Introduction

Nonmelanoma skin cancer (NMSC) is one of the most common types of cancer in the world; the two most prevalent forms are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Epidemiologic studies investigating the prevalence of NMSC in the general population indicate that the number of cases has increased rapidly over the last 2 decades. The incidence of NMSCs was estimated at 1.3 million cases for the year 2000 and is increasing. More than 1 000 000 new cases and 1000 deaths were reported in the United States in 2009. BCC is the most common skin cancer and composes 75% of NMSC. SCC is the second most common skin cancer, accounting for 20% of cases of NMSC. Although the relative mortality is low (0.1%), NMSCs may cause considerable morbidity, particularly in visible areas, such as the head and neck, with consequent unacceptable cosmetic outcomes and/or functional impairments, causing direct and indirect costs of management in the order of billions of dollars annually.

The goal of NMSC treatment is complete eradication of the tumor with preservation of the surrounding structures in an aesthetically acceptable manner. Several treatment options, both surgical and nonsurgical, are available. Mohs micrographic surgery is the therapeutic gold standard for all NMSCs in terms of cure rates, margin control, and tissue conservation. However, surgical removal can also cause significant disfigurement and functional impairment. Alternatives to the surgical management may be preferred under certain circumstances. Some tumors may be multifocal, extensive, in cosmetically sensitive areas, or not amenable to simple surgical treatment. Significant scarring may result after surgical intervention, depending on the location of the lesion, as in the case of small superficial BCCs on the shoulders and central chest, which may produce hypertrophic scarring or spread scarring disproportionate to the initial size of the lesion. In addition, as the population of older people, who may have more surgical risk factors, continues to increase, a careful assessment of surgical risk factors will need to be taken into account both preoperatively and perioperatively for an increasing proportion of patients. Skin cancer incidence increases with age, as do other medical problems; a nonsurgical option may be a strong consideration as an alternative treatment choice.

Cryotherapy, curettage and electrodesiccation, radiation therapy, photodynamic therapy, laser, interferon (IFN), imiquimod, retinoids, and 5-fluorouracil (5-FU) have been demonstrated to be effective for the treatment of NMSC.

This review article explores the available nonsurgical treatment options, their indications, and their efficacy ( Table 1 ) .

Cryotherapy

Cryotherapy involves tissue destruction by application of extreme cold to the lesion using liquid nitrogen. Vaporizing liquid nitrogen is brought into contact with the skin lesion to freeze it. This approach destroys superficial tissue. Cryotherapy is a simple, rapid, and inexpensive method ( Fig. 1 ). The optimum duration of freezing is not known, but the lowest rates of recurrence are obtained using aggressive protocols. Several cryotherapy sessions may be needed. Because not all cells die after the first freeze-thaw cycle, treatment is generally repeated. Tumor cells are known to be very sensitive to cryosurgery because of their high content of water, higher metabolism, and microcirculation. Connective tissue is less sensitive, whereas fibroblasts are relatively resistant to cold. This modality has been recommended for the treatment of actinic keratosis (AK), Bowen disease (BD), superficial BCC, small nodular BCC, and small well-differentiated SCC.

Cryotherapy device.

The practical requirements for effective cell killing by cryosurgery are rapid freezing at a rate greater than 100°C/min, tissue temperature less than −25°C, slow thawing at a rate of 10°C/min or less, and at least 2 freeze-thaw cycles. BCCs require 2 × 40 to 60 seconds, this time must be adjusted depending on the size and depth of the tumor and on individual differences; sometimes a third freeze-thaw cycle is needed. The cryotherapy of cutaneous malignancies is considered to be an alternative method because surgical excision provides histologic control and a more rapidly healing wound. Cryosurgical treatment of BCCs gives cure rates that compare favorably with other modes of therapy provided the correct technique is used and the treatment is limited to small (<20 mm), well-defined, previously untreated tumors, avoiding BCCs on the inner canthus of the eye, nasolabial and retro-auricular folds, and the hair-bearing scalp. Some investigators advocate debulking the tumor using curettage or electrosurgery before cryotherapy. The recommended temperature is between −50°C and −60°C at the base of the tumor, and the freeze time is approximately 45 seconds for a 1-cm lesion. During the past 2 decades, there has been an increased use of colder temperatures. There are some contraindications for cryosurgery. Patients who have cold urticaria, cold intolerance, cryofibrinogenemia, or cryoglobulinemia are best treated by other means. Tumors with indistinct or ill-defined borders (eg, morpheaform or infiltrative histologic subtypes) as well as deeply penetrating and very aggressive lesions are best treated by other modalities. Some anatomic areas where cryosurgery should be undertaken cautiously include the corners of the mouth, the vermilion margin of the lips, eyebrows, inner canthi, the free margin of the ala nasi, and the auditory canal because scarring or retraction of the tissue can occur.

