol.
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15. Malhotra R, Huilgol SC, Huynh NT, et al. The
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Squamous Cell Carcinoma
5
Introduction malignant neoplasm of the eyelids after basal cell

carcinoma (BCC) comprising 5–10% of all eyelid
Squamous cell carcinoma (SCC) is an invasive epi- malignancies [1–3]. However, in India, China, and
thelial malignancy that arises from the prickle– Japan, the proportion of BCC and sebaceous gland
squamous cell layers of the epidermis and shows carcinoma (SGC) was found to be almost equal,
keratinocytic differentiation. It is capable of metas- and more than SCC [6], and in most other coun-
tasis to regional lymph nodes and is potentially tries, the reported incidence of SCC relative to
lethal. SCC was first distinguished from basal cell BCC ranges from 1:11 to 1:40 [7, 8].
carcinoma (BCC) by Kompecher in 1902 [1]. The
terms “squamous cell epithelioma,” “epidermoid
carcinoma,” “epithelioma spinocellular,” “prickle Etiology
cell epithelioma,” and “spinalioma” have all been
used in the literature, but “squamous cell carci- Extrinsic risk factors for SCC include ultraviolet
noma” is the preferred terminology. light and actinic damage, exposure to arsenic,
hydrocarbons, radiation, immunosuppressive
drugs, and a high-fat diet. Intrinsic risk factors
Epidemiological Aspects include immunosuppression, fair skin, albinism,
preexisting chronic skin lesions, genetic skin dis-
The incidence of eyelid SCC varies from 0.9 to orders such as xeroderma pigmentosum and epi-
2.42 cases per 100,000 population, with the highest dermodysplasia verruciformis, and infection with
incidence reported from Australia [2–5]. In most human papillomavirus [9–11].
populations, SCC is the second most common
M. Rosner (*)
Clinical Features
Department of Ophthalmology, Eye Histopathology
Laboratory, Goldschleger Eye Institute, Sheba SCC occurs most commonly in fair-skinned
Medical Center, Sackler Faculty of Medicine, elderly individuals who have a history of chronic
Tel Aviv University, Tel Aviv, Israel
sun exposure [1, 2, 10, 12]. The majority of
I. D. Fabian patients with SCC are 60 years of age or older
Department of Ophthalmology, Ocular Oncology
[10, 11]. Men are affected two to three times as
Center, Goldschleger Eye Institute, Sheba Medical
Center, Sackler School of Medicine, Tel Aviv often as women. It has been suggested that the
University, Tel Aviv, Israel distinct male predominance may represent

increased occupational sunlight exposure by Box 5.1 Salient Diagnostic Features of

males, rather than a genetic predisposition [10]. Squamous Cell Carcinoma
Periocular SCC occurs most frequently on the
lower eyelid, followed by the medial canthus, the
upper eyelid, and the lateral canthus, in that order • Painless nodular, plaque-like, or ulcer-
of frequency. The preponderance of lower-lid ated lesions with scaling and fissuring of
involvement in SCC is not as pronounced as in the skin and irregular, rolled, pearly
BCC [1, 12]. In some series, SCC of the medial borders
canthus has outnumbered those confined to the • Microscopic findings of infiltrative neo-
eyelid. SCC also has a predilection for the eyelid plasm arising from the epidermis and
margin [1]. composed of polygonal cells with abun-
dant acidophilic cytoplasm and promi-
nent, hyperchromatic, pleomorphic
Symptoms and Signs nuclei
• Presence of dyskeratotic cells with the
Although the clinical presentation of SCC varies, formation of keratin pearls and intercel-
most often it appears as a painless, elevated, nod- lular bridges
ular, or plaque-like lesion with chronic scaling
and fissuring of the skin. Pearly irregular borders
and a tendency to develop ulceration with irregu-
lar rolled edges are also characteristic features Patients with SCC tend to have other tumors
(Box 5.1) [1, 12]. In a well-differentiated tumor, of the skin, including intraepidermal carcinoma
keratin gives the lesion a grayish-white, granular (Bowen’s disease), senile keratosis, and basal
appearance (Fig. 5.1). Additional presenting fea- cell carcinoma [1]. Squamous intraepidermal
tures include a small erythematous scaly patch, a carcinoma (Bowen’s disease) represents full-
cyst-like lesion, a papillomatous lesion, a cutane- thickness involvement of the epidermis by neo-
ous horn, and a large ulcerated lesion. The edges plastic cells (carcinoma in situ) with a relatively
of the lesion are well circumscribed in some high risk of progression to invasive SCC [10]. Its
cases and ill defined in others [1, 10, 12]. clinical manifestation is of a persistent and
a b
Fig. 5.1 Squamous cell carcinoma of the upper lid (a) and lower eyelid (b) presenting as an irregular, elevated lesion
with masses of keratin
5 Squamous Cell Carcinoma 47
slowly enlarging erythematous, scaly, or crusted Light Microscopic Features

lesion with a sharp, irregular outline [1, 13].
The invading cells show different degrees of dif-
ferentiation leading to variable histologic fea-
Histopathologic Features tures. In well-differentiated tumors, the cells are
polygonal, with abundant acidophilic cytoplasm
Pathogenesis and prominent hyperchromatic nuclei that vary in
size and staining properties. Characteristic find-
SCC arises from the epidermal prickle and squa- ings are of abnormal keratinization with dyskera-
mous cells. Although it may develop de novo, totic cells and keratin pearls and intercellular
actinic keratosis, Bowen’s disease, and radiation bridges. Poorly differentiated lesions show an
dermatoses are all precursors to the development increased degree of cellular anaplasia, with irreg-
of SCC [10, 12]. ularly shaped and sized cells, enlarged nuclei,
abnormal mitoses, little or no evidence of kerati-
nization, and loss of intercellular bridges
Evolution (Fig. 5.3).
SCC of the eyelid usually begins with an early epi-

thelial phase referred to as actinic keratosis (senile Diagnostic Evaluation
keratosis, solar keratosis), with subtotal replace-
ment of the epidermis by atypical cells (intraepithe- Because of its variable clinical presentation,
lial squamous dysplasia). Intraepithelial squamous biopsy and histological examination are required
cell carcinoma or squamous cell carcinoma in situ is for an accurate diagnosis [1]. Examination of the
diagnosed when there is complete disorganization face or extremities for other types of premalig-
of the epidermis, with numerous atypical cells that nant lesions may aid in the diagnosis [1, 12]. The
are rounded, large, and with homogeneous, eosino- diagnosis of perineural spread and orbital inva-
philic cytoplasm. Invasion of the dermis is the hall- sion may be confirmed with appropriate imaging
mark for the histopathologic diagnosis of invasive techniques.
SCC (Fig. 5.2) [1].
Fig. 5.3 Poorly differentiated squamous cell carcinoma

Fig. 5.2 Invasive well-differentiated squamous cell car- showing cellular anaplasia with irregularly shaped and
cinoma showing invasion of the dermis by tumor polygo- sized cells, enlarged nuclei, and no evidence of
nal cells that vary in size and staining properties keratinization
Differential Diagnosis section of a lymph node is considered the gold

standard in staging patients for adjuvant therapy.
SCC of the eyelid and periocular region typically However, its therapeutic value is questionable, and
has no pathognomonic feature that allows its dif- it may be associated with considerable morbidity
ferentiation from other cutaneous lesions, and it [12]. The sentinel lymph node biopsy has been
may mimic many other types of skin lesion, both suggested as a potentially useful technique to stage
benign and malignant [1, 12]. periocular SCC, especially in patients with recur-
rent, large, or highly invasive lesions or those with
perineural invasion (Chap. 21) [12, 14].
Treatment
Radiation Therapy
Preventive Radiation therapy has been used in the treatment
of eyelid malignancies since the beginning of the
Prevention by minimizing sun exposure, espe- twentieth century. SCC is relatively radioresis-
cially in childhood and adolescence, remains of tant and responds even less than BCC to radiation
prime importance in minimizing the morbidity [1]. However, postoperative radiotherapy has
and mortality associated with SCC. been recommended in all patients with micro-
scopic perineural invasion [15], as the role of sur-
gery in the treatment of perineural spread seems
Therapeutic to be only palliative [16].
Three-dimensional conformal planning or
The main treatment modality used for eyelid intensity-modulated radiation therapy is needed
SCC is surgical excision, with microscopic moni- to minimize damage to adjacent structures, and
toring of the margins or Mohs’ microsurgery. A synchronous chemotherapy should be considered
variety of other forms of therapy were suggested, to potentiate the effectiveness of radiation. It was
such as radiation therapy, cryotherapy, chemo- suggested that primary radiotherapy for SCC of
therapy, curettage with carbon dioxide laser, pho- the eyelid may provide high control rates with
todynamic therapy, and treatment with retinoids good function and cosmesis and should be con-
or α-interferon. When used alone, these therapies sidered an alternative to surgery in selected
have high recurrence rates, which are not accept- patients [17]. It was also shown that radical
able for SCC of the eyelid, where recurrent radiotherapy using electron beams for SCC of the
tumors can be more aggressive and invasive. eyelid yielded good results and could be a treat-
However, they may be appropriate for patients ment option [18].
who cannot tolerate or who decline surgery [12].
Chemotherapy
Surgery Chemotherapy may be used for patients with sys-
Only surgical excision with monitoring of the temic disease and for those who cannot tolerate
margins, using either a frozen-section, or a surgical excision or who decline surgery [19]. It
paraffin-section control, or Mohs’ micrographic is usually used as an adjuvant to surgery and
surgery, is an acceptable treatment option for radiotherapy in aggressive infiltrating SCC.
periocular SCC [1, 2, 12, 13]. The treatment of
choice for secondary orbital invasion of SCC is Topical Therapy
orbital exenteration [1, 10]. Topical treatments such as with fluorouracil
(5-FU) cream and imiquimod cream (IMQ) were
entinel Lymph Node Biopsy
S found to be effective treatments for SCC of the
The presence of regional lymph node metastases is eyelids in only very small series of patients.
the single most important prognostic factor for Topical 5% 5-FU cream was found to be useful in
most solid neoplasms, and complete lymph node the treatment of squamous cell carcinoma in situ
dissection with pathologic examination of a cross involving the eyelid, including the eyelid margin
[20]. Topical 5% IQ treatment was reported as neglected cases of eyelid SCC may spread into
successful in cases with intraepidermal as well as the lacrimal passages, the orbit, and the intracra-
invasive SCC of the eyelids [21]. nial cavity. SCC is by far the most frequent of the
secondary epithelial neoplasms in the orbit [1].
Photodynamic Therapy However, orbital invasion is a rare complication
Photodynamic therapy (PDT) is emerging as a that has been reported to occur in 2.5% of all eye-
promising treatment for patients with multiple or lid BCC and SCC [30]. Orbital invasion of eyelid
large SCC or in whom surgery is not appropriate. SCC may take years to occur, often preceded by
In such cases, PDT is associated with reasonable several surgical interventions, irradiations, and
efficacy, good cosmesis, and limited morbidity. recurrences of the tumor. If left unattended, the
However, until prospective-controlled trials are entire orbital region and a major portion of the
performed, the precise role of PDT in relation to face are destroyed in an ulcerating fungating cra-
more conventional surgical approaches remains ter [1]. Orbital spread is usually associated with
to be defined [22, 23]. complete ptosis, ophthalmoplegia, and proptosis.
Eventually, involvement of the orbital nerves and
bones causes severe and constant pain [1, 10].
Prognosis
Prognostic Factors Perineural Spread
High-risk eyelid SCC lesions are those larger Perineural spread of SCC occurs in up to 14% of
than 2 cm, with poor histological differentiation, facial lesions [31]. The perineural infiltration of
deep invasion, and the presence of perineural SCC of the eyelids along branches of the trigem-
invasion [24]. Recurrent tumors and tumors inal nerve, the extraocular motor nerves, and the
developing in scars or in immunocompromised facial nerve facilitates its spread into the orbit,
patients also imply a poor prognosis [25, 26]. The periorbital structures, and intracranial cavity
histologic variant of adenoid SCC is associated [32]. Once clinical signs or symptoms of peri-
with a better prognosis [1]. neural spread have developed, the prognosis is
poor, with around 50% recurrence after simple
excision [31].
Staging
According to the applied practical review of the Local Recurrence

American Joint Committee on Cancer (AJCC)
7th edition [27], primary SCC is classified into The 5-year local recurrence rate for SCC is about
stages I, II, III, and IV stages according to size, 23%. The 5-year metastatic rates vary between
adjacent invasion, complete resection that 5% and 45% [25, 33]. The recurrence rate of peri-
requires enucleation, exenteration or bone resec- ocular squamous intraepithelial carcinoma is 5%
tion, involvement of regional lymph nodes, and 12% for primary and recurrent lesions,
extensive invasion making the tumor not resect- respectively [13].
able, and evidence of distant metastasis. This
classification was found to be a practical tool for
staging of carcinoma of the eyelids [28, 29]. Metastasis
Unlike BCC, SCC has a tendency to metastasize

Local Spread to regional lymph nodes and distant sites through
hematogenous and lymphatic pathways. The
Eyelid SCC is potentially fatal and responsible incidence of lymph node metastasis from eyelid
for considerable morbidity [9]. Aggressive or SCC has ranged from 0% to as high as 24%, and
of distant metastasis varies from 1% to 21% [1, Epidemiology

14, 34]. The incidence of metastasis of SCC aris- The annual incidence of cutaneous keratoacan-
ing from actinic keratoses is lower than for SCC thoma varies according to geographical location
arising de novo [1]. and is estimated to be 100–150 cases per
100,000 in sun-exposed areas (e.g., northern
parts of Australia). It is considered more preva-
Mortality lent in males and affects patients in their fifth to
seventh decades [38].
The tumor-related mortality rates have been
reported to be as high as 40%, and an increased Clinical Features
rate is associated with lesions of the upper lid and The lesion begins as a small flesh-colored papule
medial canthus [1]. However, if detected early that develops rapidly over 4–8 weeks to a lesion
and treated adequately, the prognosis of SCC is typically 5–25 mm in diameter with a central,
generally excellent, and the risk of death and dis- keratin-filled crater (Fig. 5.4), followed by a sta-
ability can be minimized [10]. tionary phase of similar duration, and a resolu-
tion phase may develop in up to 6 months duration
(Fig. 5.5a, b). The keratoacanthoma has smooth
ariants of SCC Including
V borders that merge with the surrounding skin,
Keratoacanthoma and some present with erythema surrounding the
base of the lesion and with telangiectases running
Less common histologic variants of SCC include over the surface of the tumor. The macroscopic
the spindle cell and adenoid (adenoacanthoma or sequelae are rare, generally only a mildly
pseudoglandular) squamous cell carcinoma. The depressed scar. The tumor is most commonly
adenoid SCC variant is characterized by exten- seen on sun-exposed hair-bearing areas, mainly
sive acantholysis and tubular and pseudoglandu- on the face, forearms, and hands. In the eyelids, it
lar patterns [1]. Keratoacanthoma is is considered not common [38].
indistinguishable from squamous cell carcinoma There are several rare variants of keratoacan-
clinically as well as histopathologically (kerato- thoma, which include the giant keratoacanthoma
carcinoma or keratoacanthoma-like squamous
cell carcinoma) [35, 36]. However, because kera-
toacanthoma may regress, it is considered to be a
variant of squamous cell carcinoma.
Keratoacanthoma
Keratoacanthoma was first described by Sir

Jonathan Hutchinson in 1889 as a crateriform
ulcer of the face and was classified for many
years as a benign skin lesion [37]. Although there
are many variants of the disease, it usually pres-
ents as a solitary rapidly growing lesion. The eti-
ology is diverse and remains unknown, ranging
from ultraviolet exposure, viral infection by
human papilloma virus, immunosuppression, and Fig. 5.4 Keratoacanthoma is a nodular lesion with a cen-
genetic susceptibility [36]. tral keratin-filled crater
Fig. 5.5 Keratoacanthoma (a) with spontaneous resolu- Fig. 5.6 Histologically, variable squamous atypia may be
tion 2 weeks later (b) seen at the base of the lesion, and inflammatory infiltrate
is present in the dermis
(>3 cm in diameter), keratoacanthoma centrifu-

gum marginatum, subungual keratoacanthoma surgery should be considered for such lesions in
(keratoacanthoma of the nail), and mucosal kera- the periocular area [40]. Alternative treatment
toacanthoma. Keratoacanthomas are usually soli- modalities described include radiotherapy, cryo-
tary lesions. However, there are a number of therapy, topical or intralesional 5-fluorouracil,
syndromes that feature multiple keratoacantho- and topical application of 5% imiquimod cream.
mas, including the Muir–Torre syndrome, a gen-
eralized eruptive variant of Grzybowski, and the
Ferguson-Smith syndrome. References
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Sebaceous Gland Carcinoma
6
Introduction Epidemiological Aspects
Sebaceous gland carcinoma (SGC) is a malignant The incidence of SGC varies in different series. In
neoplasm capable of aggressive local behavior the USA, SGC accounts for only 5% of all malig-
and metastasis to regional lymph nodes and dis- nant eyelid tumors, whereas basal cell carcinoma
tant organs. It originates from cells of the seba- (BCC) accounts for 90%, and squamous cell car-
ceous glands and occurs most often in the cinoma (SCC) and other tumors including mela-
periorbital area, usually in the eyelid [1]. This noma represent the remaining 5% of cases. The
lesion is considered among the most lethal of all annual incidence of eyelid SGC in the USA is
ocular adnexal tumors [2]. about 0.5 per million in the White population
Thiersch may have reported the first case of older than 20 years, and the incidence may be
periorbital SGC in 1865, and Baldauf reported increasing [3, 4]. In addition, SGC is more com-
another case in 1870. However, Allaire is cred- mon in Caucasians than in African-Americans
ited with the first well-documented case of ade- [5]. A higher incidence of SGC has been observed
nocarcinoma of the meibomian gland in 1891, in China, India, and other Asian countries, where
and most of the modern understanding of eyelid it may be as prevalent as or even more common
SGC was initiated by the review of Straatsma in than periocular BCC and SCC [1]. This difference
1956 [2]. The terms “sebaceous gland carci- is attributed to the relative lack of other tumors
noma,” “sebaceous cell carcinoma,” and “seba- like BCC and SCC in Asian population [6].
ceous carcinoma” are all used interchangeably in
the literature.
Etiology
M. Rosner (*)
There are no systemic conditions that convinc-
Department of Ophthalmology, Eye Histopathology
Laboratory, Goldschleger Eye Institute, Sheba ingly predispose to SGC. Ocular or facial irradia-
Medical Center, Sackler Faculty of Medicine, Tel tion for the treatment of hereditary retinoblastoma,
Aviv University, Tel Aviv, Israel acne, cutaneous hemangioma, and eczema are
e-mail: mrosner@post.tau.ac.il
important risk factors [1]. The relationship
I. D. Fabian between the use of diuretic medications and the
Department of Ophthalmology, Ocular Oncology
development of SGC is not firmly proven [1, 4].
Center, Goldschleger Eye Institute, Sheba Medical
Center, Sackler School of Medicine, Tel Aviv Occasional reports have suggested an association
University, Tel Aviv, Israel between SGC at a relatively young age and

immune dysfunction. A possible relationship

between SGC and human papillomavirus (HPV) • Microscopic findings of an infiltrating
has also been observed [1]. mass composed of cells with lipid vacu-
oles in the cytoplasm, pronounced
nuclear pleomorphism, and mitotic
Clinical Features activity
• Flat superficial involvement of the epi-
SGC is generally a disease of older individuals, thelium—“pagetoid growth pattern”
with a reported median age at diagnosis of • Positive oil red-O stain for lipid
70–73 years [7]. However, it may develop in older • Immunohistologic expression of
children and young adults, particularly after irra- HMFG1, EMA, and BRST-1, but not of
diation for retinoblastoma [1]. Reports regarding cytokeratins
gender have varied, and while some studies have
suggested that men are 1.35–1.4 times as likely as
women to have SGC, other studies have found a
higher incidence in women [1, 7, 8]. SGC has a
marked tendency to arise in the ocular region, but Symptoms and Signs
it is estimated that approximately 25% occur in
regions other than the head and neck [9]. The Solitary Nodule of the Eyelid
majority of SGC arise from the meibomian glands
within the tarsus. About 65% occur in the upper The most common clinical variant of SGC is a
eyelid, 25% in the lower eyelid, 5% involve both solitary, firm, painless, sessile subcutaneous
eyelids [2, 8], and 5% arise in the caruncle [4, 8, round nodule fixed to the tarsus (Fig. 6.1). With
10]. Occasional cases of primary SGC of the con- thickening of the eyelid, the tumor may assume a
junctiva and even of the lacrimal gland are reported yellow color owing to the lipids it contains
[1]. Sebaceous carcinoma of the eyelid also has the (Fig. 6.2). However, SGC that arises from the
tendency to exhibit multicentric origins [5] and glands of Zeis is located at the eyelid margin and
pagetoid spread, which makes local recurrence a has no firm attachment to the tarsus. The tumor
potential problem (Box 6.1) [11]. When patients eventually causes loss of cilia, as observed with
present with a history of multiple SGCs the possi- other eyelid malignant tumors (Fig. 6.1) [1].
bility of Muir–Torre syndrome, now considered a Rarely, SGC may become ulcerated.
subtype of hereditary nonpolyposis colonorectal
cancer, needs to be considered [7].
Diffuse Thickening of the Eyelid

Box 6.1 Salient Diagnostic Features
of Sebaceous Gland Carcinoma Unilateral diffuse thickening of the eyelid is the
second most frequent presentation of SGC. The
diffuse tumor may extend into the epithelium of
• A unilateral, solitary, and sessile subcuta- the forniceal or bulbar conjunctiva and even the
neous round nodule that is firm, painless, cornea (Fig. 6.3). Rarely, SGC arising from the
and yellow masquerading as chalazion glands of Zeis can become pedunculated, keratin-
• Unilateral diffuse thickening of the eye- ized, and even appear as a cutaneous horn. When
lid and/or the conjunctiva masquerading SGC develops in the caruncle, it appears as an
as blepharoconjunctivitis irregular yellow mass that usually is not fixed to
adjacent structures [1, 12].
6 Sebaceous Gland Carcinoma 55
a b
Fig. 6.1 Sebaceous gland carcinoma arising in left upper tival origin of the lesion is evident on partial eversion the
eyelid—a firm, round nodule with prominent meibomian eyelid (b)
gland orifices and intrinsic vessels (a). The tarsoconjunc-
Fig. 6.2 Sebaceous gland carcinoma arising in left lower Fig. 6.3 Diffuse involvement of the lower eyelids by
eyelid—a firm nodule with prominent intrinsic vessels. sebaceous gland carcinoma causing loss of liod margin
Note yellow color due to lipid including cilia
Histopathologic Features the tarsus, glands of Zeis of the cilia, pilosebaceous

glands of the caruncle, and from the conjunctival
Pathogenesis epithelium [1]. It may exhibit multicentric origins
[13, 14]. Most SGC appears to arise de novo and not
Periocular SGC arises from the sebaceous glands in from a preexisting sebaceous adenoma, sebaceous
the ocular region, including meibomian glands in hyperplasia, or sebaceous (organoid) nevus [1].
a b
Fig. 6.4 Histopathologically sebaceous gland carcinoma vacuolated, frothy cytoplasm and pronounced nuclear
is an unencapsulated infiltrating mass (a, hematoxylin– pleomorphism (b, hematoxylin–eosin × 400)
eosin × 100). The tumor is composed of cells with finely
Light Microscopic Features
Histopathologically, SGC is an unencapsulated

infiltrating mass composed of cells with finely
vacuolated, frothy cytoplasm, pronounced
nuclear pleomorphism, and usually high mitotic
activity (Fig. 6.4) [1]. The presence of lipid can
be demonstrated with the oil red-O stain
(Fig. 6.5). This lipid can incite a foreign body
giant cell reaction. SGC is associated with a
chronic inflammatory response that is less intense
than in BCC [1, 14].
Pagetoid Spread Fig. 6.5 Accentuation of the lipid using oil red-O stain.
The lipid globules have a red color (Frozen section, oil
red-O × 250)
SGC exhibits peculiar intraepithelial spread into
the eyelid epidermis and the conjunctival epithe-
lium in 44–80% of cases [1, 5, 8]. This flat need for fat stains on frozen sections and may
superficial involvement of the epithelium is usu- help to differentiate SGC from basal and squa-
ally referred to as “pagetoid spread.” mous cell carcinoma. The central foamy cells of
SGC express human milk fat globulin-1
(HMFG1) and epithelial membrane antigen
Immunohistochemistry (EMA), but not cytokeratins, whereas the small
peripheral basal and duct cells generally express
The histopathologic diagnosis of SGC can usu- cytokeratin but not HMFG1 or EMA. SGC also
ally be made readily on routine light microscopy. expresses Cam 5.2 and BRST-1, whereas BCC
However, immunohistochemistry replaces the expresses neither EMA nor BRST-1, and SCC
Table 6.1 Immunohistochemistry profile of common

malignant eyelid tumors
Tumor type (% positive cases)
Sebaceous Squamous
Tumor gland Basal cell cell
antibody carcinoma carcinoma carcinoma
EMA and 64 0 36
BRST-1
EMA and 73 6 0
Cam 5.2
EMA and 55 0 0
Cam 5.2
Adipophilin 100 0 28
Androgen 100 33 0
receptor
Ber-EP4 0 100 0
P53 99 100 100
Modified from Sinard [15] and Mulay et al. [17] Fig. 6.6 A papillary growth arising from the lower eyelid
EMA anti-epithelial membrane antigen, BRST-1 anti-BCA tarsal conjunctiva. Note yellow color and prominent mei-
225, Cam 5.2 anti-low molecular weight keratin bomian gland orifices (arrow)
expresses EMA but not Cam 5.2 (Table 6.1) [1, Comedocarcinoma Pattern
15]. Additional immunohistochemical staining A large necrotic central core surrounded by via-
including adipophilin (ADP), androgen receptor ble cells characterizes the comedocarcinoma
(AR), and Ber-EP4 can also help to do the correct pattern.
diagnosis. AR was found as a sensitive marker
for SGC, especially in less differentiated tumors. Papillary Pattern
Along with other markers and morphologic fea- Papillary pattern which occurs frequently in
tures, AR can be helpful in the diagnosis of SGC small conjunctival lesions is distinguished by
and its differentiation from SCC and BCC. AR papillary projections and areas of sebaceous dif-
was also found to be more specific and reliable in ferentiation (Fig. 6.6).
identifying intraepithelial spread of SGC, espe-
cially when this component has isolated tumor Mixed Pattern
cells [16, 17]. Mixed pattern exhibits any combination of these
three patterns.
Histopathological Classification
Diagnostic Evaluation
In addition to being well, moderately, or poorly
differentiated [1], SGC can be readily classified Full-thickness excisional or incisional biopsy of
into one of four patterns: lobular, comedocarci- the eyelid that contains tarsus and tarsal conjunc-
noma, papillary, and mixed [1]. tiva is the preferred method of confirming the
suspected clinical diagnosis of SGC (Fig. 6.7).
Lobular Pattern When diffuse involvement of eyelid and conjunc-
Lobular pattern is the most common and has tiva is suspected, multiple conjunctival map biop-
architecture similar to that of a normal sebaceous sies should be performed to determine the extent
gland, with fewer differentiated cells peripherally of the disease [1, 8]. Fine-needle aspiration
and more differentiated lipid-producing cells biopsy and impression cytology have been used
located centrally. in the early diagnosis of SGC [18, 19] and to
a b
Fig. 6.7 Crater like lesions after three tarsoconjunctival biopsies were obtained using a 3.0 mm cylindrical skin punch
(a). The histopathology sample shows a tarsal tissue with meibomian gland carcinoma (b)
detect conjunctival spread, but these methods are in older patients, should undergo a biopsy to rule
generally not advisable because of the limited out SGC.
amount of tissue obtained. However, fine-needle
biopsy may be acceptable for the diagnosis of
regional lymph node metastases [1]. Only in Inflammatory Conditions
cases with suspected diffuse involvement of the
eyelid and conjunctiva is orbital imaging indi- Virtually any inflammatory condition of the eye-
cated, either before or after the initial biopsy, to lid and the conjunctiva must be included in the
rule out posterior extension [1]. differential diagnosis of SGC. These include uni-
lateral blepharitis, conjunctivitis, meibomitis,
superior limbic keratoconjunctivitis, papillary
Differential Diagnosis conjunctivitis, cicatricial pemphigoid, conjuncti-
val granuloma, and sarcoidosis. Thus, SGC
SGC is notorious for its variable clinical presen- should be suspected in every middle-aged or
tation and its ability to masquerade, both clini- older patient with a diagnosis of unilateral bleph-
cally and histopathologically, as common benign aritis or other inflammatory conditions that do
or less invasive conditions, resulting in delayed not respond to usual therapy [1].
diagnosis and treatment [1, 2, 8].
Benign and Malignant Tumors

Chalazion
Several benign and malignant tumors can have a
In the early stages, SGC of the eyelids can be clinical appearance similar to that of SGC. These
very similar to chalazion. However, in contrast to include BCC, SCC, melanoma, Merkel cell carci-
SGC, chalazion generally occurs in younger indi- noma, lymphoma, sweat gland neoplasm, junc-
viduals, is more circumscribed and painful, and tional squamous papilloma, hereditary benign
is usually not associated with loss of cilia. intraepithelial dyskeratosis, metastatic carci-
However, recurrent chalazia, as well as chalazia noma, and other rare tumors [1].
asal Cell Carcinoma

B or Mohs’ microsurgery is usually used at the time
The nodular BCC is more common on the lower lid of tumor excision, to evaluate the margins, and
and is white rather than yellow. BCC is also more the resection is continued until the margins are
likely to become ulcerated than SGC. Although histopathologically clear.
diffuse sclerosing BCC may closely simulate SGC, However, there is controversy as to which is
it very rarely exhibits diffuse invasion of the con- preferable and whether either technique is better
junctiva. Histologically, BCC typically shows than waiting for permanent sections, because of
peripheral palisading of nuclei and retraction arti- the difficulty in diagnosing SGC in frozen sec-
fact that are not seen in SGC. tions [1, 23, 24]. It has been suggested that wide
margins, of at least 5 mm, should be taken in
quamous Cell Carcinoma
S order to prevent recurrence. Orbital exenteration
SCC is more superficial and lacks a yellow color. is currently performed less often but is still indi-
Conjunctival intraepithelial neoplasia can be very cated for advanced and diffuse SGC with orbital
similar to diffuse epithelial invasion by SGC, invasion in the absence of metastasis [1].
except for eyelid involvement, which is less
likely to be present in SGC. Histopathologically,
SCC is the lesion most often confused with SGC Cryotherapy
[8, 20, 21]. Unlike SGC, SCC cells have more
abundant eosinophilic cytoplasm, lack lipid As the removal of wide margins is not possible in
vacuoles, and demonstrate eddy formation and the case of conjunctival lesions, supplemental
keratin cysts. treatment by double freeze-thaw cycle cryother-
apy is indicated. Combination therapy with cryo-
Melanoma therapy, topical chemotherapy [25–27], and
Nodular or diffuse cutaneous melanoma in the radiotherapy [28] can also be used in advanced
eyelid or conjunctiva can usually be distinguished cases [1].
from SGC by its black or brown pigmentation,
but amelanotic melanoma can resemble SGC.
Topical Chemotherapy
Other Tumors
Merkel cell carcinoma of the eyelid is distin- Topical chemotherapy with mitomycin C drops
guished by its red or red-blue color. Lymphoma has been found to be effective as an alternative to
of the eyelid arises from deeper layers than does complete conjunctivectomy or exenteration in
SGC, and in the conjunctiva, it has a characteris- selected cases [25–27].
tic “salmon patch” color. Moreover, inflamma-
tory signs that are commonly associated with
SGC are lacking in lymphoma. Sentinel Lymph Node Biopsy
The technique of sentinel node biopsy or at least

Treatment strict regional lymph node surveillance was sug-
gested as a useful method for SGC of the eyelid
Surgery and conjunctiva [29, 30] especially for patients
with eyelid sebaceous carcinoma of 10 mm or
The most acceptable management of periocular more in greatest dimension, tumors that involves
SGC is complete surgical removal [22]. full thickness of the eyelid, with invasion of adja-
Excisional biopsy of a small lesion is recom- cent ocular or orbital structures, with perineural
mended even before histopathologic verification invasion, when enucleation, exenteration, or bone
of the diagnosis [1]. Either frozen section control resection is required for its complete resection, or
when tumor is not respectable (Chap. 10) [31]. Various factors have been associated with a worse
Localized regional lymph node metastasis is prognosis, including vascular, lymphatic, and
treated by lymph node dissection or by a combi- orbital invasion; involvement of both upper and
nation of chemotherapy and radiotherapy [32]. lower eyelids; poor differentiation; multicentric
origin; duration of symptoms more than 6 months;
tumor diameter exceeding 10 mm; a highly infil-
Radiotherapy trative pattern; pagetoid invasion; and hyperex-
pression of tumor suppressor gene p53 [1, 36].
In the past, irradiation was considered as not According to the applied practical review of
highly effective in the management of SGC; it the American Joint Committee on Cancer (AJCC)
has been advocated only in selected cases [1, 28, 7th edition [37], primary SGC is classified, like
32]. However, newer studies are suggesting that all other carcinomas of the eyelids, into stages
radiation therapy is a safe and effective treatment I–IV (Box 4.2) according to the various parame-
for patients with sebaceous carcinoma of the eye- ters of the primary tumor (T category), regional
lid. It appears to contribute to prolonged survival lymph nodes (N category), and metastases (M
as a result of good tumor control, and it also facil- category). These include the size of the primary
itates functional and cosmetic preservation of the tumor; adjacent invasion; complete resection that
eyelid [33]. Postoperative radiation therapy after requires enucleation, exenteration, or bone resec-
radical surgery is suggested for adequate disease tion; involvement of regional lymph nodes;
control in advanced disease [34]. extensive invasion making the tumor not respect-
able; and evidence of distant metastasis. It was
found that the T category correlates well with
Systemic Chemotherapy outcomes in patients with sebaceous carcinoma
of the eyelid [31].
Regional spread to lymph nodes and hematoge- All patients with SGC should be followed
nous metastasis to distant organs is treated by regularly because of the risk of recurrence as well
chemotherapy [1, 32]. as the potential for metastasis and mortality.
Targeted Therapy Local Growth
The Hedgehog signaling pathway was found to Regardless of its origin, SGC can show direct
be significantly more upregulated in periocular local extension beyond its original site and
SGC compared to eyelid nodular BCC, a known involve the entire eyelid, the adjacent eyelid, and
aberrant Hedgehog pathway tumor. Furthermore, invade the orbital soft tissues, lacrimal secretory
the stroma of the SGC demonstrated Hedgehog system, lacrimal excretory system, and the cra-
upregulation, compared to eyelid nodular nial cavity. Such local growth is more likely to
BCC. Thus targeting this pathway may be a occur in neglected or recurrent cases [1, 5].
potential treatment strategy for SGC as it is for
BCC [35].
Local Recurrence
Prognosis Despite radical surgery like orbital exenteration

with extended neck dissection, locoregional fail-
Prognostic Factors ure rate may be high, and the 5-year local recur-
rence rates following wide excision have ranged
The visual prognosis varies with the extent of the from 9% to 36% [38]. Adequate disease control
disease and the type of treatment employed [1]. must be achieved by combined modality approach
Table 6.2 Survival rates with eyelid sebaceous gland carcinoma

First author Year Country Cases Mortality rate (%) Follow-up (years)
Boniuk 1968 USA 88 30 5
Ni 1979 China 100 41 5–15
Ni 1982 China 82 24 4
Rao 1982 USA 104 22 5
Doxanas 1984 USA 40 15 Not available
Zurcher 1998 England 43 9 3
Muqit 2004 Scotland 32 3 5
Esmaeli 2014 USA 50 21 5a
Modified from Muqit et al. [40] and Esmaeli et al. [31]
a
Disease specific survival rate of 79% at 5 years
of radical surgery followed by postoperative radi- [34], for patients presenting with lymph nodal
ation therapy [34]. metastases. However, increased awareness and
earlier aggressive treatment have markedly
improved this to less than 10% (Table 6.2) [2, 40].
Metastasis
The most common path of metastasis of eyelid

SGC is via the lymphatic channels to regional
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Eyelid Tumors: Cutaneous
Melanoma
7
Introduction Epidemiology
Cutaneous melanoma of the eyelid is a rare Because of its rarity, there are no data in the lit-
tumor, representing fewer than 1% of all malig- erature regarding the incidence of cutaneous mel-
nant neoplasms of the eyelid skin [1], 1% of all anoma of the eyelid. The vast majority of the
skin melanomas [2], and 7% of cutaneous malig- reported cases are of white patients from series in
nant melanomas of the head and neck region [3]. North America, Australia, and Europe [4–10], but
Many primary melanomas of the eyelid involve eyelid skin melanoma is also reported in series of
the mucosal surfaces of the palpebral and bulbar eyelid tumors in Asia [11, 12]. The incidence is
conjunctiva, and in these cases, one must manage similar in men and women [7–9]. The eyelid
not only the eyelid but also the conjunctival com- cutaneous melanomas are tumors of adults and
ponent of the lesion. One may argue reasonably the elderly, with a peak incidence in the sixth and
that primary conjunctival melanomas may affect seventh decades of life [7–10].
the eyelid secondarily.
This chapter, therefore, focuses on the rare
subset of melanomas confined to the eyelid skin. Etiology and Pathogenesis
Our knowledge of such tumors is based on a few
case series and some case reports. It is difficult to Ultraviolet radiation most likely contributes to
draw definite conclusions about the epidemiol- the etiology of eyelid melanoma. The appearance
ogy, etiology, clinical behavior, prognosis, and the of these malignancies mostly in fair-skinned
appropriate management of these malignancies. elderly adults, the histological findings of solar
elastosis in most cases of cutaneous melanomas,
the higher incidence of the tumor in the lower
eyelid, and the relatively frequent association
J. Pe’er (*) with basal cell carcinoma support this pathogen-
Ocular Oncology Service and Ophthalmic Pathology esis [7, 9, 10, 13, 14].
Laboratory, Department of Ophthalmology, Ten cases of cutaneous melanoma were
reported in eyelids and the periorbital region in
Jerusalem, Israel
e-mail: peer@hadassah.org.il patients with oculodermal melanocytosis (nevus
of Ota) [15]. This is a relatively high incidence of
R. Folberg
Oakland University William Beaumont this rare tumor in the relatively rare condition;
School of Medicine, Rochester, MI, USA thus, oculodermal melanocytosis may be

64 J. Pe’er and R. Folberg
Fig. 7.1 A partially pigmented cutaneous melanoma in Fig. 7.2 High magnification of superficial cutaneous
the lateral aspect of the lower eyelid of the right eye, near melanoma of the lower eyelid margin without involve-
the lateral canthus; the lesion changed in shape before the ment of the palpebral conjunctiva. (Photograph courtesy
photograph was taken. (Photograph courtesy of Dr. Peter of Dr. Peter A. Martin)
A. Martin)
c onsidered a risk factor for the development of the exposed cutaneous surface of elderly patients.
eyelid cutaneous melanoma. Preexisting pig- It slowly enlarges in size, although some areas
mented lesions that show a sudden or gradual may undergo regression. The lesions change
increase in size were seen in most patients in one shape and size and may change color from tan to
series [9]. brown to black. When there is progression to len-
tigo maligna melanoma, the invasive areas are
usually marked by small nodular formations and
Clinical Features are usually dark brown or black, although inva-
sion may occur without any obvious clinical
Eyelid cutaneous melanoma arises most fre- changes. Theoretically, eyelid melanomas may
quently in the lower eyelid (Figs. 7.1 and 7.2), evolve through dysplastic nevi that affect the eye-
many times from a preexisting longstanding pig- lid or as melanomas of the superficial spreading
mented lesion that increases in size gradually, type. Nodular melanomas are exceptionally rare
although a newly acquired pigmented lesion is among these already rare tumors, and small heav-
also common [9]. In one series [7] the three most ily pigmented nodules at the eyelid margin may
frequently listed clinical characteristics of the well represent pigmented basal cell carcinomas.
melanoma were pigmentation, documented Eyelid melanoma can often involve the eyelid
growth, and ulceration or hemorrhage. Other sus- margins (Fig. 7.3). In such cases, the mucocuta-
picious signs are irregular borders and variegated neous junction may be breached and the palpe-
shades of brown, red, white, blue, or dark black bral conjunctiva may be involved. It is often
color. Cutaneous melanoma can be amelanotic. difficult to know whether the melanoma origi-
It is likely that most eyelid melanomas evolve nates in the skin or in the conjunctiva. Such cases
through the lentigo maligna precursor lesion [10, have a worse prognosis, and some relate this to
13, 14, 16]. Lentigo maligna is a slowly develop- the conjunctival involvement that may grow
ing non-palpable pigmented macule, usually on unseen for many years [8].
7 Eyelid Tumors: Cutaneous Melanoma 65
Lesions that feature a roughened or exaggerated

skin texture are more likely to be of epithelial ori-
gin, even if pigmented. Thus, melanocytes may
generate pigmentation within seborrheic kerato-
sis. These lesions should never be mistaken for
melanomas because (a) the precursor lesions of
most melanomas in the periocular skin are flat
(pigmented seborrheic keratosis are elevated) and
(b) seborrheic keratosis features an irregular sur-
face texture, while invasive melanoma typically
produces a smooth nodular surface in the context
of an otherwise flat precursor lesion in which
skin markings are unaffected.
As mentioned above, basal cell carcinomas
may be pigmented by the generation of excess
Fig. 7.3 Large cutaneous melanoma of right upper eyelid
melanin pigment in an otherwise “mundane”
with involvement of the eyelid margin. (Photograph cour-
tesy of Dr. Peter A. Martin) basal cell carcinoma of the nodular type. Such
lesions are rare and may be mistaken for malig-
nant melanomas of the nodular type. The treat-
Diagnosis and Differential ment of pigmented nodular lesions of the eyelid
Diagnosis involves total resection, so the initial treatment of
these lesions is identical regardless of the even-
The clinical examination of pigmented periocular tual histological diagnosis. Spitz nevi may be
lesions requires the ophthalmologist to provide confused clinically and histologically for mela-
an exceptional level of illumination (beyond that nomas of the nodular type on and around the eye-
typically available in ophthalmic examining lid (Chap. 3).
lanes that are used for refraction, slit-lamp exam-
ination, and funduscopy). One should be pre-
pared to turn the room lights up to maximum Histopathologic Features
level and to cast additional illumination on the
affected area by a dedicated light near the exami- Lentigo maligna is remarkable for epidermal
nation chair. Magnification may help the ophthal- atrophy in the context of effacement of the rete
mologist to detect subtle changes in a lesion’s and solar elastosis. Upon this background, on
color and texture, and the lens used for indirect may encounter atypical melanocytes populating
ophthalmoscopy may be especially useful in this the basal layers of the epidermis and along
setting. Ophthalmologists should also not over- adnexal structures such as the pillar units of the
look the utility of the slit lamp in examining the eyelash. Ophthalmologists should realize that in
eyelids for malignancies of all types, not only the terminology of contemporary dermatopathol-
pigmented eyelid lesions. The slit lamp provides ogy, these lesions may be called “melanoma in
exceptional magnification and illumination, criti- situ,” meaning that atypical melanocytes are
cal to achieving a focused clinical differential within the epidermis, confined above the epider-
diagnosis. mal basement membrane.
Most nevi of the eyelid margin are nodular, a Any breach of the epidermal basement mem-
reflection of the space-occupying characteristics brane by atypical melanocytes renders the lesion
of the intradermal collection of nevus cells. a malignant melanoma. Should the invasive
c omponent arise in the context of an intradermal lid melanomas from these recommendations.
melanocytic lesion featuring melanocytes in a Early diagnosis and treatment are essential in
pagetoid distribution, one might then state that managing eyelid melanomas and especially to
the melanoma is of a superficial spreading type. attain adequate functional and cosmetic lid
The type of melanoma (lentigo maligna reconstruction. In an extensive series of cutane-
melanoma or superficial spreading melanoma)
ous eyelid melanoma from Australia, the authors
does not influence the clinical behavior of the recommended a surgical excision margin of
lesion. 3 mm for eyelid melanoma ≤1 mm in Breslow
Clark’s micro-staging of melanoma [17] does thickness and 5 mm for melanomas >1 mm in
not apply to the eyelid skin because in this loca- thickness [20].
tion, the dermis is not stratified into papillary and Modified “slow” Mohs’ surgery (mapped
reticular zones and there is no subcutaneous fat in serial excision) using paraffin sections has been
the eyelid. If one encounters adipose tissue in the recommended by several experts as the treatment
examination of an eyelid biopsy, then the pathol- of choice in cases of lentigo maligna and lentigo
ogist should conclude that the surgeon violated maligna melanoma [10, 13, 21, 22]. They found
the orbital septum. The primary prognostic that this technique offers a high early cure rate in
parameter for melanomas of the eyelid skin is the conjunction with tissue conservation. They also
depth of invasion measured by a calibrated ocular found that the recommendation of 1 cm margins
micrometer from the top of the granular layer of for melanoma of less than 1 mm thick is insuffi-
the epidermis to the point of deepest invasion into cient for complete excision. Cook and Bartley [1]
the dermis [18]. Other prognostic factors of recommended modified Mohs’ technique using
importance in cutaneous melanoma at different frozen tissue as treatment of choice, but the use
body sites include the presence of ulceration (a of frozen tissue sections for melanoma is contro-
poor prognostic sign), which is seldom seen in versial because of freeze artifacts that make accu-
primary eyelid melanomas. Cell type, so signifi- rate interpretation difficult. A recent survey of 44
cant among the histological characteristics of cases did not find that margins of excision have a
uveal melanoma, does not appear to play an inde- statistically significant effect on local, regional,
pendent role in this histological prognosis of eye- or distant recurrence [23].
lid melanomas. Resection of periorbital and eyelid melano-
mas is challenging because of the important ana-
tomic structures in this region [24]. The challenge
Treatment lies in the need to provide the best functional and
aesthetic results and to still resect the primary
Excision lesion with the intent of effecting the cure and
protecting the eye. The surgeon should not com-
There is a consensus that complete surgical exci- promise the adequate margins of resection in
sion with free surgical margins of healthy skin is order to facilitate periorbital reconstruction. The
the treatment of choice for cutaneous malignant type of reconstruction performed depends on the
melanoma in general and eyelid melanoma in size of the surgical defect and its location (e.g.,
particular. However, the ideal width of the surgi- primary closure, full-thickness skin grafts, upper
cal margins that are necessary in order to prevent lid mucocutaneous flaps, cheek advancement
recurrences is a matter of controversy. Harris flaps, cervicofacial flaps, inferiorly based nasola-
et al. [19] recommended simple excision for in bial flaps, transconjunctival flaps, frontalis mus-
situ melanoma, 1 cm margins for tumors of 1 mm cle flaps, and medial transposition Z-plasty)
thickness or less, 2 cm margins for tumors of (Chap. 10) [24]. The needs of most patients can
1–4 mm depth, and at least 2 cm for more than be met by one procedure, but in difficult cases,
4 mm depth. However, because of difficulties in two or more procedures are required. In a large
eyelid reconstruction, most studies exclude eye- series of eyelid melanoma more than a third of
the patients require more than one excision to has been reported in several cases series, suggest-
achieve clear margins, supporting delayed recon- ing a biologic interaction between these two
struction for eyelid melanoma [25]. methods [29].
Palliative Therapy Sentinel Lymph Node Biopsy
Primary use of nonsurgical ablation in cutaneous The issue of elective lymph node dissection in
melanoma is not recommended [20]. Methods of patients with periocular melanoma is controver-
treatment such as cryotherapy, radiotherapy, topi- sial [24, 30]. The procedure is probably not indi-
cal treatment with azelaic acid, and curettage cated for lesions less than 1.0 mm thick and may
electrodissection are associated with high recur- offer little advantage for lesions thicker than
rence rates. In addition, these techniques do not 4.0 mm (Chap. 21). It is currently recommended
provide tissue for histologic assessment of tumor to perform elective lymph node dissection for
thickness, the single most significant prognostic melanomas of “intermediate” thickness
parameter in the management of melanoma. (1–4 mm), which may have generated occult
Cryotherapy and external beam radiation can be nodal metastases. Sentinel lymph node mapping
used as adjuvant therapy, although according to using lymphoscintigram has been advocated in
one study [9] adjuvant radiotherapy did not add order to locate suspicious involved lymph nodes
at all to cure; thus the use of radiotherapy is at and prevent unnecessary lymph node dissection.
best palliative. One group reported a successful The technique has evolved into intraoperative
treatment with brachytherapy, using iodine-125 lymphatic mapping and facilitates selective senti-
applicator in eyelid malignant melanoma [26]. nel lymphadenectomy [31]. When positive, fine-
Recently, treatment of eyelid lentigo maligna needle aspiration biopsy or excision of the node
melanoma by the use of imiquimod cream was should be performed for histologic confirmation
reported to be an effective option as primary of the metastatic disease. In those patients with
adjuvant therapy [27]. histologic confirmation of nodal metastases but
no evidence of distant metastases, parotidectomy
or modified neck dissection is performed [24]
Chemotherapy and Immunotherapy (Chap. 21). Histologic features associated with a
positive sentinel lymph node include greater
In advanced metastatic cutaneousmelanoma, tumor thickness, a greater number of mitotic fig-
chemotherapy has been used recently with lim- ures, and ulceration [30].
ited success, mostly increasing survival but not
curing the disease. Immunotherapy has been
introduced in recent years for treating metastatic Prognosis
cutaneous melanoma. In recent years, immuno-
therapy has become a cornerstone in the treat- Prognostic Factors
ment of advanced cases of melanoma, intending
to modulate the host immunity against the tumor Factors such as age, gender, and histologic type
[28]. Currently, the leading drugs for immuno- are not of prognostic value [31]. Location of the
therapy for cutaneous melanoma are ipilimumab tumor in the upper or lower lid and in the canthi
(Yervoy), pembrolizumab (Keytruda), and does not affect prognosis, but location of mela-
nivolumab (Opdivo). Immunotherapy can be noma in the lid margin involving the mucocuta-
used in adjuvant setting after complete surgical neous junction is associated with higher mortality
excision in patients with high-risk diseases, unre- [5]. The involvement of the palpebral conjunctiva
spectable disease, or metastatic disease. A com- in such cases may explain this association. The
bination of radiation therapy and immunotherapy status of the excision margins in cutaneous eyelid
melanoma is not associated with local, regional, 5. Garner A, Koornneef L, Levene A, et al.
Malignant melanoma of the eyelid skin: his-
or distant recurrence [24]. topathology and behaviour. Br J Ophthalmol.
1985;69(3):180–6.
6. Zoltie N, O’Neill TJ. Malignant melanomas of eyelid
Recurrence skin. Plast Reconstr Surg. 1989;83(6):994–6.
7. Grossniklaus HE, McLean IW. Cutaneous mela-
noma of the eyelid. Clinicopathologic features.
Local recurrence of eyelid cutaneous melanoma Ophthalmology. 1991;98(12):1867–73.
is very frequent in incompletely excised tumor, 8. Tahery DP, Goldberg R, Moy RL. Malignant mela-
happening in most of these cases. However, noma of the eyelid. A report of eight cases and
a review of the literature. J Am Acad Dermatol.
local recurrence is not rare also when melano- 1992;27(1):17–21.
mas are completely excised [9]. Regional lymph 9. Vaziri M, Buffam FV, Martinka M, et al.
node metastases were also reported in patients Clinicopathologic features and behavior of
with completely excised eyelid melanoma. In cutaneous eyelid melanoma. Ophthalmology.
2002;109(5):901–8.
large series, local recurrence occurred in 21%, 10. Chan FM, O’Donnell BA, Whitehead K, et al.
nodal metastasis in 11%, and distant metastasis Treatment and outcomes of malignant melanoma
in 4% [A]. of the eyelid: a review of 29 cases in Australia.
Ophthalmology. 2007;114(1):187–92.
11. Wang JK, Liao SL, Jou JR, et al. Malignant eyelid
tumours in Taiwan. Eye. 2003;17(2):216–20.
Mortality 12. Takamura H, Yamashita H. Clinicopathological anal-
ysis of malignant eyelid tumor cases at Yamagata
The mortality rate from eyelid cutaneous mela- University Hospital: statistical comparison of tumor
incidence in Japan and in other countries. Jpn J
noma varies significantly in various series, rang- Ophthalmol. 2005;49(5):349–54.
ing from 7% to 58% [5, 7, 10]. The wide variation 13. Then SY, Malhotra R, Barlow R, et al. Early cure
in the reported mortality may reflect the relative rates with narrow-margin slow-Mohs surgery for
rarity of primary melanoma confined to the skin periocular malignant melanoma. Dermatol Surg.
2009;35(1):17–23.
of the eyelid, and the high mortality in a series 14. Kostopoulos E, Champsas G, Konofaos P, et al. Eyelid
from a major tertiary cancer center is likely melanoma: our experience a propos of 23 cases. Ann
explained by a selection bias with more advanced Chir Plast Esthet. 2012;57(2):158–63.
cases treated in this setting [9]. The time from 15. Patel BC, Egan CA, Lucius RW, et al. Cutaneous
malignant melanoma and oculodermal melanocyto-
diagnosis to death ranges from 8 months to sis (nevus of Ota): report of a case and review of
14 years [31]. The late recurrence in a significant the literature. J Am Acad Dermatol. 1998;38(5 Pt
number of patients reinforces the need for long- 2):862–5.
term follow-up of patients treated for cutaneous 16. Demirci H, Johnson TM, Frueh BR, et al.
Management of periocular cutaneous melanoma
eyelid melanoma. with a staged excision technique and permanent
sections: the square procedure. Ophthalmology.
2008;115(12):2295–300.
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togenesis and biologic behavior of primary human
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1969;29(3):705–27.
future prospects for the management of eyelid malig-
18. Breslow A. Thickness, cross-sectional areas and depth
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2001;108(11):2088–100.
Ann Surg. 1970;172(5):902–8.
2. Rodriguez-Sains RS, Jakobiec FA, Iwamoto
19. Harris MN, Shapiro RL, Roses DF. Malignant mela-
T. Lentigo maligna of the lateral canthal skin.
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Ophthalmology. 1981;88(12):1186–92.
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3. Batsakis J. Tumors of the head and neck. Baltimore:
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20. Harish V, Bond JS, Scolyer RA, et al. Margins of
4. Naidoff MA, Bernardino VB, Clark WH. Melanocytic
excision and prognostic factors for cutaneous eye-
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1976;82(3):371–82.
2013;66:1066–73.
21. Malhotra R, Chen C, Huilgol S, et al. Mapped 26. Stanowsky A, Krey HF, Kopp J, et al. Irradiation of
serial excision for periocular lentigo maligna malignant eyelid melanoma with Iodine-125 plaque.
and lentigo maligna melanoma. Ophthalmology. Am J Ophthalmol. 1990;110(1):44–8.
2003;110(10):2011–8. 27. Elia MD, Lally SE, Hanlon AM, et al. Periocular mel-
22. Boulos PR, Rubin PA. Cutaneous melanomas of the anoma in situ treated with imiquimod. Ophthalmic
eyelid. Semin Ophthalmol. 2006;21(3):195–206. Plast Reconstr Surg. 2016;32:371–3.
23. Esmaeli B, Youssef A, Naderi A, et al. Margins 28. Sanlorenzo M, Vujic I, Posch C, et al. Melanoma
of excision for cutaneous melanoma of the eye- immunotherapy. Cancer Biol Ther. 2014;15:665–74.
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nocytic lesions: excision and reconstruction in 40 30. Pfeiffer ML, Ozgur OK, Myers JN, et al. Sentinel
patients. Plast Reconstr Surg. 1998;102(1):19–27. lymph node biopsy for ocular adnexal melanoma.
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Adnexal Tumors
8
Martina C. Herwig-Carl and Karin U. Loeffler
Introduction Box 8.1
Eyelid adnexal tumors are frequent and comprise

a large variety of different entities because the lid • Eyelid adnexal tumors are frequent and
is rich in adnexal structures such as hairs (lashes) comprise a large variety of different
and glands. Overall, benign adnexal lesions of entities.
the eyelids are much more frequent than the • Most commonly these lesions arise from
malignant lesions [1–3]. In a series of 864 eyelid sweat glands or hair follicles.
lesions that were biopsied, 82% were benign [1]. • Histology can provide further informa-
It is reassuring to note that the accuracy of clini- tion with regard to the origin of the
cally suspected malignant eyelid tumors is lesion and its dignity.
reported in the 90% range [1, 2].
Amongst benign lesions of the eyelid, adnexal
tumors are frequent and display a variety of clini-
cal as well as histologic features. Most com- Etiopathogenesis
monly, they originate from sweat glands or hair
follicles. Malignant neoplasms are rare but can The eyelid adnexal tumors may be classified as
occur, and excision and histopathologic evalua- cystic lesions as well as benign and malignant
tion are therefore recommended even for less tumors arising from sweat glands, hair follicles,
suspicious tumors (Box 8.1). sebaceous glands, and accessory lacrimal glands
(Table 8.1). All glands can, particularly in cases
of duct obstruction, lead to retention cysts.
Epidermal inclusion cysts and epidermoid cysts
may occur following trauma, surgery, and inflam-
matory processes. Otherwise, the precise etiol-
ogy of most adnexal tumors of the eyelids is still
M. C. Herwig-Carl (*)
Department of Ophthalmology, University Clinic unknown.
Bonn, Bonn, NRW, Germany
e-mail: martina.herwig@ukbonn.de
K. U. Loeffler
Department of Ophthalmology, Division of
Ophthalmic Pathology, University Clinic Bonn,
Bonn, NRW, Germany

72 M. C. Herwig-Carl and K. U. Loeffler
Table 8.1 Classification of eyelid adnexal tumors Treatment, Follow-Up,

Types Subtypes and Prognosis
Cystic lesions Benign Epidermal inclusion cyst
Retention cyst Management is similar in the majority of these
Trichilemmal cyst
tumors; benign lesions are excised for histologic
Sweat gland Benign Apocrine hidrocystoma
tumors Eccrine hidrocystoma
confirmation, and malignant tumors are removed
Syringoma surgically with a tumor-free margin confirmed by
Eccrine spiradenoma histopathologic evaluation. Follow-up and the
Pleomorphic adenoma prognosis depend on the dignity and on the –
Syringocystadenoma extremely rare – development of metastases.
papilliferum
Malignant Sweat gland
adenocarcinoma
Mucinous sweat gland Cystic Lesions
adenocarcinoma
Apocrine gland pidermal Inclusion Cysts or
E
adenocarcinoma Epidermoid Cysts
Hair follicle Benign Trichoepithelioma
tumors Trichofolliculoma
Trichoadenoma Epidermal inclusion cysts or epidermoid cysts
Trichilemmoma usually occur as smooth dome-shaped nodules of
Pilomatrixoma varying size (Fig. 8.1a), frequently revealing a
Malignant Carcinoma of hair punctum or pore. Occasionally, they appear pig-
follicles mented. The characteristic feature is a cystic
Pilomatrix carcinoma
space filled with keratin, lined by regular keratin-
Sebaceous Benign Sebaceous gland
gland tumors hyperplasia izing stratified squamous epithelium (Fig. 8.1b).
Sebaceous gland In the case of keratin extrusion after cyst rupture,
adenoma a marked inflammatory reaction can develop.
Sebaceous epitheliomaMilia are miniature variants of epidermal cysts.
Nevus sebaceous of Histologically, comedonal cyst is similar to an
Jadassohn
epidermoid cyst in that the lining consists of
Malignant Sebaceous epithelioma
Sebaceous gland keratinizing stratified squamous epithelium.
carcinoma Clinically, a comedonal cyst is characterized as
“blackhead” (comedo with opening onto the sur-
face) or “whitehead” (comedo with blocked
Clinical Findings opening).
A “sebaceous” cyst is a clinical misnomer, as,
Benign lesions usually respect the anatomical despite the yellowish color of many cysts, histo-
structures and occur as slowly growing, well- logic findings do not qualify any of these lesions
confined tumors with a smooth surface. As with as sebaceous. Clinically, the term is used most
all malignant tumors, clinical symptoms include often for epidermoid or trichilemmal cyst.
progressive growth, recurrence after incomplete
excision, infiltrative growth, and destruction of
adjacent tissue (loss of eyelashes). Ulceration Retention Cysts
and hemorrhage can be present in advanced
stages. Pain is an uncommon presenting feature Retention cysts can develop from all glands with
in this location. the sudoriferous cyst, originating from sweat
8 Adnexal Tumors 73
a Trichilemmal (Pilar) Cysts
Trichilemmal (pilar) cysts occur frequently in the

scalp and appear as intradermal yellowish-smooth
intradermal swelling. The cyst lining is composed
of basophilic cells surrounded by a rim of fibrous
tissue. Toward the lumen the cells develop into
squamous epithelium with pale and fairly high
keratocytes that abruptly turn into keratin without
a granular layer. Sometimes calcification occurs,
and often cholesterol clefts are seen.
b Sweat Gland Tumors
Benign Tumors
There are two types of sweat glands: eccrine and

apocrine. Eccrine sweat glands are widely dis-
tributed in the body, and each gland consists of a
single duct with a coiled deeper component [4].
By contrast, the apocrine sweat glands are lim-
ited to the special regions such as axilla, nipple,
external ear, external genitalia, and the eyelids
[4]. The apocrine glands and their ductal open-
c ings are closely associated with eyelashes [5].
Apocrine hidrocystoma and eccrine hidrocys-
toma represent the majority of the benign sweat
gland tumors. In contrast to apocrine hidrocys-
toma, the eccrine hidrocystoma does not involve
the eyelid margin. This is due to the fact that the
eccrine sweat glands are distributed throughout
the eyelid skin and are not confined to the eyelid
margin unlike the apocrine glands [5].
Apocrine Hidrocystoma
Apocrine hidrocystoma (cystadenoma, apocrine
tubular adenoma, cyst of Moll) is usually a solitary
nodule affecting mostly the head (cheek) or neck
Fig. 8.1 Epidermoid cyst. Yellowish dome-shaped lesion in middle-aged people of either sex. It presents as
at the lower eyelid (a). The cyst is filled with keratin (b) a translucent or bluish-black nodule up to about
and lined by a keratinized squamous epithelium (c)
1 cm in diameter involving the eyelid m argin
(Fig. 8.2a) [6]. In rare instances, it can occur
glands, as the most frequent type. The typical lin- as multiple lesions [7, 8] and can be a feature
ing consists of a layer of nonkeratinizing glandular of Schopf-Schulz-Passarge syndrome [8, 9].
epithelium and a thin layer of myoepithelial cells. Histopathology reveals an unilocular or
a s urrounded by an outer layer representing myoepi-

thelial cells, while the inner layer frequently shows
the typical decapitation secretion. In some areas,
epithelial proliferations can be found (Fig. 8.2c).
Eccrine Hidrocystoma
A typical eccrine hidrocystoma of the eyelid
manifests in an adult as a solitary clear cystic
lesion (Smith and Chernosky type) [10], although
cases with simultaneous bilateral involvement
(Robinson type) [11] have also been reported
(Fig. 8.3a). The tumor is usually located along
the medial or lateral aspect of the eyelid. On aver-
age, eccrine hidrocystoma measures 4 mm in the
b largest dimension, and it is rare for them to be
larger than 10 mm [12]. Histologically, this tumor
probably just represents a markedly dilated sweat
gland duct with a presumably functional patho-
genesis (Fig. 8.3b). Myoepithelial cells and
decapitation secretion are absent (Fig. 8.3c).
Syringoma
Syringomas are common lesions on the upper
eyelids, especially in females. They usually pres-
ent as multiple small asymptomatic nodules
(2–3 mm) but show a wide variety of clinical pic-
c tures (Fig. 8.4a) [13]. Histology shows intercon-
necting eccrine ducts and strands, lined by two
layers of flattened cuboidal cells and sometimes
giving rise to the characteristic tadpole configu-
ration (Fig. 8.4b). Intracellular glycogen accu-
mulation can cause a clear cell variant.
Eccrine Spiradenoma
Eccrine spiradenomas are uncommon tumors
presenting as a mostly tender or painful subcuta-
neous nodule of fairly characteristic histology.
Sharply demarcated aggregations of basaloid
Fig. 8.2 Apocrine hidrocystoma. Note bluish color of the cells without connection to the dermis are
cystic lesion involving the eyelid margin (a). Histology arranged in a rosette-like fashion. Two types of
shows cyst lined by a single to double layer of epithelial
tumor cells can be distinguished: the more
cells, surrounded by flattened myoepithelial cells.
Proliferations of the epithelial lining are characteristic. peripheral small basophilic cells with round and
Typical decapitation secretion is also found (b). Note hyperchromatic nuclei and the more central cells
focal epithelial proliferation (c) with larger oval nuclei and a pale-staining eosin-
ophilic cytoplasm. Due to a rich vascular supply,
ultilocular cystic space (Fig. 8.2b) that is lined
m this tumor can resemble an angioma, hemangio-
by a single or double layer of epithelial cells, pericytoma, or glomus tumor.
8 Adnexal Tumors 75
a b
Fig. 8.3 Eccrine hidrocystoma. Note the gap between the cuboidal epithelium is double layered and the cells lack
tumor and the eyelid margin (a). There is the absence of decapitation (c)
papillary projections into the cystic cavity (b). The lining
a b
Fig. 8.4 Syringoma. Multiple syringomas of the lower eyelid in an older woman (a). The histopathology shows inter-
connecting eccrine ducts and stands which may present in a comma-shaped fashion (b)
leomorphic Adenomas (Benign

