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Clinical simulators of melanoma
Clinical Simulators of Melanoma HAGIT MATZ, MD EDITH ORION, MD VINCENZO RUOCCO, MD RONNI WOLF, MD
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he incidence of malignant melanoma has risen dramatically in recent years despite increased awareness and enhanced behavior patterns. At present, surgery for early melanoma is curative in most patients, but therapy for advanced melanoma is less successful, so the only hope for preventing death from melanoma remains early detection.
stage melanomas, ie, 34% among the GPs and 13% among the dermatologists. A higher diagnostic accuracy of skin lesions on the part of dermatologists compared with several medical specialty groups has been reported by other studies.3– 6 The differential diagnosis of malignant melanoma includes a wide variety of benign and malignant lesions that will be presented and discussed in the present article.
No One Should Die of Malignant Melanoma A prominent dermatologist suggested that “no one should die of melanoma,”1 since this neoplasm arises on a readily accessible site; specifically, it is skin-deep and can be recognized in its early stages when simple excision is usually curative. In the same breath, “What is the hardest of all? That which you hold the most simple; seeing with your own eyes what is spread out before you” (Goethe, quoted by J. P. Eckermann, in Conversations with Goethe, May 18, 1824). This is true for all skin lesions but all the more so for malignant melanoma, and the bottom line is that diagnosing melanoma in its early stages is easier said than done. The diagnosis of melanoma has always been a real challenge for dermatologists and it will probably remain so in the third millennium as well. The ability of general practitioners (GPs) and dermatologists to diagnose pigmented skin lesions in general and melanoma in particular was evaluated in one Belgian study before and after a lecture on melanoma.2 It emerged that the recognition of melanoma was proportional to melanoma exposure in everyday practice and that thick melanomas were better recognized than thin ones by both groups of physicians. After the lecture on melanoma, the sensitivity of the GPs to recognize the lesion increased from 49% o 76%, but the diagnostic ability of dermatologists was superior to theirs both for discriminating between malignant and benign disease and for correctly identifying various lesions. The number of missed melanomas was highest for the earlyFrom the Dermatology Unit, Kaplan Medical Center, Rehovot, Israel, and the Department of Dermatology, Second University of Naples, School of Medicine and Surgery, Naples, Italy. Address correspondence to Hagit Matz, MD, Dermatology Unit, Kaplan Medical Center, Rehovot 76100, Israel. E-mail address: [email protected] © 2002 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
Bowen’s Disease (Squamous Cell Carcinoma In Situ) Bowen’s disease is an intraepidermal squamous cell carcinoma. It affects mostly older white men in whom the lesions occur primarily on sun-exposed surfaces. The lesion may be found on any part of the body as an erythematous, slightly scaly and crusted, noninfiltrated patch from a few millimeters to many centimeters in diameter. The lesion is sharply defined. Bowen’s disease may be heavily pigmented, and such cases may resemble melanoma.
Pigmented Bowen’s Disease Pigmented Bowen’s disease is an unusual form of squamous cell carcinoma in situ that is characterized by a hyperpigmented appearance. This type represents ⬍2% of all cases of Bowen’s disease.7 It commonly presents as a hyperpigmented, sharply marginated plaque with a surface that may be velvety, verrucose, or flat.7–14 Scaling and erosions may be present as well. The lesions are generally asymptomatic, but they may cause pruritus or a burning pain.8 Pigmented Bowen’s disease almost exclusively affects intertriginous areas.10 Bowen’s disease is much more common in whites than in blacks,11 it ordinarily develops on sun-exposed areas, and it is rarely pigmented.8 Paradoxically, sun-protected areas are more frequently affected, and the pigmented variant is not uncommon in the relatively few cases of black patients with Bowen’s disease.11,15 The differential diagnosis of pigmented Bowen’s disease includes superficial spreading melanoma. This variation can be differentiated on the basis of clinical features and histopathology. 0738-081X/02/$–see front matter PII S0738-081X(02)00232-8
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Basal Cell Carcinoma Basal cell carcinoma (BCC) is a malignant tumor of the skin that is believed to arise from a hair follicle. Its cells show a morphologic resemblance to the relatively undifferentiated cells of the basal layers of the epidermis, and although it is a form of cancer, it is invasive only locally and rarely metastasizes. BCC is the most common cancer among whites. Its incidence rises with age, and exposure to ultraviolet light is a principal risk factor. BCC most commonly develops on the head and neck, with ⬃20% of BCC occurring in non–sun-exposed areas.16 –18 Phenotypic characteristics associated with an increased risk of BCC include light skin color, inability to tan, blond or red hair, and freckling in childhood. Genetic ancestry and a family history of skin cancer also confer increased risk. AIDS patients and patients receiving immunosuppressive drugs after organ transplantation are also at increased risk for BCC,19,20 as are individuals exposed to arsenic. Moreover, therapeutic radiation formerly used in psoriasis, eczema, and tinea capitis predisposes to the development of BCC many decades later.21 The clinical variants of BCC include the nodular type, the pigmented variant, superficial BCC, morpheaform or sclerosing BCC, nevoid BCC syndrome, and fibroepithelioma of Pinkus. The nodular type, which comprises ⬎50% of all cases of BCC, is composed of a single or a few small waxy, semitranslucent nodules that form around a central depression that may or may not be ulcerated, crusted, and bleeding. The edge of larger lesions has a characteristic rolled border. Telangiectases course through the lesion. The pigmented variant of BCC, which is not uncommon, is especially prevalent among dark-skinned persons. This variety has all the features of the nodular type in addition to variations of brown, blue, and black pigmentation. This lesion can also be large and ulcerated and can pose a diagnostic dilemma in differentiating it from nodular or superficial spreading malignant melanoma.
Darkly Pigmented Seborrheic Keratosis Seborrheic keratoses are benign skin tumors. They are exceedingly common, and most people will develop at least one such tumor in their lifetime; many develop hundreds of them. The etiology of seborrheic keratoses is not known. They are most commonly found in the over-30-year age group. These lesions can appear on any part of the body except the mucous membranes. Seborrheic keratoses typically begin as flat, sharply demarcated, brown macules and become polypoidal with an uneven surface as they progress. Their surface is usually “warty,” with multiple plugged follicles, and is usually dull or drab in color. They can become quite large, but rarely exceed 3 cm in diameter. The color of
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these lesions can vary from a pale brown with pink tones to dark brown or black. Seborrheic keratoses can resemble malignant melanoma, especially when they become inflamed or traumatized and secondary changes develop as a consequence.22 Patients with a great number of lesions sometimes have a positive family history that may reflect a genetic propensity. Since melanocytic hyperplasia is commonly seen in seborrheic keratoses, it was suggested that melanocytes or melanocyte-derived growth factors may have a role in the development of seborrheic keratoses. There are several histologic and clinically distinct forms of seborrheic keratoses. A variant that is more likely to be confused with malignant melanoma is the “melanoacanthoma.” Although it is synonymous with pigmented seborrheic keratosis, it is actually more than a darkly pigmented seborrheic keratosis: the lesion is markedly proliferated by dendritic melanocytes, which are engorged with melanin, whereas the surrounding keratinocytes contain hardly any melanin. This lesion has no malignant potential. The verrucous surface and stuck-on appearance of the melanoacanthoma facilitates its differentiation from melanoma.
Kaposi’s Sarcoma Kaposi described this vascular neoplasm in 1872 and called it “multiple benign pigmented idiopathic hemorrhagic sarcoma.” Since that first publication, five clinical types of this disease have been described, each with a different presentation, epidemiology, and prognosis. The discovery of a new human herpes virus (HHV-8) and the subsequent identification of a humoral immune response against this putative infectious agent in patients with Kaposi’s sarcoma (KS) and in individuals at risk for the development of KS have shed new light on the infectious etiology of the disease.23 Five subtypes were described: classic KS, African cutaneous KS, African lymphadenopathic KS, KS in iatrogenically immunocompromised patients, and HIVassociated KS. The morphology of the lesion in these different subtypes is the same. The early lesion appears most often as reddish, violaceous, or bluish-black macules and patches that spread and coalesce to form nodules or plaques. These have a rubbery consistency and look like purplish angiomas, which they are. There may be edema of the affected parts, and swelling due to lymphedema often later develops. The lesions may ulcerate and bleed with even minimal trauma. HIVassociated KS displays a variety of distinct clinical features that may differ considerably from those seen in other forms of the disease. In a prolonged course, KS lesions may be disseminated, and the multiplicity of lesions will differentiate it from melanoma, which is usually an isolated lesion, unless metastasis occurs.
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Melanocytic Nevus Acquired melanocytic nevi are the most common of pigmented lesions. They are classified on a clinicopathologic basis into junctional, compound, and intradermal nevi. Junctional nevi are ordinarily seen in children and young adults. They present as a flat or slightly raised, pigmented area varying in size from 1 mm to 1 cm. Their color ranges from light brown to dark brownishblack, and the center may be darker than the edge. Their shape is usually symmetrically rounded or elliptical, and their surface is smooth and flat with preserved skin furrows. The term “junctional” refers to the presence of melanocytic nests at the dermal-epidermal junction. As the nevi mature, the nevus cells drop down into the dermis, forming compound nevi with nevus cell nests at the dermal-epidermal junction and within the dermis. Compound nevi are palpable due to the presence of nests in the upper dermis. They vary from a slightly raised plaque to a papillomatous or mamillated tumor. Compound nevi are well circumscribed, hyperpigmented lesions with well-defined borders. As the nevi continue to mature, there is a development of intradermal nevi that have nests only within the dermis. These lesions are soft, dome-shaped papules that are fleshcolored due to loss of pigmentation. A clinically normal nevus is unlikely to be confused with malignant melanoma, with inflammation due to trauma, or with a ruptured follicular unit contained within the lesion that may cause a change in size, color, and symptoms such as pruritus. Melanocytic nevi normally darken and enlarge during infancy, puberty, and pregnancy. Any nevus in an adult that increases in size or undergoes any kind of change should be examined carefully. Examples of malignant melanoma that present with clinical and histopathologic characteristics resembling benign dermal nevus have been described by Wong et al.24
Congenital Melanocytic Nevi One percent of all newborns have a pathologically confirmed congenital melanocytic nevus,25 although clinical studies have suggested that twice as many infants have pigmented lesions clinically compatible with this diagnosis.26 These lesions are classified according to the size of their largest diameter: ⬍1.5 cm for small ones, 1.5–20 cm for intermediate-sized ones, and ⬎20 cm for giant ones. Congenital lesions are usually larger than the acquired variety but, in general, are still characterized by their even coloration, symmetry, and well-defined borders. Nongiant, congenital melanocytic nevi are more common than the giant variety, presenting as well-circumscribed, hyperpigmented plaques that frequently contain terminal hair. Giant congenital lesions can cover a large portion of the body, most commonly on the lower back and thigh area, and a considerable proportion of an infant’s skin may be involved. These
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lesions may have alterations in pigment, with small, dark macules and papules interspersed within a large, hyperpigmented, hairy plaque. They have a 12% incidence of developing into melanomas and require close monitoring.27
Nevus Spilus Also known as the speckled lentiginous nevus,28 this is a congenital lesion that presents after birth on the trunk and extremities. It may be several centimeters in diameter, and its clinical presentation is a combination of a flat, macular, lentiginous component, often a darker shade than the surrounding skin, with even darker central lentigolike lesions. There are also elevated darker brown areas. Although this is an entirely benign lesion, the appearance of darker areas within a pigmented lesion may cause confusion in differentiating it from melanoma.