Although hypopigmentation is a frequent consequence of cryosurgery for skin tumors, wounds tend to heal without significant tissue contraction, and this can give rise to excellent cosmetic results for some patients. Occasionally, hypertrophic scarring may develop, particularly after treatment of a large lesion; but this always improves and resolves with time, usually within months.

In the literature, it has been reported that the 5-year cure rate is 97% to 99% for nonmelanoma skin cancers. Zacarian reported an 18-year cure rate of 97.4% in the treatment of 4228 carcinomas.

Cryotherapy

Cryotherapy involves tissue destruction by application of extreme cold to the lesion using liquid nitrogen. Vaporizing liquid nitrogen is brought into contact with the skin lesion to freeze it. This approach destroys superficial tissue. Cryotherapy is a simple, rapid, and inexpensive method ( Fig. 1 ). The optimum duration of freezing is not known, but the lowest rates of recurrence are obtained using aggressive protocols. Several cryotherapy sessions may be needed. Because not all cells die after the first freeze-thaw cycle, treatment is generally repeated. Tumor cells are known to be very sensitive to cryosurgery because of their high content of water, higher metabolism, and microcirculation. Connective tissue is less sensitive, whereas fibroblasts are relatively resistant to cold. This modality has been recommended for the treatment of actinic keratosis (AK), Bowen disease (BD), superficial BCC, small nodular BCC, and small well-differentiated SCC.

Cryotherapy device.

The practical requirements for effective cell killing by cryosurgery are rapid freezing at a rate greater than 100°C/min, tissue temperature less than −25°C, slow thawing at a rate of 10°C/min or less, and at least 2 freeze-thaw cycles. BCCs require 2 × 40 to 60 seconds, this time must be adjusted depending on the size and depth of the tumor and on individual differences; sometimes a third freeze-thaw cycle is needed. The cryotherapy of cutaneous malignancies is considered to be an alternative method because surgical excision provides histologic control and a more rapidly healing wound. Cryosurgical treatment of BCCs gives cure rates that compare favorably with other modes of therapy provided the correct technique is used and the treatment is limited to small (<20 mm), well-defined, previously untreated tumors, avoiding BCCs on the inner canthus of the eye, nasolabial and retro-auricular folds, and the hair-bearing scalp. Some investigators advocate debulking the tumor using curettage or electrosurgery before cryotherapy. The recommended temperature is between −50°C and −60°C at the base of the tumor, and the freeze time is approximately 45 seconds for a 1-cm lesion. During the past 2 decades, there has been an increased use of colder temperatures. There are some contraindications for cryosurgery. Patients who have cold urticaria, cold intolerance, cryofibrinogenemia, or cryoglobulinemia are best treated by other means. Tumors with indistinct or ill-defined borders (eg, morpheaform or infiltrative histologic subtypes) as well as deeply penetrating and very aggressive lesions are best treated by other modalities. Some anatomic areas where cryosurgery should be undertaken cautiously include the corners of the mouth, the vermilion margin of the lips, eyebrows, inner canthi, the free margin of the ala nasi, and the auditory canal because scarring or retraction of the tissue can occur.

Although hypopigmentation is a frequent consequence of cryosurgery for skin tumors, wounds tend to heal without significant tissue contraction, and this can give rise to excellent cosmetic results for some patients. Occasionally, hypertrophic scarring may develop, particularly after treatment of a large lesion; but this always improves and resolves with time, usually within months.

In the literature, it has been reported that the 5-year cure rate is 97% to 99% for nonmelanoma skin cancers. Zacarian reported an 18-year cure rate of 97.4% in the treatment of 4228 carcinomas.

Curettage and electrodesiccation

Electrodesiccation and electrofulguration represent the most commonly uses of electrosurgery in dermatology. Although often used to denote the same procedure, there is a subtle technical difference between the two. With electrodesiccation, the electrode tip is in contact with the tissue; with electrofulguration, there is a 1- to 2-mm separation ( Fig. 2 ). Electrodesiccation or fulguration is commonly used in the treatment of BCCs and SCCs less than 2 cm in diameter. When treating selected BCCs and SCCs, curettage must be followed by electrodesiccation. The bulk of the tumor should be removed by vigorous curettage followed by light electrodesiccation of the base of the lesion with a 2- to 3-mm margin of surrounding skin. This modality can be used for the same spectrum of lesions as cryotherapy.

Electrocautery device.