P ucinous Sweat Gland
M
Mixed Tumor) Adenocarcinoma
Pleomorphic adenomas (benign mixed tumor) Mucinous sweat gland adenocarcinoma is rare and
usually occur in the lacrimal or salivary glands shows a predilection for the eyelid and presents as a
but can also occur in accessory lacrimal glands of slowly growing flesh-colored, erythematous, or blu-
the eyelid. This lesion presents as a slowly grow- ish nodule [19]. It is locally aggressive and fre-
ing either firm or cystic subcutaneous nodule, quently recurs, but distant metastases are
usually solitary and asymptomatic. Histologically, uncommon. Histology shows islands of tumor cells
it is multilobulated and composed of a mixture of embedded in an abundant pool of mucin, separated
epithelial glandular elements embedded in myx- by fibrous septae. The tumor cells are cuboidal with
oid stroma [14]. The stromal component can a pink-staining, sometimes vacuolated cytoplasm
become very prominent, sometimes exhibiting a and round nuclei. Often a glandular differentiation
chondroid (pseudocartilaginous) and/or hyalin- is present, and sometimes light- and dark-cell forms
ized appearance [15]. can be distinguished. Immunohistochemistry sup-
ports an eccrine derivation.
Syringocystadenoma Papilliferum
Syringocystadenoma papilliferum is usually a sol- pocrine Gland Adenocarcinoma
A
itary lesion that presents as a grey to dark-brown (Carcinoma of the Glands of Moll)
papillary or warty excrescence which is clinically Apocrine gland adenocarcinoma (carcinoma of the
often mistaken for basal cell carcinoma or cyst glands of Moll) is rare and most documented cases
[16]. Although it can grow in an endophytic or have affected the axilla. Fewer than 10 cases have
exophytic fashion, histopathology characteristi- been described to arise from the glands of Moll in
cally shows superficially located papillae commu- the eyelid [20]. The clinical appearance is of a red-
nicating with duct-like structures in the deeper dish cystic nodular lesion located at the lid margin
aspect. The lining consists of the typical double- with a smooth surface (Fig. 8.5a). The tumor cells
layered epithelium with flattened myoepithelial reveal a variably glandular, papillary, or diffuse
cells at the outer zone and tall columnar cells at the growth, sometimes with cyst formation and necro-
inner zone [17]. Further entities such as eccrine sis, and decapitation secretion is a typical feature
acrospiroma, eccrine cylindroma, eccrine spirade- (Fig. 8.5b). Occasionally, intracytoplasmic diastase-
nocylindromas, and apocrine adenomas exist. resistant, periodic acid-Schiff-positive granules,
and intracytoplasmic iron can be demonstrated
while glycogen is negative. Normal apocrine glands
Malignant Tumors are often found in close proximity to the tumor, and
occasionally a preexisting apocrine adenoma may
weat Gland Adenocarcinomas
S be evident. Since primary cutaneous apocrine carci-
(Malignant Syringoma) noma is indistinguishable from metastatic mam-
Sweat gland adenocarcinomas (malignant syrin- mary ductal apocrine carcinoma, a careful breast
goma) most frequently affect the nasolabial and assessment should be advised especially in cases
periorbital region and present nonspecifically as where the diagnosis is questionable [21].
a slowly growing plaque-like lesion, sometimes
associated with hyperkeratosis [18]. Typically,
the margins are not well delineated, and some- Hair Follicle Tumors
times pain can be present due to perineural infil-
tration. Histology shows various features Benign Tumors
including small- to medium-sized squamous
microcysts, solid strands of cells with ductular Trichoepithelioma
lumina, and small solid infiltrative strands, all Trichoepithelioma is a hamartomatous lesion that
embedded in a dense fibrous stroma. may be solitary, multiple, or even familial [22].
8 Adnexal Tumors 77
a b
Fig. 8.5 Carcinoma of the glands of Moll in the eyelid. A reddish cystic nodular lesion located at the lid margin (a).
Histologically, there is a papillary growth of tumor cells with mitotic figures and atypia (b)
The typical histologic appearance shows numer- liculoma. A trichoepithelioma with prominent
ous horn cysts, partially within nests of basaloid desmoplastic stroma is categorized as desmo-
cells that are sometimes difficult to distinguish plastic trichoepithelioma.
from basal cell carcinoma. There can be continu-
ity with the epidermis while ulceration is exceed- Trichoadenoma
ingly rare. In trichoepithelioma, however, the Trichoadenoma is a rare tumor that occurs as a
perilobular connective tissue is more conspicu- solitary asymptomatic soft or firm nodule of
ous and is frequently associated with the forma- varying size and yellowish or erythematous color
tion of papillary mesenchymal bodies [23]. [26]. Under a normal epidermis, there is a well-
Occasionally, a foreign body giant cell reaction defined fibroepithelial tumor composed of kerati-
to free keratin and calcification is seen. nous cysts and a conspicuous fibrovascular
Trichoepithelioma shows less follicular differen- stroma. The cysts are lined by keratinizing epi-
tiation than trichofolliculoma [24]. thelium including a granular layer. Sometimes
solid epithelial islands are also present, but evi-
Trichofolliculoma dence of hair follicle formation is lacking.
Trichofolliculoma is a hamartoma presenting as a
single dome-shaped papule with a central pore. Trichilemmoma
Characteristic is the presence of one or more Trichilemmoma may be solitary or multiple and
silky white threadlike hairs growing out of this presents as a small warty or smooth skin-colored
opening [25]. A wide age range is affected, papule on the face of older adults (Fig. 8.5) [27].
although lesions are very rare in children. Solitary trichilemmoma represents a prolifera-
Histologically, this tumor consists of a cystic cav- tion of the follicular outer root sheath with close-
ity (dilated hair follicle) lined by stratified squa- set lobules connecting with the epidermis. There
mous epithelium usually continuous with the is usually peripheral nuclear palisading, but pleo-
surface epithelium. Arising from its wall are morphism and mitoses tend to be absent.
numerous hair follicles. Abortive pilar differenti- Intracellular glycogen can result in a conspicuous
ation, small primitive sebaceous acini, kerato- clear cell component. Another typical feature is a
cysts, stromal granulomatous inflammation dense PAS-positive mantle surrounding individ-
surrounding hair shaft fragments, and focal calci- ual tumor lobules. A variant with marked kerati-
fication are additional features. A variant of nization, squamous eddies, and surface
trichofolliculoma with numerous additional hyperkeratosis and parakeratosis is called kera-
sebaceous glands is called sebaceous trichofol- tinizing trichilemmoma [24]. Associated with the
presence of multiple trichilemmomas is the rare two different cell populations: small basophilic
autosomal dominant condition called Cowden’s basaloid cells and the characteristic and diagnos-
(multiple hamartoma) disease [28]. tic pale-pinkish ghost cells (Fig. 8.6b). Frequently,
calcification and a foreign body giant cell reac-
ilomatrixoma (Calcifying Epithelium
P tion are encountered, and occasionally melanin
of Malherbe) pigment is found. Even bone formation and amy-
Pilomatrixoma (calcifying epithelium of loid deposition may be features. Mitoses are seen
Malherbe) usually presents as a solitary lesion in early lesions but are not abnormal and simply
but can rarely be part of an autosomal dominantly indicate a rapid growth phase (Fig. 8.7) [31].
inherited disorder or a systemic disease such as
dystrophia myotonia or Gardner’s syndrome
[29]. It is a slowly growing hard nodule of bluish Malignant Tumors
or reddish tint and frequently located subcutane-
ously beneath the eyebrow (Fig. 8.6a). Most arcinoma of Hair Follicles
C
often teenagers and older adults in the sixth and (Trichilemmal Carcinoma)
seventh decades are affected [30]. Histology Carcinoma of hair follicles (trichilemmal carci-
reveals a well-circumscribed tumor consisting of noma) is a rare tumor that is found predominantly
a b
c d
Fig. 8.6 Trichilemmoma of the lower eyelid. A solitary and a surrounding hyline membrane. Adjacent to the
papule is located (clinically suspicious for basal cell car- lesion are hair follicles (b). The cells show a clear cell
cinoma) at the eyelid margin of an older lady (a). The component (c). Sclerotic stroma is also occasionally pres-
lesion shows a lobular architecture, peripheral pallisading, ent (d)
8 Adnexal Tumors 79
a b
Fig. 8.7 Pilomatrixoma. Bluish-reddish nodule on the upper lid (a). Histology shows an epithelioid island surrounded
by pinkish ghost/shadow cells and inflammation (b)
a b
Fig. 8.8 Sebaceous gland hyperplasia. Yellowish papule with a central umbilication (a). The histologic picture shows
conglomerates of regular sebaceous glands (b)
on sun-exposed skin of the elderly. The clinical Sebaceous Gland Tumors

presentation ranges from papule or a nodule to
plaque that often ulcerates. Usually, the lesion is Benign Tumors
erythematous or flesh colored and measures
between 5 and 20 mm in diameter. Despite a his- ebaceous Gland Hyperplasia
S
tologically worrying picture, recurrences and Sebaceous gland hyperplasia usually presents as a
metastases are absent. yellowish umbilicated papule 1–2 mm in size on
the face of older adults. Clinically, it can be mis-
Pilomatrix Carcinomas taken for basal cell carcinoma. Histopathologically,
This rare tumor has been described in middle- regular mature but hyperplastic sebaceous glands
aged patients [32]. However, only a few cases are seen that are situated rather superficially in the
have been observed in the ocular adnexa [33]. dermis while the epidermis is normal (Fig. 8.8).
ebaceous Gland Adenoma

S 3. Deprez M, Uffer S. Clinicopathological features of
eyelid skin tumors. A retrospective study of 5504
Sebaceous gland adenomas are rare and present cases and review of literature. Am J Dermatopathol.
as tan, yellow, or reddish papules/nodules about 2009;31(3):256–62.
5 mm in diameter, most frequently located on the 4. Warwick R, Williams PL. Gray’s anatomy. 35th ed.
face of older people (mean age: 60 years). Edinburgh: Longman Group Ltd; 1973. p. 1168–9.
5. Warwick R. Eugene Wolf’s anatomy of the and
Clinically, they can easily be misdiagnosed as orbit. 7th ed. London: H.K. Lewis & Co. Ltd; 1976.
basal cell carcinoma. Sebaceous gland adenoma p. 195–7.
in a younger person can be an indication for the 6. Smith JD, Chernosky ME. Apocrine hidrocystoma
Muir-Torre syndrome (Chap. 11) [34]. (cystademnoma). Arch Dermatol. 1974;109(5):700–2.
7. Sacks E, Jakobiec FA, McMillan R, et al. Multiple
bilateral apocrine cystadenomas of the lower eye-
Sebaceous Epithelioma/Sebaceoma lids. Light and electron microscopic studies.
Eyelid sebaceous epithelioma, or sebaceoma, is a Ophthalmology. 1987;94(1):65–71.
rare entity [35]. It clinically appears as a nodular 8. Alessi E, Gianotti R, Coggi A. Multiple apo-
crine hidrocystomas of the eyelids. Br J Dermatol.
tumor, e.g., on the eyelid margin [36]. 1997;137(4):642–5.
Histologically basaloid cells and vacuolated 9. Verplancke P, Driessen L, Wynants P, et al. The
sebaceous cells without cellular atypia are found. Schopf-Schulz-Passarge syndrome. Dermatology.
Cells with sebaceous differentiation can be high- 1998;196(4):463–6.
10. Smith JD, Chernosky ME. Hidrocystomas. Arch
lighted immunohistochemilly by adipophilin Dermatol. 1973;108(5):676–9.
staining. Sebaceomas can be also associated with 11. Robinson R. Hidrocystoma. J Cutan Genitourinary
Muir-Torre syndrome [37]. Some authors con- Dis. 1893;11:293–303.
sider this lesion a variant of basal cell carcinoma, 12. Singh AD, McCloskey L, Andrew Parsons M,
et al. Eccrine hidrocystoma of the eyelid. Eye.
i.e., a basal cell carcinoma with sebaceous dif- 2005;19:77–9.
ferentiation [38]. 13. Lee SJ, Cho S, Cho SB. Syringomas versus sebaceous
gland prominence of the eyelids. J Cosmet Laser Ther.
evus Sebaceous of Jadassohn
N 2011;13(3):130–1.
14. Alyahya GA, Stenman G, Persson F, et al. Pleomorphic
Nevus sebaceous of Jadassohn is a complex cho- adenoma arising in an accessory lacrimal gland of
ristoma comprising abnormalities of the hair fol- Wolfring. Ophthalmology. 2006;113(5):879–82.
licles, sweat glands, sebaceous glands, and 15. Jordan DR, Nerad JA, Patrinely JR. Chondroid
epidermis [39]. All of these tissues can prolifer- syringoma of the eyelid. Can J Ophthalmol.
1989;24(1):24–7.
ate and can constitute the major part of the tumor. 16. Barbarino S, McCormick SA, Lauer SA, et al.
Malignant transformation of any of the compo- Syringocystadenoma papilliferum of the eyelid.
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the most frequent [40]. 17. Behera M, Chatterjee S. A case of syringocystad-
enoma papilliferum of eyelid with literature review.
Indian J Ophthalmol. 2015;63(6):550–1.
18. Esmaeli B, Ramsay JA, Chorneyko KA, et al.
Malignant Tumors Sclerosing sweat-duct carcinoma (malignant syrin-
goma) of the upper eyelid: a patient report with immu-
nohistochemical and ultrastructural analysis. Ophthal
ebaceous Gland Carcinoma
S Plast Reconstr Surg. 1998;14(6):441–5.
Sebaceous gland carcinoma is covered in a sepa- 19. Boynton JR, Markowitch W Jr. Mucinous eccrine
rate chapter (Chap. 6). carcinoma of the eyelid. Arch Ophthalmol.
1998;116(8):1130–1.
20. Paridaens D, Mooy CM. Apocrine sweat gland carci-
noma. Eye (Lond). 2001;15(Pt 2):253–4.
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Accuracy of clinical diagnosis of cutaneous eyelid 22. Aurora AL. Solitary trichoepithelioma of the eyelid.
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2. Margo CE. Eyelid tumors: accuracy of clinical diag- 23. Brooke JD, Fitzpatrick JE, Golitz LE. Papillary
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differentiating trichoepitheliomas from basal cell 32. Jones C, Twoon M, Ho W, et al. Pilomatrix carci-
carcinomas. J Am Acad Dermatol. 1989;21(3 Pt noma: 12-year experience and review of the literature.
1):523–8. J Cutan Pathol. 2018;45(1):33–8.
24. Tellechea O, Cardoso JC, Reis JP, et al. Benign follic- 33. Cahill MT, Moriarty PM, Mooney DJ, et al.
ular tumors. An Bras Dermatol. 2015;90(6):780–96; Pilomatrix carcinoma of the eyelid. Am J Ophthalmol.
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25. Carreras B Jr, Lopez-Marin I Jr, Mellado VG, et al. 34. Singh AD, Mudhar H, Bhola R, et al. Sebaceous
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26. Shields JA, Shields CL, Eagle RC Jr. Trichoadenoma 35. Mittal R, Tripathy D. Sebaceoma of the eyelid: a rare
of the eyelid. Am J Ophthalmol. 1998;126(6):846–8. entity. Can J Ophthalmol. 2014;49(3):e78–80.
27. Hidayat AA, Font RL. Trichilemmoma of eyelid and 36. Yonekawa Y, Jakobiec FA, Zakka FR, et al. Sebaceoma
eyebrow. A clinicopathologic study of 31 cases. Arch of the eyelid. Ophthalmology. 2012;119(12):2645
Ophthalmol. 1980;98(5):844–7. e1–4.
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disease. Ophthalmology. 1988;95(8):1038–41. plasms as markers of Muir-Torre syndrome: a diag-
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Arch Ophthalmol. 1963;70:399–406. skin with clinical correlations. London: Mosby; 1996.
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Stromal Tumors
9
Geeta K. Vemuganti and Santosh G. Honavar
Fibrous Tissue Tumors Histopathologic Features

A typical fibroma is sparsely cellular with promi-
Fibrous tissue tumors comprise several benign nent collagen bundles separated by compressed
lesions (fibroma, keloid, nodular fasciitis, and fibroblasts. Rarely it can present as multiple
proliferative fasciitis), fibromatosis, and a malig- lesions in the eyelid and face [3]. A characteristic
nant tumor (fibrosarcoma). feature is the lack of inflammation without zonal
pattern. Pleomorphic fibroma is a variant with
multinucleate giant cells.
Fibromas
Clinical Features Eyelid Keloids

Fibromas are rare tumors that could be congeni-
tal, developmental, or acquired [1]. Congenital Eyelid keloids are hypertrophic cutaneous scars or
fibroma presents as a diffusely infiltrative lower nodular outgrowths on the surface or the margin of
eyelid nodule that recurs following local exci- the eyelid that follow surgical intervention or trauma
sion. The histologic and electron-microscopic and could occur de novo. Rarely could keloids arise
features point to the hamartomatous origin of this from the tarsus and simulate a tumor [4].
tumor with partial myofibroblastic differentiation
[1]. Developmental fibroma has a propensity for
involvement of the infraorbital region and lower Nodular Fasciitis
eyelid and is diffusely infiltrative. Recurrence
often follows local excision [2]. Nodular fasciitis is, in general, a relatively com-
mon benign reactive fibroblastic proliferation of
the soft tissues with acute manifestations that
progress rapidly.
G. K. Vemuganti (*)
School of Medical Sciences, University Clinical Features
of Hyderabad, Hyderabad, Telangana, India
e-mail: gvmd@uohyd.ernet.in
Nodular fasciitis of the eyelid is rare and only
case reports have been published. It presents with
S. G. Honavar
Department of Ophthalmic Plastic Surgery and
a solitary subcutaneous nodule [5]. Although
Ocular Oncology, Centre for Sight, excisional biopsy is curative, the nodules may
Hyderabad, Telangana, India often resolve spontaneously [5].

84 G. K. Vemuganti and S. G. Honavar
Histopathologic Features a
Nodular fasciitis is an infiltrative lesion consist-
ing of proliferation of immature and activated
fibroblasts, with slit-like spaces between the
cells. Foci of myxoid change, endothelial prolif-
eration, lipid-laden macrophages, multinucleated
giant cells, and acute and chronic inflammatory
cell infiltration are also seen. Ultrastructurally,
the cells show characteristic features of myofi-
b
broblasts. Clinical presentation and histologic
appearance of a pleomorphic spindle cell neo-
plasm with frequent mitotic figures may raise the
concern of a malignant neoplasm and lead to
unnecessary and overly aggressive therapy. The
lesion is therefore called pseudosarcomatous
fasciitis.
Fibromatosis
Fibromatosis could be juvenile or adult onset.

Juvenile fibromatoses are a distinct group of
benign fibrous lesions with aggressive clinical
behavior and predilection to occur in the lower Fig. 9.1 Eyelid fibromatosis. A 6-month-old child with a
tethering of the eyelid to a deeper firm mass in the supero-
eyelid and inferior orbit [6]. Infiltration of the
nasal aspect with consequent lagophthalmos (a).
local tissues including extraocular muscle and Histopathology examination shows infiltrating bundles of
periosteum results in incomplete removal and spindle cells with lobulated pattern in few areas diagnostic
local recurrence (Fig. 9.1). of fibromatosis (b, hematoxylin and eosin, original mag-
nification ×200)
Fibrosarcoma
Histopathologic Features
Fibrosarcoma is a highly malignant tumor that The lesion consists of closely packed cells that
can be locally destructive and can metastasize. assume an interlacing woven herringbone pat-
tern. The cells contain a vesicular nucleus with
Clinical Features prominent nucleoli, tapering pointed ends with
It manifests as a rapidly progressive poorly cir- moderate mitotic activity.
cumscribed eyelid nodule or as a second malig-
nant neoplasm in hereditary retinoblastoma
survivors with or without prior radiotherapy [7]. Fibrohistiocytic Tumors
Rarely, it could occur in children with local
recurrences which could be managed conserva- Fibrohistiocytic tumors could be subclassified as
tively. Wide surgical excision or orbital exenter- benign (xanthelasma, xanthoma, dermatofibroma,
ation may minimize the risk of local tumor xanthogranuloma, juvenile xanthogranuloma,
recurrence [7]. reticulohistiocytoma), intermediate (atypical
9 Stromal Tumors 85
fibroxanthoma, dermatofibrosarcoma protuber- a

ans, angiomatoid fibrous histiocytoma), and
malignant (malignant fibrous histiocytoma,
malignant fibroxanthoma).
Xanthelasma
Xanthelasma palpebrarum is a common bilateral b

subcutaneous lesion of the eyelid seen in nor-
molipemic individuals and in those with primary
hyperlipidemia (types II and III) or secondary
hyperlipidemia (diabetes mellitus, biliary cirrho-
sis) [8]. It was found that alteration in apolipo-
protein levels in patients with xanthelasma may
predispose to cutaneous and systemic depositions
of lipids, including atherosclerosis [9].
Clinical Features
Xanthelasma manifests as a yellowish-tan soft
plaque occurs in the inner canthus in middle-
aged individuals (Fig. 9.2). Large nodular xan-
thelasma is called xanthoma or tuberous Fig. 9.2 Xanthelasma. Bilateral yellowish placoid
xanthoma, which has a known association with lesions clinically diagnostic of xanthelasma (a). Sheets of
Erdheim–Chester disease. Acute-onset eruptive large, foamy lipid-laden cells on histopathology (b, hema-
xanthoma occurs in patients experiencing a rapid toxylin and eosin, original magnification ×400)
rise in serum triglyceride levels. Management
should include systemic evaluation for the caus-
ative etiology and excision or laser [10] or Clinical Features
radiofrequency-
assisted vaporization of large Juvenile xanthogranuloma of the eyelid may be a
cosmetically unacceptable lesions [11]. part of systemic affection seen as multiple fleshy
superficial eyelid nodules with or without coex-
Histopathologic Features isting conjunctival, iris, and orbital involvement.
Microscopically, xanthelasma consists of lipid- The adult variant may be diffuse and associated
laden macrophages in the superficial dermis, with bronchial asthma (Fig. 9.3) [12]. Juvenile
around blood vessels, and adnexa. xanthogranuloma is known to spontaneously
involute, thus qualifying for observation.
Systemic corticosteroids are indicated in recalci-
Xanthogranuloma trant juvenile xanthogranuloma and as primary
therapy for the adult variant [12]. Extensive, cos-
Xanthogranuloma is an idiopathic inflamma- metically disfiguring, and steroid-resistant
tory granuloma with juvenile and adult variants lesions could be excised or treated with systemic
[12, 13]. chemotherapy or radiotherapy.
a recurrent pyogenic granuloma [14, 15].

Dermatofibrosarcoma protuberans, which mani-
fests as a rapidly growing eyelid nodule, is consid-
ered an aggressive form of malignant fibrous
histiocytoma. It has tendency for local invasion and
is known to metastasize. The mainstay of treatment
is complete surgical excision with wide margins.
Because of risk of recurrence following excision,
consideration should be given to histologic margin
b control and adjuvant radiotherapy [16].
Malignant fibrous histiocytoma differs from
benign variant in exhibiting marked nuclear pleo-
morphism, high mitotic activity, pericytoma-like
areas with foci of xanthoma cells, and multinu-
cleated giant cells.
Lipomatous Tumors
Lipoma, lipoma variants, and liposarcoma are the

lipomatous tumors affecting the eyelid [17].
Fig. 9.3 Adult-onset xanthogranuloma presenting as a

diffuse eyelid mass with a yellowish haze (a). Sheets of
foamy histiocytes and classic Touton type of multinucle- Lipoma and Lipoma Variants
ated giant cells with wreath-like arrangement of the nuclei
on histopathology (b, hematoxylin and eosin, original Lipoma could be congenital or acquired.
magnification ×250) Nasopalpebral lipoma–coloboma syndrome is an
autosomal dominant syndrome characterized by
congenital upper eyelid and nasopalpebral lipo-
Histopathologic Features mas, upper and lower eyelid colobomas, telecan-
Xanthogranuloma consists of monomorphic thus, and maxillary hypoplasia [18]. Lipoblastoma
infiltrate of histiocytes, intermixed with lympho- is an uncommon benign tumor of adipose tissue
cytes and the classic Touton giant cell with a that occurs in infants and young children [19].
wreath-like arrangement of nuclei and peripheral Intramuscular lipoma of the eyelid manifesting
clear zone. as a slowly growing globular lesion has been
described in elderly individuals. Hibernoma is a
variant of lipoma that contains embryonal brown
Malignant Fibrous Histiocytoma fat and is relatively more vascular. If treatment is
indicated for cosmetic and functional reasons,
Malignant fibrous histiocytoma is a pleomorphic complete tumor excision is adequate.
soft tissue sarcoma that occurs rarely in the
eyelid.
Liposarcoma
Clinical Features
Malignant fibrous histiocytoma presents as a Primary liposarcoma is a rare orbital tumor that
firm subcutaneous mass, sometimes mimicking a may involve the eyelid by local extension.
9 Stromal Tumors 87
Smooth Muscle Tumors Nevus Flammeus (Port-Wine Stain)
Smooth muscle tumors of the eyelid are very rare Nevus flammeus is a diffuse congenital vascular
and could be benign (leiomyoma, angiomyoma) malformation of the face, involving the periocu-
[20] or malignant (leiomyosarcoma) [21]. lar area and eyelid (Chap. 11).
Skeletal Muscle Tumors Pyogenic Granuloma
Rhabdomyoma and rhabdomyosarcoma are the Papillary endothelial hyperplasia or “pyogenic

skeletal muscle tumors of the eyelid. granuloma” is the most common acquired vascu-
lar lesion of the eyelid. It is neither “pyogenic”
nor “granuloma.”
Rhabdomyoma
Clinical Features
Rhabdomyoma is a benign tumor of the skeletal Pyogenic granuloma occurs anywhere in the eye-
muscle and is seen in two forms. The adult form lid, as a rapidly growing, pedunculated reddish-
consists of well-differentiated large rounded or pink mass with or without superficial ulceration
polygonal cells with abundant acidophilic cyto- and may easily bleed on touch (Fig. 9.4). It usu-
plasm containing lipid and glycogen. Some cells ally follows trauma or surgery. Local excision of
appear like spider cells and some may show the lesion is curative [24].
cross striations. The fetal form is very cellular
and consists of immature skeletal muscle fibers Histopathologic Features
and primitive mesenchymal cells. One case of Pyogenic granuloma consists of exuberant mass
adult-onset rhabdomyoma attributed to chronic of proliferating radiating capillaries and edema-
irritation by a prosthetic eye has been reported in tous stroma with mixed inflammatory infiltrates.
the literature [22]. Intravascular papillary endothelial hyperplasia is
a rare form of “pyogenic granuloma” in which
the angiomatous proliferation is confined entirely
Rhabdomyosarcoma within the lumen of a vessel [25].
Rhabdomyosarcoma is primarily a malignant

orbital tumor with eyelid involvement only in Capillary (Infantile) Hemangioma
about 3% of cases [23].
Capillary hemangioma of the eyelid is the most
common vascular tumor of the eyelid in children
Vascular Tumors (Fig. 9.5). It is usually congenital in origin and is
often sporadic. Occasional reports of acquired
Benign vascular tumors of the eyelid include capillary hemangiomas have been reported in
nevus flammeus, papillary endothelial hyperpla- adults. Newborns of mothers who have under-
sia, capillary hemangioma, cavernous hemangi- gone amniocentesis and in premature infants are
oma, venous hemangioma, epithelioid at a risk of developing capillary hemangioma
hemangioma, arteriovenous malformation, and [26]. The pathogenesis of this tumor is not well
lymphangioma. Angiosarcoma, lymphangiosar- understood, but the affected infants have an
coma, and Kaposi’s sarcoma are the malignant increased urinary level of basic fibroblastic
vascular eyelid tumors. growth factor, a marker of angiogenesis. Familial
a a
Fig. 9.5 Capillary hemangioma of the upper eyelid man-

ifesting as a bright red, spongy, soft mass causing total
ptosis (a). It resolved following treatment with intrale-
sional triamcinolone injection (b)
Fig. 9.4 Pyogenic granuloma. The tarsal conjunctiva of
the upper eyelid showing a vascular polypoidal reddish-
pink mass with superficial ulceration (a). subcutaneous tissue and is bluish or blue-gray in
Histopathologically, loose edematous stroma with surface color.
necrosis, proliferating blood vessels, and mixed inflam-
matory infiltrates, characteristic of inflammatory granula-
tion tissue, is present (b, hematoxylin and eosin, original Natural History
magnification ×200) Congenital capillary hemangioma grows rapidly
in size and reaches its final size by 6–12 months
of age. It then becomes stable and slowly invo-
congenital capillary hemangioma with autosomal lutes by 4–7 years of age [28]. About 70% regress
dominant inheritance with incrimination of chro- by the age of 7 years [28].
mosome 5q has been reported [27].
Clinical Features Histologically, capillary hemangioma of the eye-
Congenital capillary hemangioma usually mani- lid consists of lobules of capillaries separated by
fests at birth or within the first months of life. sparse fibrous septae. The morphology of the
There are two distinct clinical variants – superfi- lesion changes with age. An early immature
cial and deep. The superficial variant, better lesion tends to have obliterated lumen with plump
known as strawberry hemangioma, appears as a endothelial cells and occasional mitotic figures
bright red to deep purple, lobulated, spongy, soft (Fig. 9.6), while in later stages the lumina
eyelid mass that typically blanches on the appli- increases and the endothelial cells get attenuated,
cation of direct pressure and engorges when the with increasing fibrosis and fat infiltration. The
infant cries or strains. Contiguous conjunctival lobular capillary hemangioma show repeating
and orbital extension is known to occur. The units of various sizes (lobules) consisting of
superficial variant is localized to the epidermis CD34-positive, GLUT-1-negative endothelial
and dermis, whereas the deep variant lies in the cells and SMA-positive pericytes arranged in
9 Stromal Tumors 89
a b
Fig. 9.6 An older child with a large red vascular mass in by plump endothelial cells. Note the presence of a few
the upper eyelid (a) that was excised. Histopathology mitotic figures could be seen in proliferating lesions (b,
shows lobulated appearance with vascular channels lined hematoxylin and eosin, original magnification ×400)
macro- or micro-lobules. Some foci may exhibit Extensive lesions are treated with oral predniso-
ectatic vessels or diffuse nonlobular capillary lone 1–2 mg/kg body weight tapered over
proliferations [29]. 4–6 weeks. Application of topical clobetasol pro-
pionate [29] and timolol maleate [30] may help.
Systemic Association Intralesional steroid injection (Fig. 9.5) is mainly
In most instances, congenital capillary hemangi- reserved for eyelid and anterior orbital lesions.
oma is a sporadic condition, but approximately Most lesions regress after 1–3 injections of triam-
20% of patients may manifest it as multiple cinolone or a combination of dexamethasone and
tumors involving the cutaneous tissue elsewhere, triamcinolone injected at 6–8 weekly intervals
central nervous system, liver, and gastrointestinal [31]. The recommended dosage per injection is
tract [26]. Systemic lesions, especially those 6 mg/kg body weight equivalent of prednisolone.
found in association with Kasabach–Merritt syn- Although uncommon, reported complications of
drome, could aggressively proliferate and lead to intralesional steroid injection include central reti-
hemorrhage, platelet consumption, disseminated nal artery occlusion, eyelid depigmentation, fat
intravascular coagulation, cardiac failure, and atrophy, eyelid necrosis, and adrenal suppression
death [26]. [31]. Alternative treatment modalities include
interferon, laser sclerotherapy, and excision of
Treatment circumscribed anterior lesions (Fig. 9.6).
The main ocular complications are amblyopia In recent years several centers have reported
and strabismus. Amblyopia could be meridional the use of systemic β-blockers for the treatment
because of induced astigmatism or because of of infantile hemangioma, with very promising
stimulation deprivation secondary to mechanical results (Fig. 9.7) [32–34]. The dose that has
ptosis. Because most lesions spontaneously been used is 0.5–2.0 mg/kg/day for several
regress, observation, refractive correction, and months, with significant reduction in the size of
appropriate amblyopia management are the stan- the hemangioma in all babies. Side effects such
dard treatment. Active intervention is indicated if as bradycardia, hypotension, bronchospasm,
the lesion extensively involves the face or is hypoglycemia, and electrolyte disturbances
ulcerated with episodes of bleeding and if there is have been reported, leading to a reduction in the
mechanical ptosis with obscuration of pupillary dose of the drug. Topical timolol maleate 0.5%
axis or induced astigmatism with amblyopia. was also found to be effective [35].
a both clinical and histopathologic features with

angiolymphoid hyperplasia with eosinophilia
and may be clinically indistinguishable [38].
Cavernous hemangioma is composed of large
dilated vascular channels filled with blood, hemo-
siderin-laden macrophages, scattered lympho-
b plasmacytic infiltrates, and secondary changes
such as calcification, phlebolith, and fibrosis.
Arteriovenous Malformations
Arteriovenous malformations, as the name sug-

gests, are communications between arteries and
Fig. 9.7 Capillary hemangioma. A 10-month-old female
with history of failed intralesional steroid injection. After
veins that bypass normal capillary beds. In con-
pediatric cardiology examination, BP, EKG, and echocar- trast to arteriovenous fistulas, arteriovenous mal-
diogram, propranolol was started at 1 mg/kg/day in three formations are mainly congenital lesions with
divided doses daily (a, 11/11/2010), with a blood glucose multiple large feeding arteries, a central nidus,
level and repeat blood pressure check after the first dose
(blood pressure, taken in the left thigh 87/61; pulse 108;
and numerous dilated draining veins (Fig. 9.8).
glucose 80; about 2 h after the first increased dose). One Rarely, arteriovenous malformations may follow
week later (11/18/2010), the dosage was doubled to 2 mg/ trauma or surgery [39]. While surgical emboliza-
kg/day in three divided doses daily. BP, heart rate, and tion or excision alone may be possible, a com-
blood glucose were again checked about 2 h after the first
increased dose. No additional testing was performed for
bined approach is considered ideal [39].
increases above 2 mg/kg/day. Her dose was increased to
3 mg/kg/day (12/9/2010). After 3 months of treatment, the
infantile hemangioma had shown marked regression (b, Lymphangioma
2/10/11). The dose was then tapered to 1.5 mg/kg/day
(4/13/2011), 1 mg/kg/day (5/25/2011), 0.5 mg/kg/day
(6/15/2011), and finally discontinued on 7/1/2011. Lymphangioma commonly manifests in the orbit
No regrowth of infantile hemangioma was observed rather than in the eyelid. Eyelid lesion generally
represents the anterior extension of an orbital
lymphangioma [40].
Cavernous Hemangioma
Cavernous hemangioma of the eyelid is a rare, Angiosarcoma

acquired condition and is generally seen in adults
[36]. It may be associated with blue rubber bleb Angiosarcoma is an uncommon malignant vascu-
nevus syndrome [37]. lar eyelid tumor. It appears as a raised, reddish-
purple, or violaceous subcutaneous placoid
Clinical Features lesion, tan-colored nodules or a mass that tends
The lesions are ill circumscribed and bluish in to ulcerate and bleed spontaneously or with
color and may undergo slow progression. excessive edema mimicking a Morbihan disease
Epithelioid hemangioma also known as angio- or periorbital hematoma [41–43]. Angiosarcoma
lymphoid hyperplasia with eosinophilia occurs as most often develops de novo but may arise from
a nodular lesion in the eyelid. Kimura disease, preexisting benign vascular tumors such as nevus
which is predominant in Asian population, shares flammeus or irradiated lymphangioma. It is an
9 Stromal Tumors 91
a b
Fig. 9.8 Arteriovenous malformation. A lobulated soft histopathology (b, hematoxylin and eosin, original mag-
compressible upper eyelid lesion (a). Vascular channels of nification ×200)
varying sizes including medium-sized feeder vessels on
aggressive tumor that tends to recur locally and abnormally sensitive to high levels of cytokines
disseminate widely with a 5-year survival rang- seen in patients with AIDS [46]. Subsequent pro-
ing from 12% to 29% [44], although patients liferation and additional mutation result in clini-
with isolated eyelid involvement have a much cally apparent disease. Histopathologically,
better prognosis [45]. Kaposi’s sarcoma appears as a network of prolif-
erating endothelial cells that forms slit-like
spaces surrounded by spindle-shaped mesenchy-
Kaposi’s Sarcoma mal cells and collagen [46]. The tumor cells show
immunoreactivity to endothelial markers CD31
Kaposi’s sarcoma is a malignant vascular tumor and ERG (a subfamily of the ETS family tran-
that most often presents in the setting of associa- scription factors) and for human herpes virus
tion with acquired immunodeficiency syndrome HHV-8 [50].
(AIDS); it is the most common malignancy seen
in patients with AIDS [46]. However, it can also Treatment
occur in immunocompetent elderly males as well Improvement in immunological status and highly
[47, 48]. The possibility of occult AIDS should active antiretroviral therapy may result in sponta-
be entertained in a young individual with an atyp- neous regression of Kaposi’s sarcoma. Treatment
ical hordeolum or avascular eyelid mass as modalities include local methods such as exci-
Kaposi’s sarcoma sometimes mimics these sion, cryotherapy, and radiotherapy. Systemic
common lesions and represents the initial pre- chemotherapy is indicated for widespread dis-
senting sign of AIDS [46, 49]. ease [46]. Second-line paclitaxel given every
2 weeks has been reported to show complete
Clinical Features response [51].
Kaposi’s sarcoma appears as a solitary or multi-
focal, circumscribed or diffuse smooth blue sub-
cutaneous lesion. Perivascular Tumors
Histopathologic Features Perivascular tumors of the eyelid are very rare

Infection by human herpes virus 8 possibly trans- and include benign or malignant hemangioperi-
forms normal mesenchymal cells to become cytoma and glomus tumor.
Neurogenic Tumors malignant eyelid tumors and could be associated

with exposure to sun, immunosuppression or
Neurogenic tumors of the eyelid include a variety viruses [59]. A recent study has shown metastatic
of benign (neurofibroma, schwannoma, and neu- potential in 22% of cases specially those with
roglial choristoma) and malignant tumors (malig- nodal metastasis. It usually occurs in older
nant peripheral nerve sheath tumor and Merkel patients as a painless rapidly progressive vascular
cell tumor). purplish-red nodule of the upper eyelid [54, 55].
Neurofibroma On histopathology, the tumor cells are seen to
grow in interconnecting sheets and cords (trabec-
Neurofibroma of the eyelid could be plexiform, ular pattern). The individual cells are uniformly
multifocal, localized, or solitary and constitute round with scant cytoplasm, large oval nuclei,
nearly 70% of the peripheral nerve sheath tumors prominent nucleoli, and abundant mitotic figures.
of the oculoadenexal region [52]. In addition to synaptophysin, CD56, chromo-
granin, and nonspecific enolase, the tumor cells
are also immunoreactive for low molecular
Schwannoma weight cytokeratin 20 (CK20), a marker of
Merkel cell, which is now considered as a diag-
Schwannoma (neurilemoma) is one of the com- nostic feature [60].
mon benign peripheral nerve sheath tumors that
rarely grow on the eyelid. Clinically it appears as Treatment
a slow-growing well-defined firm subcutaneous Wide surgical excision with tumor-free margins
eyelid nodule that could simulate a large chala- by frozen section control achieves fair local con-
zion [53]. Solitary schwannoma lacks systemic trol, although recurrence and metastasis to
association. Multiple lesions, however, are asso- regional lymph nodes and viscera are not uncom-
ciated with neurofibromatosis type 1 [53]. mon [54–56, 61]. Adjuvant radiotherapy or
cyberknife surgery may help reduce the risk of
local recurrence if margins are suspect [62].
Merkel Cell Tumor Radiation, otherwise, is reserved for recurrent or
surgically unresectable tumors [54–56, 61].
First described in 1972, Merkel cell tumor is an Sentinel lymph node biopsy should be consid-
aggressive primary cutaneous neuroendocrine ered in cases of Merkel cell tumor of the eyelid
malignant neoplasm that arises from Merkel (Chap. 21) [63]. As per the AJCC eyelid carci-
cells, which are specialized neuroendocrine noma T classification, the disease-free state of
receptors of touch located in the eyelid and con- Merkel cell carcinoma correlates with its presen-
junctiva [54, 55]. Recent studies have implicated tation and is worse for patients with T2b or more
polyomavirus in pathogenesis of Merkel cell extensive tumors [59].
carcinoma [56, 57]. A rare occurrence was
reported in a patient of chronic rheumatoid
arthritis who was treated with tumor necrosis Lymphoid, Plasmacytic,
factor (TNF) inhibitor injection (golimumab) for and Leukemic Tumors
6 months [58].
Lymphoma represents about 13% of primary
Clinical Features malignant eyelid tumors [64]. In a recent muli-
Merkel cell tumor is rare, aggressive neuroendo- centric retrospective study, B-cell lymphoma is
crine malignancy of the skin comprising <3% of more common, of which extranodal marginal
9 Stromal Tumors 93
zone B-cell lymphoma of mucosa-associated a

lymphoid tissue is the most common type [65],
followed by follicular, diffuse large B cell lym-
phoma, Mantle cell lymphoma and Mycosis fun-
goides [66]. Worst outcomes are reported in
DLBCL and MC as compared to the EZML, FL,
and MF. Recurrence of this malignancy is more
closely related to treatment and histopathology
than to tumor size or site-specific location. It can
either be confined to the eyelid or have contigu- b
ous anterior orbital extension. It manifests as a
smooth, firm subcutaneous nodule. In contrast,
the less common T-cell lymphoma or mycosis
fungoides may present with skin infiltration and
ulceration simulating an infectious lesion.
Plasmacytoma, a tumor of plasma cell origin,
may rarely occur in the eyelid. It could be a pri-
mary extramedullary manifestation or with asso-
ciated multiple myeloma [67].
Leukemic infiltration of the eyelid presenting
as a nodular subcutaneous mass or as a diffuse
swelling can occur in patients with acute or
chronic leukemias [68]. It may even be the pri-
mary presentation in the form of granulocytic
Fig. 9.9 Rosai–Dorfman disease. An 18-year-old girl
sarcoma [39]. Relapse of leukemia in the eyelid with bilaterally symmetrical firm eyelid mass and with
is also known [68]. massive cervical lymphadenopathy and anemia (a).
Rosai–Dorfman disease is a distinct histio- Histopathology showing polymorphic population of cells
with characteristic histiocytes (arrow) showing lympho-
cytic disorder presenting with bilateral, painless,
phagocytosis (emperipolesis) (b, hematoxylin and eosin,
massive cervical lymphadenopathy with a pro- original magnification ×400)
tracted clinical course and in most instances
associated with fever, anemia, neutrophilia, ele-
vated erythrocyte sedimentation rate, and poly- Hamartomas, Choristomas,
clonal gammopathy [69]. Eyelid involvement is and Miscellaneous Tumors
one of the extranodal manifestations of the dis-
ease that is noted in 43% of these patients, pre- Dermoid could involve the eyelid as a contiguous
senting as unilateral, bilateral, or all four eyelids extension of an orbital or a conjunctival lesion. It
[70–72]. The other sites involved being skin, may, however, primarily involve the eyelid as a
nasal cavity and paranasal sinus, orbit, bone, and very rare manifestation. Cosmetically disturbing
salivary gland (Fig. 9.9) [73, 74]. The presence of and functionally significant dermoids are surgi-
benign histiocytes with emperipolesis, absence cally excised. Ectopic lacrimal gland in the eye-
of cellular atypia, immunohistochemical profile, lid may present in infancy or early childhood as a
and associated clinical features distinguish cystic mass with or without epiphora [75]. Often
Rosai–Dorfman disease from other simulating it may be a part of a complex choristoma [76].
disorder. Management options include observa- Heterotopic neuroglial tissue or neuroglial cho-
tion for mild manifestations with no cosmetic or ristoma could manifest as a congenital eyelid
functional abnormality, surgical excision or deb- mass. Its occurrence is usually associated with
ulking, and systemic corticosteroids [74]. other anomalies of cerebral organogenesis [77].
Phakomatous choristoma or Zimmerman’s References

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Surgical Techniques
10
Andrew J. Rong, Jennifer I. Hui, and David T. Tse
Introduction ing with surgical excision and reconstruction. If a

graft or flap is anticipated in the repair of the
The goals in the management of a malignant eye- defect, the surgical margins must first be evalu-
lid lesion are to establish an early accurate diag- ated microscopically to confirm tumor
nosis, to achieve a permanent cure by total eradication.
eradication of the tumor, and to preserve or If sebaceous cell carcinoma is suspected, a
restore both eyelid function and cosmesis. full-thickness excisional biopsy with 5 mm mar-
gins should be performed by removing a pentag-
onal wedge of anterior and posterior lamella [1].
General Principles Given the tumor’s propensity for pagetoid spread
and skip lesions, multiple carefully mapped biop-
Diagnostic Biopsy sies of the conjunctiva and tarsus should be con-
sidered for permanent section.
An eyelid lesion that exhibits clinical features
suggestive of malignancy should first undergo
biopsy to establish a definitive diagnosis. If the Definitive Treatment
lesion is small, an excisional biopsy including at
least a 2–3 mm margin of normal tissue should be Following histological confirmation of a malig-
considered. Following simple elliptical excision, nant lesion, definitive excision is pursued. Mohs’
the tissue margins of the specimen must be exam- micrographic surgery and excision with frozen-
ined histologically to confirm tumor clearance. If or permanent-section control yield high cure
the size of the anticipated excisional defect is rates [2]. The authors’ treatment of choice for
such that closure might cause eyelid malposition, primary periocular malignant eyelid lesions is
an incisional biopsy should first be considered to Mohs’ micrographic surgery followed by imme-
establish a pathologic diagnosis before proceed- diate reconstruction. The Mohs’ method allows
for maximal tissue conservation with careful
A. J. Rong · D. T. Tse (*) evaluation of surgical margins. First, the gross
Department of Oculofacial Plastic Surgery, Bascom mass of the tumor plus a small peripheral margin
Palmer Eye Institute, Miami, FL, USA of normal tissue is removed [2–6]. A thin layer of
e-mail: dtse@med.miami.edu tissue (2 mm) is further excised from the base and
J. I. Hui edges of the wound. The specimen is divided and
Oculofacial Plastic Surgery, The Eyelid Institute, placed on glass slides, and the edges are carefully
Palm Desert, CA, USA

98 A. J. Rong et al.
Fig. 10.1 Mohs’ Tumor excision Standard vertical frozen sections

micrographic surgery.
Frozen sections are
obtained from the
undersurface and skin
edges of the excised Specimen
lesion. Locations of
residual tumor are
marked on a map for
subsequent second stage
excision Horizontal frozen sections
marked with different-colored dyes to maintain • The eyelid is a bilamellar structure; the ante-
orientation. Frozen sections are obtained from rior lamella consists of the skin and orbicu-
the undersurface and skin edges; the locations of laris oculi muscle, and the posterior lamella of
residual tumor are mapped, and only those areas the tarsal plate and conjunctiva.
are subsequently re-excised (Fig. 10.1). Once • The anterior or posterior lamella must have its
tumor-free margins have been achieved, the ocu- own inherent blood supply.
loplastic surgeon reconstructs the eyelid defect • Provision must be made for maximal horizon-
on the same or the following day. tal stabilization with minimal vertical tension
through proper canthal fixation, and an epithe-
lialized internal surface to face the globe [8].
Sentinel Lymph Node Biopsy • Undermining should be sufficient to allow for
tension-free closure.
In a patient with a biopsy-proven malignant eye- • Identification of the transverse edge of the
lid lesion with demonstrated biological behavior levator aponeurosis and a knowledge of facial
for regional lymph node metastasis, careful eval- nerve anatomy are essential in maintaining the
uation of preauricular and submandibular lymph opening and closing functions of the eyelid.
nodes is essential. An additional consideration is
the use of lymphatic mapping and sentinel lymph
node biopsy for early accurate staging of solid Lower Eyelid Defects (Fig. 10.2)
tumors exhibiting a propensity for regional nodal
metastasis [7] (Chap. 21). nterior Lamellar Deficit,
A
Lid Margin Intact
Eyelid Reconstruction Primary Closure

In general, anterior lamellar defects without lid
Optimum functional and cosmetic outcomes are margin involvement may be closed primarily if
possible if the following general principles of this does not induce distortion. The wound is
eyelid reconstruction are taken into closed in two layers using deep, interrupted 5-0
consideration: or 6-0 Vicryl sutures and interrupted, superficial
10 Surgical Techniques 99
Fig. 10.2 Algorithm for

the repair of lower
eyelid defects Lower eyelid defects
Anterior lamellar defect, Full-thickness

margin intact eyelid defect
• Primary closure ± lateral

cantholysis Small (< 30%)
• Semicircular rotational flap • Primary closure ±
• Ellipse sliding flap lateral cantholysis
• Myocutaneous advancement
flap
Medium (30-50%)
• Myocutaneous advancement flap
• Free tarsal graft + myocutaneous
advancement / unipedicle
rotational flap
Large (> 50%)

advancement / unipedicle
rotational flap
• Periosteal strip + myocutaneous
advancement flap
• Hughes tarsoconjuctival flap +
free skin graft or myocutaneous
advancement flap
6-0 or 7-0 nylon or silk sutures in the skin. If Skin Graft

insufficient anterior lamella remains, a full- For defects that are too large to close primarily,
thickness pentagonal wedge, including the ante- full-thickness skin grafts from hairless areas may
rior lamellar defect, may be excised with Westcott be employed. Possible donor sites include the
scissors. The tarsal borders should be sharp and ipsilateral or contralateral upper eyelid, the pre-
perpendicular to the lid margin. The resulting auricular or retroauricular skin, and less com-
full-thickness defect may then be closed primar- monly the supraclavicular fossa and the upper
ily as described below. inner arm. In general, split-thickness skin grafts
are not recommended in eyelid reconstruction ered closure provides the best tissue match, a
[2]. If a skin graft is obtained from the upper smooth lid margin, and a continuous eyelash line.
eyelid or retroauricular area, it must be thinned of If tension is present and precludes proper lid mar-
subcutaneous fat and connective tissue. The graft gin reapproximation, a lateral canthotomy with
is then trimmed to size and sutured to the edges inferior cantholysis may be performed to yield
of the defect with interrupted 7-0 nylon or silk 5–6 mm of medial advancement of the temporal
sutures [9]. eyelid margin [9, 10].
The first step requires trimming of the eyelid
llipse Sliding Flap
E defect edges. The tarsal borders should be sharp
An elliptical sliding flap may also be used to and perpendicular to the lid margin. The tissue
close some anterior lamellar defects [10]. This inferior to the tarsus is cut into a wedge, forming
flap, however, should not be used to reconstruct a pentagonal-shaped defect. Direct closure may
anterior lamellar defects near the lid margin be utilized if the borders of this defect can be
because ectropion or retraction may be induced reapproximated without excess tension; other-
by excessive perpendicular tension. The ellipse wise, a lateral cantholysis is needed.
should be oriented parallel to the relaxed skin To perform a cantholysis, a 4–5 mm horizon-
tension lines. The long axis should be four times tal incision through the skin and orbicularis mus-
longer than the short axis, with the ellipse angle cle is made from the lateral canthal angle toward
at approximately 30°. The flap is secured in two the orbital rim. The tip of the Westcott scissors
layers. should be used to identify the lateral attachment
of the lower lid, and the inferior crus of the lateral
yocutaneous Advancement Flap
M canthal tendon is cut by making a vertical inci-
An ideal method to address a large anterior lamel- sion. The most important step in primary closure
lar deficit is the myocutaneous advancement flap of the pentagonal lid margin defect is precise
because it provides the best tissue match with an approximation of the tarsal edges. Accurate verti-
independent blood supply (Fig. 10.3). Incision cal alignment provides most of the tension-
lines should be oriented horizontally and blend bearing support of the wound. Following lid
within naturally occurring skin creases. Planes of margin reapproximation and repair of the tarsal
dissection should be determined before the defect as outlined in Fig. 10.4, the anterior
undermining is advanced past the lateral orbital lamella is closed in two layers.
rim [8, 9]. The flap consists of skin and muscle
and is designed to advance medially to fill an emicircular Rotational Flap
S
anterior lamellar defect. The creation of a myo- A lateral semicircular rotational flap may be used
cutaneous advancement flap begins with an to reconstruct up to two-thirds of a central lower
infralash incision that extends laterally to the lid defect if there is a sufficient temporal tarsal
canthus and arches superiorly. The key compo- remnant. The temporal tarsal remnant and a myo-
nent is a tension-bearing permanent suture (4-0 cutaneous flap are moved as a unit [9]. The first
Prolene) at the zygoma or the lateral orbital rim; step is to outline a semicircle, approximately
the flap is then closed in two layers. This tech- 20 mm in diameter, starting at the lateral canthal
nique provides an anterior lamella replacement angle. The outline should arc superiorly and tem-
with an inherent vascular supply. porally, but not pass the lateral extent of the brow.
In addition, a lateral canthotomy of the inferior
crus is performed with the scissors extending to
Full-Thickness Eyelid Defect the inside of the orbital rim. The lateral lower lid
and flap are moved medially until the lid margin
Primary Closure defect may be covered and closed without ten-
For small defects involving less than one-third of sion. Once the defect is closed, the lateral canthus
the lower eyelid margin, primary closure without is reformed. Fixation of the lateral edge of the flap
lateral cantholysis is the best option. Primary lay- is needed to provide posterior and lateral vector
a b
c d
Fig. 10.3 Myocutaneous advancement flap. A large ante- tension-bearing permanent suture (4-0 Prolene) at the
rior lamella deficit may be repaired with a myocutaneous zygoma or the lateral orbital rim is important in securing
advancement flap because it provides the best tissue the flap into position (c). Closure at the tip of the flap
match with an independent blood supply (a). A flap of suf- should be devoid of tension (d). The myocutaneous
ficient size that allows for tension-free closure is dissected advancement flap with its inherent vascular supply
from the underlying tissue (b). Proper placement of a now covers the anterior lamella defect (e)
Meibomian Meibomian
Eyelashes gland orifice Tarsus gland orifice
Tarsus
a b
Meibomian
gland orifice
Orbicularis
muscle
Fig. 10.4 Lid margin repair, full-thickness defect. The gin is closed with a vertical mattress suture using 6-0 silk
eyelid margin defect may be closed primarily if less than suture which provides proper anteroposterior alignment.
one-third of the margin is involved. An important step in A vertical lid margin suture induces puckering of the
primary closure of a full-thickness lid margin defect is the wound edges to avoid notching after healing (b). Two
precise approximation of the tarsal edges. Accurate verti- additional sutures, one posterior and another inferior to
cal alignment provides the tension-bearing support of the the lashes, are placed to align the lid margin. The three 6-0
wound. Three interrupted 5-0 Vicryl sutures are placed at silk sutures should be left long and secured away from the
partial thickness through the tarsal plate (a). The lid mar- wound onto the lower lid skin with a suture (c)
forces so that the reconstructed lower eyelid lies contralateral upper eyelid can be used for poste-
in apposition with the globe. The deep edge of the rior lamella replacement [10]. The graft provides
flap is sutured to the inner aspect of the lateral posterior lamellar support and a mucous mem-
orbital rim inferior to the superior crus using 4-0 brane lining for the reconstructed lower lid. A
Vicryl sutures. Finally, the conjunctival edge pre- myocutaneous advancement flap is then fash-
viously cut during the canthotomy is advanced ioned to provide blood supply to the free graft
superiorly and attached to the skin edge of the lat- (Fig. 10.5). This option is most appropriate for
eral lid margin with a running 7-0 Vicryl suture. patients whose involved eyelid is on the side of
the only seeing eye or who would not be able to
ree Tarsal Graft and Myocutaneous
F tolerate closure of the eyelids with a Hughes flap
Advancement Flap (see below).
For larger defects where primary closure is not The harvest of a free autogenous tarsal graft
possible, a free tarsal graft from the ipsilateral or first involves the placement of a 4-0 silk traction
a rior tarsal border determines the vertical height of

the graft. The incision is made through the con-
junctiva and full-thickness tarsus along the infe-
rior and vertical edges. Dissection is used to
separate the levator aponeurosis from the under-
lying tarsus. Mueller’s muscle and conjunctiva
are cut from the superior tarsal border, leaving
2 mm of conjunctiva attached to the graft. The
donor site is allowed to heal by secondary
intention.
The graft is secured into the defect with the
b conjunctival surface in contact with the globe and
the superior edge of the graft, with the conjuncti-
val remnant along the new lid margin. The medial
edges are secured with interrupted 5-0 Vicryl
sutures passed at partial thickness to avoid ocular
irritation. The superior edge is attached to the
superior forniceal conjunctiva and the edges of
Mueller’s muscle and levator aponeurosis using
interrupted 6-0 Vicryl sutures. The graft may sub-
sequently be covered with a vascularized myocu-
taneous advancement flap (similar to the
c
previously described rotational flap).
eriosteal Strip and Myocutaneous

P
Advancement Flap
The periosteal strip with myocutaneous advance-
ment flap is an alternative to the free tarsal graft
[9]. This method may be used to reconstruct the
lower lid when the lateral third of the tarsus is not
present. The periosteal strip may also be used in
combination with other procedures for larger
defects. When fashioning the periosteal strip, the
Fig. 10.5 Free tarsal graft plus myocutaneous advance-
ment flap. A full-thickness lower eyelid defect may be skin overlying the flap is first outlined with a
repaired with a free tarsal graft for posterior lamella marking pen in a semicircle or as a cheek flap
replacement and an overlying myocutaneous advancement extended 1–2 cm past the lateral commissure.
flap to provide vascular support (a). The free tarsal graft Once the skin–muscle flap is mobilized and
harvested from either the ipsilateral or the contralateral
upper eyelid provides posterior lamellar replacement (b). reflected, the lateral orbital rim is exposed. A
The myocutaneous advancement flap, fashioned in the rectangular strip of periosteum based at the inner
manner of a lower eyelid blepharoplasty, provides an inher- aspect of the rim is then formed. The strip should
ent blood supply to the underlying free tarsal graft. This be 1 cm wide, angled at 45° to follow the lower
figure demonstrates the key principle that either the recon-
structed anterior or posterior lamella must have its own lid contour. The distance from the lateral edge of
inherent vascular supply (pedicle flap), thus ensuring tissue the tarsal defect to the orbital rim determines the
survival and optimum surgical outcome for the patient (c) length. The fascia is dissected from the tempora-
lis muscle and separated from the bony rim with
suture through the central upper lid margin. The a periosteal elevator. The strip is reflected nasally
lid is everted to expose the tarsoconjunctival sur- to fill the tarsal defect. The anterior periosteum
face. The inferior edge of the graft is parallel to lies against the globe, and the distal end is secured
and 4 mm or more from the lid margin. The supe- to the lateral border of the remaining tarsus with
partial-thickness 5-0 Vicryl sutures. The strip advancement flap may be considered [9]. In this
thus provides posterior lamellar support for the procedure (Fig. 10.7), a tarsoconjunctival flap
reconstructed lower eyelid. The myocutaneous from the upper eyelid is passed behind the upper
advancement flap is then rotated and secured to eyelid margin remnant and advanced into the
fill the anterior lamellar defect. posterior lamellar defect of the lower eyelid. The
anterior lamella is then recreated with a skin
Free Tarsal Graft and Unipedicle Flap advancement flap or a free skin graft from the
from the Upper Eyelid preauricular or retroauricular area. The main dis-
A free tarsal graft with a unipedicle flap from the advantage is that the pupil remains covered for
upper eyelid is another method used to close full- 4–8 weeks by the tarsoconjunctival bridge. This
thickness lower eyelid defects. The free tarsal vascularized pedicle is severed and released in a
graft is first harvested. Next, a flap is harvested second procedure after the lower eyelid flap is
from excess upper lid skin and subcutaneous tis- revascularized.
sue, based at the lateral canthus (Fig. 10.6),
rotated inferiorly to fill the lower anterior lamel-
lar defect, and then closed in two layers. The uni-
pedicle flap may leave the patient with a lump of
tissue at the lateral canthus. If necessary, a sec-
ond procedure may be undertaken 6–8 weeks
later to thin the base of the flap and remove this
excess tissue.
arsoconjunctival (Hughes) Flap

T
and Free Skin Graft or Myocutaneous
Advancement Flap
For large defects involving more than 50% of the Fig. 10.6 Unipedicle flap. A unipedicle flap from the
eyelid margin, a tarsoconjunctival flap (Hughes upper eyelid with an inherent vascular supply is used to
flap) with a free skin graft or myocutaneous replace an anterior lamella defect in the lower eyelid
a b
Fig. 10.7 Hughes tarsoconjunctival flap. With the upper gin. All incisions are made through conjunctiva and tar-
eyelid everted over a retractor, a three-sided flap is created sus. The Muller’s muscle is dissected off the conjunctiva
in the central tarsal conjunctiva of the upper eyelid. The and remains in the upper eyelid proper (a). The tarsocon-
horizontal incision should be at least 4 mm from the lid junctival flap is mobilized into the lower lid defect to align
margin to avoid entropion, lid margin contour deformity, the upper lid superior tarsal border with the lower lid mar-
loss of lashes, and trichiasis. The vertical incisions course gin remnant (b)
up toward the superior fornix perpendicular to the lid mar-
Upper Eyelid Defects (Fig. 10.8) Skin Graft

For larger defects not involving the lid margin, a free
nterior Lamellar Deficit,
A full-thickness skin graft may be employed [8, 9].
Lid Margin Intact
llipse Sliding Flap
E
Primary Closure An elliptical sliding flap is a technique used to
As in the case of the lower eyelid, small defects close some anterior lamellar defects, as described
may be closed primarily if lid distortion will not in the section on lower eyelid defects [9]. The
be induced. If insufficient anterior lamella main advantage of this flap is the ability to repair
remains, a full-thickness pentagonal wedge may an anterior lamellar defect without sacrificing
be used. significant amounts of normal tissue.
Fig. 10.8 Algorithm for

the repair of upper
eyelid defects Upper eyelid defects
Anterior lamellar defect, Full-thickness eyelid defect

margin intact
• Primary closure ± lateral

cantholysis Small (< 30%)
• Semicircular rotational flap • Primary closure ±
• Ellipse sliding flap lateral cantholysis
• Myocutaneous advancement
flap
Medium (30-50%)
• Semicircular rotational flap +
myocutaneous advancement flap
advancement flap
Large (> 50%)

advancement flap
• Cutler Beard tarsoconjunctival
flap + free skin graft or
myocutaneous advancement flap
yocutaneous Advancement Flap

M arsoconjunctival Flap (Cutler–Beard
T
As with lower lid defects, a myocutaneous Flap) and Free Skin Graft or
advancement flap may also be used. Flaps pro- Myocutaneous Advancement Flap
vide the best tissue match, the best cosmetic The Cutler–Beard procedure is a less commonly
result, and an inherent vascular supply. used, two-stage method of closing large, full-
thickness upper eyelid defects involving more than
50% of the lid margin. The procedure is similar to
Full-Thickness Eyelid Defect the Hughes flap. It involves the advancement of a
lower eyelid flap, consisting of skin and muscle
Primary Closure (anterior lamella) and conjunctiva, behind the
Central upper lid defects – up to 30% in younger lower eyelid margin remnant into the defect of the
patients and 50% in older patients – may be upper eyelid. The main disadvantage of the proce-
closed using the same technique as in the lower dure is the creation of a thick, relatively immobile
lid. The main difference is that the vertical height upper eyelid without tarsal support. Modifications
of the tarsus is two to three times longer than that to the Cutler–Beard approach include combining it
of the lower lid. Also, the levator aponeurotic with a myocutaneous advancement flap, when
attachments should not be disturbed, so as to there are no alternative methods of closing the
avoid postoperative ptosis. If necessary, lateral defect [8, 9].
cantholysis may provide 3–5 mm of medial
mobilization of the remaining lateral eyelid
margin. Special Circumstances (Fig. 10.9)
emicircular Rotational Flap

S Medial Canthal Defect
Up to half of the medial or central upper lid may
be reconstructed with primary closure and a lat- edian Forehead Flap
M
eral semicircular or myocutaneous flap, similar to The median forehead flap is a unipedicle flap
that described for the lower lid [9]. The first dif- used to close large anterior lamellar defects of the
ference is an inferiorly, not superiorly, arching lower eyelid and medial canthus (Fig. 10.10) [8].
semicircle flap. The second is that the superior, The flap is based on the axis of the contralateral
not inferior, crus of the lateral canthal tendon supraorbital neurovascular bundle. Following
should be lysed. 120–180° of rotation into the defect, the flap is
secured with a two-layered closure. It may be
ree Tarsal Graft and Myocutaneous
F combined with other rotational flaps for very
Advancement Flap large defects.
With larger defects, a free tarsal graft with a myo-
cutaneous advancement flap may be needed [9]. Glabellar Flap
A free tarsoconjunctival graft may be harvested Medial canthal defects may also be repaired with
from the contralateral upper eyelid. Once the flap a glabellar flap, which is a modified V–Y rotation
is secured, the conjunctival remnant is advanced flap [8] in the shape of an inverted V, which begins
anteriorly and secured to the inferior flap skin at the midpoint of the glabella just above the brow,
edge with a running 7-0 Vicryl suture to reestab- with an angle of less than 60°. Following rotation
lish the mucocutaneous junction. Finally, the into the defect, the apex is placed at the lateral
superior eyelid must be immobilized and kept on edge and the point at the inferior tip. Finally, the
stretch to minimize postoperative retraction. A donor site is sutured in a V–Y closure which may
temporary 4-0 silk suture is tied over bolsters and induce a shortening of the interbrow distance.
placed on inferior traction. This flap may require secondary debulking.
Special circumstances
Medial canthal Insufficient posterior Insufficient anterior Insufficient vascularized

defects lamella lamella pedicle
• Glabellar flap • Tarsoconjunctival graft Tissue expansion • Galeopericranial flap

• Median forehead flap • Hard palate graft • Pericranial flap
• Rhombic flap • Nasal cartilage graft
• Ear cartilage graft
• Donor sclera
Fig. 10.9 Algorithm for surgical repair in special circumstances
a b
Fig. 10.10 Median forehead flap. This patient has a large into the area of deficient tissue (b). The large forehead
forehead and right-sided medial canthal defects following defect is not amenable to primary closure; thus it may be
excision of two lesions in these respective areas (a). The repaired with a free skin graft. This case illustrates the
medial canthal defect is repaired by rotating a median simultaneous use of two reconstructive options to correct
forehead flap, with its own inherent vascular supply, down two disparate defects (c)
a b
Fig. 10.11 Rhombic flap. First, the defect is made into a sides of the rhombus. Further lines are marked from the
rhombus by marking two lines parallel to the lines of max- end of the previous mark at a 60° angle parallel to the
imum extensibility (LME) (a). These LME are oriented sides of the rhombic defect. Of the four possible flaps that
perpendicular to the relaxed skin tension lines (RSTL). are designed, only one of the two flaps oriented to close
The first rhombic flap is made by placing two more paral- the donor site along LME, which causes the least interfer-
lel lines equal in length to and tangential to the defect at ence with surrounding structures, should be chosen. With
either 60° or 120° to the first set of lines while sacrificing medial rotation, this flap is advanced into the defect so
the minimal amount of normal tissue possible. Next, a line that point B aligns with medial point of the defect and
is drawn from each end of the shorter diagonal that bisects point A is placed in the inferior apex (b)
the 120° angle. This line should be equal in length to the
Rhombic Flap need to avoid the central palatine raphe, the ante-
The rhombic flap is a non-transposition flap used rior palatine rugae, and the area overlying the
in the closure of medial and lateral canthal defects greater palatine foramen where the anterior pala-
[9]. With minimal sacrifice of normal tissue, most tine artery exits. Xenogenic spacer grafts made
defects may be converted to a rhombic configura- from a porcine collagen matrix have also become
tion with angles of 60° and 120° and all sides of increasingly popular in cases of insufficient pos-
equal length (Fig. 10.11). terior lamella.
In patients who need more posterior lamellar
augmentation or have concomitant volume
Insufficient Posterior Lamella deficiency, a dermis fat graft can be harvested
from the postauricular area or abdomen. The
In defects with insufficient posterior lamella, tar- graft should be oversized to account for postop-
soconjunctival grafts are preferred because they erative contraction. The dermis is removed with a
provide a smooth surface over the cornea. If such diamond burr or scalpel once a graft of sufficient
a graft is not available, nasal or ear cartilage thickness is harvested. The end point or derm-
grafts, donor sclera grafts, or dermis fat grafts abrasion is fine pinpoint bleeding of the graft.
may be used to reconstruct the deficiency. Hard The graft is then placed into the eyelid defect
palate grafts harvested from the gingival surface with the dermis facing the globe. A frost suture or
of the roof of the mouth have been used with tarsorrhaphy should be used postoperatively to
greater frequency [11, 12]. The key points are the counteract contractile forces [13–15].
Insufficient Anterior Lamella silicone membrane acts to protect against dessi-

cation and provide increased tensile strength and
More extensive defects of the anterior lamella can typically be removed after 2–4 weeks. Once
may require more involved methods of repair. adequate wound integration has occurred, the
The posterior lamella is first replaced with a smaller anterior lamellar defect can undergo a
graft, as described above. If a free graft is used, secondary reconstructive procedure. In many
the anterior lamella must be reconstructed with a cases, use of a dermal substitute can allow for
vascular flap. Tissue expanders allow for the use complete closure of the defect without need for
of vascularized skin that is similar in appearance, further reconstructive techniques.
thickness, and texture to that adjacent to the
defect without sacrificing normal tissue [16].
Most importantly, tissue expansion seems to Insufficient Vascularized Pedicle
enhance the vascularity of the skin flap. Other
advantages include the non-hair-bearing nature For large defects with an insufficient vascular-
and pliability of the created tissue. The main dis- ized pedicle, galeal and pericranial flaps may be
advantage is the creation of temporary used [18]. They provide an excellent vascular
disfigurement. supply for the recipient site and any underlying
In tissue expansion, skin is recruited from the free tarsoconjunctival or overlying skin grafts.
adjacent skin, such as the forehead, the tempora- The main difference from a median forehead flap
lis and preauricular regions, and the lid proper. is that skin is not transposed with a galeal or peri-
Adequate tissue area is created in a staged proce- cranial flap. The thinner nature of these flaps
dure. A skin incision is made along the hairline, reduces the amount of bunching over the nasal
brow, or a preexisting incision line, and a recipi- bridge. Although both types of flap may be
ent pocket is dissected in the subcutaneous tissue. employed in upper eyelid reconstruction, the
The expander is soaked in an antibiotic solution, galeopericranial flap is thought to be superior to
tested for leaks, placed into the recipient pocket, the pericranial flap because of its increased
and filled with saline. A remote expander is then vascularity.
placed into the pocket as well and the wound is In the repair of large upper eyelid defects, the
closed in two layers. posterior lamella is first reconstructed using one
Serial expansion is begun 2–3 weeks after of the previously described grafts. The galeoperi-
placement. A 27-gauge needle is used to inflate cranial or pericranial flap is then created to fill the
the expander with saline percutaneously through soft tissue defect. A standard bicoronal incision is
the injection port until the expander feels taut. outlined over the skull vertex. It is important to
Usually 10–15% of the total expander volume is avoid a transverse incision of the flap two finger-
injected at any one time, and the process is usu- breadths above the superior orbital rim, as this is
ally repeated twice weekly. Once adequate tissue the region where the frontalis nerve penetrates
has been created, the expander is removed, and into the frontalis muscle. A transcoronal incision
the newly created skin is ready for use as a local is then made to access the pericranium of the
skin flap in eyelid reconstruction. forehead. For a galeopericranial flap, the plane of
In cases where tissue expansion is not viable, dissection is between the subcutaneous tissue and
the use of a bioengineered dermal substitute the galea (for pericranial flaps, the plane is subga-
allows for increased wound healing and adequate leal, leaving the loose areolar tissue and perios-
anterior lamella reconstruction [17]. The dermal teum adherent to the frontal bone). Dissection is
substitute is cut to fit over the defect and may be carried toward the supraorbital rim while pre-
sutured into place using 7-0 Vicryl. As the mate- serving the supraorbital and supratrochlear ves-
rial incorporates into the surrounding skin, its sels. The pericranium and galea are then incised
collagen matrix promotes vascularization and and elevated off the frontal bone. The flap is
cellular migration into the defect. An overlying mobilized, turned down anteriorly through the
skin defect, and subsequently serves as a well-

vascularized bed for a skin graft. 2. Semicircular rotational flap
(a) Temporal tarsal remnant + myocu-
taneous advancement flap
Summary (Box 10.1) (b) Only feasible if sufficient temporal
tarsal remnant
The treatment of malignant eyelid lesions 3. Free tarsal graft + myocutaneous
includes complete excision of the tumor as well advancement flap
as reconstruction to provide optimum function, 4. Periosteal strip + myocutaneous
globe protection, and esthetics. Mohs’ micro- advancement flap
graphic surgery technique is the preferred method 5. Free tarsal graft + unipedicle rotational
of excision of periocular malignancies, as it flap from the upper eyelid
allows for clearance of the tumor margin while 6. Hughes tarsoconjunctival flap + free skin
maximally conserving normal tissues. Repair of graft or myocutaneous advancement flap
the eyelid depends on the size of the defect and
whether or not the lid margin is involved. Most
importantly, either the reconstructed anterior or
the posterior lamella must have its own inherent Anterior lamella defect lower eyelid, eyelid
blood supply (pedicle flap), as this will ensure margin intact
tissue survival and optimal surgical outcome for 1. Primary closure
the patient. (a) With lateral cantholysis
(b) Without lateral cantholysis
Box 10.1 2. Skin graft (of non-hair-bearing skin)
(a) Ipsilateral upper eyelid
(b) Preauricular skin graft
Anterior lamella defect upper eyelid, eyelid (c) Retroauricular skin graft
margin intact (d) Supraclavicular skin graft
1. Primary closure (e) Upper inner arm skin graft
(a) With lateral cantholysis 3. Ellipse sliding flap
(b) Without lateral cantholysis 4. Myocutaneous advancement flap
2. Skin graft (of non-hair-bearing skin)
(a) Contralateral upper eyelid
(b) Preauricular skin graft
(c) Retroauricular skin graft Full-thickness eyelid defect upper eyelid
(d) Supraclavicular skin graft 1. Primary closure
(e) Upper inner arm skin graft (a) With lateral cantholysis
3. Ellipse sliding flap (b) Without lateral cantholysis
4. Myocutaneous advancement flap 2. Semicircular rotational flap
(a) Temporal tarsal remnant + myocu-
taneous advancement flap
(b) Only feasible if sufficient temporal
Full-thickness eyelid defect lower eyelid tarsal remnant
1. Primary closure 3. Free tarsal graft + myocutaneous
(a) With lateral cantholysis advancement flap
(b) Without lateral cantholysis 4. Cutler–Beard tarsoconjunctival flap + free
skin graft or myocutaneous advancement
flap
Medial canthal defect Insufficient anterior lamella

1. Median forehead flap 1. Tissue expansion
2. Glabellar flap 2. Dermal substitute
3. Rhombic flap
Insufficient posterior lamella Insufficient vascularized pedicle

1. Tarsoconjunctival graft 1. Galeopericranial flap
2. Hard palate graft 2. Pericranial flap
3. Nasal cartilage graft
4. Ear cartilage graft
5. Donor sclera
9. Kronish J. Eyelid reconstruction In: Tse DT, editor.

