Principles of Ambulatory Medicine, 7th Edition

Chapter 114

Atypical Moles and Common Cancers of the Skin

1. Elizabeth Whitmore

The three most common types of skin cancer have a definite relationship to natural and artificial ultraviolet radiation (UVR) exposure in non-Hispanic white individuals (1,2). Despite this generally known association, Americans still tend to be “sun seekers,” commonly vacationing in UVR rich locations such as the oceanside, ski slopes, and Disney World. A collection of statistics from sources including the American Academy of Dermatology, the American Cancer Society, and peer-reviewed journals sum up the next generation's UVR exposure activities (3),

1. Four out of 5 children age 12 to 17 years are aware of the potential dangers of tanning, but 60% of the same age group experience sunburn at least once a summer.
2. Fifty-three percent of girls between 12 and 17 years of age wear sunscreen, versus only about one third of boys in the same age group.
3. Persons who have used a tanning bed are 2.5 times more likely than other persons who have not to develop squamous cell carcinoma.
4. Regular use of a tanning bed is associated with an eightfold increase in melanoma risk; even casual use is associated with a threefold increase.
5. More than one third of teen girls and 11% of teen boys have used a tanning bed at least once in their lives.
6. Approximately 28% of female adolescents and 7% of male adolescents have used a tanning facility three or more times.
7. In all, more than one million people make use of a tanning salon, booth, or bed every day.

Despite the widely recognized morbidity and mortality associated with skin cancer, it seems that our risk taking through UVR exposure will probably not change until a tan is no longer deemed “fashionable.”

Atypical Moles

Atypical moles (dysplastic nevi) affect 10% to 30% of the general population. These acquired lesions have clinical and histologic features that differ from common moles (melanocytic nevi). Common moles are tan to dark brown in color, sharply circumscribed, 2- to 6-mm macules or papules that develop in childhood or early adulthood; the average adult has 20 common moles. In contrast, atypical moles or dysplastic nevi are often larger than 6 mm, irregular or ill-defined, variegated in color (Fig. 114.1, Color Plate section), and may continue to appear after age 35. Because of these atypical features, biopsy may be required to exclude the possible diagnosis of melanoma.

Patients with a few nonfamilial atypical moles and no personal history of melanoma are at increased risk for melanoma when compared with the general population, with a relative risk somewhere between 2 and 8 (4). With the goal of detecting melanomas as early as possible, these patients are asked to perform monthly self-examinations, looking for any change in the appearance of a mole, and to have physician skin examinations done every 6 to 12 months. Full body photography is very useful, aiding both patients and physicians in the detection of new or changing moles, hopefully allowing melanoma to be diagnosed at the earliest stages should it develop (5).

The familial atypical mole and melanoma (FAMM) syndrome, formerly called the dysplastic nevus syndrome, is associated with an extremely high risk of melanoma. Although the prevalence is probably greatly underestimated, it is said to affect at least 300,000 people. These individuals begin to develop atypical lesions at puberty and continue to develop new lesions throughout their lives. Patients with this syndrome have a family history of melanoma in at least one first- or second-degree relative and many nevi, often more than 50, some or many of which are atypical. Patients with the FAMM syndrome have a lifetime risk of developing melanoma approaching 100%. Patients with

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sporadic atypical mole syndrome with a mole pattern similar to that of the FAMM syndrome also have a significantly increased risk of developing melanoma. All these patients should perform monthly self-examinations, with the aid of baseline full body photographs, as noted above, looking for any changes in the appearance of their moles. Additionally, they should be examined at 3- to 12-month intervals by a dermatologist. Patients should be counseled on methods of self-examination (using their photographs placed in an photoalbum to facilitate a systematic full skin examination) and means of sun protection (avoidance of exposure during peak sun intensity hours, use of high sun-protection factor sunscreen, and appropriate protective clothing) because sun exposure increases the risk of malignancy. Also, because early detection saves lives, it should be made clear that other family members may be similarly affected and advised.

