Neoplasms of the Skin

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[edit] Neoplasms of the Skin

Bert G. Tavelli

James C. Shaw

[edit] BENIGN NEOPLASMS

There are easily dozens of benign proliferations of the skin and its appendages, each with numerous variations. Familiarization with the most common of these can help decide when it is best to treat or advise the patient and when it is best to refer.

[edit] Freckles and Lentigines

Freckles (ephelids) and solar lentigines (liver spots) are sun-induced, variably-pigmented macules that are characterized histologically by increased melanin along the basal layer of the epidermis. Solar lentigines are larger and more irregular in shape than freckles. Simple lentigines are similar in appearance to solar lentigines but appear in childhood, are symmetric, and are generally smaller. They are randomly distributed and not sun-sensitive. Histologically they have increased numbers of normal melanocytes, along with increased melanin pigmentation throughout the epidermis. No treatment is usually needed.

[edit] Melanocytic Nevi

Melanocytic nevi are a group of benign proliferations of nevus cells, forming symmetric, well-circumscribed, evenly pigmented lesions anywhere on the skin. Acquired melanocytic nevi vary considerably in clinical appearance. Typical benign nevi present as symmetric, round-to-oval lesions with distinct, rounded borders. They range in contour from flat (junctional) to slightly raised or papillated (compound) ( Plate 40 ) to dome-shaped or pedunculated (intradermal); pigmentation may vary from tan to all shades of brown or black. Many intradermal nevi eventually become flesh colored or only slightly pigmented. They tend to enlarge in proportion to body growth and may do so more rapidly during pregnancy.

Although variations in size, shape, color, and growth characteristics occur within a given individual's nevi, the “ABCD's” provide a rationale for the clinical identification of lesions suggestive of melanoma. These ABCD's are the following:

Asymmetry (not round or oval)

Border irregularity (notching or poorly defined)

Color variegation (shades of brown, red, white, black, blue, or combinations of colors)

Diameter (greater than 6 mm)

Symptoms (persistent itch or other sensation)

In addition, an otherwise benign-appearing pigmented or nonpigmented nevus that changes rapidly in any way can also represent melanoma, which is presented later in this chapter.

Several clinical variants of melanocytic nevi deserve discussion. Blue nevi are acquired and are usually solitary dark blue or blue gray papules located anywhere on the skin or mucous membranes. They are thought to represent ectopic accumulations of melanocytes in the dermis that reflect light of a blue wavelength because of their density and depth. They are benign, although clinically they can resemble melanoma ( Plate 41 ).

Atypical nevi are a more common but controversial variant that are difficult to classify and for which there are no strict diagnostic criteria. Previously referred to as “dysplastic nevi,” they are generally larger than other acquired nevi, with somewhat indistinct or irregular borders ( Plate 42 ). Pigmentation varies within lesions from dark brown to tan or flesh colored, often on a reddish background. They are usually flat but may have a centrally raised portion that can be darker than the surrounding macular area.

Clearly, an individual lesion that is large, has an asymmetric or irregular shape, and color variation might be suggestive of melanoma. However, when many such nevi occur on the same person, management becomes more difficult. Additionally, the histology of these lesions has been similarly difficult to define, with no clear-cut reproducible criteria with which to distinguish them from other pigmented lesions.

The main importance of atypical nevi lies in the possible increased risk of the development of melanoma, either in an individual lesion or in patients or families in whom these nevi are seen. These questions are highly controversial, and the field is constantly in flux, making clinical management difficult. A reasonable approach for the primary practitioner based in part on a recent National Institutes of Health consensus conference is summarized in Box 87-1.

[edit] Chondrodermatitis Nodularis

Chondrodermatitis nodularis ( Plate 43 ) is a painful, pressure-induced papule or nodule occurring primarily along the helical rim of the ear. Lesions are precipitated by focal, often minor, trauma, and develop into inflamed, intensely painful papules with central necrosis or ulceration. They may resemble basal cell or squamous cell carcinoma. Treatment with intralesional corticosteroids may be useful, but surgical excision is often necessary.

[edit] Keloids

Keloids ( Plate 44 ) are firm, smooth, often tender proliferations of scar tissue at sites of injury to the skin that occur mostly on the chest, shoulders, back, and earlobes. Treatment is problematic, since surgery usually results in a larger keloid. Early treatment is more successful, using a combination of silastic gel sheeting, intralesional corticosteroids, and specialized surgical techniques.