Blue Nevus This is an area of blue or blue-black dermal pigmentation. Since the first description of Blue nevus (BN) by Tiech in 1906, several histologic types of BN have been described, including the common dermal BN,29 cellular BN,30,31 atypical cellular BN,32 desmoplastic cellular BN,33 combined BN, and compound BN.34 Unusual clinical variants have also been reported, such as eruptive BN,35 congenital common BN,36 target BN,37 and plaque-type BN.38 – 40 Identification of the vast majority of BNs is straightforward, both clinically and histologically, and they are rarely confused with malignant melanoma. There are unusual variants, however, in which their distinction from malignant melanoma can be difficult. Two cases of plaque-type BN, an unusual variant of BN, characterized by onset in childhood, large size, and development of subcutaneous nodules of cellular BN that were misdiagnosed initially as malignant melanoma were described by Busam et al.41 The common BN is a blue-black, dome-shaped, well-circumscribed papule generally ⬍0.5 cm in diameter. It is a slowly growing benign lesion that begins in childhood and is most frequently found on the dorsum of the hands and feet. The cellular BN has a similar clinical appearance but is usually larger, measuring 1–3 cm in diameter. Common locations include the buttocks and sacrococcygeal area. It may be present before birth, but eruption in later life is not uncommon.29 Progressive growth is rare, as is malignant transformation.42 A BN is characterized by its color. The long and unchanging course should set it apart from malignant melanoma, but this suspected diagnosis is frequently submitted with surgical pathology specimens. Dermal metastases from cutaneous melanoma simulating a BN have also been described. Busam43 reported 10 BN-like lesions in three patients. All of the lesions contained pigmented
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melanocytes and melanophages in variable proportions arranged in a BN-like growth pattern. The BN-like metastases appeared in the same anatomic region as the primary tumor in two patients and near the scar of a dissected lymph node metastasis in the third.
Spitz Nevus Also referred to as benign juvenile melanoma largely due to its histopathologic appearance, this benign lesion is a smooth-surfaced, raised, round, slightly scaly, firm papule with a distinctive pink, brownish-red, or purplish-red hue. Spitz nevi mostly occur during the first two decades of life, although they appear in adulthood in about one third of the cases. They occur primarily on the face and extremities and are ⬍1 cm in diameter. This lesion may be confused with an amelanotic melanoma: it should be completely excised and the specimen examined histologically. The patient’s young age is the most helpful diagnostic clue. The polypoid form of Spitz nevus has close morphologic similarities with polypoid malignant melanoma, but these tumors can be differentiated from each other with confidence if careful attention is given to the histologic details and to the distinctive host response. A description of polypoid Spitz nevus can be found in a case report published by Fabrizi and Massi.44
Dysplastic Nevus Dysplastic nevi may exhibit one or more characteristics suggestive of melanoma, such as being ⬍5 mm and having an irregular edge, irregular pigmentation, and some degree of inflammation.45 These lesions are usually seen on the trunk and extremities but can be found anywhere on the body. They may be numerous and are characteristically larger than acquired nevi. Dysplastic nevi can be observed in members of families with dysplastic nevus syndrome as well as in isolated cases. The dysplastic nevus has been a subject of controversy.
Halo Nevus This is also known as Sutton’s nevus. It is a melanocytic nevus surrounded by a depigmented halo of otherwisenormal skin. Halo nevi are relatively common, particularly in older children and young teenagers. The back is the commonest site, and several nevi may develop halos simultaneously. Over the next few months, the central nevus will gradually disappear, leaving a macular area of nonpigmented skin. This depigmented area may persist for years and only gradually return to a normal color. It is thought that the loss of pigment results from an immunologically mediated inflammatory response that is directed against either melanin, a melanoma within the lesion, or at a distant site.46,47 Halo nevi most commonly represent a benign process, but the differential diagnosis may include an early superficial spread-
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ing melanoma with surrounding depigmentation, especially in older patients. In these cases, the surrounding area of depigmentation is usually irregular, and the central pigmented area may also be irregular in both shape and pigmentation. It is important, especially in adults, to perform a thorough examination for a possible underlying malignant melanoma, particularly if vitiliginous patches are also present. When there is any clinical doubt, excision biopsy and pathologic confirmation must be obtained.
Lentigines Lentigo simplex is a macular or slightly raised area of brown or brownish-black pigmentation with well-demarcated, smooth borders and preservation of normal skin lines. Lentigines usually appear in childhood, but they may increase in number in adult life. They are usually ⬍1 cm in diameter. The majority of lentigines remain in an inactive state throughout life, but some may mature into junctional nevi. Solar lentigines tend to occur on either acutely or chronically sun-exposed skin and are characterized by a macular area that is uniformly dark brown and irregularly shaped and that can vary in size from very small to ⬎1 cm in diameter. The “ink spot,” or reticulated black solar lentigo, poses a more difficult diagnostic dilemma.48 Such lesions are few in number and are distributed over sun-exposed areas of the body in fair-skinned individuals. They are characterized by a black macule with a markedly irregular, wiry, or beaded outline and multiple skip areas within the lesion itself. These lesions are benign, and although the clinical features of the ink spot lentigo indicate the diagnosis, any suspicion of a malignant process may require biopsy.
Pyogenic Granuloma Pyogenic granuloma is a rapidly developing vascular lesion that often develops at sites of minor trauma. The lesions are solitary, small (average size of 6.5 mm), eroded papules or nodules that bleed spontaneously or after the trauma. Common locations include the face, fingers, toes, and trunk. Pyogenic granuloma is rarely noted before 6 months of age, and the mean age at presentation is 6.7 years.49 The lesions can appear within an existing cutaneous hemangioma (port wine stain), but there is most commonly no history of a pre-existing dermatologic condition. This lesion in particular may simulate nodular amelanotic melanoma.
Senile Angioma The cherry angioma is the most ubiquitous vascular anomaly whose number increases with age. They are oval or circular, slightly elevated, 0.5– 6 mm in diameter, ruby red papules mostly found on the trunk and
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rarely seen on the hands or feet. They may mimic petechiae.
Venous Lake This bluish-purple soft swelling, 2–10 mm in diameter, is usually seen on actinically damaged skin of the lower lip of an elderly person due to a venous dilation. A venous lake may be only a trivial cosmetic problem, or it can bleed severely after trauma. Prolonged pressure with a diascope will demonstrate emptying followed by refilling with the release of pressure, thus establishing the diagnosis.50
Hemangioma Hemangioma is the most common benign tumor of childhood and may be present at birth in one third of cases, with the remaining two thirds appearing very shortly thereafter, ie, when the child is from 2 weeks to 2 months of age. It is characteristically 1– 60 mm in diameter, although as much as an entire extremity may be involved (rare). The dome-shaped lesion is usually dull red with sharp borders and a soft and easily compressed texture. Hemangiomas tend to grow over the first year or so, remain stable for a while, and then involute spontaneously in the course of months or years. Due to their vascularity, they may exhibit a blueblack coloration resembling melanoma pigment, especially when traumatized or thrombosed.50
Dermatofibroma This is a benign, nodular, dermal proliferation of unknown etiology. The lesion typically presents as a single, firm, dome-shaped, red-brown papule or nodule and is most commonly found on the limbs. The size varies from 4 mm to 1.5 cm. When the overlying epidermis is squeezed, the “dimple sign ” will appear, indicating the tethering of the overlying epidermis to the underlying lesion. The sclerosing hemangioma variant of dermatofibroma can present a diagnostic problem due to its coloration. This lesion may be blue-black as a result of an excessive amount of hemosiderin within the dermis. The static nature, well-defined borders, and symmetry of these growths are indicative of a benign process.50
Dermatofibrosarcoma Protuberans Dermatofibrosarcoma protuberans (DFSP) is a rare, spindle-cell neoplasm. Clinically, the tumor appears as an indurate plaque or nodule that may be violaceous, red-brown, or flesh-colored. From 50%– 60% of these lesions occur on the trunk, with less common involvement of the proximal extremities, the head, and neck.51,52 There is a slow but gradual growth phase that takes place over months and years, during which time
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nodules appear on a plaque surface. DFSP is usually affixed to overlying skin and is firm and indurate. It can sometimes be attached to deeper structures, such as muscle and fascia. The disease course is slowly progressive, with pain becoming increasingly prominent as the lesion increases in size. Severe pain and contractures gradually affect the general health in untreated patients. This is a neoplasm with a marked propensity for local recurrence but with a relatively low risk of metastatic spread. DFSP characteristically appears in the younger age group (20 –50 years), but it may also affect children and the elderly.53,54 There is a pigmented variant of the DFSP referred to as the “Bednar tumor,” which occurs primarily in darkly pigmented patients and is quite rare.55
Eccrine Poroma Eccrine poroma is a benign, slow-growing, slightly protruding, sessile, soft, reddish tumor that may occur anywhere but is most often seen on the sole or side of the foot and the palms. It bleeds easily with even slight trauma. The tumor grows from a cup-shaped shallow depression. The lesion tends to occur singly, although multiple lesions may also occur. One of the clinical differential diagnoses is melanoma (amelanotic and melanotic).56
Malignant Eccrine Poroma (Porocarcinoma) Most porocarcinomas arise from long-standing eccrine poromas, but the tumors may develop directly. Clinically, they are similar to poromas but may also manifest as blue or black nodules, plaques, or ulcerated tumors. The most frequent sites of involvement are the legs, feet, face, thigh, and arms. The average interval from onset to treatment is 8 years. About 10% of the cases develop distant metastases, and there is a 70% mortality rate when metastasis occurs. The differential diagnosis includes malignant melanoma.57
Trichilemmal Carcinoma This malignant form of trichilemmoma originates from the external root sheath of the hair follicle.58 In most cases, it occurs in the sun-exposed parts of the body,59 and also in patients with xeroderma pigmentosum.60 Clinically, the tumors can be nodular, ulcerated, or exophytic with a keratotic or crusted appearance.60,61 The lesions have usually been present for less than a year and exhibit a characteristic accelerated growth phase. While the tumors are locally invasive and have histologic characteristics of high-grade mitotic potential, they have a nonaggressive course and do not recur after wide excision. The differential diagnosis includes nodular malignant melanoma.
