Etiology and Epidemiology of Skin Cancer

 

The main cause of cutaneous carcinoma is exposure to sunlight. Other contributory factors include exposure to chemical carcinogens (e.g., arsenic, tar, anthracene, crude paraffin oil), chronic irritation or inflammation, and ionizing radiation. Several genetic syndromes are also associated with a higher incidence of cutaneous carcinoma. Individuals with xeroderma pigmentosum are prone to the development of basal cell and squamous cell carcinomas because of defective repair of UV light–induced deoxyribonucleic acid (DNA) damage. The basal cell nevus syndrome is a genetic form of basal cell carcinoma inherited through an autosomal dominant gene. People with epidermodysplasia verruciformis tend to develop squamous cell carcinomas within large verrucous plaques in the third and fourth decades of life. Like cutaneous carcinomas, cutaneous melanomas tend to develop in sun-exposed areas in fair-skinned people who burn rather than tan when outdoors. Blistering sunburns during childhood increase the risk of melanoma later in life. A patient with melanoma has a 3% to 5% lifetime risk of developing a second lesion, which is 900 times the risk of the general population. A patient with multiple dysplastic nevi or the uncommon familial form of melanoma has an even higher lifetime risk (4% to 10%) of developing melanoma. Individuals with occupational exposure to polyvinyl chlorides or chemicals used in brewing and leather processing are at increased risk for developing melanoma. The incidence and aggressiveness of skin cancer are greatly increased in immunosuppressed individuals (e.g., organ transplant recipients, individuals with acquired immunodeficiency syndrome [AIDS]).

 

Prevention and Screening

 

Skin cancer is an important target for preventive and screening measures because most cancer is caused by exposure to UV light and the impact of early detection and treatment on mortality and quality of life, particularly in melanoma, has been well documented. In the late 1990s, a panel of the American College of Preventive Medicine (ACPM) thoroughly reviewed the relevant medical literature and issued practice policy statements with regard to skin cancer prevention. Recommended preventive measures include avoiding exposure to sunlight, particularly by limiting time spent outdoors between 10 am and 4 pm, and wearing protective physical barriers such as hats and clothing. If exposure to sunlight cannot be limited because of occupational, cultural, or other factors, the use of sunscreen that is opaque or blocks UVA and UVB is recommended. The ACPM recommends discussing sun avoidance and sun protection measures with children and teenagers. For high-risk individuals, such as those with fair skin, multiple nevi, a family history of skin cancer, or a personal history of skin cancer, the ACPM also recommends periodic screening, including 2- to 3-minute visual inspection of the entire integument, by an adequately trained physician.

 

Patient Evaluation

 

Clinical evaluation of skin cancer consists of inspection and palpation of the involved area and the regional lymph nodes. Imaging studies, such as chest radiographs, computed tomography scans, and magnetic resonance imaging scans, should be obtained when clinically indicated.

 

Melanoma

 

Two surgical microstaging systems are used for melanoma: the Breslow system and the Clark method. Both systems are based on the recognition that for patients with melanomas, the prognosis depends on the depth of invasion rather than the greatest dimension of the tumor.The Breslow system classifies lesions by vertical thickness between the granular layer of the epidermis and the deepest part of the lesion as measured with an ocular micrometer. For ulcerated lesions, measurements are made from the surface of the skin to the deepest part of the primary tumor. The Clark method divides melanomas into five groups on the basis of the depth of invasion relative to normal tissue structures. Level I is confined to the epidermis, level II invades the papillary dermis, level III invades the papillary-reticular dermal interface, level IV invades the reticular dermis, and level V invades the subcutaneous tissue. The 2002 AJCC staging system for melanoma includes a four-stage grouping based on the Breslow thickness and the presence or absence of primary tumor ulceration, nodal involvement, and satellitosis or distant metastasis to the lung or other viscera. The Clark level of invasion is significant only for lesions less than 1 mm thick. A fifth group—stage 0, melanoma in situ—was added in 1997.

 

Primary Therapy and Results

 

Carcinoma

 

Primary Tumor

 

The general strategy for treatment of the primary tumor is the same for basal cell and squamous cell carcinomas. A variety of treatment approaches are available, including curettage and electrodesiccation (not recommended for recurrent lesions), Mohs’ surgery, cryotherapy, surgical resection, and primary radiation therapy. Nearly all treatment approaches result in 5-year recurrence rates of 1% to 10% for previously untreated cutaneous carcinomas. The choice of treatment for individual patients is determined on the basis of factors such as the location and size of the lesion; expected functional and cosmetic results; treatment time and cost; and patient age, occupation, and general physical condition. Surgical modalities are preferred for most patients, particularly those with small lesions, for whom simple surgical procedures yield high cure rates. Primary radiation therapy is most often indicated for lesions on or around the nose, lower eyelids, and ears, where radiation therapy yields better functional and cosmetic results than surgery. Similarly, primary radiation therapy is indicated for extensive lesions of the cheek, lip, or oral commissure that would require full-thickness resection.In a series of more than 1000 patients with previously untreated and recurrent basal and squamous carcinomas of the eyelid who underwent primary radiation therapy, 5-year local control rates were more than 90%. The size of the primary lesion is the major determinant of local control after radiation therapy. In a series of 646 patients with carcinomas of the eyelid, pinna, nose, and lip treated with radiation, the 10-year local control rates were 98% for tumors measuring 2 cm or smaller, 79% for 2- to 5-cm lesions, and 53% (at 8 years) for carcinomas larger than 5 cm. When results are adjusted for tumor size, local control rates seem to be slightly higher for basal cell carcinoma than for squamous cell carcinoma: 97% versus 91% for lesions smaller than 1 cm and 87% versus 76% for 1- to 5-cm lesions. Recurrent basal and squamous cell carcinomas are more difficult to control than are previously untreated lesions.

