Fitzpatrick's Color Atlas and Synopsis of Clinical Dermatology, Seventh Edition


Precancerous Lesions and Cutaneous Carcinomas


Epidermal Precancers and Cancers

Cutaneous epithelial cancers [nonmelanoma skin cancer (NMSC)] originate most commonly in the epidermal germinative keratinocytes or adnexal structures. The two principal NMSCs are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). SCC often has its origin in an identifiable dysplastic in situ lesion that can be treated before frank invasion occurs. In contrast, in situ BCC is not known, but minimally invasive “superficial” BCCs are common.

The most common etiology of NMSC in fair-skinned individuals is sunlight, ultraviolet radiation (UVR), and human papillomavirus (HPV). Solar keratoses are the most common precursor lesions of SCC in situ (SCCIS) and invasive SCC occurring at sites of chronic sun exposure in individuals of northern European heritage (see Section 10). UVR and HPV cause the spectrum of changes ranging from epithelial dysplasia to SCCIS to invasive SCC. Much less commonly, NMSC can be caused by ionizing radiation (arising in sites of chronic radiation damage), chronic inflammation, hydrocarbons (tar), and chronic ingestion of inorganic arsenic; these tumors can be much more aggressive than those associated with UVR or HPV. In the increasing population of immunosuppressed individuals (those with HIV/AIDS disease, solid organ transplant recipients, etc.), UVR-and HPV-induced SCCs are much more common and can be more aggressive.

Epithelial Precancerous Lesions and SCCIS

Dysplasia of epidermal keratinocytes in epidermis and squamous mucosa can involve the lower portion of the epidermis or the full thickness. Basal cells mature into dysplastic keratinocytes resulting in a hyperkeratotic papule, or plaque, clinically identified as “keratosis.” A continuum exists from dysplasia to SCCIS to invasive SCC. These lesions have various associated eponyms such as Bowen disease or erythroplasia of Queyrat, which as descriptive morphologic terms are helpful; terms such as UVR- or HPV-associated SCCIS, however, would be more meaningful but can be used only for those lesions with known etiology.

Epithelial precancerous lesions and SCCIS can be classified into UV-induced [solar (actinic) keratoses, lichenoid actinic keratoses, Bowenoid actinic keratoses, and Bowen disease (SCCIS)], HPV-induced[low-grade squamous intraepithelial lesions (HSIL) and Bowenoid papulosis (SCCIS)], arsenical-induced (palmoplantar keratoses, Bowenoid arsenical) keratosis, and hydrocarbon (tar) keratoses and thermal keratoses.

Solar or Actinic Keratosis

These single or multiple, discrete, dry, rough, adherent scaly lesions occur on the habitually sun-exposed skin of adults. They can progress to SCCIS, which can then progress to invasive SCC (Fig. 11-1). For a full discussion of this condition, see Section 10.


Figure 11-1. Solar keratoses and invasive squamous cell carcinoma Multiple, tightly adherent dirty looking solar keratoses (see also Figs. 10-25 to 10-27). The large nodule shown here is covered by hyperkeratoses and hemorrhagic crusts; it is partially eroded and firm. This nodule is invasive squamous cell carcinoma. The image is shown to demonstrate the transition from precancerous lesions to frank carcinoma.

Synonym: Solar and actinic keratosis is synonymous.

Cutaneous Horn ICD-9: 702.2 image ICD-10: L85.8 Image

Image A cutaneous horn (CH) is a clinical entity having the appearance of an animal horn with a papular or nodular base and a keratotic cap of various shapes and lengths (Fig. 11-2).

Image CHs most commonly represent hypertrophic solar keratoses. Non-precancerous CH formation can also occur in seborrheic keratoses and warts.

Image CHs usually arise within areas of dermatoheliosis on the face, ear, dorsum of hands, or forearms, and shins.

Image Clinically, CHs vary in size from a few millimeters to several centimeters (Fig. 11-2). The horn may be white, black, or yellowish in color and straight, curved, or spiral in shape.

Image Histologically, there is usually hypertrophic actinic keratosis, SCCIS, or invasive SCC at the base. Because of the possibility of invasive SCC, a CH should always be excised.


Figure 11-2. Cutaneous horn: hypertrophic actinic keratosis A hornlike projection of keratin on a slightly raised base in the setting of advanced dermatoheliosis on the upper eyelid in an 85-year-old female. Excision showed invasive SCC at the base of the lesion.

Arsenical keratoses ICD-9: 692.4 image ICD-10: L85.8 Image

Image Appear decades after chronic arsenic ingestion (medicinal, occupational, or environmental exposure).

Image Arsenical keratoses have the potential to become SCCIS or invasive SCC. These are currently being seen in West Bengal and Bangladesh where drinking water may still contain arsenic.

Image Two types: punctate, yellow papules on palms and soles (Fig. 11-3A); keratoses indistinguishable from actinic keratoses on the trunk and elsewhere. These are often associated with small SCCIS of the Bowen-type and hypopigmented slightly depressed macules (“raindrops in the dust”) (Fig. 11-3B),

Image Treatment—as for solar keratoses.



Figure 11-3. Arsenical keratoses (A) Multiple punctate, tightly adherent, and very hard keratoses on the palm. (B) Arsenical keratoses on the back. Multiple lesions are seen here ranging from red to tan, dark brown, and white. The brown lesions are a mix of arsenical keratoses (hard, rough) and small seborrheic keratoses (soft and smooth). The difference can be better felt than seen. The red lesions are small Bowenoid keratoses and Bowen disease (SCCIS, see Fig. 11-4). The white macular areas are slightly depressed and represent superficial atrophie scars from spontaneously shed or treated arsenical keratoses. The entire picture gives the impression of “rain drops in the dust.”

Squamous Cell Carcinoma In Situ ICD-9: 173.0 image ICD-10: M8070/2 Image

Image Presents as solitary or multiple macules, papules, or plaques, which may be hyperkeratotic or scaling.

Image SCCIS is most often caused by UVR or HPV infection.

Image Commonly arises in epithelial dysplastic lesions such as solar keratoses or HPV-induced squamous epithelial lesions (SIL) (see Sections 27 and 34).

Image Pink or red, sharply defined scaly plaques on the skin are called Bowen disease; similar but usually non-scaly lesions on the glans and vulva are called erythroplasia (see Section 34).

Image Anogenital HPV-induced SCCIS is referred to as Bowenoid papulosis.

Image Untreated SSCIS may progress to invasive SCC. With HPV-induced SCCIS in HIV/AIDS, lesions often resolve completely with successful antiretroviral therapy and immune reconstitution.

Image Treatment is topical 5-fluorouracil, imiquimod, cryosurgery, CO2 laser evaporation, or excision, including Mohs micrographic surgery.


UVR, HPV, arsenic, tar, chronic heat exposure, and chronic radiation dermatitis.

Clinical Manifestation

Lesions are most often asymptomatic but may bleed. Nodule formation or onset of pain or tenderness within SCCIS suggests progression to invasive SCC.

Skin Findings. Appears as a sharply demarcated, scaling, or hyperkeratotic macule, papule, or plaque (Fig. 11-4). Pink or red in color, slightly scaling surface or erosions, and can be crusted. Solitary or multiple. Such lesions are called Bowsen disease (Fig. 11-4).



Figure 11-4. Squamous cell carcinoma in situ: Bowen disease (A) A large, sharply demarcated, scaly, and erythematous plaque simulating a psoriatic lesion. (B) A similar psoriasiform plaque with a mix of scales, hyperkeratosis, and hemorrhagc crusts on the surface.

Red, sharply demarcated, glistening macular or plaque-like SCCIS on the glans penis or labia minora are called erythrop>lasia of Queyrat (see Section 36). Anogenital HPV-induced SCCIS may be red, tan, brown, or black in color and are referred to as Bowenoid papulosis (see Section 36). Eroded lesions may have areas of crusting. SCCIS may go undiagnosed for years, resulting in large lesions with annular or polycyclic borders (Fig. 11-5). Once invasion occurs, nodular lesions appear within the plaque and the lesion is then commonly called Bowsen carcinoma (Fig. 11-5).

Distribution. UVR-induced SCCIS commonly arises within a solar keratosis in the setting of photoaging (dermatoheliosis); HPV-induced SCCIS, mostly in the genital area but also periungually, most commonly on the thumb or in the nail bed (see Fig. 10-33 and 34-16).


Figure 11-5. Squamous cell carcinoma in situ (SCCIS): Bowen disease and invasive SCC: Bowen carcinoma A red to orange plaque on the back, sharply defined, with irregular outlines and psoriasiform scale represents SCCIS, or Bowen disease. The red nodule on this plaque indicates that here the lesion is not anymore an in situ lesion but that invasive carcinoma has developed.

Laboratory Examination

Dermatopathology. Carcinoma in situ with loss of epidermal architecture and regular differentiation; keratinocyte polymorphism, single cell dyskeratosis, increased mitotic rate, and multi-nuclear cells. Epidermis may be thickened but basement membrane intact.

Diagnosis and Differential Diagnosis

Clinical diagnosis confirmed by dermatopathologic findings. Differential diagnosis includes all well-demarcated pink-red plaque(s): Nummular eczema, psoriasis, seborrheic keratosis, solar keratoses, verruca vulgaris, verruca plana, condyloma acuminatum, superficial BCC, amelanotic melanoma, and Paget disease.

Course and Prognosis

Untreated SCCIS will progress to invasive SCC (Fig. 11-5). In HIV/AIDS, resolves with successful antiretroviral therapy (ART). Lymph node metastasis can occur without demonstrable invasion. Metastatic dissemination from lymph nodes.


Topical Chemotherapy. 5-Fluorouracil cream applied every day or twice daily, with or without tape occlusion, is effective. So is imiquimod, but both require considerable time.

Cryosurgery. Highly effective. Lesions are usually treated more aggressively than solar keratoses, and superficial scarring will result.

Photodynamic Therapy. Effective but still cumbersome and painful.

Surgical Excision Including Mohs Micrographic Surgery. Has the highest cure rate but the greatest chance of causing cosmetically disfiguring scars. It should be done in all lesions where invasion cannot be excluded by biopsy.

Invasive Squamous Cell Carcinoma ICD-9: 173.0 image ICD-10: M8076/2-3 Image

Image SCC of the skin is a malignant tumor of keratinocytes, arising in the epidermis.

Image SCC usually arises in epidermal precancerous lesions (see above) and, depending on etiology and level of differentiation, varies in its aggressiveness.

Image The lesion is a plaque or a nodule with varying degrees of keratinization in the nodule and/or on the surface. Thumb rule: undifferentiated SCC is soft and has no hyperkeratosis; differentiated SCC is hard on palpation and has hyperkeratosis.

Image The majority of UVR-induced lesions are differentiated and have a low rate of distant metastasis in otherwise healthy individuals. Undifferentiated SCC and SCC in immunosuppressed individuals are more aggressive with a greater incidence of metastasis.

Image Treatment is by surgery.

Epidemiology and Etiology

Ultraviolet Radiation

Age of Onset. Older than 55 years of age in Caucasians in the United States and Europe; in Australia, New Zealand, in Florida, Southwest and Southern California, Caucasians in their twenties and thirties.

Incidence. Continental United States: 12 per 100,000 white men; 7 per 100,000 white women. Hawaii: 62 per 100,000 whites.


Figure 11-6. Squamous cell carcinoma: predilection sites.

Sex. Males > females, but SCC can occur more frequently on the legs of females.

Exposure. Sunlight. Phototherapy and PUVA (oral psoralen + UVA). Excessive photochemotherapy can lead to promotion of SCC, particularly in patients with skin phototypes I and II or in patients with history of previous exposure to ionizing radiation.

Race. Persons with white skin and poor tanning capacity (skin phototypes I and II) (see Section 10). Brown- or black-skinned persons can develop SCC from numerous etiologic agents other than UVR.

Geography. Most common in areas that have many days of sunshine annually, i.e., in Australia and southwestern United States.

Occupation. Persons working outdoors—farmers, sailors, lifeguards, telephone line installers, construction workers, and dock workers.

Human Papillomavirus

Most commonly oncogenic HPV type-16, -18, -31 but also type-33, -35, -39, -40, and -51 to -60 are associated with epithelial dysplasia, SCCIS, and invasive SCC. HPV-5, -8, -9 have also been isolated from SCCs.

Other Etiologic Factors

Immunosuppression. Solid organ transplant recipients, individuals with chronic immunosuppression of inflammatory disorders, and those with HIV disease are associated with an increased incidence of UVR- and HPV-induced SCCIS and invasive SCCs. SCCs in these individuals are more aggressive than in nonimmunosuppressed individuals.