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Atypical Fibroxanthoma Atypical fibroxanthoma is a superficial form of the malignant fibrous histiocytoma. It is a low-grade malignancy, although it has been shown to metastasize to regional nodes in rare instances.62,63 Atypical fibroxanthoma occurs primarily in older populations and on sun-exposed surfaces, especially the ears, cheeks, nose, and scalp.64,65 Ultraviolet exposure and previous radiation are predisposing factors for its development. Although less common, it appears also on the extremities of younger individuals. Clinically, the tumor is a small, solitary papule or firm nodule, often with an eroded or crusted surface and without characteristic morphologic features. The clinical and histologic differential diagnosis includes melanoma.65
Malignant Fibrous Histiocytoma Malignant fibrous histiocytoma (MFH) is the most common soft-tissue sarcoma of middle and late adult life.66 It can be classified as either superficial or deep, with the more superficial lesions tending to be confined to the subcutaneous tissue, although they may be attached to the fascia. These tumors typically appear between the ages of 50 and 70 years and are slightly more common in white men. At presentation, the tumor is usually a painless, enlarging mass of several months’ duration. Growth of the tumor may be rapid. The deep type is usually a protruding, rounded, and solitary tumor (it can be multinodular) and is 5–10 cm in size at the time of the initial diagnosis. The superficial MFH tumors are usually smaller at the time of initial diagnosis.67 They are often reddish or dusky and are most commonly found on the extremities, the lower more than the upper ones.68 Most patients with superficial MFH tumors are asymptomatic. The prognosis of an MFH tumor correlates with its depth of invasion,67,68 location, and histologic subtypes.
Angiosarcoma This is a rare, malignant tumor of endothelial cell origin. The tumor presents with a wide morphologic spectrum, ranging from low-grade hemangioma-like tumors to highly anaplastic, poorly differentiated sarcomas.69 An angiosarcoma has a marked predilection for the skin and superficial soft tissues.69 Cutaneous angiosarcoma is seen mostly in elderly patients but can occur at any age. Men are affected twice as often as women. The most common site of involvement is the scalp and forehead.70,71 Clinically, angiosarcoma presents as an ill-defined, blue-to-red-to-purple indurated plaque or nodule. It is usually asymptomatic. As it grows, it may become more nodular, soft, and even compressible. Its margins are clinically indistinct, and multifocal areas often appear.69 It can be quite large at
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the time of presentation. Angiosarcoma spreads extensively in the skin beyond clinical margins, making complete surgical resection difficult.72 The prognosis is poor.
Primary Pigmented Carcinoma of the Breast Breast cancer that also involves the overlying skin is uncommon. Carcinoma of the breast may infiltrate the dermis and extend from there directly into the epidermis. Pigmented carcinoma of the breast is rare, and only a few reports of primary cases have appeared in the literature.73–75 The malignant cells may acquire melanin pigment, usually but not always in a small amount, and it is difficult to differentiate this lesion from melanoma. The patient described by Saitoh et al76 was a rare case of pigmented, primary carcinoma of the breast occurring in a man. The authors stated that it was difficult to diagnose whether or not this case was a malignant melanoma, and ductal breast carcinoma was determined by histologic and immunohistochemical studies.
Extramammary Paget’s Disease Extramammary Paget’s disease is a rare, intraepithelial malignancy. It is characterized by the presence of varying numbers of Paget’s cells within the epidermis. Extramammary Paget’s disease is frequently associated with an underlying glandular adnexal carcinoma or a regional internal carcinoma with or without metastasis. The most common site of involvement is the vulva, followed by the perianal area, penis, scrotum, and groin.77 The correct diagnosis is often delayed because of its benign clinical appearance, one that often mimics dermatitis. Clinically, it appears as a scaling, erythematous, eczematous patch or plaque. Secondary crusting and superficial erosions can occur. Pruritus is common, and sometimes pain may be present as well. Bleeding is a late sign. When it appears in the anal, perianal, and perineal areas, extramammary Paget’s disease needs to be differentiated from other premalignancies and malignancies, including anorectal melanoma.
Merkel Cell Carcinoma Merkel cell carcinoma is a rare, cutaneous malignancy that arises from neuroendocrine cells that show features of epithelial differentiation. The precise origin of Merkel cell carcinoma remains controversial; the tumor may derive from epidermal Merkel’s cells, dermal neuroendocrine cells, or poorly differentiated epidermal stem cells.78,79 It is rare and typically affects persons ⬎65 years of age, but it has been noted in children and young adults. Clinically, the tumor appears as a solitary, dome-shaped nodule or indurate plaque. Its color is red to violaceous, and ulcerations may occur as the tumor increases in size. Most of the tumors are ⬍2 cm in size but can achieve a size as large as 10 cm. The
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primary sites of involvement are the head and neck, especially periorbital,80 and less frequently the leg, arm, and buttock. The differential diagnosis includes amelanotic melanoma. Merkel cell carcinoma is considered an aggressive tumor with a significant incidence of local recurrence as well as a high incidence of regional and systemic metastatic disease.81 The prognosis is worse than that of malignant melanoma.
notic macules, tending to remain static in size and color. A biopsy is indicated to establish the diagnosis in atypical lesions or in any changing features of the macules, if irregularity of color or shape is evident at the initial presentation, or if there are symptoms of itching, discomfort, or bleeding.
Leiomyosarcoma
Trauma can result in hemorrhage beneath the nail plate, which typically becomes blue-black. It is the sudden occurrence, history of antecedent trauma, and lack of Hutchinson’s sign that differentiates it from an acral lentiginous melanoma. Furthermore, the dried blood can be easily scraped from the nail bed after its removal.
Leiomyosarcoma is a malignant tumor of the smooth muscle. Classification and prognosis of leiomyosarcoma depend on the site of origin and the anatomic location. Superficial leiomyosarcoma can be divided into two groups: cutaneous, arising in the dermis, and subcutaneous, arising in the subcutis. It is important to distinguish between them because of the differing prognosis and treatment.82– 85 The superficial type is most prevalent in the 40- to 60-year-old age group, with men being affected slightly more than women. The extremities are the most frequent sites of involvement, especially the hair-bearing, extensor surfaces. Superficial leiomyosarcoma typically present as a solitary tumor with associated pain or tenderness, although some patients have multiple lesions. The tumors are relatively small (⬍2 cm). Subcutaneous leiomyosarcoma can grow fast and achieve large sizes. They are usually round to oval, and the overlying epidermis usually is normal in appearance. The cause of leiomyosarcoma is unknown. Leiomyosarcomas that originate in the dermis probably come from the arrector pili; those that develop in the subcutis are probably vascular in origin. Leiomyosarcomas must be distinguished from other malignant spindle-cell tumors of the skin, such as spindle-cell melanoma.
Subungual Traumatic Hematoma
Melanonychia Striata Longitudinal brown-to-black banding of the nails occurs frequently in blacks and Orientals. Subungual melanoma may be suspected, but there are several guidelines that point to a benign process: multiple lesions without change for many years, well-defined bands of regular width, homogenous tan-to-brown color, and absence of pigment in the surrounding skin.
Subungual Bone Spur Subungual, pigmented lesions may be difficult to diagnose. Velanovich90 described a case of a bone spur causing a subungual lesion mimicking melanoma. Woo and Rasmussen91 reported a subungual exostosis arising from underneath the nail plate, having originated from the underlying bone. The characteristic appearance of this disorder may occasionally mimic a wide variety of tumors, including amelanotic melanoma.91
Genital Melanotic Macules
Subungual Epidermoid Carcinoma
Genital pigmentation may occur in isolation or as part of a syndrome. Individual lesions tend to remain static in size and color. They are benign, asymptomatic, discrete areas of hyperpigmentation, tan-to-dark brown/ black, and 0.5–2 cm. Their occurrence, usually as newly pigmented lesions appearing among adults, can cause concern because of their ability to mimic early melanoma. They occur equally in both sexes. Histologic findings have shown increased basal pigmentation without atypical features.86 – 87
Subungual Bowen’s disease and squamous cell carcinoma can clinically mimic benign conditions as well as malignant melanoma. Subungual epidermoid carcinoma should be regarded as a low-grade malignancy that can be managed by conservative surgical ablation. Histologic examination is the key for accurate diagnosis.92 A case of a woman who presented with a history of a slow-growing tumor on the distal portion of the third finger of her left hand clinically suggested an inflammatory process or an epidermoid cyst ,which was shown to be an acral lentiginous melanoma under microscopic examination.93
Labial Melanotic Macules This condition occurs in up to 3% of the population.88 The macules are isolated, pigmented lesions most commonly found on the lower lips of young women.89 Clinical features as well as histologic, immunohistochemical, and ultrastructural features all confirm their benign nature. They behave similarly to genital mela-
Tinea Nigra Tinea nigra is an asymptomatic, superficial, fungal infection generally affecting the skin of the palms. It is characterized by deeply pigmented, macular, nonscaly patches. It may mimic serious pigmentary lesions, such
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as acral lentiginous melanoma.94 A KOH examination is a simple and rapid means of verifying this entity.