[edit] Seborrheic Keratoses

Seborrheic keratoses ( Plate 45 ) are symmetric, keratotic papules or plaques that can arise anywhere on the skin and appear “stuck on.” They range in color from light tan to dark brown or black and often have a waxy consistency. Seborrheic keratoses can be distinguished from melanoma, which at times they closely resemble, by the presence of multiple, dilated follicular ostia filled with keratin. Biopsy by excision is necessary when the diagnosis is uncertain. If needed, symptomatic lesions can be treated with a light liquid nitrogen spray.

[edit] Calluses and Corns

Both calluses and corns represent hyperkeratotic, thickened skin arising in response to chronic trauma from pressure or friction. A corn is generally smaller and more focal, occurring over bony pressure points on the sides of the toes or foot. Elimination of the abnormal pressure forces and manipulating or changing footwear is often successful.

[edit] Sebaceous Hyperplasia

Sebaceous hyperplasia is the term given to symmetric, raised, 2 to 4 mm papules that appear on the face in middle age. The distinctive yellow color and typical umbilication around a central pore (follicular ostium) help distinguish them from basal cell carcinoma and other epidermal neoplasms. No treatment is needed for these benign lesions.

[edit] Hemangiomas

Hemangiomas are benign proliferations of blood vessels forming variably sized, soft, red compressible papules that occur anywhere on skin. The most common is the “cherry hemangioma,” which is small, usually less than 3 mm, and difficult to blanch. They are seen primarily on the chest and back and increase in number with age. No treatment is required, although laser removal for cosmesis has had some success.

[edit] Pyogenic Granuloma

Pyogenic granulomas ( Plate 46 ) are reddish purple, friable, vascular tumors that range in size from several millimeters to greater than a centimeter. They can arise anywhere on the skin, usually as a response to local trauma. They bleed profusely when abraded and are often ulcerated or covered with scale crust. They usually require surgical excision, and recurrences are common. Occasionally, malignant melanoma can resemble a pyogenic granuloma and should be considered in the differential diagnosis.

[edit] Lipomas

Lipomas are subcutaneous tumors of adipose tissue, usually located on the trunk and proximal extremities. They are soft, symmetric, and easily movable over deeper structures and can be confused with various cystic lesions. They may be single or multiple and any size from 1 to many centimeters in diameter. The term angiolipoma is given to a variant that histologically contains multiple small blood vessels and clinically may be associated with pain. These symptomatic lesions may be surgically excised.

[edit] Follicular Cysts

Follicular cysts are dermal tumors containing sebum and keratin debris that are derived from the lining of the hair follicle. They appear as firm, raised, slowly enlarging nodules anywhere on the skin, predominantly the scalp, face, and trunk. They are also termed wens and erroneously referred to as epidermal, inclusion, or sebaceous cysts. Most lesions are left untreated, although surgical excision may be needed for larger cysts, those in sensitive anatomic sites, or those that have become recurrently infected.

[edit] Dermatofibromas

Dermatofibromas ( Plate 47 ) are firm, scarlike, pigmented dermal nodules that occur most frequently on the extremities of women but can be found anywhere on the skin in either sex. Most present as slowly enlarging, reddish-brown, slightly elevated papules or nodules. Individual lesions can reach a centimeter or more in size and can be painful. They are not attached to fat or fascia but are affixed to overlying epidermis. Dermatofibromas should be referred for evaluation if they are large or rapidly enlarging, irregularly pigmented, bleeding, or painful, so that malignant melanoma, dermatofibrosarcoma protuberans, and other malignant processes can be excluded.

[edit] Fibrous Papule

Fibrous papules (adenoma sebaceum, angiofibroma) are smooth, 1 to 2 mm, grayish to flesh-colored papules that occur almost exclusively on the nose and central face. They are common in middle-aged individuals and usually solitary, although multiple lesions are sometimes seen and should alert the practitioner to the possibility of tuberous sclerosis. Biopsy is required at times to distinguish them from basal cell carcinoma.

[edit] Acrochordon

Acrochordons, which are also called skin tags, are extremely common. They most often involve the axillae, neckline, and groin, where they appear as pinpoint to 5 mm or larger flesh-colored papules. Acrochordons are most often confused with nevi or seborrheic keratoses. Surgical removal is used for those lesions that interfere with function or become persistently inflamed.

