Author: Mark Naylor, MD
Contributing Writer: Emma Hitt, PhD

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Nonmelanoma skin cancers (NMSCs) comprise more than one third of all cancers in the United States and are widely described as a worldwide epidemic.^[1] The term "nonmelanoma skin cancer" includes 2 major types: basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Other less common NMSCs include Kaposi's sarcoma, cutaneous lymphoma, skin adnexal tumors, certain sarcomas, and Merkel cell carcinoma.

BCC begins in the basal cell layer of the epidermis, and it accounts for about 75% to 80% of NMSCs. BCC usually develops on chronically sun-exposed areas of the skin, especially the head and neck, although about 20% of cases arise in intermittently exposed areas.^[2,3] BCC rarely metastasizes, and it is usually slow growing. However, if left untreated, it may spread locally to the bone or other tissues beneath the skin. Common forms of BCC can be classified as nodular, superficial, and morpheaform, occurring at a rate of 79%, 15%, and 6%, respectively.^[4] Nodular BCC is often found on the face and presents as a reddish-brown or pearly, translucent papule with telangiectasia (Figures 1 and 2). The lesion may have rolled borders and a central depression. Nodular BCC may bleed spontaneously or develop into an open sore sometimes referred to as a "rodent ulcer" (Figure 3). Superficial BCC (sBCC) usually appears on the trunk or limbs and presents as slow-growing, shiny pink or red, slightly scaly plaques that may bleed easily (Figure 4). Morpheaform BCC, also known as sclerosing BCC, appears as a skin-colored, waxy, thickened scar.

Figure 1. Nodular BCC. (Reproduced with permission of publisher from Halpern, AC, Myskowski, PL: X Malignant Cutaneous Tumors. 2 Dermatology. ACP Medicine Online. Dale DC, Federman DD, Eds. WebMD Inc., New York, 2002. http://www.medscape.com/px/trk.svr?exturl=http://www.acpmedicine.com)

Figure 2. Nodular BCC. (Courtesy NCI)

Figure 3. Rodent ulcer. (Reproduced with permission of publisher from Halpern, AC, Myskowski, PL: X Malignant Cutaneous Tumors. 2 Dermatology. ACP Medicine Online. Dale DC, Federman DD, Eds. WebMD Inc., New York, 2002. http://www.medscape.com/px/trk.svr?exturl=http://www.acpmedicine.com)

Figure 4. Superficial BCC. (Reproduced with permission of publisher from Halpern, AC, Myskowski, PL: X Malignant Cutaneous Tumors. 2 Dermatology. ACP Medicine Online. Dale DC, Federman DD, Eds. WebMD Inc., New York, 2002. http://www.medscape.com/px/trk.svr?exturl=http://www.acpmedicine.com)

SCC accounts for about 20% of NMSCs. In contrast to BCC, SCC arises from more superficial layers of the epidermis and tends to be more aggressive. SCC can invade tissues beneath the skin and may spread to lymph nodes and/or distant parts of the body. These cancers typically appear on sun-exposed areas of the body, such as the face, ears, neck, lips, and backs of the hands, but they can also develop within scars or skin ulcers and on the skin of the genital area. SCC can present as an erythematous to flesh-colored hyperkeratotic plaque, which may ulcerate. Another presentation is a pink-to-flesh-colored scaly, enlarging nodule (Figure 5).

Figure 5. Squamous cell carcinoma on arm. Reproduced with permission of publisher from Halpern, AC, Myskowski, PL: X Malignant Cutaneous Tumors. 2 Dermatology. ACP Medicine Online. Dale DC, Federman DD, Eds. WebMD Inc., New York, 2002. http://www.medscape.com/px/trk.svr?exturl=http://www.acpmedicine.com

Precursors to SCC include actinic keratosis (AK) and SCC in situ (also called Bowen's disease). SCC in situ is a full-thickness malignant transformation of the epidermis that, by definition, has not invaded the dermis. The incidence of SCC in situ has been estimated at about 142 out of 100,000 white individuals residing in Hawaii,^[5] and fewer than 5% of cases advance to invasive SCC.

AK is increasingly being conceptualized as the earliest clinical manifestation of SCC. While AK lesions are frequently referred to as "premalignant," many researchers think that this designation is misleading and does not accurately represent their pathobiologic behavior (Figure 6).^[6] To reflect this, it has been proposed that the term "actinic keratosis" should be replaced by the term "keratinocytic intraepidermal neoplasia."^[7] Data derived from multiple studies estimate a risk of AK progression to invasive SCC ranging from 0.025% to 16%.^[8]

Figure 6. Invasive squamous cell carcinoma (arrow) developed among several actinic keratoses on sun-damaged scalp. Biopsy was necessary for diagnosis.

