MELANOMA AND NONMELANOMA SKIN CANCERS

MELANOMA AND NONMELANOMA SKIN CANCERS

Current estimates are that one of 37 men and one of 56 women will be diagnosed with melanoma during their lifetimes. Each year in the United States, approximately 76,690 new cases of invasive melanoma are detected, and 9480 patients die of melanoma. The explanation for the rising incidence is thought to be increasing sun exposure, especially early in life. Melanoma is the leading cause of death from cutaneous malignant disease, and it accounts for 1% to 2% of all cancer deaths in the United States. Melanoma affects all age groups; the median age at diagnosis is 50 years. Melanoma is largely a disease of whites, with a very low incidence in African Americans, Asians, and Hispanics.

Exposure to sunlight, especially ultraviolet (UV) radiation, has been strongly implicated as a causative factor in the development of melanoma. Melanomas originate from melanocytes, which are located predominantly in the basal cell layer of the epidermis and use the enzyme tyrosinase to synthesize melanin pigment, which serves to protect against UV damage. Worldwide, the incidence of melanoma in whites generally correlates inversely with latitude; that is, rates are generally higher closer to the equator and become progressively lower near the poles.

Risk factors for melanoma include family history of melanoma, prior melanoma or nonmelanoma skin cancer, inherited genetic susceptibility, and sun exposure. Artificial exposure to UV radiation by indoor tanning is likewise a risk factor for melanoma. Individuals with fair complexions, blond or red hair, blue eye colour, and freckles, who have a tendency to burn rather than tan, have higher rates of melanoma. The pattern of sun exposure may also be important; intermittent intense exposure, rather than long-term exposure, may carry a higher risk of melanoma.

Individuals with an increased number of typical or benign moles, atypical moles, or dysplastic nevi also have an increased risk for melanoma. Atypical moles or dysplastic nevi are important precursor lesions of melanoma and serve as markers for increasing risk. For example, individuals with dysplastic nevi have a 6% lifetime chance of developing melanoma, and this risk increases to as high as 80% in individuals who have dysplastic nevi and a strong family history of melanoma.

Approximately 10% of patients with melanoma have a family history of melanoma. Several chromosomal loci determine susceptibility to melanoma, the most important of which is p16/CDKN2A, a gene located on chromosome 9p21. This gene is a member of a class of molecules that play a central role in cell cycle regulation. Of the members of melanoma-prone families, 25% to 40% have mutations in this gene. The risk of developing cutaneous melanoma in an individual who is a CDKN2A carrier is between 30% and 90% by age 80 years and varies by geographic location. Testing for mutations in the p16/CDKN2A locus is commercially available, but its clinical utility is unclear at this time. Genetic variability in melancortin-1 receptor (MC1R) plays a key role in pigmentation of skin and hair and more recently has been implicated in melanoma predisposition.

Somatic mutations in primary and metastatic melanoma primarily involve the mitogen activated protein kinase pathway. Activating mutations in B-RAF can be found in approximately 50% of melanomas, and 20% of melanomas are associated with a mutation in N-RAS . Recent studies have found that melanoma on mucous membranes, acral skin (soles, palms), and skin with chronic sun damage (i.e., lentigo maligna melanoma) have frequent mutations in c-kit . Thus, distinct patterns of genetic alterations are found in primary melanomas based on anatomic location and extent of sun exposure. Uveal melanoma is associated with mutations in GNAQ/GNA11 . Monosomy of chromosome 3 and somatic mutations in the gene encoding BRCA-1 associated protein (BAP) on chromosome 3 have been associated with worse outcome and the development of metastatic melanoma. The discovery of somatic mutations in melanoma and associated aberrant signal transduction pathways has provided leads for the development of molecularly targeted therapy for patients with advanced melanoma.

Early detection and recognition of melanoma are key to improving survival. The signs of early melanoma are based on the clinical appearance of the pigmented lesion and a change in the shape, colour, or surface of an existing mole. Most patients report a preexisting mole at the site of the melanoma. Itching, burning, or pain in a pigmented lesion should increase suspicion, although melanomas often are not associated with local discomfort. Bleeding and ulceration are signs of a more advanced melanoma. Most melanomas are varying shades of brown, but they may be black, blue, or pink. The ABCDEs for the recognition of melanoma are asymmetry, border irregularity, colour variation, diameter greater than 6 mm, and evolution or a change in a skin lesion. The “ugly duckling” sign is recognizing a pigmented lesion that looks different from other skin lesions and is therefore suspicious.