[edit] MALIGNANT NEOPLASMS

[edit] Nonmelanoma Skin Cancer

[edit] Epidemiology/Etiology.

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) represent the most common human malignancies. Nonmelanoma skin cancers account for greater than 1 million new cases of cancer annually in the United States and are responsible for 1200 to 1500 deaths per year. Costs of $500,000,000 have been estimated in the management of these malignancies. Fair-skinned caucasians have the highest risk for the development of nonmelanoma skin cancer. Ultraviolet (UV) light exposure has been implicated as the carcinogen most responsible for the development of these malignancies.^[1] UV light has been shown to alter DNA, such as tumor suppressor genes (p 53), thymidine dimers, and ras oncogenes, all of which are thought to contribute to the development of skin cancer. UV light has also been shown to alter the immune system by damaging epidermal immune cells and modulating cytokine activity.

[edit] Basal Cell Carcinoma

[edit] Physical Examination.

There are three main variants of BCC based on the clinical appearance.

Nodular BCC, the most common, usually develops as a papule and enlarges slowly into a nodule ( Plate 48 ). The lesion is raised, pearly or translucent in color, with telangiectasias. Ulceration or surface crusting is common ( Plate 49 ). The most common sites are the sun-exposed areas of the head and neck. Rarely, BCCs are pigmented and resemble malignant melanoma.

Sclerosing BCC ( Plate 50 ) appears as a patch of indurated scarlike change, whitish in color, usually without telangiectasias or ulceration. This variant enlarges horizontally into plaques.

Superficial BCC ( Plate 51 ) refers to a variant that resembles a dermatitis. In this variant, a patch of erythema with slight scale and friability gradually enlarges over years. A slightly raised, advancing border usually surrounds the lesion. The tumor process remains at the base of the epidermis for months to years before larger nodular growth develops.

[edit] Laboratory Evaluation.

Histologic confirmation is important and helps direct treatment. The depth of involvement, histologic type, and whether there are aggressive features are important factors in designing therapy. A punch biopsy gives the best results. There are several histologic variants of BCC, as well as numerous benign skin tumors that resemble BCC histologically.

[edit] Management

[edit] Prevention.

Sun protection beginning in childhood is the best preventive measure against BCC. This prevention includes educating adults and children about the damaging effects of excessive sun exposure, the early use of sun screens (minimum SPF 15), and protective clothing.

[edit] Treatment.

Modalities for treating BCC include curettage surgery, excision, radiation, and Mohs' surgery. The choice of treatment depends on the location, size, histologic type, and history of previous treatment. For small lesions, simple excision is usually curative. Large tumors, recurrent tumors, and those on the central face and around the ears have a higher treatment failure rate.

For these types of BCC, the use of Mohs' surgery may be indicated. Mohs' surgery is a specialized procedure that utilizes excision with frozen-section control of all margins by means of quadrant mapping of the specimen (Fig. 87-1). Radiation may be indicated in patients who cannot tolerate excisional surgery or for lesions in difficult anatomic sites.

Figure 87-1 Microscopically guided excision of cutaneous tumors—Mohs' micrographic surgery. (From Habif TP: Clinical dermatology, ed 3, St Louis, 1996, Mosby.)

[edit] Squamous Cell Carcinoma

[edit] Physical Examination.

There are several clinical presentations that are considered within the disease spectrum of SCC.

Actinic keratoses (solar keratoses) ( Plate 52 ) are considered precursors to SCC. They begin as areas of rough or thickened skin, usually with some erythema, and slowly evolve into raised hyperkeratotic plaques or nodules. They are always found on sun-damaged skin. Histologically, actinic keratoses have atypical epidermal growth that is limited to the lower portion of the epidermis. The differential diagnosis of actinic keratosis are found in Box 87-2.

Bowen's disease (SCC in situ) ( Plate 53 ) usually presents as a patch of erythematous or brown-red discoloration, slightly raised, with sharp borders. Sun-protected, as well as sun-damaged, skin can develop Bowen's disease, which demonstrates atypical epidermal growth throughout the entire thickness of the epidermis but no invasion into the dermis. Both actinic keratoses and SCC in situ have the potential to evolve into invasive SCC.