References Color atlas of ophthalmic surgery: oculoplastic sur-
gery. Philadelphia: JB Lippincott; 1992.
1. Shields JA, Demirci H, Marr BP, et al. Sebaceous 10. Kersten RC, Codére F, Dailet RA, et al. Basic and
carcinoma of the ocular region: a review. Surv clinical science course: section 7, orbit, eyelids, and
Ophthalmol. 2005;50(2):103–22. lacrimal system. San Francisco: American Academy
2. Cook BE Jr, Bartley GB. Treatment options and of Ophthalmology; 2003.
future prospects for the management of eyelid malig- 11. Bartley GB, Kay PP. Posterior lamellar eyelid recon-
nancies: an evidence-based update. Ophthalmology. struction with a hard palate mucosal graft. Am J
2001;108:2088–98; quiz 2099–2100, 2121. Ophthalmol. 1989;107:609–12.
3. Tse DT, Gilberg SM. Malignant eyelid tumors. In: 12. Beatty RL, Harris G, Bauman GR, et al. Intraoral
Krachmer JH, Mannis MJ, Holland EJ, editors. palatal mucosal graft harvest. Ophthal Plast Reconstr
Cornea: surgery of the cornea and conjunctiva. 2nd Surg. 1993;9:120–4.
ed. Philadelphia: Mosby; 2005. 13. Korn BS, Kikkawa DO, Cohen SR, et al. Treatment
4. Esmaeli B, Wang B, Deavers M, et al. Prognostic of lower eyelid malposition with dermis fat grafting.
factors for survival in malignant melanoma of Ophthalmology. 2008;115:744–751.e2.
the eyelid skin. Ophthal Plast Reconstr Surg. 14. Brock WD, Bearden W, Tann T 3rd, et al. Autogenous
2000;16:250–7. dermis skin grafts in lower eyelid reconstruction.
5. Coleman WP III, Davis RS, Reed RJ, et al. Treatment Ophthal Plast Reconstr Surg. 2003;19:394–7.
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Dermatol Surg Oncol. 1980;6:476–9. lower eyelid retractors with AlloDerm and dermis-fat
6. Zitelli JA, Mohs FE, Larson P, et al. Mohs micro- grafts in lower eyelid retraction surgery. Ophthal Plast
graphic surgery for melanoma. Dermatol Clin. Reconstr Surg. 2011;27:137–41.
1989;7:833–43. 16. Tse DT, McCafferty LR. Controlled tissue expansion
7. Esmaeli B. Sentinel lymph node mapping for in periocular reconstructive surgery. Ophthalmology.
patients with cutaneous and conjunctival malig- 1993;100:260–8.
nant melanoma. Ophthal Plast Reconstr Surg. 17. Chen TA, Ayala-Haedo JA, Blessing NW, et al.
2000;16:170–2. Erickson BP. Bioengineered dermal substitutes for
8. Nerad JA. The requisites in ophthalmology oculoplas- the management of traumatic periocular tissue loss.
tics surgery: eyelid reconstruction. In: Krachmer JH, Orbit. 2018;37(2):115–20.
editor. Requisites in ophthalmology: oculoplastic sur- 18. Tse DT, Goodwin WJ, Johnson T, et al. Use of galeal
gery. St Louis: Mosby; 2001. or pericranial flaps for reconstruction or orbital and
eyelid defects. Arch Ophthalmol. 1997;115:932–7.
Systemic Associations
11
Abbreviations Introduction
AVM Arteriovenous malformation Patients with an inherited predisposition for

BCC Basal cell carcinoma tumors tend to develop these tumors at an earlier
CHRPE Congenital hypertrophy of retinal age, have multiple tumors with bilateral involve-
pigment epithelium ment, and may have a positive family history of
CM Capillary malformations similar lesions [1]. The majority of eyelid tumors
CNC Carney complex in the setting of an inherited predisposition are
CS Cowden syndrome benign, but some malignant tumors can have a
FDA Food Drug Administration syndromic association such as ones that occur
HNPCC Hereditary nonpolyposis colorectal (Table 11.1), for example, in the setting of the
cancer Gorlin-Goltz syndrome. With eyelid tumors, one
MRI Magnetic resonance imaging of the most important clues to the presence of an
MTS Muir-Torre syndrome associated systemic disease is an unusual histo-
NBCCS Nevoid basal cell carcinoma pathologic feature. For example, tumors such as
syndrome myxomas and sebaceous adenomas of the eyelid
NF1 Neurofibromatosis type 1 are unlikely to occur in the absence of a syn-
PDL Pulsed dye laser dromic association. Eyelid tumors can also be
PDT Photodynamic therapy metastatic, but such cases are rare and account
RPE Retinal pigment epithelium for less than 1% of malignant eyelid tumors [2].
SWS Sturge-Weber syndrome
Neurofibroma in Neurofibromatosis
M. Scaramuzzi · E. I. Traboulsi (*)
Type 1
Department of Pediatric Ophthalmology
and Strabismus, Center for Genetic Eye Diseases, Neurofibroma is the hallmark of neurofibromato-
Cole Eye Institute (i-32), Cleveland Clinic sis type 1 (NF1). NF1 is inherited in an autosomal-
Foundation, Cleveland, OH, USA
e-mail: traboue@ccf.org
dominant fashion in about 50% patients and is
sporadic in the remainder [3]. The disease affects
L. T. Xu · A. D. Singh
Department of Ophthalmic Oncology,
1 out of 3000 persons and is due to mutations in
Cole Eye Institute, Cleveland Clinic, the NF1 gene on chromosome 17q11.2, which
Cleveland, OH, USA encodes the protein neurofibromin [3].

114 M. Scaramuzzi et al.
Table 11.1 Eyelid tumors that are markers of a syndromic association

Entity Eyelid tumor Associated features Locus/gene
Neurofibromatosis type 1 Neurofibroma Lisch nodules 17q
Café au lait spots NF 1 gene
Pheochromocytoma
Sturge-Weber Syndrome Diffuse hemangioma Leptomeningeal hemangioma Sporadic
Gardner syndrome Epidermoid cyst CHRPE 5q21
Fibroma Colorectal polyps/carcinoma APC gene
Orbital osteoma
Gorlin-Goltz syndrome Basal cell carcinoma Odontogenic cysts 9q 22
Bifid ribs PTC gene
Palmar pits
Ovarian tumor
Cowden syndrome Trichilemmoma Oral papilloma 10q23
Breast tumor PTEN gene
Thyroid tumor
Carney complex Myxoma Spotty mucocutaneous 17q
pigmentation
Schwannoma PRKAR1A gene
Endocrine overactivity chromosome 2
Testicular tumor
Muir-Torre syndrome Sebaceous adenoma Keratoacanthoma 2p
Basal cell carcinoma hMLH1, hMSH2
Colorectal adenocarcinoma
CHRPE congenital hypertrophy of retinal pigment epithelium
The neurofibromas appear as discrete soft been described in literature [6, 7]. Characteristics
tumors on the face (including eyelids), hands, of plexiform neurofibromas of the eyelid are
and trunk. Previously given different names, they thickening of the upper lid, S-shaped eyelid
are now designated as orbital-periorbital- deformity, “bag of worms”-like feel on palpation,
plexiformal neurofibromas in order to include all and detachment of the lateral [8] or medial can-
the locations in which they appear [4]. Cutaneous thal ligaments [9]. The extent of a neurofibroma
neurofibromas arise from small nerves or nerve cannot be determined by clinical examination
endings and protrude from the surface of the skin, alone, so MRI is necessary [10].
while subcutaneous neurofibromas are firm nod- Amblyopia can be caused by these lesions,
ules just below the surface of the skin [4]. They mainly as a result of ptosis or anisometropia, so a
tend to be small and generally appear in the sec- comprehensive ophthalmologic exam should be
ond decade of life, becoming more numerous as performed at every 6 months throughout the
the patient ages, with no risk of malignant trans- period of visual development [11]. Debulking of
formation. They rarely cause neurologic deficits the tumor mass, ptosis surgery, and canthal fixa-
[4]. In contrast, plexiform neurofibromas are tion are the treatment surgical modalities in cases
complex nerve sheath tumors that follow multi- of plexiform neurofibroma, in order to clear the
ple nerve branches, mainly diagnosed in early visual axis and improve appearance [12].
childhood [4]. They are more prone to cause Unfortunately surgery can be challenging and
functional and neurologic deficits, and there is a associated with a high risk of complications and
risk of malignant transformation [4]. In the eye recurrences, as a result of the tumor’s integration
and ocular adnexa, a plexiform pattern is more with the surrounding soft tissue [13]. With
frequent [5]. These tumors are usually associated asymptomatic, nonprogressive, and nonobstruc-
with other features of NF1. Solitary tumors are tive tumors, monitoring is an option, taking into
rare, but tumors masquerading as chalazia have consideration the fact that neurogenic tumors in
11 Systemic Associations 115
NF1 carry a risk of approximately 10% for malig- AVMs [18]. It is also important to differentiate
nant transformation [14]. This risk is greater with port-wine stain from other similar malformations
atypical neurofibromas [15], whole-gene deletion such as infantile hemangiomas, which are associ-
[16], higher numbers of plexiform neurofibro- ated with different syndromes such as PHACES
mas, larger whole body benign tumor volume, [25]. A useful diagnostic clue is that the distribu-
and younger age [17]. tion is dermatomal in nevus flammeus and seg-
mental in infantile hemangiomas [26]. Moreover
the endothelial cells of port-wine stains do not
Nevus Flammeus stain for GLUT-1, which is a specific marker for
infantile hemangiomas [18].
Nevus flammeus is also known as capillary mal- In general, only about 10% of all patients with
formation (CM) or port-wine stain, and is the nevus flammeus or port-wine stain of the eyelid
most common type of congenital vascular mal- are associated with Sturge-Weber syndrome
formation. It is usually present at birth and per- (SWS) (Fig. 11.1) [27]. SWS occurs in patients
sists throughout life, although its appearance or who have hemangiomas in the V1 or V2 areas of
color may change [18]. It is initially flat and light distribution of the trigeminal nerve. It is typically
red, or violaceous and affects the skin of the face unilateral, present at birth, and does not change
in almost all cases (90%), followed by the neck, with age [28]. The size of the nevus flammeus in
trunk, leg, arm, and hand [19]. With an incidence SWS has been found to be correlated with neuro-
of 0.3% in newborns, it usually occurs as a spo- logic severity in patients more than 5 years old
radic unifocal lesion, not associated with any [29]. Bilateral port-wine stains of the eyelids
underlying disease [18]. have a higher likelihood of being associated with
A recently proposed pathophysiologic mecha- SWS than unilateral lesions [27]. In a study of 55
nism for tissue hypertrophy is focal venous patients with SWS, glaucoma was the main ocu-
hypertension caused by venous dysplasia [20]. lar disease and was related to the extension of the
Despite this, a definitive pathogenic mechanism nevus flammeus in the palpebral area [30]. If
is still not known. A somatic activating mutation there is involvement of both upper and lower eye-
in GNAQ has been identified as the cause of lids, the risk of glaucoma is as high as 50%. The
Sturge–Weber syndrome and apparently-glaucoma is almost always ipsilateral to the facial
nonsyndromic port-wine stains [21, 22]. Nevus
flammeus associated with arteriovenous malfor-
mation subtypes have been found to result from
dominant RASA-1 gene mutations [22, 23].
Although multiple treatments are available,
the gold standard for facial nevus flammeus is the
flashlamp-pumped pulsed dye laser (PDL) treat-
ment [24]. However, when there are hypertrophic
skin changes, surgical intervention can achieve
better results [24].
Nevus flammeus is sometimes associated with
certain syndromes, such as Sturge-Weber syndrome,
macrocephaly-CM syndrome, CM-arteriovenous
malformation (AVM) syndrome, phacomatosis pig-
mentovascularis, and overgrowth syndromes such as
Klippel-Trenaunay syndrome.
It is sometimes difficult to distinguish between
Fig. 11.1 Sturge-Weber syndrome. In addition to typical
different diseases. Doppler assessment may be diffuse cutaneous involvement, note nodular
helpful in differentiating nevus flammeus from hemangioma
port-wine stain [28]. Patients without nevus flam- epithelium, soft tissue tumors, desmoid tumors,
meus in the palpebral area do not develop glau- and other cancers [34, 35]. Orbital osteoma, soft
coma or choroidal hemangioma [30]. Diffuse tissue tumors of the brows or eyelids, and epider-
choroidal hemangioma is present in about moid cysts of the eyelid may also occur [36–38] .
40–50% of patients with SWS and is usually ipsi-
lateral to the facial port-wine stain.
In the setting of phakomatosis pigmentovas- evoid Basal Cell Carcinoma
N
cularis, port-wine stain can be associated with Syndrome (Gorlin-Goltz Syndrome)
scleral and uveal hyperpigmentation, predispos-
ing to uveal melanoma, similar to that observed Nevoid basal cell carcinoma syndrome (NBCCS)
in Nevus of Ota (Volume 5 Chap. 9). is also referred to as basal cell nevus syndrome,
Diagnosis of SWS is based on the typical clin- Gorlin syndrome, or Gorlin-Goltz syndrome [39,
ical signs, facial appearance, and brain MRI with 40]. Its incidence is estimated at 1 in 50,000 with
contrast findings [28]. In the absence of lepto- no sex predilection. The median age at diagnosis
meningeal involvement, patients should only be is 23 years in sporadic cases and 12 years in
given a diagnosis of nevus flammeus, port-wine familial cases [41].
stain, or facial angioma to avoid the stigma asso- NBCCS is inherited in an autosomal-dominant
ciated with a diagnosis of SWS. In infants with fashion with complete penetrance and variable
nevus flammeus in the distribution of the trigemi- expressivity; however, about 30% of probands
nal nerve, early referral to a pediatric neurologist have a de novo mutation [40]. The mutation is in
is critical, considering that outcomes depend on the PTCH gene on chromosome 9q22.3 [42, 43].
prompt recognition of neurologic abnormalities PTCH sequence alterations can be detected in
and early seizure control [31]. There is no evi- about 60–85% of cases that meet clinical diag-
dence that a presymptomatic Sturge-Weber syn- nostic criteria for NBCCS [43]. Studies have
drome diagnosis with magnetic resonance shown that the PTCH gene may be inactivated by
imaging results in better neurodevelopmental haploinsufficiency or through dominant-negative
outcomes [31]. In SWS nevus flammeus, laser isoforms [44]. To date, approximately 448 unique
treatment should be performed early for better PTCH1 mutations are known [45]. Furthermore,
outcomes; however, its success depends on the mutations in the SUFU and PTCH2 genes have
location of the lesions: those affecting the central been detected in patients with signs and symp-
forehead respond better than central facial lesions toms of Gorlin syndrome and no PTCH1 muta-
[32]. Unfortunately, lesions that are left untreated tions [46, 47].
have a tendency to thicken and get darker with NBCCS is characterized by the classic clinical
time and, in some cases, become nodular [32]. triad of multiple basal cell carcinomas, keratocys-
tic odontogenic tumors and bifid ribs; however
cutaneous, ophthalmic and neurological abnor-
Gardner Syndrome malities may also be present [48]. Associated neo-
plasms are medulloblastoma, astrocytoma,
Gardner syndrome was first described by Eldon meningioma, and ovarian fibroma [48].
J. Gardner in 1951 as a autosomal-dominant dis- Although basal cell nevi may occur in early
order characterized by the triad of multiple osteo- childhood, it is the risk for multiple basal cell car-
mas, colonic polyposis, and benign tumors of the cinoma and developmental anomalies that char-
skin and soft tissues [33]. Gardner syndrome is a acterizes NBCCS [49]. The tumors tend to be
variant of familial adenomatous polyposis caused multiple (>5 in a lifetime) and occur before the
by a mutation in the APC gene on chromosome age of 30 years. They may arise from preexisting
5q21 [33]. Extracolonic manifestations of basal cell nevi or de novo. In general, about 0.5%
Gardner syndrome include jaw anomalies, pig- of patients with basal cell carcinoma have under-
mented ocular fundus lesions that resemble con- lying NBCCS [50]. The proportion is much
genital hypertrophy of the retinal pigment higher (22%) in patients with basal cell c arcinoma
developing before the age of 20 years [51]. White A wide variety of ophthalmic manifestations
race, age, sun exposure, and radiation therapy are may be present in 26% of patients with NBCCS
major risk factors for inducing basal cell carci- [49]. Periocular basal cell carcinoma [54, 55],
noma [52]. hypertelorism, nystagmus, and cataracts are some
Jaw keratocysts and calcification of the falx of the common features (Fig. 11.2) [49, 54]. The
cerebri are some of the most frequent (90%) occurrence of microphthalmia [56], coloboma,
manifestations of the NBCCS (Fig. 11.2) [49, combined retinal and RPE hamartoma [57], and
53]. Patients could be characterized by typical vitreoretinal abnormalities [58] in the setting of
facial features that include forehead bossing and NBCCS implicates the PTCH1 gene in ocular
macrocephaly [53]. development [56, 58]. Other less common
a b
Fig. 11.2 External photograph showing multiple facial noncontrast computed tomography scan of the skull
basal cell carcinoma (a). Orthopantomograph of the right showing of falx cerebri (arrow) and large diffuse lesion in
mandible shows odontogenic keratocysts seen as round, the medial orbit (c). (Reprinted from Honavar et al. [54].
well-circumscribed radiolucent areas (b, arrows). Coronal With permission from Elsevier)
features include subconjunctival epidermoid carcinomas after radiation or surgery, and

cysts [59], congenital orbital teratoma [60], stra- patients who cannot undergo surgery or radia-
bismus [61], epiretinal membrane and myelin- tion therapy [67]. Chemoprevention with isotret-
ated nerve fibers [62], bilateral macular holes inoin can be used when existing lesions have
[63], orbital cysts and congenital blindness [48]. been controlled [68].
Diagnosis is difficult because of the great phe- Patients with NBCCS can have a normal life
notypic variation of this disease, with over 100 span if they have adequate multidisciplinary mon-
clinical manifestations in many major organs. itoring to check for medulloblastoma and invasive
Diagnosis is based on the presence of major and or metastatic BCC, which are the most common,
minor clinical and radiological criteria albeit rare, causes of early mortality [69].
(Table 11.2) and confirmed by DNA analysis [49].
If there are no PTCH1 mutations, testing of SUFU
and PTCH2 should be considered [41]. The best ultiple Hamartoma Syndrome
M
approach in the diagnosis and management of (Cowden Syndrome)
patients with NBCCS is multidisciplinary, in
order to achieve a diagnosis and to optimize care. Cowden syndrome was first described in 1963
Basal cell carcinoma is usually treated by sur- [70]. Initially considered a predominantly derma-
gical excision, with an overall success rate of tologic disease, the phenotypic spectrum has
94–98% [64]. Other therapies are PDT, cryosur- broadened to include increased cancer risk as
gery and electrocauterization [65]. A recent well as neurodevelopmental disorders [71].
alternative therapy is Vismodegib, a small-mole- Cowden syndrome is inherited as an
cule inhibitor of the Hedgehog pathway. It is autosomal- dominant trait with 90–99% pene-
approved by the United States Food and Drug trance by the age of 30 years. Ten to 50% of indi-
Administration (FDA) for the treatment of meta- viduals with Cowden syndrome have an affected
static, and locally advanced basal cell carcino- parent [72]. It has generally been reported that
mas [66]. Treatment with Vismodegib reduces 80% of patients with Cowden syndrome have
the tumor burden and prevents new basal cell detectable PTEN (phosphatase and tensin homo-
carcinomas [66]. Sonidegib is another Hedgehog log) missense mutations [73]; however, in large
pathway inhibitor with FDA approval for use in cohorts actual mutation rates are reported to
adults with locally advanced recurrent basal cell occur in 30–35% of patients [74].
PTEN is a tumor suppressor gene located on
Table 11.2 Clinical diagnostic criteria for nevoid basal chromosome 10 that codes for a lipid phosphatase
cell nevus syndrome in the PI3K/Akt pathway to arrest the cell in G1
Major ≥2 major Jaw keratocyst phase and promote apoptosis, also acting as a pro-
criteria and ≥1 Falx calcification tein phosphatase in the MAPK pathway that regu-
minor Palmar or plantar pits lates cell survival [75]. PTEN has been
criteria Basal cell carcinoma >5 in a
hypothesized to play a role in cell migration and
lifetime or before the age of
30 years adhesion due to its homology to focal adhesion
Affected first-degree relative molecules such as tensin and auxilin [75]. As
Minor ≥1 major Macrocephaly PTEN mutations are also present in closely related
criteria and ≥3 Medulloblastoma clinical entities, Cowden syndrome is now con-
minor Lympho-mesenteric or pleural
criteria
sidered to be within the spectrum of the PTEN
cysts
hamartoma tumor syndrome, which includes
Cleft lip/palate
Vertebral anomalies Bannayan-Riley-Ruvalcaba syndrome, Proteus
Polydactyly syndrome, and Proteus-like syndrome [76].
Ovarian/cardiac fibromas As the majority of tumors in this syndrome are
Ocular anomalies hamartomatous malformations, it has also been
Based on data from Ref. [49] referred to as multiple hamartoma syndrome [77].
a b
Fig. 11.3 Clinical photograph of flesh-colored papular carcinoma cells (b, H&E original magnification ×200).
lesions at the eyelid margin (a). High-power photomicro- (Repritned from Bardenstein et al. [79]. With permission
graph of trichilemmoma with basal palisading and bland- from Elsevier)
looking cells with more cytoplasm than basal cell
Patients have greatly increased lifetime risks Other uncommon hamartomatous manifestations
for breast, thyroid, renal, and endometrial can- include gastrointestinal polyps and cerebellar
cers and slightly elevated risks for colorectal can- dysplastic gangliocytoma (Lhermitte-Duclos
cers and melanoma, without any recognized disease) [76].
genotype-phenotype correlations [78]. In 2013, Pilarski proposed a revision of the
Eyelid trichilemmomas are hallmark manifes- PTEN hamartoma tumor syndrome clinical diag-
tation of Cowden syndrome (Fig. 11.3). nostic criteria (Table 11.3) [74], with a substan-
The tumors appear as multiple flesh-colored tial improvement in the specificity of these
papular lesions of the eyelid [79]. One study criteria. Thanks to the Cleveland Clinic PTEN
found that complete PTEN loss, as determined by Risk Calculation tool, it is now possible to calcu-
immunohistochemistry, occurs in 83% of trichil- late the percentage risk for PTEN mutation and
emmomas associated with Cowden syndrome, then decide whether or not to refer the patient for
but only in 3% of sporadic trichilemmomas [80]. PTEN testing/genetics [91]. This tool is freely
Several other ophthalmic features associated available online at http://www.lerner.ccf.org/gmi/
with Cowden syndrome and PTEN mutations ccscore/. It weights score for each patient’s
have been described, such as anterior stromal and characteristic in order to help decide whether to
epithelial alterations in the cornea [81], iris recommend a genetic test.
mammillations [82], uveal ganglioneuroma [83], The presence of three or more trichilemmo-
cataract [84], retinal angioma [85], choroidal pig- mas, among other mucocutaneous manifesta-
mented schwannoma [86], proliferative retinopa- tions, should raise a strong suspicion of Cowden
thy [87], and optic nerve head drusen [88]. syndrome [74].
In addition to the ophthalmic features, muco- The management of Cowden syndrome con-
cutaneous lesions such as trichilemmomas, sists of surveillance for early cancer detection and
papillomatous papules, acral keratoses, and plan- treatment in the hope of improving survival. All
tar keratoses are most striking manifestations of patients should undergo an annual thyroid ultra-
Cowden syndrome. More significantly, this syn- sound scan and dermatologic evaluation. Women
drome has been found to be associated with a should receive an annual mammogram and breast
lifetime increased risk for breast tumors (benign MRI from the age of 30 years, along with annual
67%, malignant 25–50%) [89], thyroid tumors transvaginal ultrasound and blind suction endome-
(benign 75%, malignant 10%) [90], and uterine trial biopsies, while prophylactic mastectomy or
tumors (benign fibroids and malignant 10%). prophylactic hysterectomy may also be c onsidered
Table 11.3 Revised PTEN hamartoma tumor syndrome clinical diagnostic criteria
Operational diagnosis in an individual (either of the following)
1. Three or more major criteria, but one must include macrocephaly, Lhermitte-Duclos disease, or gastrointestinal
hamartomas
2. Two major and three minor criteria
Operational diagnosis in a family where one individual meets revised PTEN hamartoma tumor syndrome clinical
diagnostic criteria or has a PTEN mutation:
1. Any two major criteria with or without minor criteria
2. One major and two minor criteria
3. Three minor criteria
Major Breast cancer
Endometrial cancer (epithelial)
Thyroid cancer (follicular)
Gastrointestinal hamartomas (including ganglioneuromas, but excluding hyperplastic polyps; ≥3)
Lhermitte-Duclos disease (adult)
Macrocephaly (≥97 percentile: 58 cm for females, 60 cm for males)
Macular pigmentation of the glans penis
Multiple mucocutaneous lesions (any of the following):
Multiple trichilemmomas (≥3, at least one biopsy proven)
Acral keratoses (≥3 palmoplantar keratotic pits and/or acral hyperkeratotic papules)
Mucocutaneous neuromas (≥3)
Oral papillomas (particularly on tongue and gingiva), multiple (≥3) OR biopsy proven OR
dermatologist diagnosed
Minor Autism spectrum disorder
Colon cancer
Esophageal glycogenic acanthosis (≥3)
Lipomas (≥ 3)
Mental retardation (i.e., IQ ≤ 75)
Testicular lipomatosis
Thyroid cancer (papillary or follicular variant of papillary)
Thyroid structural lesions (eg, adenoma, multinodular goiter)
Vascular anomalies (including multiple intracranial developmental venous anomalies)
Based on data from Ref. [74]
after appropriate counseling. All adults with CS pulmonary chondroma, and extra-adrenal para-
should have a colonoscopy beginning at the age of ganglioma [95].
35 years and renal imaging every 2 years, begin- Carney complex is inherited as an autosomal-
ning at the age of 40 years [92]. dominant trait [96]. In about 30% of patients, the
disease is due to de novo mutations. It is a geneti-
cally heterogeneous disease, with >70% patients
Carney Complex with CNC carrying mutations of the PRKAR1A
gene [97], which encodes the 1-α regulatory sub-
Carney complex (CNC) is a multiple neoplasia unit of the cAMP-dependent protein kinase A and
syndrome characterized by cutaneous pigmen- functions as a tumor suppressor gene [98].
tary abnormalities, myxomas, endocrine tumors, Pathogenic PRKAR1A mutations include single
and schwannomas [93, 94]. It has also been des- base substitutions, small (≤15bp) deletions/inser-
ignated by descriptive acronyms such as NAME tions, combined rearrangements, and large dele-
syndrome (nevi, atrial myxomas, ephelides) and tions [99]. More than 125 PRKAR1A gene
LAMB syndrome (lentigines, atrial myxoma, mutations have been identified; however, linking
blue nevi). Carney complex should be differenti- genotype to phenotype has been challenging [100].
ated from a completely unrelated entity “Carney Although previous studies have demonstrated
triad”, which refers to gastric leiomyosarcoma, associations between specific mutations and CNC
manifestations, only 3 pathogenic variants most common presenting feature. The brown or
(c.82C > T, c.491_492delTG, and c.709–2_709–7 black lentigines may be present anywhere in the
delATTTTT) have been identified in >3 unrelated body and become prominent during puberty. The
pedigrees [97]. The other mutations are unique most common noncutaneous lesions in CNC are
(i.e., present in a single kindred) [101]. Mutations cardiac myxomas (affecting 20–40% of patients),
in PRKAR1A appear to be the most common cause which are responsible for >50% of CNC-related
of CNC. Patients carrying PRKAR1A mutations mortality [105]. Although cardiac myxomas are
have more severe disease, with earlier presentation typical, myxomas may occur in the skin and other
and higher frequency of myxomas, thyroid, and sites. Endocrine tumors and hormonal hyperse-
gonadal tumors, schwannomas, and lentigines cretion may manifest as thyroid adenoma (75%),
compared with PRKAR1A-negative patients [97]. Sertoli cell tumors (33%) in males, Cushing syn-
However, in most cases, genotype cannot predict drome (25%), and acromegaly (10%) [94].
phenotype or penetrance [101]. Psammomatous melanotic schwannoma, a rare
Periocular involvement is frequent, both by variant of schwannoma, is also a manifestation of
pigmentary changes [102] and myxomas [103]. Carney complex [106].
In a study of 63 patients, facial and eyelid lentigi- The diagnosis of CNC is made if two of the
nes were observed in 70%, conjunctival, carun- main manifestations of the syndrome are present
cular pigmentation in 27%, and eyelid myxomas (Table 11.4); these need to be confirmed by his-
in 16% of the patients (Fig. 11.4) [103]. tology, biochemical testing, or imaging; alterna-
Lentigines typically involve the centrofacial area, tively, the diagnosis is made when one of the
including the lips, and the conjunctiva [104]. criteria is present and the patient is a carrier of a
Cutaneous myxomas are usually less than 1 cm in known inactivating mutation of the PRKAR1A
diameter and often affect the eyelids, ears, and gene [94]. Clinical and biochemical screening for
nipples but can also be seen on other areas of the CNC remain the gold standard for the diagnosis
face, ears, trunk, and perineum [104]. Myxomas of CNC. Molecular testing for PRKAR1A muta-
are typically diagnosed during the teenage years tions is not recommended at present for all
and appear as sessile, small papules and large, patients with CNC, but in families with known
fingerlike, pedunculated lesions [104]. mutations may be useful for detecting affected
The median age at diagnosis is 20 years. patients and avoiding unnecessary medical sur-
Cutaneous pigmentary abnormalities are the veillance of non-carriers [107].
Considering that Carney reported that more
than 50% of patients have a significant embolic
event in their lifetime related to cardiac myxomas
and that the ophthalmic manifestations have been
shown to precede embolic events, early identifi-
cation of ocular myxomas and subsequent screen-
ing and monitoring for cardiac myxoma is
recommended [108].
Muir-Torre Syndrome
Muir-Torre syndrome is a rare cancer predisposi-

tion syndrome characterized by unusual cutane-
ous tumors and internal malignancy [109]. It is
Fig. 11.4 Eyelid myxoma in a patient with Carney com-
plex. Hypocellular myxomatous mass composed of
considered to be a subset of the hereditary non-
ground substance and collagen fibers (H&E original mag- polyposis colorectal cancer (HNPCC) or Lynch
nification ×200). (Courtesy of Ralph C. Eagle Jr., MD) syndrome [110]. The cutaneous tumors a ssociated
Table 11.4 Clinical diagnostic criteria for Carney complex

Disease Any ≥2 present Spotty skin pigmentation with a typical distribution (lips, conjunctiva and
manifestation inner or outer canthi, vaginal and penile mucosa)
Myxoma (cutaneous and mucosal)
Cardiac myxoma
Breast myxomatosis or fat-suppressed magnetic resonance imaging findings
suggestive of this diagnosis
Primary pigmented nodular adrenocortical disease or paradoxical positive
response of urinary glucocorticosteroids to dexamethasone administration
during Liddle’s test
Acromegaly due to growth hormone-producing adenoma
Large-cell calcifying Sertoli cell tumor or characteristic calcification on
testicular ultrasonography
Thyroid carcinoma or multiple, hypoechoic nodules on thyroid
ultrasonography
Psammomatous melanotic schwannoma
Blue nevus, epithelioid blue nevus (multiple)
Breast ductal adenoma (multiple)
Osteochondromyxoma of bone
Supplemental ≥1 Disease Affected first-degree relative
manifestation manifestation
≥1 Disease Inactivating mutation of the PRKAR1A gene
manifestation
Based on data from Ref. [94]
with Muir-Torre syndrome include mainly seba- rare that finding one of these tumors should alert
ceous gland neoplasms (sebaceous adenoma and the clinician to the possibility of Muir–Torre syn-
sebaceous carcinoma), keratoacanthoma, and drome [117]. Solitary or multiple sebaceous ade-
basal cell carcinoma [111]. The internal malig- nomas are uncommon. They are benign, yellow
nancies include upper gastrointestinal, colorec- flesh-colored nodular tumors, approximately
tal, endometrial, and urological tumors [112], but 0.5 cm in diameter, which occasionally ulcerate
in rare cases glioblastoma multiforme has been or bleed, and which grow slowly in older indi-
described [113]. viduals, typically on the face (Fig. 11.5) [111,
MTS is seen in about 9% of individuals with 118]. The Meibomian and Zeis glands of the eye-
HNPCC, mainly in Caucasian and men [114]. lids are modified sebaceous glands and can also
Malignant tumors appear between 23 and be the site of origin of sebaceous adenomas
89 years of age [115]. Although Muir-Torre syn- [119]. Cystic change within a sebaceous ade-
drome is characterized by autosomal-dominant noma is indicative of Muir-Torre syndrome
inheritance, sporadic cases do occur. because sporadic sebaceous adenomas do not
Similar to HNPCC, the majority of MTS cases exhibit this feature [120].
result from highly penetrant but variably Sebaceous epitheliomas are benign, yellowish
expressed germline mutations in the MSH2 and papulonodules, usually present on the face and
MLH1 genes, though a disease variant without scalp, with similar appearance, localization, and
mismatch repair (MMR) gene defects has also age incidence as basal cell carcinomas [118].
been described [116]. Ninety percent of MTS They grow slowly and tend not to recur after
patients have mutations in MSH2, but rare cases treatment [118].
with mutations in MSH6, PMS22 or MLH3 have Sebaceous carcinomas, occasionally associ-
been described [114]. ated with MTS, may arise in the ocular adnexa or
Sebaceous neoplasms, such as adenomas, epi- at extraocular sites. They clinically appear as
theliomas and carcinomas, are reported to be so painful red nodules, often on the upper eyelid, and
a b
Fig. 11.5 Sebaceous adenomas on the face in a patient staining with an antibody to MSH-2 protein was absent in
with Muir-Torre syndrome. Note a yellowish pink warty the sebaceous adenoma (d, magnification ×50). Normal
growth arising from anterior lamella of the left upper eye- positive nuclear staining of sebaceous lobules adjacent to
lid (a). Multiple yellow nodular lesions involving the cen- the sebaceous adenoma serves as an internal control (e,
tral forehead, nose, and adjacent cheek area (b). Both magnification ×50). (Reprinted from Singh et al. [119].
eyelid and facial biopsies revealed sebaceous adenomas With permission from American Medical Association)
(c, original magnification ×10). Immunohistochemical
may be mistaken for an inflammatory condition, the latter being more sensitive; these are used also
such as chalazion or blepharoconjunctivitis, for the diagnosis of hereditary non-polyposis
resulting in a delay in diagnosis [121]. Tumors colorectal cancer [126, 127]. Additional microsat-
occurring in the ocular adnexa are more common ellite instability testing or germline mutation analy-
and account for 1% of all eyelid neoplasms, while sis is recommended if all of the Amsterdam criteria
extraocular tumors are uncommon and usually or one of the Bethesda guidelines is met [126, 127].
located in the head-and-neck region [118]. The Mayo MTS risk scoring algorithm may be
Although sebaceous gland carcinomas of the eye- used to identify patients who should undergo fur-
lid and extraocular sites [122] have been reported ther germline genetic testing [128]. Management is
in patients with Muir-Torre syndrome, such based on screening recommendations and a sur-
patients also had sebaceous adenomas [123] . veillance program of patients with MTS and their
Rarely, keratoacanthomas may be associated first degree relatives (Table 11.5) [129].
with MTS. They are flesh-colored, rapidly grow- Managing cutaneous MTS is challenging
ing, dome-shaped nodules with a central keratin because patients present with multiple and disfig-
plug. They may cause local destruction, especially uring tumors. Aggressive surgical treatment usu-
if they are on the eyelids, and they tend to involute ally provides a good outcome with prolonged
spontaneously after several months [118]. survival, even in the presence of metastases
In a review of 120 patients with Muir-Torre syn- [121]. Sebaceous adenomas and sebaceous epi-
drome, sebaceous tumors were diagnosed prior to theliomas are either excised or treated with cryo-
the internal malignancy in almost 40% of patients therapy. Sebaceous carcinomas should be widely
[111]. Almost half of the patients with Muir-Torre excised. Keratoacanthomas are best treated with
syndrome develop colorectal adenocarcinoma and excision [118]. Radiation can be considered for
one-fourth develop genitourinary tumors. recurrence or local metastasis, as can
Adenocarcinoma of the colon in the setting of 5-fluorouracil and cisplatin combination chemo-
Muir-Torre syndrome tends to be multifocal and therapy [130].
occurs almost a decade earlier than in sporadic
cases [111]. In addition, the proximal colon is more
Table 11.5 Screening recommendations for patients
often affected as compared with unifocal involve- with Muir-Torre syndrome and their first-degree relatives
ment of the distal colon in sporadic cases [124]. Physical examination yearly including breast
There are significant variations in the phenotypic examination in women, testicular and prostate
manifestations of Muir-Torre syndrome, which in examination in men, and laboratory tests including full
some individuals may resemble those of hereditary blood cell count, carbohydrate antigen 125,
carcinoembryonic antigen, fecal occult blood, and
nonpolyposis colorectal carcinoma [125]. urinalysis
MTS is rarely encountered by ophthalmolo- Colonoscopy every 1–2 years from age 25 years or at
gists, who may not consider the systemic 5 years before the youngest age at diagnosis of
implications of certain periocular skin tumors. colorectal cancer in family and annually from age
40 years
Importantly, these tumors present commonly on
Pelvic examination annually in women with
the face, and ophthalmologists may receive refer- transvaginal ultrasonographic scan and endometrial
rals of patients with these lesions in the periocu- biopsy in patients with a gene mutation, from age
lar region [118]. Of the defining skin lesions, 25 years
sebaceous adenomas and epitheliomas are the Consider prophylactic colectomy in patients with a
gene mutation
most sensitive markers of the syndrome, whereas
Consider gastroscopy every 1–2 years in families with
sebaceous carcinomas and keratoacanthomas are a history of gastric cancer
much less frequently associated [118]. Consider renal ultrasonographic scan every 1–2 years
The clinical diagnostic criteria are known as in families with a history of renal tract cancer
Amsterdam criteria and the Bethesda guidelines, Based on data from Ref. [129]
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Conjunctival and Corneal Tumors:
Examination Techniques
12
Introduction External Examination
The conjunctiva is a translucent, vascular mucous Inspection should include the face as well as the
membrane [1]. It may be divided into three por- eyes, comparing both sides to detect conditions
tions: the bulbar conjunctiva, including the such as anisocoria, iris heterochromia and Nevus
corneo-conjunctival limbus, which covers the of Ota. When malignancy is suspected, it is
sclera in the anterior part of the eyeball; the supe- important to palpate the preauricular (parotid),
rior, inferior, and lateral conjunctival fornices; retro-auricular, and submandibular areas for
and the palpebral conjunctiva, including the enlarged lymph nodes, to detect any regional
mucocutaneous transitional zone in the eyelid metastases.
margin, which covers the back surface of the
upper and lower eyelids. The conjunctiva is mov-
able over the globe and in the fornix, where it is Slit-Lamp Examination
loosely adherent to the sclera, but fixed to the and Photography
posterior eyelid surface where it is markedly
adherent to the tarsal plate. The extent of the conjunctival and corneal
Conjunctival and corneal tumors are usually involvement by any tumor should be accurately
detected and diagnosed at a relatively early stage. defined by slit-lamp examination and docu-
Because many of these tumors have characteris- mented. This is particularly important if surgery
tic clinical features, the correct diagnosis can is planned, since it may be difficult to evaluate
usually be made by an experienced ophthalmolo- conjunctival lesions under the diffuse lighting of
gist by clinical examination alone. an operating microscope. Fluorescein, rose ben-
gal, and lissamine green stains can be used for
delineating abnormal epithelium and the tumor
margins, especially with diffuse lesions. Rose
bengal and lissamine green have similar staining
patterns, and the latter is better tolerated by the
J. Pe’er (*) · S. Frenkel patients [2]. The lesion should be drawn and pho-
Ocular Oncology Service and Ophthalmic Pathology tographed to document the clinical features and
the extent. A system for clinically mapping con-
Jerusalem, Israel junctival tumor location and extent has been
e-mail: peer@hadassah.org.il described for staging purposes [3].

It is essential to examine the entire conjunc- a

tiva, including the upper and lower fornices, the
palpebral conjunctiva, the plica semilunaris and
the caruncle. The superior fornix can be visual-
ized by double eversion, using a Desmarres
retractor, or by gently pinching the skin of the
upper eyelid and pulling the eyelid away from the
globe while inspecting the fornix with a loupe or
20D lens. The abnormal bulbar conjunctiva
should be gently pushed with a cotton-tipped b
applicator, to determine whether it moves freely
or whether it is tethered to the sclera as a result of
fibrosis or scleral invasion.
Fig. 12.1 Recurrent amelanotic melanoma. Clinical

Ancillary Studies photograph (a). UBM showing partial thickness scleral
extension (b)
Anterior segment imaging with high-frequency

ultrasonography (also known as ultrasound bio-
microscopy [UBM]), anterior segment OCT, and a
confocal microscopy can be useful for measuring
tumor thickness, evaluating invasion of adjacent
structures and perhaps aiding diagnosis.
Ultrasound Biomicroscopy
Conjunctival lesions can be assessed by high-

frequency ultrasonography to determine the
tumor thickness and, its extension into the sclera
and cornea or rarely, intraocular invasion [4–6]
(Fig. 12.1). Low-frequency, posterior segment
b
ultrasonography may detect advanced choroidal
and orbital invasion.
Anterior Segment OCT
Superficial conjunctival and corneal tumors that

are not pigmented can be readily identified on
high-resolution anterior segment OCT which can
provide useful information about the tumors size,
extension, shape, and internal features [7–9].
Preliminary observations suggest that OCT
findings may even assist in differentiating and Fig. 12.2 Conjunctival intraepithelial neoplasia. Clinical
photograph (a) and optical coherence tomography (b).
diagnosing ocular surface squamous neoplasia Note a hyper-reflective and thickened epithelium with an
(Fig. 12.2) from pinguecula (Fig. 12.3) and abrupt transition zone from abnormal to normal epithe-
pterygium (Fig. 12.4). lium, consistent with ocular surface squamous neoplasia
12 Conjunctival and Corneal Tumors: Examination Techniques 133
a Confocal Microscopy
In vivo confocal microscopy can be a useful tool

for structural and cellular analysis of non-
pigmented and pigmented conjunctival and cor-
neal tumors. It is a noninvasive technique for
in vivo assessment of tissue features with high
correlation to histological findings [9–13].
Systemic Imaging
Other imaging methods such as computed tomog-

b raphy (CT), magnetic resonance imaging (MRI),
and positron emission tomography/CT (PET-CT)
may be necessary to assess extensive local inva-
sion, nodal disease, and systemic spread.
Biopsy
The definitive diagnosis of conjunctival and cor-

neal tumors is the histopathologic diagnosis.
Nevertheless, benign-looking, asymptomatic
Fig. 12.3 Pinguecula. Clinical photograph (a) and opti-
cal coherence tomography (b). Note a normal surface epi- tumors, such as nevi with cysts, are often man-
thelium with underlying hyper-reflective, subepithelial aged by observation, with biopsy only when there
mass, consistent with pinguecula is evidence of growth or malignant change. If a
a b
Fig. 12.4 Pterygium. Clinical photograph (a) and optical coherence tomography (b). Note a normal surface epithelium
with underlying hyper-reflective, subepithelial mass
small tumor does require biopsy, it is preferable References

to completely excise the lesion, to avoid seeding
of tumor cells if the tumor proves to be malig- 1. Pepperl JE, Ghuman T, Gill KS, et al. Chapter 29:
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lesion, it may be appropriate to perform an inci- p. 1–30.
2. Machado LM, Castro RS, Fontes BM. Staining pat-
sional biopsy, sampling the tumor by wedge terns in dry eye syndrome: rose Bengal versus lissa-
biopsy or punch biopsy. Incisional biopsy is also mine green. Cornes. 2009;28:732–4.
appropriate when complete excision is not usu- 3. Damato B, Coupland SE. Clinical mapping of conjunc-
ally the treatment of choice (e.g., primary tival melanomas. Br J Opthalmol. 2008;92:1545–9.
4. Conway RM, Chew T, Golchet P, et al. Ultrasound
acquired melanosis) and with tumors that are biomicroscopy: role in diagnosis and management in
preferably treated by radiotherapy, chemother- 130 consecutive patients evaluated for anterior seg-
apy, and local means such as cryotherapy and ment tumours. Br J Ophthalmol. 2005;89:950–5.
topical chemotherapy. 5. Ho VH, Prager TC, Diwan H, et al. Ultrasound
biomicroscopy for estimation of tumor thickness
Exfoliative cytology has been used for diag- for conjunctival melanoma. J Clin Ultrasound.
nosing conjunctival and corneal tumors [14, 2007;35:533–7.
15]. However, this method samples only the 6. Bianciotto C, Shields CL, Guzman JM, et al.
superficial layers of the lesion and does not Assessment of anterior segment tumors with ultra-
sound biomicroscopy versus anterior segment optical
show the invasiveness of the tumor, which is coherence tomography in 200 cases. Ophthalmology.
important when planning management. 2011;118:1297–302.
Conjunctival map biopsies have been performed 7. Kieval JZ, Karp CL, Abou Shousha M, et al. Ultra-
with tumors such as the pagetoid spread of seba- high resolution optical coherence tomography for dif-
ferentiation of ocular surface squamous neoplasia and
ceous adenocarcinoma, to determine the extent pterygia. Ophthalmology. 2012;119(3):481–6.
of disease [16, 17]. 8. Thomas BJ, Galor A, Nanji AA, et al. Ultra high-
Immunohistochemistry is routine when exam- resolution anterior segment optical coherence
ining excisional or incisional biopsies of con- tomography in the diagnosis and management of
ocular surface squamous neoplasia. Ocul Surf.
junctival tumors. Advanced techniques such as 2014;12:46–58.
fluorescence in-situ hybridization (FISH), and 9. Janssens K, Mertens M, Lauwers N, et al. To study
ex-vivo fluorescence confocal microscopy have and determine the role of anterior segment optical
also been used [18, 19]. In recent years, genetic coherence tomography and ultrasound biomicroscopy
in corneal and conjunctival tumors. J Opthalmol.
tests of excised conjunctiva, such as analysis of 2016;(Epub ahead Dec 2016).
multiple DNA copy number alterations, genome- 10. Messmer EM, Mackert MJ, Zapp DM, et al. In
wide analysis, microRNA expression profile, and vivo confocal microscopy of pigmented conjunc-
whole exome profiling, have been applied tival tumors. Graefes Arch Clin Exp Ophthalmol.
2006;244:1437–45.
[20–23]. 11. Alomar TS, Nubile M, Lowe J, et al. Corneal intraepi-
Sentinel lymph node biopsy (SLNB), which is thelial neoplasia: in vivo confocal microscopic study
performed in some ophthalmic oncology centers, with histopathologic correlation. Am J Opthalmol.
especially in cases of conjunctival melanoma, is 2011;151:238–47.
12. Xu Y, Zhou Z, Xu Y, et al. The clinical value of
considered to be a safe procedure with minimal in vivo confocal microscopy for diagnosis of
complications. However, the relation between ocular surface squamous neoplasia. Eye (Lond).
SLNB and patient survival and tumor recurrence 2012;26(6):781–7.
requires further investigation [24–26] (see Chap. 13. Cinotti E, Singer A, Labeille B, et al. Handheld
in vivo reflectance confocal microscopy for the
21 for details).
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diagnosis of eyelid margin and conjunctival tumors. ing frequent 8p11.22 amplification in conjunctival
JAMA Opthalmol. 2017;135:845–51. squamous cell carcinoma. Invest Opthalmol Vis Sci.
14. Semenova EA, Milman T, Finger PT, et al. The diag- 2014;55:8604–13.
nostic value of exfoliative cytology vs histopathol- 21. Takahashi H, Usui Y, Ueda S, et al. Genome-wide
ogy for ocular surface squamous neoplasia. Am J analysis of ocular adnexal lymphoproliferative
Ophthalmol. 2009;148(5):772–8. disorders using high-resolution single nucleotide
15. Kayat KV, Correa Dantas PE, Felberg S, et al. polymorphism Array. Invest Opthalmol Vis Sci.
Exfoliative cytology in the diagnosis of ocular surface 2015;56:4156–65.
squamous neoplasms. Cornea. 2017;36:127–30. 22. Larsen AC, Mikkelsen LH, Borup R, et al. MicroRNA
16. Putterman AM. Conjunctival map biopsy to expression profile in conjunctival melanoma. Invest
determine pagetoid spread. Am J Ophthalmol. Ophthalmol Vis Sci. 2016;57:4205–12.
1986;102:87–90. 23. Galor A, Karp CL, Sant D, et al. Whole exome
17. McConnell LK, Syed NA, Zimmerman MB, et al. profiling of ocular surface squamous neoplasia.
An analysis of conjunctival map biopsies in seba- Ophthalmology. 2016;123:216–7.
ceous carcinoma. Ophthal Plast Reconstr Surg. 24. Maalouf TJ, Dolivet G, Angioi KS, et al. Sentinel
2017;33:17–21. lymph node biopsy in patients with conjunctival and
18. Mudhar HS, Smith K, Talley P, et al. Fluorescence in eyelid cancers: experience in 17 patients. Ophthalmic
situ hybridisation (FISH) in histologically challenging Plast Reconst Surg. 2012;28:30–4.
conjunctival melanocytic lesions. Br J Ophthalmol. 25. Cohen VM, Tsimpida M, Hungerford JL, et al.
2013;97:40–6. Prospective study of sentinel lymph node biopsy
19. Iovieno A, Longo C, De Luca M, et al. Fluorescence for conjunctival melanoma. Br J Ophthalmol.
confocal microscopy for ex vivo diagnosis of con- 2013;97:1525–9.
junctival tumors: a pilot study. Am J Ophthalmol. 26. Pfeiffer ML, Ozgur OK, Myers JN, et al. Sentinel
2016;168:207–16. lymph node biopsy for ocular adnexal melanoma.
20. Asnaghi L, Alkatan H, Mahale A, et al. Identification Acta Ophthalmol. 2017;95:e323–8.
of multiple DNA copy number alterations includ-
Classification and Differential
13
Diagnosis
Introduction Anatomical Features
Many different types of tumor can arise in the Epithelium

conjunctiva, which is composed of a wide variety
of cells that form the epithelium and the substan- The conjunctival epithelium near the limbus,
tia propria. The bulbar conjunctiva that lies within where it is continuous with the corneal epithe-
the palpebral fissure is exposed to sunlight, which lium, and in the mucocutaneous junction, where
may be a factor in the development of some of the it is continuous with the eyelid skin epidermis is
tumors. The entire conjunctiva may be affected a non-keratinized stratified squamous epithelium.
by a wide variety of chemical, physical, and bio- The epithelial cells are stratified columnar in the
logical insults that may influence the develop- fornix and tend to be cuboidal on the bulbar and
ment of some of the tumors. Most of the tarsal conjunctiva. Goblet cells are present in the
conjunctival and corneal tumors are diagnosed middle and superficial layers of the epithelium
early because they are readily visible. and most numerous in the lower fornix and close
Epithelial non-melanocytic and melanocytic to the plica semilunaris, being almost completely
tumors of the cornea are very rare and are usually absent in the limbal areas. Melanocytes are scat-
the result of involvement of the cornea in con- tered in the basal layer of the epithelium.
junctival tumors. Corneal stromal tumors are
almost nonexistent.
The conjunctiva may be invaded by tumors Stroma
from its surrounding structures – the eyeball,
eyelid, and orbit – and may develop metastases The conjunctival stroma is composed of a fibro-
from distant organs. vascular connective tissue that is thicker in the
fornix and thinner over the globe and the poste-
rior surface of the eyelids. It contains collagenous
and elastic tissue; vessels including arteries,
veins, and lymphatics; nerves; and accessory lac-
J. Pe’er (*) · S. Frenkel rimal glands of Krause and Wolfring. Like other
Ocular Oncology Service and Ophthalmic Pathology mucous membranes, the conjunctiva contains
associated lymphoid tissue. Numerous lympho-
Jerusalem, Israel cytes, plasma cells, mast cells, and neutrophils
e-mail: peer@hadassah.org.il are present in the conjunctival stroma.

Lymphocytes may be aggregated into nodules, The classification of conjunctival and corneal
but without the formation of follicles. tumors that appear in this section is based primar-
ily on the second edition of the World Health
Organization (WHO) International Histological
Specialized Regions Classification of Tumors, in its volume on histo-
logical typing of tumors of the eye and its adnexa
Plica Semilunaris [1]. Since this classification does not include all
The plica semilunaris is a vertical fold of con- conjunctival tumors, the list has been completed
junctiva lying lateral to the caruncle. There are by using some other major series of conjunctival
eight to ten layers of epithelial cells containing and corneal tumors [2–4]. The following list of
many goblet cells. The loose, highly vascular tumors (Tables 13.1, 13.2, and 13.3) includes
stroma may have some nonstriated muscle fibers both common and rare, sometimes very rare,
supplied by sympathetic nerves and may contain tumors, so as to familiarize the reader with the
fatty tissue. current terminology.
Caruncle
The caruncle is a fleshy prominence located in Differential Diagnosis
the medial canthus. It contains both conjunctival
and cutaneous structures. It is covered by nonke- Most conjunctival tumors are benign; malignant
ratinized stratified squamous epithelium with tumors are relatively rare. When considering the
many goblet cells and contains hair as well as differential diagnosis, it is important to take
sebaceous, sweat, and accessory lacrimal glands. account of the patient’s general health as well as
Its blood and nerve supply is abundant. Tumors the clinical features of the lesion. The more
of the caruncle can be of both mucosal and cuta- important diagnostic clues are the color of the
neous origin. lesion (i.e., pigmented, non-pigmented, red, pink,
blue, white, or yellow); consistency (i.e., hard,
soft, rubbery, gelatinous); solid or cystic nature;
Classification of Conjunctival size; number (i.e., solitary or multiple); surface
and Corneal Tumors (i.e., smooth, irregular, granular, papillary, ulcer-
ated or umbilicated, with or without keratin);
The classification of the conjunctival tumors, like
tumors of other parts of the body, is made accord-
Table 13.1 Major types of conjunctival tumor
ing to two major lines: the tissue or cell of origin
of the tumor and its being benign or malignant. In Epidermal Non-melanocytic
Melanocytic
groups of tumors, there may be subtypes of
Stromal Vascular
tumors that, due to special histological structures, Neural
features, and location of the tumor cells, can Myxoid
appear or behave differently in spite of being of Lipomatous
the same cell of origin. Melanocytic
Most conjunctival tumors are of epithelial and Fibrous tissue
melanocytic origin. The remainder arise from Histiocytic
Myogenic
various elements of the conjunctival stroma and
Lymphoproliferative
include vascular, fibrous, neural, histiocytic, Congenital Hamartoma
myogenic, myxoid, lipomatous, and lymphopro- Choristoma
liferative tumors. Three unique groups of con- Caruncular
junctival tumors are the hamartomas and Metastatic
choristomas, the caruncular tumors, and meta- Secondary
static and secondary tumors. Simulating lesions
13 Conjunctival and Corneal Tumors: Classification and Differential Diagnosis 139
Table 13.2 Classification of epidermal tumors of the conjunctiva

Types Subtypes
Non-melanocytic Benign Squamous papilloma
Keratotic plaque
Keratoacanthoma
Reactive hyperplasia (pseudoepitheliomatous hyperplasia)
Hereditary intraepithelial dyskeratosis
Oncocytoma
Dacryoadenoma
Premalignant and malignant Actinic (solar) keratosis
Conjunctival intraepithelial neoplasia (CIN)
Xeroderma pigmentosum
Mucoepidermoid carcinoma
Spindle cell carcinoma
Sebaceous gland carcinoma (pagetoid spread)
Basal cell carcinoma
Melanocytic Benign Junctional nevus
Compound nevus
Spitz nevus
Blue nevus
PAM without atypia
Congenital melanosis
Racial melanosis
Premalignant and malignant PAM with atypia
Melanoma arising from nevi
Melanoma arising in PAM
shape (i.e., flat or raised, pedunculated, papil-

lary); thickness; location (i.e., bulbar, palpebral, Melanocytic Lesions
forniceal, caruncular); layer (i.e., epithelial or Melanocytic lesions include nevi, primary
stromal); growth rate; and adherence to underly- acquired melanosis (PAM) without or with
ing structures, such as the sclera. Other diagnos- atypia, and melanomas. While melanosis is
tic clues include the patient’s race, age, gender; purely epithelial, nevi and melanomas also
as well as any present or previous systemic dis- involve the stroma. While in bulbar conjunctival
eases, such as metabolic disease or malignancy, melanosis the lesions are movable with the con-
particularly in adjacent tissues (e.g., lacrimal junctiva, in melanoma, the tumor may be fixed to
drainage system, eyelids, globe, orbit). the underlying sclera. Staging of conjunctival
melanoma can be found in the AJCC Cancer
Staging Manual [5].
Epidermal
Non-Melanocytic Lesions
Epidermal tumors are usually classified into Non-melanocytic lesions are usually epithelial.
melanocytic and non-melanocytic tumors, based Epithelial tumors, such as papilloma and carci-
on the clinical presence or absence of brown- noma, usually have irregular, granular, or papillary
black pigmentation and histological evidence of surface and may be leukoplakic (white, because
melanocytes, although non-melanocytic tumors they are covered by keratin). Sometimes they may
(e.g., squamous cell carcinoma) can rarely be be gelatinous in appearance. They may be superfi-
pigmented. cial and thin or thick and fleshy. Conjunctival car-
Table 13.3 Classification of stromal tumors of the Congenital Tumors

conjunctiva
Types Subtypes Congenital tumors diagnosed in infancy and
Vascular Capillary hemangioma childhood are usually hamartomatous or chori-
Varix
stomatous lesions.
Hemangiopericytoma
Kaposi’s sarcoma
Malignant
hemangioendothelioma Caruncular Tumors
Cavernous hemangioma
Racemose malformation Caruncular tumors present a special challenge of
Lymphangiectasia
differential diagnosis of both conjunctival and
Lymphangioma
Fibrous Nodular fasciitis
cutaneous tumors (see Chap. 19).
Benign fibrous histiocytoma
Fibroma
Malignant fibrous histiocytoma Metastatic and Secondary Tumors
Neural Neurofibroma (localized)
Schwannoma (neurilemmoma) In the case of metastatic tumors, there is usually
Neurofibroma (diffuse)
a history of primary malignancy elsewhere in the
Granular cell tumor
Histiocytic Xanthoma
body. In secondary involvement of the conjunc-
Reticulohistiocytoma tiva by tumors in surrounding structures, the pri-
Juvenile xanthogranuloma mary tumor is usually well known, except for
Myxoid Myxoma many cases of pagetoid spread of sebaceous
Myogenic Rhabdomyosarcoma gland carcinoma of the eyelid in which the pre-
Lipomatous Lipoma sentation of the malignancy can be in the
Liposarcoma
conjunctiva.
Herniated orbital fat
Lymphoproliferative Benign reactive lymphoid
hyperplasia
Leukemic infiltrates Simulating Lesions
Lymphoma
It is interesting to note that the WHO histological
classification of conjunctival tumors includes
cinoma can invade the orbit, the eyelid, and the lesions that simulate tumors such as pinguecula
globe. Staging of conjunctival carcinoma can be and pterygium. These most common conjunctival
found in the AJCC Cancer Staging Manual [6]. lesions are not real neoplasms but sometimes can
be confused with real tumors when they are cov-
ered by keratin plaque or have a gelatinous
Stromal Tumors appearance. Keloid is also included in this classi-
fication. Among conditions that may simulate
Stromal tumors, including secondary tumors and pigmented conjunctival tumors, we have to con-
metastasis have a smooth surface, being under sider drug and metallic deposits, mascara depos-
the conjunctival surface. The color of the tumor its, foreign body, post-inflammatory melanosis,
can be very helpful in the diagnosis. Most vascu- and systemic conditions with flat pigmentary
lar tumors are red, pink, or sometimes blue. patches such as in Addison’s disease [7].
Fibrous tumors are white but may be pink. Inflammatory and infectious lesions such as lep-
Neural, histiocytic, and lipomatous tumors are romatous and sarcoidal nodules and, more com-
yellow, and lymphoid tumors and leukemic monly, allergic and granulomatous nodules should
infiltrates are pink, similar to smoked salmon, be included in the differential diagnosis of con-
and thus are termed “salmon patch.” junctival tumors.
13 Conjunctival and Corneal Tumors: Classification and Differential Diagnosis 141
References 5. Conway RM, Graue GF, Pelayes D, et al. Chapter

65: Conjunctival carcinoma. In: Amin MB, et al., edi-
tors. AJCC cancer staging manual. 8th ed. New York:
1. Campbell RJ, Sobin LH. Tumors of the conjunctiva and
Springer; 2017. p. 787–93.
caruncle. In: Histological typing of tumours of the eye
6. Coupland SE, Barnhill R, Conway RM, et al. Chapter
and its adnexa, World Health Organization International
66: Conjunctival melanoma. In: Amin MB, et al., edi-
Histological Classification of Tumours. 2nd ed. Berlin:
tors. AJCC cancer staging manual. 8th ed. New York:
Springer; 1998. p. 9–15.
Springer; 2017. p. 795–803.
2. Shields CL, Shields JA. Tumors of the conjunctiva and
7. Folberg R, Jakobiec FA, Bernardino VB, et al. Benign
cornea. Surv Ophthalmol. 2004;49:3–24.
conjunctival melanocytic lesions. Clinicopathologic
3. Grossniklaus HE, Green WR, Luckenbach M, et al.
features. Ophthalmology. 1989;96:436–501.
Conjunctival lesions in adults. A clinical and histopatho-
logic review. Cornea. 1987;6:78–116.
4. Elsas FJ, Green WR. Epibulbar tumors in childhood. Am
J Ophthalmol. 1975;79:1001–7.
Benign Epidermal and Melanocytic
14
Tumors
Introduction Squamous Cell Papilloma
Benign tumors of the conjunctiva are much more Conjunctival squamous papilloma is a benign
common than malignant tumors of the conjunc- and common epithelial tumor that can be seen at
tiva. In this chapter, benign tumors of epithelial almost any age, although more commonly occurs
and melanocytic origin, which comprise the in young adults [1–4]. More males than females
majority of the conjunctival tumors, are described. develop conjunctival papilloma [4]. Conjunctival
Benign conjunctival tumors of stromal origin are squamous papillomas are often located in the
described in Chap. 17. inferior fornix or bulbar conjunctiva but may
appear in any part of the conjunctiva including
the palpebral conjunctiva, lid margin, caruncle,
Benign Tumors of the Epithelium and plica semilunaris. According to one study,
most of the papillomas are located medially and
Abnormal cellular proliferation and differentia- inferiorly, a fact that is explained by the direction
tion that is confined to the conjunctival epithe- of the tear flow [4].
lium may cause thickening, papillary or nodular
focal elevation of the conjunctiva, and sometimes Clinical Features
plaque-like opacification (leukoplakia). Such
lesions rarely progress to malignancy. Childhood Papilloma
In children, the papillomas have been docu-
mented to be associated with human papilloma
virus (HPV) (mostly types 6, 11, and 16) infec-
tion of the conjunctiva. The papilloma appears as
sessile or pedunculated pink/red fleshy fronds of
tissue or finger-like projections with an irregular
surface that sometimes resembles a cauliflower
(Fig. 14.1a). They are often asymptomatic, with-
J. Pe’er (*) · S. Frenkel out associated inflammatory reaction. However,
Ocular Oncology Service and Ophthalmic Pathology large and more pedunculated lesions are usually
symptomatic and may cause foreign body sensa-
Jerusalem, Israel tion, mucous secretion, hemorrhagic tears,
e-mail: peer@hadassah.org.il incomplete eyelid closure, and poor cosmetic

a b
Fig. 14.1 Solitary sessile squamous papilloma of the nonkeratinized squamous epithelium with central fibro-
bulbar conjunctiva. Clinical appearance (a). vascular cores (b; hematoxylin and eosin, original magni-
Histopathology shows papillomatous fronds of acanthotic fication ×4)
appearance. They are usually solitary but can be goblet cells were more frequently associated with
bilateral and multiple and may become HPV infection [7].
confluent. In adults, the squamous papilloma usually has
a broader base, and its acanthotic epithelium may
Adulthood Papilloma show varying degree of epithelial pleomorphism,
In adults, conjunctival squamous papilloma usu- and even dysplasia can occur, albeit generally
ally appears as single and unilateral lesions, com- mild. Although the lesions are usually nonkera-
monly arising close to the limbal area or bulbar tinized, moderate keratinization may be present.
conjunctiva. They are usually flat with a broad The basement membrane is typically intact.
base, may be large and cover a large area of the
conjunctiva, and may cover the cornea and inter- Treatment
fere with vision. Sometimes it may be difficult to Small papilloma in children can be observed, as
differentiate them clinically from squamous cell there usually is a slow spontaneous resolution.
carcinoma. However, larger papillomas should be treated
by complete surgical excision, where some
Histopathologic Features prefer the use of the “no-touch technique” to
Histologically, the squamous papilloma of child- avoid spreading the papilloma-related virus [3].
hood is composed of epithelial projections cov- Others find that this spread has already occurred
ered by nonkeratinized acanthotic stratified through the tears, and through hemorrhage at
squamous epithelium, which may have goblet the time of the surgery and therefore do not
cells, and have a fibrovascular core in which use this technique, and opt for adjuvant topical
acute and chronic inflammatory cells are often chemotherapy, if needed. Cryotherapy is often
found (Fig. 14.1b). The basement membrane is used in conjunction with the “no-touch” surgi-
always intact. Various types of HPV, the most cal technique, either to the conjunctiva around
common are HPV-6 and HPV-11, have been the excised lesion or to the lesion itself that is
demonstrated in these papillomas by various then excised in a frozen state. Sometimes cryo-
immunohistochemical and molecular techniques therapy may be performed without excision,
[5–7]. Some clinical and histopathological fea- letting the lesion slough off the conjunctival
tures such as extralimbal location and presence of surface later.
14 Conjunctival and Corneal Tumors: Benign Epidermal and Melanocytic Tumors 145
Conjunctival papillomas tend to recur often, distinction is made from inverted squamous pap-
usually when multiple lesions are caused by papillomas of the nasal cavity and sinuses [18].
illomavirus. Such lesions may be treated by adju- However, complete removal of these lesions is
vant interferon alpha-2B locally or systemically still recommended.
[8, 9] or topical mitomycin C [10]. Others have
used carbon dioxide laser vaporization [11], pho-
todynamic therapy [12], scanning laser photoco- Seborrheic Keratosis
agulation [13], or oral cimetidine [12, 14].
Papilloma recurrence is more common in chil- Seborrheic keratosis of the conjunctiva is
dren and adolescents than in adults [12]. In one extremely rare, and only a very few case reports
study, the recurrence after surgical excision was are found in the medical literature [19]. They
associated with epithelial atypia [15]. mostly appear as a pigmented conjunctival lesion
and may be misdiagnosed clinically as conjuncti-
val melanoma. The typical basaloid cell acantho-
I nverted Papilloma (Inverted sis and keratin-filled pseudocysts confirm the
Follicular Keratosis) diagnosis.
The lesions derive their name from the propen-

sity to invaginate inward into the underlying con- eactive Epithelial Hyperplasia
R
junctival substantia propria, instead of growing in (Pseudoepitheliomatous Hyperplasia
an exophytic manner outward like the other con- and Pseudocarcinomatous
junctival papillomas. Some of the lesions may Hyperplasia)
show a mixed inverted-exophytic papilloma [16].
This conjunctival lesion is secondary to irritation
Clinical Features by concurrent or preexisting stromal inflamma-
These are rare lesions that appear as solid or cys- tion [1–3].
tic solitary nodules in the conjunctiva, although
they may present as papillary sessile lesion [16, Clinical Features
17]. They have been reported to appear in the It appears as an elevated leukoplakic pink lesion
limbal area, plica semilunaris, and tarsal in the limbal area.
conjunctiva.
Histopathologic Features Acanthosis, hyperkeratosis or parakeratosis, and
Lobules of proliferating epithelium without kera- subepithelial inflammation are observed. Mitotic
tinization or inflammation invaginate the under- figures may be present, but cytologic atypia is
lying connective tissue. Mucus-producing goblet generally lacking. Due to the possible clinical
cells are scattered throughout the lesions, and and histological difficulty in differentiating such
mucoid material, when it exists, is found in the lesions from conjunctival squamous cell carci-
wall of the cyst. Lesions without goblet cells at noma, it should be completely excised, and addi-
all were also reported [15]. tional cryotherapy may be considered.
Unlike inverted papillomas in other sites, such
as the nose, paranasal sinuses, and lacrimal sac,
conjunctival inverted papilloma does not exhibit Keratoacanthoma
locally aggressive behavior, does not involve
extensive segments of the conjunctival epithe- This is a variant of conjunctival reactive epithe-
lium, and does not display diffuse spread or mul- lial hyperplasia that does not show spontaneous
ticentricity. Therefore, it is suggested that a clear regression [1, 3, 20].
Clinical Features United States. Using genetic linkage analysis, the