Pseudomelanoma A recurrence of an incompletely removed melanocytic nevus can be particularly difficult to distinguish from melanoma.95 It typically presents as repigmentation within a few weeks after its incomplete removal. This phenomenon was originally termed “pseudomelanoma” because the recurrent lesion may have atypical histologic features that make it difficult to differentiate from malignant melanoma.96 A review of the histologic features of the original lesion is sometimes critical for making the differentiation.95 It was reported to appear after dermabrasion,97 partial surgical removal,95,98 shave excision followed by electrodesiccation,95,98 laser therapy,99 solcoderm therapy,96 and other procedures.
Amelanotic Melanoma Amelanotic melanoma may be confused with a variety of conditions, both benign and malignant.100 The benign lesions include intradermal nevus,101 seborrheic keratosis,101 verruca vulgaris,101,102 dermatitis,103–105 pyogenic granuloma,106,107 nevus depigmentosus,108 granuloma annulare,108 scar,108 actinic keratosis,101 and lymphocytoma cutis.109 The malignant lesions include BCC,101 keratoacanthoma,108 Bowen’s disease,110 Merkel cell carcinoma,111 and atypical fibroxanthoma.109 The prognosis of primary cutaneous amelanotic melanoma is no different from its pigmented counterpart. These tumors are often more advanced at the time of diagnosis, presumably because of a delay in diagnosis.
References 1. Ackerman AB. No one should die of malignant melanoma. J Am Acad Dermatol 1985;12:115– 6. 2. Brochez L, Verhaeghe E, Bleyen L, et al. Diagnostic ability of general practitioners and dermatologists in discriminating pigmented skin lesions. J Am Acad Dermatol 2001;44:979 – 86. 3. Rampen FHJ, Rumke P. Referral pattern and accuracy of clinical diagnosis of cutaneous melanoma. Acta Derm Venereol 1988;8:61– 4. 4. Cassileth BR, Clark WH, Lusk EJ, et al. How well do physicians recognize melanoma and other problem lesions? J Am Acad Dermatol 1986;14:555– 60. 5. Cassileth BR, Temoshok L, Frederick BE, et al. Patient and physician delay in melanoma diagnosis. J Am Acad Dermatol 1988;18:591– 8. 6. Wagner RF, Wagner D, Tomich JM, et al. Diagnoses of skin disease: dermatologists vs nondermatologists. J Dermatol Surg Oncol 1985;11:476 –9. 7. Ragi G, Turner MS, Klein LE, Stoll HL. Pigmented Bowen’s disease and review of 420 Bowen’s disease lesions. J Dermatol Surg Oncol 1988;14:765–9. 8. Papageorgiou PP, Koumarianou AA, Chu AC. Pigmented Bowen’s disease. Br J Dermatol 1998;138:515– 8.
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9. Wagner RF, Grande DJ. Solitary pigmented Bowen’s disease of the scrotum. J Dermatol Surg Oncol 1986;12: 1114 –5. 10. Marschall SF, Ronan SG, Massa MC. Pigmented Bowen’s disease arising from pigmented seborrheic keratoses. J Am Acad Dermatol 1990;23:440 – 4. 11. Mora RG, Pernicario C, Lee B. Cancer of the skin in blacks, III: a review of nineteen black patients with Bowen’s disease. J Am Acad Dermatol 1984;11:557– 62. 12. Scarborough DA, Bisaccia EP, Yoder FW. Solitary pigmented Bowen’s disease. Arch Dermatol 1995;34:116 – 8. 13. Amagai N, Feldman D, Lobel S, et al. Irregularly pigmented hyperkeratotic plaque on the thumb. Arch Dermatol 1995;129:1045– 8. 14. Kamiya M, Maehara R, Iizuka S, et al. Pigmented squamous cell carcinoma with dendritic melanocyte colonization in the external auditory canal. Pathol Int 1999;49: 909 –12. 15. Krishnan R, Lewis A, Orengo Ida F, et al. Pigmented Bowen’s disease(squamous cell carcinoma in situ): a mimic of malignant melanoma. Dermatol Surg 2001;27: 673– 4. 16. Vitasa BC, Taylor HR, Strickland PT, et al. Association of nonmelanoma skin cancer and actinic keratosis with cumulative solar ultraviolet exposure in Maryland watermen. Cancer 1990;65:2811–7. 17. Gallagher RP, Hill GB, Bajdik CD, et al. Sunlight exposure, pigmentary factors, and risk of nonmelanocytic skin cancer: basal cell carcinoma. Arch Dermatol 1995; 131:157– 63. 18. Franceschi S, Levi F, Randimbison L, et al. Site distribution of different types of skin cancer: new etiological clues. Int J Cancer 1996;67:24 – 8. 19. Wang CY, Brodland DG, Su WP. Skin cancers associated with acquired immunodeficiency syndrome. Mayo Clin Proc 1995;70:766 –72. 20. Hartevelt MM, Bavinck JN, Kootte AM, et al. Incidence of skin cancer after renal transplantation in the Netherlands. Transplantation 1990;49:506 –9. 21. Ridley CM, et al. Basal cell carcinoma following X-ray epilation of the scalp. Br J Dermatol 1962;74:222. 22. Field LM. Clinical misdiagnosis of melanoma as well as squamous cell carcinoma masquerading as seborrheic keratosis. J Dermatol Surg 1994;20:222. 23. Blauvelt A. The role of human herpesvirus 8 in the pathogenesis of Kaposi’s sarcoma. Adv Dermatol 1999; 14:167–206. 24. Wong TY, Duncan LM, Mihm MC. Melanoma mimicking dermal and Spitz’s nevus (“nevoid” melanoma). Semin Surg Oncol 1993;9:188 –93. 25. Osburn K, Schosser RH, Everett MA. Congenital pigmented and vascular lesions in newborn infants. J Am Acad Dermatol 1987;16:788 –92. 26. Rhodes AR, Wood WC, Sober AJ, et al. Non-epidermal origin of malignant melanoma associated with giant congenital cellular naevus. Plast Reconstr Surg 1981;67:782– 4. 27. Kopf AW, Bart RS, Hennessey P, et al. Congenital nevocytic nevi and malignant melanoma. J Am Acad Dermatol 1979;1:123–30.
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28. Stewart DM, Altman J, Mehregan AH. Speckled lentiginous naevus. Arch Dermatol 1978;114:895– 6. 29. Dorsey CS, Montgomery H. Blue nevus and its distinction from Mongolian spot and the nevus of ota. J Invest Dermatol 1954;22:225–36. 30. Leopold JG, Richard DB. Cellular blue nevi. J Pathol Bacteriol 1967;94:247–55. 31. Rodrigues HA, Ackerman LV. Cellular blue nevus: a clinicopathologic study of forty five cases. Cancer 1968; 21:393– 405. 32. Tran TA, Carlson JA, Basaca PC, et al. Cellular blue nevus with atypia (atypical cellular blue nevus): a clinicopathologic study of nine cases. J Cutan Pathol 1998;25: 252– 8. 33. Michal M, Kerekes Z, Kinkor Z, et al. Desmoplastic cellular blue nevi. Am J Dermatopathol 1995;17:230 –5. 34. Kamino H, Tam ST. Compound blue nevus: a variant of blue nevus with an additional junctional dendritic component: a clinical, histopathologic, and immunohistochemical study of six cases. Arch Dermatol 1990;126: 1330 –3. 35. Hendricks WM. Eruptive blue nevi. J Am Acad Dermatol 1981;4:50 –3. 36. Radentz WA, Vogel P. Congenital common blue nevus. Arch Dermatol 1990;126:124 –5. 37. Bondi EE, Elder D, Guerry D IV, et al. Target blue nevus. Arch Dermatol 1983;119:919 –20. 38. Heymann WR, Yablonsky TM. Congenital appearance of plaque-type blue nevi (Letter). Arch Dermatol 1991;127: 587. 39. Pittman JL, Fisher BK. Plaque-type blue nevus. Arch Dermatol 1976;112:1127– 8. 40. Tsoitis G, Kanitakis C, Kapetis E. Nevus bleu multinodulaire en plaque, superficial et neuroide. Ann Dermatol 1983;110:231–5. 41. Busam KJ, Woodruff JM, Erlandson RA, et al. Large plaque-type blue nevus with subcutaneous cellular nodules. Am J Surg Pathol 2000;24:92–9. 42. Merkow LP, Burt RC, Hayeslip DW, et al. A cellular and malignant blue nevus :a light and electron-microscopic study. Cancer 1969;24:888 –96. 43. Busam KJ. Metastatic melanoma to the skin simulating blue nevus. Am J Surg Pathol 1999;23:276 – 82. 44. Fabrizi G, Massi G. Polypoid Spitz nevus: the benign counterpart of polypoid malignant melanoma. Br J Dermatol 2000;142:128 –32. 45. Kelly JW, Crutcher WA, Sagebiel RW. Clinical diagnosis of dysplastic melanocytic nevi. J Am Acad Dermatol 1986;14:1044 –52. 46. Epstein WL, Sagebeil R, Spitler L, et al. Halo nevi and melanoma. JAMA 1973;225:373–7. 47. Copeman PWM, Lewis MG, Phillips TM, et al. Immunological associations of the halo nevus with cutaneous malignant melanoma. Br J Dermatol 1973;88:127–37. 48. Bolognia JL. Reticulated black solar lentigo (ink spot lentigo). Arch Dermatol 1992;128:934 – 40. 49. Patrice SJ, Wiss K, Mulliken JB. Pyogenic granuloma (lobular capillary hemangioma): a clinicopathologic study of 178 cases. Pediatr Dermatol 1991;8:267–76. 50. Perez IR, Fenske NA, Brozena SJ. Malignant melanoma:
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differential diagnosis of the pigmented lesion. Semin Surg Oncol 1993;9:168 –73. Taylor HB, Helwig ED. Dermatofibrosarcoma protuberans: a study of 115 cases. Cancer 1962;15:717. Mark RJ, Bailet JW, Tran LM, et al. Dermatofibrosarcoma protuberans of the head and neck: a report of 16 cases. Arch Otolaryngol Head Neck Surg 1993;119:891– 6. Bertoni F, Capanna R, Biagini R, et al. Malignant fibrous histiocytoma of soft tissue: an analysis of 78 cases located and deeply seated in the extremities. Cancer 1985;56: 356 – 67. Gloster HM. Dermatofibrosarcoma protuberans. J Am Acad Dermatol 1996;35:355–74. Ding JA, Hashimoto H, Sugimoto T, et al. Bednar tumor (pigmented dermatofibrosarcoma protuberans): an analysis of six cases. Acta Pathol Jpn 1990;40:744 –54. Mousawi A, Kibbi AG, et al. Pigmented eccrine poroma: a simulant of nodular melanoma. Int J Dermatol 1995;34: 857– 8. Hara K, Kamiya S. Pigmented eccrine porocarcinoma. Histopathology 1995;27:86 – 8. Chan KO, Lim IJ, Baladas HG, et al. Multiple tumor presentation of trichilemmal carcinoma. Br J Plast Surg 1999;52:665–7. Boscaino A, Terracciano LM, Donofrio V, et al. Tricholemmal carcinoma: a study of seven cases. J Cutan Pathol 1992;19:94 –9. Reis JP, Tellechea O, Cunha MF, et al. Trichilemmal carcinoma: a review of 8 cases. J Cutan Pathol 1993;20: 44 –9. Swanson PE, Marrogi AJ, William DJ, et al. Tricholemmal carcinoma: clinicopathologic study of 10 cases. J Cutan Pathol 1992;19:100 –9. Helwig EB, May D. Atypical fibroxanthoma of the skin with metastases. Cancer 1986;57:368 –76. Jacobs DS, Edwards WD, Ye RC. Metastatic atypical fibroxanthoma of the skin. Cancer 1975;35:457– 63. Fretzin DF, Helwig EB. Atypical fibrous xanthoma: a clinicopathologic study of 140 cases. Cancer 1973;31:1541–52. Loo DS, De Pietro WP, Moisa II, et al. Atypical fibroxanthoma of the cheek: a case report. Cutis 1993;51:47– 8. Kearney MD, Soule EH, Ivins JC. Malignant fibrous histiocytoma: a retrospective study of 167 cases. Cancer 1980;45:167–78. Headington JT, Niederrhuber JE, Repola DA. Primary malignant fibrous histiocytoma of the skin. J Cutan Pathol 1978;5:329 –38. Weiss SW, Enzinger FM. Malignant fibrous histiocytoma-an analysis of 200 cases. Cancer 1978;41:2250 – 66. Maddox JC, Evans HL. Angiosarcoma of the skin and soft tissue: a study of forty-four cases. Cancer 1981;48: 1907–21. Holden CA, Spittle MF, Jones EW. Angiosarcoma of the face and scalp: prognosis and treatment. Cancer 1987;59: 1046 –57. Panje WR, Moran WJ, Bostwick DG. Angiosarcoma of the head and neck: review of 11 cases. Laryngoscope 1986;96:1381– 4. Barttelbort SW, Stahl R, Ariyan S. Cutaneous angiosarcoma of the face and scalp. Plast Reconstr Surg 1989;84: 55–9.