Keratoacanthoma ( Plate 54 ) is a type of SCC that in the past has been called self-healing or benign. It develops rapidly as a dome-shaped nodule that can reach a size of 1 or 2 cm within 8 weeks. Histology can be indistinguishable from invasive SCC. Although past literature suggests that keratoacanthomas can resolve spontaneously, there have been reports of metastasis, and many authors now regard keratoacanthomas as a variant of well-differentiated SCC.

SCC arising de novo without a precursor lesion usually starts with a patch of hyperkeratosis with erythema, which grows slowly into a nodular tumor or a cutaneous horn ( Plate 55 ).

[edit] Laboratory Evaluation.

Skin biopsy is required to confirm the diagnosis. No other laboratory tests are useful.

[edit] Management.

The treatment of choice for SCC is surgical excision. Actinic keratoses can be treated with cryotherapy using liquid nitrogen. Topical chemotherapy with 5-fluorouracil (5-Fu) is occasionally used when numerous actinic keratoses are present. Keratoacanthomas are treated with excision or intralesional injection with 5-FU or methotrexate. Systemic retinoids have been used in cases of multiple keratoacanthomas. SCCs in the setting of immunosuppression require aggressive treatment because of their rapid growth patterns.

[edit] Melanoma

[edit] Epidemiology/Etiology.

The worldwide incidence of melanoma is increasing faster than any other malignancy. It is predicted that by the year 2000, 1 out of 75 persons will develop melanoma during their lifetime, compared with 1 out of 600 in 1960 and 1 out of 150 in 1985. While the incidence is increasing, the death rate from cutaneous melanoma can be reduced by early detection and treatment.^[2]

Melanoma is a disease primarily of caucasians, although it does occur, although rarely, in darker-pigmented populations. Risk factors include multiple dysplastic nevi, family history of melanoma, multiple basal nevi, immunosuppression, fair skin, and a history of excessive childhood sun exposure.

[edit] Physical Examination.

There are several characteristics of melanoma that are common and are the basis for the previously mentioned ABCD'S of melanoma recognition:

Asymmetry is a common feature of melanoma, whereas most benign tumors tend to be symmetric in shape.

Border irregularity, although not pathognomonic for melanoma, is a typical finding.

Color variegation is an important diagnostic feature. Black, blue, and red hues are commonly present. Colors of the brown spectrum (tan to dark brown) are characteristic of benign lesions (nevi, seborrheic keratoses) and are rarely part of a melanoma unless it arises from a preexisting nevus of that color.

Diameter of melanoma tends to enlarge with time, whereas benign lesions remain stable. Any lesion that enlarges significantly over a period of 1 to 3 months should be evaluated.

Symptoms, such as bleeding and ulceration, may be present in larger lesions.

When examining patients with melanoma, examination of the mucous membranes and lymph nodes should be included.

[edit] Clinical Variants.

Historically, melanoma has been classified into variants based on appearance, histology, and biologic course. Although there is increasing evidence that the separations may not have prognostic significance, many authors continue to use the terms.

Superficial spreading melanoma ( Plate 56 ) is the most common type of melanoma. It is found mostly on the upper back and on the legs in women. The horizontal growth pattern results in irregular shapes. Considerable color variation can be seen.

Nodular melanoma (see Plate 21 ) is a raised lesion found anywhere on the body. It can be black, reddish, or flesh colored. The early vertical growth pattern results in the clinical nodule.

Acral-lentiginous melanoma occurs on the palms, soles, finger tips, nails, and mucous membranes. It is most common in blacks and Asians. The lesions are usually flat but become nodular if left undiagnosed and untreated. Metastatic spread is common at the time of diagnosis.

Lentigo maligna refers to a melanoma in situ that develops on sun-damaged skin of elderly patients. An enlarging pigmented patch on the face is the most common presentation. The process can remain in situ for many years before evolving into melanoma.

[edit] Laboratory Evaluation.

Expert pathologic interpretation is critical to the management of patients with melanoma. The implications of a missed diagnosis are obvious. The prognosis is based on the measured thickness of the tumor in millimeters (Breslow level) more than any other histologic finding (Table 87-1). Ideally, the lesion should be excised entirely for diagnosis. Incisional biopsies may be performed for diagnosis when complete excision is not feasible. A shallow shave biopsy should be avoided, and freezing or burning of pigmented lesions is contraindicated with the sole exception of seborrheic keratoses. The use of the sentinel node biopsy has helped identify individuals with micrometastases who would benefit from lymph node dissection or adjuvant chemotherapy.^[3] In this procedure, blue dye and radioisotope is injected into the melanoma site to identify the sentinal lymph node in the drainage site.

