ARTICLE
Cryosurgery the well-aimed and controlled destruction of diseased
tissue by application of cold is an effective and efficient method
for treating various skin diseases [1-4]. The technique has several advantages
(Table I); it provides
high cure rates and good cosmetic results with few contraindications and
a low incidence of complications.
The biological changes that occur during and after cryosurgery have
been studied in vitro and in vivo and are the result of
reduction of tissue temperature and consequent freezing. Tissue injury
is induced by cell freezing and by the vascular stasis that develops in
the tissue after thawing. The cryoreaction is, therefore, characterised
firstly by the physical and secondly by the vascular phases. A postulated
third phase of the cryoreaction, the immunological phase, has not been
well-studied in the skin. The factors affecting the effects of freezing
on tissue and the optimal parameters for the treatment of skin diseases
are shown in Table II.
Nowadays, there are many commercially available, well-functioning cryosurgical
units with variable design, function and performance characteristics [5,
6]. Sufficient cold for cryosurgery can be produced by direct or indirect
application of a solid or liquid cryogen stored at low temperatures, by
lowering the pressure of a gas (Joule-Thompson effect), electromechanically
or simply by refrigeration. The devices are mainly characterized by the
cryogen and the manner of its application to the skin (Table
III). A cryosurgical unit consists of five main components: 1)
a liquid Dewar/gas cylinder, 2) the cryogen, 3) a pressure gauge, 4) a
cryogun with tubing and 5) assorted cryoprobe/spray tips.
Clinical development of skin reaction to cryosurgery
The clinical physical course of the skin cryoreaction starts with the
whitish frozen phase followed by a peripheral erythema, occurring immediately
to 30 min after the cryosurgery. The treated area becomes oedematous between
a few minutes and some hours after the procedure. A bulla is usually formed
between one and three days later. Consequently, exudation lasts between
a few to 14 days after cryosurgery followed by mummification of the lesion,
whereas a serum crust is built up from the second to the fourth week after
treatment. Finally, the treated area presents an initially erythematous,
flat, slightly atrophic, cosmetically acceptable scar. In order to minimise
the erythema and oedema occurring after cryosurgery a mild, non-atrophogenic
steroid cream (e.g. hydrocortisone aceponate, hydrocortisone buteprate,
hydrocortisone-17-butyrate, methylprednisolone aceponate, prednicarbate)
can be applied to the lesion immediately after treatment, especially in
areas that usually react with strong oedema (e.g. face). The serous
content of the bulla is aspirated with a sterile, fine needle 48 hrs after
treatment, its roof being left on the lesion as a natural protection film.
A desinfectant-drying solution is then prescribed (e.g. Castellani
colorless solution, merbromine 2%, polyvidone-iodine 10%, chlorhexidine
2 %) or a lotion (e.g. chlorhexidine 1-2% in lotio alba aquosa)
once daily. Topical anaesthesia before cryosurgery is not usually required.
Indications for cryosurgery
in dermatology
Cryosurgery is indicated for diverse benign lesions and selected premalignant
and malignant skin tumours [1-4, 7-10]. The latter include tumours with
well-circumscribed borders: e.g. superficial basal cell carcinoma,
squamous cell carcinoma, Kaposi's sarcoma and non-operable disseminated
cutaneous metastases of malignant melanoma. The method is regarded as
the treatment of choice or as a valuable alternative treatment in several
skin diseases (Table IV).
Any area of the body can be treated and there are no age limitations.
If the therapeutic result is not sufficient after the first session, cryosurgical
treatment can be repeated as required every 20 to 30 days.
Treatment of choice
Hypertrophic scars and keloids. Over the last few years, several
studies have proved cryosurgery to be an effective and safe therapeutic
regimen in hypertrophic scars and keloids (Table
V). Because of its major advantage of a low relapse rate, the
technique, either as monotherapy or in combination, has been established
as the treatment of choice for hypertrophic scars and keloids.