Melanoma

Cutaneous malignant melanoma is the third most common type of skin cancer and the leading cause of death from skin disease (4,6). Excluding the “nonmelanoma skin cancers” (basal and squamous cell carcinomas), in the United States, melanoma ranks as the fifth and seventh most common cancer in men and women, respectively. In this country, an estimated 55,000 persons were diagnosed with melanoma and 7,900 persons died because of melanoma in 2004. Comparing melanoma statistics from 1950 to 2000, there has been a 619% increase in annual diagnosis and 165% increase in annual mortality. Melanoma remains the most common cancer diagnosed in women from 20 to 29 years of age (6).

Although melanoma occurs with greatest frequency within a small subpopulation of persons having the FAMM syndrome or nonfamilial atypical moles, most patients who develop melanoma have neither of these relatively uncommon risk factors. Six much more common independent risk factors for melanoma include family history of melanoma, blond or red hair, marked freckling on the upper back, three or more blistering sunburns before age 20, three or more summers spent outside working as a teen, and the presence of actinic keratoses. Having one or two of these risk factors increases risk by 3.5-fold and having three or more risk factors increases risk by 20-fold. Although rare in African Americans, melanomas are most often found on the hands and feet, where incidence is similar among various races. Although the cause of melanoma is unknown, ultraviolet radiation is an important risk factor. Evidence for this includes the greater incidence of melanoma found in persons living closer to the equator, persons having a history of blistering sunburns, and persons with a history of basal or squamous cell carcinoma (7).

As a general rule, all pigmented lesions should be scrutinized for atypical features that may suggest melanoma. These include the ABCDs, asymmetry, border irregularity, color variegation (variable degrees of brown, tan, black, red, white, or blue), and diameter greater than 6 mm. Although one or more of these features may be present in a given melanoma, they may be absent. Adding “E” to denote “evolving” has been proposed to aid in the diagnosis of melanomas lacking the “ABCD” features. Evolving, as defined by its proponents, may designate such things as changes in size, shape, and shades of color, itching, tenderness, and bleeding (8). The utility of this addition is easily seen in the case of a nodular melanoma. This cancer characteristically presents as a symmetric, dome-shaped, deeply but evenly pigmented, rapidlygrowing (evolving) papule or nodule, exhibiting none of the ABCDs.

Excisional biopsy of changing or atypical moles should generally be performed, and ongoing close surveillance of patients with many remaining moles or the sporadic or familial atypical mole syndrome by a dermatologist or practitioner skilled in the area should be recommended. Finally, patient education is of key importance, with focus on the appearance of atypical moles and melanomas using the ABCDEs, monthly or bimonthly self-examination, protection from the sun (sun avoidance, sunscreen use, and protective clothing), and awareness of the possible familial link (i.e., patients with atypical moles or melanoma should most certainly inform relatives of the possible genetic link and the need for skin examination).

There are four common subtypes of melanoma, superficial spreading, nodular, lentigo maligna, and acral lentiginous melanoma (9,10). Fortunately, the characteristically difficult to diagnose amelanotic melanoma, which is usually white, pink, or red, is relatively rare. Table 114.1 shows the characteristics of these melanoma subtypes.

Superficial spreading melanoma arises from a pre-existing nevus in approximately 25% to 50% of cases. Typically, radial or outward growth occurs over a period of months to years. Clinical changes caused by this malignant transformation are generally seen as a change in diameter and border irregularity. With time, growth descends vertically from the epidermal–dermal junction and the surface becomes papular. This vertical growth creates the potential for metastasis. Figure 114.2 shows a superficial spreading melanoma (see Color Platesection).

Nodular melanoma usually does not manifest any of the ABCDs, but does exhibit the “E” (evolution) of atypical pigmented lesions, as it generally has no radial but only a vertical growth phase. This type of melanoma is usually a dome-shaped or polypoid, symmetric, deeply pigmented papule. It may develop de novo or arise within a pre-existing nevus. Nodular melanoma tends to grow rapidly over weeks to months.