AKs are usually found on sun-exposed areas of the body, most commonly the face, lower lip, bald scalp, neck, arms, and hands. While lesions vary in color from reddish brown to gray, they often have a whitish appearance because of the presence of scale. AKs may be as subtle as localized erythematous or hyperpigmented macules that are difficult to see but can be felt because of their rough texture. They may also present as hyperkeratotic papules. Patients usually have multiple lesions, and the presence of an AK is often indicative of a larger area of ultraviolet (UV) radiation-damaged skin, or a "field of cancerization." According to the American Academy of Dermatology, more than half of middle-aged fair-skinned persons living in hot, sunny geographical areas have AKs.^[9] While AKs usually start to appear in middle age, these lesions are now being seen in people in their 20s and even among teenagers.

Rarer types of NMSC include Kaposi's sarcoma, which usually starts within the dermis but can also develop in internal organs. This cancer, once extremely rare, has since become more common due to its association with HIV/AIDS. Another form of NMSC, primary cutaneous lymphoma (mycosis fungoides), is a low-grade lymphoma that primarily affects the skin. Generally, it has a slow course and often remains confined to the skin, but progression of the tumor to a more aggressive, life-threatening stage is more likely the longer it has been present. Adnexal tumors, which start in the hair follicles or sweat glands, are extremely rare and usually benign. Sarcomas develop from connective tissue cells, and include dermatofibrosarcoma protuberans and angiosarcoma. Angiosarcomas occurring in the skin are in many ways the most malignant of all skin cancers. Thankfully, these are rare and in the past have been confined primarily to elderly men with the greatest lifetime UV exposure. Merkel cell carcinoma develops from neuroendocrine cells in the skin and frequently metastasizes to internal organs.

The exact number of people with NMSC is unknown because these cancers are not reported to cancer registries in most countries. However, it is estimated that more than 1 million cases of BCC or SCC occur in the United States every year,^[10] and the average increase of NMSC in white populations in Europe, the United States, Canada, and Australia was 3% to 8% per year since the 1960s.^[1] The absolute numbers and proportions worldwide vary due to differences in sun exposure and skin type (Table 1).

Table 1. World Age-Standardized Rates of Nonmelanoma Skin Cancer in White Subjects Per 100,000 Persons

Mortality is rare given the large number of cases of NMSC; about 2500 people die each year in the United States (National Cancer Institute Public Information Office; Lynn Ries, Health Statistician, Cancer Statistics Branch; personal communication; May 11, 2004). Immunocompromised individuals, including patients receiving immunosuppressive treatment after organ transplantation or for the treatment of autoimmune diseases including arthritis and lymphoma, may be at increased risk of death from NMSC.

Risk factors for NMSC can be classified as environmental and nonenvironmental, and certain skin comorbidities may predispose individuals to NMSC. The key environmental risk factor for NMSC is UV radiation from exposure to sunlight and artificial tanning lamps.^[11,12] Consequently, persons living in areas that receive intense sunlight or those who spend extended periods of time outdoors, at high altitudes, or who tan artificially are at greater risk than those who do not. Other environmental risk factors include arsenic;^[13] hydrocarbons such as tar, coal, paraffin, and certain oils;^[14] and x-rays.^[15] Tobacco smoking has recently been linked to SCC (Figure 7); after adjustment for age, sex, and sun exposure, the relative risk of SCC was 2.0 (95% confidence interval, 1.2 to 3.2; P = .008), and a dose-response relationship with number of cigarettes and pipes smoked was observed.^[16]

Figure 7. Squamous cell carcinoma on the lip of a pipe smoker.

Genetic predisposition and nonenvironmental factors such as skin type can exacerbate the risk posed by solar radiation. Fair-skinned individuals who have received high levels of sun exposure are at the greatest risk for developing these cancers. In addition, men are about twice as likely to develop NMSC as women.^[17] Studies of the genetic mechanisms in sporadic (environmentally acquired or nonfamilial) cases of BCC indicate frequent mutations in the tumor-suppressor PTCH (patched) gene system found on chromosome 9q.^[18] In addition, mutations in the tumor suppressor gene p53 appear to be an early common event in SCC development.^[19] Mutations in various oncogenes such as ras and fos are also thought to play a role, although their specific actions are currently unclear.

Certain genetic diseases and skin disorders predispose individuals to NMSC. These include albinism^[20] and xeroderma pigmentosum,^[21] which involves a defect in the repair of UV-induced radiation damage to DNA. Another predisposing factor is basal cell nevus syndrome, a rare congenital condition that causes multiple BCCs. Affected people typically develop basal cell cancers in their teens or early 20s.^[22] Organ transplant recipients are at increased risk, especially for SCC, and the rate in the population 20 years after transplant may be as high as 80% (Figure 8).^[23] The use of oral steroids (regardless of underlying disease) has recently been linked to NMSC.^[24] Patients on immunosuppressive therapy for autoimmune disease or arthritis are at increased risk for SCC, as are patients who have received extensive PUVA therapy for psoriasis.^[25] Persons with scars from severe burns, severe bone infections, and inflammatory skin diseases are also at increased risk of developing NMSCs, especially SCC. Although this risk is generally small, these tumors may be aggressive with increased risk of metastasis.