Chronic Inflammation. Chronic cutaneous lupus erythematosus, chronic ulcers, burn scars, chronic radiation dermatitis, and lichen planus of oral mucosa.

Industrial Carcinogens. Pitch, tar, crude paraffin oil, fuel oil, creosote, lubricating oil, and nitrosoureas.

Inorganic Arsenic. Trivalent arsenic had been used in the past in medications such as Asiatic pills, Donovan pills, and Fowler solution (used as a treatment for psoriasis or anemia). Arsenic is still present in drinking water in some geographic regions (West Bengal and Bangladesh).

Clinical Manifestation

Slowly evolving—any isolated keratotic or eroded papule or plaque in a suspect patient that persists for over a month is considered a carcinoma until proved otherwise. Also, a nodule evolving in a plaque that meets the clinical criteria of SCCIS (Bowen disease), a chronically eroded lesion on the lower lip or on the penis, or nodular lesions evolving in or at the margin of a chronic venous ulcer or within chronic radiation dermatitis. Note that SCC usually is always asymptomatic. Potential carcinogens often can be detected only after detailed history.

Rapidly evolving—invasive SCC can erupt within a few weeks and there is often painful and/or tender.

For didactic reasons, two types can be distinguished:

1. Highly differentiated SCCs, which practically always show signs of keratinization either within or on the surface (hyperkeratosis) of the tumor. These are firm or hard upon palpation (Figs. 11-7 to 11-9and Figs. 11-11 and 11-12).

2. Poorly differentiated SCCs, which do not show signs of keratinization and clinically appear fleshy, granulomatous, and consequently are soft upon palpation (Figs. 11-5 and 11-10).


Figure 11-7. Squamous cell carcinoma: invasive on the lip A large but subtle nodule, which is better felt than seen, on the vermilion border of the lower lip with areas of yellowish hyperkeratosis. This nodule can be felt to infiltrate the entire lip.

Differentiated SCC

Lesions. Indurated papule, plaque, or nodule (Figs. 11-111-7 and 11-8); adherent thick keratotic scale or hyperkeratosis (Figs. 11-111-7-11-9 and 11-12); when eroded or ulcerated, the lesion may have a crust in the center and a firm, hyperkeratotic, elevated margin (Figs. 11-6 and 11-9). Horny material may be expressed from the margin or the center of the lesion (Figs. 11-811-9 and 11-11). Erythematous, yellowish, skin color; hard; polygonal, oval, round (Figs. 11-7 and 11-11), or umbilicated and ulcerated.

Distribution. Usually isolated but may be multiple. Usually exposed areas (Fig. 11-6). Sun-induced keratotic and/or ulcerated lesions especially on the bald scalp (Fig. 11-1), cheeks, nose, lower lips (Fig. 11-7), ears (Fig. 11-12), preauricular area, dorsa of the hands (Fig. 11-11), forearms, trunk, and shins (females).


Figure 11-8. Squamous cell carcinoma: (SCC) A round nodule, firm and indolent with a central black eschar. Note yellowish color in the periphery of the tumor indicating the presence of keratin. The SCC shown in Fig. 11-7and here is hard and occurs on the lower lip. SCC hardly occurs on the upper lip because this is shaded from the sun. SCC on the lip is easily distinguished from nodular BCC because BCC does not develop hyperkeratosis or keratinization inside the tumor and does not occur on the vermilion lip.


Figure 11-9. Squamous cell carcinoma, well differentiated (A) A nodule on the lower arm covered with a dome-shaped black hyperkeratosis. (B) A large, round, hard nodule on the nose with central hyperkeratosis. Neither lesion can be clinically distinguished from keratoacanthoma (see Fig. 11-15).

Other Physical Findings. Regional lymphadenopathy due to metastases.

Special Features. In UV-related SCC evidence of dermatoheliosis and solar keratoses. SCCs of the lips develop from leukoplasia or actinic cheilitis; in 90% of cases they are found on the lower lip (Figs. 11-7 and 11-8). In chronic radiodermatitis, they arise from radiationinduced keratoses (see Fig. 10-33); in individuals with a history of chronic intake of arsenic, from arsenical keratoses. Differentiated (i.e., hyperkeratotic) SCC due to HPV on genitalia; SCC due to excessive PUVA therapy on lower extremities (pretibial) or on genitalia. SCCs in scars from burns, in chronic stasis ulcers of long duration, and in sites of chronic inflammation are often difficult to identify. Suspicion is indicated when nodular lesions are hard and show signs of keratinization.

Special form: carcinoma cuniculatum, usually on the soles, highly differentiated, HPV-related but can also occur in other settings (Fig. 11-13); verrucous carcinoma, also florid oral papillomatosis, on the oral mucous membranes (see Section 35).

Histopathology. SCCs with various grades of anaplasia and keratinization.

Undifferentiated SCC

Lesions. Fleshy granulating, easily vulnerable, erosive papules and nodules, and papillomatous vegetations (Fig. 11-10). Ulceration with a necrotic base and soft, fleshy margin. Bleeds easily, crusting; red; soft; polygonal, irregular, often cauliflower-like.


Figure 11-10. Squamous cell carcinoma, undifferentiated There is a circular, dome-shaped reddish nodule with partly eroded surface on the temple of a 78-year-old male. The lesion shows no hyperkeratoses and is soft and friable. When scraped it bleeds easily.

Distribution. Isolated but also multiple, particularly on the genitalia, where they arise from erythroplasia and on the trunk (Fig. 11-5), lower extremities, or face, where they arise from Bowen disease.

Miscellaneous Other Skin Changes. Lymphadenopathy as evidence of regional metastases is far more common than with differentiated, hyperkeratotic SCCs.

Histopathology. Anaplastic SCC with multiple mitoses and little evidence of differentiation and keratinization.


Figure 11-11. Squamous cell carcinoma, advanced, well differentiated, on the hand of a 65-year-old farmer The big nodule is smooth, very hard upon palpation, and shows a yellowish color, focally indicating keratin in the body of the nodule. If the lesion was incised in the yellowish areas, a yellowish-white material (keratin) could be expressed.


Figure 11-12. Squamous cell carcinoma (SCC), highly differentiated, on the ear There is a relatively large plaque covered by adherent hard hyperkeratoses. Although SCCs are in general not painful, lesions on the helix or anthelix usually are, as was the case in this 69-year-old man.


Figure 11-13. Squamous cell carcinoma (carcinoma cuniculatum) in a patient with peripheral neuropathy due to leprosy A large fungating, partially necrotic, and hyperkeratotic tumor on the sole of the foot. The lesion had been considered a neuropathic ulcer, ascribed to leprosy, but continued growing and became elevated and ulcerated.

Differential Diagnosis

Any persistent nodule, plaque, or ulcer, but especially when these occur in sun-damaged skin, on the lower lips, in areas of radiodermatitis, in old burn scars, or on the genitalia, must be examined for SCC. Keratoacanthoma (KA) may be clinically indistinguishable from differentiated SCC (Fig. 11-15).


Surgery. Depending on localization and extent of lesion, excision with primary closure, skin flaps, or grafting. Mohs micrographic surgery in difficult sites. Radiotherapy should be performed only if surgery is not feasible.

Course and Prognosis

Recurrence and Metastases. SCC causes local tissue destruction and has a potential for metastases. Metastases are directed to regional lymph nodes and appear 1–3 years after initial diagnosis. In-transit metastases occur. In solid organ transplant recipients, metastasis can be present when SCC is diagnosed/detected or shortly after. SCC in the skin has an overall metastatic rate of 3-4%. High-risk SCCs are defined as having a diameter >2 cm, a level of invasion >4 mm, and Clark levels IV or V1; tumor involvement of bone, muscle, and nerve (so-called neurotropic SCC, occurs frequently on the forehead and scalp); location on ear, lip, and genitalia; tumors arising in a scar or following ionizing radiation are usually highly undifferentiated. Cancers arising in chronic osteomyelitis sinus tracts, in burn scars, and in sites of radiation dermatitis have a metastatic rate of 31%, 20%, and 18%, respectively. SCC arising in solar keratoses has the lowest potential for metastasis.

SCCs in Immunosuppression. Organ transplant recipients have a markedly increased incidence of NMSCs, primarily high risk SCC, which is 40–50 times greater than in the general population. Risk factors include skin type, cumulative sun exposure, age at transplantation, male sex, HPV infections, the degree and length of immunosuppression, and the type of immunosuppressant. Lesions are often multiple, usually in sun-exposed sites but also in the genital, anal, and perigenital regions (Fig. 11-14). These tumors grow rapidly and are aggressive; in one series of heart-transplant patients from Australia, 27% died of skin cancer.


Figure 11-14. Squamous cell carcinomas in a renal transplant recipient on the upper thigh and buttock There are multiple firm nodules, partially ulcerated. The patient had smaller, similar lesions elsewhere on the body. Since he had psoriasis and had therefore spent considerable time in the sun, the lesions in the sun-exposed sides were probably due to UVR. The lesion shown here was probably initiated by HPV as he had a similar lesion perianally and on the glans. The ulcer on the right buttock is an excision site from which sutures were prematurely removed.

Patients with AIDS have only a slight increased risk of NMSC. In one series a fourfold increase in their risk of developing lip SCC was noted. However, SCC of the anus is significantly increased in this population (see also Section 27).

Keratoacanthoma ICD-9: 238.2 image ICD-10: L58.8 Image

Image KA is a special lesion; formerly considered a pseudocancer it is now regarded by most as a variant of SCC.

Image A relatively common, rapidly growing epithelial tumor with potential for tissue destruction and (rare) metastasis; however, in most cases there is spontaneous regression.

Image HPV -9, -16, -19, - 25, -37 have been identified in KAs; other possible etiologic factors include UVR and chemical carcinogens (pitch, tar).

Image Age of onset over 40 years. Male: female ratio 2:1.

Image A dome-shaped nodule with central keratotic plug (Fig. 11-15). Firm but not hard. Skin-colored, slightly red, brown. Removal of keratotic plaque results in a crater.

Image Predilection for sun-exposed sites.

Image Die KAs occur.

Image Spontaneous regression in 6-12 months in most cases (Fig. 11-5B, C). However, local or visceral metastases have been detected.

Image Histopathology: not always possible to rule out highly differentiated SCC.

Image Treatment is by excision.


Figure 11-15. Keratoacanthoma showing different stages of evolution (A) Initially there is a round dome-shaped, very firm nodule, reddish with a central hyperkeratotic plug. This has been partially shed leaving a central crater, (B) Hyperkeratosis has progressed and has now replaced most of the nodule, leaving only a thin rim of tumor tissue in the periphery. (C) Further progression of hyperkeratoses and keratinization has now replaced the entire tumor and will be later shed, leaving a scar. Since this evolution is not always predictable and since keratoacanthoma cannot be reliably distinguished from SCC, keratoacanthoma should always be excised in the early stages.

Basal Cell Carcinoma (BCC) ICD-9:173.0 image ICD-10: C33.M8090/3 Image

Image BCC is the most common cancer in humans.

Image Caused by UVR; PTCH gene mutation in many cases.

Image Clinically different types: nodular, ulcerating, pigmented, sclerosing, and superficial.

Image BCC is locally invasive, aggressive, and destructive but slow growing, and there is very limited (literally no) tendency to metastasize.

Image Treatment is by surgical excision, Mohs micrographic surgery, electrodesiccation, and curettage. Also cryosurgery and imiquimod cream.


Age of Onset. Older than 40 years.

Sex. Males > females.

Incidence. The most common cancer in humans. United States: 500–1000 per 100,000, higher in the sunbelt; >400,000 new patients annually.

Race. Rare in brown- and black-skinned persons.


UVR, mostly of the UVB spectrum (290–320 nm) that induces mutations in suppressor genes. The propensity for multiple BCC may be inherited. Associated with mutations in the PTCH gene in many cases.

Predisposing Factors. Skin phototypes I and II and albinos are highly susceptible to develop BCC with prolonged sun exposure. Also a history of heavy sun exposure in youth predisposes the skin to the development of BCC later in life. Previous therapy with x-rays for facial acne greatly increases the risk of BCC. Superficial multicentric BCC occurs 30-40 years after ingestion of arsenic but also without apparent cause.

Clinical Manifestation

Slowly evolving, usually asymptomatic. Erosion or bleeding with minimal trauma may be first symptom.

Skin Lesions. There are five clinical types: nodular, ulcerating, pigmented, sclerosing (cicatricial), and superficial.

• Nodular BCC: Papule or nodule, translucent or “pearly.” Skin-colored or reddish, smooth surface with telangiectasia, well defined, firm (Figs. 11-16 and 11-17). Portions of nodular BCC may have erosions or stipples of melanin pigmentation.