 

Radiation therapy usually is not recommended for patients younger than 50 years because the late effects after radiation therapy increase over time, as does the risk of a second cancer developing within the radiation portal. Postoperative radiation therapy may be beneficial in several clinical situations, including positive surgical margins, perineural involvement, invasion of bone or cartilage, extensive skeletal muscle infiltration, a positive node measuring more than 3 cm in the greatest dimension, extranodal spread, and multiple positive nodes. Series published in the 1950s and 1960s reporting the use of orthovoltage x-rays and large daily doses of radiation suggested that radiation therapy for carcinomas involving bone or cartilage resulted in an excessive risk of osteoradionecrosis or radiochondritis. However, data from more recent series using more fractionated, higher-energy radiation indicate that radiation therapy may be the treatment of choice for selected patients with bone or cartilage involvement because the risk of complications is low when proper techniques are used.

 

Regional Nodes

 

Elective nodal treatment is not indicated for cutaneous basal cell carcinomas because of the low incidence of lymphatic spread. However, elective nodal treatment is indicated for large, infiltrative, ulcerative squamous cell carcinomas or recurrent squamous cell carcinomas. The choice of treatment for patients who present with nodal disease depends on the type of therapy selected for the primary lesion and the size of the involved lymph nodes. In general, single-modality therapy (surgery or radiation therapy) is sufficient for nodal disease up to 3 cm without evidence of extracapsular spread. Taylor and colleagues reported results from 36 patients who underwent surgery and postoperative radiation therapy for lymph node metastases to the parotid region from cutaneous carcinomas. The overall regional control rate was 89%. All four recurrences occurred in patients with positive surgical margins and clinical evidence of facial nerve involvement. For a later series of 37 patients with parotid-area metastases treated in the same way, Audet and associates reported a locoregional control rate of 73% and a 3-year disease-specific survival rate of 72%. In that analysis, patients with facial nerve involvement and tumors larger than 6 cm experienced poorer outcomes. Veness and colleagues, reporting on 74 patients with nonparotid cervical metastases, found that surgery combined with postoperative radiation therapy led to lower relapse rates and better disease-free survival times than did single-modality treatment for cervical metastases.

 

Melanoma

 

For patients with localized cutaneous melanoma (stage I or II), wide local excision of the primary tumor is the standard treatment. For patients with known lymph node metastases at presentation (stage III), wide local excision plus therapeutic lymph node dissection is the accepted surgical approach. Use of adjuvant radiation therapy is based on the clinical and pathologic features of the disease.

 

Primary Tumor

 

The standard treatment for localized cutaneous melanoma (stages I and II) is wide local excision. Pathologic examination of the specimen is essential for establishment of a tissue diagnosis, assessment of the margins, and microstaging. The recommended skin margins are 1 cm for invasive lesions less than 1 mm thick and for lentigo maligna melanomas and 2 to 3 cm for melanomas at least 1 mm thick. Melanoma thickness is the most powerful determinant of local control after wide local excision. In a large multi-institutional trial, long-term local recurrence rates were 2.3% for melanomas 1 to 2 mm thick, 4.2% for melanomas 2 to 3 mm thick, and 11.7% for melanomas 3 to 4 mm thick. Local recurrence is a poor prognostic sign; most patients with local recurrence ultimately die of the disease.Radiation therapy is rarely indicated as the definitive treatment for primary malignant melanomas, except in the case of large facial lentigo maligna melanomas, for which wide local excision may necessitate extensive reconstruction. In a series of patients with lentigo maligna melanomas treated with primary radiation therapy at the Princess Margaret Hospital and followed for a period of 6 months to 8 years (median, 2 years), local control was achieved in 23 (92%) of 25 patients. The median time to complete regression of lesions was 8 months, although some lesions took 2 years to disappear. Radiation therapy was delivered with orthovoltage x-rays (100 to 250 keV) and consisted of 35 Gy in 5 fractions over 1 week for lesions smaller than 3 cm, 45 Gy in 10 fractions over 2 weeks for lesions measuring 3 to 4.9 cm, and 50 Gy in 15 to 20 fractions over 3 to 4 weeks for lesions measuring 5.0 cm or more.

 

Radiation Therapy

 

Melanoma has long had a reputation for being radioresistant, although the origins of this supposed characteristic remain somewhat obscure. Laboratory studies have confirmed that melanoma cell lines have an enhanced ability to repair sublethal damage from radiation. The labeling of melanoma as radioresistant, however, predates such studies. Most likely, early clinical experience with treating visibly and palpably advanced dermal or nodal metastases resulted in visibly and palpably progressive disease inside and outside the radiation therapy field. Whereas for most diseases, radiologic studies are the mainstay of surveillance for detecting progressing disease, melanoma tends to involve superficial sites easily observed on physical examination. Several retrospective studies have revealed response rates of about 80% when radiation is delivered in large doses per fraction (i.e., 4 Gy or more), suggesting that if treated appropriately, melanoma is responsive to radiation therapy.