Figure 8. Multiple SCCs in a heart transplant recipient (Figure courtesy of Thomas Stasko, MD).

Human papillomavirus (HPV) is found in many NMSCs and probably contributes to the molecular mechanisms of carcinogenesis, particularly certain viral subtypes. A recent study indicates that cutaneous infections with HPV5 and HPV8 may result in an increased risk of SCC development in transplant recipients.^[26] Another study suggests that persistent infections of the skin with high-risk genital HPV types associated with cervical cancer may also represent a risk factor for NMSC in a nonimmunosuppressed population.^[27] After adjusting for age, gender, and sun exposure, the odds ratio for NMSC in patients who were DNA positive for the high-risk mucosal HPV types 16, 31, 35, and 51 was 59-fold compared with controls.^[27]

Workup of patients with lesions indicative of NMSC should begin with a history and physical examination.^[28] For BCC, a complete skin examination is indicated because of the increased risk of AKs or cancers located at other skin sites in persons presenting with a suspicious lesion. For SCC, regional lymph nodes should also be examined. Once a suspicious lesion has been detected, the lesion, including the reticular dermis in most cases, should be biopsied because an infiltrative histology may sometimes be present only at the deeper, advancing margins of a tumor.^[28]

The 2 most commonly used biopsy techniques are shave biopsy and punch biopsy. Shave biopsies obtain a superficial sample of tissue, whereas punch biopsies obtain a deeper tissue sample. Each method is able to determine the cancer type and pathologic growth pattern. If BCC is suspected, a shave biopsy is generally acceptable. But if SCC is suspected, a punch biopsy may permit better evaluation of the entire depth of the lesion.^[29] In patients with SCC, the presence of a palpable regional lymph node indicates the need for a fine needle aspiration. If the aspiration is negative, an open biopsy should be performed. In rare instances, a deep extension of the NMSC, for example into bone or the orbit, may be present, and preoperative imaging studies can help assess the extent of soft tissue or bone involvement.^[28]

Therapies currently used to treat localized NMSC include surgical techniques (curettage and electrodesiccation, excision, Mohs surgery), cryotherapy, and radiation therapy. Each methodology has advantages and disadvantages for certain tumor types. More recently developed therapies include interferon-alfa, 5-fluorouracil (5-FU), topical and systemic retinoids, photodynamic therapy, laser therapy, diclofenac sodium, and imiquimod.

Goals in treating NMSC are, in order of importance, disease cure, preservation of function, and restoration of cosmesis.^[10] The type of treatment a patient receives depends on several factors. Characteristics associated with the tumor include the size, shape, and location, as well as the nature of the skin from which the tumor arises and the type and depth of the tissues underlying the tumor. Nontumor-related factors include age, cost of therapy, time necessary for therapy, wound care demands, cosmesis, and patient perception of treatment. The type of treatment a patient receives will also depend on the cure rate. Most methodologies have at least a 90% five-year cure rate for primary BCC or SCC, although recurrent BCC or SCC is more like to recur after treatment.

Both BCC and SCC have clinical courses and treatment considerations that are similar; however, several significant differences exist between BCC and SCC. For example, BCC almost never metastasizes in immunologically competent individuals, but SCC metastasizes in approximately 2.5% to 5% of cases. Furthermore, locally recurrent SCCs have a metastatic rate approaching 30% and can quickly become life threatening. Thus, while many of the treatments are similar for SCC and BCC, in general, SCC may need to be treated more aggressively than BCC.

Electrodesiccation and Curettage (E&C)

E&C involves the cauterization and destruction of the tumor and a surrounding margin of clinically unaffected tissue. The technique is considered effective for low-risk tumors. Lesions best suited for E&C are those with a low risk of metastasis that are small (1 cm or less in diameter), well defined, and primarily on flat surfaces, such as the neck, trunk, arms, or legs.^[30] E&C is not as reliable for treating hair-bearing sites because of the risk that a tumor that extends down follicular structures might not be adequately removed. Furthermore, if the tumor extends down to the subcutaneous layer, surgical excision is preferred over E&C because the effectiveness of E&C depends on differentiating between firm, normal dermis and soft tumor tissue. Atrophic skin in an elderly patient and inflamed skin may be more friable under the curette; therefore, judgment is required to avoid removal of uninvolved tissue. In addition, subcutaneous fat is softer than tumor tissue, which further complicates the selection and removal of tumor cells with this method.^[28]

