Cryosurgery: Unapproved Uses,

Dosages, or Indications
RODNEY DAWBER, MA, FRCP

ost dermatologists around the world carry

out some aspects of cryosurgery as part of
their dermatologic surgery practice. Typically, this will be limited to commoner forms of focal,
benign, premalignant and malignant epidermal lesions,
such as viral warts, keratoses, and small basal cell carcinomas.
Cold injury could be used to destroy almost any
pathology if used aggressively enough, but in clinical
practice in comparison with other modalities of treatment, one has to grade cryosurgery in relation to its
success, morbidity, failure, and recurrence rates. There
are, strictly speaking, no unapproved indications for
cryosurgery. Textbooks in the field13 show a large
range of focal skin pathologies that are treatable by
cryosurgery: if one is to use it to its limits and understand the multiplicity of potential indications, it is important to know the scientific basis of the freeze damage
used in clinical practice.

Macroscopic Changes
During and immediately after a substantial 20 30-second freeze, the skin shows a white ice field. Within a
few minutes of thawing, a violet color appears at the
periphery and moves centrally. Both on the skin and
deeper, it is clearly demarcated from the surrounding
healthy skin. Before long, the deeper tissue becomes
paler, while a hemorrhagic blister may form on the
surface. This turns into an eschar and lasts for approximately 2 6 weeks. The frozen area contracts at 10 14
days.1,4

nuclear pyknosis. Electron microscopy additionally

shows the degranulation of the endoplasmic reticulum.
Histologically, blister formation is seen to occur at the
dermoepidermal junction, with maximal cell death in
the overlying epidermis and associated melanocytes.

Mechanisms of Cellular Injury

Ice Formation
Extracellular ice damages cell membranes and is particularly disruptive to tightly packed cells in solid tumors.1,4 Intracellular ice forms in many cells during
freezing and is thought to damage mitochondria and
endoplasmic reticulum. It is thought to give rise to
cellular death, even though many cells look quite normal immediately after thawing. Large ice crystals are
more damaging than small ones. Slow thawing is associated with recrystallization of ice, and this approach is
known to be more destructive than rapid thawing. This
is the main reason why liquid nitrogen (LN2) cryosurgery is practically the best in clinical practicerapid
freezing with a slow thaw and the use of simple equipment.

Osmolarity Changes
Extracellular ice is associated with a decrease in extracellular water and an increase in solute concentrations.
A change in osmotic gradients leads to the passage of
solutes out of cells with a decrease in cellular volume
and disruption of cell membranes. Some of the damage
is irreversible, and the problems are compounded during the reverse process in thawing.

Microscopic Changes

Vascular Changes

There is essentially no difference between the change

seen after cryoprobe or cryospray therapy. Ice crystals
are seen immediately, but the first cellular changes are
delayed to about 30 minutes when the cytoplasm shows
increasing eosinophilia. There is also margination of the
chromatin and vacuolation. Up to 1 hour after freezing,
there may be no obvious cell death. Over the next few
hours, there is homogenization of the cytoplasm and

Flow through capillaries diminishes with modest cold,

and this is seen readily on the hand in winter when the
skin turns white. The effect is very much less marked in
arterioles. Experimentally after LN2, the first change is
vasoconstriction, but with 45 minutes of deep freeze,
vasodilation supervenes. Showers of microthrombi pass
through the capillaries and venules and gradually become fixed to the endothelium, so that eventually there
is no flow at all. This effect can be seen with temperatures of 15C and below. The result is an ischemic
necrosis that starts around the vessels; its extent will
depend on the depth of freeze and its lateral spread.

From the Churchill Hospital, Oxford, England.

Address correspondence to Rodney Dawber, MA, FRCP, Churchill Hospital, Oxford, OX3 7LJ UK.

2002 by Elsevier Science Inc. All rights reserved.

655 Avenue of the Americas, New York, NY 10010

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Clinics in Dermatology

564 DAWBER

Table 1.

