Section 11 -

Unusual Histologic and Clinical Variants of Malignant Melanoma Neil Crowson, MD Cynthia M. Magro, MD Martin C. Mihm, Jr., MD

Minimal Deviation Melanoma Clinical Features First decribed in 1975 by Reed (Reed et al, 1975; Reed, 1990), minimal deviation melanoma is a tumorigenic lesion with a low metastatic potential. While not widely accepted, we hold that there is a distinct entity that fits this description. These tumors form nodules that resemble vertical growth phase melanoma, but comprise cells that are nevoid in character with atypia that lacks the cytologic character of malignant cells. The prognosis has been imputed to be better than for fully evolved melanoma and limited series have supported this claim (Phillips et al., 1986; Reed and Martin, 1997). Further follow-up studies of these lesions when diagnosed by strict histologic criteria are needed. Lesions present as nodules or plaques that vary from flesh-colored to dark brown or blue-black, most often ranging in size from 0.5 to 1.0 cm (Reed et al, 1975) and located characteristically on the trunk of young adults with a mean age of 34 years, although they may occur at any site at any age. They often arise in preexisting acquired or congenital nevi; a common history is that of a mole present for years that has suddenly become larger and/or symptomatic. Those minimal deviation tumors arising in congenital nevi often manifest as a subcutaneous nodule clinically misinterpreted as an epidermal cyst. Although in most cases the lesions behave in an indolent manner, metastatic disease has been reported (Merot and Mihm, 1985; Phillips et al, 1986). Histology The light microscopic features associated with minimal deviation melanoma/borderline melanoma include (Mihm and Googe, 1990): The presence of an expansile nodule, sometimes with invasion of the reticular dermis by cords of tumor cells A uniform population of melanocytes resembling type A, B, and/or C nevus cells or spindle or epithelioid cells arranged in nests and fascicles of cells enmeshed in a delicate fibrous stroma Moderate atypia of cellsMitoses are absent or rare; no atypical mitoses are seen with the exception of the lesion termed "minimal deviation melanoma of spitzian type" No tumor necrosis No infiltration into subcutaneous fat except for those minimal deviation melanomas arising in congenital nevi Host response, either inflammation or fibrosis, usually absent Absence of microscopic satellites No invasion of vessels or lymphatics Animal Type Melanoma Case # 10. Equine/animal-type Melanoma in Humans: Malignant Melanoma with Prominent Pigment Synthesis Historical Perspective and Clinical Features Equine melanotic disease has been recognized for centuries as a pigmented neoplasm that occurs in old gray mares following the whitening of their coats (Montes et al, 1979; Lerner and Cage, 1973). Similar neoplasms in nonequine animal models can be induced with topical carcinogens (Rappaport et al, 1961). Darier first linked these lesions to human "melanosarcoma" (Darier, 1925). As the recognition of these lesions in humans has only recently been formulated, their biologic behavior is as yet unclear (Levene, 1980). A long indolent phase of behavior has been reported in one series (Levene, 1975), but we have reported cases with metastases and death (Crowson et al, 1999) and have seen sentinel lymph node metastases in several patients (personal observations). We now routinely recommend sentinel lymph node biopsy for lesions greater than 1.0 mm in depth. The epithelioid blue nevus described by Carney has features shared by the tumorous proliferation of melanocytes but with undetermined behavior (Carney and Ferreiro, 1996). In humans the lesions present as blue-black plaques or nodules that average 1 cm in size but can reach a size as great as 10 cm. Without definite predilection as to sex or site, in a limited series four of six patients were in the first or second decades of life (Crowson et al, 1999). Subsequent experience reveals a much wider age range for their incidence. These plaque-like lesions gradually seem to enlarge often with punctate areas heralding the sites of peripheral spread that in one patient progressed for several decades before melanoma appeared. There is no relationshiop so far found with this melanoma and family history, sun exposure or dysplastic nevi (Crowson et al, 1999). Histology The achitecture is that of a heavily pigmented tumor that often occupies the entire dermis from the dermoepidermal junction to the dermal subcutaneous interface. In some lesions there is a grenz zone; others show intraepidermal melanocytic hyperplasia and/or pagetoid spread. The tumor cells have either a polygonal or rounded shape centrally with fusiform cells at the periphery, often with a dendritic appearance leading to misinterpretation as a blue nevus variant. The center of the lesion exhibits confluent growth