Relative contraindications to E&C include BCC of 2 cm or more with extension into the subcutaneous fat, recurrent lesions, aggressive subtypes of BCC or SCC, tumors in high-risk anatomic locations (eg, face, ears, vertex of scalp), and tumors in areas where cosmetically unacceptable scars may result.^[29]

Excision

Excisional surgery is the most common treatment for low-risk NMSCs that extend into the reticular dermis because it results in a higher cure rate than superficial ablative therapy (ie, E&C and cryotherapy).^[31] In addition, some patients for whom superficial ablative therapy is an option prefer excisional surgery because of its superior cosmetic results and more rapid healing, although these benefits must be weighed with the possibility of postoperative restriction of activity. Standard surgical excision is usually followed by postoperative pathologic assessment of margins. Excision of clinically well-circumscribed basal cell or squamous cell tumors less than 2 cm in diameter should result in complete removal (with a 95% confidence interval) if 4-mm surgical margins are used.^[32,33] In addition, any peripheral rim of erythema around a squamous cell cancer must be included in what is considered to be the tumor.^[28] National Comprehensive Cancer Network guidelines suggest that surgical margins for squamous cell cancers should be 4-6 mm. The indications for this approach also include re-excision of low-risk primary BCC and SCC located on the trunk and extremities if positive margins are obtained after an initial excision with postoperative margin assessment.^[28]

Mohs Micrographic Surgery

Mohs micrographic surgery is a specialized form of excisional surgery that provides 100% microscopically controlled histologic margins.^[34] The technique involves tumor excision, mapping of the removed tissue, and immediate microscopic assessment of the surgical specimen. If occult tumor extension is detected microscopically, the process is repeated until a tumor-free margin is attained. Mohs surgery is curative for 99% of primary BCCs and 97% of primary SCCs -- the highest documented cure rates.^[35] In patients with recurrent SCC, Mohs surgery is associated with 5-year cure rates of 90% to 93.3%, in contrast to cure rates of 76.7% for recurrent tumors treated with standard excision.^[36] Furthermore, this technique spares normal tissue and allows for simpler reconstruction. Mohs surgery is indicated for the treatment of recurrent tumors, incompletely excised tumors, tumors larger than 2 cm, tumors with indistinct margins or aggressive histology, tumors in areas with high propensity for recurrence and metastasis, and tumors in areas where maximal tissue conservation is required.^[29]

Cryotherapy

Cryotherapy is usually reserved for smaller, clearly demarcated lesions, but it may be appropriate for patients with large superficial tumors, multiple tumors, or tumors within scars in low-risk sites.^[37] The procedure involves the application of liquid nitrogen, which destroys the tumor cells. Patients with bleeding disorders or those who cannot tolerate surgery may benefit from this option. Cure rates can be high, but this depends heavily on appropriate patient selection and the skill of the treating physician. A study of 563 primary SCCs between 0.5 and 1.2 cm in diameter suggested a cure rate of 97.3%,^[38] and a recent analysis indicated that the overall 30-year cure rate was 98.6% in more than 2000 patients with new and recurrent BCC and SCC.^[39] However, the patients included in this analysis were all treated by the same highly skilled physician. More typical 5-year cure rates with cryotherapy for primary basal cell carcinoma are estimated at 93%.^[10] Contraindications to cryotherapy include tumors with poorly defined borders, invasive SCC, aggressive subtypes of BCC, recurrent skin cancers, and tumors in hair-bearing skin that are susceptible to cryotherapy-induced alopecia.^[30] Hypopigmented scars are expected after using cryosurgery for NMSC. However, keloids and hypertrophic scars rarely occur on the chest, shoulders, and back. Another disadvantage is that the method is not always predictable, and significant necrosis of healthy tissue may result and may cause prolonged ulcers in certain susceptible patients, such as patients with diabetes. Additionally, cryotherapy requires considerable expertise for optimal efficacy despite its seeming simplicity.^[10]

For the surgical treatment of AK and Bowen's disease, cryosurgery and E&C are indicated,^[28] although these lesions can also be effectively treated with several nonsurgical methods (discussed below).

Despite the high cure rate for surgical methods, these treatments carry with them risks of morbidity, such as infection and scars, associated with any surgery. In addition, hypertrophic scars may become chronically painful or pruritic, and when NMSC is in a visible location, such as the face, surgical procedures may be unacceptably deforming. Consequently, nonsurgical methods may represent an attractive option for certain patients with NMSC, and in many cases, cure rates approach those provided by surgery.