Figure 11-16. Basal cell carcinoma: nodular type (A) A small pearly papule (arrow) on the nostril and an even smaller one (small arrow) in the nasolabial fold. These are very early stages of BCC. The gray arrow denotes a dermal NMN. (B) This is a further advanced nodular BCC. A solitary, shiny reddish nodule with large telangiectatic vessels on the ala nasi, arising on skin with dermatoheliosis.



Figure 11-17. Basal cell carcinoma: nodular type (A) A glistening, smooth plaque on the lower eyelid with multiple telangiectasias. (B) An oval, pearly nodule on the nose close to the inner canthus. (C) A smooth, pearly tumor with telangiectasia below the lower eyelid. Tumor feels hard, is well defined, and is asymptomatic. (D) A large, firm reddish glistening nodule with small ulcerations on the nose.

• Ulcerating BCC. Ulcer (often covered with a crust) with a rolled border (rodent ulcer), which again is translucent, pearly, smooth with telangiectasia, and firm (Figs. 11-18 and 11-19).



Figure 11-18. Basal cell carcinoma, ulcerated: Rodent ulcer (A) A large circular ulcer on the tip of the nose with a wall-like border. (B) A similar lesion in the retroauricular region. There is a rolled pearly border surrounding the ulcer. (C) Rodent ulcer in the preauricular region. A rolled pearly border surrounds an ulcer with yellow necroses and a tiny black crust. (D) A deep ulcer with a surrounding rolled border, smooth, glistening, and partly covered with crusts in the mandibular region. All these lesions are hard upon palpation.


Figure 11-19. A large rodent ulcer in the nuchal and retroauricular area extending to the temple The entire lesion consists of a firm granulating tissue, partially covered by hemorrhagic crusts. The diagnosis can be made only by examining the border, which is rolled, elevated, firm, and smooth.

• Sclerosing BCC. Appears as a small patch of morphea or a superficial scar, often ill defined, skin-colored, whitish but also with peppery pigmentation (Fig. 11-20). In this infiltrating type of BCC, there is an excessive amount of fibrous stroma. Histologically, finger-like strands of tumor extend far into the surrounding tissue, and excision therefore requires wide margins. Sclerosing BCC can progress to nodular or ulcerating BCC (Figs. 11-20B and 11-21).


Figure 11-20. Basal cell carcinoma: sclerosing type (A) A small inconspicuous area resembling superficial morphea, ill defined, and yellowish with telangiectasia. Upon palpation, however, a platelike induration can be felt and this extends beyond the visible margins of the lesion. After verification of the diagnosis by biopsy, it will require excision with wide margins. (B) A large depressed area resembling a scar on the nose; on the right (lateral) and medial margins of this “scar,” there is the typical rolled border of a nodular BCC. This lesion is shown to demonstrate that sclerosing and nodular BCC are simply two different growth patterns.


Figure 11-21. Basal cell carcinoma (BCC), sclerosing, nodular, and ulcerating A large lesion, which looks like morphea and is whitish and firm upon palpation but within the level of the skin, is found on the temple and in the supraciliary region. Within the lesion and at the margins, there are small nodules of BCCs. On the lateral canthus of the eye, there is a large ulcer with rolled borders representing a rodent ulcer. Again this figure is shown to demonstrate that the different types of BCC are just different growth patterns.

• Superficial multicentric BCCs: Appear as thin plaques (Figs. 11-22 and 11-23). Pink or red; characteristic fine threadlike border and telangiectasia can be seen with the aid of a hand lens. This is the only form of BCC that can exhibit a considerable amount of scaling. This can also give rise to nodular and ulcerating BCC (Fig. 11-23). BCC often bleeds with minimal excoriation. Solar keratosis, in comparison, does not bleed but is painful with excoriation.


Figure 11-22. Superficial basal cell carcinoma (BCC): solitary lesion and multiple lesions (A) This bright red lesion has a slightly elevated rolled border that can be detected with “side lighting”; although this lesion is typical enough to be diagnosed clinically, a biopsy is necessary to verify the diagnosis. (B) Many superficial BCCs on the trunk. They appear as brightly erythematous, often scaling, flat lesions, often without a rolled border. The hypopigmented areas represent superficial scars after cryotherapy of superficial BCCs.


Figure 11-23. Superficial basal cell carcinoma (BCC), invasive There are two irregular red areas with rolled borders and central telangiectasia. In the larger lesion, the BCC is elevated with an irregular surface and now assumes the morphology and growth behavior of a nodular BCC; on the right the lesion is erosive and will progress to an ulcer.

• Pigmental BCC: May be brown to blue or black (Fig. 11-24). Smooth, glistening surface; hard, firm; may be indistinguishable from superficial spreading or nodular melanoma but is usually harder. Cysticlesions may occur: round, oval shape, depressed center (“umbilicated”). Stippled pigmentation can be seen in any of BCC types.


Figure 11-24. Basal cell carcinoma (BCC), pigmented (A) A nodule with irregular borders and variegation of melanin hues easily confused with a malignant melanoma. Only histology will yield the correct diagnosis. (B) A similar black nodule but with central ulceration. This pigmented BCC is clinically also indistinguishable from nodular melanoma.

Distribution (Fig. 11-25). Isolated single lesion; multiple lesions are not infrequent; >90% occur in the face. Search carefully for “danger sites”: medial and lateral canthi (Fig. 11-17A, B, C), nasolabial fold (Fig. 11-16B), and behind the ears (Figs. 11-18B and 11-19). Superficial multicentric BCCs occur on the trunk (Figs. 11-22 and 11-23). BCC arises only from epidermis that has a capacity to develop (hair) follicles. Therefore, BCCs rarely occur on the vermilion border of the lips or on the genital mucous membranes.


Figure 11-25. Basal cell carcinoma (BCC): predilection sites Dots indicate superficial multicentric BCCs.

Laboratory Examination

Dermatopathology. Solid tumor consisting of proliferating atypical basal cells, large, oval, deep-blue staining on H&E, but with little anaplasia and infrequent mitoses; palisading arrangement at periphery; variable amounts of mucinous stroma.

Diagnosis and Differential Diagnosis

Serious BCCs occurring in the danger sites (central part of the face, behind the ears) are readily detectable by careful examination with good lighting, a hand lens, and careful palpation and dermoscopy. Diagnosis is made clinically and confirmed microscopically. Differential diagnosis includes all smooth papules such as dermal nevomelanocytic nevi, trichoepithelioma, dermatofibroma, and others; if pigmented, superficial spreading and nodular melanoma; if ulcerated, all nonpainful firm ulcers including SCC and a (extragenital) primary chancre of syphilis.


Excision with primary closure, skin flaps, or grafts. Cryosurgery and electrosurgery are options, but only for very small lesions and not in the danger sites or on the scalp.

For lesions in the danger sites (nasolabial area, around the eyes, in the ear canal, in the posterior auricular sulcus, and on the scalp) and sclerosing BCC, microscopically controlled surgery (Mohs surgery) is the best approach. Radiation therapy is an alternative only when disfigurement may be a problem with surgical excision (e.g., eyelids or large lesions in the nasolabial area) or in very old age.

There are a variety of topical treatments that can be used for superficial BCCs but only for those tumors below the neck; cryosurgery is effective but leaves a white scar that remains for life. Electrocautery with curettage is also simple and effective, but it leaves scars and should be used only in small lesions. Topical 5-fluorouracil ointment and imiquimod cream for superficial BCC, 5 times a week, for 6 weeks, are effective, do not cause visible scars, but require considerable time and may not radically remove all tumor tissue. Both require compliance by patient or caregiver. Imiquimod is especially good for young persons who do not want scars. Photodynamic therapy is effective only in very superficial lesions and radiation sessions (photodynamic dye + visible light) are painful.

Course and Prognosis

BCC does not metastasize. The reason for this is the tumor’s growth dependency on its stroma, which on invasion of tumor cells into the vessels is not disseminated with the tumor cells. When tumor cells lodge at distant sites, they do not multiply and grow because of the absence of growth factors derived from their stroma. Exceptions occur when a BCC shows signs of dedifferentiation, for instance, after inadequate radiotherapy. Most lesions are readily controlled by various surgical techniques. Serious problems, however, may occur with BCC arising in the danger sites of the head. In these sites, the tumor may invade deeply, cause extensive destruction of muscle and bone, and even invade to the dura mater. In such cases, death may result from hemorrhage of eroded large vessels or infection. In such cases, vismodegib has been reported to be effective.

Basal Cell Nevus Syndrome (BCNS) ICD-9:173.0 image ICD-10: Q82.804 Image

Image This autosomal-dominant disorder is caused by mutations in the patched gene that resides on chromosome 9q (9q22).

Image It affects skin with multiple BCCs (Fig. 11-26) and so-called palmoplantar pits (Fig. 11-27) and has a variable expression of abnormalities in a number of systems, including skeletal malformations, soft tissue, eyes, CNS, and endocrine organs.

Image Occurs mostly in whites but also in brown- and black-skinned people, and there is an equal sex incidence.

Image BCCs begin singly in childhood or early adolescence and continue throughout life.

Image There are more BCCs on the sun-exposed areas of the skin, but they also occur in covered areas and there may be hundreds of lesions.

Image Characteristic general features are frontal bossing, a broad nasal root, and hypertelorism (Fig. 11-26). A systems review may reveal congenital anomalies including undescended testes and hydrocephalus, mandibular jaw odontogenic keratocysts, which may be multiple and may be unilateral or bilateral. There may be defective dentition, bifid or splayed ribs, pectus excavatum, short fourth metacarpals, scoliosis, and kyphosis. Eye lesions include strabismus, hypertelorism, dystopia canthorum, cataracts, glaucoma, and coloboma with blindness. There may be agenesis of the corpus callosum, calcification of the falx, and medulloblastoma. However, mental retardation is rare. Fibrosarcoma of the jaw, ovarian fibromas, teratomas, and cystadenomas have been reported.

Image Skin lesions are small, pinpoint to larger nodular BCCs (Fig. 11-26), but “regular,” nodular, ulcerating, and sclerosing BCCs also occur. Tumors on the eyelids, axillae, and neck tend to be pedunculated and are often symmetric on the face. There are characteristic palmoplantar lesions, which are present in 50% and are small pits that are pinpoint to several millimeters in size and 1 mm deep (Fig. 11-27).

Image The significance of the syndrome is that a large number of skin cancers create a lifetime problem of vigilance. The multiple excisions can cause a considerable amount of scarring (Fig. 11-26). The tumors continue throughout life, and the patient must be followed carefully.

Image Synonyms: Gorlin syndrome, nevoid BCC syndrome.


Figure 11-26. Basal cell nevus syndrome: small basal cell carcinomas (BCC) Small reddish papular lesions are dispersed over the entire face. All of these represent small BCCs. Note considerable scarring from removal of previous lesions. Note also frontal bossing and strabismus.


Figure 11-27. Basal cell nevus syndrome: palmar pits Palmar surface of hand showing 1 -to 2-mm, sharply marginated, depressed lesions, i.e., palmar pits.

Malignant Appendage Tumors ICD-9:173.0 image ICD-10: C44.L40 Image

Image Carcinomas of the eccrine sweat gland are rare and include eccrine porocarcinoma, syringoid eccrine carcinoma, mucinous carcinoma, and clear cell eccrine carcinoma.

Image Carcinomas of the apocrine glands are also rare, arising in axillae, nipples, vulva, and eyelids.

Image Carcinomas of the sebaceous glands are equally rare, most commonly arising on the eyelids.

Image These lesions are clinically indistinguishable from other carcinomas and are usually more aggressive than other invasive cutaneous SCCs.

Merkel Cell Carcinoma ICD-9:173.0 image ICD-10: C44.L44 Image

Image Merkel cell carcinoma (MCC) (cutaneous neuroendocrine tumor) is a rare malignant solid tumor thought to be derived from a specialized epithelial cell, the Merkel cell. It is a nonkeratinizing, “clear” cell present in the basal cell layer of the epidermis, free in the dermis, and around hair follicles as the hair disk of Pinkus.

Image MCC occurs almost exclusively in white people.

Image MCC is 10–30 times as common in immunosuppressed patients as in nonimmunosuppressed patients.

Image The etiology is unknown but may be related to chronic UVR damage. Polyoma virus has been found in 80% of MCC.

Image The tumor may be solitary or multiple and occurs on the head and on the extremities.

Image There is a high rate of recurrence following excision, but, more important, it spreads to the regional lymph nodes in >50% of patients and is disseminated to the viscera and CNS.

Image MCC presents as a cutaneous to subcutaneous papule, nodule, or tumor (0.5-5 cm) (Figs. 11-28 and 11-29), which is pink, red to violet or reddish-brown, dome-shaped, and usually solitary. The overlying skin is intact, but larger lesions may ulcerate.