2002;20:563570

Practical treatment schedules: benign lesions (spot-freeze method when sprayed)

Lesion
Acne
Cyst
Comedones
Vulgaris (mixed lesions)
Scarring
Ice pick
Keloidalis (nape of neck)
Actinic cheilitis
Adenoma sebaceum
Alopecia areata
Angiokeratoma
Mibelli
Scrotum
Angiolymphoid hyperplasiawith
eosinophilia (Fig 1)
Cherry angioma (Campbell de
Morgan spots)
Chondrodermatitis nodularis helicis
Clear-cell acanthoma
Dermatosis papulosa nigrans
Disseminated superficial actinic
keratosis
Elastosis perforans serpiginosa
Epidermal nevus
Granuloma annulare
Granuloma faciale
Hemangioma
Hidranenitis suppurativa (Fig 2)
Hyperhidrosis, axillary
Hypertrophic scar
Idiopathic guttate melanosis
Ingrowing toenail (Fig 3)
Kyrles disease
Labial lentiginous macules (Fig 4)
Leishmaniasis (tropical sore)
Lentigo simplex
Lichen planus, hypertrophic
Lichen sclerosusvulva
Lichen simplex
Lichenoid keratosis, benign
Lupus erythematosus, discoid
Lymphangioma
Lymphocytoma cutis
Milia
Molluscum contagiosum
Mucocoelemouth
Myxoid cystdigital
Orf
Pigmented nevi
Macular
Papular
Porokeratosis
Plantaris discreta
Mibelli
Prurigo nodularis
Pruritus ani
Pruritus vulvi
Psoriasis, lichenoid
Rhinophyma

Time
(seconds)

FTC

Margin
(to be included
in ice
formation)

510
Ice formation
Ice formation
Ice formation

1
1
1
1

23
1
1
1

30
2025
1015
5

1
1
1
1

3
2
3
1

48

P or OS
P or OS
OS

10
10
15

1
1
1

1 mm
1 mm

3
3
1

8
8

10

15
20
5
35

1
1
1
1

2
23
1
1

mm
mm
mm
mm

3
1
1
1

10
5
510
510
20
15
15
2025
5
20
10
10
15
5
10
510
1520
5
5
15
20
5
5
10
2030
10
510
15

1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1

1 mm
1 mm

2 mm

2 mm
1 mm

12 mm

2
2
2
2
24
23
2
1
2
2
1
1
2
1
1
2
1
1
1
2
1
1
1
1
1
1
1
2

Ice formation
15

1
1

10
10
10
1015
20

1
1
1
1
1

Technique
P or OS
Peel16
Peel
Peel
P
Spray
P
OS

OS
OS
P or F
OS
OS
OS or P
OS or P
OS or P
P
OS
OS
OS or P
OS
OS
OS
OS or P
OS or P
OS or P
OS
OS
OS or P
OS
OS
OS
OS
P
P or OS
P
OS or P
OS
OS
P or OS
OS
OS
OS
OS or P
OS
OS
OS

2 mm
1 mm

Sessions
(maximum
number)

Interval
(weeks)
4

68
6
8
8
8
6
8

46
68

2
1

23

1
1
1
1
2

8
continued

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565

Continued

Time
(seconds)

FTC

Lesion

Technique

Rosacea
Sarcoid, granuloma
Sebaceous hyperplasia
Solar
Atrophy (fine wrinkles)
Lentigo
Spider nevus
Steatocystoma multiplex
Syringoma
Tattoos
Trichiasis
Trichoepithelioma
Venous lakeslips
Xanthoma
Xanthelasma
Nodular

OS
OS
P or OS
OS/peel
OS

10
10
5
Ice formation
5

1
1
1
1
1

P or OS
P or OS
P or OS
OS
P
P
P
OS
OS or P

10
10
5
30
5
1015
10
10
10

1
1
1
1
1
1
1
1
1

Margin
(to be included
in ice
formation)

Sessions
(maximum
number)

Interval
(weeks)

1
1
1
1
1

1
2
2
3
2
2
2
2
1

8
8
810
4
8
6
8

2 mm

P probe; OS open spray; FTC freeze/thaw cycle; F forceps.

Information as published.1,11,3,6

Venules and capillaries are more consistently occluded

by the cooling achieved in clinical practice; the vascular
necrosis resulting is often therefore a type of venous
gangrene. Major arteries and arterioles are only very
rarely blocked by freezing of this type. As with other
destructive effects of cryosurgery, these vascular
changes are more marked after a rapid freeze, slow
thaw, and refreeze (ie, two or more freeze/thaw cycles).