Table 87-1 5-Year Survival Rates in Malignant Melanoma

[edit] Management

[edit] Prevention.

Sun-avoidance behavior (Box 87-3) is currently the main emphasis in melanoma prevention. Protecting young children from sun exposure may be the most important factor that can be monitored.

[edit] Early Detection.

Early detection of melanoma can be lifesaving. The skin self-examination is now recommended to all patients with increased risk of melanoma.^[4] This examination is analogous to the breast self-examination. Patients examine their entire skin surface (using mirrors and assistance when needed) on a monthly basis and seek medical advice for changing lesions or new suspicious lesions. Annual or semi-annual physician visits have also been recommended, but studies of cost effectiveness of this practice have not been done.

The management of a patient with stage I and II melanoma (local disease only) depends on the type of melanoma and the size and thickness of the lesion.^[5] Recent studies have revised the concept of “deep and wide excisions for all melanomas.“ It is now felt that melanomas of a depth of less than 1-mm Breslow thickness can be excised with margins of 1 cm of normal skin. It is not clear what the optimal size of resection is for thicker melanomas, and wider resections continue to be done until this question is answered. The benefit of an elective lymph node dissection is also not established. For melanomas less than 1 mm thick, lymph node dissection is not needed, and for those greater than 4 mm thick, lymph node dissection does not prolong life. In lesions between 1 mm and 4 mm of thickness, there may be some value in performing a lymph node dissection, especially if a single drainage pathway can be identified. The sentinel node biopsy has been used in this group. Follow-up is every 6 to 12 months for thin melanomas (less than 1 mm thickness) and every 3 to 4 months for thicker lesions during the first 5 years, with gradual extension up to 10-to 12-month intervals. Patients need lifelong follow-up, since metastatic spread can become evident after 10 years. The management of stage III (lymph node involvement) and stage IV (systemic involvement) melanoma is beyond the scope of this section. Most treatments are designed for palliation or temporary remission.

[edit] Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphoma (CTCL) (mycosis fungoides) is a malignancy of CD4% T-lymphocytes with a predilection for involvement of the skin.^[6] Men are affected twice as much as women and blacks twice as much as whites. The disease is usually diagnosed in the fifth and sixth decades, although a trend toward earlier diagnosis has been observed recently. The incidence in the United States is twice that observed in England, Wales, Norway, the Netherlands, and Western Australia. Although the etiology of CTCL is unknown, hypotheses concerning etiology include occupational exposure, chronic antigen stimulation, and retroviruses, although none have been proved.

[edit] Pathophysiology.

The precise pathophysiology leading to the development of CTCL is uncertain. One theory is that CTCL begins as a malignancy of CD4% T-cells that is not easily detectable in early stages because of effective immune host response. The malignancy then becomes more aggressive as host response declines and the total number of malignant cells increases. An alternate theory is that CTCL is the result of chronic antigen stimulation (no antigen has yet been identified), which results in T-lymphocyte proliferation with the potential for transformation into malignant cell lines.

[edit] History.

CTCL develops slowly in most cases. Patients usually seek medical attention because of asymptomatic or pruritic patches of abnormal-appearing skin. Patients commonly report a long history of a chronic dermatitis that is unresponsive to treatment. Rarely, CTCL presents with raised tumors noticed by patients. Constitutional symptoms are usually absent but may include fever, night sweats, and weight loss.

[edit] Physical Examination.

There are three clinical stages in CTCL. The patch stage ( Plate 57 ) consists of fixed erythematous patches with slight scaling and wrinkling of the epidermis. They range in size from a few millimeters to 10 to 20 cm in diameter and can be present anywhere on the body. The plaque stage evolves from the patch stage as the lymphocytic infiltrate in the dermis enlarges and the lesions develop a raised component. The plaques can be arcuate or irregular in shape and usually take on a red-brown color. The tumor stage ( Plate 58 ) represents further evolution from the plaque stage, with raised red-brown to violaceous cutaneous tumors with central necrosis and ulceration. All three stages can be present simultaneously, and regional or generalized lymphadenopathy can be present during any of the stages. Occasionally, CTCL presents as a generalized exfoliative erythroderma. Sezary syndrome is a variant of CTCL presenting as a leukemic phase of the disease. Although this form can be present with any of the stages, it presents more frequently with erythroderma or an exfoliative dermatitis.