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73. Romanelli R, Tonicini C. Pigmented papillary carcinoma of the male breast. Tumori 1986;72:105– 8. 74. Fernandes-Figueras MT, Puig L, Casanova JM, et al. Pigmented epidermotropic ductal carcinoma of the breast in a male. J Cutan Pathol 1995;22:276 – 80. 75. Sau P, Solis J, Luptun GP, et al. Pigmented breast carcinoma. Arch Dermatol 1989;125:536 –9. 76. Saitoh K, Saga K, Okazaki M, et al. Pigmented primary carcinoma of the breast: a clinical mimic of malignant melanoma. Br J Dermatol 1998;139:287–90. 77. Heymann WR. Extramammary Paget’s disease. Clin Dermatol 1993;11:83–7. 78. Haag ML, Glass LF, Fenske NA. Merkel cell carcinoma: diagnosis and treatment. Dermatol Surg 1995;21:669 – 83. 79. Ratner D, Nelson BR, Brown MD, et al. Merkel cell carcinoma. J Am Acad Dermatol 1993;29:143–56. 80. Goepfert H, Remmler D, Silvan E, et al. Merkel cell carcinoma of the head and neck. Arch Otolaryngol 1984; 110:707–12. 81. Cotlar AM, Gates JV, Gibbs FA. Merkel cell carcinoma: combined surgery and radiation therapy. Am J Surg 1986;52:159 – 64. 82. Dahl I, Angerval L. Cutaneous and subcutaneous leiomyosarcoma-a clinicopathologic study of 47 patients. Pathol Eur 1974;9:307–15. 83. Fields IP, Helwig EB. Leiomyosarcoma of the skin and subcutaneous tissue. Cancer 1981;47:156 – 69. 84. Phelan JT, Shen W, Mesa P. Malignant smooth muscle tumors of soft tissue origin. N Engl J Med 1962;266:1027. 85. Stout AP, Hill WT. Leiomyosarcoma of the superficial soft tissue. Cancer 1964;11:844. 86. Lenane P, Keane CO, Connell BO, et al. Genital melanotic macules: clinical, histologic, immunohistochemical, and ultrastructural features. J Am Acad Dermatol 2000; 42:640 – 4. 87. Jackson R. Melanosis of the vulva. J Dermatol Surg Oncol 1984;10:119 –21. 88. Ficarra G, Shillitoe EJ, Adler-Storthz K, et al. Oral melanotic macules in patients infected with human immunodeficiency virus. Oral Surg Oral Med Oral Pathol 1990; 70:748 –55. 89. Ho KL, Dervan P, O’Loughlin S, et al. Labial melanotic macule: a clinical, histological and ultrastructural study. J Am Acad Dermatol 1993;28:33–9. 90. Velanovich V. Subungual pigmented lesion caused by a bone spur: a mimic of a subungual melanoma. Mil Med 1994;159:663. 91. Woo TY, Rasmussen JE. Subungual osteocartilaginous exostosis. J Dermatol Surg Oncol 1985;11:534 – 6. 92. Mikhail GR. Subungual epidermoid carcinoma J Am Acad Dermatol. 1984;11:291– 8. 93. Linares MD, Hardisson D, Perna C. Subungual malignant melanoma of the hand: unusual clinical presenta-
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tion: case report. Scand J Plast Reconstr Hand Surg 1998; 32:347–50. Babel DE, Pelachyk JM, Hurley JP. Tinea nigra masquerading as acral lentiginous melanoma. J Dermatol Surg Oncol 1986;12:502– 4. Kornberg R, Ackerman AB. Pseudomelanoma: recurrent melanocytic nevus following partial surgical removal. Arch Dermatol 1975;111:1588 –90. Goldenhersh MA, Scheflan M, Zeligovsky A. Recurrent melanocytic nevi after solcoderm therapy: a new cause of pseudomelanoma. J Am Acad Dermatol 1992;27:1012–3. Dwyer CM, Kerr RE, Knight SL, et al. Pseudomelanoma after dermabrasion. J Am Acad Dermatol 1993;28:263– 4. Park HK, Leonard DD, Arrington JH, et al. Recurrent melanocytic nevi: clinical and histologic review of 175 cases. J Am Acad Dermatol 1987;17:285–92. Trau H, Orenstein A, Schewach-Millet M, et al. Pseudomelanoma following laser therapy for congenital nevus. J Dermatol Surg Oncol 1986;12:984 – 6. Koch SE, Lange JR. Amelanotic melanoma: the great masquerader. J Am Acad Dermatol 2000;42:731– 4. Anderson WK, Silvers DN. Melanoma? it can’t be melanoma! a subset of melanomas that defies clinical recognition. JAMA 1991;266:3463–5. McBurney EL, Herron CB. Melanoma mimicking plantar wart. J Am Acad Dermatol 1979;1:144 – 6. Tschen JA, Fordice DB, Reddick M, et al. Amelanotic melanoma presenting as inflammatory plaques. J Am Acad Dermatol 1992;27:464 –5. Daniel WP, Bradley RR. Amelanotic lentigo maligna. Arch Dermatol 1980;116:82–3. Borkovic SP, Schwartz RA. Amelanotic lentigo maligna manifesting as a dermatitis-like plaque. Arch Dermatol 1983;119:423–5. Barnhill RL, Fitzpatrick TB, Fandrey K, Kenet RO. Nodular melanoma. In: Barnhill RL, Fitzpatrick TB, Fandrey K, et al, editors. Color atlas of pigmented lesions. New York: McGraw-Hill;1995:177– 82. Elmets CA, Ceilly RL. Amelanotic melanoma presenting as a pyogenic granuloma. Cutis 1980;25:164 –70. Rahbari H, Nabai H, Mehregan AH, et al. Amelanotic lentigo maligna melanoma: a diagnostic conundrumpresentation of four new cases. Cancer 1996;77:2052–7. Whitaker DC, Argenzi Z, Smith AC. Desmoplastic malignant melanoma: rare and difficult to diagnose. J Am Acad Dermatol 1992;26:704 –9. Holder JE, Colloby PS, Fletcher A, et al. Amelanotic superficial spreading malignant melanoma mimicking Bowen’s disease. Br J Dermatol 1966;134:519 –21. House NS, Fedok F, Maloney ME, et al. Malignant melanoma with clinical and histologic features of Merkel cell carcinoma. J Am Acad Dermatol 1994;31:839 – 42.
T
he incidence of malignant melanoma has risen dramatically in recent years despite increased awareness and enhanced behavior patterns. At present, surgery for early melanoma is curative in most patients, but therapy for advanced melanoma is less successful, so the only hope for preventing death from melanoma remains early detection.
stage melanomas, ie, 34% among the GPs and 13% among the dermatologists. A higher diagnostic accuracy of skin lesions on the part of dermatologists compared with several medical specialty groups has been reported by other studies.3– 6 The differential diagnosis of malignant melanoma includes a wide variety of benign and malignant lesions that will be presented and discussed in the present article.