Immunology
Much interest has centered on the idea that LN2 therapy
might stimulate host humoral and cellular immune processes.5,6 This stems from three early observations. The
first is that on occasions, treating part of a large wart
leads to the disappearance of the whole wart. Second,
treating one or two viral warts may lead to the quicker
resolution of other distant lesions. Third, cryosurgery of
a primary tumor has occasionally been associated with
the disappearance of distant metastases.
There is some evidence that low temperatures can
Table 2.

induce an effective immune recognition of remaining

viral or tumor cells. When cells are damaged or killed
by freezing, they release enzymes, peptides, cytoplasmic components, and so on. Some of these may act as
antigens and be taken up by antigen-presenting cells
and presented to lymphocytes. Alternatively, the damaged cells may reveal new antigens on their cell surface.
In either case, a clone of specific lymphocytes would be
induced with the capability of destroying distant, virally infected or tumor cells.

Sensory Impairment
Some degree of paraesthesia or, less commonly, anesthesia is common after freezing. Indeed, the fact that
cold can produce numbness has been known for many
centuries.7,8
The analgesic effect of cryosurgery has proved effective in the palliative management of various inoperable
tumors by direct application to the tumor, while others
have used a cryoprobe to produce analgesia in patients

Practical treatment schedules: premalignant lesions

Lesion
Actinic cheilitis
Bowens disease
Vulval (multicentric pigmented)
Penile (erythroplasia) (Fig 5)
Bowenoid papulosis
Keratoacanthoma
Lentigo maligna
Leukoplakiaoral (hypertrophic
and dysplastic)
FTC freeze/thaw cycle; OS open spray.

Technique

Time
(seconds)

FTC

Margin

OS

20

OS
OS
OS
OS
OS
OS

20
20
10
30
30
20

1
1
1
2
1
1

2 mm
2 mm
2 mm
5 mm
3 mm
23 mm

Interval
(weeks)

Response

9596%

2
1
4
2
1
12

12

6
6

8599%
97%
9497%
3040%
8494%
90%

Sessions

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Figure 2. Hidradenitis suppurativa: right axilla with gross

chronic inflammatory changes, fistulae, and sinuses before (a) and
after (b) cryosurgery.
Figure 1. Angiolymphoid hyperplasia with eosinophilia: before
(a) and after (b) single LN2 freeze.

with intractable pain by blocking peripheral nerve function. These studies have also shown that, although all
transmission is blocked in the frozen nerve, full recovery occurs after a variable period. This supports previous work of directly freezing the sciatic nerve of rabbits
with LN2; in all cases, nerve conduction was completely
interrupted, but within 100 days, rheobase and
chronaxie measurements confirmed full restoration of
normal function. Thus, if a nerve trunk underlying a
treated skin lesion is inadvertently damaged, complete
recovery of distal sensory or motor function can be
expected.
When skin rather than peripheral nerves is frozen, it
is well recognized that treatment of the affected area
can be undertaken again several days or weeks with
less pain. Pain after the initial freeze/thaw period of
cryosurgery is also usually minimal. Although many
studies have provided figures for the duration of pain
relief after cryosurgery to various peripheral nerves,
there was until recently little information on the duration of sensory loss after cutaneous cryosurgery. Patients, however, require this information, particularly
when a sensitive area such as the fingertip is to be
rendered anesthetic by freezing.

Work in Oxford7 showed that appreciation of all

three modalities of sensation tested (touch, pain, and
cold) was initially reduced in all subjects studied. The
recovery took up to 1.5 years for the longest freeze.
Compared with control skin, all treated areas sampled
within the first few weeks of cryosurgery were found to
have an absence of axons in the upper dermis and a
noticeable reduction in the deeper dermis. The longer
the freeze time, the more pronounced were these
changes. Even with the longest freeze time, however,
Schwann cell and connective tissue pathways were
present in normal numbers at all levels, with areas of
Schwann cell proliferation. Apart from mild lymphocytic infiltration around a few of the neurovascular
bundles, there was little evidence of inflammation and
minimal fibroblastic activity. Dilation of occasional superficial blood vessels was the only vascular change
detected. Biopsy specimens taken at later stages contained increasing numbers of axons at all levels.
Faber et al8 carried out sensory testing by means of a
graded bristle technique after treatment of 183 skin
lesions in 169 patientsmild, transient sensory loss was
detected in 28% of treated lesions; they noted that this
did not appear to be influenced by the freezing technique used or the type of wound healing but was site

Clinics in Dermatology

Figure 3.