Topical and Intralesional 5-FU

5-FU is the most common topical chemotherapy for AK and small superficial noninvasive NMSC.^[40] It is approved by the US Food and Drug Administration (FDA) for the treatment of AK and/or sBCC in the following formulations: 0.5% cream for the once-daily treatment of AK; 2% cream and solution for the twice daily treatment of AK; and 5% cream and solution for the treatment of AK and sBCC. A major advantage is that this treatment can be administered by the patient at home; however, application must continue for 4 to 6 weeks for NMSC.^[10] When treating BCC, all lesions should be confirmed to be superficial by biopsy before 5-FU therapy. Comprehensive follow-up is essential to ensure compliance, adequate response, and tumor resolution. Topical 5-FU is not indicated for invasive or high-risk tumors, and its use in nonsuperficial lesions may conceal deeper tumor foci.^[10]

Clearance rates with 5-FU in AK and superficial SCC (sSCC) are approximately 93%.^[41] Side effects of 5-FU include progressive inflammation, erythema, and erosions; these effects are extensions of the pharmacologic activity of the drug. Contact dermatitis with intense pruritis may occur.

A novel topical 5-FU cream that contains 0.5% 5-FU in a microsphere vehicle has been approved by the FDA for the treatment of AK, and this low-dose formulation appears to reduce AK lesions while maintaining a more tolerable irritation profile.^[42,43]

Intralesional 5-FU is also used in the treatment of AK and Bowen's disease. As with topical 5-FU, intralesional 5-FU is contraindicated in all but superficial cases of NMSC; however, a recent case report indicated that intralesional 5-FU was effective in treating a patient with SCC located at the junction of the right alar crease and right nasolabial fold. The patient was treated with 8 weekly injections of 5-FU, with doses ranging from 0.8 to 2.4 mL. A repeat biopsy after the eighth treatment showed total clearance of the cancer, and the patient was free of recurrence after 5 months.^[44] Another study of 122 patients with biopsy-proven BCCs demonstrated that treatment of BCC with 5-FU/epinephrine injectable gel was safe and effective. Overall, 91% of evaluable treated tumors (106 of 116) in all regimens had histologically confirmed complete tumor resolution.^[45]

Intralesional Interferon Alfa

A few preliminary studies have shown variable responses of BCC to intralesional interferon alfa. In one study, recombinant alpha-2 interferon injections were used to treat BCC in 8 patients.^[46] Each lesion was injected 3 times a week for 3 weeks (9 total injections) with 1.5 X 10⁶ IU (0.15 mL) of alpha-2 interferon per injection (total dose, 13.5 X 10⁶ IU). Excisional biopsy 2 months after completion of therapy revealed no evidence of BCC in any patient, and minimal side effects were observed. In addition, a large multicenter trial of 172 patients with BCC demonstrated the efficacy of alpha-2 interferon injected directly into biopsy-proved noduloulcerative BCC or sBCC 3 times weekly for 3 weeks, for a cumulative dose of 13.5 million IU.^[47] At 16-20 weeks, biopsy specimens demonstrated cure of lesions in 86% of interferon-treated patients compared with only 29% of placebo-treated patients.^[47]

In addition, a recent report concluded that intralesional alpha-2 interferon was safe and effective for both BCC and SCC, and that this modality represents a useful alternative to surgical methods and appears to be underused.^[48] The authors also discussed 8 cases in 7 patients successfully treated with intralesional alpha-2 interferon for BCC and SCC. Adverse events appear to be mild, but they are common. An estimated 75% of patients have at least 1 reaction, the most prevalent of which is headache. Other systemic reactions included fever, myalgia, arthralgia, malaise, and nausea.^[49]

Systemic Chemotherapy

Due to its side effects and poor efficacy, systemic chemotherapy with anticancer drugs is reserved for treating locally advanced or metastatic forms of NMSC. Various treatments, including cisplatin, doxorubicin, 5-FU, and mitomycin C, can temporarily delay the spread of these cancers and relieve some symptoms. The most frequently used drug is cisplatin, which is often combined with other drugs such as 5-FU or doxorubicin.

Radiation Therapy

Radiation therapy may be an appropriate choice for older patients and individuals who have BCCs or SCCs in hard-to-treat areas such as the eyelids, nose, or ears. Radiotherapy also is more suitable for recurrent tumors and for large or deep tumors that might otherwise require extensive reconstructive surgery. It may also be used as an adjunct for aggressive or incompletely resected tumors. In addition, recent studies indicate that radiation therapy may be beneficial when combined with systemic chemotherapy.^[50,51]

Laser

Possible indications for CO₂ laser vaporization include sBCCs, AK, Bowen's disease, and actinic cheilitis (AK on the lip). The Nd:YAG laser may be used for coagulation of BCCs, SCCs, Kaposi's sarcoma, and metastatic skin tumors.^[52] The CO₂ laser works by simple vaporization of water-containing cells; however, this nonselective destruction may result in textural skin changes and scarring. A very low-wattage CO₂ laser may reduce the risk of scarring and has been used effectively to treat superficial epidermal pigmented lesions such as solar lentigines. The erbium:YAG laser also vaporizes water-containing cells but may more precisely ablate superficial layers of skin and reduce scarring compared with the CO₂ laser.^[53,54]

