Case 2 -

Desmoplastic (Neurotropic) Melanoma Steven D. Billings, M.D. Andrew L. Folpe, M.D.

Clinical History 71 year-old man with a scalp lesion that had been present for several months. The clinical diagnosis was basal cell carcinoma vs. sebaceous cyst. Morphology Throughout the dermis, there was a tumor composed of fascicles and groups of atypical spindled cells. The cellularity of the tumor varied but in areas the fascicles of tumor cells were separated by dense collagenous stroma. The tumor cells exhibited moderate nuclear atypia and mitotic figures were easily identified. Perineural invasion was focally present. A mild lymphocytic infiltrate was admixed with the tumor. Within the overlying epidermis there was an atypical junctional melanocytic proliferation. Diagnosis: Desmoplastic (neurotropic) melanoma Discussion Clinical and Histopathological Features Desmoplastic melanomas (DM) comprise up to 4% of all melanomas. DM usually presents in older patients, generally in the sixth to seventh decade, but a wide age range may be affected, with rare reported cases in children. In most series men are more commonly affected than women. The most common site of presentation is the head and neck, accounting for up to 75% of all cases. However, a variety of sites may be affected, and in some series cases in women occurred most commonly in the lower extremities. Approximately half to two-thirds of cases are clinically amelanotic and present as flesh-colored papules or nodules, often resulting in a mistaken clinical impression of a benign cutaneous lesion, such as an epidermoid cyst, intradermal nevus or a non-melanoma skin cancers such as basal cell carcinoma. The diagnosis of melanoma is suspected in only about one-third of cases of cases. This innocuous clinical presentation frequently results in delayed diagnoses, and tumors may be present from months to years prior to biopsy. Desmoplastic melanoma can be a difficult diagnosis. A helpful clue to the diagnosis of DM is the presence of an overlying atypical junctional melanocytic proliferation, which can range from an atypical proliferation of single melanocytes to full-blown lentigo maligna-type melanoma in-situ. It is important to realize that the majority of DM will not have a clear-cut overlying in-situ melanoma, although some type of atypical junctional melanocytic proliferation is present in 40 to over 90% of cases. Less frequently DM is associated with superficial spreading melanoma or nodular melanomas. The diagnosis of DM should be considered for any unusual spindle cell proliferation occurring in sun-damaged skin. In our experience, the presence of nodular lymphoid aggregates, often deep in the dermis, is often the first clue that one is dealing with a DM, particularly when the junctional component is subtle or not represented. Another highly characteristic feature of DM is its distinctly "packeted" growth pattern, with aggregates of hyperchromatic spindled cells separated by dense, hyalinized collagen. In most cases, the spindled cells of DM will be large and hyperchromatic (put not pleomorphic), although some cases may consist of deceptively bland cells with wavy or buckled nuclei, simulating neurofibroma. Fortunately, most cases have at least moderate nuclear atypia with enlarged vesicular to hyperchromatic nuclei and prominent nucleoli. Melanin pigment is almost never present within the lesional cells, in contrast to blue nevus, a differential diagnostic consideration in some cases. Neurotropism, characterized by perineural or intraneural involvement by tumor cells, is present in approximately 1/3 of cases but is by no means required for diagnosis. Neurotropism is increasingly seen with deeper tumors, not surprisingly, considering that larger nerve twigs are generally present in the deeper reticular dermis. When neurotropism is present, the tumor may be referred to as a "desmoplastic neurotropic melanoma". Mitotic figures are present in variable numbers. Most DM are locally advanced tumors at the time of diagnosis, with the majority extending to the level of the reticular dermis (Clark's level IV) or subcutis (Clark's level V) at the time of diagnosis. Occasional tumors extend into skeletal muscle or the parotid gland. Only a distinct minority are limited to the papillary dermis (Clark's level II or III). The Breslow level in the majority of the DM ranges from 2.5 to >4mm. Epidermal ulceration is present in up to 25% of cases and evidence of regression may be seen in up to 15%. Immunohistochemistry is invaluable in the diagnosis of DM. Essentially all DM show strong, diffuse immunoreactivity for S-100 protein, often highlighting the very large size of the neoplastic cells and their long cytoplasmic processes. The exact number of S100-negative DM is for obvious reasons extremely difficult to measure, however, such tumors must exist. In contrast, fewer than 10% of DM are positive for any of the more specific markers of melanocytic differentiation, including HMB45, Melan A, tyrosinase and microphthalmia transcription factor (MiTF). DM may also express a variety of putative "nerve sheath" markers, including p75 neurotrophin receptor, CD57 and PGP 9.5. As discussed below, this may result in confusion with malignant peripheral nerve sheath tumors. Expression of p75 neurotrophin receptor may have a possible role in the neurotropism seen in DM. Many DM also show considerable smooth muscle actin positivity, reflective of a large number of intimately associated myofibroblasts; this apparent actin expression may result in confusion with a variety of myofibroblastic and myoid tumors. Focal anomalous cytokeratin and/ or desmin expression may also be seen, potentially resulting in misdiagnosis as a spindled carcinoma or myoid tumor, respectively. Differential Diagnosis: The differential diagnosis of DM is broad and includes a wide range of both benign and malignant entities. The primary differential diagnosis centers on other malignant spindle cell tumors of the dermis, especially spindle cell squamous cell carcinoma. Like DM both of these tumors occur in elderly patients on sun-exposed skin. In spindle cell squamous cell carcinomas, areas of more conventional squamous cell carcinoma or actinic keratosis are often present. By immunohistochemistry, most spindle cell squamous cell carcinomas will show cytokeratin expression, although this can be extremely focal or even absent. Some spindled squamous cell carcinomas