2002;20:563570

CRYOSURGERY: UNAPPROVED USES OR INDICATIONS

Ingrowing toenail: chronic granulation tissue in lateral nail wall before (a) and after (b) cryosurgery.

Figure 4. Labial lentiginous macules before (a) and after (b)

LN2 spray cryosurgeryno cosmetic sequelae.

Figure 5. Erythroplasia of Queyrat before (a) and after (b) a

single 30-second freeze (timed after ice formation).

567

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the equipment is convenient and very easy to use, and

essentially similar methods can be used for benign,
premalignant, and malignant lesions giving success
rates at least on a par with irradiation and excisional
surgery, but without the complexity of these treatment
modalities.1,3,11,13
The most popular units used in office practice are
basically small, metal or plastic vacuum flasks with a
screw-on top possessing a spray-release system and a
valve giving a working pressure of approximately 6 psi
(41.4 kPa) and a safety relief pressure of approximately
70 psi (483 kPa). The LN2 capacity of the most frequently used units is no more than 500 mL. The various
spray attachments on the unit head are either screw-on
or have a fitting like that for syringe needles. The most
widely used units have a range of screw-on spray tips
with diameters from 1 mm to 0.375 mm. Spray tips are
used at approximately 1-cm distance from the skin
surface.

Figure 6. Malignant melanoma recurrence in an elderly and

infirm patient. A constantly bleeding nodule (a) was aborted by
2 30-seconds LN2 spray cryosurgery (b).

dependent (the trunk and neck giving more prolonged

impairment than the face; on the eyelid, however, sensory loss was not detected at all). It is, of course, these
effects that may be the basis of the successful use of
cryosurgery for pruritus vulvae and ani, the symptoms
of lichen sclerosus et atrophicus, prurigo nodularis, and
lichen simplex (neurodermatitis).

Differential Cell Sensitivity to Cryosurgery

Adventitious glands are damaged by even short freeze
schedulespilosebaceous, eccrine, and apocrine.1,9 12
Thus, benign pathology of these organs may respond
particularly well to cryosurgery. Melanocytes are
readily damaged by low temperatures, whereas fibroblasts are hardy.10 This has important clinical implications. People with dark or black skin may develop
hypopigmentation at the site of freezing. On the other
hand, deep freezes required to treat tumors are unlikely
to destroy the subjacent connective tissue.

Spray Technique
For other than benign, regular lesions, the field to be
treated is delineated with a skin-marker pen. For most
benign lesions, this will be approximately 12 mm beyond the visible pathologic margin; for premalignant
and malignant lesions, a margin of up to 1 cm of clinically normal skin may be included. The directional
spray method used to treat lesions of differing sizes
may be the spot freeze, paint-spray, rotatory, or spiral
technique1; for large lesions, the segmental and fractional methods may be used.14
When ice has developed within the desired field, the
spray is maintained with sufficient pressure to keep the
field frozen for the length of time considered adequatefrom 5 to 30 seconds, depending on the pathology of the lesion; more than 30 seconds may be required
occasionally, but this can induce connective tissue disruption and scarring. The spot-freeze method is only
satisfactory for fields of up to 2-cm diameter; beyond
this size, the temperature of any ice seen to form is
greater than 15C and therefore not low enough to
give adequate cell killing; edge recurrences (or persistence) may develop, whatever the nature of the lesion.
If the lesion to be treated by the spot-freeze method is
greater than 2 cm in diameter, then the field is divided into overlapping circles of 2-cm diameter that are
each treated separately. Alternatively, the paint-spray
or spiral spray technique may be used, ensuring an
even spray and depth of freeze across the whole lesion.
The appropriate freeze regime is used, depending on
the nature of the lesion, and recorded in the treatment
notes, for example, as follows:
LN2 single ice field 1 5 seconds

Treatment Methods

NOTE:

In routine clinical practice, LN2-based equipment has

become increasingly dominant over other methods

MEANING: Liquid nitrogen, lesion 2 cm: frozen once

for 5 second after ice formed in the defined field.

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Table 3.