Image They grow rapidly and usually occur in persons >50 years.

Image Dermatopathology shows nodular or diffuse patterns of aggregated, deeply blue staining, small basaloid or lymphoma-like-looking cells that can also be arranged in sheets forming nests, cords, and trabeculae.

Image Immunocytochemistry shows cytokeratin and neurofilament markers, chromogranin A, and neuron-specific enolase; electron microscopy reveals the characteristic organelles.

Image Treatment is by excision or Mohs surgery, and sentinel node biopsy or prophylactic regional node dissection is advocated because of the high rate of regional metastases. Radiation therapy to site of MCC and regional LN is given in most cases except for very small lesions.

Image Recurrence rates are high; in one series, even without a local recurrence, about 60% of patients developed regional node metastases, as did 86% of those patients with a local recurrence. Prognosis is guarded.


Figure 11-28. Merkel cell carcinoma A small violaceous nodule above the pinna that had been present for about 2 weeks. Sentinel lymph node biopsy revealed metastasis of neuroendocrine carcinoma. Also note actinic keratoses on the helix and concha.


Figure 11-29. Merkel cell carcinoma (A) A barely noticeable 6-mm slightly dermal nodule below the hairline that had been present for about 6 weeks. Preauricular lymph node metastasis was also present. (B) A violaceous dermal nodule, 3 cm in diameter on the forearm of a 60-year-old man. There was metastasis to the axillary lymph nodes.

Dermatofibrosarcoma Protuberans (DFSP) ICD-9:173.90 image ICD-10: C49.M24 Image

Image A rare, locally aggressive tumor, slow growing, initially often misinterpreted as a scar.

Image DFSP is a firm indurated plaque, skin-colored to red-brown with exophytic nodules (Fig. 11-30). An atrophic variant may resemble sclerosing BCC, morphea, or scar.

Image Occurs on the trunk, followed by the extremities, and only 15% in the head and neck region.

Image Locally aggressive with a high rate of recurrence and rare metastases.

Image Diagnosis is made by histopathology, and therapy is wide surgical excision. Recurrences respond to Imatinib.


Figure 11-30. Dermatofibrosarcoma protuberans An irregular sclerotic skin-colored to reddish plaque of increased consistency on the back of a 40-year-old male. On the lower margin, there is a reddish nodule representing exophytic growth. This lesion needs to be excised with large margins to prevent a recurrence.

Atypical Fibrosarcoma (AFX) ICD-9:173.0 image ICD-10: C49.M12 Image

Image A not so rare rapidly growing tumor of intermediate malignant potential.

Image AFX is an asymptomatic, solitary papule, nodule, or plaque often resembling an SCC or BCC initially.

Image Occurs in sun-damaged skin of older patients especially on forehead, scalp, nose, and ears (Fig. 11-31).

Image Treatment is surgical.


Figure 11-31. Atypical fibroxanthoma This is a 57-year-old male with dermatoheliosis and a history of solar keratoses, invasive and in situ squamous carcinoma, and basal cell carcinoma. This nodule on the vertex was clinically atypical for either basal cell carcinoma or squamous cell carcinoma; histopathology revealed atypical fibroxanthoma.

1Clark level I: intraepidermal; level II: tumor invades papillary dermis; level III: tumor fills papillary dermis; level IV: tumor invades reticular dermis; level V: tumor invades subcutis.


Melanoma Precursors and Primary Cutaneous Melanoma 

Precursors of Cutaneous Melanoma

Precursors of melanoma are lesions that are benign per se but have the potential of turning malignant and thus giving rise to melanoma. Two such entities are recognized: (1) dysplastic melanocytic nevi (NMN) and (2) congenital NMN.

Dysplastic Melanocytic Nevus ICD-9: 238.2 image ICD-10: D48–5 Image

Image Dysplastic nevi (DN) are a special type of acquired, circumscribed, pigmented lesions that represent disordered proliferations of variably atypical melanocytes.

Image DN arise de novo or as part of a compound melanocytic nevus.

Image DN are clinically distinctive from common acquired nevi: larger and more variegated in color, asymmetric in outline, irregular borders; they also have characteristic histologic features.

Image DN are regarded as potential precursors of superficial spreading melanoma (SSM) and also as markers of persons at risk for developing primary malignant melanoma of the skin, either within the DN or on normal skin.

Image DN occur either sporadically or in the context of the familial DN syndrome: kindreds with familial multiple DN and melanomas (formerly FAMMM, or B-K mole syndrome).

Image Synonym: atypical melanocytic nevus.


Age of Onset. Children and adults.

Prevalence. DN are present in 5% of the general white population. They occur in almost every patient with familial cutaneous melanoma and in 30–50% of patients with sporadic nonfamilial primary melanomas of the skin.

Sex. Equal in males and females.

Race. White persons. Data on persons with brown or black skin are not available; DN are rarely seen in the Japanese population.

Transmission. Autosomal dominant.


Multiple loci have been implicated in familial melanoma/DN syndrome, and it is likely that DN is a complex heterogeneous trait. It is assumed that an abnormal clone of melanocytes can be activated by exposure to sunlight. Immunosuppressed patients (renal transplantation) with DN have a higher incidence of melanoma. DN favor the exposed areas of the skin, particularly intermittently sun exposed (e.g., back) and this may be related to the degree of sun exposure; however, DN may also occur in completely covered areas.

Clinical Manifestation

Duration of Lesions. DN usually arise later in childhood than common acquired NMN, which first appear in late childhood, just before puberty. New lesions continue to develop over many years in affected persons; in contrast, common acquired NMN do not appear after middle age and disappear entirely in older persons. DN are thought not to undergo spontaneous regression at all or at least much less than common acquired NMN. Also, whereas common NMN are usually in a roughly comparable stage of development in a given body region (e.g., junctional, compound, dermal), DN appear “out of step,” e.g., a mix of large and small, flat and raised, tan and very dark lesions (Fig. 12-1A).

Skin Symptoms. Asymptomatic.

Family History. In the familial setting, family members can develop melanoma without the presence of DN.

Clinical Features. DN show some of the features of common NMN and some of SSM, so that they occupy an intermediary position between these two morphologies (Table 12-1). No single feature is diagnostic; rather, there is a constellation of findings. They are more irregular, lighter than common NMN, usually maculopapular; have distinct and indistinct borders (Figs. 12-1 and 12-2), and a greater complexity of color than common nevi (Figs. 12-1 and 12-2) but less than melanoma. There are “fried-egg” and “targeted” types (see Fig. 12-20 and Table 12-1). Melanoma arising in a DN appears initially as a small papule (often of a different color) or change in color pattern and massive color change within the precursor lesion (Fig. 12-3).


Figure 12-1. Dysplastic nevi (A) Overview of the back of a patient with common and dysplastic nevi. Note a number of lesions are of different size and color, “out of step.” The lesion marked by an arrow was an SSM. (B) Larger magnification of two DNs. Note irregularity and variegation of color that are different in the two lesions (“out of step”). Also, the lesions are 1 cm or larger in diameter. The smaller lesions are common NMN.



Figure 12-2. Dysplastic nevi (A) A large, uniformly tan, very flat macular oval lesion. The notched border on the left and the size (>1 cm) are the only criteria making this suspicious of a DN. (B) Though relatively symmetric, this lesion is macular and papular with a variegated color and measures 1.5 cm in diameter. The smaller lesions are common NMN. (C) A highly asymmetric, both ill- and sharply defined margin, a notched border, and variegated brown to black color. It is clinically indistinguishable from an SSM (see Figs. 12-12A, B) but was histologically a DN. (D) A relatively symmetric sharply defined lesion with an eccentric, more heavily pigmented area (targetoid lesion).


Figure 12-3. Superficial spreading melanoma: arising within a dysplastic nevus The entire lesion originally was maculopapular and had the brown color still seen on the upper crescent-like rim. At a follow-up visit 6 years later, the center and lower half of the lesion had become more raised and turned black as shown here. Melanoma had evolved from a DN. Verified by histopathology.



Dermoscopy. This noninvasive technique allows for clinical improvement of diagnostic accuracy in DN by >50%. Digital dermoscopy permits computerized follow-up of lesions and immediate detection of any change over time, indicating developing malignancy.

Laboratory Examination

Dermatopathology. Hyperplasia and proliferation of melanocytes in a single-file, “lentiginous” pattern in the basal cell layer either as spindle cells or as epithelioid cells and as irregular and dyshesive nests. “Atypical” melanocytes, “bridging” between rete ridges by melanocytic nests; spindle-shaped melanocytes oriented parallel to skin surface. Lamellar fibroplasia and concentric eosinophilic fibrosis (not a constant feature). Histologic atypia do not always correlate with clinical atypia. DN may arise in contiguity with a compound NMN (rarely, a junctional nevus) that is centrally located.

Diagnosis and Differential Diagnosis

The diagnosis of DN is made by clinical recognition of typical distinctive lesions (see Table 12-1), and diagnostic accuracy is considerably improved by dermoscopy. The clinicopathologic correlations are now well documented. Siblings, children, and parents should also be examined for DN once the diagnosis is established in a family member.

Differential Diagnosis. Congenital NMN, common acquired NMN, superficial spreading melanoma, melanoma in situ (MIS), lentigo maligna, Spitz nevus, pigmented basal cell carcinoma.

Association with Melanoma. DN are regarded both as markers for persons at risk for melanoma and as precursors of SSM. Anatomic association (in contiguity) of DN has been observed in 36% of sporadic primary melanomas, in about 70% of familial primary melanomas, and in 94% of melanomas with familial melanoma and DN.

Lifetime Risks of Developing Primary Malignant Melanoma:

• General population: 1.2%.

• Familial DN syndrome with two blood relatives with melanoma: 100%.

• All other patients with DN: 18%.

• The presence of one DN doubles the risk for development of melanoma; with >10 DN, the risk increases 12-fold.


Surgical excision of lesions with narrow margins. Laser or other types of physical destruction should never be used because they do not permit histopathologic verification of diagnosis.

Patients with DN in the familial melanoma setting need to be followed carefully: in familial DN, every 3 months; in sporadic DN, every 6 months to 1 year. Photographic follow-up is important. Most reliable method is digitalized dermoscopy, which should be available in every pigmented lesion and melanoma center. Patients should be given color-illustrated pamphlets that depict the clinical appearance of DN, malignant melanoma, and common acquired NMN. Patients with DN (familial and nonfamilial) should not sunbathe and should use sunscreens when outdoors. They should not use tanning parlors. Family members of the patient should also be examined regularly.

Congenital Nevomelanocytic Nevus (CNMN)* ICD-9: 757.33 image ICD-10: D22 Image

Image CNMN are pigmented lesions of the skin usually present at birth; rare varieties of CNMN can develop and become clinically apparent during infancy.

Image CNMN may be any size from very small to very large.

Image CNMN are benign nevomelanocytic neoplasms.

Image However, all CNMN, regardless of size, may be precursors of malignant melanoma.

*Giant CNMC are very rare.


Prevalence. Present in 1% of white newborns; the majority <3 cm in diameter. Larger CNMN are present in 1:2000 to 1:20,000 newborns. Lesions >9.9 cm in diameter have a prevalence of 1:20,000, and giant CNMN (occupying a major portion of a major anatomic site) occur in 1:500,000 newborns.

Age of Onset. Present at birth (congenital). Some CNMN become visible only after birth (tardive), “fading in” as a relatively large lesion over a period of weeks.

Sex. Equal prevalence in males and females.

Race. All races.


Presumably they occur as the result of a developmental defect in neural crest–derived melanoblasts. This defect probably occurs after 10 weeks in utero but before the sixth uterine month; the occurrence of the “split” nevus of the eyelid, i.e., half of the nevus on the upper and half on the lower eyelid, is an indication that nevomelanocytes migrating from the neural crest were in place in this site before the eyelids split (24 weeks).

Small and Large CNMN. CNMN have a rather wide range of clinical features, but the following are typical (Figs. 12-4 and 12-5): CNMN usually distort the skin surface to some degree and are therefore a plaque with or without coarse terminal dark brown or black hairs (hair growth has a delayed onset) (Figs. 12-4B and 12-5B). Sharply demarcated (Fig. 12-4) or merging imperceptibly with surrounding skin; regular or irregular contours. Large lesions may be “wormy” or soft (Fig. 12-5A), rarely firm (desmoplastic type). Skin surface smooth or “pebbly,” mamillated, rugose, cerebriform, bulbous, tuberous, or lobular (Fig. 12-5B). These surface changes are observed more frequently in lesions that extend deep into the reticular dermis.