Keratoacanthoma appears as a benign, solitary, HBID gene was localized to chromosome 4
gelatinous, or leukoplakic rapidly growing nod- (4q35) [22].
ule on the bulbar conjunctiva surrounded by
dilated blood vessels [1, 3, 20, 21]. In some cases, Clinical Features
an umbilicated center is observed (Fig. 14.2a). HBID is characterized by bilateral elevated fleshy
plaques on the nasal or temporal perilimbal bul-
Histopathologic Features bar conjunctiva, with dilated conjunctival vessels
The lesion shows marked invasive acanthotic epi- around it, causing the eye to appear red [1, 3]
thelium with keratin-filled pseudocysts, hyper- (Fig. 14.3a). In mild cases, the patients are
keratosis, and parakeratosis (Fig. 14.2b). Usually asymptomatic, but in severe cases, most of the
there is minimal cytologic atypia. In cases with a bulbar conjunctiva and cornea are involved, caus-
marked degree of atypia, it may be difficult to ing corneal opacification and vascularization
distinguish the lesion from well-differentiated leading to loss of vision. Patients may complain
squamous cell carcinoma. of foreign body sensation, photophobia, and tear-
ing, especially in the spring. Similar lesions may
Treatment occur in the buccal mucosa.
Therefore, conjunctival keratoacanthoma should
be treated by complete excision, and additional Histopathologic Features
cryotherapy should be considered. The lesions are characterized by acanthosis,
prominent dyskeratosis in the surface and deep
epithelium, and severe chronic inflammation in
ereditary Benign Intraepithelial
H the stroma (Fig. 14.3b). The basement membrane
Dyskeratosis (HBID) is intact. The lesions do not have malignant
potential.
HBID is an autosomal dominant disorder with a
high degree of penetrance occurring in descen- Treatment
dants of an inbred isolate of European, African- HBID usually does not require aggressive treat-
American, and Native American (Haliwa Indian) ment. Mild cases can be treated by ocular lubri-
origin in northeastern North Carolina. HBID has cants, and, if needed, by topical corticosteroids.
been subsequently detected in other parts of the Larger lesions can be treated by local excision.
a b
Fig. 14.2 A rapidly growing keratoacanthoma of the (b; hematoxylin and eosin, original magnification ×2).
bulbar conjunctiva at the limbus. Clinical appearance
(Reprinted from Munro et al. [20]. With permission from
(a). Histopathology of the lesion demonstrates squamous Elsevier)
epithelium with invasive acanthosis and hyperkeratosis
a b
Fig. 14.3 Hereditary benign intraepithelial dyskeratosis. dyskeratosis, and marked chronic inflammation in the
Typical clinical appearance is of a white lesion of the tem- stroma beneath the intact basement membrane (b; hema-
poral conjunctiva with dilated conjunctival vessels around toxylin and eosin, original magnification ×20). (Courtesy
it (a). Histopathology showing acanthosis, hyperkeratosis, of Gordon Klintworth, MD)
Mucous membrane grafting can be used when lesion in older individuals, mostly women [2, 24,
the excision is wide. Recurrence of HBID lesions 25]. Histologically, large cells with eosinophilic
is common. granular cytoplasm are arranged in nests, cords,
or sheets and may form glandular or ductal struc-
tures. Ultrastructurally, the cytoplasm is laden
Dacryoadenoma with mitochondria. The lesion is treated by sim-
ple excision. Rarely, the tumor may undergo car-
Dacryoadenoma is a rare conjunctival tumor that cinomatous transformation.
occurs in children and young adults. It appears as
a translucent pink lesion in the bulbar, forniceal,
or palpebral conjunctiva [3]. It is uncertain Epithelial Cysts
whether the lesion is congenital or acquired.
Histologically, it is a benign epithelioid cell pro- Conjunctival cysts are common and may be con-
liferation forming glandular lobules, similar to genital or acquired. The acquired cysts are more
the lacrimal gland. In one reported case, scattered common and are mostly epithelial inclusion cysts
myoepithelial cells were associated with acinar- that can occur spontaneously or following surgi-
type epithelium, and goblet cells were intermixed cal or nonsurgical trauma [1, 3, 26] (Fig. 14.4).
[23]. The lesions are treated by simple excision. Other common cysts are ductal cysts, usually of
accessory lacrimal gland origin (Fig. 14.5).
Oncocytoma Clinical Features

The conjunctival cyst is a smooth translucent
Oncocytoma, known also as oxyphilic cell ade- lesion that contains clear fluid, although the fluid
noma, is a rather common lesion of the lacrimal may be turbid (Fig. 14.6) or contain epithelial
gland. It often arises in the caruncle or adjacent debris in the lumen that is layered like pseudohy-
plica semilunaris and canthal conjunctiva as a popyon (Fig. 14.7). In dark-skinned patients, the
slowly-growing benign yellow-tan or reddish cyst can be pigmented.
a b
Fig. 14.4 Epithelial inclusion cyst. Multiple cysts in the inferior fornix (a). A large conjunctival cyst in the nasal bulbar
conjunctiva that occurred after strabismus surgery (b)
a b
Fig. 14.5 Ductal cyst. Bluish cyst in the temporal bulbar ductal-type cyst, possibly from an accessory lacrimal
conjunctiva. Posterior margin of the cyst cannot be visual- gland. Apocrine differentiation may be metaplastic
ized (a). The cyst lined by two cell layers, with luminal (b, hematoxylin and eosin stain, 40× magnification).
cells showing apical snouts, consistent with apocrine dif- (Reprinted with permission from Bryn Mawr
ferentiation. The double cell lining is consistent with a Communications. Aponte et al. [51])
Histopathologic Features Treatment

The epithelial inclusion cyst is lined by conjunc- The cyst can be stable and asymptomatic or can
tival epithelium. The lumen can be clear or it can enlarge and become symptomatic, necessitating
contain mucinous material, epithelial debris, and excision. In most cases, over the long-term fol-
occasionally keratin. Ductal cysts are lined by low-up, the cyst eventually undergoes spontane-
two layers of epithelium and may contain PAS- ous resolution. Successful removal of conjunctival
positive material. cysts with high-frequency radio-wave electrosur-
gery was reported [27].
a b
Fig. 14.6 Conjunctival epithelial cyst with lipid contents (a). Anterior segment OCT reveals fat filled content
(b, droplets)
a b
Fig. 14.7 Conjunctival epithelial cyst with layered contents (a). Anterior segment OCT reveals multiple levels within
cysts (b)
Keratotic Plaque Actinic Keratosis
This is a leukoplakic lesion that may develop in Actinic keratosis of the conjunctiva is a rarely-
the limbal or bulbar conjunctiva, usually in the diagnosed focal leukoplakic lesion occurring at
interpalpebral region (Fig. 14.8) [1, 2]. the intrapalpebral limbus, usually located over a
Histologically, there is a focal thickening of kera- chronically inflamed pinguecula or pterygium [2,
tin and epithelial layer, characterized mainly by 3, 28]. Rare cases of tarsal conjunctival involve-
acanthosis, hyperkeratosis, or parakeratosis. No ment were reported [29]. Actinic Keratosis is
dyskeratosis is seen. These lesions have little or classified among precancerous lesions, and it is
no potential for carcinomatous changes. also referred to as conjunctival dysplasia, actinic
a b
Fig. 14.8 Keratotic plaque. Clinical appearance (a). degeneration (b, Hematoxylin & Eosin ×20). (Courtesy of
Conjunctiva with loss of goblet cells, hyperkeratotic epi- Gabreilla Yeaney, MD, Cleveland, Ohio)
thelium, and Underlying stroma with basophilic elastotic
keratosis variety. Histologically, the epithelium It appears in all races, although it is more com-
exhibits acanthosis, hyperkeratosis, and mon in Caucasians. Many ophthalmic oncolo-
occasionally parakeratosis. The degree of dyspla- gists and pathologists will consider nevi that
sia is minimal. Due to suspicion of a squamous appear at birth or within the first 6 months of life
cell carcinoma, these lesions are usually excised. as congenital nevi, and those that appear more
Treatment by topical Imiquimod was successful than 6 months after birth to be acquired. Most
in one reported case [30]. acquired conjunctival nevi will appear during the
first two decades of life. Melanocytic conjuncti-
val lesions that appear later in life should be sus-
Benign Melanocytic Tumors picious for PAM or melanoma (Box 14.1).
Conjunctival nevi are the most common conjunc- Box 14.1. Clinical Features of Conjunctival
tival lesions. The various types of nevi are dis- Nevus that Are Suspicious for Melanoma
cussed herein, together with other benign
melanocytic lesions of the conjunctiva, the epi-
sclera and sclera, such as complexion-associated • Onset in adulthood
melanosis, ocular melanocytosis, and primary • Recent growth of the nevus
acquired melanosis (PAM) without atypia. There • Recent color change of the nevus
are many other pigmented conjunctival lesions • Location other than bulbar conjunctiva,
that are not of melanocytic origin and should plica semilunaris, or caruncle
always be included in the differential diagnosis of • Prominent feeder vessels
melanocytic conjunctival lesions (see Chap. 15). • Recurrence of excised lesion
Conjunctival Nevus
Clinical Features
Introduction Conjunctival nevi are typically located in the
The circumscribed nevus is the most common interpalpebral bulbar conjunctiva, commonly
melanocytic conjunctival tumor [31, 32]. near the limbus, and rarely involve the cornea
[32]. The finding of melanocytic tumors in loca- Nevi may become darker or lighter but usually
tions other than bulbar conjunctiva, plica will not change in size and color after adoles-
semilunaris, and caruncle is rare and should raise cence. Changes in adulthood should raise the
the suspicion for PAM or malignant melanoma. suspicion for malignant transformation. The
Clinically, conjunctival nevus is a discrete, vari- overall risk of malignant transformation is about
ably pigmented, slightly elevated sessile lesion, 1% [32]. The presence of cystic structures can
which in most cases contains cystic structures help in differentiating nevi from other possible
that can be seen by the naked eye, slit-lamp bio- amelanotic conjunctival lesions. In childhood
microscopy (Fig. 14.9), or anterior segment and adolescence, conjunctival nevi may become
OCT (Fig. 14.10). Conjunctival nevi may vary in more pink and congested, due to inflammatory
size from tiny lesions to ones that occupy large infiltration. These inflamed nevi will be dis-
parts of the bulbar conjunctiva (Fig. 14.11) [33]. cussed separately.
a b
Fig. 14.9 A typical partially pigmented compound (a). Histopathology of a compound nevus of the conjunc-
conjunctival nevus with cystic elements, in an atypi-
tiva with cystic structures lined by conjunctival epithelium
cal location in the upper bulbar conjunctiva at the limbus (b; hematoxylin and eosin, original magnification ×10)
a b
Fig. 14.10 A partially pigmented conjunctival nevus. Intrinsic cysts are not readily identified (a). Anterior segment
OCT reveals multiple cysts within the nevus (b)
a b
Fig. 14.11 Large conjunctival nevus. Clinical appearance (a). Histopathology revealed a compound nevus with cystic
structures lined by conjunctival epithelium (b; hematoxylin and eosin, original magnification ×10)
Histopathologic Features Compound Nevus

Conjunctival nevi range from junctional through Compound conjunctival nevi represent an inter-
compound to subepithelial nevi and reflect mediate stage between the early junctional and
stages in the evolution of the nevus. Most late subepithelial nevus stage. They usually
excised nevi that are examined in the ophthal- appear as elevated, well-circumscribed, pig-
mic pathology laboratories are compound nevi. mented lesions. Nests of nevus cells are found in
Two distinctive types of nevus cells were the substantia propria in addition to the junctional
described in the conjunctiva, balloon cells and area and have less cytoplasm, which may reflect
spindle cells [34, 35], and they usually appear in maturation. Solid nests of epithelium and
otherwise typical conjunctival nevus. About half epithelial cysts are very common within a com-
of the conjunctival nevi express BRAF and pound nevus and may confuse the pathologist
NRAS mutations [36]. who is not familiar with conjunctival nevi
(Fig. 14.11).
Junctional Nevus
The junctional nevi usually appear as focal, flat, Subepithelial Nevus
well-circumscribed lesions with various amounts Subepithelial nevi are believed to represent the
of pigmentation. They are found only early in life last stage of conjunctival nevus, characterized by
and shows nests of nevus cells along the interface migration of intraepithelial nevus cells into the
of the epithelium and the substantia propria. The substantia propria, followed by the disappearance
cells in the junctional nevus can be round to oval, of the junctional component. They appear as ele-
plump, epithelioid, cuboidal, or lymphocyte-like vated, well-circumscribed, pigmented lesions.
cells. They can form single, confluent, or irregu- Microscopically, these nevi typically appear as a
lar nests anterior to the epithelial basement mem- symmetrically arranged intrastromal prolifera-
brane which is in general intact. The epithelium tion of predominantly small lymphocytoid mela-
overlying the nests is commonly reduced to a thin nocytes, often organized in large nests. Cystic
rim. These lesions may be confused with primary and solid nests of conjunctival epithelium
acquired melanosis; the latter usually appears in entrapped in melanocytic proliferation are seen
adults. in about half of the lesions [31].
Clinicopathologic Variants the epithelial surface and are uniformly and sym-
metrically arranged, unlike spindle cells in typi-
Spitz Nevus cal conjunctival nevi that are oriented parallel to
A more distinctive type of conjunctival nevus is the surface. Mitotic figures reflect the rapid clini-
the Spitz nevus, which has been reported only in cal growth and do not indicate malignancy [31].
childhood and adolescence [37]. Clinically, these
lesions are rapidly growing non-pigmented Blue Nevus
lesions that should be differentiated from granu- Blue and cellular blue nevi are rare conjunctival
lation tissue (“pyogenic granuloma”) and, more lesions that arise from neural crest cells, are situ-
importantly, from melanoma, which is extremely ated in the deep conjunctival substantia propria,
uncommon in children. Histologically, conjuncti- and do not reach the surface epithelium (Fig. 14.12).
val Spitz nevi feature fascicles of spindle nevus Clinically, they appear brown or black and have a
cells that are usually oriented perpendicular to benign clinical course [31, 38, 39]. They can be
a b
c d
Fig. 14.12 Conjunctival blue nevus. The nevus is located stain reveals abundant cytoplasm, bland nuclei and incon-
under the conjunctival stroma (a) confirmed by anterior spicuous nucleoli (e, ×40). Immunohistochemistry for
segment OCT (b). Appearance following excision that SOX10 highlights the melanocytic nuclei, (f, ×40 red chro-
involved partial thickness scleral dissection, requiring mogen) HMB45 the melanocytic cytoplasm (g, ×40 red
scleral graft (c). Histopathology showing flat collection of chromogen), and CD163 highlights admixed macrophages
densely pigmented spindle melanocytes and melanophages (h, ×40 red chromogen). (Courtesy of Gabreilla Yeaney,
on scleral surface (d, Hematoxylin & Eosin ×20). Bleached MD, Cleveland, Ohio)
e f
g h
Fig. 14.12 (continued)
located in any part of the conjunctiva although lesional redness, often shows cystic structures,
most commonly in the bulbar conjunctiva [39]. and can be surrounded by vascular congestion
Histologically, the blue nevus is composed of spin- [41]. Therefore, these lesions are frequently
dle-shaped cells with uniform melanin pigmenta- approached with undue concern by patients and
tion. Elements of a blue nevus may be present in a clinicians, usually suspecting malignancy. More
typical conjunctival nevus. Such lesions have been than half of these nevi are amelanotic, and
termed “mixed nevus.” In cellular blue nevi, the changes in the pigmentation of amelanotic lesions
fascicles of spindle-shaped cells are admixed with have been documented (Fig. 14.13a).
fibrillar collagen. There has been only one report Histologically, these rapidly growing lesions
of conjunctival melanoma arising from a blue do not differ from simple compound conjunctival
nevus [40]. nevi in their benign histopathological features
[41]. Cystic and solid epithelial elements are
Inflamed Juvenile Conjunctival Nevus found in most of these nevi. In all lesions, there is
Inflamed juvenile conjunctival nevus (IJCN) is a significant polyclonal lymphocytic infiltration in
benign, juxta-limbal nevus that appears in chil- and around the nevus, and significant infiltration
dren and adolescents, can grow rapidly, shows of eosinophils is found in areas in most of these
a b
Fig. 14.13 Amelanotic inflamed juvenile conjunctival nevus nests with marked chronic inflammation around it
nevus in the temporal conjunctiva with cystic elements and a remarkable number of eosinophils (b; hematoxylin
and dilated vessels around it (a) Histopathology showing and eosin, original magnification ×40)
nevi (Fig. 14.13b) [41, 42]. Periods of rapid local excision of the lesion should be considered
growth of inflamed nevi represent inflammatory [32]. In general, incisional biopsy is contraindi-
infiltration and cystic enlargement, rather than cated in lesions that can be resected entirely.
malignant proliferation. Some of the indications for excisional biopsy of
IJCNs are almost always associated with conjunctival nevi include the recent growth of
symptomatic allergic conjunctivitis or asymp- the nevus, recent color change of the nevus, cos-
tomatic conjunctival papillary reaction. Increased metic concerns, recurrence of the excised lesion,
expression of nerve growth factor (NGF), eosino- and clinical suspicion of malignant melanoma.
phils, and mast cells in IJCN and modulation of Parts of the lesion can be amelanotic, which may
eosinophil properties by lesion fibroblasts partly lead to an incomplete surgical resection. At the
through NGF suggest a possible association time of excision, the entire mass is removed, and
between IJCN and allergic inflammation [43]. if adherent to the globe, a thin lamella of under-
Typical cases of IJCN can be differentiated on lying sclera is also removed with the lesion.
clinical grounds from conjunctival melanoma. Excision of wide margins and cryotherapy to the
IJCN should also be differentiated from “salmon tumor bed and the resection margins are
patch” lesions of conjunctival lymphoma, which employed by some surgeons to prevent recur-
is exceedingly rare in childhood, and the poly- rence, as the majority of cases that are excised
clonality of the lymphoid infiltrate that rule out are due to suspicion for malignant transforma-
the diagnosis of lymphoma [42]. The patient’s tion. Laser photoablation of conjunctival nevi
young age and the cystic nature of typical lesions has been shown to be a safe and effective treat-
are indicators of a benign lesion. ment [44, 45].
In cases of typical IJCN, observation alone
Treatment may suffice, although excisional biopsy is recom-
Most conjunctival nevi do not require excision, mended in atypical lesions or whenever the clini-
since most patients relate that the lesion has been cian cannot make a definite diagnosis of
present and stable for many years, often since IJCN. Similarly, lesions causing functional prob-
childhood or adolescence. The best management lems, such as dellen, interference with contact
is usually periodic observation with a photo- lens wear, or a significant cosmetic blemish,
graphic comparison. If growth is documented, should be excised.
Complexion-Associated Conjunctival Clinical Features

Pigmentation (Racial Melanosis) The surface of the eye appears slate gray or blue
and not brown or black as seen in conjunctival
Complexion-associated conjunctival pigmenta- melanocytic lesions, due to the Tyndall effect of
tion, also known as racial pigmentation, is a com- the pigmented melanin that is seen through the
mon, bilateral condition of flat conjunctival layers of the episclera and sclera (Fig. 14.14).
pigmentation found in individuals with a dark
complextion [3, 31]. However, distribution of Histopathologic Features
pigmentation may be asymmetric. Since the pigmentation is due to dendritic mela-
nocytes that are present within the episcleral and
Clinical Features scleral tissue, it does not move with the bulbar
The pigmentation is commonly present at the conjunctiva.
limbus, often for 360°, and may involve the adja-
cent cornea and limbal conjunctiva. Uncommonly, Treatment
pigmentation may involve the fornix and rarely Conjunctival melanoma has not been described
the palpebral conjunctiva. in melanosis oculi. However, the risk of uveal
melanoma is 1:400. Therefore, affected patients
Histopathologic Features should be followed regularly for the development
The basal layer of the conjunctival epithelium of uveal melanoma [47].
appears hyperpigmented due to benign melano-
cytes located in this layer.
rimary Acquired Melanosis (PAM)
P
Treatment Without Atypia
As malignant transformation is extremely rare in
complexion-associated melanosis, apart from Primary acquired melanosis appears as a flat,
observation, there is no need for surgical variably brown, and usually monocular lesion.
treatment. Histologically, PAM lesions are flat, intraepithe-
ongenital Melanosis Oculi

C
(Congenital Ocular Melanocytosis)
Congenital melanosis oculi is a pigmentary con-

dition of the sclera and uvea that can be associ-
ated with periocular skin, orbit, meninges, and
soft palate pigmentation [3, 31]. In this condition,
the conjunctiva is usually not pigmented; it is
included here because it is often considered in the
clinical differential diagnosis of a conjunctival
pigmented lesion. Due to its diffuse pattern, con-
genital melanosis oculi is often confused with
conjunctival primary acquired melanosis. When
the periocular skin is involved, the condition is
called “oculodermal melanocytosis” or “nevus of Fig. 14.14 Congenital melanosis oculi with gray-blue
Ota” [46] (Fig. 14.8). pigmentation of the sclera
lial melanocytic lesions and divided into two 9. Lass JH, Foster CS, Grove AS, et al. Interferon-alpha
therapy of recurrent conjunctival papillomas. Am J
major groups: PAM without atypia and PAM Ophthalmol. 1987;103:294–301.
with atypia. Both types of PAM are discussed in 10. Hawkins AS, Yu J, Hamming NA, et al. Treatment of
Chap. 15. recurrent conjunctival papillomatosis with mitomycin
C. Am J Ophthalmol. 1999;128:638–40.
11. Bosniak SL, Novick NL, Sachs ME. Treatment of
recurrent squamous papillomata of the conjunctiva
Tumors of the Caruncle by carbon dioxide laser vaporization. Ophthalmology.
1986;93:1078–82.
The caruncle contains both conjunctival and 12. Kaliki S, Arepalli S, Shields CL, et al. Conjunctival
papilloma: features and outcomes based on
cutaneous elements. Consequently, any tumor of age at initial examination. JAMA Ophthalmol.
the conjunctiva and skin may occur in the carun- 2013;131:585–93.
cle. In large series of caruncular lesions [48–50], 13. Belfort RN, Isenberg J, Castillejos AG, et al. Novel
the vast majority were benign lesions, led by nevi treatment of papillomatous conjunctival lesions using
pattern scanning laserphotocoagulation: 1-Year results.
and squamous papillomas. The caruncle is the Ocul Surf. 2018;16:337.
most common site for oncocytoma [24, 25]. Only 14. Shields CL, Lally MR, Singh AD, et al. Oral cimeti-
about 5% of the lesions in these series were pre- dine (Tagamet) for recalcitrant, diffuse conjunctival
malignant and malignant tumors (for details, see papillomatosis. Am J Ophthalmol. 1999;128:362–4.
15. Yazu H, Dogru M, Miyauchi J, et al. Association of
Chap. 19). epithelial atypia with recurrence after surgical excision
in conjunctival papilloma. Eye Contact Lens. 2017:1.
https://doi.org/10.1097/ICL.0000000000000330.
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papilloma of the conjunctiva. Am J Ophthalmol.
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1. Spencer WH. Chapter 2, Conjunctiva. In: Spencer
17. Stagner AM, Jakobiec FA, Chi A, et al. Conjunctival
WH, editor. Ophthalmic pathology, an atlas and
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2. Campbell RJ, Sobin LH. Tumors of the conjunctiva
18. Jakobiec FA, Harrison W, Aronian D. Inverted muco-
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19. Tseng SH, Chen YT, Huang FC, et al. Seborrheic
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3. Shields CL, Shields JA. Tumors of the conjunctiva
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4. Sjo N, Heegaard S, Prause JU. Conjunctival papil-
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21. Oellers P, Karp CL, Shah RR, et al. Conjunctival kera-
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22. Allingham RR, Seo B, Rampersaud E, et al. A dupli-
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Dacryoadenoma. A unique tumor of the conjunctival
7. Mlakar J, Kocjan BJ, Hošnjak L, et al. Morphological
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24. Say EA, Shields CL, Bianciotto C, et al. Oncocytic
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8. Schechter BA, Rand WJ, Velazquez GE, et al.
Surg. 2012;28:14–21.
Treatment of conjunctival papillomata with
25. Østergaard J, Prause JU, Heegaard S. Oncocytic
topical interferon Alfa-2b. Am J Ophthalmol.
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2002;134:268–70.
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Acta Ophthalmol. 2011;89:263–7. of the conjunctiva. Ophthalmology. 1992;99:1714–7.
26. Kalantzis GK, Verity DH, Rose GE. Periocular 39. Sayed-Ahmed I, Murillo JC, Monsalve P, et al.
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Saunders; 1996. p. 125–55. 45. Park YM, Lee JE, Lee JS. Efficacy of Pattern Scan
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32 cases. JAMA Ophthalmol. 2013;131:857–63. 47. Singh AD, De Potter P, Fijal BA, et al. Lifetime
34. Thompson JM, Bermudez-Magner JA, Barker NH, prevalence of uveal melanoma in white patients
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1989;21:176–9. cyst of lacrimal origin. Adv Ocul Care. 2010:29–30.
Ocular Surface Squamous
15
Neoplasia
Jacob Pe’er, Shahar Frenkel, and Arun D. Singh
Introduction the term OSSN does not distinguish between pre-

malignant squamous epithelial dysplasia includ-
Ocular surface squamous neoplasia (OSSN) is a ing carcinoma in situ from invasive SCC, it
term used for the precancerous and cancerous should not be used in surgical pathology reports
epithelial lesions of the conjunctiva and cornea to avoid mismanagement and can be used only
[1, 2]. It includes dysplasia, carcinoma in situ clinically [4].
(CIS), and invasive squamous cell carcinoma
(SCC). The most common previously used names
for the intraepithelial lesions are “intraepithelial Epidemiological Aspects
epithelioma,” “Bowen’s disease” of the conjunc-
tiva, or “Bowenoid epithelioma.” Because of dif- OSSN is found in all races. It is uncommon in
ferences in histology of conjunctiva and skin, the Northern countries but common in countries that
term Bowen’s disease should be reserved only for are closer to the equator and where exposure to
cutaneous lesions. Other terms for the intraepi- sunlight is greater. In an NIH study, the inci-
thelial ocular surface neoplasia are conjunctival dence of OSSN was 0.3 per million in the United
intraepithelial neoplasia [3], corneal intraepithe- States [5]. In a study that was performed in
lial neoplasia (CIN), or both corneal and con- Uganda, the incidence of OSSN was 1.3 per mil-
junctival intraepithelial neoplasia (CCIN). Since lion, and in Australia, the incidence is reported
to be as high as 19 per million population [1].
OSSN occurs predominantly in adults, although
a few cases in children have been reported, espe-
cially in those with xeroderma pigmentosum [6].
J. Pe’er (*) · S. Frenkel
Ocular Oncology Service and Ophthalmic Pathology In most series, OSSN is more common in men
Laboratory, Department of Ophthalmology, [5], an occurrence which is explained by their
Hadassah - Hebrew University Medical Center, greater exposure to sunlight. In one large series,
Jerusalem, Israel
men also showed higher-grade lesions [7].
e-mail: peer@hadassah.org.il
According to some studies, patients with CIN
A. D. Singh
are younger by 5–9 years than those with inva-
Cole Eye Institute, Cleveland Clinic, sive SCC, a fact that implies the precancerous
Cleveland, OH, USA nature of the CIN [8].

160 J. Pe’er et al.
Etiology and Associated Diseases Human Papillomavirus
There are several possible factors and mecha- In recent years, human papillomavirus (HPV),
nisms that may explain or are associated with the mainly type 16, has been demonstrated in tissues
development of OSSN. The most important ones of OSSN [13]. DNA of HPV was found in fresh
are exposure to solar ultraviolet radiation, human tissue of OSSN, using amplification with PCR
papillomavirus, AIDS, and the stem cell theory. and sequencing of the DNA, in ocular surface
swabs of patients with OSSN and in studies of
formalin-fixed paraffin-embedded tissue, using
Sunlight Exposure immunostaining. However, HPV was also
detected in uninvolved eyes with apparently
Exposure to solar ultraviolet radiation has been healthy conjunctiva and in cases of persistence of
identified in many studies as a major etiologic infection many years after successful eradication
factor in the development of OSSN [3, 8]. The of OSSN lesions. In one study, where evidence
rarity of OSSN in Europe and North America and for HPV was analyzed by immunohistochemistry
its higher incidence in sub-Saharan African coun- and multiplex polymerase chain reaction (PCR),
tries and in Australia [1], where people are more no HPV was detected in OSSN lesions [14].
exposed to sunlight, suggests an important role Another study showed no statistically significant
for solar ultraviolet light in the development of association between anti-HPV antibody status
OSSN. Lee and Hirst [1] observed a relationship and the risk of conjunctival neoplasia [15]. These
between lifetime exposure to solar ultraviolet facts lead to the assumption that HPV alone may
light and the risk of developing OSSN. Newton be incapable of causing OSSN [16], and that
et al. [9] noted that the incidence of ocular SCC other factors in conjunction with HPV are
increases by 29% per unit increase in ambient involved in causation of OSSN. According to a
solar ultraviolet light exposure, corresponding to study from India, HPV was a predictor of better
a 49% increase in incidence with each 10° decline survival in OSSN patients [17].
in latitude.
A history of actinic skin lesions such as solar
keratoses and SCC is also strongly associated Acquired Immunodeficiency
with the development of OSSN. It is well known Syndrome (AIDS)
that ultraviolet B rays cause damage to DNA in
human epithelial cells. Failure of DNA repair, as The incidence of OSSN has increased signifi-
occurs in xeroderma pigmentosum, leads to cantly since the eruption of the AIDS epidemic,
somatic mutations and the development of can- especially in sub-Saharan African countries [18].
cerous cells of OSSN. According to a study on In studies from Rwanda, Uganda, Congo,
the pathophysiology of OSSN [10], UV radiation Kinshasa, and Zimbabwe, HIV infection was
damages DNA and produces pyrimidine dimers strongly associated with an apparent increase in
in the DNA chain. Specific CC -- > TT base pair the incidence of OSSN. In a study from Kenya,
dimer transformations of the p53 tumor- 74% of patients with OSSN were HIV positive
suppressor gene occur in OSSN, allowing cells [19]. In these countries, the OSSN occurs at a
with damaged DNA past the G1-S cell cycle younger age than was previously reported and the
checkpoint. In recent years, several studies dem- disease tends to be aggressive (Fig. 15.1).
onstrated that ultraviolet light-signature – the Although HIV infection seems to be an obvious
telomerase reverse transcriptase (TERT) pro- risk factor by itself, its interaction with ultravio-
moter – mutations are common in OSSN lesions, let light and HPV, which are also prevalent in
supporting UV induction as the major source of African countries, can accelerate the develop-
mutagenesis in these lesions [11, 12]. ment of OSSN.
15 Conjunctival and Corneal Tumors: Ocular Surface Squamous Neoplasia 161
a b
Fig. 15.1 A 52-year-old African woman was diagnosed In the interim she was started on antiretroviral therapy
with HIV, with a CD4 count of 56 × 106/mm3 and viral (zidovudine, lamivudine, and efavirenz). Over the next
load >100,000 copies/mL. At presentation, a fleshy con- several months her symptoms improved. At 12 months,
junctival growth extending onto the cornea was initially CD4 count was 221 × 106/mm3 and the viral load unde-
diagnosed as a pterygium (a). The ocular symptoms wors- tectable. The conjunctival mass had completely resolved
ened with enlargement of the mass, which on CT scan (b). In the setting of HIV, even Kaposi’s sarcoma and non-
revealed extension into the medial rectus muscle inser- Hodgkin’s lymphoma are recognized as responding to
tion. Conjunctival biopsy confirmed diffusely infiltrating highly active antiretroviral therapy via immune restora-
invasive, moderately differentiated squamous cell carci- tion. (Reprinted from Holkar et al. [81]. With permission
noma. The patient declined lid-sparing exenteration. from Sage Publications)
Post Transplantation nucleotide excision repair genes related to Bloom

and Immunosuppression syndrome, Nijmegen breakage, and other DNA
repair disorders (Fig. 15.3). Patients with XP have
Solid organ transplantation and consequent severe sun sensitivity and are prone to develop skin
immunosuppression is an important risk factor cancers including basal cell, skin SCC, and mela-
for development of squamous cell carcinoma, noma (Fig. 15.4) [26]. Patients with XP require
basal cell carcinoma, melanoma, and lymphoma multidisciplinary care monitoring for ocular mani-
[20–22]. The incidence of squamous cell carci- festations [27]. Cornea undergoes progressive scar-
noma varies with the type, intensity, and duration ring, vascularization, pannus formation due to
of the immunosuppressive treatment [23]. OSSN limbal stem cell deficiency and even endothelial
have also been observed in the setting of immu- loss [28, 29], The conjunctival and corneal neo-
nosuppression [24]. Such tumors tend to be bilat- plasms tend to occur in early age with bilateral,
eral, aggressive, and non-responsive to topical multiple, recurrent, aggressive, and invasive behav-
interferon therapy [25] (Fig. 15.2). ior and are difficult to manage (Fig. 15.5) [30].
Xerodermatic Pigmentosum Stem Cell Theory

and Other DNA Repair Disorders
Because of the tendency for OSSN to arise in the
Xerodermatic pigmentosa (XP) is caused by limbal area, where the stem cells for the corneal
Autosomal Recessive inheritance of defective and conjunctival epithelium are located, Lee and
a b
c d
Fig. 15.2 A 55-year-old male s/p simultaneous liver kid- interferon alpha-2b (3million units/0.5 ml) given at
ney transplant about 10 years prior with nodular thicken- 1–2 weeks interval. Response is evident after second
ing left lower eyelid (basal cell carcinoma) and biopsy injection. Note subconjunctival hemorrhage (c). There
proven CIN right eye (a). The lesion was adherent to was total resolution after the sixth injection. The patient
underlying sclera. UBM excluded deep scleral extension has remained recurrence-free at 6 months after last
(b). He was treated with six subconjunctival injections of injection (d)
Hirst [1] proposed the limbal transition zone/

stem cell theory for the development of Clinical Features
OSSN. Based on Tseng’s concept of the
long-living and high proliferation rate of stem Symptoms
cells in the limbal area, they postulated that alter-
ations in this anatomical site influenced by other In addition to the presence of the lesion on the
factors cause abnormal maturation of the con- ocular surface, other symptoms include ocular
junctival and corneal epithelium resulting in the redness and irritation. Visual acuity is usually not
formation of OSSN. It has been postulated that reduced, unless the center of the cornea is affected
limbal epithelial stem cells are the possible pro- [31]. OSSN may grow within weeks to years; in
genitor cells in OSSN [10]. most cases, the history is of several months.
GGR TCR
CPD
6-4 PPs
DNA DNA
damage damage
Recognition XPC CSA
XP CSB
RNAPII
HHR23B
XP CS
XPG
XPD
XPA
TTDA
RPA
TFIIH
XPB
XPG
Unwinding XPA
RPA
XPF
ERCC1
XPF XPG Excision and synthesis

Incision XPA
ERCC1
RPA
Fig. 15.3 Overview of the NER system as the genetic merase II function. Pathways overlap after initial damage
basis for XP and related disorders. TCR removes dam- recognition, in a process involving XPB, XPG, XPA, and
aged DNA from genes that are actively transcribed, while replication protein A (RPA). Finally, XPF and XPG
GGR works in the remaining genome. In GGR, the DNA remove the damaged regions by making incisions of ∼30
damage by UV radiation leads to the formation of nucleotides, followed by DNA synthesis to fill the gaps.
cyclobutane pyrimidine dimers (CPDs) or 6–4 photoprod- (Reprinted from Suarez et al. [30] With permission from
ucts (PPs), which are recognized by XPC proteins. S. Karger AG, Basel © 2016)
Meanwhile in TCR, DNA damage blocks RNA poly-
a b
Fig. 15.4 A 33-year-old Asian female with xeroderma ciency (b). OCT at 6 o’clock position (c) showing
pigmentosum. Note pterygium like changes in the left eye thickened corneal epithelium indicating CIN within the
(a) and peripheral corneal opacification and vasculariza- corneal pannus (d)
tion of the right cornea attributed to limbal stem cell defi-
c d
Signs Differential Diagnosis
Clinically, it may be difficult to distinguish The main lesions in the differential diagnosis of
between conjunctival epithelial dysplasia, carci- OSSN are pinguecula (Fig. 15.14), pterygium
noma in situ, and invasive squamous cell carci- (Fig. 15.15), and squamous papilloma
noma, although suspicion towards one of these (Fig. 15.16) [3].
three lesions may exist. These lesions arise com-
monly within the interpalpebral fissure, mostly at
the limbus (Figs. 15.6 and 15.7). OSSN may Diagnostic Evaluation
appear gelatinous with superficial vessels; papil-
liform when it has a papillary appearance It may be difficult to clinically distinguish
(Fig. 15.8); or leukoplakic, with a white keratin between intraepithelial and invasive squamous
plaque covering the lesion [3] (Fig. 15.9). It may neoplasia and between these and other lesions
also appear as a nodular lesion (Fig. 15.10), espe- such as pinguecula and pterygium, especially
cially when it is invasive SCC, or as a diffuse with leukoplakia and squamous papilloma.
lesion masquerading as chronic conjunctivitis.
OSSN may rarely occur in tarsal or forniceal con-
junctiva (Fig. 15.11). The limbal component may Staining Patterns
be inconspicuous with predominant corneal
extension (Fig. 15.12). Usually, OSSN appears as In our experience, the use of fluorescein staining
a nonpigmented lesion, although pigmented con- can help in the diagnosis, emphasizing the pap-
junctival SCC has been reported (Fig. 15.13). illary or granular surface of part of the OSSN
According to one study, clinical characteristics lesion and delineating its borders (Fig. 15.17)
that may predict high-grade lesions are temporal [31, 32]. Others have used rose bengal, lissa-
and superior location, papillomatous and nodular- mine green [33, 34], or 1% toluidine blue eye
appearing lesions, and size of lesional area [6]. drops [35].
Fig. 15.5 Spectrum of

a b
differentiation of
squamous neoplasia in
XP. XP patients develop
a variety of squamous
lesions, including CIN
with variable dysplasia
(a, b) and well-
differentiated, highly
keratinized eyelid SCCs
(patient 3; c, d). A
subset of tumors may be
less differentiated and
demonstrate increased
pleomorphism (e, f).
(Reprinted from Suarez
et al. [30]. With c d
permission from
S. Karger AG, Basel ©
2016)
e f
Imaging Techniques “Conjunctival and Corneal Tumors: Examination

Techniques”). However, the definitive diagnosis
Recent publications have described the use of must be a histological one.
high-frequency ultrasound in the diagnosis of
OSSN and particularly in estimating the depth of
invasion [36]. Others have used confocal micros- Diagnostic Cytology
copy [37] or ultrahigh-resolution optical coher-
ence tomography [38] even with coexisting Preoperative cytologic diagnosis may be of value
ocular surface diseases (Figs. 15.12, 15.13, in planning surgery in order to prevent unneces-
15.14, 15.15, and 15.16) [39] (Chap. 12 sary removal of large areas of normal conjunctiva
Fig. 15.6 Papillomatous ocular surface squamous Fig. 15.7 Papillary conjunctival SCC invading into the
neoplasia upper half of the cornea
a b
Fig. 15.8 Papillomatous limbal CIN with prominent intrinsic and feeder vessels (a). Note subtle corneal extension (b,
arrows) visualized by OCT as abruptly (c, small arrow) thickened hyperreflective epithelium (c, large arrow)
in the case of a benign lesion and to prevent par- ability to sample multiple sites, also simplifying
tial excision of malignant lesions. follow-up evaluation after treatment. The major
disadvantage is that only superficial cells are
Exfoliative Cytology obtained with this technique. Sometimes only
Cells from the conjunctival surface are obtained keratinized cells are obtained. Exfoliative cytol-
with a platinum spatula, brush, or cotton-wool ogy does not provide information on the degree
tip. The cells are then smeared onto slides and of the tumor invasion, which may be crucial in
fixed in 90% alcohol. Papanicolaou and Giemsa the overall management.
stains are used to examine the specimen [40, 41].
The advantages of this technique are the ability to Impression Cytology
obtain prospective cytologic information on the Another method of obtaining cells from the sur-
nature of the lesion, mainly in differentiating face of the conjunctival lesion is by impression
between benign and malignant lesions, and in the cytology [42]. With this technique several types of
Fig. 15.9 Leucoplakic CIN Fig. 15.11 CIN originating in the inferior fornix
a b
Fig. 15.10 Nodular CIN (a). UBM excluded deep scleral or intraocular extension (b)
a b
Fig. 15.12 CIN presenting as limbal/ peripheral corneal opacity (a). Small area of leukoplakia offers the diagnostic
clue (b, arrow). OCT reveals abruptly (c, small arrow) thickened and hyperreflective epithelium (c, large arrow)
a b
Fig. 15.13 Invasive conjunctival squamous carcinoma in superficial epithelial involvement with shadowing due to
an Indian man. The lesion is pigmented, resembling con- pigmentation (b)
junctival melanoma (a). Anterior segment OCT indicates
a b
Fig. 15.14 Faint yellow white lesion of conjunctiva resembling pinguecula (a, encircled by dots). OCT reveals abruptly
thickened and hyperreflective epithelium (b, arrow)
a b
Fig. 15.15 Pterygium with nodular thickening mimicking CIN (a). OCT reveals normal corneal epithelium over a
stromal nodular change both in the transervse (b, arrow) and longitudinal scan (c, arrow)
a b
Fig. 15.16 Squamous papilloma. Lesion with limbal No goblet cells were present within the lesion. Features of
involvement from 11 to 4 o’ clock, with corneal and con- high-grade dysplasia such as full thickness basaloid popu-
junctival extension (a). Histopathology demonstrated a lation lacking orderly maturation were not identified.
papillary squamoproliferative lesion characterized by (Hematoxylin and eosin, 100×). (Reprinted from
acanthotic squamous epithelium and fibrovascular cores. Ganapathy et al. [82]. With permission from Elsevier)
a b
Fig. 15.17 Diffuse corneal involvement by CIN showing and clearly delineates the border between the affected and
hazy and irregular corneal surface (a). Staining with fluo- nonaffected areas (b)
rescein shows the granular surface of the involved cornea
filter paper, such as cellulose acetate filter paper,

millipore filter paper, or biopore membrane device, Histopathologic Features
are gently placed in contact with the ocular sur-
face, sampling the most superficial cells. These are Only histological evaluation of excised lesions,
fixed and stained with Papanicolaou stain. The either from incisional or excisional biopsy, can
advantages and disadvantages of exfoliation cytol- differentiate between the three lesions in the
ogy also apply to impression cytology. spectrum of OSSN [1, 2].
a b
Fig. 15.18 Histological picture of acanthotic conjunction the right side (a, hematoxylin and eosin, original mag-
val epithelium with dysplastic changes involving most of nification × ~ 100). Note deep invasion of tumor cell
the epithelial thickness. The epithelium lost its normal islands of well-differentiated conjunctival SCC (b, hema-
cellular polarity. Normal conjunctival epithelium is seen toxylin and eosin, original magnification × ~ 100)
Dysplasia Invasive Squamous Cell Carcinoma
Dysplastic lesions exhibit mild, moderate, or Invasive squamous cell carcinoma shows features
severe degrees of cellular atypia that may involve similar to carcinoma in situ, but the basement
various thicknesses of the epithelium, starting membrane of the epithelium is breached and the
from the basal layer outwards (Fig 15.18a). These subepithelial tissue of the conjunctiva is invaded
lesions show modification of epithelial cell orga- (Fig. 15.18b). Most conjunctival SCCs are well-
nization with various degrees of loss of the nor- differentiated, and they often show surface kera-
mal cellular polarity. Usually the most superficial tinization. The tumor may show various degrees
layers are uninvolved. In cases with severe dys- of cellular pleomorphism. In examining such
plastic changes, it may be difficult to distinguish lesions, hyperplastic and hyperchromatic cells,
the lesion from carcinoma in situ. individually keratinized cells (dyskeratosis), con-
centric collections of keratinized cells (horn
pearls), loss of cellular cohesiveness, and atypi-
Carcinoma In Situ cal mitotic figures may be observed. The subepi-
thelial tissue in invasive SCC is usually inflamed
Carcinoma in situ may show all the histological and contains islands of atypical epithelial cells.
features of SCC; however, it usually is confined In pigmented individuals, OSSN can be pig-
to the epithelium, respecting the basement mem- mented due to abnormal proliferation of melano-
brane. Carcinoma in situ usually shows a total cytes in the lesions. Genetic studies of OSSN
loss of normal cellular maturation and affects the tumors found multiple chromosomal alterations,
full thickness of the epithelium. The cells are losses and gains, which may be important in
large and usually elongated. Keratinized cells tumor formation and growth [43]. Another study
may be identified and mitotic figures can be pres- showed differential expression of stem cell mark-
ent in all layers. ers in OSSN tumors, which can indicate the
important role that stem cells, especially limbal tumors invading the orbit with or without further
epithelium stem cells, play in the genesis of extension, divided to four sub-staging, T4a, T4b,
OSSN [44]. T4c, and T4d. The intraepithelial neoplasia which
is not subdivided in the AJCC staging has been
catergorized by others as mild dysplasia (grade
Staging 1/3), moderate dysplasia (grade 2/3), and severe
dysplasia (grade 3/3 or carcinoma in situ) [47].
In the recent editions of the American Joint While some studies found that the AJCC category
Committee on Cancer (AJCC) staging system, the of OSSN is a reliable predictor of clinical out-
primary OSSN tumors are classified according to come [48], others did not find this staging a useful
the degree of depth of invasion, as found in histo- guide for initial management, and these authors
pathological evaluation; the size of the lesions; suggest a partial reclassification [47].
and the involvement of neighboring structures
(Table 15.1) [45, 46]. The OSSN lesions are
divided into carcinoma in situ – Tis – and four Histopathologic and Clinical Variants
stages of invasive SCC: T1 for tumors ≤5 mm in
greatest dimension, T2 for tumors >5 mm in Several types of invasive conjunctival SCC with
greatest dimension, T3 for tumors invading adja- rather aggressive behavior have been reported
cent structures (excluding the orbit), and T4 for [2]. Because of the aggressiveness of these vari-
ants, which often invade the eyeball and the
orbital tissue and which even metastasize to lym-
Table 15.1 AJCC (8th ed.) Definition of primary tumor phatics and distant sites, they should be histo-
(T) [45, 46]
pathologically differentiated from less aggressive,
T category T criteria
conventional SCC.
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ pindle Cell Squamous Carcinoma
S
T1 Tumor (<5 mm in greatest dimension) Spindle cell variant of SCC exhibits spindle-
invades through the conjunctival basement shaped cells, which may be difficult to distin-
membrane without invasion of adjacent guish from fibroblasts.
structures
T2 Tumor (>5 mm in greatest dimension)
invades through the conjunctival basement Mucoepidermoid Carcinoma
membrane without invasion of adjacent Mucoepidermoid carcinoma is a variant of con-
structures junctival SCC that shows, besides the squamous
T3 Tumor invades adjacent structures cells, mucus-secreting cells that are positively
(excluding the orbit)
stained for mucopolysaccharides.
T4 Tumor invades the orbit with or without
further extension
T4a Tumor invades orbital soft tissue without denoid Squamous Cell Carcinoma
A
bone invasion Another aggressive variant of conjunctival SCC
T4b Tumor invades bone is the adenoid squamous carcinoma, which histo-
T4c Tumor invades adjacent paranasal sinuses
logically shows extracellular hyaluronic acid but
T4d Tumor invades brain
no intracellular mucin.
Used with permission of the American Joint Committee
on Cancer (AJCC), Chicago, Illinois. The original and pri-
mary source for this information is the AJCC Cancer quamous Cell Carcinoma of Cornea
S
Staging Manual, Seventh Edition (2010) published by OSSN arising in the corneal epithelium is rare [8,
Springer Science+Business Media. & Used with permis- 49]. There is controversy about its origin. Some
sion of the American College of Surgeons, Chicago,
Illinois. The original and primary source for this informa-
authors support the possible potential of the
tion is the AJCC Cancer Staging Manual, Eighth Edition corneal epithelium to undergo dysplastic and

(2017) published by Springer International Publishing cancerous changes, while others believe that the
a b
Fig. 15.19 Squamous cell carcinoma of cornea resembling filamentary keratitis (a). Examination of the limbus reveals
small area of conjunctival thickening with fine intrinsic vascularity (b)
origin of corneal OSSN is at the limbus and deep surgical margins. In order to avoid
(Fig. 15.19) histologically, the corneal intraepi- recurrence, it is recommended to excise the tumor
thelial neoplasia is similar to that in the limbal tissue with wide surgical margins of 2–3 mm [3,
region and conjunctiva. Usually, the Bowman’s 51] (Fig. 15.22). When the deep cornea or sclera
layer is intact. Corneal intraepithelial neoplasia is involved, deep lamellar keratectomy or scle-
has a tendency to recur because of inadequate rectomy is performed. Recurrence rates follow-
scraping, but with current methods of treatment ing excision of OSSN alone range from 15% to
(topical therapy), this rarely occurs (Fig. 15.20) 52%, with an average of 30% [1]. Erie et al. [8]
[31, 32]. found 5% recurrence when the surgical margins
were free and 53% recurrence when they were
quamous Cell Carcinoma
S involved. Similarly, Pizzarello and Jakobiec
in Anophthalmic Socket found 69% recurrence when dysplastic tissues
Review of nine published cases indicates a long were left at the surgical margins [3].
interval between enucleation and the diagnosis of Therefore, techniques to ensure clear surgical
SCC (mean, 45 years), predominant diffuse margins have been applied. Frozen sections were
involvement of the upper eyelid, advanced stage used by Char et al. to assess the surgical margins
at diagnosis, and tendency for metastases [52]. However, there was a disparity between the
(Fig. 15.21). It is speculated that the presence of apparently free surgical margins and recurrence
prosthesis-induced chronic inflammation may be of the OSSN. Buus et al. have used a modified
a factor in initiating and masking the signs and Mohs’ micrographic technique that was devel-
symptoms of OSSN [50]. oped for cutaneous tumors, to ensure clear surgi-
cal margins [53]. No recurrences were
documented in their series of 19 patients.
Treatment Excision with large margins, especially when
cryotherapy is applied to the tumor bed and the
Surgery margins, may necessitate the use of an amniotic
membrane graft to close the surgical wound.
Surgical excision of the OSSN lesion is the tradi- Two cases of OSSN with intraocular involve-
tional method of treatment (Chap. 22). Its suc- ment were managed by local excision. Char et al.
cess depends on the involvement of the peripheral [52] reported a successful iridocyclochoroidectomy
a b
c d
Fig. 15.20 Corneal CIN. Patient treated for nonspecific shows strips of thickened epithelium with nuclei that are
keratitis with topical steroids for several months (a). Note large, hyperchromatic, and are haphazardly arranged sug-
superficial corneal opacity on transillumination (b). OCT gestive of CIN (d). Topical treatment interferon alpha-2b
reveals abruptly (C, small arrow) thickened and hyperre- (one million units/ml) led to total resolution within
flective epithelium (c, large arrow). Diagnostic biopsy 3 months (e)
a b
Fig. 15.21 Recurrent squamous cell carcinoma in the areas were suggestive of sebaceous differentiation, oil red
superior nasal aspect of tarsal conjunctiva of the upper lid O and immunostaining for androgen receptor were both
in anophthalmic socket (a). Poorly differentiated invasive negative (b, 40× magnification, hematoxylin and eosin).
carcinoma without keratinization was associated with an (Reprinted from Espana et al. [50]. With permission from
overlying squamous carcinoma in situ. Although some Elsevier)
a b
Fig. 15.22 CIN Local excision. Pretreatment appearance (a). Following excision with 2 mm clear margins alcohol
epitheliectomy double freeze thaw cryotherapy application and primary closure (b)
with adjunctive cryotherapy. Most eyes with intra- advocated the use of cryosurgery in the treatment
ocular invasion of OSSN are enucleated [54], and in of eyelid and ocular surface tumors [55]. Later
cases with orbital invasion, exenteration is required. on, he and others reported the use of combined
excision and cryotherapy treatment for OSSN
with recurrence rate as low as 0–12%.
Cryotherapy Cryotherapy acts both by destroying the tumor
cells and obliterating its microcirculation, result-
Because of the high recurrence rate of OSSN ing in ischemic infarction of both normal and
after surgical excision alone, Fraunfelder et al. tumor tissue. Side effects include iritis, altera-
tions in intraocular pressure, inflammation, cor- since the early 1990s (Fig. 15.11) [31]. Our pro-
neal edema, scarring, and superficial corneal tocol since then includes the use of 0.02%
vascularization, sector iris atrophy, ablation of (0.2 mg/ml) MMC drops four times daily for
the peripheral retina, and ectropion. 2 weeks of treatment and then 2 weeks without it
[2, 31, 32], with repetitions as needed and with a
response rate of 95%. Other groups have used
Brachytherapy 0.04% MMC in various lengths of cycles and
periods between cycles with a good response
Brachytherapy has been used for many years in (Fig. 15.24) [61–63]. The use of a low dose of
the treatment of OSSN. The most commonly 0.002% has also been reported [64].
used radioactive material has been strontium 90 The main adverse reactions to MMC are con-
with a recommended dose of 20–180 Gy to the junctival hyperemia, superficial punctate epithe-
tumor surface [56]. Other beta sources are ruthe- lial erosions, allergic conjunctivitis, pain,
nium 106 with a recommended dose of 290– photophobia, and blepharospasm. In using the
320 Gy to the tumor bed (Fig. 15.23) [57] and higher concentration of 0.04% MMC, there was
phosphorus 32 [58]. Gamma radiation using one case of punctal stenosis [61], and repeating
Iodine 125 applicators was also reported [59]. this concentration in multiple courses, limbal cell
Reported complications include post-irradiation deficiency was reported [61, 63, 65]. In treating
conjunctivitis, dry eye, conjunctival telangiecta- OSSN, there is no reason to use 0.04% MMC. In
sis and scarring, symblepharon, scleral ulcer- using 0.02% MMC, the side effects disappear
ation, corneal perforation, and cataract. within 2 weeks of stopping the treatment with or
Recurrence rates after brachytherapy have ranged without addition of lubricants and topical
from 2% to 47%; therefore, brachytherapy alone steroids.
is not recommended. However, in cases of intra- MMC is the most potent topical drug for treat-
ocular invasion, brachytherapy can effectively ing OSSN, showing a fast response. It is cheap and
treat the invasion and preserve the eye. Treatment stable. Because of its superficial effect, it should
of two cases of invasive SCC with proton beam not be used for invasive SCC as a primary treat-
therapy was also reported [60]. ment. However, it has been used successfully in
treating patients with partially excised invasive
conjunctival SCC without evidence of recurrence
Topical Chemotherapy [66]. It has also been used intraoperatively [67, 68].
and Immunotherapy
5-Fluorouracil Drops
Because of the possible complications of surgical 5FU has been used for OSSN as a sole treatment
excision, cryotherapy, and brachytherapy, topical or as an adjuvant treatment to surgical excision,
medical therapy has become an expanding field. with a good response and a low recurrence rate
Topical drops of mitomycin C (MMC), [68–70]. 5FU 1% has been administered in differ-
5-
fluorouracil (5FU), and interferon alpha-2b ent protocols, such as four times daily for 1 week
(INF-α2b) by injections and drops have shown followed by 3 weeks off with repetitions up to four
promising results as primary therapy for cycles [69]. Others used it four times daily for
OSSN. They have also been used as an adjuvant 4 weeks [70]. In these recent reports, complete
to surgical excision (Chap. 20, Pharmacotherapy tumor regression was achieved in 82–83%.
for Eyelid and conjunctival malignancies). With 5FU patients experience toxic keratocon-
junctivitis including conjunctival hyperemia,
itomycin C Drops
M superficial keratitis, filamentary keratitis, and
Mitomycin C is an antineoplastic/antibiotic drug sometimes pain, tearing and photophobia, but usu-
that acts as an alkylating agent. Our group intro- ally, no long-term side effects are found [68–70].
duced and promoted the use of topical MMC 5FU is a potent, relatively cheap and stable drug.
a b
c d
e f
Fig. 15.23 Invasive conjunctival SCC with extension comfort for the duration of the implant placement (48 h).
into sclera (a) treated with iodine 125 brachytherapy The patient is recurrence-free at 5 years with visual acuity
(45 Gy to the depth of 3 mm) (b). The plaque was covered of 20/25 due to minimal cataract (e) and without radiation
with donor pericardium (c) followed by temporary trans- retinopathy (f)
marginal tarsorrhaphy (d) to minimize postoperative dis-
a b
Fig. 15.24 Diffuse CIN treated with MMC. Pretreatment appearance (a). Note partial resolution with 1 week of topical
MMC (0.04% qid) (b)
a b
Fig. 15.25 Multiple recurrent CIN associated with lim- one million units/ml for 3 months, there was complete
bal stem cell deficiency due to multiple previous excisions regression of the focal CIN (b)
(a). Following treatment with topical interferon alpha-2b
SCC to topical interferon alpha-2b [72]. Shields

Interferon Alpha-2b and colleagues used interferon alpha-2b as an
The use of recombinant interferon alpha-2b, ini- adjuvant treatment to surgical excision with com-
tially by intralesional injections and later by topi- plete control in 95% [73]. Krilis et al. [74]
cal applications, was pioneered and promoted by showed a higher response to treatment by inter-
Karp and colleagues for the treatment of CIN feron alpha-2b when combining it with topical
[71]. In using interferon alpha-2b four times retinoic acid every other day, achieving a 97.75%
daily with a dose of one million IU/ml, the response rate.
response rate was 81%, and in using three million Topical INF–α2b eye drops are well tolerated
IU/ml, the response rate was 92% (Figs. 15.20 with minimal side effects such as conjunctival
and 15.25). There was no response of invasive hyperemia and occasional follicular conjunctivi-
Table 15.2 Local Chemotherapy for OSSN

a
MMC 5FU INF-α2b
Response rate 82–100% 80–93% 80–
100%
Time to Fast Medium Slow
resolution
Side effects +++ (0.04%) ++ +
++ (0.02%)
Systemic side − − −
effects
b Availability +++ +++ ++
Cost Low Low High
Stability at room High High Low
temperature
diseases and adding, irrespective of histological

clearance, brachytherapy for invasive disease.
This combinatorial approach was successful both
Fig. 15.26 Diffuse conjunctival and corneal CIN right
in preserving the ocular surface and effective in
eye (a). He was treated with four subconjunctival injec-
tions of interferon alpha-2b (three million units/0.5 ml) treating the OSSN.
given at 1–2 weeks interval combined with topical inter-
feron alpha-2b (1million units/ml). There was total resolu-
tion after the 6 months of topical therapy (b). The patient
has remained recurrence-free for 24 months
Reconstruction
Reconstruction of the ocular surface may be

tis [72]. When injecting subconjuctivaly, the needed after a large excision of ocular surface
patients also experience systemic side effects tumors, and the use of autologous conjunctival
such as a “flu-like” syndrome (Figs. 15.2 and transplantation and autologous limbal transplants
15.26) [75]. to restore corneal and limbal areas after treating
Using INF–α2b, tumor resolution takes longer OSSN by surgery and cryotherapy have been
than with MMC and 5FU, on average 4 months, described (Chap. 22). Amniotic membrane trans-
with a high response rate of 92.5% and recur- plantation has been used for reconstruction after
rence of 0–17% [73–76]. The downsides of topi- excision of large ocular surface neoplasia
cal INF–α2b are its high cost and that it must be (Fig. 15.27) [77, 78].
refrigerated.
Table 15.2 compares the main features of
MMC, 5FU, and INF–α2b. For more details see Prognosis
Chap. 20.
Local Recurrence
The Combined Approach OSSN is considered to be of low-grade malig-

nancy [3, 8]. Conjunctival intraepithelial neopla-
The fact that tumors recur after the most meticu- sias (CIN), including dysplasia and carcinoma in
lous surgery even with the addition of cryother- situ, are regarded as precancerous lesions that
apy hints to that not all the tumor cells have been rarely progress to invasive SCC. However, recur-
destroyed. Thus, our group and others combined rences of these lesions are common after surgical
a surgical approach without wide surgical mar- excision, depending on the involvement of the
gins or cryotherapy, but adding local chemother- surgical margins [3, 8]. Erie et al. [8] reported
apy using mitomycin C or 5FU for intraepithelial 24% recurrence after excision of CIN and 41%
a b
Fig. 15.27 Conjunctival reconstruction. Incompletely horizontally. The conjunctiva was mobilized and
excised CIN (a). Repeat surgical excision was 2 mm out- anchored on the sclera. The remaining defect was cov-
side the visible margin. The surgical bed was also shaved ered with an amniotic membrane graft, tied in position
off with partial thickness scleral dissection. The area of using 8–0 Vicryl sutures. A 20-mm bandage contact lens
conjunctival defect was 15 mm vertically and 10 mm was applied (b)
after excision of SCC. Lee and Hirst [1] found with involvement of the Schlemm’s canal, tra-
recurrence rate of 17% for conjunctival dyspla- becular meshwork, anterior chamber, iris, ciliary
sia, 40% for carcinoma in situ, and 30% for body, suprachoroidal space, and choroid, some-
SCC. In this series, 31% had a second recurrence, times extending even behind the equator. In very
and 8% had more than two recurrences. Galor advanced cases the tumor may involve the entire
et al. [79] found that higher-grade lesions, tarsal orbit (Fig. 15.28b).
involvement, and positive margins in the histo-
pathologic evaluation are predictors of recur-
rence. Most recurrences develop within 2 years, Metastasis
but later recurrences have been reported. New
methods of treatment reduce the recurrence rate Metastasis of conjunctival SCC is extremely rare
significantly, as was discussed in the treatment [8, 51]. Sites of metastasis include preauricular,
section. submandibular, and cervical lymph nodes;
parotid gland; lungs; and bones (Fig. 15.29). The
main cause of metastasis is a delay in diagnosis
Intraocular Invasion and treatment. Regional lymph node involvement
preceded the development of distant metastases;
Intraocular invasion, although rare, may occur in therefore, regular examination of these lymph
OSSN [52, 80]. It occurs in older patients who nodes should be performed in suspicious patients,
had SCC located near the corneoscleral limbus to enable lymph node and radical neck dissection
with one or more recurrences after surgical exci- in cases of nodal involvement. Local invasion
sion (Fig. 15.28a). Histopathologic examination and distant metastases may lead to the patient’s
may show growth of the SCC through the limbus death in very rare cases [51].
a b
Fig. 15.28 Intraocular invasion of conjunctival SCC (a). Advanced conjunctival SCC protruding through the eyelid
aperture. The tumor invaded the eyeball and the orbit (b)
a b
c d
Fig. 15.29 Conjunctival SCC with orbital extension (a). hypermetabolic on PET scan (d, large arrow. The con-
Note enlargement of parotid and cervical lymph nodes junctival/orbital tumor is also detectable (d, small arrow)
(b). CT shows enlarged lymph node (c, arrow) which is
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Primary Acquired Melanosis
16
Introduction melanocytic hyperplasia” and “atypical melano-

cytic hyperplasia” [5] to describe the histology of
The name applied to the condition described in this lesions that were predisposed to evolve into mela-
chapter has evolved over many years. Each name noma if not treated appropriately. The histological
carried with it implications for diagnosis and ther- name, however, could not be applied in a clinical
apy. Hutchinson, who was the first to describe these setting by ophthalmologists.
lesions clinically in 1892, called them “senile The term “primary acquired melanosis” (PAM)
freckle” or “lentigo melanosis” [1], while Dubreuilh, was adopted by the World Health Organization in
who was the first to describe these lesions histologi- 1980, representing flat, brown, intraepithelial con-
cally in 1912, used the term “melanose circonscrite junctival lesions, in its International Histological
precancereuse” [1]. Miescher in 1936 used the term Classification of Tumors [6]. “Primary” denotes
“melanotische precancerose” [1] and Reese in 1966 that the lesion is not the result of generalized
“precancerous melanosis” [2]. The name itself— (racial) dark pigmentation, systemic disease (e.g.,
“precancerous”—prompted surgeons at that time to Addison’s disease), or local factors (foreign body,
perform radical surgery, including orbital exentera- injury, inflammation, medication, etc.). “Acquired”
tion, to treat a condition that is confined to the epi- distinguishes these lesions from those that are con-
thelium and that poses no risk of metastasis. In genital. “Melanosis” indicates that the pigment in
reaction to the overtreatment of these lesions, the lesion is derived specifically from the produc-
Zimmerman proposed the name “benign acquired tion of melanin rather than another pigment or a
melanosis” in 1966 [3, 4], but the inclusion of the drug deposit (Table 16.1) [7].
word “benign” led ophthalmologists to treat these The terminology—primary acquired melano-
lesions conservatively, and patients managed by sis or PAM—may be used by the ophthalmolo-
observation often developed malignant melanoma. gist in a clinical setting to describe any form of
Silvers, in 1978, used the terms “intraepithelial flat acquired conjunctival pigmentation that can-
not be attributed to a secondary influence. This
J. Pe’er (*) identification should trigger a biopsy that will
Ocular Oncology Service and Ophthalmic Pathology allow the pathologist to determine if melanocytic
Laboratory, Department of Ophthalmology, atypia is present (PAM with atypia) or represents
Jerusalem, Israel
conjunctival pigmentation without any melano-
e-mail: peer@hadassah.org.il cytic atypia (PAM without atypia). The designa-
R. Folberg
tion of atypia is reserved for the pathologist
Oakland University William Beaumont because it is not possible to predict melanocytic
School of Medicine, Rochester, MI, USA atypia from clinical criteria alone.
Table 16.1 Types of conjunctival melanosis