with variable but often striking cytoplasmic pigmentation. Focally the cells are arranged in swaths or rounded bundles that represent cross-sectioned fascicles. The density of the pigment is so great that it leads to misinterpretation of the cells as melanophages; careful inspection reveals that they are tumor cells with prominent nucleoli. The mitotic rate is low in most lesions. The cytology is variable with some cells having bland nuclei and others showing irregular nuclear shapes, anisonucleosis and nucleolation, albeit not fully-evolved malignant criteria. Other lesions exhibit overtly malignant cytology. The best clue to the true nature of the lesion is the architectural effacement by the expansile nodule. There is often close apposition of the tumor cells to the follicles that has led to designation of pilar neurocristic hamartoma (Tuthill et al, 1982; Crowson et al, 1996; Crowson et al, 1999). It is conceivable that this follicle based lesion is a form of hamartoma that gives rise to a pigment synthesizing melanoma. Differential Diagnosis The cellular blue nevus, the blue nevus with hypercellularity, malignant blue nevus, the heavily pigmented epithelioid cell nevus and regressed melanoma with tumoral melanosis must all be considered in differential diagnosis. Malignant Blue Nevus (Melanoma arising in blue nevus) This rare lesion occurs most often on the scalp but does occur elsewhere on the body including on the extremities (Ozgur et al, 1997). The lesion usually arises in association with a cellular blue nevus (Merkow et al, 1969; Mishima et al, 1970; Hernandez, 1973), but has been described in association with the nevi of Ito and Ota (van Krieken et al, 1989). Malignant transformation in a preexisting lesion usually occurs in an older age group (Connelly and Smith, 1991) and manifests as rapid enlargement, ulceration, and change in color. The diagnosis of malignant cellular blue nevus should be considered when a lesion that has arisen in a preexisting cellular blue nevus exhibits highly atypical epithelioid melanocytes with bizarre tumor giant cells and numerous abnormal mitoses. Characteristically, there is a preexisting lesion such as a cellular blue nevus (Hernandez, 1973; Aloi et al, 1996) adjacent to the malignant component, identifiable as a markedly disorganzied and highly infiltrative lesion with hyperchromasia and often a moderately dense inflammatory infiltrate at the base. The malignant component shows pleomorphic spindle and epithelioid cells disposed in fascicles and nodules that efface the dermal architecture and extend into the subcutis with areas of necrosis. Admixed with the pleomorphic cells are bizarre tumor giant cells. Numerous abnormal mitotic figures are observed, averaging 8 to 9 per mm2 (Aloi et al, 1997). Nevoid Malignant Melanoma The term nevoid melanoma was first proposed by Schmoeckel and co-workers (Schmoeckel, et al 1985) to describe a heterogeneous group of lesions that shared histologic features that at low power resembled a benign nevus by virtue of their symmetry, dome-shaped or verrucous silhouette and compostion of nevus-like cells with apparent maturation. (Schmoeckel et al, 1985; Wong et al,1993). The lesions appear as protuberant or verrucous tan to flesh-colored nodule greater 1 cm in size, most often on the trunk or proximal limbs of young adults and occasionally on the scalp. Our experience is similar to that described by Blessing and co-workers (Blessing et al, 2000) but differs from that described by others (McNutt et al, 1995). Although in the original series of 33 patients, 15 developed metastases and 8 died of disseminated melanoma (Schmoeckel et al, 1985), we hold that these cases were in fact small epithelioid melanomas whereby the pleomorphic confluent growth and high mitotic rate distinguish the lesions from nevoid melanoma as the term is understood today. When strict microscopic criteria are followed the prognosis is much better as described by Wong and coworkers (Wong et al, 1995). The histology was discussed above. Metaplastic Change In Malignant Melanoma Melanoma may exhibit metaplastic transformation and so lead to misdiagnoses such as osteogenic sarcoma and chondrosarcoma; some cases with metaplastic bone formation have been associated with iatrogenic procedures (Moreno et al, 1986; Hoorweg et al, 1987; Toda et al, 1997). Such changes in a melanoma may result from an alteration in host response to the tumor, or from abnormal differentiation wherein the melanoma cells acquire the ability to produce, for example, osteoid or cartilage; malignant chondroid matrix has been described, sometimes associated with bone formation as reported in a nasal mucosal primary and its metastasis (Hoorweg et al, 1987). Similar changes have been reported in subungual melanoma associated usually with a history of trauma (Toda et al, 1997). The totipotent capacity of the stroma has been