Figure 12-4. Congenital nevomelanocytic nevus (A) Small, variegated brown plaque on the nose. The lesion was present at birth. (B) Congenital nevomelanocytic nevus, intermediate size. Sharply demarcated chocolate-brown plaque with sharply defined borders in an infant. With increasing age, lesions may become elevated and hairy and very discrete hairiness is also noted in this lesion.


Figure 12-5. A Giant congenital nevomelanocytic nevus (A) In this baby the lesion involves the majority of the skin, with complete replacement of normal skin on the back and multiple smaller CNMN on the buttocks and thighs. There is hypertrichosis in the lower portion. Melanoma developing in a giant CNMN is difficult to diagnose early in a setting of such highly abnormal tissue. (B) Giant CNMN in the same child 5 years later. The CNMN has thickened and has become rugose and more hairy in the sacral region. The lesion is now lighter, i.e. more brown than black and the smaller CNMN on the buttocks have increased in size and number.

Color. Light or dark brown, black. With dermoscopy, a fine speckling of a darker hue with a lighter surrounding brown hue is seen; often the pigmentation is follicular. “Halo” CNMN are rare.

Size. Small (Fig. 12-4), large (>20 cm), or giant (Fig. 12-5). Acquired NMN >1.5 cm in diameter should be regarded as probably tardive CNMN or they represent DN.

Shape. Oval or round.

Distribution of Lesions. Isolated, discrete lesion in any site. Fewer than 5% of CNMN are multiple. Multiple lesions are more common in association with large CNMN. Numerous small CNMN occur in patients with giant CNMN, in whom there may be numerous small CNMN on the trunk and extremities away from the site of the giant CNMN (Fig. 12-5).

Very Large (“Giant”) CNMN

Giant CNMN of the head and neck may be associated with involvement of the leptomeninges with the same pathologic process; this presentation may be asymptomatic or manifested by seizures, focal neurologic defects, or obstructive hydrocephalus. Giant CNMN is usually a plaque with surface distortion, covering entire segments of the trunk, extremities, head, or neck (Fig. 12-5).

Melanoma in CNMN

A papule or nodule arises within CNMN (Fig. 12-6). Often melanoma arises in dermal or subcutaneous nevomelanocytes and can be far advanced when detected.


Figure 12-6. Melanoma: arising in small CNMN A black plaque on the thigh of a 36-year-old female, which has been present since birth. Recently, a slightly less pigmented excentric nodule had appeared in this lesion. This is a melanoma.

Differential Diagnosis

Common acquired NMN, DN, congenital blue nevus, nevus spilus, Becker nevus, pigmented epidermal nevi, and café-au-lait macules should be considered in the differential diagnosis of CNMN. Small CNMN are virtually indistinguishable clinically from common acquired NMN except for size, and lesions >1.5 cm may be presumed to be either tardive CNMN or DN.

Laboratory Examination

Histopathology. Nevomelanocytes occur as well-ordered clusters (theques) in the epidermis and in the dermis as sheets, nests, or cords. A diffuse infiltration of strands of nevomelanocytes in the lower one-third of the reticular dermis and subcutis is, when present, quite specific for CNMN. In large and giant CNMN, the nevomelanocytes may extend into the muscle, bone, dura mater, and cranium.

Course and Prognosis

By definition, CNMN appear at birth, but CNMN may arise during infancy (tardive CNMN). The life history of CNMN is not documented, but CNMN can be observed in elderly persons, an age when the common acquired NMN have disappeared.

Large or Giant CNMN. The lifetime risk for development of melanoma in large CNMN has been estimated to be at least 6.3%. In 50% of patients who develop melanoma in large CNMN, the diagnosis is made between the ages of 3 and 5 years. Melanoma that develops in a large CNMN has a poor prognosis because it is detected late.

Small CNMN. The lifetime risk of developing malignant melanoma is 1–5%. The expected association of small CNMN and melanoma is <1:171,000 based on chance alone. Nonetheless, small CNMN should be considered for prophylactic excision at puberty if there are no atypical features (variegated color and irregular borders); small CNMN with atypical features should be excised immediately.


Surgical Excision. The only acceptable method. Small and large CNMN: Excision, with full-thickness skin graft, if required; swing flaps, tissue expanders for large lesions. Giant CNMN: Risk of development of melanoma is significant even in the first 3–5 years of age, and thus giant CNMN should be removed as soon as possible. Individual considerations are necessary (size, location, degree of loss of function, or amount of mutilation). New surgical techniques utilizing the patient’s own normal skin grown in tissue culture can now be used to facilitate removal of very large CNMN. Also, tissue expanders can be used.

Cutaneous Melanoma ICD-9:172 image ICD-10: C43 Image

Image Cutaneous melanoma is the most malignant tumor of the skin. Melanoma arises from the malignant transformation of melanocytes at the dermal–epidermal junction or from the nevomelanocytes of DN or CNMN that become invasive and metastasize after various time intervals.

Classification of Melanoma

I.  De novo melanoma.

A. Melanoma in situ (MIS).

B. Lentigo maligna melanoma (LMM).

C. Superficial spreading melanoma (SSM).

D. Nodular melanoma (NM).

E. Acral lentiginous melanoma (ALM).

F. Melanoma of the mucous membranes.

G. Desmoplastic melanoma.

II. Melanoma arising from precursors.

A. Melanoma arising in dysplastic NMN.

B. Melanoma arising in congenital NMN.

C. Melanoma arising in common NMN.

Four Important Messages Concerning Cutaneous Melanoma

1. Melanoma of the Skin Is Approaching Epidemic Proportions

In 2009, it was estimated that in the United States roughly 122,000 men and women were diagnosed with melanoma of which 69,000 were invasive. Melanoma is a common malignancy and its incidence is on the rise. In the United States, the lifetime risk of invasive melanoma in 2010 was 1 in 50. The US surveillance epidemiology and end results (SEER) estimated 8,650 deaths due to melanoma in the United States. The number of melanomas in the United States continues to increase by 7% per year. Cutaneous melanoma currently represents 5% of newly diagnosed cancer in men and 6% in women. It is the leading fatal illness arising in the skin and is responsible for 80% of deaths from skin cancer. US cancer statistics show that melanoma had the second highest mortality rate increase among men >65 years old. On the other hand, deaths from melanoma occur at a younger age than deaths from most other cancers, and melanoma is among the most common types of cancer in young adults.

2. Early Recognition and Excision of Primary Melanoma Result in Virtual Cure

Current cutaneous melanoma education stresses the detection of early melanoma, with high cure rates after surgical excision. Of all the cancers, melanoma of the skin is the most rewarding for detection of early curable primary tumors, thereby preventing meta-static disease and death. Curability is directly related to size and depth of invasion of the tumor. At present, the most critical tool for conquering this disease is, therefore, the identification of early “thin” melanomas by clinical examination. Total skin examination for melanoma and its precursors should be done routinely.

About 30% of melanomas arise in a preexisting melanocytic lesion; 70% arise in normal skin. Almost all melanomas show an initial radial growth phase followed by a subsequent vertical growth phase. Since metastasis occurs only infrequently during the radial growth phase, detection of early melanomas (i.e., “thin” melanomas) during this phase is essential.

There is the paradox that even with a rising mortality rate, there has been an encouraging improvement in the overall prognosis of melanoma with very high 5-year survival rates (approaching 98%) for thin (<0.75 mm) primary melanoma and an 83% rate for all stages. The favorable prognosis is entirely attributable to early detection.

3. All Physicians and Nurses Have the Responsibility of Detecting Early Melanoma

Early detection of primary melanoma ensures increased survival. The seriousness of this disease thus places the responsibility on the health-care provider in the pivotal role: not to overlook pigmented lesions. Therefore, it is recommended that in clinical practice, no matter what is the presenting complaint, total examination of the body should be requested of all Caucasian patients at the time of the first encounter and that all body regions, including the scalp, toe webs, and orifices (mouth, anus, vulva), be examined.

4. Examination of All Acquired Pigmented Lesions According to the ABCDE Rule

This rule analyzes pigmented lesions according to symmetry, border, color, diameter, growth, and elevation (see p. 261 and Table 12-1). While it does not apply to all types of melanoma, it permits differential diagnostic separation of most melanomas from common nevi and other pigmented lesions.

Etiology and Pathogenesis

The etiology and pathogenesis of cutaneous melanoma are unknown. Epidemiologic studies demonstrate a role for genetic predisposition and sun exposure in melanoma development. The major genes involved in melanoma development reside on chromosome 9p21. Twenty-five to forty percent of members of melanoma-prone families have mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A) and a few families in cyclin-dependent kinase 4 (CDK4). These are tumor-suppressor genes that provide a rational basis for the link to susceptibility to melanoma. Sixty-six percent of melanomas have a mutation of the BRAF gene, others of MC1R.

There is convincing evidence from epidemiologic studies that exposure to solar radiation is the major cause of cutaneous melanoma. Cutaneous melanoma is a greater problem in light-skinned whites (skin types I and II), and sunburns during childhood and intermittent burning exposure in fair skin seem to have a higher impact than cumulative UV exposure over time. Other predisposing and risk factors are the presence of precursor lesions (dysplastic melanocytic nevi and congenital NMN) and a family history of melanoma in parents, children, or siblings. Risk factors for melanoma are listed in Table 12-2.


• Genetic markers (CDKN2a), BRAFMC1R

• Photo skin type I/II

• Family history of dysplastic nevi or melanoma

• Personal history of melanoma

• Ultraviolet irradiation, particularly sunburns during childhood and in termittent burning exposures

• Number (>50) and size (>5 mm) of melanocytic nevi

• Congenital nevi

• Number of dysplastic nevi (>5)

• Dysplastic melanocytic nevus syndrome

Melanoma Growth Patterns

Almost all melanomas show an initial radial growth phase followed by a subsequent vertical growth phase. Radial growth phase refers to a mostly intraepidermal, preinvasive, or minimally invasive growth pattern; vertical growthrefers to growth into the dermis and thus into the vicinity of vessels that serve as avenues for metastasis. Since most melanomas produce melanin pigment, even preinvasive melanomas in their radial growth phase are clinically detectable by their color patterns. The prognostic difference among the clinical types of melanoma relates mainly to the duration of the radial growth phase, which may last from years to decades in LMM, from months to 2 years in SSM, and 6 months or less in NM.

Melanoma Recognition

Six Signs of Malignant Melanoma (ABCDE Rule), (does not apply to nodular melanoma)

A. Asymmetry in shape—one-half unlike the other half.

B. Border is irregular—edges irregularly scalloped, notched, sharply defined.

C. Color is not uniform; mottled—haphazard display of colors; all shades of brown, black, gray, blue, red, and white.

D. Diameter is usually large—greater than the tip of a pencil eraser (6.0 mm); others use D for “ugly duckling” sign: lesion is different from other pigmented lesions (nevi) on the body with respect to change in size, shape, and color.

E. Elevation is almost always present and is irregular—surface distortion is assessed by side lighting. MIS and acral lentiginous lesions initially macular; others use E for Evolving. A history of an increase in the size of lesion is one of the most important signs of malignant melanoma.

Clinical Presentations of Melanoma

The clinical characteristics of the four major types of melanoma are summarized in Table 12-3. Frequency of melanoma by type of tumor: SSM, 70%; NM, 15%; LMM, 5%; and acral and unclassified melanoma, 10%. Also discussed in this section are MIS and desmoplastic melanoma.



Melanoma in Situ (MIS) ICD-9: 232 image ICD-10: D02 image

Image The clinical features of MIS are not always clearly presented. MIS is primarily a histopathologic definition, and the term is used when melanoma cells are confined to the epidermis, above the basement membrane; basilar melanocytic atypia, hyperplasia, and spread occur either in single-file alignment along the basal membrane or are distributed throughout the epidermis (pagetoid spread). Every melanoma starts as an in situ lesion, but MIS is clinically diagnosable only when the radial growth phase is long enough for it to become visually detectable. Such lesions are flat, within the level of the skin, and thus a macule (Fig. 12-7) or a macule with barely perceptible elevation (Fig. 12-8), with irregular borders and marked variegation of color: brown, dark brown, and black or reddish tones but without gray or blue, as this occurs only when melanin (within macrophages) or melanocytes or melanoma cells are located in the dermis. The clinical distinction between MIS and severely atypical DN may not be possible.

Image The clinical correlations of MIS are lentigo maligna (Fig. 12-7) and flat SSM (Fig. 12-8) and these are discussed in the respective sections below.


Figure 12-7. Melanoma in situ: lentigo maligna A large, very irregular, and asymmetric macule on the preauricular region of a 78-year-old male. There is striking variegation of pigmentation (tan, brown, dark brown, black).