No One Should Die of Malignant Melanoma A prominent dermatologist suggested that “no one should die of melanoma,”1 since this neoplasm arises on a readily accessible site; specifically, it is skin-deep and can be recognized in its early stages when simple excision is usually curative. In the same breath, “What is the hardest of all? That which you hold the most simple; seeing with your own eyes what is spread out before you” (Goethe, quoted by J. P. Eckermann, in Conversations with Goethe, May 18, 1824). This is true for all skin lesions but all the more so for malignant melanoma, and the bottom line is that diagnosing melanoma in its early stages is easier said than done. The diagnosis of melanoma has always been a real challenge for dermatologists and it will probably remain so in the third millennium as well. The ability of general practitioners (GPs) and dermatologists to diagnose pigmented skin lesions in general and melanoma in particular was evaluated in one Belgian study before and after a lecture on melanoma.2 It emerged that the recognition of melanoma was proportional to melanoma exposure in everyday practice and that thick melanomas were better recognized than thin ones by both groups of physicians. After the lecture on melanoma, the sensitivity of the GPs to recognize the lesion increased from 49% o 76%, but the diagnostic ability of dermatologists was superior to theirs both for discriminating between malignant and benign disease and for correctly identifying various lesions. The number of missed melanomas was highest for the earlyFrom the Dermatology Unit, Kaplan Medical Center, Rehovot, Israel, and the Department of Dermatology, Second University of Naples, School of Medicine and Surgery, Naples, Italy. Address correspondence to Hagit Matz, MD, Dermatology Unit, Kaplan Medical Center, Rehovot 76100, Israel. E-mail address: [email protected] © 2002 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
Bowen’s Disease (Squamous Cell Carcinoma In Situ) Bowen’s disease is an intraepidermal squamous cell carcinoma. It affects mostly older white men in whom the lesions occur primarily on sun-exposed surfaces. The lesion may be found on any part of the body as an erythematous, slightly scaly and crusted, noninfiltrated patch from a few millimeters to many centimeters in diameter. The lesion is sharply defined. Bowen’s disease may be heavily pigmented, and such cases may resemble melanoma.
Pigmented Bowen’s Disease Pigmented Bowen’s disease is an unusual form of squamous cell carcinoma in situ that is characterized by a hyperpigmented appearance. This type represents ⬍2% of all cases of Bowen’s disease.7 It commonly presents as a hyperpigmented, sharply marginated plaque with a surface that may be velvety, verrucose, or flat.7–14 Scaling and erosions may be present as well. The lesions are generally asymptomatic, but they may cause pruritus or a burning pain.8 Pigmented Bowen’s disease almost exclusively affects intertriginous areas.10 Bowen’s disease is much more common in whites than in blacks,11 it ordinarily develops on sun-exposed areas, and it is rarely pigmented.8 Paradoxically, sun-protected areas are more frequently affected, and the pigmented variant is not uncommon in the relatively few cases of black patients with Bowen’s disease.11,15 The differential diagnosis of pigmented Bowen’s disease includes superficial spreading melanoma. This variation can be differentiated on the basis of clinical features and histopathology. 0738-081X/02/$–see front matter PII S0738-081X(02)00232-8
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Basal Cell Carcinoma Basal cell carcinoma (BCC) is a malignant tumor of the skin that is believed to arise from a hair follicle. Its cells show a morphologic resemblance to the relatively undifferentiated cells of the basal layers of the epidermis, and although it is a form of cancer, it is invasive only locally and rarely metastasizes. BCC is the most common cancer among whites. Its incidence rises with age, and exposure to ultraviolet light is a principal risk factor. BCC most commonly develops on the head and neck, with ⬃20% of BCC occurring in non–sun-exposed areas.16 –18 Phenotypic characteristics associated with an increased risk of BCC include light skin color, inability to tan, blond or red hair, and freckling in childhood. Genetic ancestry and a family history of skin cancer also confer increased risk. AIDS patients and patients receiving immunosuppressive drugs after organ transplantation are also at increased risk for BCC,19,20 as are individuals exposed to arsenic. Moreover, therapeutic radiation formerly used in psoriasis, eczema, and tinea capitis predisposes to the development of BCC many decades later.21 The clinical variants of BCC include the nodular type, the pigmented variant, superficial BCC, morpheaform or sclerosing BCC, nevoid BCC syndrome, and fibroepithelioma of Pinkus. The nodular type, which comprises ⬎50% of all cases of BCC, is composed of a single or a few small waxy, semitranslucent nodules that form around a central depression that may or may not be ulcerated, crusted, and bleeding. The edge of larger lesions has a characteristic rolled border. Telangiectases course through the lesion. The pigmented variant of BCC, which is not uncommon, is especially prevalent among dark-skinned persons. This variety has all the features of the nodular type in addition to variations of brown, blue, and black pigmentation. This lesion can also be large and ulcerated and can pose a diagnostic dilemma in differentiating it from nodular or superficial spreading malignant melanoma.
Darkly Pigmented Seborrheic Keratosis Seborrheic keratoses are benign skin tumors. They are exceedingly common, and most people will develop at least one such tumor in their lifetime; many develop hundreds of them. The etiology of seborrheic keratoses is not known. They are most commonly found in the over-30-year age group. These lesions can appear on any part of the body except the mucous membranes. Seborrheic keratoses typically begin as flat, sharply demarcated, brown macules and become polypoidal with an uneven surface as they progress. Their surface is usually “warty,” with multiple plugged follicles, and is usually dull or drab in color. They can become quite large, but rarely exceed 3 cm in diameter. The color of
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these lesions can vary from a pale brown with pink tones to dark brown or black. Seborrheic keratoses can resemble malignant melanoma, especially when they become inflamed or traumatized and secondary changes develop as a consequence.22 Patients with a great number of lesions sometimes have a positive family history that may reflect a genetic propensity. Since melanocytic hyperplasia is commonly seen in seborrheic keratoses, it was suggested that melanocytes or melanocyte-derived growth factors may have a role in the development of seborrheic keratoses. There are several histologic and clinically distinct forms of seborrheic keratoses. A variant that is more likely to be confused with malignant melanoma is the “melanoacanthoma.” Although it is synonymous with pigmented seborrheic keratosis, it is actually more than a darkly pigmented seborrheic keratosis: the lesion is markedly proliferated by dendritic melanocytes, which are engorged with melanin, whereas the surrounding keratinocytes contain hardly any melanin. This lesion has no malignant potential. The verrucous surface and stuck-on appearance of the melanoacanthoma facilitates its differentiation from melanoma.
Kaposi’s Sarcoma Kaposi described this vascular neoplasm in 1872 and called it “multiple benign pigmented idiopathic hemorrhagic sarcoma.” Since that first publication, five clinical types of this disease have been described, each with a different presentation, epidemiology, and prognosis. The discovery of a new human herpes virus (HHV-8) and the subsequent identification of a humoral immune response against this putative infectious agent in patients with Kaposi’s sarcoma (KS) and in individuals at risk for the development of KS have shed new light on the infectious etiology of the disease.23 Five subtypes were described: classic KS, African cutaneous KS, African lymphadenopathic KS, KS in iatrogenically immunocompromised patients, and HIVassociated KS. The morphology of the lesion in these different subtypes is the same. The early lesion appears most often as reddish, violaceous, or bluish-black macules and patches that spread and coalesce to form nodules or plaques. These have a rubbery consistency and look like purplish angiomas, which they are. There may be edema of the affected parts, and swelling due to lymphedema often later develops. The lesions may ulcerate and bleed with even minimal trauma. HIVassociated KS displays a variety of distinct clinical features that may differ considerably from those seen in other forms of the disease. In a prolonged course, KS lesions may be disseminated, and the multiplicity of lesions will differentiate it from melanoma, which is usually an isolated lesion, unless metastasis occurs.
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Melanocytic Nevus Acquired melanocytic nevi are the most common of pigmented lesions. They are classified on a clinicopathologic basis into junctional, compound, and intradermal nevi. Junctional nevi are ordinarily seen in children and young adults. They present as a flat or slightly raised, pigmented area varying in size from 1 mm to 1 cm. Their color ranges from light brown to dark brownishblack, and the center may be darker than the edge. Their shape is usually symmetrically rounded or elliptical, and their surface is smooth and flat with preserved skin furrows. The term “junctional” refers to the presence of melanocytic nests at the dermal-epidermal junction. As the nevi mature, the nevus cells drop down into the dermis, forming compound nevi with nevus cell nests at the dermal-epidermal junction and within the dermis. Compound nevi are palpable due to the presence of nests in the upper dermis. They vary from a slightly raised plaque to a papillomatous or mamillated tumor. Compound nevi are well circumscribed, hyperpigmented lesions with well-defined borders. As the nevi continue to mature, there is a development of intradermal nevi that have nests only within the dermis. These lesions are soft, dome-shaped papules that are fleshcolored due to loss of pigmentation. A clinically normal nevus is unlikely to be confused with malignant melanoma, with inflammation due to trauma, or with a ruptured follicular unit contained within the lesion that may cause a change in size, color, and symptoms such as pruritus. Melanocytic nevi normally darken and enlarge during infancy, puberty, and pregnancy. Any nevus in an adult that increases in size or undergoes any kind of change should be examined carefully. Examples of malignant melanoma that present with clinical and histopathologic characteristics resembling benign dermal nevus have been described by Wong et al.24
Congenital Melanocytic Nevi One percent of all newborns have a pathologically confirmed congenital melanocytic nevus,25 although clinical studies have suggested that twice as many infants have pigmented lesions clinically compatible with this diagnosis.26 These lesions are classified according to the size of their largest diameter: ⬍1.5 cm for small ones, 1.5–20 cm for intermediate-sized ones, and ⬎20 cm for giant ones. Congenital lesions are usually larger than the acquired variety but, in general, are still characterized by their even coloration, symmetry, and well-defined borders. Nongiant, congenital melanocytic nevi are more common than the giant variety, presenting as well-circumscribed, hyperpigmented plaques that frequently contain terminal hair. Giant congenital lesions can cover a large portion of the body, most commonly on the lower back and thigh area, and a considerable proportion of an infant’s skin may be involved. These
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lesions may have alterations in pigment, with small, dark macules and papules interspersed within a large, hyperpigmented, hairy plaque. They have a 12% incidence of developing into melanomas and require close monitoring.27
Nevus Spilus Also known as the speckled lentiginous nevus,28 this is a congenital lesion that presents after birth on the trunk and extremities. It may be several centimeters in diameter, and its clinical presentation is a combination of a flat, macular, lentiginous component, often a darker shade than the surrounding skin, with even darker central lentigolike lesions. There are also elevated darker brown areas. Although this is an entirely benign lesion, the appearance of darker areas within a pigmented lesion may cause confusion in differentiating it from melanoma.
