Background

Cryosurgery was introduced at the turn of twentieth century, but was not popularized for the treatment of skin cancers until the 1960s and has been in widespread use since. Liquid nitrogen exists at a temperature of −195°C, and is sufficient to induce tissue temperatures in the −50°C to −60°C range, which are adequate for tissue destruction.

Technique

Cryotherapy is rapid, simple, well tolerated, and effective, though there are few randomized controlled trials documenting its effectiveness, and variation in technique makes generalization of results difficult. Techniques include intralesional, direct-contact, and open-spray techniques, all with or without the use of a thermocouple to directly monitor temperature. Most current use entails use of the open-spray technique with the so-called cryo-gun, which simultaneously permits storage of cryogen and a constant rate of spray discharge. There is no consensus on the number of freeze-thaw cycles, the amount of surrounding tissue that should be frozen, or the appropriate thaw time. In general, malignant lesions require a more prolonged freeze, which is associated with deeper penetration and a higher volume of tissue destruction. Much of the current data is from large case series, short of the gold standard of randomized, prospective trials. Several comparative trials, discussed below, have methodological shortcomings, using substandard freezing times or too few cycles of cryotherapy, with predictably poor results. Still needed are large, well-designed, prospective, randomized studies.

Indications

Cryosurgery is recommended for treatment of actinic keratoses (AK) and nonmelanoma skin cancer (NMSC) in recommendations from the British Association of Dermatologists (BAD), American Academy of Dermatologists (AAD), and National Comprehensive Cancer Network (NCCN). A 2011 review found better cosmesis and lower recurrence rates with surgical excision, as well as a preference among both patients and providers for surgical excision over cryotherapy in treatment of NMSC. Because of the uncertainty in appropriate technique and general lack of high-quality data, NCCN guidelines recommend that in patients with low-risk shallow cancers, such as squamous cell carcinoma (SCC) in situ (SCC-IS) or low-risk superficial basal carcinoma, vigorous cryotherapy may be considered. In clinical practice in the United States, cryotherapy is used mostly for the treatment of AK and benign lesions (eg, verruca vulgaris).

Actinic Keratoses

Cryosurgery is very effective in the treatment of AK, with a cure rate of nearly 99% in a large retrospective series. In direct comparison trials, cryotherapy has been shown to be both equivalent to and inferior to photodynamic therapy in the treatment of AK. However, the trial that showed equivalence used 2 cycles of cryotherapy whereas the second trial used a single cycle of cryotherapy with only 20 seconds of thaw time, highlighting the problem of variability in technique. Given the high prevalence of AK and the number and location of typical lesions, cryotherapy remains a recommended standard treatment by both the AAD and the BAD. In the United States, it is the first-line treatment for AK.

Basal Cell Carcinoma and Squamous Cell Carcinoma

At present, there are insufficient data to permit routine recommendation of cryotherapy for treatment of nonmelanoma skin cancer, notwithstanding the relatively impressive cure rates reported in large series. The BAD guidelines recommend cryotherapy for treatment of low-risk basal cell carcinoma (BCC) and “caution” in using cryotherapy for SCC. This sentiment is echoed in the NCCN guidelines, which state “since cure rates can be lower, superficial therapies should be reserved for those patients where surgery or radiation is contraindicated or impractical.”

A 1990 article by Graham and Clark compared the results of more than 20 years of data from both their clinic and that of Zacarian, with a combined 6800 patients and 9267 skin cancers, 8124 of which were BCC (87%), with the remainder including SCC, SCC-IS, lentigo maligna, keratoacanthoma (KA), and Kaposi sarcoma. Both open-spray and direct-probe techniques with a single freeze-thaw cycle were used for most lesions, and a double cycle was used for those tumors deemed more resistant because of location, size, depth, or history of recurrence. A thermocouple was used, with at least 60 seconds of measured thaw time. Documented 5-year cure rates were 97% for BCC, 97% for SCC, and 97% for all other lesions treated. Cure rates were nearly identical in the series from Zacarian, using a double freeze-thaw cycle. A more recent series from 2004, also using a double freeze-thaw cycle and the open-spray technique, included 30 years of treatment and 4406 new and recurrent BCC and SCC, with an overall cure rate of 98.6%. A randomized trial of cryotherapy versus photodynamic therapy for SCC-IS noted a relatively poor response rate at 1 year of 67%, but closer inspection reveals that a single cycle of cryotherapy, maintained for “a minimum of 20 seconds,” is likely far below the required time for adequate treatment. Part of the problem with using cryotherapy for malignant lesions is the uncertainty regarding the duration of the freeze-thaw cycle and the lack of routine availability of thermocouples to monitor temperature. As a consequence, recurrence rates in clinical practice are unacceptably high, and cryotherapy is not routinely used for treatment of nonmelanoma skin cancer in the United States. An ancillary process is the peripheral damage to normal tissue induced by a prolonged freeze-thaw cycle, and the attendant posttreatment tissue necrosis, pain, delayed healing, loss of function, and scarring.

A single randomized trial has been done comparing curettage plus cryotherapy (n = 51) with surgical excision (n = 49) in the treatment of BCC. The investigators found a trend toward higher recurrence rates with cryosurgery, though not statistically significant, and concluded that “owing to the trend toward lower recurrence rates, better cosmetic results, and reduced wound healing time, we believe that SE [surgical excision] should be preferred to C&C [curettage and cryotherapy] in the treatment of primary, nonaggressive BCC of the head and neck.”