Figure 12-8. Melanoma in situ, superficial spreading type (A) Barely elevated plaque on the arm of a 75-year-old white male was first noted 5 years previously, gradually increasing in size. The lesion is asymmetric and there is also asymmetry in the distribution of color that is variegated and shows dark-brown specks against a tan background. Dermatopathology of the lesion showed a superficial spreading melanoma in situ. (B) An almost oval, barely elevated small plaque that has a relatively regular border but is striking with regard to the variegation in color: tan, dark brown, and even black with an orange portion on the right. Dermatopathology again showed MIS with a pagetoid growth pattern of intraepidermal melanoma cells.

Lentigo Maligna Melanoma (LMM) ICD-9: 232 image ICD-10: D02 Image

Image The least common (<5%) of the four principal melanoma types of white persons (Table 12-3).

Image It occurs in older persons on the most sun-exposed areas—the face and forearms.

Image Sunlight is the most important pathogenic factor.

Image LMM always starts as lentigo maligna (LM), which represents a macular intraepidermal neoplasm and is an MIS (Figs. 12-7 and 12-10). LM is thus not a precursor but an evolving lesion of melanoma.

Image Focal papular and nodular areas signal a switch from the radial to the vertical growth phase and thus invasion into the dermis; the lesion is now called LMM (Fig. 12-9).

Image For the most important clinical characteristics, see Table 12-3.


Figure 12-9. Lentigo maligna melanoma Illustrated on the right of the lesion is a large, variegated, freckle-like macule (not elevated above the plane of the skin) with irregular borders; the tan areas show increased numbers of melanocytes, usually atypical and bizarre, and are distributed single file along the basal layer; at certain places in the dermis, malignant melanocytes have invaded and formed nests (radial growth phase). At the left is a large nodule that is heavily pigmented and composed of epithelioid cells that have invaded the dermis (vertical growth phase); the nodules of all four main subtypes of melanoma are indistinguishable from each other.


Age of Onset. Median age 65.

Sex. Equal incidence in males and females.

Race. Rare in brown-skinned persons (e.g., Asians, East Indians) and extremely rare in black-skinned (African Americans and Africans) persons. Highest incidence in whites, skin phototypes I, II, and III.

Incidence. 5% of primary cutaneous melanomas.

Predisposing Factors. Same factors as in sun-induced nonmelanoma skin cancer: older population, outdoor occupations (farmers, sailors, construction workers).


In contrast to SSM and NM, which appear to be related to intermittent high-intensity sun exposure and occur on the intermittently exposed areas (back and legs) of young or middle-aged adults, LM and LMM occur on the face, neck, and dorsa of the forearms or hands (Table 12-3); furthermore, LM and LMM occur almost always in older persons with evidence of heavily sun-damaged skin (dermatoheliosis). The evolution of the lesion most clearly reveals the transition from the radial to the vertical growth phase and from a clinically recognizable MIS to invasive melanoma (Fig. 12-9).

Clinical Manifestation

LMM very slowly evolves from LM over a period of several years, sometimes up to 20 years. There is practically always a background of dermatoheliosis.

Skin Lesions. Lentigo Maligna. Uniformly flat, macule (Fig. 12-7); 0.5 cm or larger, up to 20 cm (Fig. 12-10A). Usually well defined, in some areas also blurred borders or highly irregular borders, often with a notch; “geographic” shape with inlets and peninsulas (Fig. 12-10B). Early lesions tan, advanced lesions: striking variations in hues of brown and black (speckled), appears like a “stain” (Fig. 12-7); haphazard network of black on a background of brown (Fig. 12-10A). No hues of red and blue.


Figure 12-10. Lentigo maligna (A) A very large lentigo maligna on the right cheek with the typical variegation in color (tan, brown, black) and highly irregular shape. The lesion is flat, macular, and thus represents an in situ melanoma. (B) The classically macular lentigo maligna is highly irregular in shape and variegated in color. However, there is a bluish component and a large pink nodule in the infraorbital region, indicating a switch from the radial to the vertical growth phase and thus invasiveness: the lesion is now called lentigo maligna melanoma.

Lentigo Maligna Melanoma. The clinical change that indicates the transition of LM to LMM is the appearance of variegated red, white, and blue and of papules, plaques, or nodules (Fig. 12-10B). Thus, LMM is the same as LM plus (1) gray areas (indicate focal regression) and blue areas [indicating dermal pigment (melanocytes or melanin)] and (2) papules or nodules, which may be blue, black, or pink (Fig. 12-10B). Rarely, LMM may be nonpigmented. It is then skin colored and patchy red and clinically not diagnosable (see Fig. 12-18A).

Distribution. Single isolated lesion on the sun-exposed areas: forehead, nose, cheeks, neck, forearms, and dorsa of hands; rarely on lower legs.

Other Skin Changes in Areas of Tumor. Suninduced changes: solar keratosis, freckling, telangiectasia, thinning of the skin, i.e., dermatoheliosis.

General Medical Examination. Check for regional lymphadenopathy.

Laboratory Examination

Dermatopathology. LM shows increased numbers of atypical melanocytes distributed in a single layer along the basal layer and above the basement membrane of an epidermis that shows elongation of rete ridges. Atypical melanocytes are usually singly dispersed but may also aggregate to small nests and extend into the hair follicles, reaching the middermis, even in the preinvasive stage of LM. In LMM, they invade the dermis (vertical growth phase) and expand into the deeper tissues (Fig. 12-9).

Differential Diagnosis

Variegate Tan-Brown Macule/Papule/Nodule. Seborrheic keratoses may be dark but are exclusively papules or plaques and have a characteristic stippled surface, often with a verrucous component, i.e., a “warty” but greasy surface that, when scratched, exhibits fine scales. Solar lentigo, although macular, does not exhibit the intensity or variegation of brown, dark brown, and black hues seen in LM. Dermoscopy is essential.


Summarized in Table 12-5.


See also p. 282283.

1. Very early LM lesions: Imiquimod.

2. Excise with 1 cm beyond the clinically visible lesion where possible and provided the flat component does not involve a major organ. Use of Wood lamp and dermoscopy help in defining borders.

3. Sentinel node to be done in lesions >1.0 mm in terms of thickness.

Superficial Spreading Melanoma ICD-9: 232 image ICD-10: D02 Image

Image SSM is the most common melanoma (70%) type in persons with white skin.

Image It arises most frequently on the upper back and occurs as a moderately slow-growing lesion over a period of up to 2 years.

Image SSM has a distinctive morphology: an elevated, flat lesion (plaque). The pigment variegation of SSM is similar to, but more striking than, the variety of color present in most LMM. The color display is a mixture of brown, dark brown, black, blue, and red, with slate-gray or gray regions in areas of tumor regression.

Image For most important clinical characteristics, see Tables 12-1 and 12-3.


Age of Onset. 30–50 (median, 37) years of age.

Sex. Slightly higher incidence in females.

Race. White-skinned persons overwhelmingly predominate. Only 2% brown or black skinned. Furthermore, brown and black persons have melanomas usually occurring on the extremities; half of brown and black persons have primary melanomas arising on the sole of the foot (see below).

Incidence. SSM constitutes 70% of all melanomas arising in white persons.

Predisposing and Risk Factors (see Table 12-2). In order of importance, these are presence of precursor lesions (DN, CNMN; p. 252 and p. 256); family history of melanoma in parents, children, or siblings; light skin color (skin phototypes I and II); and sunburns, especially during preadolescence. Especially increased incidence in young urban professionals, with a frequent pattern of intermittent, intense sun exposure (“weekenders”) or winter holidays near the equator.


In the early stages of growth, there is an intraepidermal, or radial, growth phase during which tumorigenic pigment cells are confined to the epidermis and thus cannot metastasize. At this stage, SSM is an MIS (Figs. 12-8 and 12-11). This “grace period” of the radial growth phase, with potential for cure, is followed by the invasive vertical growth phase, in which malignant cells consist of a tumorigenic nodule that vertically invades the dermis with potential for metastasis (Fig. 12-11).

The pathophysiology of SSM is not yet understood. Certainly, in some considerable number of SSMs, sunlight exposure is a factor, and SSM is related to occasional bursts of recreational sun exposure during a susceptible period (<14 years). About 10% of the SSMs occur in high-risk families. The rest of the cases may occur sporadically among persons without a specific genetic risk.

Clinical Manifestation

The usual history of SSM is a change in a previously existing pigmented lesion (mostly a DN). It should be noted, however, that 70% of melanomas arise in “normal” skin, but since initial growth is slow and melanomas often occur in persons with many nevi, an early SSM may be mistaken for a preexisting nevus by the patient.

The patient or a close relative may note a gradual darkening in one area of a “mole” (see Figs. 12-3 and 12-8) or a change in shape; and as the dark areas increase, there will develop variegation of color with mixes of brown, dark brown, and black. Also, the borders of a previously regularly shaped lesion may become irregular with pseudopods and a notch.

With the switch from the radial to a vertical growth phase (Fig. 12-11), and thus invasion into the dermis, there is the clinical appearance of a papule and later nodule on top of the slightly elevated plaque of an SSM. Since many SSMs initially have the potential for a tumor-infiltrating lymphocyte (TIL)-mediated regression, albeit only partial, other areas of the SSM plaque may sink to the level of surrounding normal skin and the color mixes of brown to black are expanded by the addition of red, white, and the tell-tale blue and blue-gray.

Skin Lesions (Figs. 12-12 and 12-13). SSM is the lesion to which the ABCDE rule (p. 261) best applies. Initially a very flat plaque 5–12 mm or smaller (Fig. 12-8); older lesions, 10–25 mm (Fig. 12-12). Asymmetric (one-half unlike the other) (Figs. 12-12A–C) or oval with irregular borders (Fig. 12-12D) and often with one or more indentations (notches) (Figs. 12-12 and 12-13). Sharply defined. Dark brown, black, with admixture of pink, gray, and blue-gray hues—with marked variegation and a haphazard pattern. White areas indicate regressed portions (Figs. 12-12C and D). An SSM is thus a flat plaque with all shades of brown to black plus the American flag or the tricolore (red, blue, white) (Fig. 12-12D). No benign pigmented lesion has these characteristics. As the vertical growth phase progresses, nodules appear (Fig. 12-13B); eventually, erosions and even superficial ulceration develop (Figs. 12-13C and D).

Distribution. Isolated, single lesions; multiple primaries are rare. Back (males and females); legs (females, between knees and ankles); anterior trunk and legs in males; relatively fewer lesions on covered areas, e.g., buttocks, lower abdomen, bra area.

Dermoscopy. Increases diagnostic accuracy by more than 50%.


Figure 12-11. Superficial spreading melanoma The border is irregular and elevated throughout its entirety; biopsy of this plaque surrounding the large nodule shows a pagetoid distribution of large melanocytes throughout the epidermis in multiple layers, occurring singly or in nests, and uniformly atypical (radial growth phase). On the left is a large nodule, and scattered throughout the surrounding portion of the plaque are smaller papular and nodular areas (vertical growth phase). The nodules may also show epithelioid, spindle cells, or small malignant melanocytes as in lentigo maligna melanoma and NM.



Figure 12-12. Superficial spreading melanoma, radial growth phase (A) A flat-topped, elevated, asymmetric, and irregular plaque with variegated color (brown, black) on the trunk with sharply demarcated margins. The surface is also irregular with a cobblestone pattern (see also Fig. 12-3). (B) An asymmetric, flat plaque with irregular and sharply defined margins and a cobblestone-like surface. The melanin pigmentation ranges from light brown to dark brown, black, and there are lighter areas interspersed. (C) A highly irregular lesion with dark-brown to bluish-black papules forming a ring around a white macular area with a central brownish to bluish papule. This white area marks spontaneous regression. (D) A relatively symmetric but large (8 cm) plaque with sharply defined and notched border and a considerable variegation of color: black, blue, red, and white.



Figure 12-13. Superficial spreading melanoma, vertical growth phase (A) An only minimally irregular plaque with variegate color (brown, black). In the center, there is a small black, dome-shaped nodule. This is the switch to the vertical growth phase. (B) An irregular very flat plaque with notched borders and highly variegated color (tan, brown, black, and red). Slightly off center there is a large partially crusted nodule (vertical growth phase). (C) A highly irregular and asymmetric plaque with a cobblestone-like surface and variegated color (black, brown). On the right there is an excentric, eroded black to blue nodule representing the vertical growth phase. (D) A highly irregular, asymmetric bluish to black plaque with brown, red, and white (regression). Off center is an eroded black nodule (vertical growth).

General Examination. Always search for enlarged regional nodes.