Cryosurgery as monotherapy was first used by Shepherd and Dawber in
1982. They treated 17 patients with keloids with a single cryosurgical
session achieving 80% improvement of the lesions, however, they observed
a high recurrence rate of 33% [11]. With the exception of case or technical
reports, further monotherapy studies have probably been delayed by this
rather disappointing recurrence rate, until Mende [12] as well as Zouboulis
and Orfanos [13] showed that repeated cryosurgical sessions can provide
a beneficial effect in hypertrophic scars and keloids and additionally
prevent relapses. In the meantime, 72 out of 89 patients with hypertrophic
scars (81%) and 241 out of 356 patients with keloids (68%) in a series
of studies have shown a higher than 50% improvement or complete regression
after cryosurgery [12, 14-17] (Fig.
1). Acne keloids have also shown a 73% improvement or complete
regression in 16 patients treated [18]. To achieve these results one to
more than 20 sessions, of an average of 30 sec each, applied once a month
using the contact method of treatment were required. Progression or recurrence
was rare (2%). The number of sessions and the duration of lesions correlated
significantly with the result of the treatment, i.e. more than
3 sessions and lesions younger than 2 years provided the best results.
The age and the sex of the patient, the size and the localization of lesions
and pretreatment with another method did not influence the outcome of
cryosurgical treatment [14]. Cryosurgery has been shown to produce significantly
better results than intralesional triamcinolone (5 mg/lesion) in a randomized
study involving 11 patients with multiple acne keloids, especially in
early, vascular lesions [19].
Cryosurgery was initially applied in the treatment of hypertrophic scars
and keloids as a weak cryotherapy regimen prior to intralesional corticosteroids
in order to induce tissue oedema and to facilitate intralesional injections.
This procedure was advanced to a combination regimen by Hirshowitz et
al. [20] and produced significant regression of keloids in 119 out
of 159 patients (75%) treated [16, 17, 20, 21]. However, the combined
therapy with intralesional triamcinolone (2 mg/cm2) was not
found to be superior to cryosurgery alone in a randomized trial with 40
patients with keloids [17].
Lesions refractory to cryosurgery or cryosurgery
combined with intralesional corticosteroids can be surgically removed
and postsurgical cryoprevention with or without intralesional corticosteroids
can be applied in order to reduce the risk of recurrence. This regimen
has to be applied for large keloids [22] (Fig.
2). Intramarginal excision is advisable because there is a lower
recurrence rate when compared to extramarginal excision. Removal of the
lesion by surgery or carbon dioxide laser presents similar recurrence
rates, however, the carbon dioxide laser provides a high degree of haemostasis
and avoidance of suture scarring.
Granuloma annulare. Cryosurgery induced complete resolution
of persistent granuloma annulare in 31 patients with 90% good to excellent
cosmetic results. Relapses occurred in only one of 11 patients followed
up for more than 2 years [23] (Fig.
3). This method provides more favourable therapeutic results that
any other regimen reported. A contact freezing of 20 sec with nitrous
oxide ( 86° C) provided optimum results, however, in childhood
skin shorter exposure times (10-15 sec) can also be effective. The entire
surface has to be treated in small lesions and the active rim of lesions
with a diameter >= 4 cm.
Capillary haemangioma of the newborn. Capillary haemangioma of
the newborn shows an excellent response to contact cryosurgery [24, 25]
(Fig. 4). Although these
lesions may regress spontaneously, immediate treatment is indicated in
areas such as the periocular area, the nose, the lips and the anogenital
area. A single session of 10 to 20 sec using the contact technique at
86° C or 196° C is often sufficient. The cosmetic
results are excellent, haemangiomas usually disappear within 4 weeks,
leaving no trace.
Cryosurgery as alternative
treatment
Other benign lesions. A single freeze-thaw cycle is usually sufficient
to treat certain benign skin lesions, i.e. common warts, condylomata
accuminata, cutaneous leishmaniasis, larva migrans, necrobiosis lipoidica,
chronic discoid lupus erythematosus, lichen ruber verrucosus, prurigo
nodularis, verrucous epidermal naevus, solar lentigo, senile haemangioma,
while others, i.e. xanthelasma, syringoma, require repeated treatments
[1-4,26]. Large lesions should be treated over several sessions. In necrobiosis
lipoidica treatment of the active rim only is required.