Blue Nevus This is an area of blue or blue-black dermal pigmentation. Since the first description of Blue nevus (BN) by Tiech in 1906, several histologic types of BN have been described, including the common dermal BN,29 cellular BN,30,31 atypical cellular BN,32 desmoplastic cellular BN,33 combined BN, and compound BN.34 Unusual clinical variants have also been reported, such as eruptive BN,35 congenital common BN,36 target BN,37 and plaque-type BN.38 – 40 Identification of the vast majority of BNs is straightforward, both clinically and histologically, and they are rarely confused with malignant melanoma. There are unusual variants, however, in which their distinction from malignant melanoma can be difficult. Two cases of plaque-type BN, an unusual variant of BN, characterized by onset in childhood, large size, and development of subcutaneous nodules of cellular BN that were misdiagnosed initially as malignant melanoma were described by Busam et al.41 The common BN is a blue-black, dome-shaped, well-circumscribed papule generally ⬍0.5 cm in diameter. It is a slowly growing benign lesion that begins in childhood and is most frequently found on the dorsum of the hands and feet. The cellular BN has a similar clinical appearance but is usually larger, measuring 1–3 cm in diameter. Common locations include the buttocks and sacrococcygeal area. It may be present before birth, but eruption in later life is not uncommon.29 Progressive growth is rare, as is malignant transformation.42 A BN is characterized by its color. The long and unchanging course should set it apart from malignant melanoma, but this suspected diagnosis is frequently submitted with surgical pathology specimens. Dermal metastases from cutaneous melanoma simulating a BN have also been described. Busam43 reported 10 BN-like lesions in three patients. All of the lesions contained pigmented
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melanocytes and melanophages in variable proportions arranged in a BN-like growth pattern. The BN-like metastases appeared in the same anatomic region as the primary tumor in two patients and near the scar of a dissected lymph node metastasis in the third.
Spitz Nevus Also referred to as benign juvenile melanoma largely due to its histopathologic appearance, this benign lesion is a smooth-surfaced, raised, round, slightly scaly, firm papule with a distinctive pink, brownish-red, or purplish-red hue. Spitz nevi mostly occur during the first two decades of life, although they appear in adulthood in about one third of the cases. They occur primarily on the face and extremities and are ⬍1 cm in diameter. This lesion may be confused with an amelanotic melanoma: it should be completely excised and the specimen examined histologically. The patient’s young age is the most helpful diagnostic clue. The polypoid form of Spitz nevus has close morphologic similarities with polypoid malignant melanoma, but these tumors can be differentiated from each other with confidence if careful attention is given to the histologic details and to the distinctive host response. A description of polypoid Spitz nevus can be found in a case report published by Fabrizi and Massi.44
Dysplastic Nevus Dysplastic nevi may exhibit one or more characteristics suggestive of melanoma, such as being ⬍5 mm and having an irregular edge, irregular pigmentation, and some degree of inflammation.45 These lesions are usually seen on the trunk and extremities but can be found anywhere on the body. They may be numerous and are characteristically larger than acquired nevi. Dysplastic nevi can be observed in members of families with dysplastic nevus syndrome as well as in isolated cases. The dysplastic nevus has been a subject of controversy.
Halo Nevus This is also known as Sutton’s nevus. It is a melanocytic nevus surrounded by a depigmented halo of otherwisenormal skin. Halo nevi are relatively common, particularly in older children and young teenagers. The back is the commonest site, and several nevi may develop halos simultaneously. Over the next few months, the central nevus will gradually disappear, leaving a macular area of nonpigmented skin. This depigmented area may persist for years and only gradually return to a normal color. It is thought that the loss of pigment results from an immunologically mediated inflammatory response that is directed against either melanin, a melanoma within the lesion, or at a distant site.46,47 Halo nevi most commonly represent a benign process, but the differential diagnosis may include an early superficial spread-
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ing melanoma with surrounding depigmentation, especially in older patients. In these cases, the surrounding area of depigmentation is usually irregular, and the central pigmented area may also be irregular in both shape and pigmentation. It is important, especially in adults, to perform a thorough examination for a possible underlying malignant melanoma, particularly if vitiliginous patches are also present. When there is any clinical doubt, excision biopsy and pathologic confirmation must be obtained.
Lentigines Lentigo simplex is a macular or slightly raised area of brown or brownish-black pigmentation with well-demarcated, smooth borders and preservation of normal skin lines. Lentigines usually appear in childhood, but they may increase in number in adult life. They are usually ⬍1 cm in diameter. The majority of lentigines remain in an inactive state throughout life, but some may mature into junctional nevi. Solar lentigines tend to occur on either acutely or chronically sun-exposed skin and are characterized by a macular area that is uniformly dark brown and irregularly shaped and that can vary in size from very small to ⬎1 cm in diameter. The “ink spot,” or reticulated black solar lentigo, poses a more difficult diagnostic dilemma.48 Such lesions are few in number and are distributed over sun-exposed areas of the body in fair-skinned individuals. They are characterized by a black macule with a markedly irregular, wiry, or beaded outline and multiple skip areas within the lesion itself. These lesions are benign, and although the clinical features of the ink spot lentigo indicate the diagnosis, any suspicion of a malignant process may require biopsy.
Pyogenic Granuloma Pyogenic granuloma is a rapidly developing vascular lesion that often develops at sites of minor trauma. The lesions are solitary, small (average size of 6.5 mm), eroded papules or nodules that bleed spontaneously or after the trauma. Common locations include the face, fingers, toes, and trunk. Pyogenic granuloma is rarely noted before 6 months of age, and the mean age at presentation is 6.7 years.49 The lesions can appear within an existing cutaneous hemangioma (port wine stain), but there is most commonly no history of a pre-existing dermatologic condition. This lesion in particular may simulate nodular amelanotic melanoma.
Senile Angioma The cherry angioma is the most ubiquitous vascular anomaly whose number increases with age. They are oval or circular, slightly elevated, 0.5– 6 mm in diameter, ruby red papules mostly found on the trunk and
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rarely seen on the hands or feet. They may mimic petechiae.
Venous Lake This bluish-purple soft swelling, 2–10 mm in diameter, is usually seen on actinically damaged skin of the lower lip of an elderly person due to a venous dilation. A venous lake may be only a trivial cosmetic problem, or it can bleed severely after trauma. Prolonged pressure with a diascope will demonstrate emptying followed by refilling with the release of pressure, thus establishing the diagnosis.50
Hemangioma Hemangioma is the most common benign tumor of childhood and may be present at birth in one third of cases, with the remaining two thirds appearing very shortly thereafter, ie, when the child is from 2 weeks to 2 months of age. It is characteristically 1– 60 mm in diameter, although as much as an entire extremity may be involved (rare). The dome-shaped lesion is usually dull red with sharp borders and a soft and easily compressed texture. Hemangiomas tend to grow over the first year or so, remain stable for a while, and then involute spontaneously in the course of months or years. Due to their vascularity, they may exhibit a blueblack coloration resembling melanoma pigment, especially when traumatized or thrombosed.50
Dermatofibroma This is a benign, nodular, dermal proliferation of unknown etiology. The lesion typically presents as a single, firm, dome-shaped, red-brown papule or nodule and is most commonly found on the limbs. The size varies from 4 mm to 1.5 cm. When the overlying epidermis is squeezed, the “dimple sign ” will appear, indicating the tethering of the overlying epidermis to the underlying lesion. The sclerosing hemangioma variant of dermatofibroma can present a diagnostic problem due to its coloration. This lesion may be blue-black as a result of an excessive amount of hemosiderin within the dermis. The static nature, well-defined borders, and symmetry of these growths are indicative of a benign process.50
Dermatofibrosarcoma Protuberans Dermatofibrosarcoma protuberans (DFSP) is a rare, spindle-cell neoplasm. Clinically, the tumor appears as an indurate plaque or nodule that may be violaceous, red-brown, or flesh-colored. From 50%– 60% of these lesions occur on the trunk, with less common involvement of the proximal extremities, the head, and neck.51,52 There is a slow but gradual growth phase that takes place over months and years, during which time
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nodules appear on a plaque surface. DFSP is usually affixed to overlying skin and is firm and indurate. It can sometimes be attached to deeper structures, such as muscle and fascia. The disease course is slowly progressive, with pain becoming increasingly prominent as the lesion increases in size. Severe pain and contractures gradually affect the general health in untreated patients. This is a neoplasm with a marked propensity for local recurrence but with a relatively low risk of metastatic spread. DFSP characteristically appears in the younger age group (20 –50 years), but it may also affect children and the elderly.53,54 There is a pigmented variant of the DFSP referred to as the “Bednar tumor,” which occurs primarily in darkly pigmented patients and is quite rare.55
Eccrine Poroma Eccrine poroma is a benign, slow-growing, slightly protruding, sessile, soft, reddish tumor that may occur anywhere but is most often seen on the sole or side of the foot and the palms. It bleeds easily with even slight trauma. The tumor grows from a cup-shaped shallow depression. The lesion tends to occur singly, although multiple lesions may also occur. One of the clinical differential diagnoses is melanoma (amelanotic and melanotic).56
Malignant Eccrine Poroma (Porocarcinoma) Most porocarcinomas arise from long-standing eccrine poromas, but the tumors may develop directly. Clinically, they are similar to poromas but may also manifest as blue or black nodules, plaques, or ulcerated tumors. The most frequent sites of involvement are the legs, feet, face, thigh, and arms. The average interval from onset to treatment is 8 years. About 10% of the cases develop distant metastases, and there is a 70% mortality rate when metastasis occurs. The differential diagnosis includes malignant melanoma.57
Trichilemmal Carcinoma This malignant form of trichilemmoma originates from the external root sheath of the hair follicle.58 In most cases, it occurs in the sun-exposed parts of the body,59 and also in patients with xeroderma pigmentosum.60 Clinically, the tumors can be nodular, ulcerated, or exophytic with a keratotic or crusted appearance.60,61 The lesions have usually been present for less than a year and exhibit a characteristic accelerated growth phase. While the tumors are locally invasive and have histologic characteristics of high-grade mitotic potential, they have a nonaggressive course and do not recur after wide excision. The differential diagnosis includes nodular malignant melanoma.