Laboratory Examination

Dermatopathology. Malignant melanocytes expand in a pagetoid pattern, i.e., in multiple layers within the epidermis (if confined to the epidermis, the lesion is an MIS) and superficial papillary body of the dermis—the radial growth phase. They occur singly and in nests (see Fig. 12-11) and are S-100 and HMB-45 positive. In the vertical growth phase, presenting clinically as small nodules, they expand further into the reticular dermis and beyond (Fig. 12-11). For microstaging, see Table 12-4 and p. 282.




Course and Prognosis

If left untreated, SSM develops deep invasion (vertical growth) over months to years. Prognosis is summarized in Table 12-5.




Clinically according to the ABCDE rule, verified by dermoscopy. In case of doubt, biopsy; total excisional biopsy with narrow margins is optimal biopsy procedure. Incisional or punch biopsy acceptable when total excisional biopsy cannot be performed or when lesion is large, requiring extensive surgery to remove the entire lesion. Shave biopsy should not be done, as it does not allow assessment of the level of invasion.


Surgical Treatment. See p. 282–283.

Nodular Melanoma ICD-9: 232 image ICD-10: D02

Image NM is second in frequency after SSM.

Image Occurring largely in middle life in persons with white skin and, as in SSM, on the less commonly exposed areas.

Image The tumor from the beginning is in the vertical growth phase (Fig. 12-14).

Image NM is uniformly elevated and presents as a thick plaque or an exophytic, polypoid, or dome-shaped lesion.

Image The color pattern is usually not variegated, and the lesion is uniformly blue or blue-black or, less commonly, can be very lightly pigmented or nonpigmented (amelanotic melanoma).

Image NM is the one type of primary melanoma that arises quite rapidly (a few months to 2 years) from normal skin or from a melanocytic nevus as a nodular (vertical) growth without an adjacent epidermal component, as is always present in LMM and SSM.

Note: For the most important clinical characteristics, see Table 12-3.


Figure 12-14. Nodular melanoma This arises at the dermal–epidermal junction and extends vertically in the dermis (vertical growth phase). The epidermis lateral to the areas of this invasion does not demonstrate atypical melanocytes. As in lentigo maligna melanoma and superficial spreading melanoma, the tumor may show large epithelioid cells, spindle cells, small malignant melanocytes, or mixtures of all three.


Age of Onset. Middle life.

Sex. Equal incidence in males and females.

Race. NM occurs in all races, but in the Japanese it occurs nine times more frequently (27%) than SSM (3%).

Incidence. NM constitutes 15% (up to 30%) of the melanomas in the United States.

Predisposing and Risk Factors. See p. 260 and Table 12-2.


Both NM and SSM occur in approximately the same sites (upper back in males, lower legs in females), and presumably the same pathogenetic factors are operating in NM as were described in SSM. For the growth pattern of NM, see Fig. 12-14. The reason for the high frequency of NM in the Japanese is not known.

Clinical Manifestation

This type of melanoma may arise in a preexisting nevus, but more commonly arises de novo from normal skin. In contrast to SSM, NM evolves over a few months and is often noted by the patient as a new “mole” that was not present before.

Skin Lesions. Uniformly elevated “blueberry-like” nodule (Figs. 12-15A and B) or ulcerated or “thick” plaque; may become polypoid. Uniformly dark blue, black, or “thunder-cloud” gray (Figs. 12-15A and B); lesions may appear pink with a trace of brown or a black rim (amelanotic NM, see Fig. 12-18C). Surface smooth or scaly, eroded (Fig. 12-15C) or ulcerated (Fig. 12-15D). Early lesions are 1–3 cm in size but may grow much larger if undetected. Oval or round, usually with smooth, not irregular, borders, as in all other types of melanoma. Sharply defined, may be pedunculated (Fig. 12-15D).



Figure 12-15. Nodular melanoma (A) A 9-mm dome-shaped smooth nodule with a flatter brownish rim arising on the back of a 38-year-old male. (B) A 1-cm black papule on the posterior thigh of a 60-year-old female. The lesion had been present for less than 1 year. (C) An eroded, bleeding, brown nodule having a mushroom-like configuration giving it a stuck-on appearance. Such lesions can be mistaken for a vascular lesion such as a pyogenic granuloma. (D) Large (5 cm) irregular, black, bleeding nodule sitting on the skin like a mushroom. The lesion had grown for over a half year and the 56-year-old male patient had not seen a physician out of fear “it might be melanoma.”

Distribution. Same as SSM. In the Japanese, NM occurs on the extremities (arms and legs).

General Medical Examination. Always search for nodes.

Laboratory Examinations

Dermatopathology. Malignant melanocytes, which appear as epithelioid, spindle, or small atypical cells, show little lateral (radial) growth within and below the epidermis and invade vertically into the dermis and underlying subcutaneous fat (see Fig. 12-14). They are S-100 and usually HMB-45 positive. For microstaging, see p. 282.

Serology. Serum levels of S-100 beta and melanoma-inhibiting activity, S-cysteinyldopa, and lactate dehydrogenase (LDH) levels are markers for advanced melanoma patients. LDH is to date the only statistically significant marker for progressive disease.


Clinical and with the help of dermoscopy. However, dermoscopy may fail in uniformly black lesions. In case of doubt, biopsy. Total excisional biopsy with narrow margins is optimal biopsy procedure, where possible. If biopsy is positive for melanoma, reexcision of site will be necessary (see Management, p. 282). Incisional or punch biopsy acceptable when total excisional biopsy cannot be performed or when lesion is large, requiring extensive surgery to remove the entire lesion.

Differential Diagnosis

Blue/Black Papule/Nodule. NM can be confused with hemangioma (long history) and pyogenic granuloma (short history—weeks) (see Fig. 12-15C) and is sometimes almost indistinguishable from pigmented basal cell carcinoma, although it is usually softer. However, any “blueberry-like” nodule of recent origin (6 months to 1 year) should be excised or, if large, an incisional biopsy is mandatory for histologic diagnosis.


Summarized in Table 12-5.


Surgical Treatment. See p. 282 283

Desmoplastic Melanoma (DM) Image

Image The term desmoplasia refers to connective tissue proliferation and, when applied to malignant melanoma, describes (1) a dermal fibroblastic component of melanoma with only minimal melanocytic proliferation at the dermal–epidermal junction; (2) nerve-centered superficial malignant melanoma with or without an atypical intraepidermal melanocytic component; or (3) other lesions in which the tumor appears to arise in lentigo maligna or, rarely, in ALM or superficial spreading melanoma.

Image Also, DM growth patterns have been noted in recurrent malignant melanoma.

Image DM may be a variant of LMM in that most lesions occur on the head and neck in patients with dermatoheliosis.

Image DM is more likely to recur locally and metastasize than LMM, however. DM is rare and occurs more frequently in women and persons >55 years old.

Image At diagnosis, DM lesions have been present from months to years. DM is asymptomatic, usually not pigmented and is therefore overlooked by the patient. Early lesions may appear as variegated lentiginous macules or plaques, at times with small blue-gray specks of color. Later lesions may appear as dermal nodules, and although they commonly lack any melanin pigmentation, they may have gray to blue papular elevations (Fig. 12-16). Borders, when discernible, are irregular as in LM.

Image The diagnosis requires an experienced dermatopathologist; S-100 immunoperoxidase-positive spindle cells need to be identified in the matrix collagen. HMB-45 staining may be negative. A typical junctional melanocytic proliferation, either individual or focal nests, occurs, resembling LM. S-100-positive spindle-shaped cells are embedded in matrix collagen that widely separates the spindle cell nuclei. Small aggregates of lymphocytes are commonly seen at the periphery of DM. Neurotropism is characteristic, i.e., fibroblast-like tumor cells around or within endoneurium of small nerves. Often, DM is seen with a background of severe solar damage to the dermis.

Image There are mixed views about the prognosis of DM. In one series, approximately 50% of patients experienced a local recurrence after primary excision of DM, usually within 3 years of excision; some patients experienced multiple recurrences. Lymph node metastasis occurs less often than local recurrence. In one series, 20% developed metastases, and DM was regarded as a more aggressive tumor than LMM.

Image For management, see p. 282.


Figure 12-16. Desmoplastic melanoma A bluish-black very hard nodule on the cheek of an 85-year-old woman. It recurred 1 year after primary excision: histopathologically, it was a desmoplastic melanoma with a thickness of greater than 3.4 mm and showed neural invasion.

Acral Lentiginous Melanoma ICD-9: 232 image ICD-10: D02Image

Image ALM is a special presentation of cutaneous melanoma arising on the sole, palm, and fingernail or toenail bed.

Image ALM occurs most often in Asians, sub-Saharan Africans, and African Americans, comprising 50–70% of the melanomas of the skin found in these populations.

Image It occurs most often in older males (>60 years) and often grows slowly over a period of years.

Image The delay in development of the tumor is the reason these tumors are often discovered only when nodules appear or, in the case of nail involvement, the nail is shed; therefore, the prognosis is poor.


Age of Onset. Median age is 65.

Incidence. 7–9% of all melanomas; in whites, 2–8% and in Asians, Africans, African Americans, 50% of melanomas.

Sex. Male:female ratio, 3:1.

Race. ALM is the principal melanoma in the Japanese (50–70%) and in American and subSaharan African blacks.


The pigmented macules that are frequently seen on the soles of African blacks could be comparable with DN. ALM has a similar growth pattern as LMM.

Clinical Manifestation

ALM is slow growing (about 2.5 years from appearance to diagnosis). The tumors occur on the volar surface (palm or sole) and in their radial growth phase may appear as a gradually enlarging “stain.” ALM as subungual (thumb or great toe) melanoma appears first in the nail bed and involves, over a period of 1–2 years, the nail matrix, eponychium, and nail plate. In the vertical growth phase, nodules appear; often there are areas of ulceration, and nail deformity and shedding of the nail may occur.

Skin Lesions Acral and Palm/Sole. Macular or slightly raised lesion in the radial growth phase (Fig. 12-17), with focal papules and nodules developing during the vertical growth phase. Marked variegation of color including brown, black, blue, depigmented pale areas (Fig. 12-17). Irregular borders as in LMM; usually well defined but not infrequently ill defined. This type of ALM occurs on soles, palms, dorsal, and palmar/plantar aspects of fingers and toes (Fig. 12-17).



Figure 12-17. Acral lentiginous melanoma (A) An ALM arising on the thumb. Lentiginous component on the dorsal skin of the thumb: macular, sharply and ill-defined brown and gray-bluish spots. Subungual and distal ulcerated nodular component. (B) The tumor has replaced the entire nail bed and surrounding skin: macular and of variegated color resembling a lentigo maligna. The nail has been shed. This is ALM that has led to destruction of the nail matrix and was first diagnosed as nail dystrophy. (C) ALM on the heel. There is a highly variegated macular component—brown to gray and black; the nodular component is hyperkeratotic, reddish, and ulcerated. (D) Lentigo maligna melanoma on the sole. This is an advanced lesion with a macular component and a reddish, ulcerated nodule. The lesion measured 10 mm in depth, and there were enlarged inguinal lymph nodes.

Subungual. Subungual macule beginning at the nail matrix and extending to involve the nail bed and nail plate. Papules, nodules, and destruction of the nail plate may occur in the vertical growth phase (Fig. 12-17B). Dark brown or black pigmentation that may involve the entire nail and surrounding skin looking like LM (Figs. 12-17A and B). As the lesion switches to the vertical growth phase, a papule or nodule appears and the nail is shed (Figs. 12-17A and B). Often the nodules or papules are unpigmented. Amelanotic ALM is often overlooked for months and, since there are no pigmentary changes, may first present as nail dystrophy.

Differential Diagnosis

ALM (plantar type) is not infrequently regarded as a “plantar wart” and treated as such. Dermoscopy is of decisive help. Also, often misdiagnosed as tinea nigra.

Subungual Discoloration. ALM (subungual) is usually considered to be traumatic bleeding under the nail, and subungual hematomas may persist for over 1 year; however, usually the whole pigmented area moves gradually forward. Distinction of ALM from subungual hemorrhage can easily be made by dermos-copy. With the destruction of the nail plate, the lesions are most often regarded as “fungal infection.” When nonpigmented tumor nodules appear, they are misdiagnosed as pyogenic granuloma.

Laboratory Examination

Dermatopathology. The histologic diagnosis of the radial growth phase of the volar type of ALM may be difficult and may require large incisional biopsies to provide for multiple sections. There is usually an intense lymphocytic inflammation at the dermal–epidermal junction. Characteristic large melanocytes along the basal cell layer may extend as large nests into the dermis, along eccrine ducts. Invasive malignant melanocytes are often spindle shaped, so that ALM frequently has a desmoplastic appearance histologically.