Category Subtype Etiology
Congenital Ocular melanosis Developmental episcleral hyperpigmentation
Oculodermal melanosis
Acquired Racial Normal pigmentation in darker races
Primary Idiopathic
Secondary Localized Post-inflammatory Posttraumatic
Foreign body Drug deposition
Systemic Addison’s disease Ochronosis
Syndromic Carney complex Peutz-Jeghers syndrome
Most recently, Damato and Coupland sug- junctival pigmentation is encountered, the oph-
gested that the term “PAM” be reserved only to thalmologist should first consider either
clinical diagnosis and offered the term “conjunc- complexion-associated conjunctival pigmenta-
tival melanocytic intraepithelial neoplasia tion or a systemic condition associated with bilat-
(C-MIN) with or without atypia” for the histo- eral conjunctival pigmentation.
logical terminology of these lesions, with more
severe changes regarded as “melanoma in situ”
[8]. Jakobiec in a recent paper recommended that Sunlight Exposure
“intraepithelial melanocytic proliferation” be
adopted for histopathological diagnosis [9]. The The importance of sun exposure in the develop-
authors of this chapter consider that the hybrid ment of PAM is not apparent. However, in one
nomenclature—one term for the ophthalmologist study [10], those who lived south of Washington,
and another for the pathologist—neither adds DC, for 5 or more years had a significantly higher
value to the classification of the disorder nor does prevalence of PAM lesions of their exposed intra-
it improve the management. For the remainder of palpebral conjunctiva than those who did not.
the chapter, therefore, the terminology PAM will Also, patients with pinguecula or pterygium had
be used in a clinical context and PAM with and a higher prevalence of PAM. Silvers et al. [5]
without atypia when discussing pathology. noted a high incidence of solar elastosis in biopsy
The prevalence and natural behavior of PAM specimens from patients with conjunctival pig-
are controversial. One study [10] reported the mented lesions. These facts suggest a possible
prevalence of PAM in Caucasians with no known role of sunlight exposure, but while they might
non-European ancestry to be 36%. This number explain PAM arising in the bulbar conjunctiva in
is exceptionally high compared with other stud- the interpalpebral fissure, they do not account for
ies. It is important to consider that the authors of cases in which PAM originates in the fornices
this study included lesions that were detectable and the palpebral conjunctiva.
only by high-magnification slit-lamp examina-
tion, and some lesions were so small that they
would not have been detected on routine clinical elationship to Nevi and Dysplastic
R
inspection. Furthermore, there was no histologi- Nevus Syndrome
cal confirmation of the diagnosis in this series.
The prevalence of PAM has been shown to
increase significantly as the number of facial nevi
Etiology increases [10]. Seregard et al. [11], in a case-con-
trol study, observed that ocular melanocytic
PAM is more prevalent in fair-complexioned lesions, including PAM, are not more common in
individuals than in patients with dark skin tones individuals with dysplastic nevus syndrome than
and is almost always unilateral. If bilateral con- in the general population.
16 Conjunctival and Corneal Tumors: Primary Acquired Melanosis 187
Cigarette Smoking 42%; and superior, 37%. In the same study, the
anatomic locations of PAM included bulbar con-
Cigarette smoking and hypertension have been junctiva in 91%, limbal conjunctiva in 55%, cor-
observed as significant independent factors in the nea in 23%, forniceal conjunctiva in 13%,
development of PAM [10]. No other etiological palpebral conjunctiva in 12%, and caruncle in
factors have been implicated in the development 11%. In some patients with widespread lesions,
of PAM. the eyelid epidermis may also be involved [7].
PAM occurs typically in middle-aged or elderly
white patients, although it may also appear in
Clinical Features young adults, but usually not in children. In one
study [13], the mean age at the time of diagnosis
Primary acquired melanosis appears clinically as
a flat and variably brown conjunctival lesion,
ranging from golden brown to dark chocolate in
color (Figs. 16.1 and 16.2) [7]. There are no pub-
lished size criteria for the clinical diagnosis of
PAM [9], although in one large series [12], PAM
extended circumferentially for a mean of 3 clock
hours, ranging from 1 to 12 clock hours. PAM is
usually monocular, although binocular cases may
occur. The lesion may involve any area of the
conjunctiva in a contiguous or multi-spotted pat-
tern, necessitating eversion of the eyelids to
examine both the upper and lower palpebral
zones. PAM develops most commonly at the lim-
bus and epibulbar intrapalpebral region and may
extend into the corneal epithelium (Fig. 16.3).
According to Shields et al.’s experience with 311 Fig. 16.1 PAM without atypia. Would the lesion be
eyes [12], the conjunctival quadrants affected by enough to make the diagnosis of PAM and justify a
PAM were temporal, 57%; inferior, 45%; nasal, biopsy?
a b
Fig. 16.2 Diffuse PAM with atypia entirely covering the temporal bulbar conjunctiva (a). After treatment with topical
mitomycin C. Some pigmentation, probably PAM without atypia, has remained unchanged for 6 years (b)
a b
Fig. 16.3 Conjunctival PAM with atypia, with corneal involvement (a). Another case that has progressed to corneo-
limbal melanoma (b)
was 45 years, and in another study, this was showed a thick basal epithelial hyperreflective
62 years [10]. There is no significant difference band in all instances of PAM using OCT [15]
in the prevalence of PAM between males and (Figs. 16.4 and 16.5), and Shousha et al. also
females [10], although in one extensive study showed correlation between histopathological
[12], 62% of patients with PAM were female. findings and ultra-high-resolution OCT [16]. A
Primary acquired melanosis lesions may Wood’s lamp may help in the detection of sub-
remain stable for long periods of time or may clinical pigmentation but is seldom used in clini-
grow in size. A “waxing and waning” phenome- cal practice [17].
non in which areas in the lesions darken or lighten
is well known [7]. Parts of, or rarely the entire,
PAM lesion can be amelanotic (PAM sine pig- Histopathologic Features
mento); thus, the borders of the lesion often can-
not be identified, and the clinically recognized Histologically, PAM is divided into two major
borders are misleading [13]. groups: PAM without atypia and PAM with
atypia. Most conjunctival melanomas arise in the
context of PAM with atypia. PAM with atypia is
Ancillary Studies confined to the epithelium and is called by some
pathologists “melanoma in situ” [1] and is thus
The clinical suspicion of PAM is based on the not associated with any risk of metastasis.
features described in the previous section. However, 11–46% transform to conjunctival mel-
Because PAM lesions are flat and intraepithelial, anoma [12, 13]. The mortality of conjunctival
there are no established imaging tools that can melanoma is approximately 25%. Therefore, a
aid in the diagnosis. However, Messmer et al. particularly effective treatment for conjunctival
[14], using in vivo confocal microscopy (OCT), melanoma is through prevention by completely
could display small dendritic cells and hyperre- extirpating lesions showing histological evidence
flective granules confined to the basal epithelium of PAM with atypia. The lesion designated as
in PAM without atypia and extensive networks of PAM without atypia does not evolve into mela-
hyperreflective dendritic cells and hyperreflective noma. As mentioned above, it is important to
granules and patches throughout the epithelium remember that there are no clinical criteria by
in all cases of PAM with atypia. Alzahrani et al. which ophthalmologists can anticipate the histo-
a b
Fig. 16.4 Diffuse conjunctival PAM (a) without atypia. to the basal layer (b, below) (hematoxylin and eosin, orig-
Note (arrow) basal epithelial hyperreflective band of inal magnification, 200×). (Reprinted from Alzahrani
approximately 20 micron thickness (b, above) and corre- et al. [15]. Copyright © 2015, © 2015 S. Karger AG,
sponding melanotic hyperpigmentation that is restricted Basel)
Fig. 16.5 Corneal PAM. (a) Clinical appearance. (b) Note corresponding epithelial hyperreflective band. (Reprinted
from Alzahrani et al. [15]. Copyright © 2015, © 2015 S. Karger AG, Basel)
logical diagnosis. For that reason, an ophthalmol- Light Microscopy

ogist who encounters a fair-complexioned patient
with a unilateral, acquired, flat patch of brown Histologically, the detection of conjunctival epi-
pigmentation should biopsy the lesion to allow thelial pigmentation with or without melanocytic
the pathologist to classify the lesion as PAM hyperplasia—but, without melanocytic atypia—
without atypia or PAM with atypia. qualifies a lesion to be designated as PAM with-
a b
Fig. 16.6 Histologic picture of conjunctival PAM with- is no evidence of melanocytic hyperplasia or atypia. This
out atypia, with pigmented melanocytes located only lesion would, therefore, be designated histologically as
along the basal layer of the epithelium (a) (hematoxylin conjunctival PAM without atypia (b) (hematoxylin and
and eosin, ×20). In this case, melanin pigmentation is dis- eosin, ×20)
tributed throughout the conjunctival epithelium, yet there
a b
Fig. 16.7 Histologic picture of conjunctival PAM with nests. Note the lack of contact between these cells and the
atypia, showing atypical melanocytes in the basal layers epithelium. This lesion should be designated as PAM with
(a hematoxylin and eosin, ×20). Highly atypical melano- atypia (b, hematoxylin and eosin, ×40)
cytes populate the conjunctival epithelium singly and in
out atypia (Fig. 16.6). One might think cal and architectural features. Melanocytic atypia
conceptually of such a lesion as an “ephilis” is identified through the detection of melanocytes
(freckle) or lentigo (despite the fact that there are of different size and shape that appear to have a
no rete structures in the normal conjunctiva and “disregard” (i.e., they are spatially separated from)
therefore “lentigo” is difficult to identify in this for adjacent epithelial cells (Fig. 16.7). These
location). Histologically, the detection of atypical atypical cells may be small and round, spindle-
melanocytes within the epithelium qualifies the shaped, or even epithelioid. Architecturally, the
lesion to be designated as PAM with atypia. atypical melanocytes may be distributed along the
In rendering a diagnosis of PAM with atypia, epithelial basement membrane (basilar hyperpla-
the pathologist should take note of both cytologi- sia pattern), may be segregated into nests that
appear to be anchored along the basement mem- with or without atypia showed BRAF [24] or
brane, or may be dispersed upward into the more GNAQ mutations [25].
superficial layers of the epithelium, either individ-
ually or as intraepithelial nests (pagetoid spread).
In some areas, the atypical melanocytes may com- Differential Diagnosis
pletely replace the epithelium. PAM with atypia
that extends into pseudoglands of Henle should Primary acquired melanosis should be differenti-
not be mistaken for invasion (the lining of the ated from all pigmented lesions of the conjunc-
pseudoglands is considered to be contiguous with tiva, especially flat ones [26]. Like PAM,
the epithelium). conjunctival nevi are always movable. The pres-
It is important for both pathologists and oph- ence of cysts within the lesion supports a diagno-
thalmologists to understand that junctional nevi sis of conjunctival nevus rather than PAM,
of the conjunctiva are exceptionally rare—even although PAM may arise in the context of a
in children. Therefore, the diagnosis of “junc- nevus; therefore, the presence of cysts does not
tional nevus” when rendered by a pathologist “guarantee” a diagnosis of nevus. In episcleral
who is not experienced in ophthalmic pathology melanosis, as in congenital ocular melanosis or
should prompt a review, especially if the lesion is oculodermal melanosis, the pigmentation is blue-
not taken from a young child: the lesion is likely gray, non-movable, and usually multifocal.
to represent PAM with atypia. The histological Conjunctival melanoma is typically elevated or
identification and differential diagnosis of PAM nodular, but in early stages, when it arises from
with atypia are among the most difficult tasks in PAM with atypia, it may appear flat.
the practice of surgical ophthalmic pathology. In Other melanocytic lesions of the conjunctiva
two studies, the researchers graded the cellular include pigmentation associated with a dark skin
changes in PAM with atypia and showed higher tone that is usually bilateral and typically most
rates of recurrence [18] and transformation to intense at the limbus, fading in intensity toward
melanoma [19] in the highly-graded lesions. A the fornices (Fig. 16.8). Other conditions that can
detailed description of the histological differen- be included in a differential diagnosis are post-
tial diagnosis is beyond the scope of this chapter, inflammatory melanosis and systemic conditions
and the reader is referred to a more specialized with flat bilateral conjunctival pigmented patches
discourse for details [20]. such as Addison’s disease. Various benign and
malignant conjunctival tumors that are usually
amelanotic may be pigmented so as to simulate a
Immunohistochemistry conjunctival pigmented lesion, which when flat
may resemble PAM.
Chowers et al. [21] showed that on immunostain-
ing for Ki-67 and PCNA, PAM with atypia had
significantly higher proliferation activity than Treatment
PAM without atypia. Sharara et al. [22] observed
significantly higher expression of HMB-45 in The management of PAM remains controversial.
PAM with atypia compared to PAM without
atypia and conjunctival nevi. Jiang et al. found
that Melan-A labels all melanocytes without dis- Observation
criminating between benign and malignant cells,
while atypical melanocytes were most specifi- A small minority of ophthalmologists believe that
cally labeled with HMB-45, which positively subtle PAM lesions do not meet the criteria for
increases significantly with worsening atypia biopsy and recommend periodic follow-up [10].
[23]. In investigating mutations in conjunctival They advise a thorough examination of the bulbar
melanocytic lesions, none of the PAM lesions and palpebral conjunctiva and documentation of
a b
Fig. 16.8 Race-associated melanosis in an African- eye is more prominent because of globe shrinkage (atro-
American patient. (a) Note perilimbal superficial flat pig- phic bulbi) and because of a possible secondary effect of
mentation in the right eye. (b) The pigmentation in the left chronic inflammation
each lesion’s location, size, and appearance. Brownstein et al. [27] and Jakobiec et al. [28]
However, biopsy should be performed if a PAM recommended adding cryotherapy to the surgical
lesion differs from the characteristic, subtle excision. Shields et al. [29] suggest a six-step
lesions, including widespread or large lesions, surgical procedure: alcohol corneal epitheliec-
dark lesions, lesions of the palpebral conjunctiva, tomy, no-touch local removal of distinct lesions,
and progressive lesions. staging conjunctival biopsy specimens, limbal
peritomy, double freeze-thaw cryotherapy to the
involved bulbar conjunctiva, and wound closure.
Surgery In the Jakobiec series [28], none of the patients
treated by surgical excision and cryotherapy pro-
The overwhelming consensus among ophthalmic gressed to invasive melanoma.
oncologists and pathologists endorses biopsy of As mentioned above, in patients with PAM,
all conjunctival lesions that meet the clinical cri- clinical examination may not indicate the full
teria of PAM [13, 22]. Small lesions should be extent of the intraepithelial melanocytic
excised entirely, while in widespread lesions, lesions. Additionally, the waxing-and-waning
incisional biopsies should be performed at vari- phenomenon of PAM may prevent identifica-
ous sites of the affected conjunctiva (“map biop- tion of all locations of proliferating intraepithe-
sies”). The specimen(s) should be examined to lial melanocytes that require treatment.
determine the presence or absence of cytologic Therefore, local excision and localized cryo-
atypia, and, in the case of excisional biopsies, the therapy, even in cases of PAM that seem to be
surgical margins should also be assessed. localized, may not cover the entire lesion.
Furthermore, cryotherapy can cause complica-
tions such as scarring of the substantia propria,
Cryotherapy loss of eyelashes, ptosis, lax eyelids, tarsal flop-
piness, symblepharon, pseudopterygium, iritis,
Because of the tendency for PAM with atypia to anterior segment necrosis, macular edema,
recur, with the risk of melanoma development, scleral melting, and cataract [27].
Topical Mitomycin C Chemotherapy Prognosis
To cover the entire conjunctival and corneal sur- The study of the natural history of PAM in
face, treating hidden areas of PAM and prevent- humans is not possible. A successful attempt in
ing the complications of cryotherapy, we an animal model [39], generated by applying a
originally managed a patient with widespread 1% solution of DMBA to the conjunctiva in rab-
PAM with atypia by using mitomycin C [30]. bits, showed a spectrum of disease, ranging from
Summarizing our experience with the first 12 increased melanin production and melanocytic
consecutive patients [31], we recommended a hyperplasia without atypia through atypical
protocol of 0.04% (0.4 mg/ml) mitomycin C melanocyte hyperplasia of PAM.
drops four times daily for 2 weeks. This regimen The incidence of PAM recurrence depends on
is repeated as necessary with a pause of 2 weeks the presence or absence of atypia [13]. Recurrence
between courses, until disappearance or stabili- after excision is rare in PAM without atypia;
zation of the remnants of the pigmentation. At when this happens, it appears without cytological
least three courses were recommended. In all atypia. On the other hand, about 60% of lesions
patients, there was a complete or partial disap- designated as “PAM with atypia” recur after
pearance of pigmentation. In four patients, the excision alone; half of these recur as malignant
pigmentation disappeared, whereas in eight melanoma. In one study [13], the median interval
patients, some remnants of pigmentation between the biopsy of PAM and the biopsy of
remained (Fig. 16.2). In one patient, there was melanoma was 2.5 years. Progression after
regrowth of the PAM, which was treated again by 6 years is very rare, and progression to melanoma
0.04% mitomycin C, with success. Other groups more than 10 years after the biopsy of PAM with
have shown similar results in treating PAM with atypia has not been observed. Recurrence is more
atypia by mitomycin C [32–34]. All patients had likely when the lesion is incompletely excised or
conjunctival hyperemia during the treatment, and when the cornea is involved. Thus, when treating
some complained of irritation, tearing, and eyelid PAM with atypia, it is essential to treat the entire
swelling; these side effects resolved after cessa- conjunctival and corneal lesion.
tion of therapy. The most severe adverse effect of It is important to note that the mortality rate from
this treatment is limbal stem cell deficiency conjunctival melanoma is about 25% with no differ-
(LSCD) [35]. This outcome led us to change the ence between patients who had melanoma with
mitomycin C concentration to 0.03%, resulting in PAM and those who had melanoma without PAM
a similar response of the PAM and preventing (Fig. 16.3) [22]. However, no mortality has been
LSCD. reported from PAM without transformation to mel-
It is important to note that treatment with anoma. Although patients with PAM without atypia
mitomycin C should be applied only to intraepi- tend to be younger than patients with PAM with
thelial lesions and should not be used for invasive atypia [13], there is no evidence to indicate progres-
conjunctival melanoma. sion of PAM without atypia to PAM with atypia.
Topical Interferon α-2b References
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melanosis of the conjunctiva is melanoma in situ.
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evaluate its use. Am J Ophthalmol. 1966;61:1272–7.
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Melanoma
17
Introduction 450–900 times more common than conjunctival

melanoma, a ratio that is increasing.
Conjunctival melanoma may arise de novo, from Due to the rarity of conjunctival melanoma,
preexisting conjunctival nevus or PAM with atypia incidence studies based on population-based data
or from a combination of nevus and PAM with are scarce. According to a Dutch survey, the
atypia. All these arise from melanocytes that annual incidence of conjunctival melanoma
migrate from the neural crest to reside in the con- ranges between 0.28 and 0.34 per million inhab-
junctival epithelium. In the medical literature, con- itants [3]. A Swedish study showed a significant
junctival melanoma is sometimes labeled together increase in the incidence of conjunctival mela-
with uveal melanoma as “ocular melanoma.” The noma from 1960 to 2005, from 0.10 cases/mil-
clinical behavior, molecular biology, and the histo- lion to 0.74 cases/million in males and from 0.06
pathologic features of conjunctival and uveal mel- cases/million to 0.45 cases/million in females
anoma are clearly different; therefore, conjunctival [4]. Population-based registry data from the
melanoma should be approached as an entity sepa- Surveillance, Epidemiology and End Results
rate from uveal melanoma. (SEER) program of the National Cancer Institute
(NCI) of the USA show a significant increase in
the incidence rate of conjunctival melanoma
Epidemiological Aspects from 0.22 cases per million per year in 1973–
1979 to 0.46 in 1990–1999 [5]. The most signifi-
According to several studies, conjunctival mela- cant increase is for white men. Because changes
noma accounts for 2–5% of ocular melanomas in incidence coincide with those seen in cutane-
[1] and fewer than 3% of excisional biopsies of ous melanoma, the authors suggest a link to sun-
conjunctival lesions [2]. Cutaneous melanoma is light exposure. A recent study from Denmark has
also shown an increase in the incidence of con-
J. Pe’er (*) junctival melanoma between 1960 and 2012 to
Ocular Oncology Service and Ophthalmic Pathology 0.5 cases per million per year, mostly caused by
Laboratory, Department of Ophthalmology, an increase in older patients (>65 years) [6].
Population-based data indicate that an equal
Jerusalem, Israel
e-mail: peer@hadassah.org.il number of men and women develop conjunctival
melanoma [3, 4], but recent studies report a
R. Folberg
Oakland University William Beaumont higher incidence in males [5]. Conjunctival mela-
School of Medicine, Rochester, MI, USA noma is more common in middle-aged and older

persons, between the fourth and seventh decades

of life [3, 4], and only few cases in children have
been reported [7]. When conjunctival melanoma
develops in xeroderma pigmentosum – a rare
event – younger patients are affected [8].
Conjunctival melanoma is less common in the
black population and in other non-white individ-
uals [1, 5], and according to the SEER program,
the overall white-to-black incidence ratio in con-
junctival melanoma is 2.6:1 [9].
Etiology and Associated Diseases
Until recently, there was no clear evidence that

Fig. 17.1 Melanoma of the peri-limbal bulbar conjunc-
ultraviolet radiation is a causative factor in the
tiva with “feeder vessels” entering the tumor
development of conjunctival melanoma, even
though most of these tumors develop in the
sunlight-
exposed bulbar conjunctiva [1, 10].
However, in recent molecular studies, mutations
in the telomerase reverse transcriptase (TERT)
promoter, typical of UV-induced DNA damage
and identical to mutations in cutaneous mela-
noma, were found in conjunctival melanoma but
not in uveal melanoma [11–13]. About 70–75%
of conjunctival melanomas are associated with
PAM with atypia, while 7–17% are associated
with conjunctival nevus, and 8–19% develop de
novo [14, 15]. No significant association with
cutaneous melanoma, dysplastic nevus syn-
drome, or ocular or oculodermal melanocytosis
has been observed.
Fig. 17.2 Conjunctival PAM with atypia, which has pro-

Clinical Features gressed to corneo-limbal melanoma
Conjunctival melanoma usually affects one eye

and is typically pigmented. Amelanotic con- Conjunctival nevi are very rare in the palpebral
junctival melanoma does occur and can be mis- conjunctiva and fornix. Therefore, pigmented
taken clinically for squamous cell carcinoma. lesions in these areas should be viewed as suspi-
Careful high-magnification slit-lamp examina- cious for melanoma and should be excised. In
tion typically reveals flecks of pigmentation vivo confocal microscopy [16], ultrasound bio-
even in amelanotic melanomas. Any region of microscopy [17], and high-resolution optical
the conjunctiva including the caruncle and plica coherence tomography (HR-OCT) [18] serve as
semilunaris may be affected (Figs. 17.1, 17.2, additional diagnostic tools in differentiating
17.3, 17.4, 17.5, and 17.6). Most conjunctival conjunctival melanoma from other conjunctival
melanomas, however, develop at the limbus. melanocytic lesions.
17 Conjunctival and Corneal Tumors: Melanoma 199
Fig. 17.3 Melanoma of the plica semilunaris Fig. 17.5 Multifocal melanoma arising from PAM with
atypia, with a tumor in the bulbar conjunctiva and a tumor
in the lower fornix
Fig. 17.4 Melanoma of the upper palpebral conjunctiva
Fig. 17.6 Extensive conjunctival melanoma with

involvement of the entire upper palpebral conjunctiva,
Variants which could be seen only upon inversion of the upper eye-
lid. No involvement of the bulbar conjunctiva was noted,
leading to a delay in diagnosis
onjunctival Melanoma Associated
C
with PAM
Microinvasive melanoma arising in PAM with one or more nodules in flat lesions [19, 20].
atypia can be difficult to identify clinically; there- Multifocal melanomas are usually associated
fore, one should search carefully for subtle plac- with PAM with atypia and may appear simultane-
oid thickening within the area of PAM. The more ously or sequentially in different parts of the con-
dramatic clinical evidence for development of junctiva [19, 20]. Melanoma with PAM may also
melanoma from PAM is the sudden emergence of involve the adjacent eyelid skin [14].
onjunctival Melanoma Associated

C Epithelial Tumors (Non-melanocytic)
with Nevus
Non-melanocytic epithelial tumors such as squa-
Conjunctival melanoma arising from a nevus or mous papilloma, conjunctival intraepithelial neo-
de novo appears clinically as a solitary pigmented plasia, and invasive squamous cell carcinoma
or non-pigmented smooth vascularized nodule, may acquire melanin in darkly-complexioned
commonly in the limbal area. Rarely, these individuals [21].
lesions are pedunculated [1].
Intraocular Tumors
Primary Melanoma of the Cornea
Epibulbar extension of uveal melanoma or mela-
Primary melanoma of the cornea is very rare, nocytoma should also be considered in the dif-
although several cases have been reported [1]. ferential diagnosis of conjunctival melanoma
Many of these cases represent examples of cor- [22]. In these cases, the trans-scleral nature of the
neal invasion from a limbal melanoma. It is lesion can be identified by high-frequency ocular
important to remember that Bowman’s layer is a ultrasound.
barrier to invasion of the corneal stroma.
Therefore, pigmented neoplasms affecting the
cornea are usually superficial to Bowman’s layer Miscellaneous Lesions
unless this tissue has been violated by previous
surgery. Staphyloma, subconjunctival hematoma, foreign
body, and hematic cyst may also be confused
clinically with conjunctival melanoma [1]. Rare
Differential Diagnosis occurrence of metastatic cutaneous melanoma to
the conjunctiva has been reported [23].
Any conjunctival pigmented lesion may simulate
conjunctival melanoma.
Conjunctival Nevus Light Microscopy
Conjunctival nevi may be elevated and dark, and The definitive diagnosis of conjunctival mela-
in the absence of cysts (typical of compound con- noma is made by histopathologic examination.
junctival nevi), it may be difficult to differentiate Most cases can be diagnosed with confidence by
the nevus from melanoma by clinical examina- light microscopy (Fig. 17.7). Four types of atypi-
tion alone [20]. Most conjunctival nevi are cal melanocytes have been described in conjunc-
noticed in childhood and adolescence. Therefore, tival melanoma: small polyhedral, spindle,
any newly-elevated pigmented conjunctival balloon, and round epithelioid cells with eosino-
lesion that develops in adulthood should be philic cytoplasm [20]. Invasive melanoma is
viewed with suspicion. Conjunctival nevi almost often accompanied by intraepithelial PAM with
always develop in the bulbar conjunctiva and car- atypia, which may be the precursor to the mela-
uncle. Therefore, any pigmented lesion present- noma (Fig. 17.8). Any breeching of the basement
ing in the palpebral conjunctiva or fornix should membrane by atypical melanocytes in PAM with
be considered suspicious for melanoma [20]. atypia should be considered as invasive mela-
gists without experience in ophthalmic pathology,

who may mistakenly consider these findings as
signs of malignancy.
Immunohistochemistry
and Molecular Pathology
If in doubt, immunohistochemical stains such as

HMB-45, MELAN-A, and SOX-10, either indi-
vidually or in a cocktail, can demonstrate the
presence of melanocytes [24–26], and Ki-67 pro-
liferation index may help to differentiate mela-
noma from nevi [27]. BRAF mutations are found
in about half of conjunctival melanoma cases,
Fig. 17.7 Low-magnification histological picture show- similar to cutaneous melanoma, while BRAF
ing thick conjunctival melanoma involving the specimen’s mutations are seldom encountered in uveal mela-
margin (hematoxylin and eosin; original magnification ×4)
nomas [28–31]. Conversely, GNAQ mutations,
which occur in uveal melanomas, are not found
in conjunctival melanomas [32]. TERT promoter
mutations with a UV signature are found in
32–41% of conjunctival melanomas [11–13].
NRAS mutations and NF1 mutations are also
found in these tumors [31, 33]. Expressions of
programmed cell death protein-1 (PD-1) and pro-
grammed death-ligand 1 (PD-L1) [34, 35], as
well as specific micro RNA [36], are reported in
conjunctival melanoma. All these markers may
have therapeutic implications.
Histopathologic Prognostic Factors

Fig. 17.8 This photomicrograph illustrates conjunctival
melanoma arising in the context of PAM with atypia. Note
the lack of maturation or architectural organization from There are several histopathologic features that
top to bottom and the presence of atypical intraepithelial indicate a poor prognosis in patients with con-
melanocytes that do not appear to be cohesive or to have junctival melanoma. The major prognostic factor
any architectural relationship with the epithelial cells
(hematoxylin and eosin; original magnification ×20)
predictive of metastasis is the depth of invasion,
measured with an ocular micrometer from the top
of the epithelium to the deepest point of invasion.
noma. The presence of atypical melanocytes The other important histologic prognostic factors
within the epithelium of subepithelial cysts is are presence of pagetoid spread, mixed cell
considered to represent PAM with atypia and not tumors versus spindle cell tumors, histologic evi-
invasive melanoma. The common presence of dence of lymphatic invasion, increased lymphan-
cystic and solid epithelial inclusions in com- giogenic activity, high number of mitotic figures,
pound conjunctival nevi may confuse patholo- and high cell proliferation index using immuno-
histochemical stains such as PCNA or Ki-67 [1, has been attributed to shedding of exfoliated mel-
14, 37, 38]. Ulceration in conjunctival melanoma anoma cells in the tear film, by direct extension,
is also an important histopathologic predictor for and as regional hematogenous metastases [1].
adverse outcome [37, 39]. The presence of PAM Epistaxis or epiphora may indicate extension and
with atypia does not appear to be a prognostic recurrence of the conjunctival melanoma in the
indicator [14]. nasolacrimal system [44]. Rarely, conjunctival
melanoma invades the eyeball or extends directly
into the orbit [1, 45].
Clinical Course
Local Recurrence Regional and Distant Metastasis
Local recurrence of conjunctival melanoma has Conjunctival melanoma can metastasize to any
been reported in 56–65% of the patients, and organ in the body. In about half of the patients
nearly half of these patients develop more than with metastases, regional lymph node metastases
one recurrence [1, 3, 4, 40]. The mean interval are detected before systemic disease [40, 46].
between the first treatment and the first recur- Other common locations are the brain, liver, and
rence is 2.5 years. Some authorities report that lung [40]. It is important, however, to emphasize
patients treated by surgical excision alone have that in conjunctival melanoma, the most common
more recurrences than those receiving adjuvant primary locations of the metastases are the
treatment such as cryotherapy or brachytherapy, regional parotid (preauricular) and submandibu-
but it is not known if this recommendation applies lar lymph nodes. This reflects an important dif-
to surgical resection with clear margins. For ference between conjunctival and uveal
example, patients with multifocal disease, usu- melanoma, which tends to disseminate almost
ally originating in PAM with atypia, are prone to exclusively to the liver, at least initially. Therefore,
develop recurrences because it can be difficult to ophthalmologists should be specific when refer-
ensure a clear resection margin. Other risk fac- ring patients with conjunctival melanoma to
tors for developing recurrence are melanoma oncologists and must avoid applying the general
in locations other than the limbus and involve- term “ocular melanoma” lest the oncologist
ment of surgical margins [40]. Therefore, the assumes, incorrectly, that the first target for
pathologist’s report should specifically comment metastasis is likely to be the liver as is the case
on the tumor involvement of surgical margins. with uveal melanoma.
Local recurrences are managed as the primary
melanoma.
Treatment
Local Spread Surgery
Conjunctival melanoma can spread locally in the The primary treatment of conjunctival melanoma
conjunctiva and can metastasize to regional is surgical excision of the entire tumor. Most
lymph nodes systemically [41]. “In-transit” authorities recommend an excision margin of
metastases of conjunctival melanoma, which are 3–5 mm, but this is not always feasible. Complete
believed to represent local lymphatic spread tumor excision should always be combined with
within the conjunctiva, have been described [42, adjuvant therapy. When deep limbal and scleral
43]. Dissemination of melanoma cells at the time involvements are suspected, lamellar scleral exci-
of tumor excision has also been reported. Spread sion should be considered [47]. When the cornea
of conjunctival melanoma through the nasolacri- is involved, some surgeons use absolute alcohol to
mal duct to the nasal cavity and paranasal sinuses devitalize corneal epithelial cells adjacent to a
limbal melanoma before excision [47]. Areas of ing radical surgery over a conservative approach
PAM with atypia, either around the excised mela- in treating conjunctival melanoma [60].
noma or distant from it, must be treated because Therefore, exenteration of the orbit, including the
these lesions can give rise to recurrent melano- eyelids in order to include the palpebral and for-
mas. The PAM can be treated by surgery, cryo- niceal conjunctiva, is currently performed only as
therapy, or brachytherapy and/or topical a palliative treatment for advanced disease.
chemotherapy using mitomycin C (see Chap. 16). Exenteration is not usually performed when there
is systemic metastatic disease.
Cryotherapy
Reconstruction
Cryotherapy to the surgical margins and/or to the
surgical bed, using a double freeze-thaw cycle, is When wide excision is performed, reconstruc-
the usual form of adjunctive therapy [19]. tion of the conjunctiva is often needed. Such
However, it should not be used as a primary treat- reconstruction can be achieved by transplanting
ment modality. mucosal tissue either from the mouth or from
the contralateral conjunctiva. The successful use
of amniotic membrane after excision of large
Radiotherapy conjunctival melanoma, in order to prevent con-
junctival scars and symblepharon, has been
Conjunctival melanoma is not radio-sensitive; described [61].
therefore, brachytherapy should not be used as
the sole treatment modality [48]. However,
brachytherapy has been advocated as a supple- Regional and Distant Metastasis
mental therapy, usually using beta radiation, and
has been reported to be superior to cryotherapy as Regional lymph node metastasis is associated
adjuvant therapy after surgical excision [48–52]. with a poor prognosis [60]; however, it has been
Proton beam radiotherapy has also been advo- found that patients with regional metastases tend
cated in treating extensive conjunctival mela- to live longer than those with systemic metasta-
noma as an alternative to exenteration [53]. ses. Regional metastases can be treated by
lumpectomy and adjuvant radiotherapy [60].
Disseminated conjunctival melanoma has been
Topical Chemotherapy treated with systemic chemotherapy, with a pos-
and Immunotherapy sible combination of interferon or interleukin-2.
However, the results are poor, and the life expec-
In recent years, topical mitomycin C [54–56] and tancy is a few months.
topical interferon alpha-2b [57–59] have been In recent years, there has been impressive
used successfully as adjuvant treatment to surgi- progress in the treatment of systemic metastases
cal excision in treating conjunctival malignant of cutaneous melanoma by biological drugs.
melanoma. Because of the similarities between conjunctival
and cutaneous melanoma, such treatment has
been suggested for conjunctival melanoma, and
Orbital Exenteration clinical trials are currently ongoing to further
evaluate and optimize these targeted therapies, as
In the past, orbital exenteration was the preferred well as immunotherapy [62]. The drugs that have
treatment for conjunctival melanoma and been tried are BRAF/MEK inhibitors, such as
PAM. However, a review of the literature has vemurafenib (zelboraf) and dabrafenib (tafinlar)
failed to demonstrate advantages of such mutilat- [63–65], and immune checkpoint inhibitors
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Conjunctival Stromal Tumors
18
Introduction Pyogenic Granuloma
The conjunctival stroma contains various tissue The term “pyogenic granuloma” is a misnomer,
elements such as vascular, fibrous, and neural; since it is neither pyogenic nor granulomatous. It
naturally, benign and malignant tumors may orig- is granulation tissue, although some consider it as
inate from these types of tissue (Table 18.1). a polypoid form of acquired capillary hemangi-
However, conjunctival stromal tumors are rare. oma [2]. Pyogenic granuloma is a fibrovascular
This chapter describes the salient features of con- response to tissue insult such as surgical or non-
junctival stromal tumors according to their tissue surgical trauma or inflammation, although spon-
of origin. taneous pyogenic granulomas have also been
reported. Pyogenic granuloma is commonly
observed in the conjunctiva after chalazion sur-
Vascular Tumors gery, strabismus surgery, and excision of con-
junctival lesions and in the anophthalmic socket
Vascular tumors of the conjunctiva are uncom- following enucleation, considered as an aberrant
mon, and with the exception of Kaposi’s sar- wound-healing response.
coma, most are benign lesions that have no
malignant potential. According to one large series Clinical Features
[1], the most common conjunctival vascular Pyogenic granuloma has been reported in every
lesions are lymphangioma/lymphangiectasia and part of the conjunctiva and even in the limbus and
pyogenic granuloma. the cornea, mostly following a corneal epithelial
defect [3]. Pyogenic granuloma appears as a
fleshy, elevated, red, often pedunculated, richly
vascularized mass (Fig. 18.1a).
J. Pe’er (*) · S. Frenkel Pyogenic granuloma is composed of granulation
Ocular Oncology Service and Ophthalmic Pathology tissue with marked chronic inflammation with
lymphocytes, plasma cells, and neutrophils and
Jerusalem, Israel proliferation of small, mostly capillary-sized
e-mail: peer@hadassah.org.il blood vessels (Fig. 18.1b).

Table 18.1 Classification of stromal tumors of the conjunctiva

Category Subtypes
Vascular tumors Pyogenic granuloma Racemose malformation
Capillary hemangioma Hemangiopericytoma
Cavernous hemangioma Kaposi’s sarcoma
Acquired sessile hemangioma Lymphangiectasia
Varix Lymphangioma
Malignant hemangioendothelioma
Fibrous tumors Fibroma Nodular fasciitis
Benign fibrous histiocytoma Malignant fibrous histiocytoma
Neural tumors Neurofibroma (localized) Neurofibroma (diffuse)
Schwannoma (neurilemoma) Granular cell tumor
Histiocytic tumors Xanthoma Juvenile xanthogranuloma
Reticulohistiocytoma
Myxoid tumors Myxoma
Myogenic tumors Rhabdomyosarcoma
Lipomatous tumors Lipoma Herniated orbital fat
Liposarcoma
Lymphoproliferative tumors Benign reactive lymphoid hyperplasia Lymphoma
Leukemic infiltrates
Choristomas Dermoid Dermolipoma
Osseous choristoma Lacrimal gland choristoma
Complex choristoma
Metastatic tumors
Secondary tumors
a b
Fig. 18.1 Pyogenic granuloma. A 31-year-old man with Note prominent vascularity (a). Polypoid lesion with lob-
a 3-week history of a rapidly growing recurrent conjuncti- ular pattern of capillary proliferation. The vessels are vari-
val vascular growth in the inferonasal conjunctival fornix. ably dilated (b) (original magnification ×4)
Treatment report of a small case series, pyogenic granu-

Pyogenic granuloma often responds to topical loma of the ocular surface showed complete
corticosteroids when diagnosed early, but many resolution after treatment with topical 0.5%
cases require surgical excision. In a recent timolol [4].
18 Conjunctival Stromal Tumors 211
Capillary Hemangioma stroma in children and adolescents (Fig. 18.3a)

[5]. This lesion is usually isolated but may be
Capillary hemangioma appears during early associated with syndromes [1]. It may cause a
infancy and, like its counterpart in the skin, may recurrent subconjunctival hemorrhage [7].
grow over several months and then regress spon- Histologically, similar to such lesions in other
taneously within several years. locations, it is composed of large blood-filled
spaces, lined by endothelial cells and separated
Clinical Features by fibrous septa (Fig. 18.3b). It can be managed
Capillary hemangioma is a distinct or diffuse red, by a surgical excision.
elevated conjunctival lesion that can occur any-
where in the conjunctiva. It can be an isolated
lesion or in association with an eyelid or orbital Acquired Sessile Hemangioma
capillary hemangioma (Fig. 18.2a).
Shields et al. [8] described vascular lesions of
Histopathologic Features adults that consist of a sessile network of convo-
Similar to capillary hemangiomas in other loca- luted blood vessels immediately beneath the con-
tions, it shows numerous capillary channels and junctival epithelium, usually on the bulbar
proliferation of endothelial cells (Fig. 18.2b). conjunctiva. Histologically the lesion comprises of
two to three layers of dilated congested blood ves-
Treatment sels that are otherwise of normal appearance. There
Usually, no treatment is needed, and the child should are no systemic associations. Since most of these
only be observed. There are rare cases, especially lesions remain stable and have no known compli-
when the lesion is large and potentially amblyo- cations, they should be managed by observation.
genic, in which surgical excision or local or systemic
corticosteroids are employed [1, 5]. The experience
in treating conjunctival capillary hemangioma by Varix and Racemose Hemangioma
beta-blockers is still limited and showed response to
oral propranolol in one of two babies [6]. Conjunctival Varix
Varix and racemose hemangioma are rare vascu-
lar malformations of the conjunctiva. Varix is a
Cavernous Hemangioma mass of dilated venous channels that may range
from a single channel to complex venous chan-
Cavernous hemangioma presents as a red or blue nels. Many of them are anterior extensions of
multiloculated lesion in the deep conjunctival orbital varix. The color ranges from blue-red to
a b
Fig. 18.2 Capillary hemangioma. Color photograph of a sal conjunctival stroma revealed numerous thin-walled
circumscribed vascular conjunctival lesion overlying the capillary-type vessels, most of which contained red blood
upper tarsus (a). On histopathology examination, the tar- cells within their lumen (H&E 10×) (b)
a b
c d
Fig. 18.3 Cavernous hemangioma. A clustered “grape- defined lesions with many low reflective intrinsic cystic-
like” lesion involving the temporal conjunctiva was like pockets (c). Large, well-circumscribed vascular
observed on slit-lamp examination (a). On OCT, there proliferation of thin-walled veins that completely replaced
were clear spaces located into the subepithelial layer of the conjunctival stroma (H&E 4×). Most of the lumina
the conjunctiva (b). Ultrasonography showed two well- were engorged with blood (d)
black [1]. It is usually movable and not fixed to tumor composed of spindle-shaped pericytes and
the sclera. Thrombosis is frequent. Some con- small blood vessels [9]. Treatment is by complete
sider it to be in the spectrum of lymphangioma. surgical excision with tumor-free margins and
Management should be conservative, by observa- close follow-up.
tion and symptomatic treatment. When it is
symptomatic, surgical excision should be consid-
ered, although the surgeon should bear in mind Kaposi’s Sarcoma
the risk of prolonged bleeding [1, 3].
Prior to the AIDS era, Kaposi’s sarcoma in gen-
onjunctival Racemose Hemangioma
C eral, and the conjunctiva in particular, was a rare
Conjunctival racemose hemangioma is a lesion of tumor that mainly affected elderly and immuno-
dilated arteries and veins communicating directly suppressed patients. Since the eruption of the
without a capillary bed between them. It appears AIDS epidemic, this malignant tumor is diag-
as a loop of dilated vessels in the conjunctival nosed much more frequently in AIDS patients.
stroma (Fig. 18.4). It should be managed conser- Sometimes conjunctival Kaposi’s sarcoma is the
vatively by observation. Wyburn–Mason syn- first sign of AIDS [10]. However, in recent years,
drome should be ruled out in such cases [5]. it has been diagnosed less frequently because of
the more effective treatment of AIDS in devel-
oped countries.
Hemangiopericytoma
Clinical Features
Hemangiopericytoma is very rare in the conjunc- Kaposi’s sarcoma appears as a single isolated or
tiva. It appears as an elevated pedunculated red multiple confluent red painless conjunctival
mass (Fig. 18.5). Histologically, it is a solid masses.
a b
c d
Fig. 18.4 Racemose hemangioma. A multilobulated vas- ultrasonography (b). Vascular proliferation composed of a
cular lesion was identified in the medial canthal region mixture of thick-walled arteries and thin-walled veins
that was extending posteriorly along the anterior margin within a fibrotic conjunctival stroma (H&E, 4×) (c). The
of the caruncle (a). The lesion consisted of highly reflec- endothelial cells were negative for lymphatic marker
tive portions with well-defined, low reflective channels on D2–40 (10×) (d)
a b
Fig. 18.5 Hemangiopericytoma. Patient at presentation inconspicuous small blood vessels (b, H&E,450×).
showing a large ovoid conjunctival lesion that protruded (Reprinted from Grossniklaus et al. [9]. With permission
over her right lower lid (a). Histopathology shows a rela- from Elsevier)
tively solid tumor composed of spindle-shaped cells and
Histopathologic Features Histopathologic Features

The tumors are composed of malignant spindle- The lesion shows markedly dilated lymphatics,
shaped cells with elongated oval nuclei, well- which may be filled with blood, partially sur-
formed capillary channels, and vascular slits rounded by scattered inflammatory cells. The
containing blood but no definite endothelial phenomenon is intermittent, with resolution of
lining. the channels’ congestion and the chemosis
between episodes.
Treatment
Localized tumors can be excised surgically, with Treatment
or without the addition of cryotherapy. However, Usually, no treatment is required, although surgi-
Kaposi’s sarcoma is responsive to chemotherapy cal excision without or with amniotic membrane
and low-dose radiation therapy [11]. A giant con- transplant or conjunctival autograft has been
junctival Kaposi’s sarcoma in HIV-positive described [15]. Recently, treatment of symptom-
patients responded with complete remission to atic conjunctival lymphangiectasia by liquid
highly active antiretroviral therapy and systemic nitrogen cryotherapy [17], high-frequency radio
chemotherapy [12]. Treatment using intralesional wave electrosurgery, and limited surgical drain-
interferon alpha-2b [13] or intralesional mitomy- age has been reported [18, 19]. A case of con-
cin C [14] has been reported. junctival lymphangiectasia fully resolved after
subconjunctival injection of bevacizumab was
reported [20].
Lymphangiectasia
and Lymphangioma
Conjunctival Lymphangioma
Lymphangiectasia
Conjunctival lymphangioma is a benign tumor
When lymphatic channels in the conjunctiva are of the lymphatic vessels that usually appears in
dilated and prominent, the condition is called the first decade of life. It can occur as an iso-
“lymphangiectasia.” lated conjunctival lesion but more often repre-
sents a superficial component of an orbital
Clinical Features lymphangioma.
Conjunctival lymphangiectasia can either be uni-
lateral or bilateral with focal or diffuse bulbar che- Clinical Features
mosis [15]. As a result of the communication with Conjunctival lymphangioma appears as a multi-
conjunctival veins, these dilated channels may be loculated lesion composed of dilated cystic
filled with blood and if so are termed “hemor- spaces. These spaces may contain clear fluid, but
rhagic lymphangiectasia” (lymphangiectasia hem- often parts of them contain blood and are called
orrhagica conjunctivae of Leber) [16]. The “chocolate cysts.” Inflammation in the area, such
surrounding conjunctiva appears edematous, and as an upper respiratory tract infection, causes
occasionally, an associated subconjunctival hem- congestion and dilation of the spaces. Because of
orrhage is present. This phenomenon can occur the common connection of the conjunctival part
spontaneously or after trauma or inflammation to an orbital part, dilatation of the lymphangioma
(Fig. 18.6). Congenital cases have been reported. cysts may cause proptosis of the eye.
a b
c d
e f
Fig. 18.6 Lymphangiectasia. Slit-lamp photograph dem- sels in the background (g, *). Immunohistochemistry for
onstrating the appearance of prominent circumferential CD34, a marker of fibroblasts and the vascular endothe-
vessels (a–d). FA image demonstrating complete absence lium, shows that dilated channels are CD34 negative (con-
of hyperfluorescence in the lesion (e). Histopathology consistent with lymphatics) (h). Blood vessels show mild
firmed dilated tortuous empty channels (top and bottom, CD34 positivity, and background stromal cells are posi-
arrows) next to normal vessels containing blood. Stroma is tive. Slit-lamp photograph demonstrating appearance
free of inflammation. Bar represents 50 mm (f, hematoxy- 4 months after surgical drainage (i). Anterior segment
lin and eosin). Immunohistochemistry for D2–40/podo- OCT demonstrating dilated conjunctival lymphatic chan-
planin highlights lymphatics. Dilated channels are lined by nels (j). (Reprinted from Goshe et al. [18]. With permis-
D2–40-positive endothelium. Note the negative blood ves- sion from Wolters Kluwer Health, Inc.)
g h
i j
Histopathologic Features Fibrous Tumors

Conjunctival lymphangioma shows dilated lym-
phatic channels filled with lymph and/or blood, Fibroma
lined by endothelium, and separated by thin
walls. Clinical Features
Fibroma of the conjunctiva is rare [26]. It is gen-
Treatment erally a slowly-progressing acquired white stro-
Treatment of lymphangioma is difficult, and sur- mal tumor in adults and may range from a
gical excision or radiotherapy usually does not well-circumscribed lesion to a multinodular
eradicate the tumor. Carbon dioxide laser [21] and lesion. One case of malignant fibrosarcoma has
brachytherapy [22] have been used for treating also been reported [27].
conjunctival lymphangioma, with partial success.
When dilatation of the spaces raises the orbital Histopathologic Features
pressure and threatens the optic nerve, a percuta- The tumor is composed of compact fibroblasts
neous drainage of blood may offer a temporary and collagen. Rare variants such as elastofibroma
relief. Drainage and sclerotherapy has been oculi, giant cell angiofibroma, and solitary
offered as a safe and effective treatment [23–25]. fibrous tumor have been described [28].
Treatment FH generally occurs in adults, but a case of FH in

Conjunctival fibroma is treated by complete sur- a child with xeroderma pigmentosum has also
gical excision. been reported [30].
enign and Malignant Fibrous

B Clinical Features
Histiocytoma Conjunctival FH appears as an amelanotic mass
that can range from a well-circumscribed mass to
Fibrous histiocytoma (FH) of the conjunctiva can a diffuse one. It often presents in the limbus
be benign, locally aggressive, or malignant [29]. (Fig. 18.7) [31].
a b
Fig. 18.7 A 10-year-old black boy presented with a lim- lesion, and there are scattered inflammatory cells, mostly
bal lesion that was excised about 2 months previously. lymphocytes (b, Hematoxylin and eosin stain, 40×). A
The lesion recurred (a). Further excision with cryotherapy final diagnosis of benign fibrous histiocytoma (extension
was performed. For yet another recurrence, excision was to margin) was made. Repeat cryotherapy was performed
repeated. Histopathology revealed a moderately cellular to the surgical site. Over a 6-year follow-up, there was no
spindle cell lesion composed of bland spindle cells recurrence, and the patient maintained normal visual acu-
arranged in a vaguely storiform configuration. Entrapped ity (c). (Courtesy of David Meisler, MD and Thomas
collagen bundles are witnessed at the periphery of the Plesec, MD, Cleveland Clinic, Ohio)
Histopathologic Features Nodular Fasciitis

FH shows a mixture of spindle-shaped fibro-
blasts, often arranged in a storiform pattern, and Nodular fasciitis is a benign rare nodular tumor
lipid-laden histiocytes. Conjunctival FH with of unknown cause that can occur at any age.
benign histological appearance may show a
malignant clinical course. Malignant FH of the Clinical Features
conjunctiva is extremely rare and shows marked Nodular fasciitis appears as a solitary white epi-
pleomorphism, many mitotic figures, and multi- scleral enlarging nodule at the limbus or over the
nucleated giant cells. Malignant FH is accepted sclera anterior to the insertion of one of the rectus
as originating from primitive mesenchymal cells muscles and can cause discomfort or pain [33]
with the capacity to differentiate along either or (Fig. 18.8). The nodule may grow quickly and
both histiocytes and fibroblasts [32]. Malignant show signs of inflammation. It is thought to origi-
FH can metastasize to regional lymph nodes and nate from the Tenon’s capsule [34].
hematogenously to distant organs, causing death.
Treatment The lesion tends to be round or oval and is not
While benign FH can be treated by complete sur- encapsulated. It is composed of bundles of fibro-
gical excision, malignant FH should be treated by blasts that vary in configuration from spindle to
radical surgery that may include exenteration and stellate. There is a variable amount of intercellu-
radical dissection of regional lymph nodes. lar myxoid ground substance interspersed with
a b
c d
Fig. 18.8 Preoperative (a) and postoperative (b) appear- of spindle cells with variable positivity, consistent with
ance on slit-lamp examination. Spindle cell proliferation myofibroblastic differentiation (d). (Reprinted from
composed of regular delicate cells with pale chromatin McClintic et al. [33]. With permission from Wolters
and small nucleoli arranged in short, irregular fascicles (c, Kluwer Health, Inc.)
hematoxylin and eosin, 200×). Smooth muscle actin stain
slit-like vascular spaces or capillaries and scanty Clinical Features

infiltration of chronic inflammatory cells. Neurilemmoma (Schwannoma) appears as a
Numerous mitotic figures can lead to its being pink-yellow elevated mass in the conjunctival
misdiagnosed as a sarcoma [35]. stroma.
Treatment Histopathologic Features

The prognosis is excellent, and complete exci- The tumor is the result of proliferation of
sion is usually sufficient therapy, although recur- Schwann cells of a peripheral nerve sheath and is
rence can occur. composed of spindle cells that may be arranged
in Antoni A pattern or Antoni B pattern.
Neural Tumors Treatment

Conjunctival neurilemmoma is treated by com-
Neurofibroma plete excision within the tumor capsule.
Incomplete excision may lead to recurrence.
Neurofibroma is a peripheral nerve sheath tumor Malignant Schwannoma has not been recorded in
that can occur in the conjunctival stroma as a the conjunctiva.
solitary circumscribed, or as a diffuse or plexi-
form, tumor [36]. The solitary type usually is not
associated with systemic disease, while the latter Granular Cell Tumor
is generally associated with neurofibromatosis
type 1 (von Recklinghausen’s disease). Conjunctival granular cell tumor, known also as
myoblastoma, is a very rare benign tumor of dis-
Clinical Features puted origin [39]. After being thought of striated
The solitary neurofibroma is an amelanotic, trans- muscle origin, the recent suggestion is that it is of
lucent, gelatinous circumscribed growing mass neural derivation, probably from Schwann cells.
[37], while the plexiform neurofibroma is diffuse.
Clinical Features
Histopathologic Features The tumor appears as a pink, elevated smooth
Neurofibroma demonstrates benign proliferation mass of the conjunctival stroma, indistinguish-
of Schwann cells, axons, and endoneural fibro- able from other well-circumscribed tumors.
blasts, which may be difficult to differentiate
from other spindle cell tumors. Histopathologic Features
The tumor is composed of groups and cords of cells
Treatment with small round to oval nuclei and voluminous
Solitary tumors are usually treated by complete cytoplasm containing fine eosinophilic granules.
surgical excision. Plexiform neurofibroma may
be difficult to excise completely. In such cases, Treatment
debulking of the tumor is performed. The tumor should be completely excised.
Neurilemmoma (Schwannoma) Histiocytic Tumors
Neurilemmoma (Schwannoma) of the conjunc- Xanthoma

tiva is a benign rare ocular tumor that can arise
from any part of the conjunctiva – bulbar, forni- Conjunctival xanthoma appears as a yellow sub-
ceal, or palpebral [38]. epithelial mass on the epibulbar surface. In a case
of xanthoma disseminatum, in which multiple pink stromal mass, usually near the limbus
lesions are found, lesions have been described in (Fig. 18.9) [42]. Sometimes associated systemic
the limbus of both eyes [40]. Histopathologically, findings may not be present [42]. Bilateral con-
the lesion shows subepithelial infiltrate of lipid- junctival xanthogranuloma in adults has also
laden histiocytes, eosinophils, and Touton giant been recorded [43].
cells. Cases of atypical fibroxanthoma of the con-
junctiva have also been reported [41]. Histopathologic Features
The lesions show typical findings of histiocytes
and Touton giant cells; in addition, lympho-
Xanthogranuloma cytes, plasma cells, and eosinophils can be
found. Immunohistochemical stainings are pos-
Clinical Features itive for CD68 (histiocytic marker) and nega-
Conjunctival involvement in juvenile xantho- tive for CD1a and S-100 (Langerhans cell
granuloma usually occurs as a solitary orange- markers) [44].
a b
Fig. 18.9 Juvenile xanthogranuloma. A 3-year old cells (b, hematoxylin and eosin, 40× magnification). The
female was referred by her pediatrician for evaluation of a giant cells have characteristic wreath of nuclei in central
“red spot” in her right eye (a). As there was no response to part of the cell surrounded by foamy cytoplasm (c, oil
topical steroids, excisional biopsy was performed. On his- immersion. 100× magnification). Dermatologic evalua-
topathology, there was submucosal infiltrate consisting of tion was negative
foamy histiocytes, lymphocytes, and typical Touton giant
a b
Fig. 18.10 Conjunctival myxoma appearing as a cyst- tive tissue in the conjunctival stroma containing abundant
like mass in nasal bulbar conjunctiva of the right eye (a). hyaluronidase-sensitive mucopolysaccharides stained
Histologically, myxoma is a mass of very loose connec- positively with Alcian blue (b) (original magnification ×4)
Treatment Myxoid Tumors (Myxoma)

Most lesions are treated by excision. When xan-
thogranuloma is suspected clinically, it may be Clinical Features
observed for spontaneous resolution or can be
treated by topical or systemic corticosteroids. In Conjunctival myxoma is a rare benign stromal tumor
resistant cases, brachytherapy has been success- that occurs in adults. It appears as a slowly-growing
fully applied. asymptomatic, freely movable, usually unilateral
solitary lesion in any part of the conjunctiva but pri-
marily located in the temporal bulbar conjunctiva
Reticulohistiocytoma [46, 47] (Fig. 18.10a). The lesion may appear pink or
fleshy in color. Eyelid and conjunctival myxoma
Clinical Features may be associated with Carney complex (Chap. 24).
Reticulohistiocytoma is a rare benign conjuncti-
val lesion that usually occurs as an isolated skin
nodule or as part of a systemic disorder known as Histopathologic Features
“multicentric reticulohistiocytosis.” The cases
reported in the ocular surface were of a single, The tumors are well-circumscribed, located in
painless mass localized to the cornea and limbus the conjunctival substantia propria, and covered
without systemic disease [45]. by conjunctival epithelium. They are hypocellu-
lar and composed of stellate- and spindle-shaped
Histopathologic Features cells, some with small intracytoplasmic and
The lesions are composed predominantly of large intranuclear vacuoles that represent dilated cis-
mononuclear and a few multinucleated cells with ternae of rough-surfaced endoplasmic reticulum.
finely granular “ground glass” cytoplasm and The stroma contains abundant mucoid material,
large nuclei with prominent nucleoli. which stains positively for hyaluronidase-
sensitive mucopolysaccharides, and sparse retic-
Treatment ulin and delicate collagen fibers (Fig. 18.10b).
The lesions are treated by complete excision. Scattered mast cells are found in many lesions
[46, 47]. Immunohistochemistry (IHC) demon- function. In most cases, the treatment also
strates positivity for vimentin and negativity for includes chemotherapy and radiotherapy.
smooth muscle actin, SOX10, and GLUT1 [45].
Other Myogenic Tumors

Treatment
Some other myogenic tumors of the conjunctiva
Simple surgical excision is curative. such as infantile myofibroma [51], leiomyosar-
coma, and myofibrosarcoma have been very
rarely recorded (Fig. 18.11) [52–54].
Myogenic Tumors
Rhabdomyosarcoma Lipomatous Tumors
Rhabdomyosarcoma (RMS) is the most common True lipomatous tumors of the conjunctiva are
childhood primary orbital malignancy, but the very rare. On the other hand, herniated orbital fat
occurrence of this tumor in the conjunctiva alone, under the conjunctiva is not rare and may be mis-
without orbital involvement, is rare. taken for a lipomatous tumor. Dermolipoma is
discussed later in this chapter.
Clinical Features
Rhabdomyosarcoma appears as pink, rapidly
growing conjunctival vascular mass. The initial Lipoma
clinical manifestation of the tumor may be a non-
inflamed pedicle of soft tissue, but occasionally Conjunctival lipoma occurs in adults and
swelling and erythema precede visible tumor for- appears as a yellow-pink stromal mass.
mation [48]. Histopathologically, they are usually of the
pleomorphic type and show variable-sized adi-
Histopathologic Features pocytes surrounded by stellate cells. The stroma
Most conjunctival rhabdomyosarcomas are of the shows loose myxoid connective tissue. Floret
embryonal type, and as a submucosal tumor, some giant cells and nuclear pyknosis were described
call it “botryoid” rhabdomyosarcoma (sarcoma bot- in this tumor. Mitotic activity is absent [55].
ryoides) [48, 49]. Prognosis used to rely on the his-
topathologic type of the tumor. Recently the weight
has shifted to the gene fusion status of forkhead box Liposarcoma
protein O1 (FOXO1). The European Paediatric Soft
Tissue Sarcoma Study Group (EpSSG) found that Liposarcoma of the conjunctiva shows clinical
the FOXO1 fusion status in patients with lymph features similar to lipoma. Histopathologically,
node-positive (N1) alveolar rhabdomyosarcoma is a the tumor reveals numerous neoplastic cells con-
powerful predictor of prognosis [50]. The fusion taining stellate and hyperchromatic nucleus [56].
status will be used to stratify these patients in the The cytoplasm of these cells contains vacuoles
next EpSSG RMS study, and treatment will be resembling lipid droplets, and signet-ring-type
intensified in patients with fusion-positive tumors. cells can be observed. The stroma may be myxo-
matous. The tumor is treated by complete surgi-
Treatment cal excision. A case of conjunctival liposarcoma
Complete surgical excision is recommended showing multiple recurrences and metastatic dis-
when this is possible without affecting ocular ease was reported [57].
Lymphoproliferative Tumors systemic lymphoma, which can be present

simultaneously with the conjunctival disease or
The conjunctival lymphoid tumors may be subdi- during follow-up. Lymphoid tumors may
vided into reactive lymphoid hyperplasia, atypi- involve additional ocular sites, mainly the orbit,
cal lymphoid hyperplasia, and the more common but the simultaneous involvement of the eyelid
conjunctival lymphoma. The conjunctival lym- and uvea has also been reported [59]. Most con-
phoid tumors belong to the group of lymphoid junctival lymphoid tumors occur in adults,
tumors that affect the orbit and the eyelids – the commonly manifested in individuals aged
ocular adnexal lymphoma [58]. 60–70 years [60], but occurrence in children
has also been found [61]. An association
between conjunctival lymphoma and
Clinical Features Chlamydophila psittaci [62] or Helicobacter
pylori [63] has also been reported. However, it
Conjunctival lymphoid tumors can occur as an appears that that bacterial involvement in the
isolated lesion of the conjunctiva, but in up to pathogenesis of conjunctival lymphoma is
one-third of patients, it is a manifestation of linked to the geographic location [64].
a b
c d
Fig. 18.11 Myofibrosarcoma. Slit-lamp appearance at CAM5.2 (not shown). Five years after initial presentation.
presentation (a). Outcome after excision, cryotherapy to Slit-lamp photo of area treated with triple episcleral
the conjunctival margins, and first episcleral brachyther- brachytherapy (f). Position of episcleral plaques (g). A
apy (b). Superior marginal recurrence (c). Histopathologic planned dose of 85 Gy at a depth of 3 mm was used for the
examination revealed cells with spindle nuclei in a fas- first and second plaques, and 60 Gy at a depth of 4 mm
cicular patter with poorly defined eosinophilic cytoplasm was used for the third plaque. Note absence of radiation
(d. Hematoxylin and eosin, 100× magnification). retinopathy on wide-field fluorescein anagram (h) and by
Immunoreactivity to smooth muscle actin was positive (e. OCT (h, inset). (Reprinted from Platt et al. [54]. With per-
100× magnification) and negative to H-caldesmon, des- mission from Wolters Kluwer Health, Inc.)
min, myoglobin, S-100, melan A, HMB45, AE1/3, and
e f
g h
Symptoms ris but almost never appear in the palpebral

Most patients diagnosed as having lymphoprolif- conjunctiva.
erative conjunctival lesions are symptomatic at
the time of diagnosis. Symptoms include the pre-
sentation of a conjunctival mass, or irritation, Histopathologic Features
and, less commonly, ptosis, epiphora, blurred
vision, proptosis, and diplopia. Some of the As it is not possible to differentiate between
patients are asymptomatic [59]. benign and malignant conjunctival lymphoid
tumors by clinical examination, a biopsy is needed
Signs to establish the diagnosis. The vast majority of
The lymphoproliferative tumors of the conjunc- conjunctival lymphomas are non- Hodgkin’s
tiva appear as a diffuse, slightly elevated pink B-cell lymphoma, mostly of low grade [60]; T-cell
mass, resembling smoked salmon in color; hence, lymphoma is extremely rare in the conjunctiva
it is termed “salmon patch” (Fig. 18.12). Most [65]. The major lymphoma subtypes, according to
conjunctival lymphoid tumors are located at the the Revised European and American Lymphoma
bulbar conjunctiva and fornix, usually hidden by (REAL) classification, include extranodal mar-
the eyelid in the superior and inferior quadrants ginal zone B-cell lymphoma (EMZL) which is by
and not in the horizontal exposed parts of the bul- far the most common type, followed by follicular
bar conjunctiva or the limbus. Some of these lymphoma (FL), mantle cell lymphoma (MCL),
tumors appear in the caruncle or plica semiluna- diffuse large B-cell lymphoma (DLBCL) and the
a b
Fig. 18.12 Conjunctival lymphoma with typical infiltrative appearance (a). Three months following treatment with
radiation therapy (Total dose 25 Gy, 12 fractions) (b)
rare plasmacytoma, and lymphoplasmacytic lym- because of possible recurrence in extranodal

phoma/immunocytoma [57, 59]. sites. In one study, systemic lymphoma was
eventually discovered in 15% of patients at
5 years and in 28% at 10 years [58].
Treatment Since most conjunctival lymphomas are low
grade, the mortality rate of conjunctival lym-
Systemic evaluation should be performed to phoma is low. The main prognostic factor for the
exclude the presence of systemic lymphoma which risk of developing systemic lymphoma is the his-
is common in DLBCL and MCL [60]. Localized tological subtype with MCL and DLBCL having
disease is commonly treated with low-dose exter- a markedly poorer prognosis then EMZL and FL
nal beam radiation (2000–4000 cGy) [60], local [60]. Older age also was found to be an important
interferon alpha injections [66, 67], and brachy- prognostic factor [60, 73].
therapy using an ophthalmic applicator or a radio-
active plaque [68]. In cases of widespread
lymphoma and when systemic lymphoma is diag- Leukemic Infiltrates
nosed, chemotherapy is applied [60]. Intravenous
anti-CD20 monoclonal antibody (rituximab) has Leukemic infiltration in the eye most commonly
been used successfully with or without chemother- occurs in the choroid and retina, but conjunctival
apy as primary treatment [69] and in treating infiltration is also a well-recognized complication
relapsed mucosa-associated lymphoid tissue lym- of many types of leukemia. Conjunctival involve-
phoma of the conjunctiva [70, 71]. Recently, intra- ment in leukemia shows myriad clinical presenta-
lesional rituximab has been used successfully for tions that can involve one or both eyes, have focal
conjunctival lymphoma [72]. or diffuse infiltration of the substantia propria, can
occur on the bulbar or palpebral conjunctiva, and
can cause microvascular changes due to hypervis-
Prognosis cosity (leukostasis) from markedly elevated leu-
kemic cell counts. Conjunctival lesions have also
Local treatment is usually effective, but semian- been reported as the presenting manifestation of
nual systemic evaluation should be performed acute leukemia in patients who were not
r ecognized to have the disease, and in others, they Choristoma

signified disease relapse [74, 75]. Conjunctival
leukemic involvement is consistent with good Choristomas are congenital lesions representing
visual acuity, with no reports of vision reduction normal tissue in an abnormal location. When the
associated with the conjunctival infiltration; how- lesion is composed of one type of tissue, it is con-
ever, it portended a poor prognosis with median sidered to be a simple choristoma; when combi-
survival of 3 months. Although clinical reports of nations of displaced tissue are involved, it is
conjunctival leukemia in the literature are rela- termed “complex choristoma.” Epibulbar choris-
tively uncommon, autopsy studies of leukemic tomas are the most common epibulbar tumors in
patients indicate that many harbor unsuspected children [77]. Among them, dermoids and der-
disease and that most cases of conjunctival leuke- molipomas are very common [78]. Epibulbar
mia are probably subclinical or go unrecognized. choristomas affect the cornea, limbus, or subcon-
junctival space and range in appearance from a
small, flat lesion to large masses filling most of
Clinical Features the epibulbar region. They often can cause astig-
matism. Epibulbar choristomas can affect other
Conjunctival leukemia occurs most commonly in parts of the eye and orbit and may be associated
patients with acute leukemia. Leukemic infiltra- with coloboma, Goldenhar syndrome, or organ-
tions are often firm and not tender, may appear as oid nevus syndrome [77].
a pink smooth mass, and are usually associated
with small areas of hemorrhage [74]. Granulocytic
sarcoma (chloroma) may appear in the ocular Dermoid
adnexa in the course of acute myelogenous leuke-
mia (AML) and appear as a gray-green mass in the Epibulbar dermoid is a well-circumscribed firm,
eyelid or the forniceal or tarsal conjunctiva [76]. solitary congenital mass that involves the bulbar
conjunctiva and often the corneoscleral limbus
(Fig. 18.13). Rarely, more than one is found.
Clinical Features
Clinicopathological studies indicate that con- Conjunctival dermoid is usually a solid yellow-
junctival leukemic lesions are cellular invasions white mass, and sometimes fine hairs protrude
that occur at all levels of the substantia propria; from the lesion. The size of epibulbar dermoids is
they can be diffuse or patchy and are generally variable, from the more common small limbal
localized along the blood vessels. dermoid through large dermoid involving most or
the entire corneal surface to extensive dermoids
that involve also the anterior chamber and the
Treatment iris. The typical dermoid occurs in the inferotem-
poral limbus. It may be associated with Goldenhar
The treatment includes various combinations of syndrome that, in addition to the epibulbar der-
chemotherapy and, commonly, local radiother- moid, may include preauricular skin appendages,
apy, with good local response in most cases. vertebral anomalies, eyelid coloboma, hearing
However, patients who achieve a complete local loss, and mandibular hypoplasia. Epibulbar der-
response may eventually die of the systemic dis- moid, in addition to being a cosmetic blemish,
ease. These patients die from refractory leukemia can cause severe astigmatism and amblyopia,
or leukemia-related complications, most com- affecting the vision according to the level of cor-
monly from infections. neal involvement [79].
a b
Fig. 18.13 Limbal dermoid in the lower temporal aspect of the cornea and conjunctiva (a). Note hair. Appearance after
surface excision (b)
Epibulbar dermoid is a simple choristoma that
consists of dense fibrous tissue covered by strati-
fied squamous epithelium. It usually contains
dermal elements such as hair follicles, sebaceous
glands, sweat glands, and sometimes fat tissue.
Treatment
When the epibulbar dermoid is very small and
does not cause visual symptoms, it can be man-
aged by observation alone. Larger dermoids can
be managed by excision (lamellar keratosclerec-
tomy) without or with conjunctival flap. In most
cases, a corneal scar will remain in the excision
site. Lamellar or penetrating keratoplasty may be Fig. 18.14 Dermolipoma in the temporal part of the bul-
needed in advanced cases. When amblyopia is bar conjunctiva
present, early treatment is advised.
temporal conjunctival fornix. Epibulbar dermoli-
poma often extends between the lateral rectus
Dermolipoma and superior rectus muscles to lie close to the
lacrimal gland. They also may extend posteriorly
Clinical Features into the orbit or anteriorly toward the limbus.
Dermolipoma is a yellowish-tan, soft, fusiform Dermolipoma should be differentiated from sub-
tumor, usually localized to the temporal or conjunctival orbital fat prolapse [80].
supero-temporal aspect of the conjunctiva, near
the lateral canthus (Fig. 18.14). Although it is H istopathologic Features
congenital, it may remain asymptomatic for years The epithelium on the surface of the dermoli-
until detected when it protrudes from the supero- poma is stratified squamous epithelium that may
be partially keratinized. The stroma contains pealing, it may be treated by surgical excision.
variable quantities of dense collagenous tissue When lesions adhere to the sclera, superficial
and large amounts of adipose tissue, mainly in sclerectomy may be warranted. Imaging of the
the deeper aspects of the lesion. Pilosebaceous globe with the tumor may aid in avoidance of iat-
structures are usually absent. rogenic globe perforation during surgical exci-
sion [83, 84].
Treatment
The majority of the dermolipomas require no
treatment, but when symptomatic or cosmetically acrimal Gland Choristoma (Ectopic
L
blemished, it can be managed by simple excision Lacrimal Gland)
of the anterior portion of the lesion or by excising
the entire lesion, including the orbital part, Clinical Features
through the conjunctival fornix. When the con- Epibulbar lacrimal gland choristoma is a simple
junctiva over the dermolipoma is adherent to the choristomatous congenital lesion which presents
lesion and has to be excised, rotational conjuncti- as an asymptomatic pink stromal mass, typically
val flap and free conjunctival autograft have been in the supero-temporal or temporal parts of the
applied to cover the conjunctival defect [81, 82]. conjunctiva, but it has been described also in the
limbal area [85, 86].
Osseous Choristoma Histopathologic Features