[edit] Diagnosis

[edit] Differential Diagnosis.

The diagnosis of CTCL can be difficult to make on the basis of clinical appearance, especially in the early phases. Allergic contact dermatitis, other chronic dermatitis, pigmented purpura, psoriasis, and drug eruptions can be in the differential diagnosis of patch stage. Once raised lesions are present, the differential diagnosis includes other cutaneous malignancies, deep fungal infections, granulomatous disease, and deep forms of vasculitis. In all phases of CTCL, diagnosis is made by biopsy.

[edit] Diagnostic Procedures.

Confirmation of the diagnosis requires histopathologic examination from lesional skin. The hallmark of CTCL is the presence of a dense accumulation of mature and atypical lymphocytes in the upper dermis. In most cases the lymphocytes are also present within the epidermis (epidermotropism), a feature that may be lost in late tumor stages. Multiple biopsies over time may be necessary to confirm the diagnosis. In addition to routine histopathologic examination, cell surface markers and gene rearrangement studies of the T-cell antigen receptors from sampled lymph node tissue can help make the diagnosis. Laboratory evaluation for evidence of systemic involvement includes routine hematology and chemistry, a Sezary cell count (greater than 5% Sezary cells is suggestive of Sezary syndrome), flow cytometry, molecular studies, and imaging studies of liver, spleen, and paraaortic lymph nodes. Staging is by the TNM classification (Table 87-2).

Table 87-2 Staging of Cutaneous T-Cell Lymphoma: TNM Classification

[edit] Management.

The treatment of CTCL depends on the level of involvement and frequently requires a team approach utilizing the skills of dermatologists, oncologists, and radiation therapists. Because the therapies available for late stage disease are disappointing, early treatment of the patch and plaque stages of the disease yields the best responses. Topical nitrogen mustard has been used in early disease for many years and has been associated with remissions for up to 12 years in approximately 20% of those treated. UV light treatment (UVB or PUVA [psoralens plus UV light A]) is also effective in early disease, although recurrences usually develop if treatment is stopped. Total body electron beam therapy has been the most successful treatment, with total remissions achieved in 80% to 95% of patients with early disease and disease-free periods of up to 4 years. Other beneficial treatments include extracorporeal photopheresis (especially in erythodermic stages), single and multiple drug chemotherapy, and combinations of electron beam plus adjuvant chemotherapy. These treatments are palliative.

[edit] Lymphoma Cutis

All types of lymphoma can rarely involve the skin. The most common presentation is the development of asymptomatic erythematous to violaceous firm nodules that require biopsy for diagnosis. Treatment is systemic treatment of the underlying lymphoma.

[edit] Leukemia Cutis

Leukemia can rarely involve the skin with infiltrative nodules and plaques ( Plate 59 ). Diagnosis is based on histopathologic examination, and treatment is directed toward the leukemic process.

[edit] Cutaneous Metastases

Cutaneous metastasis of an underlying malignancy is rare, occurring in approximately 1% or 2% of patients with malignancy. The incidence by tumor classification of cutaneous metastasis reflects the incidence of the underlying malignancy: lung cancer and colon cancer are most common in men, and breast cancer is most common in women. Any area of the body can be involved. Lesions usually develop rapidly and are usually asymptomatic. Cutaneous metastases usually consist of firm dermal nodules measuring 0.5 cm to 1.5 cm in diameter. The color is erythematous or red-brown with occasional violaceous hues ( Plate 60 ). Diagnosis is made by biopsy, and treatment is directed toward the underlying malignancy.

[edit] REFERENCES

[edit] ADDITIONAL READINGS

• Elder D Lever's histopathology of the skin. ed 8. Philadelphia: Lippincott-Raven; 1991:
• Maize JC Ackerman AB Pigmented lesions of the skin. Philadelphia: Lea and Febiger; 1987:
• National Institutes of Health (NIH): Diagnosis and treatment of early melanoma. NIH Consensus Statement 1992; 10 (1):