A recent report indicated that full-face laser resurfacing provides long-term effective prophylaxis against AKs and may reduce the incidence of AK-related sSCC.^[55] A retrospective chart review of 24 patients with widespread facial AKs (more than 30) treated with full-face CO₂ and/or Er:Yag laser resurfacing found that 12 patients (87%) remained lesion-free for at least 1 year, and 14 of the 24 patients (58.3%) showed no new lesions during a 2-year follow-up.

Imiquimod

Imiquimod is referred to as an immune response modifier. Topical imiquimod 5% cream has been approved by the FDA for the treatment of external genital warts and, more recently, AK (nonhyperkeratotic, nonhypertrophic on the face or scalp in immunocompetent patients). A major advantage of this treatment is that it is patient-applied at home. Imiquimod is also being investigated for the treatment of sBCC and other NMSCs. The drug will probably receive FDA approval for sBCC in 2004.

Two phase 3, randomized trials^[56] evaluated the efficacy of imiquimod 5% cream used 2 times per week for 16 weeks in the treatment of AK lesions on the face and balding scalp. The 436 participants had 4 to 8 clinically diagnosed AK lesions. The complete clearance rate was 45.1% for the imiquimod group vs 3.2% for the vehicle group, and the partial clearance rate (greater than or equal to 75% clearance) was 59.1% for the imiquimod group and 11.8% for the vehicle group. Local skin reactions were common in both the treatment and vehicle groups. Erythema was experienced by 97.2% of participants in the treatment group and 93.6% of participants in the vehicle group. Only 2 patients in the imiquimod group (1%) discontinued treatment because of severe local skin reactions.

Imiquimod is currently under investigation for the treatment of Bowen's disease^[57,58] and sBCC.^[59] In 2 phase 3 trials^[59] enrolling 724 subjects, participants with 1 sBCC were randomized to treatment with imiquimod or vehicle cream once daily 5 or 7 times per week for 6 weeks. The lesion site was clinically examined 12 weeks posttreatment and then excised for histologic evaluation. Pooled data indicated that the clearance rates (combined clinical and histological assessments) for the 5x/week and 7x/week imiquimod groups were 75% and 73%, respectively, and histologic clearance rates were 82% and 79%, respectively. The differences in clearing between the 2 treatment regimens were not clinically or statistically significant.

The most frequent adverse reactions were application site reactions (most commonly itching, burning, and pain at target site) and local skin reactions (erythema, edema, induration, vesicles, erosion, ulceration, scaling, flaking, scabbing/crusting). Headache was reported by 7.6% of subjects in the 5x/week imiquimod group and 6.1% of subjects in the 7x/week group. Four percent of subjects in the imiquimod 5x/week group and 2% of subjects in the 7x/week group discontinued because of an adverse reaction or local skin reaction.

Local skin reactions were more intense in the treatment groups than in the vehicle groups, but were managed by medication rest periods. Erythema was the most common and intense local skin reaction, and greater intensities of erythema, erosion, and scabbing/crusting were associated with higher clearance rates. Local skin reactions are thought to be caused by the imiquimod-induced immune response, and are thus an expected part of the treatment process that may actually be indicative of treatment efficacy.

Imiquimod has also been evaluated in an open-label series for BCCs with Mohs surgery resection for confirmation of treatment.^[60] The therapy was used in 15 subjects, 3 times a week for 12 weeks. At week 15, treatment sites were surgically excised using Mohs micrographic surgery. All 15 treatment subjects were clear of BCC, and at the 18-month follow-up, no patients had recurrent tumor.

The mechanism of action of imiquimod has yet to be fully understood. Topical imiquimod may facilitate local and acquired immune response by interacting with toll-like receptor 7, a surface receptor found on dendritic and inflammatory cells (Figures 9 and 10).^[61] Consequently, it may facilitate the immunologic recognition of disease and augment natural immune responses, at least in part through inducing the synthesis and release of multiple cytokines. These may include interferon-alpha, tumor necrosis factor alpha, macrophage chemotactic protein, and several interleukins (IL-1, IL-2, IL-6, IL-8, and IL-12). It is also thought that imiquimod may enhance migration of Langerhans cells to regional lymph nodes, which, in turn, could promote the activation and recruitment of directed T lymphocytes.^[62,63]

Figure 9. Imiquimod signaling pathway. (Adapted with permission from Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2:675-680.)