Atrophic acne scars can be treated by a freezing peel (cryopeeling),
a full face, superficial cryosurgical treatment is especially useful in
patients with mild to moderate ice pick scars [27]. Results are similar
to those obtained with superficial chemical peeling but not as good as
those obtained with dermabrasion. A single aggressive session or repeated
mild treatments, sometimes over 2 to 3 years, are required for optimum
results.
Premalignant lesions. Destruction of tissue is required
for treatment of premalignant (epithelial) lesions, therefore, a longer
freezing time is needed [1-4]. However, both the cosmetic result and the
duration of healing are also taken into consideration when planning treatment.
Freezing is an excellent treatment modality for actinic keratoses (Fig.
5). A cure rate of approx. 99% was reported in the treatment of
70 patients with 1,002 lesions [28]. Both the spray and the contact techniques
have been successfully used and one session is usually sufficient, however,
long-term recurrences are common. Like actinic keratoses, actinic cheilitis
responds well to cryosurgery [2, 10]. Mucosal epithelium is more sensitive
to cryosurgery than epidermis, therefore, the treatment plan has to be
adequately modified (Table IV).
Cryosurgery of lichen sclerosus et atrophicus is often followed by recurrences,
therefore, as for other therapeutic modalities used, a close follow-up
is required.
Malignant skin lesions. Cryosurgery for epithelial skin
tumours is well established in the USA with large numbers of cases reported
[29-33]. In Europe, results on smaller series have been presented [34-43]
(Table VI). Initially,
treatment plans also considered the cosmetic result, however, the rather
high recurrence rates has led over the last 15 years to the increased
use of lower temperatures, greater use of debulking techniques, and a
trend towards more aggressive treatment. Liquid nitrogen is the refrigerant
of choice and a double freeze-thaw cycle is required for treatment of
epithelial skin tumours. A lateral spread of freezing of at least 5 mm
(basal cell carcinoma) to 1 cm (squamous cell carcinoma) beyond the tumour
margins is required and depth of freeze has to be monitored to increase
the security of treatment. Recurrences usually develop during the first
2 years after cryosurgery but can appear at any time. The recurrence rate
depends on the localisation, the size and the histological type of the
tumour, the history of previous recurrence, the safety margins, and the
duration of follow-up. Superficial tumours on the trunk, especially multiple
ones, are the best candidates for cryosurgery (Fig.
6), while recurrent tumours, tumours without defined margins,
voluminous tumours and tumours localised at the folds of the central face
are not suitable for cryosurgical treatment. However, after comparing
the various therapeutic regimens for basal cell carcinoma, only Moh's
micrographic surgery seems to be more efficient than cryosurgery. Moh's
surgery presents 5-year recurrence rates of 1.0% for new and 5.6% for
recurrent tumours, as shown in controlled studies [29, 30]. All other
regimens display similar or higher recurrence rates compared to cryosurgery:
8.7% and 9.8% 5-year recurrence rates were assessed for radiation therapy
of new and recurrent tumours respectively, 10.1% and 17.4% for surgical
excision, 7.7% and 40.0% for curettage and electrodessication. Cryosurgery
could be, therefore, proposed for treating new, histologically confirmed,
superficial, epithelial skin tumours, where it is not appropriate to use
Moh's surgery, a time consuming and expensive technique. Multiple tumours
in elderly patients are suitable for cryosurgical treatment. Shave excision
or curettage preceding cryosurgery is beneficial with regard to the curative
effect [2, 3, 7]. Follow-up has to exceed 5 years after treatment at least,
and, if possible, to be life-long.