Cutaneous melanoma has been divided into four subtypes. Superficial spreading melanoma, which accounts for 70% of all melanomas, can be located on any anatomic site. Lentigo maligna melanoma, which represents 4 to 10% of all melanomas, tends to occur more commonly in chronically sun-exposed skin in older patients, frequently on the head and neck; clinically, it appears as a macular (flat) lesion, arising in a lentigo maligna. Nodular melanoma accounts for 15% to 30% of melanomas and manifests as a rapidly enlarging elevated or polypoid lesion, often blue or black. The ABCDE rule does not always apply as well to nodular melanomas. Acral lentiginous melanoma manifests as a darkly pigmented, flat to nodular lesion on the palm, on the sole, or subungually; sunlight is not thought to play a causative role in this form of melanoma. Histologic subtype does not directly correlate with clinical behaviour. However, recent data suggest that histologic subtype may correlate with specific genetic abnormalities.

Ocular melanomas arise from the pigmented layer of the eye. Uveal melanoma is the most common intraocular malignancy of adults. Melanomas can also arise from noncutaneous sites, including mucosal epithelium in the gastrointestinal tract, anorectal area, genitourinary tract, and nasal and nasopharyngeal mucosa. Melanomas of the vulva and vagina are relatively rare. In general, mucosal melanomas are diagnosed at a more advanced stage of disease. The mainstay of treatment is surgical.

Any skin lesion suggestive of melanoma should be sampled using biopsy with complete excision, including a 1- to 2-mm margin of normal skin and some subcutaneous fat. An incisional biopsy may be necessary for lesions too large for complete excision. The role of sentinel lymph node biopsy (SLNB) is explained in detail in the Treatment section. Shallow shave biopsies, curettage, cryosurgery, laser, and electrodessication are contraindicated in lesions suggestive of melanoma. Other lesions that can be confused with melanoma include blue nevi, pigmented basal cell carcinoma (BCC), seborrheic keratosis, and haemangiomas.

CLINICAL FEATURES OF COMMON NEVI, DYSPLASTIC NEVI, AND MELANOMAS

DISEASE CHARACTERISTICS
Common acquired nevi (moles) These tend to be small, flat, and round; the border is regular, smooth, and well defined; the colour is homogeneous, usually no more than two shades of brown; any site is affected; lesions are usually <6 mm.
Dysplastic nevi (atypical moles) These occur predominantly on the trunk; they tend to be large, usually >5 mm, with a flat component; the border is characteristically fuzzy and ill defined. The shape can be round, oval, or misshapen. The colour is usually brown but can be mottled with dark brown, pink, and tan. Some individuals have only one to five moles; others have more than 100.
Melanoma The border is more irregular; lesions tend to be larger, often >6 mm; substantial heterogeneity of colour is noted, ranging from tan-brown, dark brown, black, pink, red, grey, blue, or white.

As with most malignancies, the outcome of melanoma depends on the stage and extent of disease at presentation. For localized melanoma, the most important prognostic factor is involvement of regional lymph nodes. The most important prognostic factor related to the primary tumour is the depth of invasion (Breslow’s thickness) of the melanoma, which is measured in millimetres from the top of the epidermis to the underlying dermis. Increasing thickness is associated with an increased risk for recurrence, regional lymph node involvement, and death from melanoma. Whereas patients whose melanomas are smaller than 1 mm thick have about an 80% to 90% 10-year survival rate, patients whose melanomas are greater than 4 mm thick have only a 40% to 50% 10-year survival rate. Other poor prognostic factors related to the primary melanoma include the presence of ulceration, an increasing level of invasion (Clark’s level), a high mitotic rate, and the presence of microscopic satellites. Regional lymph node involvement (stage III) has a major impact on survival, with 5-year survival rates ranging from 20% to 70%, depending on the number of involved lymph nodes. Melanomas that arise on the extremity tend to have a better prognosis, and women tend to do better than men.