The large, multiple superficial BCCs found on the trunk are effectively and easily treated by curettage and electrodesiccation. Small lesions (5–20 mm) of the nodular or cystic type may be treated satisfactorily by this method in most locations. Central facial BCCs and those of infiltrating, micronodular or morphealike histologic type are prone to recurrence if treated with curettage and desiccation. These lesions are, thus, better treated by methods, such as excision or Mohs microsurgery, that permit examination of the margins. Cure rates have been reported as 97% to 98% with curettage and electrodesiccation for BCC. Paradoxically, despite these high cure rates, histologic examination after curettage and electrodessication shows that some residual tumor is present in almost 30% of cases. Thus, cure must also depend on other factors, such as residual tumor cell mass, inflammatory reaction, and healing responses.

Curettage and electrodessication can be used for small SCCs in situ and well-differentiated primary SCCs less than 1 cm in diameter. For larger and higher-risk tumors, microscopically controlled surgery is recommended. These high-risk SCCs include lesions arising on scars; ears; lips; areas of radiation or thermal injury; chronic ulcers or sinuses; BD; non–sun-exposed sites; and large (>2 cm), thick (>4 mm), poorly differentiated and recurrent SCCs or those arising in immune-compromised patients.

Because the procedure does not divide the upper dermis connective tissue network, healing is usually predictable and occurs in most cases with mild scarring. However, hypopigmentation or hypertrophic scar formation may occur, the latter particularly when the upper trunk is treated.

Photodynamic therapy

Photodynamic therapy (PDT) may be briefly defined as the use of cytotoxic oxygen radicals (primarily singlet oxygen) generated from photoactivated molecular species to achieve a therapeutic response. The necessary components are photoactivating light, an exogenous photosensitizer, tissue oxygen, and a target cell. Photosensitizers may be administered systemically as intact macrocycles or topically as prophotosensitizers, which are metabolized to photoactive macrocycles. A time period is required after drug administration to allow photosensitizer production and partitioning into targeted tissue and cellular compartments. Visible light from coherent (laser) or noncoherent sources is used to illuminate the skin. The light can be either low power, nonthermal, and continuous wave or high power, photothermal, and pulsed; the latter type introduces varying degrees of photothermal injury via biologic chromophores, augmenting overall clinical injury. Target cells may undergo apoptosis caused by membrane-bound photosensitizers or ischemic necrosis caused by vascular injury from photosensitizers concentrated in endothelial cells or both. There is also evidence that PDT may act as a biologic response modifier. PDT is a broadly inflammatory event; cytokines, chemokines, and other immunogenic proteins released by injured and dying cells create an inflammatory and immunologically active milieu.

The most common and perhaps most sought-after oncologic indication for PDT remains BCC. Studies comparing its efficacy against standard therapies, such as cryosurgery, surgical excision, or Mohs micrographic surgery, are limited or absent. Systemic porphyrin-based PDT clearly showed that BCCs respond 80% to 100%, but these studies relied on short-term follow-up and clinical responses. The systemic photosensitizer agents used to treat BCCs in the studies included porfimer sodium, benzoporphyrin derivative monoacid ring A, and meta-tetrahydroxyphenylchlorin, whereas 5-aminolevulinic acid (ALA) and methyl-esterified ALA (mALA) were the primary topical agents. Although response rates were encouraging with systemic PDT, there were several expected drawbacks, including generalized photosensitivity, facial edema, and pain. Topical approaches to the photodynamic treatment of BCC have been based almost entirely on ALA and more recently mALA. Topical photosensitization for PDT offers clinical advantages of ease of drug delivery and photosensitivity confined to the application site. No generalized photosensitivity occurs because of the limited systemic absorption of ALA or protoporphyrin IX. An attractive feature of topical PDT is the ability to treat relatively large body surface areas with a single intervention, often with a minimal amount of scarring. Topical delivery of mALA proved effective in treating nonmelanoma skin cancer. Three to six months after the PDT session, 87.5% (310 out of 350) of the BCCs responded completely. Ninety-three percent of BCCs received a single treatment session, 6% a second session.

SCC in situ is also quite responsive to PDT. High cure rates have been observed with both systemic and topical photosensitizers. Few reports detail the photodynamic treatment of invasive cutaneous SCC and, thus far, the results have been unsatisfactory compared with surgical excision. Primary treatment of SCC with PDT should be reserved for early invasive disease (<1 mm) and must take advantage of multiple treatments and high doses of deeply penetrating red light. In advanced head and neck SCC, PDT should be considered an adjunctive treatment modality. Reports of higher recurrence rates in NMSC suggest that photodynamic therapy may be best reserved for select situations when better-established methods are not feasible.