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


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.