Staging and prognosis for melanoma are based on the TNM system, in which T refers to tumour, N to nodes, and M to metastasis, which was updated in 2009. Stages I and II indicate clinically localized primary melanoma, stage III indicates regional involvement (lymph nodes or in-transit metastases), and stage IV is metastatic disease beyond the regional lymph nodes (i.e., lung, liver, brain).

TUMOUR, NODE, METASTASIS STAGING CATEGORIES FOR CUTANEOUS MELANOMA

CLASSIFICATION THICKNESS (MM) ULCERATION STATUS OR MITOSES
T
Tis NA NA
T1 ≤1.00 ·         a: Without ulceration and mitosis <1/mm 2

·         b: With ulceration or mitoses ≥1/mm2

T2 1.01-2.00 ·         a: Without ulceration

·         b: With ulceration

T3 2.01-4.00 ·         a: Without ulceration

·         b: With ulceration

T4 >4.00 ·         a: Without ulceration

·         b: With ulceration

NO. METASTATIC NODES NODAL METASTATIC BURDEN
N
N0 0 NA
N1 1 ·         a: Micrometastasis *

·         b: Macrometastasis 

N2 2-3 ·         a: Micrometastasis *

·         b: Macrometastasis 

·         c: In transit metastases or satellites without metastatic nodes

SITE SERUM LDH
M
M0 No distant metastases NA
M1a Distant skin, subcutaneous, or nodal metastases Normal
M1b Lung metastases Normal
M1c All other visceral metastases Normal
Any distant metastasis Elevated

LDH = lactate dehydrogenase; NA = not applicable.

* Micrometastases are diagnosed after sentinel lymph node biopsy.
† Macrometastases are defined as clinically detectable nodal metastases confirmed pathologically.

The initial evaluation of a patient with melanoma includes a personal history, a family history, a total skin examination, and palpation of regional (draining) lymph nodes. The focus is to identify risk factors, signs or symptoms of metastases, dysplastic nevi, and additional melanomas. A chest radiograph and liver enzyme tests may be performed at the discretion of the physician. Most patients who present with melanoma do not have distant metastatic disease at presentation; therefore, extensive evaluations with computed tomography (CT) to search for distant metastases have an extremely low yield and are not indicated in asymptomatic patients. More extensive staging evaluation with CT or positron emission tomography (PET) can be considered in patients with high-risk disease (primary melanoma >4 mm thick or node-positive disease), in whom the risk of distant metastatic disease is higher.

After melanoma is diagnosed, the standard treatment is surgical excision. Several prospective randomized trials have been conducted to define the optimal surgery for primary melanoma. The extent of the surgery depends on the thickness of the primary melanoma. Large surgical excisions are no longer required, and most wide excisions can be performed with primary closure. For melanoma in situ, excision with a 0.5-cm border of clinically normal skin is sufficient. For melanomas less than 1 mm thick, a 1-cm margin is recommended. If the thickness is between 1 and 4 mm, a 1- to 2-cm margin is recommended. For melanomas thicker than 2 mm, 2-cm resection margin also is sufficient and safe. In cosmetically sensitive areas (face) or anatomically difficult areas (ear, hands), it may be difficult to achieve the desired margin, but at least a 1-cm margin should be obtained whenever possible.

In approximately 10% to 20% of patients who do not have clinically apparent lymph node involvement, lymph nodes contain occult micrometastases. The risk for occult lymph node involvement rises with increasing tumour thickness. Results from randomized trials fail to show a survival benefit from elective or prophylactic lymph node dissections in patients with clinically negative lymph nodes.

Sentinel lymph node biopsy is a technique that accurately evaluates whether microscopic melanoma cells involve regional lymph nodes. The technique relies on the concept that specific regions of the skin drain specifically to an initial lymph node within the regional nodal basin through an organized pathway of afferent lymphatic channels. This technique is performed by injecting the primary melanoma site with blue dye (isosulfan blue), radiolabelled colloid, or both. When both modalities are used in combination, a sentinel node can be identified in 98% of patients; biopsy of the node accurately determines whether melanoma cells have metastasized to that specific lymph node basin. The sentinel node technique also promotes a more comprehensive histologic examination of lymph nodes because limited amounts of pathologic material are submitted.