2002;20:563570

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569

Practical treatment schedules: malignant lesions

Time
(seconds)

FTC

OS
OS
OS
OS or P2

30
30
30
30

2
2
2
2

5
5
5
5

OS
OS

30
30

1
2

Lesion

Technique

BCC (postradiotherapy)
SCC
Lentigo maligna melanoma
Melanoma metastasespalliation
(Fig 6)
Kaposis sarcoma
AIDs-related
Non-AIDS

Sessions

Interval
(weeks)

mm
mm
mm
mm

1
1
1
1

8695%
9498%
8596%
92% flat, healed, and
no clinical activity1

5 mm
5 mm

1
1

84%
7493%

Margin

Response

FTC freeze/thaw cycle; BCC basal cell carcinoma; SCC squamous cell carcinoma; OS open spray; P probe.

The spot-freeze method was developed in an attempt to

standardize cryosurgery treatment so that:
Y Medical personnel of limited experience could use
the method in exactly the same way and obtain the
same success rates as more experienced practitioners;
Y Accurate knowledge could be obtained regarding
the relative sensitivity or resistance of different lesions to cryosurgery;
Y If treatment should fail, then one could exactly repeat or lengthen the second spray.
The techniques involved in various centers to define the
adequacy of ice field formation and satisfactory cell
killing vary considerably, particularly with regard to
assessing the depth of freeze. It is generally agreed that
the lateral spread of ice is the most practical method of
judging depth. Using the spot-freeze method, for each
2-cm circle treated, the maximum depth of adequate ice
formation in the center of the lesion will be at least 0.5
cm (ie, a 4:1 ratio). That adequate killing temperatures are obtained within this field has been confirmed
by animal-model studies (ie, temperatures lower than
40C occur within this field).
Probe Technique.
All of the commercially available handheld and benchbased machines with spray attachments also have a
variety of metal probes through which LN2 is circulated
to cool the tip, which is to be applied to the lesion.
These vary in size and are usually circularfrom 1 mm
up to several centimeters in diameter. To obtain adequate skin contact with the cooled probe, the probe is
dried before freezing, and lubricant jelly is applied to
the skin. A probe is selected of a size equivalent to the
field to be treated. The probe is placed on the lesion and
cooling is commenced. The probe adheres to the lubricant jelly and skin within 5- 6 seconds. It is then gently
retracted from the skin, thereby protecting surrounding
tissues from unnecessary freezing and inflammation.
The treatment is then continued for 10 seconds to 2
minutes, depending on the diameter and pathology of
the treatment field. The probe cannot immediately be

removed at this stage because of the ice ball effect

between the skin and probeallow between 10 and 30
seconds for sufficient thawing to permit separation to
occur. Many other spray and probe techniques have
been described, which are detailed in larger texts.1,3

Treatment Schedules
As previously stated, the nature of the cold injury
caused by cryosurgery shows that virtually any focal,
superficial skin pathology could be destroyed by its
use. In clinical practice, cryosurgery is placed alongside
all of the other modalities used in dermatologic surgery,
and for every lesion diagnosed, the clinician assesses
the credit and debit of each technique.1,11,15 It is the
authors opinion that for many less common conditions,
cryosurgery is very much underused. Tables 1 through
3 show a range of conditions for which it has been used
with success, but this is not to suggest that it is therefore
the treatment of choice. The treatment times refer to
after ice formation; the times quoted are not fixed times
for all lesions but are average schedules for average
skin lesions in each diagnostic group.

References
1. Dawber RPR, Colver G, Jackson A. Cutaneous cryosurgery. 2nd ed. London: Martin Dunitz, 1997.
2. Kufflik EG, Gage AA. Cryosurgery treatment for skin
cancer. New York: Igaku-Shoin Medical Publishers, 1990.
3. Korpan NN. Basics of cryosurgery. Vienna: Springer-Verlag, 2001.
4. Helpap B. Morphologic and cell kinetic investigations of
the cryolesion. In: Breitbart EW, Dachow-Siwiec E, editors. Clinics in dermatology: advances in cryosurgery.
New York: Elsevier, 1990;2:529.
5. Johnson JP. Immunologic aspects of cryosurgery: potential modulation of immune recognition and effector cell
maturation. In: Breitbart EW, Dachow-Siwiec E, editors.
Clinics in dermatology: advances in cryosurgery. New
York: Elsevier, 1990;8:39 47.
6. Ikekawa S. Cryoimmunology and cryoimmunotherapy.
In: Korpan NN, editor. Basics of cryosurgery. Vienna:
Springer-Verlag, 2001:2530.
7. Sonnex TS, Jones RL, Weddell AG, Dawber RPR. Long-

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