Lacrimal gland tissue, similar to normal lacrimal
Clinical Features gland, is seen in the conjunctival stroma.
Epibulbar osseous choristoma is a rare solitary Epibulbar complex choristoma may contain
congenital lesion that most frequently presents as lacrimal gland tissue together with other tissue
an isolated epibulbar lesion in the supero- elements [87, 88].
temporal quadrant but may occur in other loca-
tions on the surface of the globe or in association Treatment
with other choristomatous lesions [83, 84]. Excision of the lesion usually suffices.
Bilateral lesions have been reported. The lesion
may be freely movable or adherent to the bulbar
conjunctiva and the sclera. Not uncommonly, the Complex Choristoma
lesion may involve the extraocular muscle sheath.
Complex choristoma is a congenital, unilateral
Histopathologic Features lesion that contains tissue derived from two germ
The lesion is composed of mature, compact bone layers – ectoderm and mesoderm.
surrounded by connective tissue in which addi-
tional choristomatous elements occasionally may Clinical Features
be found. Epibulbar complex choristoma has a variable
clinical appearance and ranges from a localized
Treatment lesion to a lesion that covers much of the epibul-
Epibulbar osseous choristoma typically remains bar surface. A large pedunculated mass protrud-
undetectable until palpated by the patient, who ing through the eyelid aperture has been reported
feels the hard lesion. The diagnosis can be con- [89] (Fig. 18.15a). The choristoma may invade
firmed by ultrasonography or computed tomogra- the cornea. The consistency and color depend on
phy that illustrates the calcifications. The tumor the types of tissue present in the choristoma; for
is generally managed by periodic observation, example, dermal elements containing fat appear
but if causing ocular inflammation, foreign body yellowish, while lacrimal tissue appears pink. A
sensation, and tearing, or is cosmetically unap- case series of epibulbar choristoma containing
a Treatment
The management of epibulbar complex choris-
toma depends on the extent of the lesion and the
symptoms it causes. Asymptomatic small lesions
can be observed, while large symptomatic lesions
should be excised. Reconstruction of the ocular
surface is sometimes needed. In very advanced
cases, enucleation may be needed.
Metastatic and Secondary Tumors
Metastatic Tumors
b Metastatic tumors to the conjunctiva are rare and

usually appear at an advanced stage of the sys-
temic malignancy when there is evidence of other
ocular and organ metastases [91]. Similar to
sources of metastases in other ocular sites, the
primary tumors are usually carcinomas, led by
breast carcinoma or cutaneous melanoma.
The metastatic carcinoma appears as fleshy,
yellow or pink, vascularized stromal tumors,
while metastatic cutaneous melanoma may be
pigmented. The metastasis may be located in any
Fig. 18.15 Epibulbar complex choristoma in a 5-day-old part of the conjunctiva and is usually solitary but
child, associated with linear nevus sebaceous. A large may be multiple. Conjunctival metastases are
pedunculated mass protrudes temporally through the left
treated by excisional biopsy, radiotherapy, and
eyelid aperture (a). CT scan shows calcifications (bone) in
the tumor base and a cyst-like structure in the polypoid chemotherapy. The survival time after diagnosis
mass (b) of the conjunctival metastasis is in the range of
months.
cartilage, smooth muscle bundles, and fibrous

connective tissue covered by pterygia was Secondary Tumors
reported [90].
The conjunctiva may be secondarily involved by
Histopathologic Features extraocular extension of intraocular tumors and
Complex choristoma may include a variable by extension of eyelid and orbital tumors [5].
combination of ectopic tissue such as dermal tis- The most important tumor in this category is
sue containing adipose tissue, collagen and pilosebaceous gland carcinoma of the eyelid, which
sebaceous structures, lacrimal gland, smooth often exhibits pagetoid invasion into the con-
muscle, cartilage, bone, nerves, and blood ves- junctival epithelium. Ciliary body melanoma,
sels. It may appear cystic (Fig. 18.15b). Epibulbar when extending through the sclera into the sub-
complex choristoma may be associated with conjunctival tissue, may simulate conjunctival
organoid nevus syndrome, of which the most fre- melanoma. Orbital tumors, such as rhabdomyo-
quent cutaneous feature is the sebaceous nevus of sarcoma in children, can present first in the
Jadassohn [89]. conjunctiva.
a b
c d
Fig. 18.16 IgG4 sclerosing disease. Slit-lamp photos of phoid follicles (c, hematoxylin and eosin, original magni-
left eye conjunctival lesion at presentation show a tempo- fication ×100). Photomicrograph of immunohistochemical
ral conjunctival bulbar lesion that is raised, tan-colored, stain for IgG4, in the same area as H&E photomicrograph
vascular, and immobile (a). Ultrasound biomicroscopy of (d). There are numerous IgG4-positive plasma cells,
the conjunctival lesion measuring 7.5 × 8 × 1.2 mm with which, in conjunction with the H&E morphology and
low reflectivity and shallow focal invasion into the sclera IgG4:IgG ratio of 64%, are diagnostic of IgG4-RD.
(b). Photomicrograph of conjunctival lesion demonstrat- (Reprinted from Li et al. [94]. With permission from
ing haphazard fibrosis with intermixed plasma cell-rich Wolters Kluwer Health, Inc.)
inflammation as well as many eosinophils and a few lym-
IgG4-Related Disease and orbit) is a rare entity. Varied presentations,

vague symptoms, and rare incidence result in
Isolated conjunctival inflammation from IgG4- delayed or missed diagnoses (Fig. 18.17) [95–
related disease should be on the differential for 99]. Immunohistochemistry (IHC) [100], and,
chronic and minimally symptomatic solitary con- more recently, mass spectrometry (MS) allows
junctival lesions. Assessment of IgG4-RD is for amyloid protein subtype analysis [101]. MS
based on the combination of clinical history, offers increased accuracy in protein subtype
physical exam, histopathology, laboratory results, identification and may also allow for identifica-
and radiology studies [92–94] (Fig. 18.16). tion of new protein subtypes [102]. A recent
study, with comprehensive review of the litera-
ture, concluded that amyloidosis-AL is the most
Amyloidosis common form of amyloid deposit in ocular
adnexal structures [103]. Hence work up to
Amyloid deposit in ocular adnexal structures exclude systemic involvement or associated
(conjunctiva, eyelid, lacrimal gland and sac, underlying lymphoproliferative disorder is
extraocular muscles, levator palpebrae muscle, warranted.
a b
c d
Fig. 18.17 A 63-year-old white woman with past history arrow). Congo red-stained section of conjunctival mucosa
of sarcoidosis was noted to have an incidental left-sided shows lobular accumulation of amorphous congophilic
conjunctival orbital mass (a). The mass was yellowish in material in deep stroma (c, Congo red) which exhibits
color, multinodular, and firm in consistency. Ocular motil- apple-green birefringence with polarized light (d).
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Caruncle Tumors
19
Hans E. Grossniklaus, Daniel R. Capiz-Correa,
and Jill R. Wells
Caruncle Tumors artery. The lymphatics drain to the submaxillary

lymph nodes and are innervated by the infratroch-
The caruncle (diminutive of the Latin word lear nerve. The function of the caruncle is not
Caro = flesh) is a fleshy structure located at the well understood, but it may participate in lacri-
inner canthus at the lacrimal lake. It has a tail that mal drainage through contractions of Horner’s
blends to the skin of the medial canthal angle and muscle [1–4].
a round to ovoid head medial to the plica semilu- Because the caruncle is a transitional zone
naris. The distance from the common canaliculus structure, it can give rise to tumors found in the
is about 0.85 mm [1–3]. The caruncle develops skin, conjunctiva, and lacrimal gland. Few car-
from the nasal aspect of the lower lid fold and is uncle lesion series have been published since the
sequestered from the lower lid by the growth of first report by Von Graefe in 1858 [4–11]. Lesions
the lower canaliculus. It has an irregular surface, of the caruncle are rare, and because of their mul-
measuring about 5 mm vertically, 3 mm trans- tiple components, clinical diagnosis and manage-
versely, and 1.5 mm in thickness, containing con- ment can be difficult. Caruncle lesions correspond
junctival and skin elements. The caruncle has a to 0.3–1.1% of all specimens submitted to an
nonkeratinized stratified squamous epithelium ophthalmic pathology laboratory [4–9].
with goblet cells. The stroma contains fibroblasts Inconsistency between clinical and histopatho-
and melanocytes interspersed with collagen, adi- logic diagnosis as high as 50% has been reported
pose tissue, sebaceous glands associated with [5–9]. In a report by Ostergaard of 574 caruncle
hair follicles, striated muscle fibers (Horner’s lesions, 96% of lesions were classified as benign,
muscle), inflammatory cells, and, in some indi- with the benign nature of these tumors being rec-
viduals, sweat glands and accessory lacrimal tis- ognized in only 29% prior to histopathologic
sue. Its blood supply is from the medial palpebral study [9].
In the series reported by Ostergaard, tumors
H. E. Grossniklaus (*) · J. R. Wells were classified as benign in 96% of lesions, pre-
Department of Ophthalmology, Emory University malignant in 1.7%, and malignant in 2.4%. The
School of Medicine/Emory Eye Center, most affected age group was from 20 to 29 years
Atlanta, GA, USA
(71%). Nevus and papilloma were the most com-
e-mail: ophtheg@emory.edu
mon benign neoplasms, occurring in 43% and
D. R. Capiz-Correa
22% of cases, respectively. Less common lesions
Department of Orbit and Oculoplastic, Fundacion
Hospital Nuestra Senora de la Luz, I.A.P., included inclusion cysts (6.1%), sebaceous gland
Mexico City, Mexico hyperplasia (5.4%), and chronic inflammatory

236 H. E. Grossniklaus et al.
lesions (4.4%). Rare lesions included oncocy- Table 19.1 (continued)

toma in 16 cases, primary basal cell carcinoma in Category n %
3 cases of secondary basal cell carcinoma, lym- Neoplasia
phoma in 4 cases and sebaceous gland carcinoma Papilloma with dysplasia 4 0.7
Dysplasia 2 0.3
[2], melanoma [2], and Kaposi’s sarcoma [2].
Melanocytic
Vascular tumors were also found, corresponding Primary acquired melanosis with 4 0.7
to nine hemangiomas, seven pyogenic granulo- atypia
mas, and four lymphangiomas. Ectopic lacrimal Malignant 14 2.4
gland was found in seven cases (Table 19.1) [9]. Neoplasia
Epithelial
Basal cell carcinoma (primary) 1 0.2
Basal cell carcinoma (secondary) 3 0.5
Table 19.1 Pathologic diagnoses of lesions of the Sebaceous gland carcinoma 2 0.3
caruncle
Lymphoid
Category n % Lymphoma 4 0.7
Benign 550 96 Melanocytic
Degeneration Melanoma 2 0.3
Elastoid degeneration 2 0.3 Vascular
Amyloid deposits 1 0.2 Kaposi’s sarcoma 2 0.3
Inflammation Total 574 100.0
Chronic inflammation 25 4.4 Modified from Ostergaard et al. [9]. With permission from
Chalazion 4 0.7 John Wiley & Sons
Foreign body 3 0.5
Abscess 1 0.2
Folliculitis 1 0.2
Neoplasia Epithelial Lesions
Cystic
Inclusion cyst 35 6.1
Ductal cyst 9 1.6
Squamous Papilloma
Epithelial
Papilloma 127 22.1 Papillomas are benign epithelial tumors of the
Sebaceous gland hyperplasia 31 5.4 conjunctiva with a cauliflower-like appearance,
Oncocytoma 16 2.8 most of which are exophytic, and can be sessile
Ectopic lacrimal gland 7 1.2 or pedunculated, and they are more common in
Sebaceous gland adenoma 3 0.5
adults between 20 and 39 years of age and chil-
Hidrocystoma 1 0.2
dren. They can be solitary or multiple [4–5, 11,
Lymphoid
Reactive lymphoid hyperplasia 2 0.3 13]. They are intimately related to human papil-
Mesenchymal loma virus especially serotypes 6 and 11 [4, 5, 8,
Leiomyoma 1 0.2 9, 12, 13]. Histologically, they are composed of
Melanocytic multiple fronds or fingerlike projections of con-
Nevus 248 43.2 junctival epithelium, which enclose cores of vas-
Primary acquired melanosis 5 0.9
cularized connective tissue [8, 13]. After removal,
Vascular
recurrence rates range from 6% to 27% [8].
Hemangioma 9 1.6
Lymphangioma 4 0.7 Topical alpha-interferon can be used in case of
Pyogenic granuloma 7 1.2 recurrence or multiple lesions (Fig. 19.1).
Miscellaneous
Normal tissue 5 0.9
Dermoid tumor 1 0.2 Sebaceous Hyperplasia
Fribrolipoma 1 0.2
Xanthoma 1 0.2
Sebaceous hyperplasia can present as a slow-
Premalignant 10 1.7
growing, painless, yellow, “greasy,” granular,
19 Caruncle Tumors 237
a b
Fig. 19.1 Squamous papilloma: (a) Pedunculated and lomatous configuration overlaying central vascular cores
sessile papilloma arising from the caruncle (clinical pho- (H&E stain, 10×)
tograph). (b) Acanthotic epithelium arranged in a papil-
nodular lesion, which is associated with overly-

ing telangiectatic vessels of unknown etiology,
although some reports present cases experiencing
pain [4, 14]. Histologically, they are formed of
hyperplastic glandular lobules situated around a
single duct where the sebaceous cells maintain
their normal maturation with a single, outer, dark,
germinal layer changing abruptly to clear vacuo-
lated cells in the inner layers. Excisional biopsy
is recommended if malignancy is suspected, to
improve cosmesis or lesion debulking (Fig. 19.2).
Fig. 19.2 Sebaceous hyperplasia: Lobules of enlarged

Oncocytoma
subepithelial sebaceous glands, with normal maturation
(H&E stain, 25×)
Oncocytomas constitute 5.1% of caruncle lesions
[15]. In the ocular region, they are most com-
monly found in the caruncle, but can arise from Lymphocytes can be present but are scanty, and
the conjunctiva, eyelid, lacrimal gland, and lacri- lymphoid follicles are rare (Fig. 19.3).
mal sac. Clinically, they are slow-growing nod-
ules, red, orange-tan, or red-blue in color,
sometimes with a lobulated, fleshy, or cystic Sebaceous Carcinoma
appearance, found in patients over 50 years of
age (range, 51–89), with slightly higher preva- More than 95% of sebaceous carcinomas origi-
lence in women. They develop from oncocytic nate in the eyelids, usually from the Meibomian
metaplasia of the lacrimal or salivary acinar cells, glands of the tarsus and less often from the Zeiss
or from conjunctiva adjacent to the caruncle. glands, with only about 2% to 5% developing in
Histologically, they are composed of polygonal the caruncle [16, 17]. Clinically, they can be mis-
epithelial cells with round, central to paracentral, diagnosed as sebaceous gland hyperplasia.
nuclei and abundant, finely granular, eosinophilic Histologically, this tumor is composed of lobules
cytoplasm containing abundant mitochondria. of sebaceous gland with pleomorphic vacuolated
a b
Fig. 19.3 Oncocytoma: (a) dark subepithelial nodule (clinical photograph). (b) Oncocytes forming glands. These cells
have small, displaced nuclei with abundant eosinophilic cytoplasm (H&E stain, 100×)
cells and mitotic activity. The standard local junctival nevi [19]. They are usually noticed
treatment is complete surgical removal with neg- around the age of puberty and are regarded as
ative margins and map biopsies to rule out paget- hamartomas. They are mildly elevated, brown,
oid spread and regional and distant metastasis. pigmented lesions with a cystic component, but
Follow-up is recommended (Fig. 19.4). they can be amelanotic. Feeder and intrinsic ves-
sels can be seen is up to one of three cases. Nevi
are usually asymptomatic, but occasionally the
Basal Cell Carcinoma patient can report a foreign body sensation.
Surgical removal is mainly done for cosmetic
Basal cell carcinoma is a rare tumor of the car- reasons or if there is a clinical suspicion of malig-
uncle, although some studies report the incidence nancy. Histologically, nevi are composed of nest
as being similar to that of melanoma [4, 7, 9]. of nevus cells. Most are compound nevi, but
Because of its close proximity to the medial can- some can have a subepithelial or junctional com-
thus, it is not rare to find caruncular involvement ponent (Fig. 19.5).
from a basal cell carcinoma arising in the skin of
the medial canthus. Clinically, most lesions are
vascularized and nodular, more common in men, Melanoma
between the range of 24 and 82 years [18]. Basal
cell carcinoma can arise from basal cells of the Melanoma has been reported to be the most
epithelium or infundibular cells of the hair folli- prevalent malignant lesion of the caruncle.
cles or from pluripotent stem cells. They should Melanoma involving the caruncle has relatively
be treated by complete excision whenever poor prognosis (together with melanomas in the
possible. palpebral conjunctiva, plica semilunaris, and
fornix) compared to epibulbar conjunctival
lesions. One feature to distinguish melanoma
Pigmented Lesions from nevus is the absence of intralesional cysts
on slit lamp examination. Treatment for con-
Nevus junctival melanoma includes surgical removal
with clear margins plus cryotherapy and/or
Nevus is the most commonly reported lesion of radiotherapy, with topical chemotherapy for dif-
the caruncle [4–6, 8, 9, 15]. In a report by Shields, fuse disease and exenteration if there is orbital
caruncular nevus accounted for 15% of all con- invasion. Melanoma can arise from primary
a b
c d
Fig. 19.4 Sebaceous carcinoma: (a) Fleshy nodule aris- nuclei with prominent nucleoli, lobules of tumor sur-
ing from the caruncle (clinical photograph). (b) Tumor rounded by chronic inflammatory cells (H&E stain, 40×).
composed of lobules of hyperplastic sebaceous glands (d) Sebaceous differentiation, with positive staining for
(H&E stain, 10×). (c) Higher magnification showing cells adipophilin (adipophilin immunostain, 100×)
with sebaceous differentiation, pleomorphic amphophilic
a b
Fig. 19.5 Caruncle nevus: (a) Dark pigmented lesion with well-demarcated margin, note the absence of cysts (clinical
photograph). (b) Subepithelial nest of nevus cells, some with melanin pigment in their cytoplasm (H&E stain, 25×)
acquired melanosis in up to 40% of cases, from

nevi in 30% or de novo in 30% of cases [5]
(Figs. 19.6 and 19.7).
Inflammatory Lesions
Most inflammatory lesions of the caruncle have

been reported as unspecified nongranulomatous
chronic inflmaation [8, 9]. Other reported inflam-
matory lesions include foreign body granuloma,
abscess, folliculitis, actinomycosis, inflamma-
Fig. 19.6 Caruncle PAM with associated conjunctival
tory pseudotumor, ocular cicatricial pemphigoid, melanoma: Extensive areas of PAM extending to the bul-
cytomegalovirus infection, molluscum contagio- bar and tarsal conjunctiva, and the caruncle. Melanoma
sum, and spherocytosis (Fig. 19.8). arising from PAM affecting the superior fornix (clinical
photograph)
a b
c d
Fig. 19.7 Caruncle melanoma: (a) Exophytic, fleshy with spindle-shaped and round nuclei with prominent
lesion originating from the caruncle (clinical photograph). nucleoli. There are also epithelioid cells and occasional
(b) Tumor composed of sheets of spindle and epithelioid mitotic Figs. (100×). (d) Caruncle melanoma: Positive
cells with a moderate amount of eosinophilic cytoplasm staining for HMB-45 immunostain in tumor cells (HMB-
(H&E stain, 25×). (c) Higher magnification showing cells 45 immunostain, 100×)
Lymphoproliferative Tumors have been reported in the different series, of

which low-grade B-cell lymphoma (MALT) was
Reactive lymphoid hyperplasia is the most com- the most common. The clinical presentation of a
mon lymphoproliferative disorder affecting the salmon-colored mass on the caruncle should
caruncle, accounting for up to 3% of all caruncular raise suspicion of a lymphoproliferative disorder.
lesions [9, 10]. A few caruncular lymphomas Incisional biopsy is recommended (Fig. 19.9).
a b
Fig. 19.8 Chronic inflammation with secondary pigmentation: (a) Mild redness of caruncle and plica. (b) Cellular
infiltrate with reactive vascular channels and secondary pigmentation (H&E stain, 100×)
Fig. 19.9 Marginal zone B-cell (MALT type) lym- immunostain, 100×). (d) Kappa light chain positive stain-
phoma: (a) Lymphocytic infiltrate in the substantia pro- ing in scattered CD20 positive lymphocytes (Kappa light
pria, composed of small, round lymphocytes and chain immunostain, 150×). (e) Lambda light chain posi-
occasional plasma cells (H&E stain, 150×). (b) CD3 positive staining in scattered CD20 lymphocytes in a greater
tive staining in lymphocytes (CD3 immunostain, 100×). > 2:1 ratio (Lambda light chain immunostain, 150×)
(c) CD20 positive staining in many lymphocytes (CD20
b c
d e
Vascular Tumors
Capillary Hemangioma
A case report on capillary hemangioma of the

caruncle by Ozdal reported three patients who
developed a rapidly growing mass arising in the
caruncle, without prior history of surgery or
trauma, and all three lesions were nodular, lobu-
lated and ulcerated, and excised because malig-
nancy was suspected [20]. Histologically,
capillary hemangiomas are composed by lobules
of small, thin, and irregular vessels lined by a Fig. 19.10 Capillary hemangioma: Small and irregular
vessels lined by a single row of endothelial cells with sur-
single layer of flattened, mature endothelial cells
rounding fibrous septa (25×)
separated by thin fibrous septa (Fig. 19.10).
References 11. Von Graefes A. Geschwulste der Tranenkarunkel.

Archiv fur Ophthalmologie. 1854;1:289–91.
12. Sjö NC, Heegaard S, Prause JU, et al. Human papillo-
1. Spencer W. Ophthalmic pathology: an atlas and text-
mavirus in conjunctival papilloma. Br J Ophthalmol.
book, vol. 1. 4th ed: Saunders: Philadelphia; 1996.
2001;85(7):785–7.
2. Kathuria SS, Howarth D, Hurwitz JJ, et al. An ana-
13. Eagle R. Eye pathology and atlas and text. 2nd ed.
tomic and histologic study of the caruncle. Ophthal
Lippincot Willims and Wilkins/Wolters Kluwer:
Plast Reconstr Surg. 1999;15(6):407–11.
Philladelphia; 2011.
3. Mori M. The structure of the caruncula lacri-
14. Ogawa M, Shinzawa M, Dogru M, et al. Caruncular
malis of Japanese. Okajimas Folia Anat Jpn.
and pericaruncular sebaceous gland hyperplasia: a
1965;41(5):277–83.
report of 2 cases and literature review. Eye Contact
4. Kaeser PF, Uffer S, Zografos L, et al. Tumors of
Lens. 2016;44(Suppl 1):S316–9.
the caruncle: a clinicopathologic correlation. Am J
15. Kapil JP, Proia AD, Puri PK. Lesions of the lacrimal
Ophthalmol. 2006;142(3):448–55.
caruncle with an emphasis on oncocytoma. Am J
5. Luthra CL, Doxanas MT, Green WR. Lesions of
Dermatopathol. 2011;33(3):227–35.
the caruncle: a clinicohistopathologic study. Surv
16. Shields JA, Shields CL, Marr BP, et al. Sebaceous
Ophthalmol. 1978;23(3):183–95.
carcinoma of the caruncle. Cornea. 2006;25(7):858–9.
6. Santos A, Gómez-Leal A. Lesions of the lacrimal car-
17. Pfeiffer ML, Yin VT, Myers J, et al. Regional nodal
uncle. Clinicopathologic features. Ophthalmology.
recurrence of sebaceous carcinoma of the caruncle
1994;101(5):943–9.
11 years after primary tumor resection. JAMA
7. Shields CL, Shields JA, White D, et al. Types and fre-
Ophthalmol. 2013;131(8):1091–2.
quency of lesions of the caruncle. Am J Ophthalmol.
18. Ugurlu S, Ekin MA, Altinboga AA. Primary basal
1986;102(6):771–8.
cell carcinoma of the caruncle: case report and
8. Levy J, Ilsar M, Deckel Y, et al. Lesions of the car-
review of the literature. Ophthal Plast Reconstr Surg.
uncle: a description of 42 cases and a review of the
2014;30(3):e62–4.
literature. Eye (Lond). 2009;23(5):1004–18.
19. Shields CL, Fasiuddin AF, Mashayekhi A, et al.
9. Ostergaard J, Prause J, Heegard S. Caruncular lesions
Conjunctival nevi: clinical features and natural
in Denmark 1978–2002: a histopathological study
course in 410 consecutive patients. Arch Ophthalmol.
with correlation to clinical referral diagnosis. Acta
2004;122(2):167–75.
Ophthalmol Scand. 2006;84:130–6.
20. Ozdal PC, Kargi S, Göka S, et al. Capillary hem-
10. Solari HP, Ventura MP, Orellana ME, et al. Histopath
angioma of the caruncle. Can J Ophthalmol. 2004;
ological study of lesions of the caruncle: a 15-year
39(5):560–2.
single center review. Diagn Pathol. 2009;4:29.
Pharmacotherapy for Conjunctival
Malignancies
20
Ghada Al Bayyat, Dan Arreaza-Kaufman,
Anat Galor, Jacob Pe’er, and Carol L. Karp
cular Surface Squamous

O fused with OSSN including pterygium, corneal
Neoplasia pannus, pyogenic granuloma, sebaceous cell car-
cinoma, and amelanotic melanoma [5]. In many
Introduction parts of the world, the pendulum has now shifted
from surgical resection to a medical approach in
Ocular surface squamous neoplasia (OSSN) OSSN [7]. Surveys done by Adler et al. [8] have
involves a broad spectrum of neoplastic squamous shown increased use of medical therapies for
epithelial abnormalities from squamous dysplasia OSSN (see Chap. 15).
to intraepithelail neoplasia in situ to squamous
cell carcinoma (SCC). OSSN is usually slow
growing and remains localized. However, SCC Treatment
has the ability to invade the eye, orbit, or rarely
even metastasize [1, 2]. Exposure to ultraviolet In the past, the gold standard for the diagnosis
(UV) radiation in sunlight is the strongest risk fac- and treatment of OSSN was surgical removal, but
tor [3]. Other environmental risk factors include topical chemotherapeutic drugs are becoming a
human immunodeficiency virus (HIV), human viable alternative [8, 9]. The advantages of sur-
papilloma virus (HPV), smoking, and immuno- gery are that it is both diagnostic and therapeutic
suppression [4]. Features of OSSN can include a and it provides rapid resolution. It is covered by
fleshy gelatinous mass, leukoplakia, abnormal insurers in the USA and is a readily available
vascularity, and irregular corneal borders, and modality for most patients. The disadvantage to a
these features can be seen in isolation or combina- surgical approach includes residual tumor from
tion [5, 6]. A wide variety of lesions can be con- positive margins, limbal stem cell deficiency
from extensive excisions, symblepharon, and
ocular surface issues. Medical therapy has the
G. Al Bayyat · D. Arreaza-Kaufman advantage of covering the entire ocular surface,
A. Galor · C. L. Karp (*) including any subclinical disease. Especially in
Department of Ophthalmology, Bascom Palmer Eye cases of extensive, annular, recurrent OSSN, top-
e-mail: ckarp@med.miami.edu
ical therapies can cure the neoplasia with mini-
mal sequelae to the ocular surface. Due to the
J. Pe’er
Ocular Oncology Service and Ophthalmic Pathology
mostly superficial effect of topical chemotherapy,
Laboratory, Department of Ophthalmology, their use for invasive SCC as primary treatment is
Hadassah - Hebrew University Medical Center, not advised.
Jerusalem, Israel

246 G. Al Bayyat et al.
Interferon Alpha-2b (IFNα-2b) OSSN, but the high cost and need for daily use
can be prohibitive (Fig. 20.1).
Pharmacology
Interferons are a group of pleiotropic proteins Dosage
produced by human leukocytes that have antiviral For the topical treatment, 1 MIU/ml of IFNα-2b
and antineoplastic properties. There are three is typically dosed four times daily continuously
types of interferons, alpha (α), beta (β), and until resolution of the tumor, followed by 1 or 2
gamma (γ), based on their antigenic specificities. more months of treatment even after clinical res-
Interferon alpha-2b (IFNα-2b) is an immunomod- olution. Higher doses of 3 MIU/ml have also
ulatory cytokine consisting of 165 amino acid been used but seem similar in effect without a
residues, with arginine in position 23 [10, 11]. therapeutic advantage over 1 MIU/ml dose [15].
The effects of interferons are to inhibit the biosyn- The average time from the start of treatment to
thetic enzymes, induce apoptosis to cells, decrease resolution is about 4 months [6, 13, 15]. The dose
blood vessels proliferation, inactivate viral RNA, for subconjunctival injection ranges from 3 MIU
and enhance phagocytic and cytotoxic mecha- in 0.5 cc given weekly or more [13, 16].
nisms. Alpha-interferon is well absorbed via the
intramuscular and subcutaneous routes. Peak con- Side Effects
centrations occur at about 2 hours following the Topical IFNα-2b eye drops are very well tolerated
intramuscular injection and 4 hours following the with minimal to no side effects. Unlike other topi-
subcutaneous route [11]. cal agents like mitomycin and 5-fluorouracil, there
is rarely hyperemia, but occasional follicular con-
Role in OSSN junctivitis and rare corneal microcysts have been
Interferon activates the immune system by stimu- reported [6, 13, 15, 17, 18]. When injected subcon-
lating the expression of IL-2 and IFN-γ mRNA junctivally, patients do experience systemic side
and decreasing the expression of IL-10. This pro- effects. These include a “flu-like” syndrome that
cess helps immune cells recognize and remove ensues after each injection. Pretreatment with oral
tumor cells. Interferon in the form of topical eye antipyretic (e.g., acetaminophen, ibuprofen) is typ-
drops and intralesional IFNα-2b have been used ically used to mitigate postinjection symptoms.
in the treatment of OSSN, both as primary ther- Our protocol is to administer 1000 mg of acetamin-
apy and as an adjuvant after surgery [12–14]. ophen prior to the injection and then every
IFNα-2b is one of our preferred treatments for 4–6 hours as needed (Table 20.1).
a b
Fig. 20.1 Slit-lamp photograph of a left eye with ocular complete resolution of the conjunctival neoplasia after
surface squamous neoplasia (OSSN). Note large area of treatment with topical interferon 1 MIU/ml four times
leukoplakia and adjacent gelatinous mass (a, arrow). Note daily for 4 months (b)
20 Pharmacotherapy for Conjunctival Malignancies 247
5-Fluorouracil (5-FU) cacy, low cost, easy drop cycling schedule, and
generally tolerable side effect profile [21–24].
Pharmacology
5-FU is a pyrimidine analog of the purine base Dosage
uracil that works by inhibiting thymidine syn- Several dosing regimens have been reported for
thase, altering DNA and RNA synthesis, and the primary treatment of OSSN [21, 22, 25].
reducing the rate of proliferation of neoplastic Our protocol is to use compounded 1% 5-FU
cells [19, 20]. drops four times daily for 1 week, followed by
3 weeks off the medication [21] (Fig. 20.2). This
ole in the Treatment of OSSN
R pattern is generally repeated for 4 cycles. Other
5-FU is another agent available as a primary protocols have used 5-FU cycles four times a
treatment in OSSN. 5-FU is one of our preferred day for 4 days per month [25] or four times a
options when treating OSSN given its high effi- day for 4 weeks [22]. We advocate refrigeration
of the 5-FU, but it has been used at room
temperature [21].
Table 20.1 Common topical treatment drops for ocular
surface squamous neoplasia
Side Effects
OSSN- 5-FU is associated with more side effects than
preferred
treatment Most common
IFNα-2b as it affects the synthesis of DNA and
options dosage Main side effects RNA of epithelial cells on the ocular surface
IFNα-2b 1 MIU/ml 4 times Minimal side [22]. Side effects include lid edema, conjuncti-
daily continuously effects val hyperemia, filamentary keratitis, superficial
5-FU 1% 4 times a day for Mild pain, lid keratitis, and on rare occasion superficial stro-
1 week with 3 weeks edema,
off, cycled epitheliopathy mal melting [22]. Lubricating drops and topical
MMC 0.02% to 0.04% 4 Hyperemia, steroids can help reduce symptoms. While sys-
times a day for of keratopathy, pain temic 5-FU treatment can lead to punctal and
1–2 weeks, photophobia canalicular stenosis, this side effect has not been
2–3 weeks off,
cycled
reported with topical 5-FU, and punctal plugs
are not normally placed before treatment [6]
IFNα-2b interferon alpha-2b, 5-FU 5-fluorouracil, MMC
mitomycin, LSCD limbal stem cell deficiency (Table 20.1).
a b
Fig. 20.2 Slit-lamp photograph of a right eye post- after four 1-week per month cycles of 5-FU 1% showing
penetrating keratoplasty with large OSSN. Note large partial regression of the lesion (b). Residual tumor was
papillary ocular surface squamous neoplasia at limbus and still present on the corneal surface, and treatment was
extending onto cornea and graft (a, arrow). Appearance continued until fully resolved
Mitomycin C primary treatment of OSSN concentration [6,

28–30]. Low dose (0.002%) has also been
Pharmacology reported [32]. One protocol included treatment
Mitomycin (MMC) is an antineoplastic/antibiotic with 0.02% (0.2 mg/ml) MMC drops four times
isolated in 1958 from the bacterium Streptomyces daily for 2 weeks with repetitions as needed [28].
caespitosus and other Streptomyces bacterial spe- In another protocol the compounded 0.04% drops
cies. It acts as an alkylating agent and binds to the are used four times daily for 1 week, followed by
cell DNA during the entire cell cycle [26]. This 2–3 weeks off until the eye is white and quiet. In
leads to irreversible cross-linking and inhibition general, three to four cycles are used. If intolerant
of nucleotide synthesis. MMC also reacts with of the 0.04%, lower concentrations of 0.03% or
molecular oxygen-free radicals, causing cytotox- 0.02% may be used (Fig. 20.3). Other centers
icity through lipid peroxidation. Therefore, MMC have reported 7-day on/7-day off regimens and
is toxic to both proliferating and nonproliferating 14-day on regimen with a variable amount of
cells. Applying MMC also inhibits fibroblast cell time between cycles [29, 33]. In one study, MMC
migration and leads to apoptosis [27]. 0.002% was applied four times daily continu-
ously for a month [32]. The optimal regimen in
ole in Treatment of OSSN
R terms of length of time, number of cycles, and
As topical drops, MMC is a potent medical ther- dose for MMC use is yet to be determined, but
apy for OSSN but with more ocular surface toxic- the majority of clinicians use 0.02% or 0.04%
ity than the other agents mainly when using the four times daily and cycled [30]. MMC is best if
higher concentration [28–30]. It is also used refrigerated at (4 °C) [34].
intraoperatively as an adjunct to surgical tumor MMC can also be used intraoperatively as an
removal [31]. In terms of topical use as a primary adjuvant to surgical removal. One protocol
treatment modality, we typically do not use MMC involves applying 0.02% MMC soaked on a sur-
as a first-line therapy for OSSN. Instead, we use gical sponge to the scleral bed for 2–3 minutes,
it as a secondary agent when individuals fail followed by closure of the conjunctiva [31].
interferon and/or 5-FU. Postoperatively, topical MMC has been used in
patients with positive surgical margins [35, 36].
Dosage Topical 0.04% was used four times a day for a
Several dosing regimens, using primarily 0.02– week after epithelial healing followed by a week
0.04% concentrations, have been reported for the off and then repeated [35].
a b
Fig. 20.3 Slit-lamp photograph of a left eye with exten- subtle leukoplakia is noted on the bulbar surface (b,
sive OSSN on the bulbar, limbal, and corneal surface (a). arrows) and inferior fornix. The patient remains in
After three weekly cycles of MMC 0.04% with 2 weeks treatment
between cycles, the tumor is dramatically reduced, but
Side Effects on the role of retinoic acid as sole agent in primary

Topical eye drops of MMC have more side effects treatment of OSSN is limited.
compared to IFNα-2b and 5-FU, especially when
used in the higher concentration. The most com- Dosage
mon reported side effects are hyperemia, superfi- Retinoic acid can be prepared into a 0.01% drop
cial punctate epithelial erosions, allergic and is administered once every second day and
conjunctivitis, photophobia, pain, and blepharo- can be also used with topical IFNα-2b drops of 1
spasm [28, 37]. Especially when using high con- MIU/ml four times daily for an average of
centration of 0.04% MMC, limbal cell deficiency 3–12 months [45]. Herbort et al. described reti-
may occur [38]. Alternate weeks of topical MMC noic acid 0.05% ointment, 1–3 times a day for
increase patient comfort and compliance. Topical 1–2 weeks, reporting complete resolution, but
steroids are very helpful to mitigate the inflam- some cases needed to be treated for a month so
mation from the MMC. Some have advocated the dose was then lowered to 0.01% in order to
also using cyclosporine 0.05% combined with decrease skin irritation [44]. In another case
the MMC therapy [39]. One case of punctal ste- report, 0.01% 1 eye drop was applied every sec-
nosis was reported; therefore, punctal plugs are ond day for 9 months [47].
typically placed before treatment in some centers
[40] (Table 20.1). Side Effects
Topical retinoic acid is generally well tolerated
but can cause lid irritation [44]. One case of epi-
Retinoic Acid thelial microcysts and one case of marginal kera-
titis have been described with its use [45].
Pharmacology
Vitamin A (retinol), as well as its natural and syn-
thetic derivatives (retinoid), is involved in several Aloe Vera Drops
important physiological processes such as cell
reproduction, proliferation, differentiation, and Pharmacology
growth [41]. There is evidence that retinoids have Aloe plants exhibit antineoplastic properties
potent growth-inhibiting effects on cancer in vitro through three important mechanisms: antiprolif-
and in vivo [42]. It regulates the activity of sig- erative, immunostimulatory, and antioxidant.
naling pathways involved in either cellular Aloe antiproliferative actions are mediated by
growth or differentiation. Retinoids can also sup- anthraquinoic molecules such as aloin and aloe
press the proliferation of cells by blocking cell emodin [48, 49]. The aloe emodin has been
cycle or by inducing apoptosis [41]. This effect shown to induce apoptosis in vitro in multiple
has been used to treat epithelial cancers, precan- cell lines. Aloe’s immunostimulating effects are
cerous lesions, and acute promyelocytic leuke- thought to be driven by acemannan and aloe-
mia (APL) [43]. mannan [49].

R ole in Treatment of OSSN
R
Retinoic acid has been used as an adjuvant therapy There has been one case published using com-
for treatment of OSSN alone and in combination mercially available skin aloe vera product for
with IFNα-2b [44, 45]. In the study of combined the primary treatment of clinically diagnosed
use with interferon, it is not possible to distinguish OSSN [49].
the effect of retinoic acid from that of IFNα-2b.
However, in theory, combination treatment may Dosage
lead to more rapid tumor resolution based on syn- In the only reported case, aloe vera oil drops
ergistic mechanisms of action [45–47]. The data (Aloe Fleur de Jouvence® [Forever Living
Products®; Scottsdale, Arizona]) three times the vascular endothelial growth factor (VEGF).
daily for 3 months were used [49]. Bevacizumab binds to VEGF and inhibits VEGF
receptor binding, thereby preventing the growth
Side Effects and maintenance of tumor blood vessels [53, 54].
The drops were well tolerated without side effects
[49]. ole in Treatment of OSSN
R
The role of anti-VEGF therapy in OSSN remains
uncertain. It has been used topically and intrale-
Cidofovir sionally. Studies had mixed results using ranibi-
zumab [55] and bevacizumab [53, 56, 57]. Most
Pharmacology of the tumors needed subsequent surgical
Cidofovir is an active metabolite that inhibits viral intervention.
replication with its activity against a broad spectrum
of DNA viruses [50, 51]. As human papilloma virus Dosage
has been implicated as a likely etiologic agent in the Topical bevacizumab (5 mg/ml) has been used as
pathogenesis of squamous cell carcinoma of the an eye drop four times a day for a period up to
conjunctiva, this is possibly its mechanism of action, 8 weeks [53]. Perilesional/subconjunctival bevaci-
and only one case has been published [50–52]. zumab injections (2.5 mg in 0.1 ml) were given
1 week apart, with a total of two injections [57]. In
R another study, bevacizumab (1.25 mg in 0.05 ml)
There is only a single case report of topical cido- was injected once [56]. Ranibizumab was injected
fovir for the primary treatment of histologically perilesional (0.05 mg of 10 mg/ml) monthly or
proven OSSN [52]. twice monthly with mean of 22 injections [55].
Dosage Side Effects

In this case report, topical cidofovir eye drops No side effects have been reported with topical or
(2.5 mg/ml) were used at a frequency of 1 drop perilesional/subconjunctival injections of bevaci-
every 2 hours for 2 weeks, then four times daily zumab [53, 55, 56]. Accidental intravitreal injec-
for 2 weeks, and then thrice daily for 2 weeks. tions can cause endophthalmitis, rhegmatogenous
Most of the superior tarsal lesion resolved with retinal detachment, intraocular inflammation,
this therapy. A focal area remained, which was intraocular pressure elevation, and ocular hemor-
excised with focal cryotherapy. There was no rhage [58].
recurrence over a 2-year follow-up [52].
Side Effects Lymphoma of the Conjunctiva

In the above case, 6 months after treatment with
cidofovir and cryotherapy, the patient developed Introduction
cicatrization of the inferior punctum [52]. In our
experience, topical cidofovir causes significant Lymphomas are malignant neoplasms that arise
ocular surface irritation, which resolves with from lymphocytes [59]. Extranodal marginal zone
drop cessation. lymphoma (EMZL) is the predominant type of
lymphoma seen in the conjunctiva and ocular
adnexa. The systemic prognosis for conjunctival
nti-Vascular Endothelial Growth
A lymphomas varies with the cell type. It is best
Factor (VEGF) Therapy with EMZL and worse with mantle cell or diffuse
B-cell subtypes [59–61]. Typically, a subconjunc-
Pharmacology tival salmon patch lesion is seen in the bulbar con-
Bevacizumab and ranibizumab are recombinant junctiva (Fig. 20.4). Older age, exposure to
humanized monoclonal antibody directed against radiation, and immunodeficiency are the principal
a b
Fig. 20.4 Slit-lamp photograph of a left eye with conjunctival lymphoma. Note elevated salmon-colored lesion on the
superior temporal conjunctiva (a, arrow). After 20 sessions of external beam radiation over one month showing resolu-
tion of the conjunctival lymphoma(b)
Table 20.2 Common pharmacotherapeutic treatment options for ocular adnexal lymphoma
Lymphoma-
preferred
treatment options Most common dosage Main side effects
IFNα-2b Subconjunctival injection: 1 MU or 1.5 MU of IFNα-2b is Subconjunctival injections:
administered 3 times a week for a total of 4 weeks Flu-like syndrome, local
inflammation
Rituximab IV: 375 mg/ml rituximab every 3 weeks, maintenance dose every IV: Varicella Zoster Virus.
2–3 months for 2 years. Subconjunctival injections: 1.5 cc of Subconjunctival injections:
rituximab (10 mg/ml) with xylocaine 2% is received 4 times a Pain at the site of injection
week followed by a monthly injection for the next 6 months
Ibritumomab IV rituximab 250 mg/m2 followed by an infusion of 90 Y Thrombocytopenia, anemia,
ibritumomab tiuxetan with a dose that depends on the platelet and neutropenia
count. For patients with a platelet count of 100,000/mm3–149,000/
mm3, 0.3 Ci/kg was used and 0.4 Ci/kg for patients with counts
of >150,000/mm3
IFN-α2b interferon alpha-2b, IV intravenous
risk factors associated with lymphoma. Bacterial (Table 20.2). Rarely, aggressive bilateral disease
and viral agents such as Helicobacter pylori, or conjunctival lymphoma accompanied by sys-
Borrelia burgdorferi, Chlamydophila psittaci, temic lesions will be treated with CHOP (cyclo-
and hepatitis C virus have all been implicated in phosphamide, doxorubicin, vincristine,
the pathogenesis. Lymphoma has a wide differen- prednisone), CVP (cyclophosphamide, vincris-
tial diagnosis ranging from benign lesions like tine, prednisolone), or chlorambucil. Interferon,
reactive lymphoid hyperplasia, pyogenic granu- rituximab, and ibritumomab are more commonly
loma, and lymphangiectasis to malignant tumors used for local treatment [62] (see also Chap. 18).
such as squamous cell carcinoma and amelanotic
melanoma [60, 61] (see Chap. 18).
Interferon Alpha-2b (IFNα-2b)
Treatment Pharmacology
Discussed above in OSSN section.
Radiation therapy has been the mainstay for uni-
lateral isolated conjunctival lymphoma. Medical Role in Lymphoma
therapies have been utilized as alternative for uni- The use of IFNα-2b has been described as a
lateral disease and in systemic disease possible alternative in patients with unilateral

localized conjunctival lymphoma who are not into the left lacrimal gland with B-scan ultra-
amenable to radiation treatment. There are case sound guidance. In a patient with adnexal lym-
reports using intralesional injections of IFNα-2b phoma, this was followed by another injection
as a part of the primary therapy [63, 64]. 7 months later [70].
Dosage Side Effects

The dose of the intralesional IFNα-2b used was 1 Side effects of rituximab are rare but include
MIU/0.5 cc or 1.5 MIU/0.5 cc, administered three Varicella zoster virus (VZV) reactivation follow-
times a week for a total of 4 weeks. ing intravenous administration [67]. In addition,
intravenous rituximab has been associated with
Side Effects hematologic side effects, such as neutropenia and
For intralesional injections of IFNα-2b, side thrombocytopenia [71, 72].
effects are rare as discussed above and include
flu-like syndrome and malaise [63, 64].
Ibritumomab Tiuxetan (Zevalin)
Rituximab Pharmacology
Ibritumomab tiuxetan (Zevalin, Spectrum phar-
Pharmacology maceuticals, Henderson NV) links yttrium-90 to
Rituximab is an anti-CD20 monoclonal antibody a monoclonal antibody that targets CD20 of the
that kills CD20+ B cells via multiple mechanisms. lymphocytes [73].
These include direct effects on complement-
mediated cytotoxicity and antibody-dependent Role in Lymphoma
cell-mediated and an indirect effect on cell struc- As ocular and adnexal EMZL is highly sensitive
tures, both of which lead to apoptosis. In addi- to radiotherapy, it is certainly possible that radio-
tion, rituximab sensitizes cancer cells to other immunotherapy may also be very effective in
chemotherapy drugs [65, 66]. controlling the disease as well as preventing
relapse [73]. Preliminary studies suggest that
Role in Lymphoma Zevalin can be an effective alternative for the
Rituximab has been used systemically for bilat- treatment of conjunctival lymphoma [73, 74].
eral ocular and adnexal lymphoma or for patients
with systemic disease. In addition, there have Dosage
been case reports of patients treated with intrave- Patients receive intravenous rituximab 250 mg/
nous and intralesional injections for localized m2 followed by an infusion of 90Y ibritumomab
disease [67–70]. tiuxetan with the dose adjusted according to the
platelet count. For patients with a platelet count
Dosage of 100,000/mm3–149,000/mm3, 0.3 Ci/kg is
Intravenous rituximab was administered in used, with 0.4 Ci/kg being administered to
6 cycles of 375 mg/m2 every 3 weeks with a patients with platelet counts exceeding 150,000/
maintenance dose every 2–3 months for 2 years mm3 [73, 74].
[67]. The intralesional (subconjunctival) dose
reported is 1.5 ml of rituximab (10 mg/ml) with Side Effects
xylocaine 2%, given four times a week followed Principal side effects are hematologic.
by a monthly injection for the next 6 months [69]. Thrombocytopenia, anemia, and neutropenia
Another protocol, used by Demirci et al., con- have been noted in patients treated with this med-
sisted of 1 ml of rituximab (50 mg/1 ml) injected ication [75, 76].
Clarithromycin aminoacyl-tRNA to the ribosomal complex, thus

interfering with protein synthesis and interrupt-
Pharmacology ing proper cell function [80].
Clarithromycin is a member of the macrolide anti-
biotic family, structurally similar to erythromycin. Role in Lymphoma
The pharmacokinetic profile is more favorable As mentioned above, due to the association
than erythromycin, and it is dosed twice daily. between chronic antigen stimulation and lym-
Clarithromycin is well distributed in tissues, phoma, doxycycline has been used with the aim
including the eye. Clarithromycin inhibits bacte- of eradicating bacterial infection to induce
rial protein synthesis by preventing peptidyltrans- regression of the lymphoma. Recent studies sug-
ferase attachment to a growing peptide chain [61]. gest that the use of doxycycline in patients with
Cp DNA-positive infections can be beneficial,
Role in Lymphoma and interestingly, it has a positive impact on
Because of the association between lymphoma tumor regression in Cp DNA-negative patients as
and chronic infections, and due to the antineo- well. It has been used as a part of primary treat-
plastic effect of macrolide antibiotics, clarithro- ment or in patients with relapse of lymphoma. In
mycin has been used in patients with relapsed or two large prospective studies [81, 82], a total of
refractory ocular adnexal EMZL. In addition, 117 patients were treated with oral doxycycline
there is some data on the use of clarithromycin as 100 mg twice daily in 1–2 cycles. Out of the 117,
a primary therapy. In two large prospective stud- 10 (8%) patients achieved complete response,
ies, the regimen consisted in using clarithromy- and 27 (23%) had partial response. Approximately
cin orally (500 mg bid) for 6 months [77] or 2 40% had minimal to no response to treatment.
grams daily in 2-week cycles for 3 months [78]. When discontinued, relapse rates were approxi-
Of the 36 patients treated, 8 (22%) had complete mately 25% [82] over 14–40 months.
response, and 9 (25%) showed partial response.
Half did not respond to the treatment. At Dose
24 months, relapse rates were 30–50% [77, 78]. Doxycycline, 100 mg, administered twice a day
for 3 weeks in cycles [81, 82].
Dosage
Clarithromycin (500 mg) is taken orally, twice Side Effects
daily, for 6 months [77]. The most common side effects of doxycycline
Clarithromycin (2 grams) is taken daily for are nausea, vomiting, and skin rash [83].
14-day cycles with 1 week off and repeated for
3 months [78].
Pigmented Conjunctival Lesions
Side Effects
Few side effects have been reported with clar- Introduction
ithromycin. Most common side effects are nau-
sea, diarrhea, and abnormal taste [79]. Pigmented lesions of the ocular surface include
conjunctival nevus, complexion associated mela-
nosis, conjunctival primary acquired melanosis
Doxycycline (PAM) with atypia, and conjunctival malignant
melanoma (CMM) [84], all arising from the con-
Pharmacology junctival melanocytes residing in the basal layer
Doxycycline is a member of the tetracycline anti- of the epithelium. PAM with atypia is the most
biotic family. It works by binding to the 30s ribo- common progenitor of CMM and appears clini-
somal subunit and blocking the binding of cally as a flat and variably brown conjunctival
a b
Fig. 20.5 Slit-lamp photograph of a right eye with pri- surgical excision of the tumor cryotherapy followed by
mary acquired melanosis with foci of conjunctival mela- 2 cycles of postoperative topical weekly MMC 0.04%
noma (a, arrow). Note minimal conjunctival scarring after four times daily (b)
lesion [84] (Fig. 20.5). CMM can arise also from

conjunctival nevus and de novo. CMM typically ole in Pigmented Conjunctival Lesions
R
presents as a unilateral, pigmented, immobile, Topical MMC can be used as an adjuvant to exci-
vascular lesion with heterogeneous pigmenta- sion preoperatively or postoperatively. MMC is
tion. It is commonly seen on the bulbar conjunc- not typically used as a primary therapy in con-
tiva with associated feeder vessels. CMM can junctival malignant melanoma (CMM) as results
also present as an amelanotic lesion with variable are poor [88]. Whereas in PAM preoperatively, a
vascularity. While the traditional treatment of short regimen can be used to chemoreduce the
PAM with atypia is surgical excision, in recent tumor. It has also been used for extensive and
years, topical chemotherapy and immunotherapy unresectable PAM as primary treatment with
have been used widely as adjuvant treatment (see some success. In three large retrospective studies
Chaps. 16 and 17). [89–91], a total of 26 patients were treated pri-
marily with MMC for PAM. The regimen con-
sisted of topical MMC 0.02–0.04%, four times a
Treatment day for 28 days. Of the 26, 12 (46%) had com-
plete response, and 12 (46%) showed partial
Complete surgical excision is the mainstay of treat- response. One patient had no response to the
ment for conjunctival melanoma. Due to the high MMC. Follow-up ranges were 4–144 months,
rate of local recurrence, surgical excision should and relapse rates were approximately 27%
always be combined with adjuvant therapy such as [89–91].
cryotherapy, chemotherapy, immunotherapy, and
brachytherapy [85, 86]. Chemotherapy is used for Dosage
diffuse disease (i.e., PAM with atypia and pagetoid When used pre- or postoperatively as an adju-
spread from CMM). In terms of topical therapy, vant therapy, MMC is typically administered at
MMC has been the most studied therapy, followed 0.04% four times a day for 7–28 days [90, 91].
by IFN-α2b when MMC was not tolerated [5, 87]. MMC can be administered intraoperatively as
These two drugs are used often also in treating PAM well [92].
with atypia after diagnostic biopsy (Fig. 20.6).
Interferon Alpha-2b
Mitomycin C (MMC)
Pharmacology
Pharmacology Described above in OSSN section.
Described above in section on OSSN.
Pigmented conjunctival lesions
PAM CMM
Without
With atypia Excision cryotherapy
atypia
& AMT. Adjuvant
chemotherapy
Observation Excision cryotherapy &

Adjuvant chemotherapy
Plaque
MMC IFNα-2b
radiotherapy
MMC IFNα-2b
PAM: Primary acquired melanosis; CMM: Conjunctival malignant

melanoma; MMC: Mitomycin; IFNα-2b: Interferon alpha 2b; AMT:
Amniotic membrane transplant.
Fig. 20.6 Algorithm for management of pigmented conjunctival lesions
ole in Pigmented Conjunctival Lesions

R rogramed Cell Death 1 (PD-1)
P
IFNα-2b is not commonly used in the treatment Inhibitors
of pigmented conjunctival lesions as evidence is
limited. However, due to its enhancement of the Pharmacology
MHC class 1 surface antigen expression, there is Pembrolizumab is a humanized monoclonal
biologic plausibility that it may have a positive immunoglobulin (Ig) G4 antibody directed
immune response signaling for the removal of against human cell surface receptor PD-1 (pro-
tumor cells. It can be administered topically and gramed cell death 1). It mediates immune
as subconjunctival/perilesional injections [84, responses against tumor cells. In 2017, it was
88]. The data for topical IFNα-2b for PAM is lim- approved by the US Food and Drug Administration
ited. In four retrospective studies [93–96], a total (FDA) for the treatment of metastatic cutaneous
of 25 patients with PAM/MMC were treated with melanoma and of unresectable or metastatic solid
1 MIU four to five times a day for 6–36 weeks. tumor with certain genetic anomalies [99].
Of the 25 patients treated, 7 (28%) had eventual Pembrolizumab and other checkpoint inhibitors
complete response to treatment, and 13 (52%) are known to cause proinflammatory side effects
showed partial response. Approximately 20% did in the body including in the eye [100].
not respond to the IFNα-2b treatment. The fol-
low-up of the previous studies was short (range, ole in Pigmented Conjunctival Lesions
R
4–17 months) [93–96]. Data using checkpoint inhibitors for conjunctival
lesions is limited. Ford et al. described one patient
Dose with an invasive caruncular melanoma that was
The dose of topical IFNα-2b is 1 MIU four or five treated with total surgical excision and adjunctive
times a day, for 3–6 months [88, 93–98]. topical MMC therapy. Five years later, the patient
developed breast and chest metastases, which 11. Houglum JE. Interferon: mechanisms of action and
clinical value. Clin Pharm. 1983;2(1):20–8.
were treated with PD-1 inhibitors. Complete res- 12. Shah SU, Kaliki S, Kim HJ, Lally SE, Shields JA,
olution of the metastatic disease was achieved. Shields CL. Topical interferon alfa-2b for manage-
Kini et al. described another patient who had a ment of ocular surface squamous neoplasia in 23
recurrence of conjunctival melanoma after surgi- cases: outcomes based on American Joint Committee
on Cancer classification. Arch Ophthalmol (Chicago
cal excision and cryotherapy. The patient was III: 1960). 2012;130(2):159–64.
treated with systemic pembrolizumab, 150 mg, 13. Karp CL, Galor A, Chhabra S, Barnes SD, Alfonso
which was administered intravenously every EC. Subconjunctival/perilesional recombinant inter-
3 weeks for 6 months. The patient showed a clini- feron alpha2b for ocular surface squamous neoplasia: a
10-year review. Ophthalmology. 2010;117(12):2241–6.
cal reduction of the conjunctival lesions with no 14. Vann RR, Karp CL. Perilesional and topical interferon
adverse effects [99]. alfa-2b for conjunctival and corneal neoplasia11The
authors have no proprietary interest in the develop-
Dosage ment or marketing of any drug mentioned in this arti-
cle. Ophthalmology. 1999;106(1):91–7.
Systemic pembrolizumab, 150 mg, administered 15. Galor A, Karp CL, Chhabra S, Barnes S, Alfonso
intravenously every 3 weeks for 6 months [99]. EC. Topical interferon alpha 2b eye-drops for treatment
of ocular surface squamous neoplasia: a dose compari-
son study. Br J Ophthalmol. 2010;94(5):551–4.
16. Rishi P, Shields CL. Intralesional and topical inter-
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Sentinel Lymph Node Biopsy
for Eyelid and Conjunctival
21
Malignancies
Oded Sagiv and Bita Esmaeli
Introduction of successful SLN localization compared to the

rate with blue dye alone [5].
In the 1990s, the technique of sentinel lymph SLN biopsy has been used for many years for
node (SLN) biopsy was developed as a less mor- patients with melanoma and breast cancer. The
bid alternative to complete lymphadenectomy first reports of SLN biopsy in patients with eyelid
[1–3]. SLN biopsy is based on the principle that and conjunctival neoplasms (e.g., melanoma,
the disease status of the first node in the lym- squamous cell carcinoma, sebaceous carcinoma,
phatic chain to which the tumor drains is repre- Merkel cell carcinoma) appeared around the year
sentative of the disease status of the rest of the 2000 [6]. In this chapter, we will describe the
nodes in the chain. If pathologic analysis demon- clinical principles underlying SLN biopsy for
strates that the SLN is cancer-free, then there is periocular malignancies and then discuss various
no need for complete lymphadenectomy. aspects of the application of this technique in
Various approaches have been used to identify clinical practice.
SLNs. In 1992, Morton et al. described identify-
ing SLNs through the use of intraoperative lym-
phatic mapping with vital dyes [3]. A year later, ymphatic Drainage of the Eyelid
L
Alex and Krag introduced injection of radioac- and Periocular Region
tive tracer followed by use of a handheld gamma
probe passed over the skin to allow dissection of The human eyelid has two distinct lymphatic sys-
SLNs through a small incision [4]. In 1996, Glass tems: a superficial system between the skin and
et al. investigated the combination of dye and orbicularis muscle and a deeper system between the
radiotracer; they concluded that using dye plus orbicularis muscle and tarsus [7]. The lymphatic
radiotracer had the potential to increase the rate drainage pattern for the periocular area was histori-
cally believed to be preauricular for the lateral
aspect and submandibular for the medial aspect.
The authors of the chapter would like to thank Dr. Vivian However, in 2002, Cook et al. published a report
T. Yin for her contribution towards previous edition of this demonstrating that the drainage pattern was more
chapter.
complex [8]. Using lymphoscintigraphy in a mon-
O. Sagiv · B. Esmaeli (*) key model, these investigators confirmed that the
Department of Plastic Surgery, Orbital Oncology and lateral canthus drained to the preauricular nodes,
Ophthalmic Plastic Surgery, The University of Texas
MD Anderson Cancer Center, Houston, TX, USA but they found that the central upper eyelid drained
e-mail: besmaeli@mdanderson.org to both preauricular and submandibular-anterior