Lentigo maligna melanoma occurs on sun-exposed skin, most commonly on the face. It arises from a pre-existing

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lentigo maligna, which is a tan, brown, or brown/black, typically irregularly outlined macule on a sun-exposed site, usually present for many years. In fact, the term lentigo means freckle. Lentigo maligna melanoma has a radial growth phase like that of superficial spreading melanoma and therefore commonly shows the ABCDs of atypical pigmented lesions.

Acral lentiginous melanoma occurs with equal frequency in both light and deeply pigmented persons. This is in contrast to all other types of melanomas, which are rare in deeply pigmented persons. It is the most frequent type of melanoma occurring in African Americans and Asians. It presents on the peripheral parts (hence the name), especially the palms, soles, or subungually (underneath the nail plate) within the nail unit, and usually displays some of the ABCDs of atypical pigmented lesions. Hutchinson sign marked by pigment extending onto the skin of the nailfold in association with a subungual pigmented lesion is highly suggestive of melanoma, and biopsy is mandatory. Acral lentiginous melanoma frequently has a poor

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prognosis because diagnosis is often delayed. Up to 50% of patients with acral lentiginous melanoma give a history of preceding trauma of the skin in the area of the lesion. This history and the mistaken acceptance by the patient and physician that the pigment change or nail dystrophy is the result of trauma often contributes to a delay in biopsy and diagnosis.

Although the U.S. Preventive Services Task Force has not found sufficient evidence to recommend routine full body skin examination for melanoma, an argument can be made that early detection and excision is associated with a lower incidence of melanoma associated morbidity and mortality. With the latter in mind, our urgent aim is to detect melanoma as early in evolution as possible. At present, this seems best facilitated through public and professional education. A study involving 102 patients (47 male, 55 female) diagnosed with melanoma seen at one institution between 1995 and 1997 found that 55% of malignancies were self-detected, whereas 24% were detected by the health care provider. Those detected by professionals were thinner than those detected by patients (0.23 mm versus 0.9 mm, p<.001). These data should motivate continued patient and professional education (11).

Patients with suspicious lesions should be referred to a dermatologist or surgeon for evaluation for possible melanoma. In contrast to patients with suspected basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) in whom a delay of 4 to 6 weeks is acceptable, patients with melanoma should be seen within a week or two. The suspected lesion will likely be fully excised for diagnosis. When full excision of the lesion is not possible because of anatomic location or size, an incisional biopsy of the most atypical and elevated area of the lesion is performed. If the diagnosis of melanoma is confirmed histologically, re-excision with an appropriate margin of normal surrounding tissue, as dictated by the vertical thickness of the melanoma, is necessary, 0.5 cm for melanoma in situ; 1 to 2 cm for melanoma 1 to 2 mm in thickness; and at least 2 cm for melanoma 2 mm or more in thickness. The exact optimal re-excision margin in this last case (melanoma thickness of 2 mm or greater) is felt “yet to be determined” (12). Simultaneous sentinel lymph node excision or elective lymph node dissection in patients with melanoma clinically limited to the skin remains controversial. Although data are still being gathered regarding the use of sentinel lymph node biopsy, many centers routinely perform sentinel lymph node biopsies for melanomas 1 mm or greater in thickness (6,13).

In otherwise asymptomatic patients, followup surveillance for Stage I melanoma (thickness up to 2 mm without ulceration and no nodal or distant spread) entails yearly, or more frequent, full skin and lymph node examination. Surveillance for Stage II (excluding Stage I melanoma, any thickness, with or without ulceration, and again, no evidence of nodal or distant spread) is similar. Surveillance testing such as serum lactate dehydrogenase (LDH), chest radiograph, and other imaging studies are not generally recommended. For patients with greater risk for additional melanomas, such as those with atypical moles, full skin examination is often recommended at 3- to 6-month intervals (6). Full-body photography to aid in ongoing self and physician skin examination (as above, placing these photographs in an orderly fashion in a photoalbum to facilitate a systematic full body skin examination) for changing or new “moles” (or melanoma!) is believed to aid in the diagnosis of melanoma (5). Finally, the need for ocular examination for melanocytic lesions in person with cutaneous melanoma is debated. Data seem to be stronger for the converse of this (i.e., skin examination in persons with a history of ocular melanoma) (14).