Figure 10. Effect of imiquimod on inflammatory cells. Secretion of IL-12 by antigen-presenting cells induces IFN-gamma secretion by naive T cells during cell-cell interactions and results in the development of a Th1-lymphocyte-mediated immune response. GM-CSF = granulocyte-macrophage colony-stimulating factor; IL = interleukin; APC = antigen-presenting cell; MCP = monocyte chemotactic protein; TLR7 = toll-like receptor-7; Th2 = T-helper cell type 2; NF-kappaB = nuclear factor kappa B; PMN = polymorphonuclear neutrophil; Th1 = T-helper cell type 1; TNF = tumor necrosis factor; MIP = macrophage inflammatory protein; IFN = interferon; MIG-CSF = granulocyte colony-stimulating factor; NK = natural killer cell.

Fas-Fas ligand interactions may play a role in the mechanism of imiquimod on tumors. BCC cells constitutively express Fas ligand on their cell surfaces. Interferon-alpha, which is released from dendritic cells by imiquimod, can induce tumor cells to also upregulate the Fas receptor, resulting in a situation in which adjacent tumor cells can induce apoptosis in each other.^[64,65] Infiltrating lymphocytes that express Fas ligand can further contribute to the destruction of tumor cells through coupling with the upregulated Fas receptor on tumor cell surfaces.

In addition, Schön and colleagues^[66] reported that imiquimod may have direct antineoplastic activity. In in vitro studies in human keratinocyte and SCC cell lines, imiquimod appeared to induce skin tumor cell-specific apoptosis, independent of membrane-bound death receptors such as Fas. Imiquimod also appeared to induce tumor-selective apoptosis via Bcl-2-dependent translocation of cytochrome c from the mitochondria to the cytosol, resulting in activation of caspase-3 and caspase-9. Therefore, direct effects such as induction of apoptosis may enhance the immunomodulatory activities of topical imiquimod to effectively treat NMSC.

Diclofenac Sodium

Topical 3% diclofenac in 2.5% hyaluronan gel has recently been approved by the FDA for the treatment of AKs. Diclofenac is a nonsteroidal anti-inflammatory drug, but the mechanism of action against AK is not fully understood. Arachidonic acid metabolites have been associated with the conversion of procarcinogens into carcinogens, inhibition of apoptosis, and increased cell invasion and angiogenesis.^[67] Therefore, the actions of diclofenac may be related to antineoplastic properties resulting from inhibition of cyclo-oxygenase and a subsequent reduction in arachidonic acid metabolites.^[68]

The gel is applied to lesions twice daily, and the recommended duration of therapy is 60-90 days. Sun exposure should be avoided during therapy, and the optimal therapeutic effect may not be apparent until 30 days after therapy stops.

A multicenter, double-blind, placebo-controlled study of 195 AK patients found that treatment with 3.0% diclofenac in 2.5% hyaluronan gel was effective when used for 60 days and was well tolerated.^[69] A reduction in AKs of 50% to 65% was observed in patients completing active treatment, and one third of patients exhibited complete clearance, compared with only 10% of those treated with vehicle alone.

Another randomized, double-blind, placebo-controlled trial^[68] of 96 patients with AKs also found topical diclofenac gel to be effective and well tolerated. Treated sites were the forehead, central face, scalp, hands, or arms, and each treated site was affected by at least 5 AKs. Topical diclofenac or placebo was applied twice daily for 90 days, and efficacy was evaluated 30 days after the discontinuation of treatment. Complete lesion clearance was achieved by 47% of participants in the treatment group and 19% in the vehicle group. Complete or partial lesion clearance was achieved by 79% of patients in the treatment group and 45% in the vehicle group.

The most common adverse events, reported in 70% to 80% of patients treated with diclofenac 3% gel, were reversible, mild-to-moderate local application site reactions, such as pruritus, dry skin, erythema, and paresthesia.^[68,69] Comparable rates of adverse events were reported in both active and vehicle-treated groups.

Photodynamic Therapy (PDT)

PDT is a relatively new treatment modality that requires the application of a photosensitizing drug, such as 5-aminolevulinic acid (5-ALA), followed by activation with light. The most commonly used light wavelengths are 640 nm (red light) and 400-450 nm (blue light).^[70] After topical application, the photosensitizing drug diffuses into the skin, where it preferentially accumulates in tumor and dysplastic cells and is converted into the photosensitizer protoporphyrin IX (PpIX). When PpIX is activated by light, cytotoxic reactive oxygen species are generated that selectively destroy cells and may cause malignant and nonmalignant hyperproliferative tissue to be destroyed or decrease in size.^[48,70,71]

Topical PDT with 5-ALA and visible blue light has been approved by the FDA for the treatment of nonhyperkeratotic AKs of the face and scalp (Figure 11). This therapy is a multistep process that begins with the application by a healthcare professional of topical 5-ALA to visible lesions. The next day, lesions are exposed to blue light in the physician's office, and, over the next few days, the lesions develop scales or crusts, which then heal.