Sentinel lymph node biopsy allows earlier identification of metastases and is an important staging tool. The likelihood of detecting melanoma in SLNB increases with thickness of the primary lesion. SLNB is recommended to patients with melanoma 1 mm thick or thicker. The use of this technique for patients with thinner melanomas, that is, less than 1 mm thick can be considered if the primary has high risk features, is controversial. The SLNB is generally performed at the same time as the wide excision of the primary tumour. If the SLNB result is negative for melanoma, no further lymph node surgery is required. If melanoma is detected by the SLNB, complete lymph node dissection remains the standard of care. A recently reported randomized trial showed that the use of SLNB in patients with intermediate-thickness of thick primary melanomas provides accurate and important staging information; enhances regional disease control; and among patients with nodal metastases, improved melanoma-specific survival.

Surgical (therapeutic) lymphadenectomy is the preferred treatment of cytologically (fine-needle aspiration) positive or pathologically proven regional lymph node involvement with melanoma. The goal is to provide long-term, disease-free survival and reduce local morbidity of enlarged lymph nodes.

Postsurgical adjuvant therapy can be considered for patients at high risk for recurrence (melanomas ≥4 mm thick or node-positive disease). These patients have at least a 25% to 75% chance of dying of melanoma. Adjuvant treatment options include interferon-α (IFN-α), enrolment in a clinical trial, or observation. High-dose IFN-α is the only U.S. Food and Drug Administration (FDA)—approved adjuvant therapy for patients with melanoma. Randomized clinical trials have shown that therapy with IFN-α can prolong disease-free survival but has not consistently demonstrated improvement in overall survival. The treatment is given for 1 year and is associated with considerable side effects, which require close monitoring. Intermediate and low doses of IFN-α as well as pegylated IFN-α have also been evaluated in a series of clinical trials. Pegylated IFN-α was recently approved by the FDA for treatment of patients with stage III melanoma. Numerous vaccine studies are ongoing but are considered experimental at present. Ipilimumab, a monoclonal antibody targeting CTLA-4, has been shown to prolong survival in patients with metastatic melanoma. Currently, ipilimumab is being studied in multiple phase III trials as an adjuvant therapy in patients with high risk melanoma.

Melanoma can metastasize to virtually any organ, especially the lung, skin, liver, and brain. Until recently, the overall survival period for patients with metastatic melanoma has ranged from 5 to 11 months, with a median survival period of 9 months. However, new approaches with immunotherapy and molecularly targeted therapy based on somatic mutation profile have led to several recent FDA approvals of new agents that have redefined the standard of care for patients with metastatic melanoma.

New immunotherapy approaches include ipilimumab, which blocks cytotoxic T-lymphocyte antigen 4 (CTLA-4). Immunotherapy with ipilimumab has been shown to be better than dacarbazine alone (3-year survival rate, 21% vs. 12%) for previously untreated metastatic melanoma. Ipilimumab, 3 mg/kg intravenously every 3 weeks for a total of four doses, is FDA approved for patients with unresectable stage III or stage IV melanoma. Treatment with ipilimumab results in immune-mediated adverse reactions, including enterocolitis, hepatitis, dermatitis, and endocrinopathies such as hypopituitarism and hypothyroidism. Dose interruption of ipilimumab and corticosteroids are the main stays of treatment for this side effect mediated by T-cell activation and proliferation.

A second investigational approach to inhibit regulation of T-cell activation is to block the PD-1/PD-L1 (programmed cell death) pathway. Monoclonal antibodies targeting both PD-1 and PD-L1 are now in clinical trials. The first-in-class anti PD-1 antibody nivolumab, a fully human IgG4 monoclonal PD-1 antibody, has shown impressive clinical activity in patients with advanced melanoma. Another PD-1 inhibitor recently FDA approved is lambrolizumab, which also has significant clinical activity (response rate >40%) with fewer immune adverse events than traditionally seen with ipilimumab. Combining anti-CTLA-4 with anti-PD-1 immunotherapy has been encouraging in early non-randomized studies.