The prognosis for a patient after excision of a primary cutaneous melanoma depends on the thickness of the melanoma and whether there is evidence of spread to lymph nodes or distant metastases. Ten-year survival rates, based on melanoma thickness, are as follows, ≤1 mm, 88%; >1 to 2 mm, 79%; >2 to 4.0 mm, 64%; >4 mm, 54%. If ulceration is present, 10-year survival rates decrease to 83%, 64%, 51%, and 32%, respectively. In patients with microscopic metastases to the regional lymph nodes, the 5-year median survival is less than 70%; with macroscopic lymph node metastases, less than 60%; and with noncutanous or subcutaneous distant metastases, less than 10% (15).

Adjuvant therapy for persons at “high risk” for recurrence and mortality after definitive surgery is controversial. High dose interferon α-2b, approved by the U.S. Food and Drug Administration (FDA), may be considered for those with Stage IIB or IIC (melanoma without evidence of spread and “thicker than 2 mm with ulceration” or “thicker than 4 mm with or without ulceration”) and Stage III (melanoma associated with spread limited to regional lymph nodes). High-dose interferon causes unpleasant and sometimes intolerable side effects including flu like symptoms with fatigue, fever, headache, and nausea, as well as weight loss, depression, and also possible myelosuppression, and is associated with only modest efficacy. It is best reserved for eligible patients who are otherwise healthy with an expected life expectancy of greater than 10 years in whom the chance of recurrence is believed to be greatest (6). Therapeutic melanoma vaccines hold promise but are still investigational (6).

Actinic Keratosis and Nonmelanoma Skin Cancer

Actinic Keratosis

Actinic keratoses are sun-induced precancers or focal areas of epidermal dysplasia (Table 114.2). Although occasionally seen in teenagers, they generally begin to develop

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in the fourth or fifth decades of life in fair-skinned persons with other evidence of sun damage, such as freckling or solar lentigines (liver spots). Lesions appear as ill-defined erythematous, generally 2- to 8-mm scaly macules or minimally elevated hyperkeratotic papules on sun-exposed sites (Fig. 114.3, Color Plate section). They are most easily detected by gently running the fingertips over the area because they feel like islands of fine sandpaper. Although precancerous, less than 1% progress to invasive SCC.

Options for treatment of actinic keratoses include topical 5-fluorouracil cream (Carac, Fluoroplex, Efudex), imiquimod cream (Aldara) (16), or cryotherapy using liquid nitrogen to destroy the abnormal epidermis. With cryotherapy, the treated area may blister, crust, and then heal in 1 to 2 weeks without scarring. However, postinflammatory hypopigmentation or depigmentation, leaving a whitish macule, is not uncommon. If one is unfamiliar with either of these forms of therapy, referral to a dermatologist is appropriate. New lesions are likely to occur, and patients with actinic keratoses should be examined every 6 to 12 months.

Nonmelanoma Skin Cancers

The two most common skin cancers and the most common cancers in humans, BCC and SCC, make up 95% of the estimated 1.3 million skin cancers expected in 2001 in the United States. The anticipated ratio of BCC to SCC is 4,1 (17,18).

The most important risk factors for nonmelanoma skin cancers (NMSCs) include cumulative sun exposure (for most Americans, over 80% of the lifetime sun exposure occurs before age 18), fair skin color, and older age. Less well-established but important risk factors for SCC include tobacco smoking and sunlamp or suntan parlor use.

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Even though almost all NMSCs occur on sun-exposed surfaces, covered or usually covered sites such as the hair-bearing scalp, genitalia, or lower extremities may develop cancers. In these sites normally protected from sun exposure, other risk factors are usually involved, such as a distant history of scalp irradiation for treatment of tinea or a hemangioma, prior genital human papilloma virus infection, and chronic ulceration (e.g., hidradenitis suppurativa, chronic leg ulcer).