262 O. Sagiv and B. Esmaeli
cervical nodes [8]. Furthermore, these investigators radiolabeled molecules, and radiolabeled macro-
demonstrated that the medial upper eyelid and molecules. Colloids are phagocytosed by macro-
medial canthus drained to the preauricular region, phages in lymph nodes and thus have a longer
whereas the medial and central lower eyelid drained resident time in the lymph nodes than noncol-
to the submandibular-anterior cervical region. loidal macromolecules such as human serum
Nijhawan et al. demonstrated the variable drain- albumin. Antimony sulfide colloid is the most
age patterns in the normal human eyelid. Their widely used colloid because of its ideal size,
study included 28 patients who underwent injection 3 nm to 25 nm, and its clearance rate of 40%
of radioactive tracer followed by lymphatic map- over 4 h [13]. Colloids can be filtered to select
ping using a gamma camera. Sites of injection of for smaller particles, which will have shorter
radiotracer included the lateral and medial upper transit times. An example of a filtered colloid is
eyelid, medial canthus, and medial and lateral lower filtered technetium 99mTc sulfur colloid.
eyelid [9]. In the 25 patients with identifiable nodes, Many different technetium 99mTc-labeled com-
the preauricular area was the most common site of pounds have been tried for lymphoscintigraphy in
SLNs irrespective of the radiotracer injection site. cutaneous melanoma, including sulfur colloid, tin
Conversely, for each of the radiotracer injection colloid, phytate, and human serum albumin. 99mTc-
sites, drainage could be to the preauricular area or labeled human serum albumin has also been used
the submandibular and deep cervical chains. commonly in melanoma involving the trunk. When
99m
Tc-labeled human serum albumin is injected
intradermally, it drains rapidly; some would argue
Fundamentals that this radiotracer is associated with better defini-
of Lymphoscintigraphy tion of the lymphatic system and better reproduc-
ibility of results than sulfur colloid [14].
Lymphoscintigraphy is mapping of the lymphatic
system through administration of a radioactive
tracer followed by sequential or dynamic imag- echnical Considerations in SLN
T
ing (Fig. 21.1). Biopsy for Eyelid and Conjunctival
One key factor in optimal lymphoscintigraphy Tumors
is the imaging method. A cobalt 57 source behind
the patient is useful for anatomical delineation of Preoperative Lymphoscintigraphy
drainage along with lateral views [10]. The use of
single photon emission computed tomography/ Preoperative identification of the SLN through
computed tomography (SPECT/CT) in addition lymphoscintigraphy aids in surgical planning
to traditional lymphoscintigraphy has been advo- and preoperative patient counseling. For SLN
cated to help identify additional SLNs and drain- biopsy of the eyelid or conjunctival tumors,
age locations (Fig. 21.1b) [11, 12]. SPECT/CT is most authors to date have performed preopera-
a system with a dual-head gamma camera and CT tive lymphoscintigraphy using filtered 99mTc-
scanner. This system allows high-resolution ana- labeled sulfur colloid. The lymphoscintigraphy
tomical images to be fused with functional procedure is usually done 1–2 days before the
images from the radioactive tracer. SLN biopsy procedure as described in the fol-
The other key factor in optimal lymphoscin- lowing paragraphs.
tigraphy is tracer characteristics. The smaller the The filtered 99mTc-labeled sulfur colloid is
tracer, the faster its drainage. Tracer smaller than injected intradermally 1–2 mm around the eyelid
5 nm can penetrate the capillary membrane and tumor or, in the case of conjunctival tumors, in
enter the bloodstream, whereas tracer larger than the subconjunctival space at two to four spots
500 μm may be unable to migrate from the injec- around the tumor. The dose of 99mTc-labeled sul-
tion site [10]. The types of radioactive com- fur colloid used is from 0.3 to 0.4 mCi in a vol-
pounds used can be categorized as radiocolloids, ume of 0.2 mL [15, 16]. It is important to ensure
21 Sentinel Lymph Node Biopsy for Eyelid and Conjunctival Malignancies 263
RT Lateral 07 LT Lateral 08 RT Lateral TRANS 09
b c
Fig. 21.1 Preoperative lymphoscintigraphy in a patient blue) in the lower eyelid is seen (c). The draining sentinel
with a lower eyelid melanoma (a). The area of injection lymph node (in blue) in the right parotid area is seen with
and the draining nodes are seen. SPECT/CT scan in the much higher anatomic resolution compared with the stan-
same patient (b). The area of injection of technetium (in dard lymphoscintigraphy image
that the injection is in the area immediately sur- eters for CT acquisition depend on the CT scan-
rounding the tumor of interest so that the lym- ner used and site-specific protocols. Figure 21.1b,
phatic drainage mapped reflects the pattern of c shows the specific identification of an SLN in a
lymphatic drainage from the tumor site. patient with conjunctival melanoma using
At 15 min after radiotracer injection and every SPECT/CT and traditional lymphoscintigraphy.
5 min thereafter, a gamma camera is used to take A study of 403 patients with cutaneous mela-
dynamic photos at 30 seconds per frame (Fig. 21.1a). noma in which 149 (37%) patients had preoperative
Transmission images are also taken with a low- SPECT/CT found that lymphoscintigraphy plus
activity cobalt 57 sheet source every 3 min. It is SPECT/CT identified more SLNs per patient than
important to obtain lateral images with and without lymphoscintigraphy alone: a median of 0.34 SLNs
transmission images. Anatomical markers with versus 0.32 SLNs [12]. The increase in the number
cobalt 57 disks are also taped at the thyroid cartilage of SLNs per patient with SPECT/CT compared to
and suprasternal notch for reference [15, 16]. lymphoscintigraphy alone was particularly pro-
To allow more precise anatomical delineation, nounced in patients who were obese (body mass
SPECT/CT has been utilized in conjunction with index of 30 kg/m2 or higher): 25% of such patients
preoperative lymphoscintigraphy [17]. In this had SLNs detected with SPECT/CT, and only 9.1%
approach, SPECT images are acquired with a had SLNs detected with lymphoscintigraphy alone.
matrix size of 128 × 128 pixels, at 22 seconds per Furthermore, univariate and multivariate analysis
view over 180°. Axial CT images are used for showed the use of SPECT/CT to be significantly
classification of lymph node level, but the param- correlated with better disease-free survival.
Intraoperative SLN Detection Alternatively if the preoperative lymphoscintig-

raphy or SPECT/CT scan is scheduled 1 day
In the preoperative holding area, approximately prior to surgery, there is usually no need for rein-
1–1.5 h prior to planned surgery, 99mTc-labeled jection of sulfur colloid. Intraoperatively, the sur-
unfiltered sulfur colloid (0.3 mCi in 0.2 mL) can geon passes a handheld gamma probe (Fig. 21.2a)
be injected in the same fashion as described over the skin in the area where SLNs were identi-
above for preoperative lymphoscintigraphy. fied on preoperative lymphoscintigraphy, using
a b
c d
Fig. 21.2 Steps involved in sentinel lymph node biopsy node from the primary eyelid or conjunctival lesion. (d)
for a conjunctival melanoma are outlined. (a) Subconjunctival injection of blue dye can be done using a
Intraoperative photograph of the gamma probe which 30-gauge needle, but given the very small volume that
detects the area of increased radioactive uptake (of tech- would be required to avoid nonspecific spread of the blue
netium) corresponding to the draining sentinel lymph dye in the subconjunctival space, the yield of “blue nodes”
nodes based on the preoperative lymphoscintigraphy or was so low in our early experience that the use of the blue
preoperative SPECT/CT scan. (b) This photograph shows dye was abandoned after the first 16 patients who had
small skin incisions that are made directly overlying the SLN biopsy for conjunctival tumors as part of the pro-
areas of increased uptake in the draining lymphatic basins spective clinical trial at MD Anderson. We now use tech-
to facilitate biopsy of the sentinel lymph nodes. (c) The netium only as the tracer for sentinel lymph node biopsy
photograph shows a sentinel lymph node that has been for conjunctival and eyelid tumors and find excellent iden-
removed from its lymphatic basin. The amount of radioac- tification rate of the sentinel lymph nodes using techne-
tivity in the sentinel node is checked compared with the tium alone. (Reprinted from Esmaeli [83]. With permission
background to ensure it represents the draining lymph from Wolters Kluwer Health, Inc.)
the lymphoscintigram as a guide. Once the area lead to the detection of very small foci of micro-
of high radioactivity is identified, an incision is scopic metastasis that are well below the resolu-
made directly over this area (Fig. 21.2b). The tion of even the most sophisticated imaging
SLN is then carefully dissected and sent for his- studies (Fig. 21.3).
topathologic evaluation (Fig. 21.2c). Immunohistochemical staining is done if
Some authors have injected isosulfan blue hematoxylin–eosin staining of the bread-loafed
dye (Fig. 21.2d) in addition to technetium 99mTc sections is negative for metastasis or when there
sulfur colloid to facilitate visual identification are areas of suspicious morphology.
of SLNs in patients with eyelid and conjuncti- Immunohistochemical stains used to evaluate
val tumors, but this technique has proven to be SLNs include anti-S100, HMB-45, anti-MART1,
of no additional value. One possible reason for and anti-tyrosinase for melanoma [18]; cytokera-
the lack of benefit is the fast transition in the tin 20, chromogranin, and antibodies to Cam5.2
head and neck region. Another possible reason for Merkel cell carcinoma and sebaceous carci-
is that in the case of conjunctival melanoma, noma [19]; and anti-adipophilin and anti-perilipin
the volume of blue dye injected is smaller antibodies for sebaceous carcinoma [20].
(0.2 cc) than for tumors at other anatomic sites
in order to avoid diffuse infiltration of the blue
dye in all conjunctival quadrants and thus inac- I ndications for SLN Biopsy for Eyelid
curate and nonspecific drainage [15]. This small and Conjunctival Tumors
volume of blue dye used for conjunctival
tumors is probably not large enough to make Accurate determination of regional lymph node
the SLN blue. status in patients with eyelid and conjunctival
neoplasms not only is important for staging dis-
ease and estimating prognosis but also may
Histopathologic Processing increase survival through early detection of
microscopic metastasis. This begins with the
The histologic evaluation of SLNs is one of the clinical examination on palpation of the lymph
most important aspects of SLN biopsy and can nodes in the preauricular, submandibular, or cer-
significantly impact the rate of detection of vical areas. If no enlarged lymph node is pal-
micrometastases. In the past, lymph nodes dis- pated, we routinely request an ultrasonographic
sected during elective lymph node dissection examination of the head and neck by an experi-
were bisected through the hilum, which contains enced radiologist to detect suspicious lymph
a number of lymphatic vessels, and then cut into nodes which can then undergo a fine needle aspi-
5- to 7-μm-thick sections. However, this method ration biopsy. Large areas of lymph node metas-
can be inconsistent when the nodes are small and tasis could sometimes be detected on standard
can leave areas of the capsule unexamined. computed tomography or positron–emission
Pathologic evaluation of the SLN entails making tomography/computed tomography (PET/CT)
very thin slices perpendicular to the long axis prior to surgery, but smaller metastases may be
from one end of the node to the other to yield 1- detected on ultrasonography and otherwise
to 2-mm-thick slices, a technique sometimes missed on CT or PET/CT. If any of the above
referred to as “bread loafing the SLN.” Each slice examinations show a suspicious lymph node, a
is then cut into 5- to 7-μm-thick sections, which fine needle aspiration (FNA) is done to assess for
are stained with hematoxylin–eosin in the usual malignant cells in the lymph node. Sentinel
fashion. The bread-loafing technique allows for lymph node biopsy is only appropriate after the
better evaluation of the capsule but may miss the above tests are done and are negative. Here, we
hilum. If the initial section is negative, deeper discuss the rationale for and indications for SLN
sections of the block are cut [18]. Using careful biopsy for the major types of eyelid and conjunc-
serial sectioning of the sentinel lymph nodes can tival neoplasm.
a b
c d
Fig. 21.3 (a) External photograph of a lower eyelid tinel lymph node shows a very small focus of metastatic
amelanotic melanoma (Breslow thickness 3.8 mm Clark melanoma that measures 0.8 × 0.5 mm with no extracap-
level IV). The patient had a negative systemic work-up sular extension. (d) High-power magnification of the
including a negative MRI of head and neck and a negative microscopic melanoma metastasis in the sentinel lymph
ultrasound of the parotid area prior to undergoing sentinel node. This patient subsequently underwent completion
lymph node biopsy. (b) Wide surgical excision of the neck dissection and parotidectomy which did not reveal
lesion was carried out along with sentinel lymph node any additional positive lymph nodes. (Reprinted from
biopsy. One positive lymph node was detected in the Sanchez et al. [84]. With permission from Wolters Kluwer
parotid tail. (c) Histologic section through the parotid sen- Health, Inc.)
Melanoma vival, and overall survival compared with

patients with s imilar characteristics who did not
Experience with SLN biopsy for cutaneous have SLN biopsy. Five-year melanoma-specific
malignancy started with melanoma, and most of survival rate with Kaplan–Meier analysis was
the research to date on SLN biopsy for cutane- 84.8% in patients with SLN biopsies versus
ous malignancy has been done in patients with 80.3% without [21]. The international
this disease. A study of 670 consecutive patients Multicenter Selective Lymphadenectomy Trial
with melanoma found that patients who had (MSLT-I) randomly assigned 1661 patients with
SLN biopsy had a significantly better recur- primary cutaneous melanoma to undergo wide
rence-free survival, distant metastasis-free sur- excision and nodal observation with lymphade-
nectomy for nodal relapse (observation group), than T2b tumor (AJCC 7th edition) had nodal
or wide excision and SLN biopsy with immedi- metastatic at presentation, compared with none
ate lymphadenectomy for nodal metastases of 46 patients who presented with the T cate-
detected on biopsy (biopsy group). The 10-year gory of T2b or less (p = 0.0026).
results of this important study found that the Another study, of 29 patients with eyelid skin
10-year disease-free survival rates were signifi- melanoma from Australia, found that 17% of
cantly improved in the biopsy group as com- patients experienced local recurrence and 7% (2
pared with the observation group, among of 29 patients) of patients died of metastatic mel-
patients with intermediate-thickness melanomas anoma [26]. Several studies have demonstrated
(defined as 1.20–3.50 mm; 71.3% vs. 64.7%, that the risk of nodal metastasis increases with
p = 0.01) and those with thick melanomas increasing tumor thickness [24, 27].
(defined as >3.50 mm; 50.7% vs. 40.5%, The first report of an SLN biopsy for conjunc-
p = 0.03). They found that biopsy-based man- tival melanoma came from our institution in 2001
agement improved the 10-year rate of distant and served as a proof of concept that preoperative
disease-free survival and the 10-year rate of lymphoscintigraphy and SLN biopsy can be per-
melanoma-specific survival for patients with formed safely in patients with conjunctival mela-
intermediate-thickness melanoma with a posi- noma [15]. Since then we have published our
tive SLN compared with those who had nodal experience with SLN biopsy of melanoma of the
metastasis discovered during the observation eyelid or conjunctiva in several reports [28–30].
period. The authors concluded that biopsy- In the largest series to date of SLN biopsy for
based staging of melanomas thicker than 1.2 mm ocular adnexal melanomas, 51 patients with con-
provides important prognostic information and junctival and/or eyelid melanoma had SLN
early identification of patients with nodal metas- biopsy [27]. The report was a mix of eyelid mela-
tases leads to better survival outcomes for the noma and conjunctival melanoma, since eight
subset of patients with melanoma who harbor patients (16%) had melanoma involving both
nodal metastasis [22]. The subsequent MSLT-II structures. When comparing patients with and
study found that immediate completion LN dis- without nodal metastases, histologic features
section was not associated with increased mela- associated with a positive SLN included greater
noma-specific survival among 1934 patients tumor thickness (median thickness 3.5 mm vs.
with sentinel node metastases, underscoring the 2.2 mm, p = 0.04), greater number of mitotic fig-
potential therapeutic effect of SLN biopsy [23]. ures (median count/10hpf of 6 vs. 2, p = 0.03),
Based on a study of 44 patients with eyelid and presence of ulceration (80% vs. 26%,
skin melanoma, the Collaborative Eyelid Skin p = 0.003) (Fig. 21.4) [27]. Cohen et al. con-
Melanoma Group concluded that melanoma of ducted a prospective study in which they per-
the eyelid has a regional nodal metastasis rate formed SLN biopsy on patients with conjunctival
of 11% and a distant metastasis rate of 7%, with melanoma who met the following selection crite-
a mean follow-up of 34 months [24]. A larger ria: tumor thickness ≥2 mm, were in an unfavor-
single-center study of 64 well-documented able (e.g. non-bulbar) location, or recurrent
cases of eyelid melanomas reported 10% of conjunctival melanoma associated with the
patients diagnosed with lymph node metastasis “florid phase” of primary acquired melanosis
at presentation (8% via SLN biopsy and 2% via [31]. These features were determined based on
ultrasound-guided FNA) [25]. In this series, 5 previous reports that found thickness greater than
of 14 patients (36%) who had SLN biopsy had 1–2 mm to carry a higher risk for metastases [32,
a positive SLN detected, and all 5 patients had 33]. Only 26 patients met the selection criteria, of
a T category greater than T2b (AJCC 7th edi- 70 patients who presented with conjunctival mel-
tion) Breslow thickness greater than 1.5 mm anoma to that center over the 4 years of the study,
and more than one mitotic figure per mm2. Six and 22 patients eventually consented to undergo
of 17 patients (35%) who presented with greater SLN biopsy. Their SLN identification rate using
a b
Fig. 21.4 (a) Left lower eyelid melanoma (Breslow node). The photograph shows the incision for the paroti-
thickness 7.2 mm with histologic ulceration Clark level II) dectomy/neck dissection which is much larger than the
with no palpable lymph nodes with a negative ultrasound incisions needed for the sentinel lymph node biopsy;
and MRI of the regional lymph nodes. The patient under- parotidectomy and completion lymph node dissection
went surgical removal of the melanoma simultaneous with only become necessary in patients who have a positive
sentinel lymph node biopsy which demonstrated one posi- sentinel lymph node. (c) This patient was doing well with-
tive sentinel lymph node in the parotid gland. (b) The out evidence of disease at last follow-up 3 years after
patient subsequently had completion neck dissection and removal of her eyelid melanoma and additional treatments
parotidectomy which showed two additional positive for her positive sentinel lymph node. (Reprinted from
nodes (in addition to the previous positive sentinel lymph Savar et al. [30]. With permission from Elsevier Inc.)
99m
Tc injection was 82%, which the authors term 6–36). A recently published review of the litera-
“injection failure” and attribute to previous local ture by Aziz et al. confirmed that high-risk fea-
surgeries that led to scarring and disruption of the tures for nodal involvement associated with
normal lymphatic drainage. Two of 18 patients conjunctival melanoma included clinical features
(11%) had an SLN which was positive for metas- of nonlimbal location and thickness >2 mm and
tases, and no false-negative cases were identified histologic features of ulceration and mitotic
over a median follow-up of 20 months (range rate >1 per mm2 [34].
Squamous Cell Carcinoma Experience with SLN for periocular SCC has
been reported in small case-series. Maalouf et al.
Although it accounts for only 9% of eyelid reported their experience with SLN biopsy in
tumors, squamous cell carcinoma is the second nine patients with squamous cell carcinoma of
most common eyelid malignancy after basal cell the eyelid and conjunctiva with a median follow-
carcinoma [35]. Squamous cell carcinoma has a up of 22 months. SLNs were successfully identi-
higher rate of local recurrence than basal cell car- fied in all nine patients, and one of the nine
cinoma, and squamous cell carcinoma, unlike patients had a positive SLN [44]. There were no
basal cell carcinoma, has the potential for local recurrences or deaths in their series. In
regional nodal metastasis. In a series of 111 another small case series, Chak et al. described
patients with advanced eyelid squamous cell car- five patients with a large (2.0–4.3 cm) primary
cinoma treated at our center, local recurrence poorly differentiated periocular squamous cell
occurred in 41 patients (36.9%), and regional carcinoma who underwent SLN biopsy using
nodal metastasis occurred in 27 patients (24.3%) preoperative 99mTc injection and intraoperative
[36]. Distant metastasis occurred in only seven isosulfan blue injection after imaging failed to
patients, but five of them died of the metastatic show metastatic disease. All patients were found
disease. In a more recent review of less advanced to have a positive SLN and therefore had adju-
cases from MD Anderson, we found that local vant radiation or systemic treatment [45].
recurrence occurred in 7 of 65 patients (11%) With advances in medical treatments for meta-
with a median time of 30 months from presenta- static cutaneous carcinomas, for example, the
tion to local recurrence, and no patient was found efficacy of immune checkpoint inhibitors and
to have distant metastases at last follow-up EGFR inhibitors for metastatic squamous carci-
(median, 27 months; range, 1–150 months) [37]. nomas, and given the potential prognostic impli-
These had routine screening for LN metastases cation of a positive SLN biopsy, there may be a
prior to surgery (see paragraph 21.5) but did not role for an SLNB in cases with periocular SCC
undergo SLN biopsy. Four patients (6%) had with high-risk features, such as lesions wider
regional LN metastasis at the time of diagnosis than 2 cm, locally recurrent disease, or those with
(with T-stage tumors of T2b, T3b, and T4), and depth of invasion greater than 4–5 mm.
two patients with a T3a and T4 disease (AJCC
7th edition) were found with LN metastases on
follow-up 2 weeks and 8 months after surgery, Sebaceous Carcinoma
respectively. These findings may suggest a poten-
tial role for sentinel lymph node biopsy or at least Sebaceous carcinoma is often associated with a
strict nodal surveillance for patients with tumors delay in diagnosis because it can mimic benign
more advanced than T2b. lesions such as chalazion and blepharoconjuncti-
A recent review of the literature found 14 ret- vitis. In a series of 60 patients with sebaceous
rospective studies and case series that reported an carcinoma of the eyelid, 11 patients (18%) had
SLN biopsy positivity rate of 0–44% in patients local recurrence, and 5 patients (8%) had clinical
with SCC (in various locations in the body) and nodal metastasis. Of the patients with clinically
high-risk features [38]. The definition of high- palpable nodal metastasis, 4 patients (80%) died
risk features was variable between studies but of metastatic disease [46]. Another study of 50
mostly included size >2 cm, depth of invasion patients demonstrated that lymph node metasta-
>4–5 mm, perineural invasion, and anatomic sis was correlated with American Joint Committee
location. Some of these retrospective studies sug- on Cancer (AJCC) T category for eyelid
gest that positive SLN biopsy was associated carcinoma (7th edition) in patients with eyelid
with worse prognosis [39–42], but this was not sebaceous carcinoma [29, 47]. This study further
consistent in all studies [43]. demonstrated that the T category of T2b is sig-
nificantly associated with worse prognosis and of positive SLNs in patients with Merkel cell car-
that patients with the T category of T3b or worse cinoma who present with localized disease has
(AJCC 7th edition) at presentation had poorer been reported to be as high as 20–30% [50]. An
disease-specific survival. In our most recent analysis of the National Cancer Data Base that
series of 100 patients with eyelid sebaceous car- included more than 5800 patients with Merkel
cinoma, 10 patients (10%) had LN metastases cell carcinoma found that the 5-year survival rate
and none had distant metastases at presentation was 76% in patients with pathologically proven
(unpublished data, manuscript under review at negative nodal status but only 42% in patients
the time of writing this chapter). During a median with positive nodes [51]. A recent report of 150
follow-up of 32 months (range, 1–192), 12 addi- patients with MCC (in various body locations)
tional patients (12%) developed LN metastasis who underwent SLN biopsy found that 26% had
for a total of 22% lymph node metastasis during a positive SLN, and patients with a positive SLN
the study period. had a higher risk for in-transit recurrence [52].
At the University of Texas MD Anderson This study, however, failed to find a difference in
Cancer Center, we have performed SLN biopsy overall survival or disease-specific survival
for sebaceous carcinoma of the eyelid as part of a between patients with a positive or negative SLN
prospective clinical trial for the past 17 years. In [52]. The importance of nodal status in Merkel
an early report of ten patients with sebaceous car- cell carcinoma is reflected in the 2018 American
cinoma of the eyelid, one patient had a positive Joint Committee on Cancer staging system 8th
SLN [29]. In a later report, we described a patient edition, in which disease associated with positive
with a T3 tumor (AJCC 7th edition) in the upper lymph nodes, or micrometastasis, is classified as
eyelid who had a positive SLN identified at the stage III irrespective of tumor size. The National
time of tumor excision. The patient underwent Comprehensive Cancer Network (NCCN) guide-
complete neck dissection and parotidectomy and lines for MCC also include SLN biopsy for
adjuvant radiation therapy and was without recur- patients with clinical N0 disease as part of the
rence at 20 months of follow-up [48]. These early management algorithm (NCCN guidelines for
reports suggested that SLN biopsy can be suc- Merkel cell carcinoma, version 1.2018).
cessfully carried out for sebaceous carcinoma of MCC is rare in the periocular region, and data
the eyelid, can identify microscopic metastasis, is available from relatively small cohorts. In a
and may be most appropriate for tumors with the study of 14 patients, lymph node metastasis
T category greater than T2b (AJCC 7th edition) occurred in 3 patients (21.4%), all of whom had
[47]. In our most recent data of 100 patients with negative margins at surgery [53]. Two of these
eyelid sebaceous carcinoma, 30 patients (30%) patients had metastasis to the parotid nodes and
underwent SLN biopsy, and 5 of them (20%) one to the submandibular nodes. The time from
with T3c tumor (3 patients, AJCC 8th edition), diagnosis to nodal metastasis ranged from
T4a (1 patient), and T4b (1 patient) were found to 11 months to 30 months. Only one patient died of
have positive lymph nodes (unpublished data, metastatic disease, and this patient was one of the
personal communication, B Esmaeli). patients with nodal involvement. As a proof of
concept, in 2002 we described a 61-year-old man
with Merkel cell carcinoma of the eyelid who had
Merkel Cell Carcinoma a positive SLN in the parotid area and subsequent
underwent parotidectomy and neck dissection,
Merkel cell carcinoma is a rare and aggressive which revealed Merkel cell carcinoma in an addi-
malignancy. Twenty percent of all cases of tional lymph node and the deep parotid gland
Merkel cell carcinoma occur in the periocular [54]. This report provided proof of the principle
and eyelid area [49]. The 5-year survival rate is that SLN biopsy can be successfully carried out
only 40–45% overall and 25% in patients diag- for Merkel cell carcinoma of the eyelid. Since
nosed with distant metastasis [32]. The incidence then SLN biopsy has become part of the
management algorithm recommended by periocular region showed that complications

NCCN. In a more recent study of 18 patients with were rare and insignificant [27, 29]. An infre-
periocular MCC from MD Anderson Cancer quent (6%) reported side effect is the temporary
Center, 22% of patient had LN involvement at weakness of the marginal mandibular branch of
presentation with the T category of T3a in three the facial nerve that resolved spontaneously after
patients and Tx in one patient (AJCC 7th edition) a few weeks [27].
[55]. Of these four patients, two had clinically The SLN biopsy procedure typically adds
positive LN verified by biopsy, and two of three 30–90 min of additional surgery time and proba-
other patients who underwent SLN biopsy were bly is best done at the same time as the definitive
found with a positive LN. In a series of 21 patients surgery for the eyelid tumor. In our prospective
with MCC of the eyelid from five different cen- trials at MD Anderson of SLN biopsy for more
ters from Australia and the United Kingdom, the than 90 patients with sebaceous carcinoma and
authors reported regional nodal metastatic rate of melanoma of the ocular adnexa, we used the blue
10% and distant metastatic rate of 19% and with dye in only the first 16 patients and then stopped
the lowest T-category tumor of T2a (AJCC 7th using it and now use technetium as a tracer only.
edition for eyelid carcinoma) measuring 8 mm to This is due to the fact that the addition of blue
develop either [56]. However, the methodology dye did not improve the rate of detection of
of systemic work-up in this study was inconsis- SLNs. Furthermore for conjunctival tumors, in
tent between centers, and only one patient under- particular, the volume of blue dye needed to
went SLN biopsy, and only eight patient had expect a draining blue lymph node which is typi-
head/neck imaging. cally 1 cc would be too large to inject in the sub-
Recent advances in medical therapy for MCC, conjunctival space and would lead to nonspecific
such as the use of immune checkpoint inhibitors, drainage from the wide area of the ocular surface.
make a more compelling argument to support the In the 16 patients who had blue dye injection in
use of SLNB, and future studies will examine its our early experience with SLN biopsy for con-
effect on survival [57, 58]. junctival melanomas we used only 0.2 cc volume
of blue dye. In these 16 patients, there were no
blue SLNs although among these patients some
dverse Effects of SLN Biopsy
A had microscopically positive SLNs found using
in the Head and Neck technetium as the tracer. Furthermore, there were
and Periocular Region no cases of permanent blue discoloration of the
ocular surface, and there were no cases of ana-
SLN biopsy is a relatively noninvasive procedure phylactic shock secondary to the blue dye [29].
associated with much less morbidity than elective
neck dissection. A meta-analysis of the morbidity
of SLN biopsy in patients with melanoma found Salient Diagnostic Findings
that SLN biopsy is associated with lymphedema
in 0.66–6% of patients, hematoma or seroma in Lymph Node Identification Rate
1.12–2.31%, and wound infection in 1.08–4%
[59]. In the same study, pain was reported by only The SLN identification rate for ocular tumors
0.75% of patients. (eyelid and conjunctival tumors) is high and
Analyses of SLN biopsy specifically in the reported to be more than 95% in most series. Of
head and neck region also indicate that complica- the three largest series published to date on SLN
tions are rare. In a study by Wasserberg et al. of biopsy for ocular tumors, two are from MD
35 patients who had SLN biopsy in the head and Anderson and describe patients enrolled in
neck region, one patient had seroma, and one prospective trials of SLN biopsy for melanoma
patient had sensory disturbance [60]. and sebaceous carcinoma; the third report is from
Furthermore, a large series of SLN biopsy in the France.
In the earlier report from MD Anderson, pub- (53%) had correlation in at least one basin. More
lished in 2007, Ho et al. reported successful iden- recently, the use of intraoperative indocyanine
tification of SLNs in 24 of 25 patients with green angiography has been reported for sentinel
sebaceous carcinoma of eyelid (10 patients) and lymph node biopsy for breast carcinomas
melanoma (15 patients) [29]. One patient had an [61–63].
SLN identified on preoperative lymphoscintigra-
phy, but no SLN was identified intraoperatively
with use of a gamma probe. In a follow-up report False-Negative Rate
from MD Anderson on SLN biopsy in conjuncti-
val and eyelid melanomas, Savar et al. reported Findings on SLN biopsy are deemed false-
successful SLN identification in 29 of 30 patients negative if a patient in whom SLN biopsy is neg-
(96.7%) on preoperative lymphoscintigraphy and ative (meaning no microscopic metastasis found)
in all 30 patients on intraoperative mapping using is later diagnosed with clinical nodal metastasis.
a gamma probe [30]. Yet an updated report with a In an early report from MD Anderson, Ho et al.
larger cohort of patients with longer follow-up found that with a median follow-up time of
from MD Anderson reported an overall intraop- 25 months, one of ten patients with sebaceous
erative identification rate of 98% [27]. We have carcinoma who had a negative SLN biopsy result
observed that in the rare patient who has poor developed nodal metastasis after SLN biopsy
drainage on preoperative lymphoscintigraphy, [29]. In this patient, rereview of the pathology
often a slight modification of the injection tech- slides of the SLN demonstrated the presence of a
nique leads to successful drainage on the day of microscopic focus that had been missed during
surgery. We have also observed that in patients the initial pathologic review.
with sebaceous carcinoma, who often have had In a more recent updated report from MD
multiple eyelid procedures prior to correct diag- Anderson in a larger cohort of patients and with
nosis and appropriate referral for definitive onco- longer follow-up time, Pfeiffer et al. reported on
logic surgery, lymphatic drainage may be altered, 51 patients with ocular adnexal melanoma, of
and as a consequence, there may be no drainage whom 41 patients had a negative SLN. Three of
during lymphoscintigraphy or surgery. these 41 patients later developed a nodal recur-
Maalouf et al. reported on results of SLN rence, making the false-negative rate to be 7%
biopsy in 17 patients with a variety of types of (95%CI, 1.5–9.9) [27]. The authors pointed out
eyelid tumors, including melanoma (4 patients), that all three patients with false-negative findings
Merkel cell carcinoma (4 patients), squamous on SLN biopsy were among the first patients who
cell carcinoma (8 patients), and sebaceous carci- had SLN biopsy at MD Anderson; there were no
noma (1 patient) [44]. SLNs were identified in all false-negative events in any of the subsequent
patients; however, the authors did not specify patients after the year 2004 suggesting the pres-
whether SLNs were identified on lymphoscintig- ence of a learning curve and importance of expe-
raphy, SLN biopsy, or both. rience with sentinel lymph node biopsy in the
Although both preoperative lymphoscintigra- head and neck region and for ocular adnexal can-
phy and intraoperative use of a gamma probe are cers in particular.
associated with high rates of SLN identification, Maalouf et al. reported no false-negative
it is important to use the two techniques in com- events—none of their patients with negative
bination. Savar et al. in one of the published findings on SLN biopsy had had a nodal recur-
reports from MD Anderson found a poor correla- rence at median follow-up times of 18.7 months
tion between findings on preoperative lymphos- for the 4 patients with Merkel cell carcinoma,
cintigraphy and findings on intraoperative use of 22 months for the 8 patients with squamous cell
a gamma probe [30]. Only 7 of 30 patients (23%) carcinoma, 27.2 months for the 4 patients with
had correlation between preoperative and intra- melanoma, and 30 months for the 1 patient with
operative findings in all basins, and 16 patients carcinoma [44].
Care of Patients with a Positive SLN resulted in longer relapse-free and overall sur-
vival than GMK vaccine at a median follow-up
Once micrometastasis is discovered on SLN time of 16 months [73].
biopsy, historically completion lymph node dis- Despite these not so great historical data for
section is recommended according to the 2018 patients with metastatic melanoma, we have seen
National Comprehensive Cancer Network a remarkable improvement in disease-free and
Melanoma Practice Guideline (version 2.2018). overall survival in patients with metastatic mela-
In a series of 90 patients with cutaneous melanoma in large part due to the advent of immune
noma and positive SLNs, 15–29% of patients checkpoint inhibitors for the treatment of meta-
with positive SLNs had metastasis in non-SLNs static or recurrent melanoma [74, 75]. These
based on findings on completion lymphadenec- promising results provide an even stronger argu-
tomy [64–66]. In a recent publication of the ment for identifying patients with microscopi-
Multicenter Selective Lymphadenectomy Trial cally positive early metastasis in the sentinel
II, immediate-completion lymph node dissection lymph nodes so that we can offer early adjuvant
increased the rate of regional disease control and treatments with immune checkpoint inhibitors. In
provided prognostic information. However, it did addition to melanoma patients, immune check-
not increase the melanoma-specific survival of point inhibitors have demonstrated efficacy for
patients with melanoma and SLN metastases at a several other historically resistant solid tumors,
median follow-up of 43 months [23]. The authors such as head and neck SCC and MCC [57, 76,
conclude that the lack of survival benefit with 77]. We have reported a positive response to anti-
completion lymph node dissection suggests that PD1 immune checkpoint inhibitor therapy in sev-
any increase in survival with early surgery eral patients with metastatic conjunctival
occurred in patients with disease that was limited melanoma or with melanoma metastatic to the
to the SLN and that in patients with non-SLN orbit [78].
metastases, the timing of that intervention did not
seem to be critical.
Adjuvant high-dose radiation therapy, with or Future Research
without concurrent chemotherapy, has been
shown to be effective in obtaining local–regional The studies to date on SLN biopsy for eyelid and
control for patients with melanoma [67], squa- conjunctival tumors have proven the feasibility of
mous cell carcinoma [68], sebaceous carcinoma SLN biopsy for this anatomic location; demon-
[69], and Merkel cell carcinoma with positive strated excellent rates of success in identification
lymph nodes [70]; however, a long-term survival of SLNs; and demonstrated positive SLNs in
benefit from radiation with or without concurrent patients with eyelid melanoma, conjunctival mel-
chemotherapy has not been established. Systemic anoma, sebaceous carcinoma of the eyelid, squa-
chemotherapy alone has also been used as post- mous cell carcinoma of the eyelid, and Merkel
operative adjuvant therapy for patients with cell carcinoma of the eyelid. These findings sup-
lymph node metastasis. Historically, adjuvant port continued use and further study of SLN
systemic chemotherapy with single agents, with biopsy for ocular tumors. A positive SLN indi-
multiple agents, or in combination with inter- cates a more advanced cancer stage and should
feron had not demonstrated benefit over observa- prompt additional treatments. A negative SLN,
tion [71]; similar negative results were found in on the other hand, augurs a better prognosis.
patients with melanoma treated with immune Given the steep learning curve for SLN biopsy
stimulants or vaccination [72]. Some benefit had studies in the head and neck region and for ocular
been observed from adjuvant use of interferon as tumors in particular and given the risk, albeit low,
demonstrated in the Eastern Cooperative of false-negative events, we recommend contin-
Oncology Group trial E1694, of 774 patients ued surveillance of the regional lymph nodes in
with melanoma, high-dose interferon-alpha-2b all patients with high-risk tumors with negative
SLNs. There is no question that early detection of had a stage T2b or higher tumor (AJCC 7th edi-
microscopic metastasis in the regional lymph tion) and 18 mm or higher in greatest diameter at
nodes leads to earlier interventions for nodal presentation [37]. For sebaceous carcinoma, we
metastasis and potential eligibility of patients for have previously found that primary tumors with
additional systemic treatments. This is particu- the T category greater than T2b (AJCC 7th edi-
larly true given the recent drug discoveries for tion) are associated with a higher risk of nodal
metastatic melanoma and the very real possibility metastasis [47]. For Merkel cell carcinoma we
that early microscopic detection of metastasis found that in our series of 18 patients, all patients
would allow for earlier treatments with immune with a positive nodal metastasis had a T3a dis-
checkpoint inhibitors, or multi-drug targeted ease (AJCC 7th edition eyelid carcinoma criteria)
therapy, all recent strategies that have proven except for 1 patient who had a Tx disease [55].
effective and associated with prolonged survival Similar studies are currently underway to
for patients with metastatic melanoma. determine what tumor size and what other histo-
Whether there is a survival benefit from the logic features are associated with a higher risk of
addition of SLN biopsy to the treatment regimen nodal metastasis for squamous carcinoma of the
for patients with eyelid or conjunctival tumors eyelid and for Merkel cell carcinoma of the eye-
specifically is more difficult to address. lid. The long-term goal of these studies is to help
Determining whether such a benefit exists would determine which patients are the optimal candi-
require much larger studies and longer follow-up dates for SLN biopsy. Multi-institutional con-
times than are reflected in the currently available trolled studies of SLN biopsy for ocular tumors
literature on SLN biopsy for ocular tumors. would be optimal for yielding higher-level evi-
However, the MSLT I, in which 1347 patients dence regarding the indications for and yield of
with intermediate-thickness (1.2–3.5 mm) cuta- SLN biopsy for ocular adnexal tumors.
neous melanoma were randomly assigned to
SLN biopsy or observation, showed a signifi-
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evaluation improves prognostic accuracy in Merkel and adjuvant therapy in thick 4 mm melanoma mul-
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Surgical Techniques
22
Anat Galor, Bennie H. Jeng, Arun D. Singh,
and Carol L. Karp
Introduction for extension of lesions and to palpate the preau-

ricular and submandibular areas for enlarged
A variety of tumors affect the conjunctiva and lymph nodes. Corneal involvement must be accu-
cornea, ranging from benign growths to malig- rately documented since it is difficult to appreci-
nant neoplasms. Several types of conjunctival ate under the diffuse lighting of an operating
neoplasms originate from or involve the limbus microscope. Rose Bengal stain can be used to
region and extend into the cornea. Therefore, sur- help delineate abnormal epithelium. A drawing
gical techniques involve excision of both corneal or photograph clearly depicting the extent of
and conjunctival tissues. involvement, which can be readily seen during
surgery, is helpful for obtaining adequate surgical
margins. Free movement of the abnormal con-
Presurgical Evaluation junctiva, as tested by gentle pushing with a
cotton-tipped applicator, indicates sparing of the
A detailed slit lamp examination is not only vital sclera.
to correctly diagnose conjunctival and corneal Anterior segment optical coherence tomogra-
tumors but also critical for planning the appropri- phy (OCT) [1, 2] and ultrasound biomicroscopy
ate surgery. It is also important to evaluate the can greatly aid in the preoperative evaluation of
upper and lower palpebral conjunctivae to look surface extension (OCT) and depth (UBM) of
conjunctival lesions (Chap. 12).
Anesthesia
A. Galor (*) · C. L. Karp
Department of Ophthalmology, Bascom Palmer Eye Local anesthesia can be used for most proce-
Institute, Miami, FL, USA dures, depending on patient cooperation. Most
e-mail: agalor@med.miami.edu
authors recommend retrobulbar anesthesia with
B. H. Jeng sedation to avoid disruption of conjunctival
Department of Ophthalmology and Visual Sciences,
architecture and to control the pain associated
University of Maryland School of Medicine,
Baltimore, MD, USA with conjunctival manipulation and cryotherapy
[3]. Others prefer subconjunctival injection of
A. D. Singh
Department of Ophthalmic Oncology, Cole Eye 1% lidocaine with epinephrine to elevate the
Institute, Cleveland Clinic, Cleveland, OH, USA lesion from underlying sclera [4].

280 A. Galor et al.
General Surgical Principles mary therapy for an ocular surface squamous neo-
plasia (OSSN). This procedure can be performed
The goal of surgery is the total removal of tissues at the slit lamp under topical anesthesia. Forceps
(conjunctiva, cornea, sclera) that are affected by are used to grasp nearby uninvolved tissue and
the neoplasm. All but the most extensive conjunc- scissors are then used to remove a sufficient tumor
tival lesions can be approached by excisional sample. Given the certainty of positive margins,
biopsy to achieve this goal. However, incisional specimen orientation is not needed. The sample is
biopsy may be performed in some circumstances. positioned on a small piece of paper and placed in
formalin to allow for pathologic review. A Beaver
blade then can be used to separate and remove
General Surgical Technique abnormal corneal epithelium, which should also
be sent to the pathologist. While this technique is
In general, the surgical technique depends on loca- a good option in cases of suspected OSSN, it
tion and the type of tumor. The surgical procedure should be avoided in cases of suspected mela-
can be divided into four sequential steps: conjunc- noma as complete excisional biopsy is preferred
tival excision, corneal excision (if corneal involve- in the latter malignancy.
ment is present), supplemental cryotherapy (if
needed), and ocular surface reconstruction. imple Conjunctival Excision
S
Benign lesions that do not penetrate the Tenon or
sclera can be removed by a simple excisional
Conjunctival Excision biopsy. The surrounding conjunctiva is grasped
with non-toothed forceps and excised along with a
The removal technique for the conjunctival por- 1- to 2-mm margin of clinically non-affected tis-
tion of a neoplasm depends on the type of lesion sue using scissors. The depth of incision can be
and its depth of invasion. limited only to the full thickness sparing the under-
lying Tenon’s fascia or may extend up to the sclera
imple Incisional Biopsy
S (including Tenon’s fascia) (Fig. 22.1). It is impor-
A simple incisional biopsy should be considered tant not to touch the affected conjunctiva and use
in cases where medical therapy is the planned pri- different instruments for affected and non-affected
a b
Fig. 22.1 Simple conjunctival excision for PAM. The The wound (8 × 6 mm) was left to heal by secondary
depth of incision was limited to the full thickness of intention (with approximation – avoiding sutures or glue).
the conjuctiva sparing the underlying Tenon’s fascia (a). Note full surface epithelialization at 4 weeks (b)
conjunctiva so as not to iatrogenically plant tumor is to denature the cells, thereby minimizing the
cells on the unaffected tissue [5]. risk of seeding of cancer cells. Alcohol is applied
to dry cornea so as to limit spillage. The unin-
omplex Conjunctival Excision
C volved cornea may also be protected with a vis-
For potentially malignant tumors, a more exten- coelastic applied to unaffected areas. The corneal
sive excision is suggested with a wider margin of epithelium is removed in one piece, placed on a
excision of clinically non-affected tissue filter paper, and submitted to pathology.
(3–4 mm) and lamellar sclerectomy if scleral An alternative approach is to first loosen and
involvement is present. The area to be resected is remove epithelium and then proceed with con-
first outlined with a surgical marker, with care to junctival resection of tumor.
include 3–4 mm of unaffected conjunctival tis-
sue. Using a no-touch technique, the conjunctiva
and Tenon’s fascia are then incised with scissors Supplemental Cryotherapy
to expose the underlying sclera (Fig. 22.2a).
Once the conjunctival margins have been Cryotherapy with a flat-tipped nitrous oxide
released, tumor removal should be completed by probe is used as a supplemental treatment of
cutting flush with the corneal margin. Bipolar malignant lesions to decrease recurrence rates.
cautery is applied to the episcleral vessels to Galor et al. demonstrated that application of
achieve hemostasis. In cases where scleral cryotherapy to the surgical margins decreased the
involvement is suspected, a partial sclerectomy OSSN recurrence rate by approximately 50%
should be performed with a fresh no. 57 Beaver (31% versus 16% at 5 years) [6]. The probe is
blade by fashioning a semicircular groove, placed on the underside of the conjunctival edge,
approximately 20% of scleral depth and 2 mm lifting the conjunctiva to avoid damage to the
posterior to the tumor margin (Fig. 22.2b). A thin sclera, and applied to the tissue for 3–10 s
scleral flap can then be dissected with a crescent (Fig. 22.2d) [5]. The tissue is allowed to thaw
blade anteriorly up to the limbus (Fig. 22.2c). For spontaneously and is refrozen in a similar man-
tumors extending more than 5 mm posterior to ner for a “double freeze-thaw” cycle. The probe
the limbus, it is helpful to hook and isolate the is applied to the margin to overlap with the previ-
appropriate rectus muscle with a suture to pro- ously treated area, and the process is repeated
vide traction, to allow for better exposure and to until all margins have been treated. The affected
avoid inadvertent injury to the muscle. limbus is then similarly treated with a double
freeze-thaw cycle.
Corneal Excision
Ocular Surface Reconstruction
As corneal involvement by a conjunctival tumor
tends to be superficial, the corneal excision is To prevent the possibility of planting tumor cells
usually limited to removal of corneal epithelium on unaffected tissue, it is important to use a dif-
(corneal epitheliectomy). Care must be taken not ferent set of instruments for reconstructing the
to disrupt Bowman’s layer as it is thought to ocular surface than those that were used for lesion
serve as a natural ocular barrier to invasion. removal. The preferred technique involves cutting
Deeper invasion of the cornea, if present, neces- an amniotic membrane to the appropriate size,
sitates lamellar keratectomy. Prior to scraping off placing it (substrate side down) over the defect
the affected epithelium with no. 57 Beaver blade, area, and tucking the margins under the healthy
absolute alcohol is applied for 1 min with a conjunctivae. Fibrin glue is then utilized to secure
Weck-cell applicator to the involved corneal epi- the membrane to the underlying sclera. The
thelium and a 2-mm margin of clinically non- thicker component (fibrinogen) is first introduced
affected tissue. The purpose of alcohol application under the graft with a 27-gauge cannula and
282 A. Galor et al.
a b
c d
Fig. 22.2 Complex conjunctival excision. Large con- Beaver blade. (c) Lamellar scleral dissection with a cres-
junctival lesion being excised with a 4-mm margin of cent blade. (d) Cryotherapy to the edges of the conjuncti-
unaffected conjunctiva. (a) Conjunctival flap being fash- val wound. (e) Closure of the wound
ioned. (b) Partial-thickness scleral incision with a no. 57
gently spread so that a thin layer of uniform onjunctival Malignant Melanoma

C
thickness is achieved. The thinner component Conjunctival melanomas are managed by exci-
(thrombin) is then introduced under the graft sion and cryotherapy [13, 14]. Recurrent con-
with a separate cannula, and again, a thin layer is junctival melanoma is managed by repeat
applied. A muscle hook is then used to smooth excision, cryotherapy, MMC eye drops, or irra-
the graft and remove excess glue. Once graft diation. More extensive recurrences may require
position is acceptable, a 2-min wait is usually exenteration [5].
sufficient for good adherence to develop between
the graft and underlying sclera (Fig. 22.2e). Use
of amniotic membrane helps to decrease inflam- Squamous Tumors
mation and to facilitate epithelialization [7–9].
Superficial excision that spare the Tenon’s fascia quamous Cell Papilloma
S
can be left to heal by secondary intention (with If removal is contemplated, combined modality
approximation – avoiding sutures or glue). treatment should be used since simple excision
often leads to a more extensive recurrence than
the original lesion [5]. Cryotherapy, as described
Specific Surgical Techniques above, is the supplemental treatment of choice.
Alternatively, a medical approach using inter-
Melanocytic Tumors feron alpha 2b drops or injections may be
utilized.
Conjunctival Nevus
Excision of conjunctival nevus is considered for onjunctival Epithelial Neoplasia
C
cosmetic reasons, ocular irritation, or parental Combined modality treatment (excision supple-
concern. A simple excisional biopsy is the proce- mented with cryotherapy) as described above is
dure of choice [5]. advocated given the high rate of recurrence of
simple excision [5]. Other variations to the above
rimary Acquired Melanosis
P technique have been described and include
Because of the diffuse nature of primary acquired application of cryotherapy to the scleral bed as
melanosis (PAM), the surgical approach is differ- well as the surrounding conjunctivae [15] and
ent from that of an isolated conjunctival lesion. performing cryosurgery prior to and after exci-
Corneal epitheliectomy is performed if corneal sion [4]. A variant of Mohs’ micrographic sur-
involvement is documented. Suspicious nodules gery has been described as an approach to
are excised to evaluate for the possibility of mela- treating CIN [16]. Topical interferon alpha [17,
noma. Staging consists of removing 3-mm pieces 18], topical MMC [19, 20], or topical 5-fluoro-
of bulbar conjunctiva with the use of fresh forceps uracil [21] can be used as an adjuvant treatment
and scissors halfway between the rectus muscles for patients with incompletely excised lesions
and fornix in all four quadrants. These small areas (i.e., those with positive surgical margins). In
can be left to heal without sutures [3]. Complete patients with positive surgical margins, the use
removal is possible with small areas of PAM, of postoperative interferon therapy reduced
whereas diffuse areas may be treated with double recurrences to a level similar to the one seen in
freeze-thaw cycle cryotherapy alone (one quad- patients with negative surgical margins [6].
rant per session) if atypia is documented histo- Medical modalities can also be considered as a
pathologically [10]. Topical mitomycin-C (MMC) primary treatment, especially in patients with
has also been reported as a possible primary or diffuse disease or in those with multiple recur-
adjuvant treatment for diffuse PAM [11, 12]. rences after surgery [22].
284 A. Galor et al.
Substantia Propria Tumors
Lymphoid Tumor
An incisional approach is typically reserved for
suspected lymphoid tumors. Tissue must be kept
fresh to allow for flow cytometric assessment to
differentiate between hyperplasia and malig-
nancy. Medical approaches including external
beam radiation or chemotherapy are typically
used to treat such malignancies.
Limbal Dermoid
Limbal dermoids can cause irregular astigma-
tism, irritation, or unacceptable cosmesis. Given
the deep extent of these tumors, one surgical Fig. 22.3 Intraoperative photograph demonstrating the
orientation of an ocular surface squamous neoplasia after
approach is a lamellar sclerectomy and keratec- excisional removal and prior to placement in formalin.
tomy [5]. The lesion can be excised manually by (Courtesy of Dr. Carol L. Karp, Bascom Palmer Eye
lifting the conjunctival edge with forceps and Institute, Miami, Florida)
locating a plane of normal sclera under the tumor
with a blade. Alternatively, a handheld trephine
on bare sclera can be used to delineate the bound- Postsurgical Management
aries of the lesion. A slightly oversized trephine
is then used to remove donor corneoscleral tissue Following surgery, topical antibiotics are used
after a lamellar dissection is performed of equal until reepithelialization is complete. A corticoste-
depth. The donor is sewn into the recipient bed roid eye drops is typically used for approximately
with interrupted 10-0 nylon sutures [23]. Another 1 month, on a tapering schedule. However, the
surgical approach involves cutting the lesion frequency and duration is titrated based on the
flush with the surrounding tissue [24]. degree of inflammation in the surgical bed.
Patients in whom a graft is used may require a
bandage contact lens and topical treatment for a
Specimen Preparation longer time [5].
Prior discussion with a pathologist is important

to identify the proper fixative agent; most com- Complications
monly, 10% formalin is used. For suspected lym-
phoid tumors, tissue should be transported fresh Although uncommon, complications can occur
in a small amount of saline for flow cytometric after surgical resection including infection,
analysis. Specimens are prepared by laying the bleeding, delayed epithelial healing, pyogenic
tissue flat, epithelial side up, on sterile paper wet- granuloma formation, Tenon’s cyst formation,
ted with balanced salt solution. Orientation is conjunctival and corneal scarring, restrictive stra-
drawn with a graphite pencil. bismus, and limbal stem cell deficiency.
The tissue can then be sent to pathology for Complications related to MMC use include
final diagnosis and margin assessment (Fig. 22.3). scleral ischemia and cataract formation. Vigorous
cryotherapy to the scleral bed can result in dam- 11. Finger PT, Czechonska G, Liarikos S. Topical
mitomycin C chemotherapy for conjunctival mela-
age to the sclera, iris, and ciliary body [5]. These noma and PAM with atypia. Br J Ophthalmol.
complications can be minimized by adhering to 1998;82(5):476–9.
good surgical techniques. 12. Pe’er J, Frucht-Pery J. The treatment of primary
acquired melanosis (PAM) with atypia by topical mito-
mycin C. Am J Ophthalmol. 2005;139(2):229–34.
13. Jakobiec FA, Rini FJ, Fraunfelder FT, et al. Cryo
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2. Thomas BJ, Galor A, Nanji AA, et al. Ultra high- 15. Fraunfelder FT, Wingfield D. Management of intraep-
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tomography in the diagnosis and management of nomas. Am J Ophthalmol. 1983;95(3):359–63.
ocular surface squamous neoplasia. Ocul Surf. 16. Buus DR, Tse DT, Folberg R, et al. Microscopically
2014;12:46–58. controlled excision of conjunctival squamous cell car-
3. Shields JA, Shields CL, De Potter P. Surgical cinoma. Am J Ophthalmol. 1994;117(1):97–102.
management of conjunctival tumors. The 1994 17. Chen HC, Chang SW, Huang SF. Adjunctive treat-
Lynn B. McMahan Lecture. Arch Ophthalmol. ment with interferon alpha-2b may decrease the risk
1997;115(6):808–15. of papilloma-associated conjunctival intraepithelial
4. Peksayar G, Altan-Yaycioglu R, Onal S. Excision and neoplasm recurrence. Cornea. 2004;23(7):726–9.
cryosurgery in the treatment of conjunctival malignant 18. Karp CL, Moore JK, Rosa RH Jr. Treatment of
epithelial tumours. Eye (Lond). 2003;17(2):228–32. conjunctival and corneal intraepithelial neoplasia
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Radiation Therapy: Conjunctival
and Eyelid Tumors
23
Christopher Fleming, Shlomo Koyfman,
and Arun D. Singh
Introduction able reductions in dose to nearby organs at risk

(Volume 1: Chapter 11). Dose sparing can be fur-
Several forms of radiation therapy are used to ther achieved with the use of spacers, lead eye
treat eyelid and conjunctival malignancies. As shields, and eye deviation. Brachytherapy is
with other ocular tumors, the goal of radiation another commonly used modality, especially for
therapy is to sterilize the tumor while conserving conjunctival tumors. Such brachytherapy is deliv-
visual function and avoiding collateral damage. ered via handheld applicators, plaques, or inter-
In this chapter, we overview the role of radiation stitial seeds; compared to external beam,
therapy in the treatment of selected eyelid and brachytherapy has more rapid dose falloff, but
conjunctival tumors. More detailed information with higher surface doses and more difficulty
(e.g., dosimetry) is provided in the relevant with reproducible application for eyelid tumors.
chapters.
Eyelid Tumors
Techniques of Radiation Therapy
Squamous Cell Carcinoma
Radiation therapy for eyelid tumors is most com-
monly delivered via external beam radiation ther- The primary treatment for squamous cell carci-
apy (EBRT), including traditional megavoltage noma (SCC) of the eyelid is surgical excision,
photons, proton therapy, orthovoltage X-rays, performed either using Mohs micrographic tech-
and electron beam therapy. The rapid adoption of nique or with wide safety margins. Radiation
intensity-modulated radiation therapy (IMRT) therapy may alternatively be recommended for
and image-guided radiation therapy (IGRT) over patients with advanced disease, where surgical
the past decade has significantly improved the excision would result in poor cosmesis and loss
conformality of treatment plans, leading to size- of eyelid function, and for patients unable to
undergo extensive surgery because of poor health
C. Fleming · S. Koyfman (Chap. 5). For both squamous and basal cell car-
Department of Radiation Oncology, Taussig Cancer cinomas, many different radiation therapy doses
Center, Cleveland Clinic, Cleveland, OH, USA have proved efficacious, ranging from single
A. D. Singh (*) fraction to multi-week treatment courses deliver-
Department of Ophthalmic Oncology, Cole Eye ing 20–60 Gray via external beam radiation ther-
Institute, Cleveland Clinic, Cleveland, OH, USA apy (Fig. 23.1). Interstitial brachytherapy is
e-mail: singha@ccf.org

288 C. Fleming et al.
a b
Fig. 23.1 Squamous cell carcinoma (eyelid). This man ric modulated arc radiation therapy (VMAT) delivering
presented with a large squamous cell carcinoma of the 64 Gy in 32 daily fractions (a). Note response 3 months
right upper eyelid. He was treated primarily with volumet- after completion of radiation therapy (b)
another available technique, whereby radioactive apy (fractionated, total dose 40–70 Gy) [13]. All
sources are inserted into the tumor using a plastic tumors showed histopathological remission
tubing system. Surface brachytherapy, where a within 3 months and sustained clinical remission
radiation therapy source is placed on the tumor, is was documented in each patient at 24 months.
yet another treatment option for smaller tumors. Overall, cosmesis and functional results were bet-
SCC of the skin is generally quite radio- ter with IMQ than with radiation therapy [13].
responsive. Retrospective studies have generally Lesions that are recurrent after prior surgery have
reported excellent long-term local control rates worse control rates than those treated primarily
of 70–95% for both EBRT [1–3] and brachyther- with radiation therapy [14].
apy [4–8]. Experiences with proton therapy have
been published showing feasibility of the tech-
nique [9]. Sebaceous Gland Carcinoma
Sebaceous gland carcinoma is a rare cancer with

Basal Cell Carcinoma limited data on efficacy for radiation therapy
(Chap. 6). Initial reports suggested radio-
Multiple large retrospective series have reported resistance of this tumor [1], though recent studies
long-term local control with radiation therapy to have challenged this notion, showing long-term
be 90% or higher (Fig. 23.2). These results are local control rates of 90% or higher [15, 16].
consistent between EBRT and brachytherapy Doses greater than 55 Gy are associated with
(Chap. 4) [4–8, 10–12]. Assuming equal extent of increased local control [17], and brachytherapy
disease, radiation therapy dosing is not signifi- has also been used to successfully treat sebaceous
cantly different between squamous cell carcinoma gland carcinoma [8].
and basal cell carcinoma. Comparison of topical
therapy with imiquimod cream (IMQ) and radia-
tion therapy was assessed in 27 patients with clin- Melanoma
ical and histopathological diagnosis of nodular
BCC randomized to receive IMQ 5% cream once Melanoma is generally considered less radio-
daily, 5 days/week for 6 weeks or radiation ther- responsive than squamous and basal cell
23 Radiation Therapy: Conjunctival and Eyelid Tumors 289
a b
c d
Fig. 23.2 Basal cell carcinoma (eyelid). A patient with a treatment (b). The radiation therapy is delivered using
large basal cell carcinoma of the lower eyelid, treated with VMAT plan consisting of non-coplanar arcs oriented per-
radiation therapy alone at a dose of 35 Gy in five fractions. pendicular to each other, where the dose is continuously
A blue spacer is placed over the eye to increase the dis- delivered and modulated, while the gantry is in motion
tance between the target volume and the globe. around the patient (c). The isodose lines are shaped to
Proparacaine drops are first placed on the eye for topical avoid the right globe while still providing acceptable cov-
anesthesia. Once the spacer is placed, the eye is then taped erage of the target (d). The spacer is seen anterior to the
shut. Wiring outlines the anticipated treatment volume globe to increase the distance between the target
(a). A custom mask is made to immobilize the head during volume (purple region) and the globe
carcinoma. Primary radiation therapy alone is Merkel Cell Carcinoma

therefore not recommended, though it may be
used as an adjuvant for more invasive lesions, Merkel cell carcinoma is very radiosensitive.
particularly those with regional nodal metastases Radiation therapy is commonly delivered post-
(Chap. 7). The use of I-125 brachytherapy has operatively to the tumor bed and regional lymph
been reported, though is not standard [18]. nodes, as the risk for residual/recurrent local
d isease and regional lymph node metastases is for wide surgical safety margins and, in some
high (Chap. 9) [17, 19]. EBRT is the most cases, the use of an amniotic membrane graft.
commonly employed modality, though there are As with other disease of the head and neck,
published case reports on the efficacy of brachy- patients with regional but not distant metastatic
therapy with I-125 seed implantation [20]. disease should undergo external beam radiation
therapy post-operatively, if surgery is not feasible
(Chap. 17). The presence of regional nodal dis-
Conjunctival Tumors ease indicates a poor prognosis, and these patients
will likely require additional systemic therapy
Conjunctival Melanoma [27]. Advanced conjunctival melanomas may be
treated by local excision with adjunctive external
For neoplasms of the conjunctiva, brachytherapy beam radiation therapy as an alternative to exen-
is generally favored over external beam radiation teration for carefully selected patients (Fig. 23.4);
therapy due to its rapid dose fall off and the rela- experience with proton therapy delivering 45 Gy
tive ease of application at this site. Strontium-90 in eight fractions has been published [28].
brachytherapy has been used as an adjuvant ther-
apy for incompletely excised conjunctival mela-
noma showing long-term local control rates of onjunctival Invasive Squamous
C
80–95% for cumulative doses of 50–60 Gy; sig- Carcinoma
nificantly worse tumor control is observed in
patients who receive doses less than 40 Gy [21]. Management of conjunctival carcinoma is similar
Primary therapy with Sr-90 brachytherapy has to conjunctival melanoma, with resection being
also been reported [22, 23]. Ru-106 brachyther- the primary treatment modality. Strontium-90
apy prescribed to 100 Gy, used as adjuvant ther- brachytherapy has been used post-operatively in
apy, shows significantly improved local control the treatment of ocular surface squamous neopla-
compared to patients treated with adjuvant cryo- sia with doses of 30 Gy in a single fraction and
therapy (Fig. 23.3) [24]. Other radioactive 60 Gy in four fractions. Higher doses of 60 Gy
sources, including I-125, have also been utilized single fraction and 140 Gy in seven fractions are
[25, 26]. Adjunctive radiotherapy avoids the need used in the primary treatment setting (i.e., patients
a b
Fig. 23.3 Conjunctival melanoma. Nodular conjunctival 106 episcleral implant (b) 34 months after treatment,
melanoma of the left eye of a 62-year-old man (a). there was an absence of residual pigmentation or recurrent
Following resection and brachytherapy with ruthenium- tumor. (Case provided by Dr. Bertil Damato)
a b
Fig. 23.4 Conjunctival melanoma. Fungating conjuncti- teration (a). Following extensive resection and external
val melanoma of the left eye of an 87-year-old woman. beam radiation therapy (b), note absence of residual pig-
The tumor obscured almost the entire cornea and had mentation or recurrent tumor over a period of 28 months.
invaded the orbit; however, the patient had declined exen- (Case provided by Dr. Bertil Damato)
who do not undergo surgical resection) [29]. lymphoma confined to the conjunctiva or eyelid
Small applicators have increased risk of marginal [38, 39]. Higher-grade lymphomas (e.g., diffuse
failure [30, 31]. I-125 and Ru-106 are other large B-cell lymphoma and mantle cell lym-
radioactive isotopes that may be used for brachy- phoma) are treated with higher doses (30–
therapy [14]. The main indication is scleral inva- 45 Gy) with similar efficacy or may be managed
sion or deep margin being positive on with systemic therapy alone [40, 41].
histopathology (Chap. 15). As above, external Brachytherapy carries increased risk of local
beam radiation therapy may be used for very recurrence at the treatment margins [42] and is
advanced tumors as an alternative to exenteration therefore not recommended.
[32–34].
Radiation-Induced Ocular
Conjunctival Lymphoma Morbidity
Lymphomas are exquisitely radiosensitive neo- The likelihood and severity of toxicity are deter-
plasms with a high tendency for local, regional, mined by total and daily dose of radiation ther-
and distant spread. Therefore, radiation therapy apy, as well as irradiated volume of the affected
alone or in combination with systemic therapy organ at risk (Volume 1: Chapter 12) [43].
is the preferred modality for treatment. Generally, a more protracted treatment will
Pathology generally reveals indolent histologic deliver improved cosmesis and is therefore
subtypes, the most common being extranodal selected for more locally invasive tumors.
marginal zone and follicular lymphoma [35]. Potential side effects of radiation therapy include
Doses of 24–30 Gy have shown 10-year local keratoconjunctivitis sicca, corneal stem cell defi-
control rates up to 100% [36], although patients ciency, cataract, radiation retinopathy, and radia-
remain at high risk for distant relapse [37]. For tion optic neuropathy (Fig. 23.5) [10, 14, 15,
retrobulbar or lacrimal gland involvement, the 44–46]. When used in conjunction with surgery,
entire orbit is the target of radiation therapy, radiation may lead to worse toxicity than when
although partial orbit radiation is acceptable for used alone as definitive treatment [9].
5. Mareco V, Bujor L, Abrunhosa-Branquinho AN, et al.

Interstitial high-dose-rate brachytherapy in eyelid
cancer. Brachytherapy. 2015;14(4):554–64.
6. Caccialanza M, Piccinno R, Gaiani F, et al. Relevance
of dermatologic radiotherapy in the therapeutic strat-
egy of skin epithelial neoplasms: excellent results in
the treatment of lesions localized on eyelids and skin
overlying the cartilage of the nose. G Ital Dermatol
Venereol. 2013;148(1):83–8.
7. Conill C, Sanchez-Reyes A, Molla M, et al. Brachy
therapy with 192Ir as treatment of carcinoma of the
tarsal structure of the eyelid. Int J Radiat Oncol Biol
Phys. 2004;59(5):1326–9.
8. Frakulli R, Galuppi A, Cammelli S, et al.
Brachytherapy in non melanoma skin cancer of eye-
lid: a systematic review. J Contemp Brachytherapy.
2015;7(6):497–502.
Fig. 23.5 Radiation toxicity. A patient with recurrent 9. Holliday EB, Esmaeli B, Pinckard J, et al. A multi-
high-grade apocrine adenocarcinoma of the right lower disciplinary orbit-sparing treatment approach that
eyelid, for which he underwent complete resection fol- includes proton therapy for epithelial tumors of the
lowed by adjuvant radiation. During treatment he devel- orbit and ocular adnexa. Int J Radiat Oncol Biol Phys.
oped radiation-induced conjunctivitis and keratitis 2016;95(1):344–52.
10. Krema H, Herrmann E, Albert-Green A, et al.
Orthovoltage radiotherapy in the management of
Brachytherapy has rapid dose falloff, which may medial canthal basal cell carcinoma. Br J Ophthalmol.
reduce toxicity compared to EBRT, though may 2013;97(6):730–4.
11. Schlienger P, Brunin F, Desjardins L, et al. External
not be feasible for all locations [8]. radiotherapy for carcinoma of the eyelid: report
of 850 cases treated. Int J Radiat Oncol Biol Phys.
1996;34(2):277–87.
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surgical treatments of primary, non-melanoma eye-
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Radiotherapy for basal cell carcinoma of the medial
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15. Hata M, Koike I, Maegawa J, et al. Radiation ther-
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Systemic Associations
24
Abbreviations in about one-fourth of cases [2]. Similar pigmen-

tation of the skin is also present on the lips and
AL Light chain genital mucosa (Table 24.1) [3].
CHRPE Congenital hypertrophy of the retinal
pigment epithelium
GS Goldenhar syndrome Peutz–Jeghers Syndrome
MEN Multiple endocrine neoplasia
OAV Oculoauriculovertebral dysplasia Peutz–Jeghers syndrome (PJS) refers to the associa-
OAVS Oculoauriculovertebral spectrum tion of gastrointestinal hamartomatous polyposis
PJS Peutz–Jeghers syndrome and mucocutaneous pigmentation [4]. Peutz–
PS Proteus syndrome Jeghers syndrome is inherited in an autosomal dom-
TTR Transthyretin inant fashion and results from mutations of STK11
XP Xeroderma pigmentosum (also known as LKB1), a tumor suppressor gene on
chromosome 19p13.3 in about 70–90% of patients
[5, 6]. Many missense mutations and deletions
occur throughout the whole LKB1 gene without any
Carney Complex particular genotype/phenotype correlation [6].
Congenital hypertrophy of the retinal pigment
Carney complex is characterized by cutaneous epithelium (CHRPE)-like lesions of the fundus
pigmentary abnormalities, myxomas, endocrine that are characteristic of patients with familial
tumors, and schwannomas [1]. Benign conjuncti- adenomatous polyposis (Gardner syndrome) do
val and caruncular pigmentation may be present not occur in Peutz–Jeghers syndrome [7].
However, pigmented spots of the eyelids and
conjunctiva have been observed (Fig. 24.1) [8].
M. Scaramuzzi · E. I. Traboulsi (*)
Department of Pediatric Ophthalmology and The three clinical features of PJS are mucocu-
Strabismus, Center for Genetic Eye Diseases, Cole taneous melanin hyperpigmentation, multiple
Eye Institute (i-32), Cleveland Clinic, distinctive intestinal hamartomatous polyps, and
Cleveland, OH, USA
a dominant inheritance of the condition with a
e-mail: traboue@ccf.org
positive family history [6]. Hamartomatous pol-
L. T. Xu · A. D. Singh
yps are non-cancerous tumors that occur mainly
Cole Eye Institute, Cleveland Clinic, in the small bowel. Dysplastic transformation of
Cleveland, OH, USA a PJS polyp is very rare [6].