The discovery of somatic genetic mutations in melanoma has provided leads for the development of molecularly targeted therapies. The MAP (mitogen-activated protein) kinase pathway, which is activated in most melanomas because of mutations in BRAF NRAS , and c-kit , has been the focus of most clinical investigations of signal transduction (kinase) inhibitors. In patients with metastatic melanoma whose tumours harbour the V600E BRAF mutation, vemurafenib (960 mg orally twice daily), trametinib (2 mg orally twice daily), and dabrafenib (150 mg orally twice daily) each can increase 6-month survival rate significantly compared with dacarbazine. Squamous cell carcinoma (SCC) and keratoacanthomas develop in approximately 20% of patients with melanoma treated with vemurafenib because of paradoxical activation of MAPK signalling. Nevertheless, vemurafenib provides a median overall survival time of about 16 months in treated patients with BRAF V600 –mutant metastatic melanoma. Recently, combination targeted therapy with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) has been FDA approved based on results showing a 70% response rate and an acceptable safety profile. Combination therapy with several different regimens has now been shown to provide better progression free survival, better overall survival, and no increase in side effects in patients with metastatic melanoma. Preliminary results also show that imatinib can induce regression in patients whose melanomas are driven by KIT mutations.

Patients should be educated on the clinical characteristics of melanoma, the importance of safe sun exposure strategies, and the performance of monthly self-examinations of the skin. Patients should be followed regularly for evidence of local or regional recurrence, distant metastatic disease, and a second primary melanoma. The intensity of the surveillance and the extent of the investigation are influenced by risk for recurrence with more frequent follow-up visits in patients who have thicker tumours or node-positive disease because these patients are at greater risk for recurrence.

For patients with low-risk melanoma (≤1 mm), visits are recommended every 6 months for 2 years and then annually. The surveillance guidelines for patients with high-risk melanoma include evaluation every 3 to 4 months for 2 years and then every 6 months for 3 years. After 5 years, patients are seen once a year. Patients are generally followed for 10 years. However, lifelong dermatologic examination is recommended, particularly for patients with dysplastic nevi or a family history of melanoma. In general, a history and physical examination are performed at each visit. Periodic chest radiographs, laboratory studies, and other imaging studies are performed at the discretion of the treating physician. The physical examination should include a thorough skin examination because at least 3% of patients develop an additional primary cutaneous melanoma within 3 years. Regional lymph nodes should be thoroughly examined, especially in patients without prior nodal surgery. For the remainder of the examination, one should keep in mind the frequency of metastases to lung, liver, and brain. Follow-up studies may include a complete blood cell count and chemistry studies, including liver enzyme tests. An elevated lactate dehydrogenase level suggests metastatic melanoma.

The most important measures to prevent melanoma are to reduce excessive sun exposure, particularly to the midday sun, and to avoid sunburns. Sunscreen products with a sun protection factor (SPF) of 15 or greater and protective clothing are recommended, and one randomized trial found that regular sunscreen use reduced incident melanoma by 50% and invasive melanoma by 75%. Sunscreens block primarily UVB rays, which are considered to be the major causative agent of cutaneous cancers. Newer sunscreen products also block UVA rays, which may contribute to the risk of melanoma.

Screening for skin cancer, whether by self-examination or by a health care provider, is controversial. Many public health experts do not recommend screening for adults in the general population, but some organizations do. On the basis of the type and number of nevi, family history of melanoma, prior melanoma, and history of severe sunburns, clinicians can identify patients who are at high risk for melanoma and who may benefit from screening programs. In several population studies, screening has detected melanomas at an earlier, curable stage. Physicians, other health care providers, and the public should be educated regarding the early signs of melanoma and the need for prompt biopsy of a suspicious pigmented lesion.

Patients with clinically atypical nevi, particularly if they have a family history of melanoma, require a regular dermatologic surveillance program. Regular skin examinations should be performed every 6 to 12 months, preferably assisted by the use of serial photography.