Note should be made that patients at risk for skin cancer who subsequently receive organ transplantation acquire a much greater risk for skin cancer after transplantation due to ongoing immunosuppressive therapy. The frequency of SCCs developing in the first 20 years after transplantation in these patients exceeds 40% in temperate climates and 80% in less temperate climates (i.e., Australia) (19). A recent study has confirmed that the level of “global immunosuppression” as opposed to the specific immunosuppressive therapy regimen used determines the risk of skin cancer. In persons with greatest risk of cutaneous SCC, which may potentially metastasize and ultimately lead to death, immunosuppression should be titrated to the lowest dose required to maintain the transplanted organ (20).

Finally, certain genetic disorders lead to an increased rate and early onset of skin cancer in affected individuals. The most common of these disorders is basal cell nevus syndrome, an autosomal dominant inherited disorder in which patients develop palmar pits (ice pick-like indentations), jaw cysts, and calcification of the falx cerebri, in combination with multiple BCCs, usually beginning in the teens or twenties. A mutation in the Patched (Ptc) gene on chromosome 9 is believed to be responsible for this syndrome as well as some sporadic BCCs (21). Another disorder, xeroderma pigmentosum, is an autosomal recessive condition with childhood onset of SCCs, BCCs, and occasionally melanomas. Patients have a defect in excision or postreplication repair of ultraviolet radiation-induced DNA changes.

Basal Cell Carcinoma

Eighty percent of BCCs develop on the head and neck. Other commonly affected sites include the upper trunk in both sexes and the legs in women. Patients typically give a history of a new lesion or a lesion that repeatedly gets red, peels, or bleeds and then improves, only to repeat the cycle. BCC may be divided into subtypes based on clinical morphology, nodular ulcerative, superficial, morpheaform or sclerosing, and pigmented.

Nodular ulcerative BCC accounts for approximately half of all cases of BCC. Typically, the lesion is first noted as a firm, pink/white to semitranslucent (“opalescent”) papule with telangiectasias. If allowed to progress to a nodule, the vascular supply may become insufficient and ulceration may occur forming the classic “rodent ulcer” (Fig. 114.4; see Color Plate). Before ulceration, the differential diagnosis includes an intradermal nevus, fibrous papule, inflamed follicle, and seborrheic keratosis. Several points may help distinguish these entities. A nevus is soft and typically present for many years, an inflamed hair follicle should resolve in no longer than a few weeks from onset, and a seborrheic keratosis has a stuck-on appearance and a fine papulated or pebbly surface. If the diagnosis of BCC cannot be excluded clinically, a biopsy should be performed. Suspected BCCs should also be biopsied to confirm the diagnosis for definitive treatment.

Superficial BCC appears as a sharply circumscribed, erythematous, scaly, 3-mm to many centimeter macule or a slightly elevated plaque with a characteristic thread-like border. The differential diagnosis includes actinic keratosis, Bowen disease (SCC in situ), extramammary Paget disease, dermatitis (nummular or contact), psoriasis, and tinea.

Morpheaform or sclerotic BCC develops as a spontaneous, macular, slightly elevated or depressed scar. It has a white, faint pink, or yellow appearance, looking devoid of vessels and appendygeal structures (hair and sebaceous and eccrine glands). The differential diagnosis includes a traumatic or surgical scar, localized scleroderma (morphea), and, less often, granuloma annulare and cutaneous sarcoidosis.

Pigmented BCCs are similar in appearance to nodular or superficial BCCs but are pigmented. They occur most often on more deeply pigmented whites, Asians, and African Americans. The differential diagnosis includes melanoma, seborrheic keratosis, and nevus.

Squamous Cell Carcinoma

SCC may develop de novo or may arise from an actinic keratosis (17). It appears as a firm to hard erythematous to brawny nodule, often with central hyperkeratotic (stacked) scale or ulceration (Fig. 114.5; see Color Plate). The hyperkeratotic scale may form a horn (pointed surface protrusion). The differential diagnosis includes keratoacanthoma, wart, and seborrheic keratosis. Keratoacanthoma mimics SCC both clinically and histologically but is believed to be a benign self-healing tumor. It develops over several weeks, beginning as a rapidly enlarging papule with a central hyperkeratotic plug that spontaneously involutes over several weeks.