Table 24.1 Conjunctival tumors that are markers of syndromic association

Conjunctival
Pattern Entity features Associated features Locus/gene
Pigmentation Carney complex Conjunctival Spotty mucocutaneous 17q
pigmentation pigmentation
Schwannoma
Endocrine overactivity PRKAR1A gene
Testicular tumor chromosome 2
Peutz–Jeghers Conjunctival Mucocutaneous 19p13.3
syndrome pigmentation pigmentation STK11
Gastrointestinal polyposis
Benign Dermoid Organoid nevus Epibulbar dermoid Cutaneous sebaceous Sporadic
tumors syndrome Coloboma nevus
Goldenhar Epibulbar dermoid Preauricular appendages Sporadic
syndrome Pretragal fistula
Vertebral anomalies
Proteus Epibulbar dermoid Connective tissue nevi Sporadic
Strabismus Lipoma
Orbital exostoses Vascular malformations
Epidermal nevi
Neuroma MEN 2B Conjunctival Thickened corneal nerves 10q11.2
neuroma Mucocutaneous neuroma RET proto-oncogene
Endocrine tumor
Malignant tumors Xeroderma Conjunctival Skin atrophy with Variable
pigmentosum xerosis pigmentary changes
Keratitis Neurological
Ocular surface abnormalities
neoplasms
Amyloidosis Conjunctival Variable Sporadic
nodule
Conjunctival Familial
hemorrhage
MEN multiple endocrine neoplasia
a b
Fig. 24.1 Pigmentation of lips (a) and eyelid (b) in a patient with Peutz–Jeghers syndrome
The pigmentation appears usually around the pathognomonic, particularly if it occurs across
lips, eyes, hands, or feet, forming smooth mela- the vermilion border of the lips. Oral mucosa and
nin deposits in a round or oval shape, and fades fingertips are also commonly affected. About
with advancing age [6]. Perioral pigmentation is 50% of patients develop a wide variety of cancers
24 Conjunctival and Corneal Tumors: Systemic Associations 297
Table 24.2 Peutz–Jeghers syndrome diagnostic criteria plex and usually are dermoid or lipodermoid in
Positive Any number of histologically confirmed nature. The HRAS and KRAS mutations lead to
family PJS polyps, or characteristic, prominent, activation of MAPK and PI3K-Akt signaling and
history of mucocutaneous pigmentation
PJS
cellular proliferation, which are associated with
Negative ≥3 histologically confirmed PJS polyps, many cancers, providing an explanation for the
family or any number of histologically high incidence of secondary tumors in approxi-
history of confirmed PJS polyps and characteristic mately 25% of cases [13]. Trichoblastomas and
PJS pigmentation
syringocystadenoma papilliferum are the most
PJS Peutz–Jeghers Syndrome common benign tumors, while malignant tumors
occur in <1% [13].
such as breast, colorectal, and pancreatic cancers
in adulthood [9]. An overexpression of COX-2
has been reported in polyps and cancers related to Goldenhar Syndrome
PJS [10]. and the Oculoauriculovertebral
Diagnostic criteria were suggested by Van Spectrum
Lier et al. (Table 24.2) [11]. An annual physical
examination with a complete blood count to Goldenhar described a triad of epibulbar der-
detect iron-deficiency anemia because of occult moids, preauricular appendages, and pretragal
bleeding from GI tract polyps or cancer is impor- fistula [17]. The etiology of Goldenhar syndrome
tant, and a baseline endoscopic screening of the (GS) has yet to be elucidated, but it has been sug-
gastrointestinal tract is usually initiated around gested that a vascular insult and/or neural crest
the age of 8 years [10]. abnormality during embryogenesis could account
for this syndrome [18]. Since then, the spectrum
of manifestations has expanded to include verte-
Sebaceous Nevus Syndrome bral anomalies and is also called oculoauriculo-
vertebral dysplasia (OAV) [19].
Sebaceous nevus syndrome (of Jadassohn), also Currently, GS is included in the oculoauricu-
known as Schimmelpenning–Feuerstein–Mims lovertebral spectrum (OAVS) that encompasses
syndrome, is a distinct clinical disorder within different overlapping diagnoses such as hemifa-
the spectrum of epidermal nevus syndrome (of cial microsomia, first and second branchial
Solomon) characterized by cutaneous seba- arches syndrome, otomandibular dysostosis,
ceous nevus and extracutaneous manifestations facioauriculovertebral syndrome, and Goldenhar
[12]. Up to 95% of patients have heterozygous syndrome, all representing a phenotypic contin-
mutations in HRAS, with the mutation uum of the same entity [20].
c.37G > C (p.Gly13Arg) accounting for the The majority of cases occur sporadically, but
majority of cases; most other cases result from exceptional cases with autosomal dominant and
mutations in KRAS (c.35G > A or c.35G > T) recessive inheritance patterns have also been
[13]. The HRAS and KRAS mutations are found reported [21]. Rooryck et al. identified 12% of
in lesional keratinocytes only, confirming a familial cases in a cohort of 95 patients [22]. A
mosaic RASopathy [13]. more recent study described that up to 45% of
The classic triad is one of facial lesions, sei- relatives of probands with OAVS do have minor
zures, and mental retardation [14]. Ocular OAVS manifestations [23]. Environmental causes
involvement is observed in about 40% of cases have also been suggested, particularly twinning,
with epibulbar choristomas and coloboma of the assisted reproductive techniques, and maternal
eyelid being most common. Posterior segment pre-pregnancy diabetes [24, 25]. Hence the phe-
tumors have included chondroid choristomas notype is probably affected by other genetic and
(intrascleral cartilage) with ossification [14–16]. non-genetic factors, in line with an oligogenic or
The limbal choristomas can be simple or com- even a multifactorial etiology [20].
a b
Fig. 24.2 Epibulbar dermoids in Goldenhar syndrome. Limbal (a) and extralimbal (b)
Epibulbar dermoid is a necessary diagnostic association of GS with the VATER anomaly (ver-
feature of Goldenhar syndrome (Fig. 24.2). The tebral defects, anal atresia, tracheoesophageal
epibulbar dermoids are almost always located fistula with esophageal atresia, and radial dyspla-
near the limbus in the inferotemporal quad- sia) and CHARGE syndrome (coloboma, heart
rants. Secondary irregular astigmatism and anomaly, choanal atresia, retardation, genital and
anisometropic amblyopia may also be present, ear anomalies) [33].
but no association with central corneal lesions Due to the variable phenotypic expressivity
was found [26]. Dermolipomas are typically in and the overlap with other conditions, it has been
the subconjunctival plane and appear as a yel- difficult to reach a general consensus regarding
low soft mass in the superotemporal quadrant. the minimum diagnostic criteria for OAVS, but it
In an observational case series of 55 patients has been proposed that they should include
with eyelid coloboma, 13 (45%) were due to microtia or hemifacial microsomia, together with
GS [27]. Other associated anomalies include milder malformations and an associated family
Duane syndrome [28] and caruncular anoma- history of OAV [20].
lies [29]. Involvement of the globe itself mani- All OAVS patients should be referred for audi-
festing as microphthalmia [30], bilateral ology screening, ophthalmic examination, and
cataracts [31], or exudative vitelliform macu- x-rays of the spine, ideally anteroposterior and
lopathy [32] is rare. lateral views of the whole spine.
A recent study of 51 patients with OAVS
showed that the most common systemic manifes-
tations were ear abnormalities in 92% of patients, Proteus Syndrome
hearing loss in 85%, and hemifacial microsomia
in 90% of patients [20]. Ocular anomalies were Proteus syndrome is a severe and highly variable
present in 29% of patients, while vertebral anom- disorder characterized by asymmetric and dispro-
alies were confirmed in 20% of cases [20]. portionate overgrowth of body parts and hamar-
In addition to ophthalmic, ear, and vertebral tomas, along with a susceptibility to tumors [34].
anomalies, about 50% of cases have other mal- Proteus syndrome was first recognized as a spe-
formations such as micrognathia, macrostomia, cific entity in 1979 and named after the Greek
cleft lip and palate, developmental defects of the god Proteus, as he could change his shape or
heart and brain, and urogenital or limb abnormal- form, emphasizing the varied manifestations of
ities [20, 23]. There is a statistically significant the syndrome [35].
Proteus syndrome is inherited in a sporadic Table 24.3 Ocular manifestations of Proteus syndrome
fashion as it is due to mutations that are lethal Strabismus
unless they occur in a mosaic fashion [36]. It Nystagmus
does not seem to recur in families but does appear High myopia
Retinal pigmentary abnormalities
in disconcordant monozygotic twins, suggesting
Retinal detachment
a somatic mutation that is lethal when constitu- Cataract
tive [34]. More recent studies have supported a Posterior segment hamartomas
role for the AKT1 c.49G → A variant in the Epibulbar tumor
pathogenesis of Proteus syndrome [34]. Eyelid hamartomas
The systemic manifestations of Proteus syn- Eyelid ptosis
drome are usually present at birth, progress dur- Retinal coloboma
Glaucoma
ing childhood, and are almost always asymmetric
Pale optic disk
[37]. The disorder primarily manifests as postna- Anisocoria
tal overgrowth, with irregular, distorting, and Heterochromia iridis
quickly progressive overgrowth that can include
many tissues, although the bone, connective tis-
Table 24.4 Revised diagnostic criteria for Proteus
sue, and fat are the most commonly involved tis- syndrome
sues, but the central nervous system, spleen, Must have all the general criteria and various specific
thymus, colon, and other tissues could be inter- criteria
ested too [37]. Connective tissue nevi are pathog- General All of the
nomonic; other features include lipoma (92%), criteria following:
Mosaic
vascular malformations (88%), and epidermal
distribution
nevi (67%) [38]. of lesions
Ophthalmic involvement is common in Sporadic
Proteus syndrome. Epibulbar and eyelid der- occurrence
Progressive
moids, strabismus, nystagmus, high myopia,
course
orbital exostoses, and posterior segment hamar- Specific Category A Cerebriform connective
toma are most commonly observed [39]. criteria tissue nevus
Strabismus and nystagmus may be a consequence Two from Linear epidermal nevus
of low vision or severe congenital malfunction of category B Asymmetric,
disproportionate
the neuroretinal network. Retinal abnormalities
overgrowth
typically accompany high myopia and retinal Specific tumors before
detachment may occur when there is lattice second decade (bilateral
degeneration. Cataracts can be the consequence ovarian cystadenoma or
parotid monomorphic
of retinal detachment [39]. A complete list of
adenoma)
published ophthalmic findings is given in Three from Dysregulated adipose
Table 24.3 [39]. category C tissue
Due to its varied manifestations, the diagnosis Vascular malformations
of Proteus syndrome is frequently missed. A criti- Lung cysts
Facial phenotype
cal review of published cases revealed that only
47% of cases met the diagnostic criteria [40]; for
this reason, a more recent list of diagnostic crite- syndrome, Maffucci’s syndrome, Ollier’s disease,
ria has been proposed (Table 24.4) [39]. and Bannayan–Riley–Ruvalcaba syndrome.
Individuals with significant clinical features but The management is challenging, due to the
who do not meet the diagnostic criteria are labeled postnatal overgrowth. Furthermore, patients with
as having Proteus-like syndrome. The differential PS have an increased risk of premature death,
diagnosis of Proteus syndrome includes neurofi- commonly caused by deep venous thrombosis
bromatosis type 1, Klippel–Trenaunay–Weber and pulmonary embolism [41].
ultiple Endocrine Neoplasia

M ciation with mucosal neuromas and corneal
Type 2B abnormalities [42].
MEN 2B is inherited as an autosomal domi-
Multiple endocrine neoplasia (MEN) is a condi- nant trait, but about half the cases are due to de
tion characterized by a genetic predisposition to novo mutations, with more than 95% of
develop benign and malignant tumors of various cases resulting from a point mutation in the
endocrine glands. Based upon the pattern of glan- RET gene [43].
dular involvement, MEN is classified as type 1 A comprehensive review of all published
and type 2. MEN type 2 is comprised of three cases of MEN 2B reveals that common ophthal-
subtypes: familial medullary thyroid carcinoma, mic manifestations include prominent corneal
MEN 2A, and MEN 2B. MEN 2B, also called nerves (100%), eyelid neuroma or thickening
mucosal neuroma syndrome or Wagenmann– (88%), subconjunctival neuroma (79%), and dry
Froboese syndrome, is the only MEN subgroup eyes (48%) (Fig. 24.3) [44, 45]. The presence of
that is of ophthalmic interest because of its asso- prominent corneal nerves in an otherwise normal
a b
c d
Fig. 24.3 Characteristic features of MEN 2B syndrome. thickened abnormal nerves in the substantia propria (d).
Submucosal lip and tongue neuroma (a, arrow). Prominent ((a) Reprinted from Jacobs and Hawes [44]. With permis-
corneal nerves (b). Plexiform subconjunctival neuroma sion from Wolters Kluwer Health, Inc. (c) Reprinted from
(c). Histopathologic section of the conjunctiva shows Eter et al. [45]. With permission from Springer Nature)
cornea should lead to investigations to exclude States, Japan, and Western Europe is 1 in 250,000,
MEN 2B [46]. Other infrequent causes of promi- 1 in 22,000, and 1 in 500,000, respectively [51].
nent corneal nerves such as neurofibromatosis, XP is inherited as an autosomal recessive trait
leprosy, and congenital ichthyosis should also be with full penetrance. There are eight known XP
considered in the differential diagnosis [46]. complementation groups (XP-A to XP-G and
However, none of these conditions are associated XP-V), which correspond to the eight genes that
with perilimbal neuromas or alacrima [47]. are implicated in this condition [51]. The proteins
Histopathologic studies of the cornea have shown encoded by the XPA to XPG genes are involved in
that prominent corneal nerves are axonal bundles nucleotide excision repair of DNA damaged by
of nonmyelinated nerves in association with UV light. The eighth gene (POLH) codes for a
Schwann cells [48]. special polymerase used to replicate damaged
A clinical diagnosis of MEN 2B is suspected DNA [52]. XP-C, E, and V patients have normal
in the presence of a marfanoid body habitus, sunburn reactions for skin type and do not
mucosal neuromas of the lips and tongue, promi- develop manifest neurodegeneration; however,
nent corneal nerves, and medullary thyroid carci- they have an earlier age of onset of first skin can-
noma [42]. As medullary thyroid carcinoma tends cer [51]. XP-A, B, D, F, and G have severe and
to be aggressive, early prophylactic thyroidec- exaggerated sunburn reactions on minimal sun
tomy is recommended [49]. Patients may also exposure and suffer neurodegeneration [51].
have chronic constipation and colonic cramping Ophthalmic complications are present in
due to megacolon disorder [49]. About half of about 20–90% of cases, probably due to high
patients with MEN 2B also develop pheochromo- exposure of the eye to UVR, as well as the role
cytoma, while involvement of the parathyroid the eye has within the neurological system, which
gland is rare. It remains elusive whether vascular underscores the importance of regular ophthal-
anomalies are related to MEN type 2B [47]. mic examinations of XP patients [51, 52]. Eyelid
skin atrophy with pigmentary changes and loss of
lashes is common. Similar changes of the con-
Xeroderma Pigmentosum junctiva such as xerosis and pigmentation also
occur (Fig. 24.4). Corneal complications include
Xeroderma pigmentosum (XP) refers to a group keratitis, pterygium, vascularization, and corneal
of genetic disorders characterized by extreme ulceration. Most significant is the predisposition
sensitivity to sunlight and a constellation of cuta- to develop multiple eyelid and ocular surface
neous, ophthalmic, and neurological findings neoplasms including basal cell carcinoma, squa-
[50]. The estimated incidence of XP in the United mous cell carcinoma, and melanoma [52].
a b
Fig. 24.4 Xeroderma pigmentosum with bilateral corneal and conjunctival squamous neoplasia (a. right eye; b. left
eye)
Table 24.5 Ocular signs and symptoms in xeroderma The cutaneous findings are the defining fea-
pigmentosum
tures of this entity [48]. A tendency to sunburn is
Ectropion or lagophthalmos evident in early childhood and may be the earliest
Periocular cancers
sign of XP. This is followed by freckling in sun-
Photophobia
Conjunctival injection
exposed areas. These changes eventually progress
Conjunctival corkscrew vessels to parchment-like dry pigmented skin and hence
Interpalpebral melanosis regardless of skin the name xeroderma pigmentosum [50]. There is
pigmentation a 1000-fold increased risk of developing cutane-
Pterygium ous cancers such as squamous cell carcinoma,
Pinguecula basal cell carcinoma, and melanoma [50]. Tumors
Corneal scar or neovascularization
tend to be multifocal and occur at a median age of
Superficial punctate keratopathy
Ocular surface cancer less than 10 years. If protected from sunlight at an
Sluggish pupils early life, the debilitating cutaneous changes can
Strabismus be almost completely avoided.
Abnormal extraocular movement Neurological abnormalities, present in about
Lens abnormality 20% of cases, include the absence of deep tendon
Retinal abnormality reflexes due to axonal loss and demyelination,
progressive hearing loss, and ataxia [50].
Patients in groups XP-C, E, and V had signifi-
cantly more ocular surface abnormalities, but a
lower association with pupillary abnormality Amyloidosis
[49]. One case of iris melanoma has been reported
[53]. The posterior segment is rarely affected, but Amyloidosis refers to the extracellular deposition
there have been reported cases of optic atrophy, of insoluble proteinaceous material called amy-
retinal degeneration, and mild macular edema, all loid. Amyloid deposits exhibit characteristic
secondary to neurodegeneration [54]. A complete staining reaction to iodine and Congo red stain
list of ocular signs and symptoms in XP is given (birefringence) [55]. From a clinical standpoint,
in Table 24.5. amyloidosis can be classified into systemic
Lim et al. reported that in their study, 6% of forms, in which there is a multisystem involve-
patients initially presented to ophthalmologists ment due to underlying neoplastic, inflammatory,
with ocular surface signs related to XP, and genetic, iatrogenic, or idiopathic causes, or local-
before any formal diagnosis of XP had been ized forms where amyloid deposits in isolated
made, underpinning the role of ophthalmologists organs without evidence of systemic involve-
in the diagnosis of this group of disorders [51]. ment; the latter forms are associated with aging
Examinations facilitate the detection and treat- and diabetes [56]. Another classification system
ment of any eye pathology as well as eyelid and is based on the nature of the fibril-forming pro-
ocular surface tumors. Some of the most impor- teins such as immunoglobulin light chains (AL),
tant areas of management include the treatment serum amyloid A (the most common form of sys-
of dry eyes, watery eyes, lagophthalmos, ectro- temic amyloidosis), and transthyretin [56].
pion, pterygia, ocular surface cancers, eyelid can- Inherited forms of amyloidosis (familial amy-
cers, strabismus, and double vision. In addition, loidosis) result from inherited protein mutations.
ophthalmologists play a fundamental role in The most common protein involved is trans-
advising and facilitating adequate ophthalmic thyretin (TTR), also called prealbumin, that
UVR protection. The gold standard for this is a functions as transport protein for both thyroxine
full-face visor, which is 100% protective of ultra- and vitamin A [57]. Over 100 TTR point muta-
violet A and ultraviolet B waves [51]. tions have been reported in the literature with
differing phenotypes [58]. TTR is synthesized observed in the retina over the arterioles and
mainly in the liver but also in the choroid plex- venules, which are otherwise clinically and angi-
uses of the brain and in retinal pigment epithelial ographically normal, probably due to direct infil-
cells; in fact, almost 25% of patients with TTR tration with amyloid, which has been described
mutations have ophthalmic involvement [59]. for oculoleptomeningeal amyloidosis [67]. Ando
Much less commonly, abnormalities of several et al. found abnormal conjunctival vessels to be
other proteins, including fibrinogen, ApoA1, the most common ocular manifestation of TTR
ApoA2, lysozyme, gelsolin, and beta-2 micro- amyloidosis (75.5%), followed by pupillary
globulin, have been known to cause a category abnormalities (43.2%), keratoconjunctivitis sicca
classified as non-TTR amyloidosis [60]. (KCS) (40.5%), glaucoma (19.2%), and vitreous
Ophthalmic amyloidosis can affect the eye- opacification (5.4%) [68].
lids, conjunctiva, orbital tissues, cornea (lat- Systemic amyloidosis can lead to ocular mor-
tice corneal dystrophy), and vitreous. bidity, such as involvement of the temporal artery,
Unilateral or bilateral eyelid involvement is cornea, extraocular muscles, trabecular meshwork,
frequent in systemic amyloidosis, in which and cranial nerves in AL amyloidosis or corneal
clinical manifestations include recurrent pur- dystrophy in gelsolin familial amyloidosis [60].
pura or periorbital bleeding because of a ten- The most common form of systemic amyloi-
dency for perivascular deposition of amyloid dosis is AL amyloidosis, which may be idiopathic
[61] and waxy nodules [62]. in origin or associated with multiple myeloma.
Conjunctival amyloidosis appears as a pale Amyloid A amyloidosis occurs most frequently
yellow nodule associated with recurrent subcon- as a complication of chronic inflammatory dis-
junctival hemorrhage. In general, conjunctival amy- ease, and its disease course is dominated by renal
loidosis tends to be localized but association with dysfunction [69].
systemic amyloidosis has also been reported. Familial amyloidosis most frequently results
Orbital amyloidosis may involve the lacrimal gland, from mutations that lead to misfolding of the pro-
extraocular muscles, orbital fat, and lacrimal sac, tein transthyretin. Manifestations vary depending
mimicking inflammatory or lymphoproliferative on the individual TTR mutation [59]. Because of
disorders [63]. Deposition within the levator muscle the hepatic production of TTR, mutations lead to
may lead to a presentation of ptosis of unknown eti- systemic manifestations of familial amyloidosis
ology. Glaucoma can be the result of amyloid depo- that include peripheral neuropathy, autonomic
sition in the trabecular meshworks [64]. neuropathy, and cardiomyopathy [59]. Vascular
With rare exceptions, amyloid deposits in the changes occur and can result in cardiac or pulmo-
vitreous are indicative of the familial neuropathic nary involvement; many patients with TTR amy-
form of amyloidosis due to mutations in the loidosis have sleep-disordered breathing as well
transthyretin gene; this is a slowly progressive as cardiopulmonary amyloidosis [70].
peripheral polyneuropathy with sparing of the Patients with systemic amyloidosis may
central nervous system [57]. The vitreous depos- present to the ophthalmologist for ocular symp-
its are grayish, cobweb-like, and may be attached toms before other systemic symptoms are appar-
to the posterior surface of the lens as white dots ent. Almost 7% of patients with systemic
resembling foot plates (pseudopodia lentis) [65]. amyloidosis presented with ophthalmic signs
The natural history of vitreous amyloidosis tends and symptoms such as conjunctival masses, per-
to involve floaters that progress, leading to visual sistent subconjunctival hemorrhages, or diplo-
impairment, which can be so significant that it pia related to infiltration of the extraocular
leads to only light perception vision. Vision muscles [60]. In addition, the vast majority of
impairment can be reversed with vitrectomy, and adnexal amyloidosis is AL type, necessitating
some patients can have a complete restoration of systemic workup to exclude underlying lym-
vision [59, 66]. Similar white opacities may be phoproliferative disorder [71].
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Index
A Adulthood papilloma, 144

Acanthotic conjunctival epithelium, 171 conjunctival and corneal tumors, 144
Acquired immunodeficiency syndrome (AIDS), 91, Adult-onset xanthogranuloma, 86
160–161, 212 Albinism, 33, 45
OSSN, , , ExenterationAcquired nevi, 12, 23, 26, 160, Aloe vera, 249
161 conjunctival malignancies, OSSN, 249, 250
Acquired sessile hemangioma, 210, 211 Alpha-interferon, 39, 236, 246
Actinic keratosis, 20–22, 149, 150 squamous papilloma, 236
Adenoid squamous cell carcinoma, 172 Amblyopia, 89, 114, 226, 227, 298
OSSN, 172 Amyloidosis, 230
Adjuvant high-dose radiation therapy, 273 conjunctival and corneal tumors, 302, 303
Adnexal tumors, 10–12, 71 Angiosarcoma, 11, 87, 90–91
classification, 72 Anophthalmic socket, 175, 209
clinical findings, 72 squamous cell carcinoma in, 173
cystic lesions Anterior lamella defect lower eyelid, 110
epidermal inclusion cysts/epidermoid cysts, 72 Anterior lamellar deficit
retention cysts, 72, 73 ellipse sliding flap, 105, 106
trichilemmal cysts, 73 elliptical sliding flap, 100
etiopathogenesis, 71 myocutaneous advancement flap, 100
hair follicle tumors primary closure, 98, 99, 105
carcinoma of hair follicles, 78, 79 skin graft, 99, 100, 105
pilomatrix carcinomas, 79 Anterior segment OCT, 132, 133, 151, 153, 168
pilomatrixoma, 78 Antimony sulfide colloid, 262
trichilemmoma, 77, 78 Apocrine gland adenocarcinoma, 10, 72, 76
trichoadenoma, 77 Apocrine hidrocystoma, 73, 74
trichoepithelioma, 76, 77 Arteriovenous malformations, 11, 87, 90, 91, 115
trichofolliculoma, 77 Atypia, 185
sebaceous gland tumors diffuse PAM with, 187
nevus sebaceous of Jadassohn, 80 PAM without, 187
sebaceous epithelioma/sebaceoma, 80 Atypical (Clark’s)/dysplastic nevus, 28
sebaceous gland adenomas, 80 Atypical melanocytes, 65, 190, 191, 193, 200, 201
sebaceous gland carcinoma, 80 Atypical melanocytic hyperplasia, 185
sebaceous gland hyperplasia, 79
sweat gland tumors
apocrine gland adenocarcinoma, 76 B
apocrine hidrocystoma, 73, 74 Basal cell carcinoma (BCC), 33, 45, 65, 118
eccrine hidrocystoma, 74 caruncle tumors, 238
eccrine spiradenomas, 74 clinical features, 34
mucinous sweat gland adenocarcinoma, 76 diagnostic evaluation
pleomorphic adenomas, 76 excisional/incisional biopsy, histopathologic
sweat gland adenocarcinomas, 76 examination of, 37
syringocystadenoma papilliferum, 76 exfoliative cytology, 37
syringomas, 74 imaging, 37
treatment, follow-up and prognosis, 72 noninvasive methods, 37

J. Pe’er et al. (eds.), Clinical Ophthalmic Oncology, https://doi.org/10.1007/978-3-030-06046-6
308 Index
Basal cell carcinoma (BCC) (cont.) Carcinoma in situ (CIS), 20, 22, 46, 48, 159,
differential diagnosis, 37, 38 171, 172, 179, 180
epidemiological aspects, 33 OSSN, 171
etiology, 33 Carcinoma of hair follicles, 10, 72, 78–79
follow-up, 39 Carcinoma of Moll glands, 77
histopathologic features, 35–37, 40 Carney complex (CNC), 120–122
metastases and mortality, 41 conjunctival and corneal tumors, 295, 296
pathogenesis, 33 Cartilage tumors, 11
prognosis Caruncle melanoma, 240
local spread, 41 Caruncle nevus, 239
prognostic factors, 39, 41 Caruncle PAM, 240
recurrence, 41 Caruncle tumors, 235, 236
radiation therapy, 288, 289 conjunctival and corneal tumors, 138, 157
SGC, 59 epithelial lesions
staging, 41, 42 basal cell carcinoma, 238
symptoms and signs, 34 oncocytomas, 237, 238
cystic, 34, 35 sebaceous carcinoma, 237, 238
infiltrating, 35 sebaceous hyperplasia, 236, 237
nodular, 34 squamous papilloma, 236
pigmented, 34 inflammatory lesions, 240, 241
treatment, 38 lymphoproliferative tumors, 241
cryotherapy, 38 pathologic diagnoses, 236
curettage and electrodesiccation, 38 pigmented lesions
interferon, 39 melanoma, 238
PDT, 39 nevus, 238
radiation therapy, 39 vascular tumors, capillary hemangioma, 242
surgical excision, 38 Caruncular tumors, 140
vismodegib, 39 Cavernous hemangioma, 90, 211, 212
Basex–Dupré syndrome, 33 Cellular anaplasia, 47
B-cell lymphoma, 92 Chalazion, SGC, 58
Benign melanocytic tumors, conjunctival Chemotherapy, 38, 67
and corneal, 150 BCC
complexion-associated conjunctival interferon, 39
pigmentation, 156 PDT, 39
congenital melanosis oculi, 156 vismodegib, 39
conjunctival nevus, 150–155 melanoma, 203
PAM, 156 OSSN, 176, 179
Bevacizumab, 250 SCC, 48
Biopsy, conjunctival and corneal Childhood papilloma, conjunctival and |
tumors, 133 corneal tumors, 143, 144
Blue nevus, 24 Choristomas, 12, 93, 94
conjunctival nevus, 153, 154 conjunctival stromal tumors, 226
Bone tumors, 9, 11 complex choristoma, 228, 229
Brachytherapy, 291, 292 dermoid, 226, 227
melanoma, 203 dermolipoma, 227, 228
OSSN, 176 lacrimal gland choristoma, 228
BRAF mutations, 23, 201 osseous choristoma, 228
Bulbar conjunctiva, 137, 143, 146, 154 Cidofovir, 250
conjunctival malignancies, OSSN, 250
Cigarette smoking, PAM, 187
C CIN local excision, 175
Capillary hemangioma, 88, 90, 211, 242 Clarithromycin, 253
clinical features, 88 conjunctival malignancies, lymphoma, 253
histopathologic features, 88, 89 Clark’s nevus, 28
natural history, 88 Comedocarcinoma pattern, SGC, 57
systemic association, 89 Comedonal cyst, 72
treatment, 89 Comparative genomic hybridization (CGH), 28
Capillary malformation (CM), 115 Complex choristoma, 80, 93, 210, 226, 228–229
Carbon dioxide laser, 38, 48, 145, 216 Complex conjunctival excision, conjunctiva and
SCC, 48 cornea tumors, 281, 282
Index 309
Complexion-associated conjunctival keratoacanthoma, 145, 146

pigmentation, 156, 186 keratotic plaque, 149
Compound nevus, 10, 16, 23, 139, 151, 152 oncocytoma, 147
conjunctival nevus, 152 reactive epithelial hyperplasia, 145
Confocal microscopy, 132–134, 165, 188, 198 seborrheic keratosis, 145
Congenital hypertrophy of the retinal pigment squamous cell papilloma, 143–145
epithelium (CHRPE)-like lesions external examination, 131
of the fundus, 295 Goldenhar syndrome and oculoauriculovertebral
Congenital melanosis oculi, 156 spectrum, 297, 298
Congenital nevus, 23 histopathologic diagnosis, 133
blue nevus, 24 melanoma (see Melanoma)
NCM, 23 MEN, 300, 301
nevus of Ota, 24 ocular surface reconstruction, 281, 283
split nevus, 23 OSSN (see Ocular surface squamous
Congenital ocular melanocytosis, 156, 157 neoplasia (OSSN))
Congenital tumors, 140 PAM (see Primary acquired melanosis (PAM))
Conjunctiva, 137 PJS, 295–297
epidermal tumors, 139 postsurgical management, 284
stromal tumors, 140 presurgical evaluation, 279
Conjunctival amyloidosis, 303 Proteus syndrome, 298, 299
Conjunctival and corneal tumors, 131 sebaceous nevus syndrome, 297
amyloidosis, 302, 303 simple conjunctival excision, 280, 281
anatomical features simple incisional biopsy, 280
caruncle, 138 slit-lamp examination and photography, 131, 132
epithelium, 137 specimen preparation, 284
plica semilunaris, 138 surgical principles, 280
stroma, 137 surgical techniques, 280
ancillary studies, 132 melanocytic tumors, 283
anterior segment OCT, 132 squamous tumors, 283
biopsy, 133, 134 substantia propria tumors, 284
confocal microscopy, 133 xeroderma pigmentosum, 301, 302
systemic imaging, 133 Conjunctival and eyelid tumors, see Radiation therapy
ultrasound biomicroscopy, 132 Conjunctival epithelial cyst, 149
anesthesia, 279 Conjunctival epithelial neoplasia, surgical
benign melanocytic tumors, 150 techniques, 283
complexion-associated conjunctival Conjunctival intraepithelial neoplasias (CIN), 132,
pigmentation, 156 167, 170, 179
congenital melanosis oculi, 156 Conjunctival invasive squamous carcinoma,
conjunctival nevus, 150–155 radiation therapy, 290, 291
PAM, 156 Conjunctival lymphangioma, conjunctival
Carney complex, 295, 296 stromal tumors, 214, 216
caruncle, 157 Conjunctival lymphoma, 225, 251
classification, 138, 139 radiation therapy, 291
complex conjunctival excision, 281, 282 Conjunctival malignancies
complications, 284, 285 lymphoma, 250
corneal excision, 281 clarithromycin, 253
cryotherapy, 281 doxycycline, 253
differential diagnosis, 138, 139 ibritumomab tiuxetan, 252
epidermal, 139 interferon alpha-2b, 251, 252
melanocytic lesions, 139 radiation therapy, 251
metastatic and secondary tumors, 140 rituximab, 252
non-melanocytic lesions, 139, 140 OSSN, 245
simulating lesions, 140 aloe vera, 249, 250
stromal tumors, 140 cidofovir, 250
epithelium, benign tumors of, 143 5-FU, 247
actinic keratosis, 149, 150 interferon alpha-2b, 246
dacryoadenoma, 147 mitomycin C, 248, 249
epithelial cysts, 147, 148 retinoic acid, 249
HBID, 146, 147 treatment, 245
inverted papilloma, 145 VEGF, 250
310 Index
Conjunctival malignancies (cont.) acquired sessile hemangioma, 211

pigmented conjunctival lesions, 253 capillary hemangioma, 211
interferonalpha-2b, 254, 255 cavernous hemangioma, 211
mitomycin C, 254 hemangiopericytoma, 212
programmed cell death 1 inhibitors, 255, 256 Kaposi’s sarcoma, 212, 214
treatment, 254 pyogenic granuloma, 209
Conjunctival malignant melanoma varix and racemose hemangioma, 211, 212
(CMM), 253, 254, 283 Conjunctival tumors, 296
Conjunctival melanocytic intraepithelial neoplasia radiation therapy
(C-MIN), 186 conjunctival invasive squamous
Conjunctival melanoma, 201, 264 carcinoma, 290, 291
radiation therapy, 290, 291 conjunctival lymphoma, 291
Conjunctival melanosis, types of, 186 conjunctival melanoma, 290
Conjunctival myxoma, 221 types of, 138
Conjunctival nevus, 150 Conjunctival varix, 211, 212
clinical features, 150–152 Cornea, primary melanoma of, 200
clinicopathologic variants Corneal CIN, 174
blue nevus, 153, 154 Corneal epitheliectomy, 283
IJCN, 154, 155 Corneal excision, conjunctiva and
spitz nevus, 153 cornea tumors, 281
histopathologic features, 152 Corneal PAM, 189
compound nevus, 152 Corticosteroid, 284
junctional nevi, 152 Cowden syndrome, 118–120
subepithelial nevi, 152 Cryosurgery, 38
melanocytic tumors, 283 Cryotherapy, 38, 67, 144
melanoma, 200 conjunctiva and cornea tumors, 281
treatment, 155 melanoma, 203
Conjunctival PAM, 188, 190, 198 OSSN, 175, 176
Conjunctival racemose hemangioma, 212 PAM, 192
Conjunctival reconstruction, 180 SCC, 48
Conjunctival SCC, 181 SGC, 59
Conjunctival squamus neoplasia, 301 squamous cell papilloma, 283
Conjunctival stromal tumors Curettage, 38
amyloidosis, 230 Cutaneous horn, 20
choristomas, 226 Cutaneous horn/nonspecific keratosis, 19, 20
complex choristoma, 228, 229 Cutaneous melanoma, 63
dermoid, 226, 227 clinical features, 64, 65
dermolipoma, 227, 228 diagnosis and differential diagnosis, 65
lacrimal gland choristoma, 228 epidemiology, 63
osseous choristoma, 228 etiology and pathogenesis, 63, 64
conjunctival lymphangioma, 214, 216 histopathologic features, 65, 66
fibrous tumors prognosis
fibroma, 216, 217 mortality, 68
fibrous histiocytoma, 217, 218 prognostic factors, 67
nodular fasciitis, 218, 219 recurrence, 68
IgG4 related disease, 230 treatment
leukemic infiltration, 225, 226 chemotherapy and immunotherapy, 67
lipomatous tumors, 222 excision, 66
lymphangiectasia, 214 palliative therapy, 67
lymphoproliferative tumors, 223–225 sentinel lymph node biopsy, 67
metastatic tumors, 229 Cutaneous myxomas, 121
myogenic tumors, 222 Cutler–Beard procedure, 106
myxoid tumors, 221, 222 Cystic BCC, 34, 35
neural tumors Cystic tumors, 10–12
granular cell tumor, 219 Cytokeratin 20 (CK20), 92
histiocytic tumors, 220, 221
neurilemmoma, 219
neurofibroma, 219 D
secondary tumors, 229 Dacryoadenoma, 147
vascular tumors, 209 Dermis, 4, 7, 15, 17, 21–28, 47, 51, 66, 85, 108
Index 311
Dermoid, 12, 93, 210, 226, 227, 284, 296–299 keratoacanthoma, 145, 146
Dermolipoma, 227, 228 keratotic plaque, 149
Desmarres retractor, 132 oncocytoma, 147
Diffuse choroidal hemangioma, 116 reactive epithelial hyperplasia, 145
Diffuse CIN, 178 seborrheic keratosis, 145
Diffuse conjunctival and corneal CIN, 179 squamous cell papilloma, 143–145
Diffuse conjunctival PAM, 189 Erdheim–Chester disease, 85
Diffuse corneal involvement, 170 Excision, 66, 67
Diffuse PAM, 187, 283 Exenteration, 48–50, 60, 84, 161, 203, 290, 291
Divided nevus, 23 Exfoliative cytology, 37, 42, 134, 167
DNA repair disorders, OSSN, 161 OSSN, 167
Doxycycline, conjunctival malignancies, 253 Extensive conjunctival melanoma, 199, 203
Drainage, 4, 8, 9, 214–216, 261–263, 265, 268, 271, 272 External beam radiation, 67, 225, 284, 287, 290, 291
Ductal cyst, 147, 148 External beam radiation therapy (EBRT), 287, 288, 290
Dysplasia, OSSN, 171 Extranodal marginal zone B-cell
Dysplastic nevus, 28 lymphoma (EMZL), 224
Dysplastic nevus syndrome, 28, 186 Extranodal marginal zone lymphoma (EMZL), 250
Eyelid and conjunctival tumors, SLN biopsy
histopathologic processing, 265, 266
E intraoperative SLN detection, 264, 265
Eccrine hidrocystoma, 11, 72–75 melanoma, 266–268
Eccrine spiradenomas, 10, 72, 74 Merkel cell carcinoma, 270, 271
Ectopic lacrimal gland, 12, 93, 228, 229, 236 preoperative lymphoscintigraphy, 262, 263
Electrodessication, 38 sebaceous carcinoma, 269, 270
Elliptical sliding flap, 100 squamous cell carcinoma, 269
upper eyelid defects, 105 Eyelid compound nevus, 26
Epibulbar choristomas, 226, 297 Eyelid fibromatosis, 84
Epibulbar complex choristoma, 228, 229 Eyelid keloids, 83
Epibulbar dermoids, 226, 227, 296–298 Eyelid margin, 8, 9, 12, 26, 27, 54, 65,
in Goldenhar syndrome, 298 73, 80, 100, 104, 106, 131, 204
Epidermal inclusion cysts, 72 Eyelid margin blue nevus, 25
Epidermal melanocytic tumors, 12 Eyelid neoplasia, 1–2, 5
Epidermal non-melanocytic tumors, 12 symptoms of, 1
Epidermal tumors, 139 Eyelid nevus, 22, 27
classification of, 16 Eyelid reconstruction, 98, 100, 109
Epidermis, 15, 19, 23, 24, 27, 33, 45–47, 51, Eyelid sebaceous carcinoma, 59, 269, 270
56, 66, 77, 80, 88, 137, 187 Eyelid skin, 7, 8, 12, 63, 66, 73, 199, 267, 301
Epidermoid cysts, 72, 73, 114, 116, 118 Eyelid stromal tumors, see Stromal tumors
Epiphora, 4, 93, 202, 224 Eyelid trichilemmomas, 119
Epistaxis, 202 Eyelid tumors
Epithelial cysts, conjunctival and corneal anatomical features, 7
tumors, 147, 148 eyelid margin, 8
Epithelial inclusion cysts, 147, 148 eyelid skin, 7, 8
Epithelial lesions nerve supply, 8
basal cell carcinoma, 238 orbicularis oculi, 8
oncocytomas, 237, 238 palpebral conjunctiva, 8
sebaceous carcinoma, 237, 238 tarsus, 8
sebaceous hyperplasia, 236, 237 vascular system, 8
squamous papilloma, 236 classification of, 8–10
Epithelial membrane antigen (EMA), 56, 57 cutaneous melanoma (see Cutaneous melanoma)
Epithelial tumors, melanoma, 200 diagnostic evaluation
Epithelioid blue nevus, 24, 122 ancillary laboratory and imaging studies, 4
Epithelium, 7, 8, 15–17, 37, 51, 78, 137, biopsy, 4
174, 187, 188, 191, 201, 227, 253 dermatoscopy, 4
conjunctival and corneal tumors, 137, 143 differential diagnosis, 9, 11
actinic keratosis, 149, 150 adnexal and cystic tumors, 10–12
dacryoadenoma, 147 epidermal melanocytic tumors, 12
epithelial cysts, 147, 148 epidermal non-melanocytic tumors, 12
HBID, 146, 147 inflammatory and infective simulating
inverted papilloma, 145 conditions, 12, 13
312 Index
Eyelid tumors (cont.) free tarsal graft and myocutaneous

stromal tumors, 12 advancement flap, 102, 103
examination, 2 free tarsal graft and unipedicle flap, 104
eye, 4 periosteal strip and myocutaneous
eyelid, 2, 3 advancement flap, 103, 104
ocular adnexal, 3 primary closure, 100
history, 1 semicircular rotational flap, 100, 102
past medical history, 2 tarsoconjunctival flap and free
presenting symptoms, 1, 2 skin graft/myocutaneous
rate of onset, 2 advancement flap, 104
markers, 114 upper eyelid defects
signs of, 3 free tarsal graft and myocutaneous
treatment planning, 5 advancement flap, 106
types of, 9 primary closure, 106
semicircular rotational flap, 106
tarsoconjunctival flap and free
F skin graft/myocutaneous
False-negative rate, 272, 273 advancement flap, 106
Falx cerebri, 117
Familial amyloidosis, 302, 303
Familial atypical mole and melanoma syndrome G
(FAM-M), 28 Gap, 35
Fibrin glue, 281 Gardner syndrome, 114, 116, 295
Fibrohistiocytic tumors, 84 Glabellar flap, 106, 107, 111
malignant fibrous histiocytoma, 86 Glands of Zeis, 8, 54, 55
xanthelasma palpebrarum, 85 Glandular tumors, 7, 8
xanthogranuloma, 85, 86 GNAQ mutations, 191, 201
Fibromas, 83, 216, 217 Goblet cells, 137, 138, 144, 145, 150, 170
Fibromatosis, 83, 84 Goldenhar syndrome (GS), 297, 298
Fibrosarcoma, 11, 84, 216 Gorlin-Goltz syndrome, 33, 113, 116–118
Fibrous histiocytoma (FH), 217, 218 Granular cell tumor, 140, 210, 219
Fibrous tissue tumors, 83
eyelid keloids, 83
fibromas H
clinical features, 83 Hair follicle tumors
histopathologic features, 83 carcinoma of hair follicles, 78, 79
fibromatosis, 84 pilomatrix carcinomas, 79
fibrosarcoma, 84 pilomatrixoma, 78
nodular fasciitis, 83 trichilemmoma, 77, 78
clinical features, 83 trichoadenoma, 77
histopathologic features, 84 trichoepithelioma, 76, 77
Fibrous tumors, 11, 140 trichofolliculoma, 77
fibroma, 216, 217 Hamartomas, 12, 93, 94, 120, 238, 298, 299
fibrous histiocytoma, 217, 218 Hard palate grafts, 107, 108, 111
nodular fasciitis, 218, 219 Hedgehog signaling pathway, 39, 60
Filamentary keratitis, 173, 176, 247 Hemangiopericytoma, 74, 91, 140,
Fine needle aspiration (FNA), 265 210, 212, 213
biopsy, 67 Hereditary benign intraepithelial
Fluorescence in situ hybridization dyskeratosis (HBID), 146, 147
(FISH), 28, 134 Hereditary nonpolyposis colorectal
5-Fluorouracil (5FU), 176 cancer (HNPCC), 121, 122
conjunctival malignancies Hibernoma, 11, 86
OSSN, 247 Histiocytic tumors
SCC, 48 reticulohistiocytoma, 221
Forkhead box protein O1 (FOXO1), 222 xanthogranuloma, 220, 221
Free skin graft, 104, 106, 107 xanthoma, 219, 220
Free tarsal graft, 102–104, 106, 110 Hughes flap, 102, 104, 106
Free tarsal graft and myocutaneous advancement Hughes tarsoconjunctival flap, 104, 110
flap, 102, 103, 106 Human milk fat globulin-1 (HMFG1), 54, 56
Full-thickness eyelid defect, 99, 102
Index 313
Human papillomavirus clinical features, 145

(HPV), 143, 144, 245 histopathologic features, 145
OSSN, 160 Ionizing radiation, 33, 41
I J
Ibritumomab tiuxetan, 251, 252 Junctional nevus, 26
conjunctival malignancies, conjunctival nevus, 152
lymphoma, 252 Juvenile fibromatoses, 84
IgG4 related disease, 230 Juvenile xanthogranuloma, 84, 85, 140, 220
IgG4 sclerosing disease, 230
Imiquimod, 29, 39, 48, 51, 67, 150, 288
Imiquimod cream (IMQ), 39 K
SCC, 48 Kamino bodies, 27
Immune dysfunction, 33, 54 Kaposi’s sarcoma, 91
Immunohistochemistry (IHC) clinical features, 91
amyloidosis, 230 conjunctival stromal tumors, 212, 214
PAM, 191 histopathologic features, 91
Immunosuppression, 2, 20, 45, treatment, 91
50, 92, 161, 245 Keratinocytes, 17–20, 297
OSSN, 161, 162 Keratoacanthoma, 19, 50, 51
Immunotherapy, 38, 67 clinical features, 50, 51
melanoma, 203 conjunctival and corneal tumors, 145, 146
OSSN, 176 epidemiology, 50
Impression cytology, 57, 167–170 histopathologic features, 51
OSSn, 167, 170 treatment, 51
Incisional biopsy, 37, 57, 97, 134, Keratoacanthomas, 51, 124
155, 241, 280 Keratotic plaque, 139, 149, 150
Infantile hemangiomas, 89, 115 Kissing nevus, 23
Infective lesions, 94
Infiltrating BCC, 35, 36
Inflamed juvenile conjunctival nevus L
(IJCN), 154, 155 Lacrimal gland choristoma, 210, 228, 229
conjunctival nevus, 154, 155 Left lower eyelid melanoma, 268
Inflammatory infiltrate, 21, 35, 51, 87, 88 Lentigines, 22, 121
Inflammatory lesions, 13, 94, 240 Lentigo maligna, 28, 29, 64, 65
caruncle tumors, 240, 241 Lentigo simplex, 10, 16, 22
Insufficient anterior lamella, 99, 105, 109, 111 Leukemic infiltration, 93, 225, 226
Insufficient posterior lamella, 108, 111 Leukemic tumors, 92, 93
Insufficient vascularized pedicle, 109, 110 Leukostasis, 225
Interferon, 39 Lid margin repair, 102
Interferon alpha-2b (IFNα-2b) Light microscopy, 56, 189–191, 200–201
conjunctival malignancies PAM, 189, 191
lymphoma, 251, 252 Limbal choristomas, 297
OSSN, 246 Limbal dermoids, 226, 227, 284
pigmented conjunctival lesions, 255 surgical techniques, 284
OSSN, 178, 179 Limbal stem cell deficiency (LSCD), 193, 247
PAM, 193 Linear basocellular hamartoma, 33
Intraepithelial melanocytic hyperplasia, 185 Lines of maximum extensibility (LME), 108
Intraocular invasion, 37, 41, 132, 176 Lipoblastoma, 86
OSSN, 180, 181 Lipoma, 11, 86, 140, 210, 222, 296, 299
Intraocular tumors, 229 Lipomatous tumors, 11, 86, 222
melanoma, 200 lipoma and lipoma variants, 86
Intravenous anti-CD20 monoclonal liposarcoma, 86
antibody, 225 Liposarcoma, 86, 140, 222
Invasive conjunctival squamous carcinoma, 168, 177 Lips, pigmentation of, 296
Invasive squamous cell carcinoma Liver kidney transplant, 162
OSSN, 171, 172 Lobular pattern, 210
Inverted follicular keratosis, 17, 18, 145 SGC, 57
Inverted papilloma, 145 Lower eyelid, 3
314 Index
Lower eyelid amelanotic melanoma, 266 lentigo maligna, 28, 29

Lower eyelid defects lentigo simplex, 22
anterior lamellar deficit, lid margin intact melanocyticnevus
elliptical sliding flap, 100 acquired nevi, 26
myocutaneous advancement flap, 100 atypical/dysplastic nevus, 28
primary closure, 98, 99 congenital nevus, 23, 24
skin graft, 99, 100 spitz nevus, 27, 28
full-thickness eyelid defect solarlentigo, 22
free tarsal graft and myocutaneous Melanocytic lesions, conjunctival and corneal
advancement flap, 102, 103 tumors, 139
free tarsal graft and unipedicle flap, 104 Melanocytic nevus
periosteal strip and myocutaneous advancement acquired nevi, 26
flap, 103, 104 congenital nevus, 23, 24
primary closure, 100 spitz nevus, 27, 28
semicircular rotational flap, 100, 102 spitznevus, 27
tarsoconjunctival flap and free skin graft/ Melanocytic tumors, surgical techniques, 283
myocutaneous advancement flap, 104 Melanoma, 197
Lower eyelid defects, repair of, 99, 103–106 caruncle tumors, 238, 240
Lymphangiectasia, 209, 210, 214, 215 clinical course
conjunctival stromal tumors, 214 local recurrence, 202
Lymphangioma, 87, 90, 209, 210, 212, 214, 236 local spread, 202
Lymphoid tumors, 12, 92, 93, 284 regional and distant metastasis, 202
surgical techniques, 284 clinical features, 198
Lymphoma, conjunctival malignancies, 250 differential diagnosis
clarithromycin, 253 conjunctival nevi, 200
doxycycline, 253 epithelial tumors, 200
ibritumomab tiuxetan, 252 intraocular tumors, 200
interferon alpha-2b, 251, 252 miscellaneous lesions, 200
radiation therapy, 251 epidemiological aspects, 197
rituximab, 252 etiology and associated diseases, 198
Lymphoproliferative tumors, 223–225 histopathologic features
caruncle tumors, 241 immunohistochemistry and molecular
Lymphoscintigraphy, SLN biopsy, 262, 263 pathology, 201
Lynch syndrome, 121 light microscopy, 200, 201
prognostic factors, 201, 202
prognosis, 204
M radiation therapy, 288, 289
Malignant eyelid lesion, 97 SGC, 59
definitive treatment, 97, 98 SLN biopsy, for eyelid and conjunctival tumors,
diagnostic biopsy, 97 266–268
eyelid reconstruction, 98 treatment
sentinel lymph node biopsy, 98 chemotherapy and immunotherapy, 203
Malignant fibrous histiocytoma, 85, 86, 140, 217 cryotherapy, 203
Map biopsies, 5, 57, 134, 192, 238 orbital exenteration, 203
Marginal zone B-cell (MALT type) lymphoma radiotherapy, 203
(EMZL), 224, 241 reconstruction, 203
Mass spectrometry (MS), amyloidosis, 230 regional lymph node metastasis, 203
Medial canthal defect sentinel lymph node biopsy, 204
glabellar flap, 106 surgery, 202, 203
median forehead flap, 106 variants
rhombic flap, 108 conjunctival melanoma associated
Median forehead flap, 106, 107 with nevus, 200
Meibomian glands (MG), 25, 54 conjunctival melanoma associated with PAM, 199
Melanocytes, 7, 15, 22, 24, 26, 65, 66, 190, cornea, primary melanoma of, 200
191, 200, 201, 253 Melanoma in situ, 65, 188
Melanocytic atypia, 185, 189, 190 Melanose circonscrite precancereuse, 185
Melanocytic benign epidermal tumors Melanotic Freckle of Hutchinson, 28, 29
familial atypical mole and melanoma Melanotische precancerose, 185
syndrome, 28 Merkel cell carcinoma (MCC)
freckles/ephelides, 22 radiation therapy, 289
Index 315
SGC, 59 Merkel cell tumor, 92

SLN biopsy neurofibroma, 92
for eyelid and conjunctival tumors, 270, 271 schwannoma, 92
Merkel cell tumor, 92 Nevoid basal cell carcinoma syndrome
Metastasis, OSSN, 180, 181 (NBCCS), 116–118
Metastatic tumors, 94 Nevus
conjunctival stromal tumors, 229 caruncle tumors, 238
Miscellaneous tumors, 93, 94 melanoma, 200
Mitomycin C (MMC), 59, 176, 193 Nevus flammeus, 115, 116
conjunctival malignancies Nevus of Ota, 24, 156
OSSN, 248, 249 Nevus sebaceous of Jadassohn, 80
pigmented conjunctival lesions, 254 Nodular BCC, 34
PAM, 283 Nodular CIN, 167
Mixed pattern, SGC, 57 Nodular fasciitis, 83, 84, 218, 219
Modified “slow” Mohs’ surgery, 66 clinical features, 83
Modified Mohs’ technique, 66 histopathologic features, 84
Mohs micrographic technique, 287 Non-melanocytic lesions, conjunctival and
Mohs’ method, 97 corneal tumors, 139, 140
Mohs’ micrographic surgery, 38, 98 Nonspecific keratosis, 19, 20
Mohs’ microsurgery, 38, 48, 59 Nonsurgical ablation, 67
Molluscum bodies, 19 No-touch technique, 144
Molluscum contagiosum, 17–19
Motor symptoms, 2
Mucinous sweat gland adenocarcinoma, 76 O
Mucoepidermoid carcinoma, OSSN, 172 Ocular adnexal lymphoma, 251
Mucosal neuroma syndrome, 300 Ocular melanoma, 197
Muir-Torre syndrome (MTS), 33, 121–124 Ocular surface reconstruction, conjunctiva and
Multicenter Selective Lymphadenectomy cornea tumors, 281, 283
Trial (MSLT-I), 266 Ocular surface squamous neoplasia
Multifocal melanoma, 199 (OSSN), 159, 246, 280
Multiple endocrine neoplasia (MEN) carcinoma in situ, 171
type 2B, 300, 301 conjunctival malignancies, 245
Multiple facial basal cell carcinoma, 117 5-FU, 247
Multiple hamartoma syndrome, 118–120 aloe vera, 249, 250
Multiple recurrent CIN, 178 cidofovir, 250
Muscular tumors, 11 interferon alpha-2b, 246
Myoblastoma, 219 mitomycin C, 248, 249
Myocutaneous advancement flap, 100, 101, 103, 106 retinoic acid, 249
Myofibrosarcoma, 223 treatment, 245
Myogenic tumors, 222 VEGF, 250
Myxoid tumors, 221, 222 diagnostic evaluation, 164
Myxoma, see Myxoid tumors exfoliative cytology, 167
imaging techniques, 165
impression cytology, 167, 170
N staining patterns, 164
Nasopalpebral lipoma–coloboma syndrome, 86 differential diagnosis, 164
Necrosis, 35 dysplasia, 171
Neoplasia, 1 epidemiological aspects, 159
NER system, 163 etiology and associated diseases, 160
Nerve supply, 8 AIDS, 160, 161
Neural tumors, 11 HPV, 160
granular cell tumor, 219 post transplantation and immunosuppression, 161
histiocytic tumors, 220, 221 stem cell theory, 161, 162
neurilemmoma, 219 sunlight exposure, 160
neurofibroma, 219 xerodermatic pigmentosum and
Neurilemmoma, 219 DNA repair disorders, 161
Neurocutaneous melanosis (NCM), 23 histopathologic and clinical variants, 172
Neurofibroma, 92, 219 adenoid squamous cell carcinoma, 172
neurofibromatosis type 1, 113–115 mucoepidermoid carcinoma, 172
Neurogenic tumors spindle cell squamous carcinoma, 172
316 Index
Ocular surface squamous neoplasia (OSSN) (cont.) Phosphatase and tensin homolog (PTEN)
squamous cell carcinoma in anophthalmic missense mutations, 118
socket, 173 Photodynamic therapy (PDT), 37–39
squamous cell carcinoma of cornea, 172, 173 SCC, 49
invasive squamous cell carcinoma, 171, 172 Pigmented BCC, 34
keratoplasty with, 247, 248 Pigmented conjunctival lesions, 253
pharmaco-therapeutic treatment options, 251 algorithm, management of, 255
prognosis interferonalpha-2b, 254, 255
intraocular invasion, 180, 181 mitomycin C, 254
local recurrence, 179, 180 programmed cell death 1 inhibitors, 255, 256
metastasis, 180, 181 treatment, 254
signs, 164 Pigmented lesions
staging, 172 melanoma, 238
symptoms, 162 nevus, 238
treatment, 247 Pilar cysts, 73
brachytherapy, 176 Pilomatrixoma, 78, 79
chemotherapy, 179 Pilosebaceous glands, 55
chemotherapy and immunotherapy, 176 Pinguecula, 132, 133, 169
combined approach, 179 Plasmacytic tumors, 93
cryotherapy, 175, 176 Plasmacytoma, 93
5FU, 176 Pleomorphic adenomas, 76
interferon alpha-2b, 178, 179 Pleomorphic fibroma, 83
mitomycin C, 176 Plica semilunaris, 199
reconstruction, 179, 180 conjunctival and corneal tumors, 138
surgery, 173, 175 Plomatrix carcinomas, 79
Oculoauriculovertebral spectrum, conjunctival Port-wine stain, 115
and corneal tumors, 297, 298 Prealbumin, 302
Oculodermal melanocytosis, 156 Prickle cell epithelioma, 45
Oncocytomas, 147, 237, 238 Primary acquired melanosis (PAM), 156, 185, 253, 254
Ophthalmic amyloidosis, 303 ancillary studies, 188
Orbicularis oculi, 8 clinical diagnosis, 186
Orbital exenteration, 59 clinical features, 187, 188
melanoma, 203 conjunctival melanoma associated with, 199
Osseous choristoma, 228 differential diagnosis, 191
Oxyphilic cell adenoma, 147 etiology, 186
cigarette smoking, 187
nevi and dysplastic nevus syndrome, 186
P sun exposure, 186
Pagetoid spread, 56 histopathologic features, 188, 189
Palisading, 35 immunohistochemistry, 191
Palliative therapy, 67 light microscopy, 189, 191
Palpebral conjunctiva, 8 melanocytic tumors, 283
Papillary conjunctival SCC, 166 prevalence and natural behavior, 186
Papillary endothelial hyperplasia, 87 prognosis, 193
Papillary pattern, SGC, 57 treatment
Papillomatous limbal CIN, 166 cryotherapy, 192
Papillomatous ocular surface squamous neoplasia, 166 interferon alpha-2b, 193
Pembrolizumab, 255, 256 mitomycin C, 193
Peri-limbal bulbar conjunctiva, 198 observation, 191
Perineural spread of SCC, 47, 49 surgery, 192
Periocular BCC, 33 with atypia, 201
Periocular SCC, 46 without atypia, 187
Periocular sebaceous carcinomas, 61 Programmed cell death 1 inhibitors
Periocular SGC, 55, 60 (PD-1), 201, 204, 255, 256
Periosteal strip and myocutaneous advancement conjunctival malignancies, pigmented
flap, 103, 104 conjunctival lesions, 255, 256
Perivascular tumors, 11, 91 Proparacaine, 289
Peutz–Jeghers syndrome (PJS), conjunctival and corneal Proteus syndrome, conjunctival and corneal
tumors, 295–297 tumors, 298, 299
Phakomatous choristoma, 94 Pseudoepitheliomatoushyperplasia, 19
Index 317
Pseudosarcomatous fasciitis, 84 Sebaceous carcinoma, 237, 239

Pterygium, 132, 133, 169 SLN biopsy, for eyelid and conjunctival
Pyogenic granuloma, 87, 88, 153, 209, 210 tumors, 269, 270
Sebaceous carcinomas, 122, 124
Sebaceous cyst, 72
R Sebaceous epitheliomas, 80, 122
Race-associated melanosis, 192 Sebaceous gland adenomas, 80
Racemose hemangioma, 213 Sebaceous gland carcinoma (SGC), 53
Racial pigmentation, 156 clinical features, 54
Radiation, 124 diagnostic evaluation, 57, 58
Radiation therapy, 39, 287 differential diagnosis
BCC, 288, 289 BCC, 59
conjunctival tumors chalazion, 58
conjunctival invasive squamous inflammatory condition, 58
carcinoma, 290, 291 melanoma, 59
conjunctival lymphoma, 291 Merkel cell carcinoma, 59
conjunctival melanoma, 290 SCC, 59
melanoma, 288, 289 epidemiological aspects, 53
Merkel cell carcinoma, 289 etiology, 53
radiation-induced ocular morbidity, 291, 292 histopathologic features
SCC, 48, 287, 288 immunohistochemistry, 56, 57
sebaceous gland carcinoma, 288 light microscopic features, 56
techniques of, 287 pagetoid spread, 56
Radiation-induced ocular morbidity, 291, 292 pathogenesis, 55
Radiotherapy, 38 histopathological classification
melanoma, 203 comedocarcinoma pattern, 57
SGC, 60 lobular pattern, 57
Ranibizumab, 250 mixed pattern, 57
Reactive epithelial hyperplasia, 145 papillary pattern, 57
Reactive hyperplasia, 20 left lower eyelid, 55
Reconstruction melanoma, 203 left upper eyelid, 55
Recurrent amelanotic melanoma, 132 lower eyelids, diffuse involvement of, 55
Recurrent squamous cell carcinoma, 175 prognosis
Regional lymph node metastasis, 41, 42, 60, 98, 203 local growth, 60
melanoma, 203 local recurrence, 60
Relaxed skin tension lines (RSTL), 108 metastasis, 61
Retention cysts, 72, 73 mortality, 61
Reticulohistiocytoma, 221 prognostic factors, 60
Retinoic acid, 178, 249 radiation therapy, 288
conjunctival malignancies, OSSN, 249 symptoms and signs
Retinoids, 48 diffuse thickening of eyelid, 54
Rhabdomyoma, 87 solitary nodule, of eyelid, 54
Rhabdomyosarcoma (RMS), 87, 222 treatment
Rhombic flap, 108 cryotherapy, 59
Rituximab, 225 radiotherapy, 60
conjunctival malignancies, sentinel lymph node biopsy, 59, 60
lymphoma, 252 surgery, 59
Rombo syndrome, 33 systemic chemotherapy, 60
Rosai–Dorfman disease, 93 targeted therapy, 60
topical chemotherapy, 59
Sebaceous gland hyperplasia, 79
S Sebaceous gland tumors
Salmon patch, 224 nevus sebaceous of Jadassohn, 80
Sarcoidosis, 231 sebaceous epithelioma/sebaceoma, 80
Schimmelpenning–Feuerstein–Mims sebaceous gland adenomas, 80
syndrome, 297 sebaceous gland carcinoma, 80
Schwannoma, 92, 219 sebaceous gland hyperplasia, 79
Sclerotherapy, 216 Sebaceous hamartoma of Jadassohn, 33
Sebaceoma, 80 Sebaceous hyperplasia, 237
Sebaceous adenomas, 123 Sebaceous neoplasms, 122
318 Index
Sebaceous nevus syndrome, 20 histopathologic features

conjunctival and corneal tumors, 297 evolution, 47
Seborrheic keratosis, 16, 17, 65 light microscopic features, 47
Secondary pigmentation, 241 pathogenesis, 47
Secondary tumors, conjunctival stromal tumors, 229 keratoacanthoma, 50
Senile lentigo, 22 clinical features, 50, 51
Sentinel lymph node (SLN) biopsy, 67, 98, 134, 261 epidemiology, 50
care of patients with, 273 histopathologic features, 51
diagnostic findings treatment, 51
false-negative rate, 272 prognosis
lymph node identification rate, 271, 272 local recurrence, 49
for eyelid and conjunctival tumors local spread, 49
histopathologic processing, 265, 266 metastasis, 49
intraoperative SLN detection, 264, 265 mortality, 50
melanoma, 266–268 perineural spread, 49
Merkel cell carcinoma, 270, 271 prognostic factors, 49
preoperative lymphoscintigraphy, 262, 263 staging, 49
sebaceous carcinoma, 269, 270 radiation therapy, 287, 288
squamous cell carcinoma, 269 SGC, 59
eyelid and periocular region, lymphatic SLN biopsy, for eyelid and conjunctival
drainage of, 261, 262 tumors, 269
head and neck and periocular region, symptoms and signs, 46, 47
adverse effects, 271 treatment
lymphoscintigraphy, 262, 263 chemotherapy, 48
melanoma, 204 PDT, 49
research, 274 prevention, 48
SCC, 48 radiation therapy, 48
SGC, 59, 60 sentinel lymph node biopsy, 48
steep learning curve for, 273 surgery, 48
studies, 273, 274 topical therapy, 48
survival benefit, 274 upper lid, 46
Simple conjunctival excision, conjunctiva Squamous cell papilloma, 15, 143
and cornea tumors, 280, 281 adulthood papilloma, 144
Simple incisional biopsy, conjunctiva and childhood papilloma, 143
cornea tumors, 280 histopathologic features, 144
Skin graft, 99, 100 surgical techniques, 283
upper eyelid defects, 105 treatment, 144, 145
Slit-lamp examination, conjunctival and Squamous epithelial hyperplasia, 19
corneal tumors, 131, 132 Squamous intraepithelial neoplasia, 22
Smooth muscle tumors, 87 Squamous neoplasia, 165
Soft tissue tumors, 83 Squamous papilloma, 16, 170, 236, 237
Solar keratosis, 20–22 Squamous papillomata, 12
Solar lentigo, 22 Squamous tumors
Solitary nodule, of eyelid, 54 actinickeratosis, 20–22
Solitary sessile squamous papilloma, 144 cutaneous horn/nonspecific keratosis, 19, 20
Sonidegib, 118 inverted follicular keratosis, 17
Spinalioma, 45 keratoacanthoma, 19
Spindle cell squamous carcinoma, OSSN, 172 molluscum contagiosum, 17, 19
Spitz nevus, 23, 24, 27, 28, 65 sebaceous nevus syndrome, 20
conjunctival nevus, 153 seborrheickeratoses, 16, 17
Squamous atypia, 51 squamous cell papilloma, 15
Squamous cell carcinoma (SCC), 45 squamous epithelial hyperplasia, 19
in anophthalmic socket, OSSN, 173 surgical techniques, 283
clinical features, 45, 46 Stem cell theory, OSSN, 161, 162
of cornea, OSSN, 172, 173 Stroma, 235
of cornea resembling filamentary keratitis, 173 conjunctival and corneal tumors, 137
diagnostic evaluation, 47 Stromal tumors, 12, 140
differential diagnosis, 48 classification of, 210
epidemiological aspects, 45 fibrohistiocytic tumors, 84
etiology, 45 malignant fibrous histiocytoma, 86
Index 319
xanthelasma palpebrarum, 85 T
xanthogranuloma, 85, 86 Tarsoconjunctival flap, 106
fibrous tissue tumors, 83 Tarsus, 8
eyelid keloids, 83 Tenon’s fascia, 280
fibromas, 83 Transepidermal elimination, 27
fibromatosis, 84 Transplantation, OSSN, 161, 162
fibrosarcoma, 84 Transthyretin (TTR), 302
nodular fasciitis, 83, 84 Trichilemmal carcinoma, 79
hamartomas, choristomas, and miscellaneous Trichilemmal cysts, 73
tumors, 93, 94 Trichilemmoma, 78
inflammatory and infective lesions, 94 Trichoadenoma, 77
lipomatous tumors, 86 Trichoepithelioma, 76, 77
lipoma and lipoma variants, 86 Trichofolliculoma, 77
liposarcoma, 86
lymphoid, plasmacytic and leukemic
tumors, 92, 93 U
metastatic tumors, 94 Ultrasound biomicroscopy, 132
rhabdomyoma, 87 Ultraviolet (UV) irradiation, 33
rhabdomyosarcoma, 87 Ultraviolet light, SCC, 45
smooth muscle tumors, 87 Ultraviolet radiation, OSSN, 160
vascular tumors, 87 Unipedicle flap, 104
angiosarcoma, 90, 91 Upper eyelid defects
arteriovenous malformations, 90 anterior lamellar deficit
capillary hemangioma, 87–89 ellipse sliding flap, 105, 106
cavernous hemangioma, 90 primary closure, 105
Kaposi’s sarcoma, 91 skin graft, 105
lymphangioma, 90 full-thickness eyelid defect
neurogenic tumors, 92 free tarsal graft and myocutaneous
nevus flammeus, 87 advancement flap, 106
perivascular tumors, 91 primary closure, 106
pyogenic granuloma, 87 semicircular rotational flap, 106
Strontium-90 brachytherapy, 290 tarsoconjunctival flap and free
Sturge-Weber syndrome (SWS), 115, 116 skin graft/myocutaneous
Subepithelial nevi, conjunctival nevus, 152 advancement flap, 106
Substantia propria tumors, surgical techniques, 284 repair of, 105
Sunlight exposure, OSSN, 160 Upper palpebral conjunctiva, 199
Superficial cutaneous melanoma, 64
Surgery
melanoma, 202, 203 V
OSSN, 173, 175 Varix and racemose hemangioma, 211, 212
PAM, 192 Vascular system, 8
SCC, 48 Vascular tumors, 11, 87, 209
SGC, 59 acquired sessile hemangioma, 211
Surgical excision, BCC, 38 angiosarcoma, 90, 91
Sweat gland adenocarcinomas, 76 arteriovenous malformations, 90
Sweat gland tumors capillary hemangioma, 87–89, 211, 242
adnexal tumors cavernous hemangioma, 90, 211
apocrine hidrocystoma, 73, 74 hemangiopericytoma, 212
eccrine hidrocystoma, 74 Kaposi’s sarcoma, 91, 212, 214
eccrine spiradenomas, 74 lymphangioma, 90
pleomorphic adenomas, 76 neurogenic tumors
syringocystadenoma papilliferum, 76 Merkel cell tumor, 92
syringomas, 74 neurofibroma, 92
apocrine gland adenocarcinoma, 76 schwannoma, 92
mucinous sweat gland adenocarcinoma, 76 nevus flammeus, 87
sweat gland adenocarcinomas, 76 perivascular tumors, 91
Syringocystadenoma papilliferum, 76 pyogenic granuloma, 87, 209
Syringomas, 74, 75 varix and racemose hemangioma, 211, 212
Systemic chemotherapy Venous drainage, 8
SGC, 60 Vismodegib, 118
320 Index
Vismodegib (Erivedge), 39 Xanthogranuloma, 85, 86, 220, 221

Vitamin A, 249 Xanthoma, 219, 220
Xanthomatous lesions, 12
Xenogenic spacer grafts, 108
W Xeroderma pigmentosum (XP), 33, 163, 165
Wagenmann–Froboese syndrome, 300 conjunctival and corneal tumors, 301, 302
Weck-cell applicator, 281 OSSN, 161
X Z
Xanthelasma, 85 Zimmerman’s tumor, 94
Xanthelasma palpebrarum, 85

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Clinical Ophthalmic

ISBN 978-3-030-06045-9 ISBN 978-3-030-06046-6 (eBook)

Library of Congress Control Number: 2019933401

© Springer Nature Switzerland AG 2019

Jerusalem, Israel Jacob Pe’er, MD

1 Eyelid Tumors: Examination Techniques�������������������������������������� 1

14 Conjunctival and Corneal Tumors:

Ghada Al Bayyat, MD Department of Ophthalmology, Bascom Palmer Eye

Santosh G. Honavar, MD, FACS Department of Ophthalmic Plastic

David T. Tse, MD Department of Oculofacial Plastic Surgery, Bascom

Introduction Presenting Symptoms

History Box 1.1 Symptoms of Eyelid Neoplasia

The history begins with a description of the

© Springer Nature Switzerland AG 2019 1

• Telangiectasia Ocular Adnexal Examination

Dermatoscopy is an in vivo noninvasive tech-

Treatment Planning A systematic approach to the evaluation of sus-

Introduction Eyelid Skin

© Springer Nature Switzerland AG 2019 7

Orbicularis Oculi The eyelid margin is a flat area on the edge of

Tarsus Vascular System

Table 2.2 Classification of epidermal tumors of the eyelid

Table 2.3 Classification of adnexal and cystic tumors of the eyelid

Table 2.3 (continued)

Epidermal Melanocytic Tumors Inflammatory and Infective

Introduction of the skin, but they may also include conjuncti-

© Springer Nature Switzerland AG 2019 15

Seborrheic Keratosis also been referred to as basal cell papilloma, seb-

Fig. 3.3 Inverted follicular keratosis.

Molluscum contagiosum is characterized by ing dermis is usually inflamed but without

the lesion [15]. Treatment should be determined

Sebaceous Nevus (of Jadassohn)

Sebaceous nevus syndrome (of Jadassohn), an

Actinic (Solar) Keratosis

Actinic or solar keratosis is most frequently a

a plasia. In a study wherein histopathologic

Fig. 3.7 External photo showing tan-colored linear nasal

1–2 mm in diameter. Pigmentation is usually uni-

A melanocytic nevus is considered as a hamar-

[30]. Despite evidence supporting origin of

ing with a differential including scar, dermatofi-

Blue Nevus Nevus of Ota

Acquired Nevus clear cytoplasm and variable melanin. Typically the

Introduction the USA, the incidence of BCC is more than 500

© Springer Nature Switzerland AG 2019 33

Approximately 95% of all BCCs occur in people Nodular

Symptoms and Signs

Infiltrating Histopathologic Features

The infiltrating BCC presents as an indurated, BCC is characterized by a proliferation of cells

Fig. 4.6 An infiltrative BCC is composed mainly of elon-

Fig. 4.7 In many cases, different growth patterns of BCC

cinomas have an impact on prognosis. highly questionable, otherwise excisional biopsy

• Painless, firm, nodular, or flat skin

Other Noninvasive Methods

Radiation Therapy tural damage. IMQ is an immune response modi-

greater recurrence after treatment [1]. More Staging

• Stage I A – primary BCC 5 mm or less

Jerusalem, Israel Jacob Pe’er, MD

1 Eyelid Tumors: Examination Techniques�� 1

14 Conjunctival and Corneal Tumors:

Introduction Presenting Symptoms

History Box 1.1 Symptoms of Eyelid Neoplasia

• Telangiectasia Ocular Adnexal Examination

Treatment Planning A systematic approach to the evaluation of sus-

Introduction Eyelid Skin

Orbicularis Oculi The eyelid margin is a flat area on the edge of

Tarsus Vascular System

Epidermal Melanocytic Tumors Inflammatory and Infective

Introduction of the skin, but they may also include conjuncti-

Seborrheic Keratosis also been referred to as basal cell papilloma, seb-

Sebaceous Nevus (of Jadassohn)

Actinic (Solar) Keratosis

Acquired Nevus clear cytoplasm and variable melanin. Typically the

Introduction the USA, the incidence of BCC is more than 500

Approximately 95% of all BCCs occur in people Nodular

Symptoms and Signs

Infiltrating Histopathologic Features

Other Noninvasive Methods

Radiation Therapy tural damage. IMQ is an immune response modi-

greater recurrence after treatment [1]. More Staging

Introduction malignant neoplasm of the eyelids after basal cell

slowly enlarging erythematous, scaly, or crusted Light Microscopic Features

Differential Diagnosis section of a lymph node is considered the gold

Prognostic Factors Perineural Spread

According to the applied practical review of the Local Recurrence

of distant metastasis varies from 1% to 21% [1, Epidemiology

Histopathologic Features 1. Reifler DM, Hornblass A. Squamous cell carcinoma

Introduction Epidemiological Aspects

Diffuse Thickening of the Eyelid

Histopathologic Features the tarsus, glands of Zeis of the cilia, pilosebaceous

Light Microscopic Features

Benign and Malignant Tumors

asal Cell Carcinoma

Targeted Therapy Local Growth

Prognosis Despite radical surgery like orbital exenteration

Palliative Therapy Sentinel Lymph Node Biopsy

Introduction Box 8.1

Table 8.1 Classification of eyelid adnexal tumors Treatment, Follow-Up,

a Trichilemmal (Pilar) Cysts

b Sweat Gland Tumors

a s urrounded by an outer layer representing myoepi-

leomorphic Adenomas (Benign

on sun-exposed skin of the elderly. The clinical Sebaceous Gland Tumors

ebaceous Gland Adenoma

Fibrous Tissue Tumors Histopathologic Features

Clinical Features Eyelid Keloids

Smooth Muscle Tumors Nevus Flammeus (Port-Wine Stain)

Skeletal Muscle Tumors Pyogenic Granuloma

Cavernous hemangioma of the eyelid is a rare, Angiosarcoma

Histopathologic Features Perivascular tumors of the eyelid are very rare

Neurogenic Tumors malignant eyelid tumors and could be associated

Introduction ing with surgical excision and reconstruction. If a

Eyelid Reconstruction Primary Closure