Figure 11. Mode of action of 5-ALA PDT therapy. (Courtesy Dusa Pharmaceuticals; Copyright 2003)

The safety and efficacy of PDT with 5-ALA and visible blue light in the treatment of AKs of the face and scalp has been demonstrated in 3 investigator-blinded, phase 3, multicenter trials enrolling a total of 243 patients with lesions on the face or scalp.^[72] Patients, most of whom had 4 to 7 lesions, were randomized to receive vehicle or 5-ALA followed 14-18 hours later by PDT. Follow-up visits occurred at 24 hours, and 1, 4, 8, and 12 weeks following PDT. By week eight, 77% of treated patients experienced 75% or greater clearing of lesions, compared with 18% in the vehicle group. By week 12, these figures were 89% and 13%, respectively.

Patients experienced stinging and burning during administration of the blue light, and 90% of patients reported moderate to severe discomfort. However, these sensations decreased rapidly after treatment, and after 24 hours only 2% of patients reported severe stinging or burning and only 28% reported any discomfort. One week after PDT, only 7% of patients had any discomfort. Most patients experienced erythema and edema at treated sites, which improved or resolved within 1-4 weeks after treatment. Other local responses to PDT include crusting, pruritus, and scaling.

PDT with topical 20% ALA has been used successfully with Bowen's disease, particularly for large or widespread lesions or at sites that are difficult to treat with surgery. Complete clinical response of 95% or more has been observed.^[73,74] The results for SCC are less promising, with the 2 largest PDT studies showing recurrences rates of more than 50%.^[75,76]

In Europe, the methyl ester of ALA (mALA) and exposure to red light is approved for the treatment of AK and BCC, and it may penetrate the skin more rapidly and be more selective than ALA. A recent randomized trial compared mALA PDT vs standard excisional surgery in 101 patients with nodular BCC and showed comparable response rates between groups at 3 months. A trend for higher recurrence was observed in the PDT group compared with the surgery-treated group, although cosmesis was superior in patients receiving PDT.^[77]

Systemic and Topical Retinoids

Retinoids inhibit growth and induce normal differentiation of malignant cell lines.^[78] Retinoids may have some efficacy in treating precancerous lesions when taken systemically or applied topically; they may also be useful in preventing new cancers from forming. However, side effects of systemic retinoids include dryness of the nasal, buccal, and conjunctival mucosae, hair loss, dermatitis, arthralgia, and myalgia. In addition, systemic retinoids are highly teratogenic. Some studies have indicated that retinoids may prevent the development of NMSC, specifically in high-risk populations such as transplant patients and patients with xeroderma pigmentosum.^[78-80]

In addition, a recent literature review indicates that systemic retinoids, specifically acitretin, are effective in inhibiting tumor development in organ transplant patients, and that topical retinoids have some effect in the treatment of AKs.^[81] However, to maintain efficacy, long-term treatment with acitretin is necessary, and patients should be monitored regularly for triglyceride and cholesterol levels and transaminases.

Regular follow-up is especially important for patients with a history of NMSC because they are at greater risk than the general population for the development of skin cancer. In about 36% to 50% of patients with an NMSC, a second primary tumor develops within 5 years.^[82] These patients are also at increased risk of developing cutaneous melanoma. During follow-up, a head-to-toe skin examination, including careful inspection of previous treatment sites, is essential. In patients with a history of SCC, palpation of the regional lymph nodes is indicated. In patients with a history of high-risk SCC, a skin exam should be conducted every 3 months; for those with a history of low-risk BCC, the skin should be examined every 12 months.^[83] In addition, any patient with a history of NMSC should be followed regularly for at least 5 years because 96% of SCC recurrences and 82% of BCC recurrences will take place during that time.^[36] During follow-up, care should also be taken to educate patients about avoiding sun exposure and performing self-examination.^[28]

NMSC affects more than 1 million people in the United States each year, about the same number as all the other cancers combined. Epidemiologic evidence suggests that these tumors are becoming ever more frequent, driven by the strong public sentiment to pursue cosmetic tanning in ever greater numbers and to participate in more outdoor leisure activities than ever before in our history. Mortality from NMSC is rare, but adequate and early treatment of NMSC is essential for preventing mortality. The newest developments in the treatment of NMSC have focused on nonsurgical alternatives, including PDT and imiquimod. PDT shows potential in the treatment of NMSC such as Bowen's disease and some BCCs. Likewise, the immune response modifier imiquimod represents a promising new approach for the treatment of sSCC. While cure rates with established surgical techniques are high, the progress represented by these novel therapies may match surgical cure rates while at the same time being noninvasive and preserving cosmesis.

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