Freezing of tumours on the face can be beneficial because a minimum
amount of tissue is sacrificed. Eyelid epithelial cancer, especially tumours
in the vicinity of the lacrimal duct system can be sussessfully treated
with minimal anatomical damage [2, 3]. In tumours larger than 10 mm, fractional
cryosurgery can be performed stepwise: the center of the lesion is frozen,
resulting in a reduction of the tumour; this procedure is repeated, as
necessary, until the diameter of the lesion is smaller than 10 mm; the
standard cryosurgical procedure is then carried out [44].
Squamous cell carcinomas in situ have
shown excellent response rates to cryosurgery, ranging between 97.1 and
97.3% during a follow-up period of 6 months to 5.5 years in two studies
involving 399 lesions [33, 37]. Relapsing tumours, however, responded
with rates of 82.1% only, therefore, this regimen is not recommended.
Bowen's disease is a good target for cryosurgery, reponse rates of 95.5-99.2%
(150 lesions) during a follow-up of six months to 5.5 years having been
reported [33, 37].
Cryosurgery is ideal for patients with macular or maculopapular lesions
of classical and HIV-associated Kaposi's sarcoma, but eradication of large
plaques is difficult [45, 46]. Hand-held spray devices are used and double
freeze-thaw cycles are employed. Lesions can be treated again if they
are persistent or if the disease is progressive. Short-term cure rates
of 70% have been reported [46].
Treatment of lentigo maligna and malignant melanoma with cryosurgery
is generally not recommended, however, the regimen may be administered
in selected cases: large, inoperable lentigo maligna or lesions in older,
inoperable patients have to be aggressively treated with a double freeze-thaw
cycle at 196° C and a 1 cm lateral spread of freeze to also
destroy follicular melanocytes. However, a 10% recurrence rate has been
documented in several reports [2]. Cryosurgery ( 196° C) has
also been used for lentigo maligna which was excised without security
margins [10]. The cryosurgical treatment of malignant melanoma can only
be considered as palliative therapy for multiple cutaneous metastases
in patients with multiorgan metastases. In addition to the local mechanical
effect, an immunological reaction against distant lesions has been assumed
[47, 48], however, this effect has to be further investigated.
Complications and contraindications
Of the various temporary or permanent complications described after
cryosurgery [2, 4, 8, 49], local pain during and/or shortly after treatment
which can been easily managed, bulla formation and local oedema are inevitable
temporary adverse effects; lesional hypopigmentation and/or peripheral
hyperpigmentation is the most common by occurring permanent complication.
Headache after treatment of the head-neck area, haemorrhagic necrosis,
temporary scar hypertrophy 1-3 months after treatment, wound infection,
large local oedema, atrophic scar, haemorrhage, local hypoaesthesia, formation
of milia and cicatricial alopecia of the hair-bearing sites have been
reported in individual patients [14, 41]. Temporary scar hypertrophy at
the central part of the lesion can occur during the first 3 months after
treatment which usually disappears spontaneously. Follow-up of such lesions
(pseudo-recurrence) can distinguish them from a tumour recurrence, the
latter usually presents at the periphery of the treated area and is persisting.
Photodynamic diagnosis with 5-aminolaevulenic acid is advisable here.
Delayed wound healing is an additional adverse effect which mostly occurs
after the combined regimen of cryosurgery and intralesional corticosteroids
or after treatment at the extremities. Rare complications are haemorrhage
during treatment, which can be easily managed, and more complicated nerve
damage. Cartilage damage is also rare because stromal tissue such as cartilage,
connective tissue, and bone is less cold-sensitive than cellular elements
[49]. Patients who developed traumatic neuroma, pyogenic granuloma, and
fibroxanthoma have also been reported [37]. The complications are associated
with the duration of freezing and the number of freeze-thaw cycles employed.
There are a few absolute contraindications including cold-induced urticaria,
cryoglobulinemia, cryofibrinogenemia and Raynaud's disease [4]. As relative
contraindications are suggested collagen diseases, lesions at the extremities
of older patients and black skin because of the long-term depigmentation
occurring due to melanocyte death.
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