Pathogenesis of Nonmelanoma Skin Cancers

BCC and SCC are derived from keratinocytes; BCC specifically arises from basal keratinocytes of the epidermis and adnexa. It is believed that damage caused by ultraviolet B radiation (wavelengths 290 to 320 nm) to deoxyribonucleic acid (DNA) in the form of cyclobutane pyrimidine dimers, inadequacy of DNA repair mechanisms, and suppression of the local immune surveillance system are all important in the development of NMSC.

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Prognosis and Therapy of Nonmelanoma Skin Cancer

Although BCC rarely metastasizes (<0.03%), SCC may do so in approximately 3% of patients. Rates are greatest for SCCs developing on the lips, in scar tissue, and in areas of chronic inflammation. Sites of metastasis may include regional lymph nodes, liver, lung, bone, and brain. Metastatic SCC is associated with a 5-year survival rate of approximately 15% to 40%. People who have had one NMSC are at increased risk for future skin cancers. Within 5 years of one NMSC, a patient has a 50% chance of developing a second tumor (22). Patients with previous NMSC have a 17-fold increased risk of developing melanoma (7).

Patients suspected of having NMSC should have biopsy confirmation before definitive treatment. Treatment options for cancers include excisional therapy, Mohs micrographic surgery (a procedure in which the visible cancer is excised and the specimen immediately examined histologically to ensure that the margins are free of cancer; if cancer is still present, a deeper section is taken and examined; this is repeated until the resected tissue is free of cancer), electrodesiccation and curettage, cryosurgery, or radiation therapy. The treatment modality depends on the type of cancer (cell type, primary or recurrent), location, the patient's age and ability to tolerate a procedure, local availability of the procedure, and patient preference. Nonsurgical nonradiation therapies are under study and hold promise. Imiquimod cream, an immune response modifier that enhances local cutaneous cytokine production when applied topically, has proven effective in the treatment of nonfacial superficial BCC up to 2 cm in diameter, and is now FDA-approved for this indication (23).

In patients who develop many NMSC, such as those with organ transplants, basal cell nevus syndrome, or xeroderma pigmentosum, as described above, chemoprophylaxis with retinoids may be considered. The two retinoids used in dermatology for the primary indications of cystic acne and psoriasis, isotretinoin or acitretin, respectively, have been used prophylactically with some successs in these patients. Unfortunately, the retinoid must be continued indefinitely to maintain the reduction in the rate of skin cancer formation. Retinoids have many potential side effects; in addition to being teratogenic and often causing elevation of lipids, they may cause tendon calcification and vertebral hyperostosis with chronic administration. Additionally, patients not infrequently experience uncomfortable peeling of the palmar skin and dry skin and lips, as well as significant hair loss (24). Recent data suggests a lower retinoid dose might be advantageous in increasing acceptance by transplant patients while still yielding effective chemoprophylaxis (19). As stated above, the other therapeutic arm in skin cancer prophylaxis in transplant patients (i.e., minimization of immunosuppression) should also be addressed (20).

Specific References

For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.

1. Eide MJ, Weinstock MA. Association of UV index, latitude, and melanoma incidence in nonwhite populations—US Surveillance, Epidemiology, and End Results (SEER) Program, 1992 to 2001. Arch Dermatol 2005;141:477.
2. Preston DS, Stern RS. Nonmelanoma cancers of the skin. N Engl J Med 1992;327:1649.
3. May 2005. Available at: http://www.dermatologynetguide.com.
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18. National Melanoma/Skin Cancer Detection and Prevention Month, May 1996. JAMA 1996; 275:1537.
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20. Fortina AB, Piaserico S, Caforio ALP, et al. Immunosuppressive level and other risk factors for basal cell carcinoma and squamous cell carcinoma in heart transplant recipients. Arch Dermatol 2004;140:1079.
21. Johnson RL, Rothman AL, Xie J, et al. Human homology of patched, a candidate gene for the basal cell nevus syndrome. Science 1996;272: 1668.
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24. Bouwes Bavinck JN, Tieben LM, Van Der Woude FJ, et al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol 1995;13:1933.