Recent studies have focused on the impact of vitamin D levels on the risk for melanoma, and results have been conflicting. The potential health benefits of vitamin D continue to be evaluated, both in terms of melanoma prevention and risk.

Nonmelanoma skin cancer (BCC and SCC) is the most common malignant disease in the United States. Although national statistics are imprecise, an estimated 900,000 to 1,200,000 of nonmelanoma skin cancers are diagnosed annually in the United States. SCC accounts for 20%, and most of the remainder are BCC. SCC is associated with a higher absolute mortality rate; most of the 2300 annual deaths from nonmelanoma skin cancer in the United States arise from this tumour.

Overall, skin cancer incidence rates are rising because of increased recreational sun exposure, longer life expectancy, and depletion of the ozone layer. More than 99% of nonmelanoma skin cancers occur in whites. These skin cancers are most commonly seen in elderly persons, especially those with fair skin and long-standing sun exposure. However, nonmelanoma skin cancers are increasingly being seen in people in their 30s and 40s. The lifetime risk of developing BCC is 30%.

Basal cell carcinoma arises from a pluripotential stem cell within the skin. Acquired mutations in the patched gene 1 (PTCH1), a tumour suppressor gene in the hedgehog signalling pathway, have been identified in cases of sporadic BCC. Sporadic BCC are also associated with mutations in the genes encoding p53 and ras.

Squamous cell carcinoma of the skin is a malignant disease of epidermal keratinocytes. Many such carcinomas are derived from actinic keratosis, a precursor that appears as a rough, scaly, often erythematous papule, which often is more apparent on palpation than on visual examination. Estimates of the likelihood of progression of actinic keratosis to SCC range from 0.025% to as high as 20%. Mutations in the gene encoding the p53 protein and in the RAS oncogene have been found in both actinic keratosis and SCCs. Mutations in p16 have also been reported in SCCs.

The most important risk factor is exposure to UV radiation from sunlight. The most clearly established association is with UVB radiation, but increasing evidence suggests that UVA is probably carcinogenic as well. The timing and pattern of sun exposure are associated with different types of skin cancer. In general, SCC is associated with cumulative sun exposure and occurs most frequently in areas maximally exposed to the sun (e.g., the face, back of hands, and forearms). Intermittent, intense exposure to the sun, particularly in childhood, is associated with an increased risk for BCC. There is evidence for a dose-response relationship between artificial UV radiation exposure by use of tanning beds and the risk of skin cancers, especially BCC, and the association is stronger for individuals with a younger age at exposure. Individuals who have fair skin, light-coloured eyes, red hair, a tendency to burn rather than tan, and a history of severe sunburns are at increased risk for nonmelanoma skin cancers. Other risk factors, primarily for SCC, include chronic arsenic exposure, therapeutic radiation, chronic inflammatory skin conditions, psoralen plus UVA (PUVA) treatment for psoriasis and other diseases, and immunosuppression. Most cases in African American patients are associated with scarring or burns rather than UV exposure. Human papillomavirus infection has also been implicated in some SCCs, particularly in the autosomal dominant disorder epidermodysplasia verruciformis.

Basal cell carcinoma can be seen in association with several conditions, including the basal cell nevus syndrome (also called nevoid basal cell carcinoma syndrome or Gorlin syndrome), albinism, and xeroderma pigmentosum. The basal cell nevus syndrome is a rare autosomal dominant disorder caused by germline mutations in the patched gene (PTCH).

Approximately 90% of BCCs occur on sun-exposed areas such as the face, neck, ears, scalp, and arms. The nose is the most common site. Typical BCC appears as slowly growing, shiny, skin-coloured to pink translucent papules with telangiectasia and a “pearly,” rolled border. As the tumour grows, the centre may become ulcerated and bleed, although there is usually no associated pain or tenderness. BCC rarely metastasizes and is usually curable with a variety of treatments. Although the mortality rate is low, these cancers may result in significant morbidity owing to invasive local growth with potential disfigurement and destruction of skin, bone, and cartilage. Clinical trials with inhibitors of the hedgehog pathway for patients with advanced BCC have demonstrated very encouraging clinical activity.