amply demonstrated with the documentation of rhabdomyoblastic, lipoblastic, and neurogenous elements in melanomas arising in these lesions (Hendrickson and Ross, 1981). Balloon Cell Melanoma Clinical and Histologic Features This rare form of vertical growth phase melanoma is characterized by a nodular proliferation of neoplastic balloon cells that arises typically in the background of a superficial spreading melanoma (Pernicario, 1997). The clinical appearance of these lesions is usually a soft, rubbery, or firm nodule surmounting a plaque with a polypoid or papillomatous contour (Kao et al., 1992). As in other types of melanoma, tumor thickness is of great import to prognosis. The poor patient survival statistics usually reflect the depth of the tumor at the time of its presentation with 57.5% of patients succumbed with metastatic disease 2 months to 12 years following surgery (Kao et al., 1992). Nests and sheets of large cells that exhibit an abundant quantity of clear or finely vacuolated cytoplasm define a lesion that at first glance resembles a balloon cell nevus, but manifests effacement of the dermal architecture by sheets of neoplastic cells with no intervening stroma, nuclear atypia and mitoses and at times necrosis. Ultrastructural studies have shown that the vacuoles are either empty or represent degenerating melanosomes, similar to the changes seen in balloon cell nevi (Kao et al, 1992; Novak et al, 1998) or, in a single case, lipid (Martiniez et al, 1990). The cells of balloon cell melanoma and its metastases express S100 and gp100 protein. Myxoid Melanoma Myxoid melanoma is a rare variant that manifests large malignant cells amidst a basophilic mucinous matrix comprising mesenchymal acidic mucopolysaccharides that decorate with alcian blue at a low pH; epithelial mucin preparations such as mucicarmine and PAS-diastase are negative. While tumors are usually amelanotic, melanin can be shown by Fontana-Masson preparations and melanosomes are evident by electron microscopic examination (Zelger et al, 1997; Collina et al, 1997). The origin of the matrix is likely the stromal cells, as the tumor cells do not contain cytoplamic mucin. As primary cutaneous myxoid melanoma is rare, one should always consider the possiblity that the lesion is a seconday deposit from a mucosal or paramucosal neoplasm when confronted with such morphology in a skin biopsy (Lodding et al, 1990; Auger et al, 1994; Chetty et al, 1994; Hitchock and White, 1998). The determination of the primary nature of the tumor rests upon finding an intraepidermal or intraepithelial source. Strong expression of S100 protein is typical, whereas HMB-45 is less often demonstrable (Zelger et al., 1997). Signet Ring Cell Melanoma A signet ring morphology in lesions of malignant melanoma, appearing in 0.5 % of cases (Nakleh et al, 1990) commonly reflects metastatic or recurrent lesions Tsang et al, 1983). The cells may show a small cell, large cell or giant cell morphology. Because their presence always raises the possiblity of a metastatic adenocarcinoma (Tsang et al, 1983; Simons and Martin, 1991) particularly in pleural or peritoneal effusion cytology (Neimann and Thomas, 1995) they must be evaluated by antibodies to S100 protein, HMB-45 or Melan-A immunostains, all of which are usually positive Small Cell Malignant Melanoma The small cell variant of melanoma is most often encountered arising in a giant congenital nevus as a protuberant or ulcerated nodule. Prominent nuclear molding reminiscent of small cell carcinoma is a common histology, but a dyshesive growth pattern resembling lymphoblastic lymphoma may also be observed. These lesions always occur usually exhibit an aggressive course. Differential diagnoses include lymphoblastic lymphoma, and other 'small round blue cell tumors' of childhood. Judicious use of immunostains for common leukocyte antigen, CD99 (MIC2), myoid markers and synaptophysin and chromogranin respectively should resolve this dilemma (Crowson et al, 2001). Other Rare Manifestations of the Morphological Diversity of Malignant Melanoma Malignant melanoma has been called "the great histologic mimic" of other forms of neoplasia. In one study of 335 malignant melanomas at the University of Minnesota, 27 predominantly amelanotic neoplasms were identified that had unusual histologic features, 14 of which showed small cell, myxoid, or signet ring patterns already discussed above. An additional nine tumors had an adenoid or pseudopapillary pattern and two had an hemangiopericytoma-like appearance (Nakleh et al, 1990). These neoplasms tended to be located in unusual sites such as vulvovaginal, sinonasal, or rectal sites, and one arose in a congenital giant hairy nevus (Nakleh et al, 1990). Because of the histologic diversity primary melanomas are occasionally mistaken for primary soft tissue malignancies. Dermatofibrosarcoma protuberans, atypical