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Atypical Fibroxanthoma Atypical fibroxanthoma is a superficial form of the malignant fibrous histiocytoma. It is a low-grade malignancy, although it has been shown to metastasize to regional nodes in rare instances.62,63 Atypical fibroxanthoma occurs primarily in older populations and on sun-exposed surfaces, especially the ears, cheeks, nose, and scalp.64,65 Ultraviolet exposure and previous radiation are predisposing factors for its development. Although less common, it appears also on the extremities of younger individuals. Clinically, the tumor is a small, solitary papule or firm nodule, often with an eroded or crusted surface and without characteristic morphologic features. The clinical and histologic differential diagnosis includes melanoma.65
Malignant Fibrous Histiocytoma Malignant fibrous histiocytoma (MFH) is the most common soft-tissue sarcoma of middle and late adult life.66 It can be classified as either superficial or deep, with the more superficial lesions tending to be confined to the subcutaneous tissue, although they may be attached to the fascia. These tumors typically appear between the ages of 50 and 70 years and are slightly more common in white men. At presentation, the tumor is usually a painless, enlarging mass of several months’ duration. Growth of the tumor may be rapid. The deep type is usually a protruding, rounded, and solitary tumor (it can be multinodular) and is 5–10 cm in size at the time of the initial diagnosis. The superficial MFH tumors are usually smaller at the time of initial diagnosis.67 They are often reddish or dusky and are most commonly found on the extremities, the lower more than the upper ones.68 Most patients with superficial MFH tumors are asymptomatic. The prognosis of an MFH tumor correlates with its depth of invasion,67,68 location, and histologic subtypes.
Angiosarcoma This is a rare, malignant tumor of endothelial cell origin. The tumor presents with a wide morphologic spectrum, ranging from low-grade hemangioma-like tumors to highly anaplastic, poorly differentiated sarcomas.69 An angiosarcoma has a marked predilection for the skin and superficial soft tissues.69 Cutaneous angiosarcoma is seen mostly in elderly patients but can occur at any age. Men are affected twice as often as women. The most common site of involvement is the scalp and forehead.70,71 Clinically, angiosarcoma presents as an ill-defined, blue-to-red-to-purple indurated plaque or nodule. It is usually asymptomatic. As it grows, it may become more nodular, soft, and even compressible. Its margins are clinically indistinct, and multifocal areas often appear.69 It can be quite large at
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the time of presentation. Angiosarcoma spreads extensively in the skin beyond clinical margins, making complete surgical resection difficult.72 The prognosis is poor.
Primary Pigmented Carcinoma of the Breast Breast cancer that also involves the overlying skin is uncommon. Carcinoma of the breast may infiltrate the dermis and extend from there directly into the epidermis. Pigmented carcinoma of the breast is rare, and only a few reports of primary cases have appeared in the literature.73–75 The malignant cells may acquire melanin pigment, usually but not always in a small amount, and it is difficult to differentiate this lesion from melanoma. The patient described by Saitoh et al76 was a rare case of pigmented, primary carcinoma of the breast occurring in a man. The authors stated that it was difficult to diagnose whether or not this case was a malignant melanoma, and ductal breast carcinoma was determined by histologic and immunohistochemical studies.
Extramammary Paget’s Disease Extramammary Paget’s disease is a rare, intraepithelial malignancy. It is characterized by the presence of varying numbers of Paget’s cells within the epidermis. Extramammary Paget’s disease is frequently associated with an underlying glandular adnexal carcinoma or a regional internal carcinoma with or without metastasis. The most common site of involvement is the vulva, followed by the perianal area, penis, scrotum, and groin.77 The correct diagnosis is often delayed because of its benign clinical appearance, one that often mimics dermatitis. Clinically, it appears as a scaling, erythematous, eczematous patch or plaque. Secondary crusting and superficial erosions can occur. Pruritus is common, and sometimes pain may be present as well. Bleeding is a late sign. When it appears in the anal, perianal, and perineal areas, extramammary Paget’s disease needs to be differentiated from other premalignancies and malignancies, including anorectal melanoma.
Merkel Cell Carcinoma Merkel cell carcinoma is a rare, cutaneous malignancy that arises from neuroendocrine cells that show features of epithelial differentiation. The precise origin of Merkel cell carcinoma remains controversial; the tumor may derive from epidermal Merkel’s cells, dermal neuroendocrine cells, or poorly differentiated epidermal stem cells.78,79 It is rare and typically affects persons ⬎65 years of age, but it has been noted in children and young adults. Clinically, the tumor appears as a solitary, dome-shaped nodule or indurate plaque. Its color is red to violaceous, and ulcerations may occur as the tumor increases in size. Most of the tumors are ⬍2 cm in size but can achieve a size as large as 10 cm. The
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primary sites of involvement are the head and neck, especially periorbital,80 and less frequently the leg, arm, and buttock. The differential diagnosis includes amelanotic melanoma. Merkel cell carcinoma is considered an aggressive tumor with a significant incidence of local recurrence as well as a high incidence of regional and systemic metastatic disease.81 The prognosis is worse than that of malignant melanoma.
notic macules, tending to remain static in size and color. A biopsy is indicated to establish the diagnosis in atypical lesions or in any changing features of the macules, if irregularity of color or shape is evident at the initial presentation, or if there are symptoms of itching, discomfort, or bleeding.
Leiomyosarcoma
Trauma can result in hemorrhage beneath the nail plate, which typically becomes blue-black. It is the sudden occurrence, history of antecedent trauma, and lack of Hutchinson’s sign that differentiates it from an acral lentiginous melanoma. Furthermore, the dried blood can be easily scraped from the nail bed after its removal.
Leiomyosarcoma is a malignant tumor of the smooth muscle. Classification and prognosis of leiomyosarcoma depend on the site of origin and the anatomic location. Superficial leiomyosarcoma can be divided into two groups: cutaneous, arising in the dermis, and subcutaneous, arising in the subcutis. It is important to distinguish between them because of the differing prognosis and treatment.82– 85 The superficial type is most prevalent in the 40- to 60-year-old age group, with men being affected slightly more than women. The extremities are the most frequent sites of involvement, especially the hair-bearing, extensor surfaces. Superficial leiomyosarcoma typically present as a solitary tumor with associated pain or tenderness, although some patients have multiple lesions. The tumors are relatively small (⬍2 cm). Subcutaneous leiomyosarcoma can grow fast and achieve large sizes. They are usually round to oval, and the overlying epidermis usually is normal in appearance. The cause of leiomyosarcoma is unknown. Leiomyosarcomas that originate in the dermis probably come from the arrector pili; those that develop in the subcutis are probably vascular in origin. Leiomyosarcomas must be distinguished from other malignant spindle-cell tumors of the skin, such as spindle-cell melanoma.
Subungual Traumatic Hematoma
Melanonychia Striata Longitudinal brown-to-black banding of the nails occurs frequently in blacks and Orientals. Subungual melanoma may be suspected, but there are several guidelines that point to a benign process: multiple lesions without change for many years, well-defined bands of regular width, homogenous tan-to-brown color, and absence of pigment in the surrounding skin.
Subungual Bone Spur Subungual, pigmented lesions may be difficult to diagnose. Velanovich90 described a case of a bone spur causing a subungual lesion mimicking melanoma. Woo and Rasmussen91 reported a subungual exostosis arising from underneath the nail plate, having originated from the underlying bone. The characteristic appearance of this disorder may occasionally mimic a wide variety of tumors, including amelanotic melanoma.91
Genital Melanotic Macules
Subungual Epidermoid Carcinoma
Genital pigmentation may occur in isolation or as part of a syndrome. Individual lesions tend to remain static in size and color. They are benign, asymptomatic, discrete areas of hyperpigmentation, tan-to-dark brown/ black, and 0.5–2 cm. Their occurrence, usually as newly pigmented lesions appearing among adults, can cause concern because of their ability to mimic early melanoma. They occur equally in both sexes. Histologic findings have shown increased basal pigmentation without atypical features.86 – 87
Subungual Bowen’s disease and squamous cell carcinoma can clinically mimic benign conditions as well as malignant melanoma. Subungual epidermoid carcinoma should be regarded as a low-grade malignancy that can be managed by conservative surgical ablation. Histologic examination is the key for accurate diagnosis.92 A case of a woman who presented with a history of a slow-growing tumor on the distal portion of the third finger of her left hand clinically suggested an inflammatory process or an epidermoid cyst ,which was shown to be an acral lentiginous melanoma under microscopic examination.93
Labial Melanotic Macules This condition occurs in up to 3% of the population.88 The macules are isolated, pigmented lesions most commonly found on the lower lips of young women.89 Clinical features as well as histologic, immunohistochemical, and ultrastructural features all confirm their benign nature. They behave similarly to genital mela-
Tinea Nigra Tinea nigra is an asymptomatic, superficial, fungal infection generally affecting the skin of the palms. It is characterized by deeply pigmented, macular, nonscaly patches. It may mimic serious pigmentary lesions, such
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as acral lentiginous melanoma.94 A KOH examination is a simple and rapid means of verifying this entity.
Pseudomelanoma A recurrence of an incompletely removed melanocytic nevus can be particularly difficult to distinguish from melanoma.95 It typically presents as repigmentation within a few weeks after its incomplete removal. This phenomenon was originally termed “pseudomelanoma” because the recurrent lesion may have atypical histologic features that make it difficult to differentiate from malignant melanoma.96 A review of the histologic features of the original lesion is sometimes critical for making the differentiation.95 It was reported to appear after dermabrasion,97 partial surgical removal,95,98 shave excision followed by electrodesiccation,95,98 laser therapy,99 solcoderm therapy,96 and other procedures.
Amelanotic Melanoma Amelanotic melanoma may be confused with a variety of conditions, both benign and malignant.100 The benign lesions include intradermal nevus,101 seborrheic keratosis,101 verruca vulgaris,101,102 dermatitis,103–105 pyogenic granuloma,106,107 nevus depigmentosus,108 granuloma annulare,108 scar,108 actinic keratosis,101 and lymphocytoma cutis.109 The malignant lesions include BCC,101 keratoacanthoma,108 Bowen’s disease,110 Merkel cell carcinoma,111 and atypical fibroxanthoma.109 The prognosis of primary cutaneous amelanotic melanoma is no different from its pigmented counterpart. These tumors are often more advanced at the time of diagnosis, presumably because of a delay in diagnosis.
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