This type of skin cancer usually appears on areas of skin that are heavily damaged by sun exposure. The most common sites include the head or neck, back, forearms, and dorsum of the hand. Clinically, SCC occurs as a discrete scaly erythematous papule on an indurated base that can develop on normal-appearing skin or on an actinic keratosis. The lesion may grow over time and may become ulcerated, itchy, or painful and may bleed. Keratoacanthoma is a variant that is characterized by rapid growth and a crateriform appearance with a central plug. Bowen disease, or SCC in situ, manifests as an erythematous, scaly, sharply defined plaque.

Untreated SCC may cause significant local destruction. However, unlike BCC, SCC carries a 0.5% to 5% risk for metastasis. Higher risk lesions are those that are larger than 2 cm, are moderately or poorly differentiated, have perineural involvement, are located on the ear or the lip, arise in scars, or occur in immunosuppressed patients. Most metastases develop in regional lymph nodes, although metastases may also occur in lung, liver, brain, skin, or bone. For patients with lymph node metastases, the 5-year survival rate is less than 50%.

The diagnosis of BCC and SCC is frequently suspected by inspection alone, but histologic confirmation is usually indicated. Either a shave or a punch biopsy technique is acceptable. Care should be taken to include the base of the lesion if a shave biopsy technique is used.

Basal cell carcinomas are classified as low or high risk based on their clinical features, location, and histology. Treatment options includes cryotherapy (liquid nitrogen), electrosurgery (i.e., curettage and electrodessication), topical treatment (i.e., 5-fluorouracil, photodynamic therapy, or imiquimod), surgical excision, Mohs’ surgery, or radiation therapy. Mohs’ microsurgery involves serial excisions of a skin cancer with subsequent microscopic examinations for residual tumour, providing histologic control of the surgical margins to achieve the lowest recurrence rate while maximally preserving uninvolving tissue. The procedure should be considered when treating recurrent cases; microscopically aggressive forms, such as the morpheaform subtype; lesions greater than 2 cm in greatest diameter; and tumours of the ears, eyelids, nose, nasolabial folds, and lips. Cure rates for BCC range between 90% and 99%.

Treatment of advanced BCC and metastatic BCC can now be approached using targeted therapy. Vismodegib, an inhibitor of the hedgehog signalling pathway, has recently been FDA approved. In a nonrandomized study, treatment with vismodegib provided objective tumour responses in 30% to 43% of patients and a complete response in 20% of patients with locally advanced or metastatic basal-cell carcinoma. Side effects associated with therapy include muscle spasms, taste abnormalities, diarrhoea, and fatigue.

As with BCC, SCC can also be cured by traditional surgical excision or Mohs’ surgery, cryotherapy, topical therapies, and radiation therapy. Topical 5-fluorouracil, photodynamic therapy, and imiquimod have roles in the management of in situ SCC. The optimal approach for a specific patient requires consideration of likelihood of the lesion recurring or metastatic potential, cosmetic factors, and the expertise of the treating physicians.

Mohs’ micrographic surgery provides the lowest recurrence rate, with cure rates greater than 90%. Mohs’ microsurgery is especially useful for recurrent tumours or lesions that have an increased risk of metastasis. Cetuximab, a monoclonal antibody that targets epidermal growth factor receptor (EGFR), has some antitumor activity in patients with advanced SCC of the skin.

Patients with BCC and SCC require ongoing follow-up to detect local recurrences and to recognize new skin cancers. The likelihood of developing a second BCC or SCC has been estimated to be 15% over 3 years. In addition, these patients have an increased risk of developing cutaneous melanoma. Patient education regarding modification of risk factors (i.e., sun exposure) is an important component of follow-up.

Primary prevention strategies are aimed at reducing long-term sun exposure. Public education and patient education should encourage the regular use of sunscreens with a SPF of 15 or greater, especially in childhood, and sun-protective clothing (e.g., a broad-brimmed hat). Avoidance of tanning parlours and minimizing of total sun exposure, especially to the midday sun, is recommended. The thinning of the ozone layer has been linked to increased UV radiation and increases in the incidence of nonmelanoma skin cancers. Currently, no evidence indicates that total-body skin examination is effective at reducing mortality or morbidity from nonmelanoma skin cancer.

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