The volar type of ALM can be deceptive in its clinical appearance, and “flat” lesions may be quite deeply invasive. Five-year survival rates are <50%. The subungual type of ALM has a better 5-year survival rate (80%) than does the volar type, but the data are probably not accurate. Poor prognosis for the volar type of ALM may be related to inordinate delay in the diagnosis.


In considering surgical excision, it is important that the extent of the lesion be ascertained by viewing the lesion with dermoscopy. Subungual ALM and volar-type ALM: amputation [toe(s), finger(s)]; volar and plantar ALM: wide excision with split skin grafting. Sentinel lymph node procedure necessary in most cases (see “Management of Melanoma” p. 282).

Amelanotic Melanoma ICD-9: 232 image ICD-10: D02 Image

Image All types of melanoma can be amelanotic.

Image Since they do not have the characteristic pigment marker, they are a diagnostic challenge (Fig. 12-18).

Image However, often there are pigmented clones in the tumor, which reveal its nature as a melanoma (Figs. 12-18B and C).

Image In most cases, only biopsy will reveal the correct diagnosis (Figs. 12-18A and D).



Figure 12-18. Amelanotic melanoma (A) Amelanotic LMM. The red nodule was soft and diagnosed as pyogenic granuloma and was excised. Histopathology revealed melanoma and subsequent punch biopsies performed in the erythematous skin of the cheek revealed lentigo maligna (LM). The outlines of the LM lesion as determined by further punch biopsies are marked with green circles. Note that over the mandible lesion is also nodular (vertical) growth. (B) Amelanotic superficial spreading melanoma. The true nature of this red nodule is revealed by the blue crescent at its base and the variegated brown-red plaque with which it is contiguous. (C) Amelanotic nodular melanoma. This cherry-red nodule has a brown, macular extension at 4, 6, 9 and 12 o’clock, giving away the correct diagnosis. (D) Amelanotic ASM on the heel. This cherry-red lesion was clinically diagnosed as eccrine poroma. Biopsy revealed deeply invading ALM.

Malignant Melanoma of the Mucosa ICD-9:232imageICD-10:D02 Image

Image Malignant melanomas arising in the mucosal epithelial lining of the respiratory tract and gastrointestinal and genitourinary tracts are very rare, with an annual incidence of 0.15% per 100,000 individuals.

Image Major sites of the mucosal melanomas are the vulva and vagina (45%) and the nasal and oral cavity (43%).

Image Mucosal melanomas are so rare that there are no large databases compared with those for cutaneous melanoma.

Image Therefore, pathologic microstaging has not been possible, and the fine-tuning of the prognosis that has been useful in cutaneous melanoma (Breslow thickness) has so far not been possible in mucosal melanoma.

Melanomas of the Oral Cavity

There is a delay in diagnosis of melanoma of the oral and nasal surfaces. Although melanosis of the mucosa is common in blacks and East Indians, it involves the buccal and gingival mucosa bilaterally (see Section 33); when there is a single area of melanosis, a biopsy should be performed to rule out melanoma; this is also true of pigmented nevi in the oral cavity, which should be excised.

Melanomas in the Genitalia

These melanomas mostly arise on the glans or prepuce (see Section 36) and the labia minora; there are fewer on the clitoris and the labia majora. Most tumors extend to the vagina at the mucocutaneous border. They look and evolve like LM and LMM (see Section 34). Vulva melanomas are often flat like LMM with large areas of MIS, and this is important to ascertain in planning excision of all the lesions to prevent recurrence. Dermoscopy should be used to outline the periphery of the lesion, as is done in LMM.

Anorectal Melanoma

Often presents with a localized, often polypoid or nodular primary tumor, but it may also present similarly to LMM.

Metastatic Melanoma

Image Metastatic melanoma occurs in 15–26% of stage I and stage II melanomas (see below).

Image The spread of disease from the primary site usually occurs in a stepwise sequence: primary melanoma → regional metastasis (see Fig. 12-20) → distant metastasis.

Image Distant metastasis can occur, skipping the regional lymph nodes and indicating hematogenous spread.

Image Distant metastases occur anywhere but usually in the following organs: lungs (18–36%), liver (14–29%), brain (12–20%), bone (11–17%), and intestines (1–7%).

Image Most frequently, however, melanoma first spreads to distant lymph nodes, skin (Fig. 12-20B), and subcutaneous tissues (42–57%) (Fig. 12-20D).

Image Local recurrence occurs if excision has not been adequate (Fig. 12-19) or it can involve the skin of an entire region both with and without adequate surgical treatment (Figs. 12-20A and C).

Image Widespread metastasis can also lead to single metastatic melanoma cell lodgement in all organs with melanosis of the skin (Fig. 12-21), mucous membranes, liver, kidney, heart muscle, and other tissues.

Image Metastatic melanoma without a primary tumor is rare, 1–6%. It is the result of metastasis from a melanoma that underwent total spontaneous regression.

Image Melanoma may have a late recurrence (>10 years). The usual time is 14 years, but there have been “very late” recurrences (>15 years) in one series at the Massachusetts General Hospital, with 0.072% (20 of 2766 cases).

Image Patients with a solitary metastasis confined to the subcutaneous, nonregional lymph nodes or lung are most likely to benefit from surgical intervention.


Figure 12-19. Metastatic melanoma: recurring in excision scar (A) A pigmented lesion on the shin of a 35-year-old male, present for <2 years. Dermatopathology was initially interpreted as a spindle cell (Spitz) nevus. The primary lesion site was therefore not reexcised. (B) Two papules are seen around the excision site scar, one of which has a blue-brown color. The histology from the excised lesion was reviewed and revised as a superficial spreading melanoma, and the histopathology of the two papules seen here was metastatic melanoma.



Figure 12-20. Metastatic melanoma (A) Local recurrence and in-transit cutaneous metastases after excision of primary melanoma on the scalp and split skin grafting. Note: metastases are both in the surrounding skin and the graft. (B) Advanced metastases in the axillary lymph nodes and in-transit metastases of the mammary skin. The primary tumor had been a pitch-black nodular melanoma and had been just lateral to the breast (the scar can still be seen). Note that both the in-transit and axillary nodules extending into the skin are amelanotic. (C) Multiple melanoma metastases to the skin after hematogenous spread. (D) Subcutaneous melanoma metastases by hematogenous spread. Since they are not bluish, they are amelanotic. Primary and metastatic melanoma may differ with regard to pigmentation potential.



Figure 12-21. Universal melanosis due to metastatic melanoma (A) Single-cell metastases are found throughout the skin and mucous membranes of the white patient and circulating metastatic melanoma cells were found in the blood. The urine was black (melanogenuria), and upon autopsy the internal organs were also black. (B) The patient’s hand is shown beside the hand of a nurse to demonstrate the difference in color.

Staging of Melanoma

Image Staging of melanoma depends on its TNM classification (primary tumor, regional nodes, metastases, Table 12-4).

Image Clinical staging of melanoma differentiates between local, regional, and distant disease and is based on microstaging of the melanoma and clinical and imaging evaluation for metastases.

Image Pathologic staging consists of microstaging of the primary tumor and pathologic evaluation of regional lymph nodes (Table 12-5). Staging of melanoma is strongly correlated with survival.


Microstaging is done according to Breslow method. The thickness of the primary melanoma is measured from the granular layer of the epidermis to the deepest part of the tumor. The thickness of melanoma (level of invasion) is the most important single prognostic variable and thus decisive for therapeutic decisions (Table 12-4). Primary mitotic rate is also a major criterion for melanoma staging (Table 12-4).

Clark microstaging (Clark level I, intraepidermal; level II, invades papillary dermis; level III, fills papillary dermis; level IV, invades reticular dermis; level V, invades subcutaneous fat) according to tissue level of invasion is no longer considered a significant prognostic variable.

Sentinel Lymph Node Biopsy

Sentinel lymph node biopsy can predict the presence of clinically nondetectable metastatic melanoma within regional lymph nodes with the identification of malignant cells in H&E sections; staining for S-100 protein, HMB-45, and tyrosinase.

When the nodes are not palpable, it is not certain if there are micrometastases; these can be detected by the sentinel node technique. The hypothesis is that the first node draining a lymphatic basin, called the sentinel node, can predict the presence or absence of metastasis in other nodes in that basin. Either lymphatic mapping (LM) or sentinel lymphadenectomy (SL) is performed on the same day with a single injection of filtered 99mTc subcutaneously into the site of the primary melanoma for probe-directed LM and SL. Alternatively, one day after lymphoscintigraphy, sentinel node biopsy is performed, guided by a gamma probe and blue dye also injected into the primary site; the sentinel node is subjected to histopathology and immunohistochemistry. LM is very useful in locating the drainage areas, especially in primary tumors on the trunk, which can drain on either side and to both the axillary and inguinal lymph nodes.

Lymph node dissection is performed only if micrometastasis is found in the sentinel node. The sentinel node technique is also essential in making a decision about the use of adjuvant therapy.

Prognosis of Melanoma

Prognosis of melanoma can be either excellent or grave, depending on whether the tumor is diagnosed early or late, when regional or distant metastases have occurred (Table 12-5). This emphasizes the importance of early diagnosis, of questioning patients for melanoma risks, of screening individuals belonging to risk groups, and of total-body examination of any patient seeing a physician for medical examination. Prognosis relating to stage grouping for cutaneous melanoma is shown in Table 12-5.

Management of Melanoma

The only curative treatment of melanoma is early surgical excision.

Guidelines for Biopsy and Surgical Treatment of Patients with Melanoma

I. Biopsy.

A. Total excisional biopsy with narrow margins—optimal biopsy procedure, where possible.

B. Incisional or punch biopsy acceptable when total excisional biopsy cannot be performed or when lesion is large, requiring extensive surgery to remove the entire lesion.

C. When sampling the lesion: If raised, remove the most raised area; if flat, remove the darkest area.

II. Melanoma in situ.

A. Excise with 0.5-cm margin.

III. Lentigo maligna melanoma.

A. Excise with a 1-cm margin beyond the clinically visible lesion or biopsy scar—unless the flat component involves a major organ (e.g., the eyelid), in which case lesser margins are acceptable.

B. Excise down to the fascia or to the underlying muscle where fascia is absent. Skin flaps or skin grafts may be used for closure.

C. No node dissection is recommended unless nodes are clinically palpable and suspicious for tumor.

D. See recommendation for sentinel node studies for thickness >1 mm (p. 282).

IV. SSM, NM, and ALM.

A. Thickness <1 mm.

1. Excise with a 1-cm margin from the lesion edge.

2. Excise down to the fascia or to the underlying muscle where fascia is absent. Direct closure without graft is often possible.

3. Node dissection is not recommended unless nodes are clinically palpable and suspicious for tumor.

B. Thickness 1–4 mm.

1. Excise 2 cm from the edge of the lesion, except on the face, where narrower margins may be necessary.

2. Excise down to the fascia or to the underlying muscle where fascia is absent. Graft may be required.

3. The sentinel node procedure for tumors with thickness >1 mm is recommended.

4. Lymphadenectomy is selectively performed and only for those nodal basins with occult tumor cells (i.e., positive sentinel lymph node). If the sentinel node is negative, then the patient is spared a lymph node dissection.

5. Therapeutic nodal dissection is recommended if nodes are clinically palpable and suspicious for tumor.

6. If regional node is positive and completely resected with no evidence of distant disease, adjuvant therapy with interferon-α-2b (IFN-α-2b) is considered.

Adjuvant Therapy

This is treatment of a patient after removal of all detectable tumor, but the patient is considered at high risk for recurrence (i.e., stages IIb and III). As mentioned above, IFN-α-2b (both high and low dose) is subject to intensive investigation; however, despite early promising results to date, no clear benefit on overall survival has been convincingly demonstrated.

Management of Distant Metastases (Stage IV)

Currently, this can be considered palliative at best. Surgical removal of accessible metastases can provide excellent palliation. Chemotherapy encompasses a large list of drugs (dacarbazine/temozolomide, cisplatin, vindesine/vinblastine, fotemustine, taxol/taxotere) employed as single agents or in combination. Dacarbazine is still the most effective monotherapeutic agent, but all in all chemotherapeutic treatment of stage IV melanoma is disappointing, showing only a <20% response rate and no effect on overall survival. There are a large number of melanoma vaccination trials presently being performed, and the field is rapidly expanding to include gene-therapeutic approaches. Radiotherapy has only palliative effects, but stereo-tactic radiosurgery with the gamma-knife has shown considerable palliation.

In advanced metastatic melanoma (stage IV) testing positive for BRAF V600 mutations (>50% of melanomas), oral therapy with vismodegib has demonstrated a 70% response rate. Also, the tyrosine kinase inhibitor imatinib targeting CLA4+ lymphocytes has demonstrated significant response rates in patients with metastatic melanoma.