fibroxanthomas, storiform-pleomorphic malignant fibrous histiocytoma, myxofibrosarcoma, malignant hemangiopericytoma, and malignant Schwannoma were the most frequent misdiagnoses in one series (Nakleh et al, 1990). These variants have corresponding aberrant immunophenotypes, expressing cytokeratins, desmin, smooth muscle actin, CD68, carcinoembryonic antigen, epithelial membrane antigen, VS38 and, very rarely, neurofilament or glial fibrillary acidic protein (Banerjee and Harris, 2000). Melanoma in Childhood Melanoma in childhood can be considered in three main settings: congenital melanoma; melanoma developing de novo; and melanoma arising in a preexisting lesion such as a giant hairy nevus (Ceballos et al, 1995; Scalzo et al, 1997; Berg and Lindelof, 1997). Histology Most studies suggest that childhood melanoma is diagnosed at a time when lesions are more advanced with many exhibiting thicknesses greater than 1.5 mm and invasive to levels IV and V. Most de novo cases are superficial spreading in type, followed by nodular and unclassifiable melanomas (Scalzo et al, 1997; Berg and Lindelof, 1997). The histology of lesions that clinically resemble adult melanoma are similar to those of adults as discussed above. More problematic are those melanomas that resemble spindle and epithelioid nevi. Several parameters are helpful in assessing the malignant character of these lesions. First is the thickness; the mean thickness of Spitz nevi lies in the 0.7-1.2 mm range, while lesions that are several millimeters in depth or that penetrate the subcutis raise concern (Spatz et al, 1999). Lesions greater than 10.0 mm in diameter are worrisome (Spatz et al, 1999) as are lesions with ulceration. The relationship of the nests of cells and of the individual cells one to another is another helpful feature. In childhood melanoma there is great variability in nest sizes and dermal nests are larger than intraepidermal nests. In Spitz nevi cells at any given level are similar to one another. In childhood melanoma there is striking "side-by-side" nuclear pleomophism at any given level of the lesion. The absence of maturation is another key factor as is the presence of a deep expansile nodule, especially if it is mitotically active. Mitoses are a key diagnostic criterion; when greater than 6 per mm2 in the dermis or present within 0.25mm of the lesional edge, these are highly significant (Spatz et al, 1999; Crotty et al, 1992); atypical mitoses are of special concern. Some have found that the presence of fine dusty melanin pigment in cytoplasm in deep nests were associated with a risk of metastasis (McCarthy et al, 1994). Those features that favor benignancy are age less than 10, sharp demarcation, symmetry, diffuse maturation, spindle cells and spindled nuclei, few or absent mitoses, epithelial hyperplasia and Kamino bodies (Crowson et al, 2001; Spatz et al, 1999; Crotty et al, 1992; McCarthy et al, 1994). Nevertheless, it is considered that 6-8% of Spitzoid melanocytic proliferations prove to be unclassifiable (Rapini, 1999). Barnhill and co-workers (Barnhill et al, 1999) note that significant discrepancies occur even between expert observers due to lack of objective criteria. Even when Spitz-like tumors metastasize in childhood, they are uncommonly fatal; of 3 of 9 such tumors that metastasized in one series, 2 did not spread beyond the first draining lymph node station at the time of reporting (Barnhill, 1998). A diagnosis of melanoma in childhood can be difficult and is not made on the basis of any isolated criterion, but is rather a construction based upon an assesment of multiple features of cytology, architecture, and clinical history (Spatz et al, 1999; Crotty et al, 1992; McCarthy et al, 1994). Notwithstanding the combined experience of the authors, we encounter lesions that defy precise classification and that do not permit confident prediction of biological behavior. For these difficult lesions we often recommend the performance of a sentinel lymph node biopsy, a technique that allows one to obtain information concerning the possibility of metastatic behavior. Whether this has relevance to the overall prognosis of atypical melanocytic proliferations in childhood will only be determined with passage of time and carefully evaluated clinical data. Metastatic Melanoma Clinical and Histological Features The most common presentation of metastatic melanoma is as a dermal or subcutaneous nodulee (Elder, 1978). Most metastases have epithelioid malignant melanocytes; the great majority show no epidermal component. However, when an epidermal component is present, as reported in 3.9% of lesions (Beardmore and Davis, 1975), distinction from a primary melanoma becomes difficult (White and Hitchcock, 1998). Although it was formerly held that a junctional component was pathognomonic of primary melanoma, it is clear that metastases can involve to the epidermis and thus histologically mimic in situ melanoma (Abernathy et al, 1994). Histologic criteria will not, in that scenario, enable differentiation of such a lesion from a primary tumor and clinical information will be essential to proper diagnosis (Bengoechea-Beeby et al, 1993). That said, certain histologic clues are helpful, such as the fact that often the intraepidermal component of a metastasis does not extend beyond the dermal component and in may be much smaller in breadth than that in the dermis, a finding at variance with primary melanoma in radial growth phase (Kornberg et al, 1978). The presence of regression and a lichenoid inflammatory infiltrate below the epidermal component is much more common in primary radial growth phase melanoma than it is in metastatic disease (Heenan and Clay, 1991); the reverse is true when tumor is seen in vascular channels (Heenan and Clay, 1991). Expression of similar CD44 glycoprotein isoforms intrinsic to cell motility and adhesion have been documented on the surface of cells in the epidermotropic metastases and in intraepidermal primary melanoma cells (Fernandez-Figueras, 1996). In reported cases of recurrent crops of melanoma occurring over a prolonged period after initial diagnosis and therapy, the tumors tend to be well-differentiated, manifesting a more banal cytology with few mitoses (Heenan and Clay, 1991). In one study patients who exhibited in first set lymph node dissections a diffuse infiltrate in all metastatic deposits had a significantly improved survival compared to patients who had little or no inflammation (Mihm et al, 1996). The presence of a single metastasis confers better survival than multiple metastases. This observation holds especially true in lymph node deposits but also in visceral depostis. Thus, single deposits to lung, skin, subcutis and nodes has a much better survival than solitary mestastases to other organs. Metastases to the brain and gastrointestinal tract are least favored sites as far as survival is concerned and the treatment of single metastases has shown some survival benefit (Chen et al, 2000). Melanoma of Soft Parts (Clear Cell Sarcoma) Clinical and Histologic Features Melanoma of soft tissue was first described by Enzinger in 1968 under the designation clear cell sarcoma of tendons and aponeuroses. (Enzinger, 1968). These neoplasms manifest clear cytoplasms, thus their designation as clear cell sarcoma, but demonstrate evidence of melanocytic differentiation by ultrastructure and immunohistochemical analyses (Chung and Enzinger, 1983); the term melanoma of soft parts is sometimes substituted as a synonym. Distincitve clinical and pathologic features include; presentation most often in young adults aged 20-40, with a median age of 27 but a range of 7-83 years in one series (Chung and Enzinger, 1983) with a slight female predominance. Tumors present typically as a tender nodule, less that 5.0 cm in diameter in the distal extremities, particularly the foot and ankle (Chung and Enzinger, 1983) with other sites of involvement including the knee, thigh and hand; the head and neck is only rarely involved. Masses typically enlarge slowly with an average duration of symptoms of two years. More than one-half of patients will ultimately develop metastases, typically to the lymph nodes, lung or bone; the 20 year survival of unselected patients is held to be roughly 20% although 60% are alive 5 years following resection (Fletcher, 2000). With respect to cytogenetics, three-quarters of cases manifest a unique t(12; 22) (q13; q12) translocation which is absent in malignant melanoma. This translocation fuses the EWS gene of chromosome 22 to the transcription factor ATF-1 on chromosome 12 in a fashion similar to that of a translocation seen in Ewing's sarcoma (Antonescu et al, 2001). Tumors typically manifest a uniform pattern of cohesive cell groups bounded by fibrous trabecula or a framework of delicate collagen fibers that is in continuity with the fascia or tendon structure to which the tumor appears connected. The tumor lobules manifest a rather uniform population of cells with oval to round nuclei containing prominent nucleoli and having cytoplasms which are abundant in quantity with either a clear or granular eosinophilic staining quality. Spindle shaped cells are often admixed. Most cases manifest multi-nucleated giant cells showing marginated or peripheral nuclei fashioning a wreath around a central cytoplasmic zone. Mitoses are uncommon and typically number 2 to 4 per 10 40X HPF. Intracellular melanin can be identified with Masson-Fontana preparations in roughly half of cases although melanin is difficult to identify with conventional histologic stains. By immunohistochemical evaluation, clear cell sarcomas ubiquitously express S-100 protein in the majority of cells; most also manifest melan-A, HMB45 and microphthalmia transcription factor positivity (Change and Folpe, 2001).