may express only high molecular weight cytokeratin isoforms, identified by antibodies such as 34-beta-E12 or antibodies to cytokeratins 5/6. Spindled squamous cell carcinomas are negative for S-100 protein, in contrast to DM, although they may contain entrapped S100 protein-positive dendritic cells. Atypical fibroxanthoma and DM share a common clinical presentation, as amelanotic lesions on sun-exposed skin of the head and neck of elderly patients. The more common storiform, pleomorphic examples of atypical fibroxanthoma generally show more random nuclear atypia with bizarre multinucleated tumor giant cells than commonly seen in DM. The more spindled examples of atypical fibroxanthoma can bear a striking resemblance to DM. The associated junctional melanocytic proliferation see in most examples of DM can help in the diagnosis. Immunoreactivity for S-100 protein, except for some entrapped dendritic cells, is not a feature of atypical fibroxanthoma. Cutaneous leiomyosarcoma can sometimes be mistaken for DM. Clinically, cutaneous leiomyosarcoma is less common on the head and neck. Microscopically, the fascicles in leiomyosarcoma have a more ordered intersecting pattern and have more elongated, blunt ended nuclei than DM. Immunoreactivity for smooth muscle actin and desmin and the absence of immunoreactivity for S100 protein are helpful adjuncts in this diagnosis. Rare examples of spindle cell angiosarcoma can sometimes be relatively "bloodless" and mimic DM. Immunostains for vascular markers CD31 and/or CD34 are helpful in this differential diagnosis. Malignant peripheral nerve sheath tumor is often mentioned in the differential diagnosis of DM. However, in most cases this is not a practical problem. Examples of malignant peripheral nerve sheath tumor arising in the skin are quite rare and are often (~40%) in the setting of previously documented neurofibromatosis. Malignant peripheral nerve sheath tumors usually are a more cellular tumor without the interposing collagenous stroma or the admixed lymphocytes of DM. A co-existing precursor neurofibroma is often present in cases of cutaneous malignant peripheral nerve sheath tumor. Cutaneous malignant peripheral nerve sheath tumors often have an epithelioid morphology as well. The pattern of S100 protein expression is may be less helpful in distinguishing DM from cutaneous malignant peripheral nerve sheath tumors, as some cutaneous malignant peripheral nerve sheath tumors show strong S100 protein expression. Benign entities in the differential diagnosis include melanocytic nevi. Desmoplastic nevi and amelanotic blue nevi are the most difficult benign melanocytic tumors to differentiate from DM. Desmoplastic nevi occur on average in a slightly younger population, most frequently in middle-aged patients, and more commonly arise on the trunk. As in DM, desmoplastic nevi may show a junctional melanocytic proliferation, although it should not show nuclear atypia or a predominant single cell growth pattern. Desmoplastic nevi may show some nuclear variability, but should not show the distinct hyperchromatism seen at least focally in DM. Desmoplastic nevi (and blue nevi) may show tracking of cells along the epineurium of cutaneous nerves, which should be rigorously distinguished from the true perineurial invasion seen in DM. Mitotic activity is very sparse to absent in desmoplastic nevi, with a correspondingly much lower KI-67 labeling index than is seen in DM. Finally, desmoplastic nevi generally do not show involvement of the subcutaneous fat, a common finding in DM. Immunohistochemical stains are of limited utility in this differential diagnosis as both typically show strong immunoreactivity for S-100 protein. Desmoplastic nevi are, however, much more likely to express specific melanocytic markers, such as HMB45. Amelanotic blue nevi may also be confused with DM. Amelanotic blue nevi do not have an associated junctional melanocytic proliferation, lack cytologic atypia and do not show mitotic activity. Additionally, blue nevi generally show diffuse immunoreactivity for HMB45, in contrast to DM. In terms of benign fibroblastic entities, DM needs to be differentiated from scars. On the surface this seems are trivial matter. However, this can be somewhat problematic in re-excision specimens. Well formed scars are fairly easy to distinguish from DM because of the horizontally oriented fibroblasts and vertically oriented blood vessels. However, more recent scars are more cellular and less organized and may have mild cellular atypia, potentially causing confusion with recurrent or residual DM. In the setting of recurrent or residual DM the volume of tumor cells may be relatively low and more intimately admixed with bland fibroblastic cells of the scar. Therefore careful examination may be necessary to recognize the presence of occult residual tumor. It has been suggested that S-100 protein immunostains may be helpful in this setting to highlight the tumor cells hiding in the background of a scar. Unfortunately, S-100 positive spindle cells are a normal constituent of dermal scars, seen in both recent and well organized scars. These S-100 positive cells most likely represent entrapped dendritic cells such as Langerhans cells. Because CD1a expression on Langerhans cells is lost during migration through the dermis, this is not helpful for discriminating these cells from the tumor cells of DM. Thus, the differential diagnosis of recurrent/residual DM vs. a scar ultimately rests of routine histologic evaluation. In most cases this is not too problematic. There is generally sufficient nuclear atypia to allow distinction between DM and scars. However, in cases which cytologic features are bland, this is a potential diagnostic problem. In such cases, more vertical orientation of tumors, the clustering of tumor cells and the presence of histologic features such as intranuclear cytoplasmic inclusions can be helpful clues to the presence of residual DM. Benign fibrous histiocytomas are conceivably in the differential diagnosis, especially the cellular and atypical variants (see Case 4 discussion). Desmoplastic melanoma does not have the peripheral collagen trapping or overlying epidermal hyperplasia seen in fibrous histiocytomas. Fibrous histiocytomas are essentially negative for S100 protein. Prognosis/Outcome: Our understanding of the clinical behavior of DM continues to evolve. DM was initially believed to be a particularly aggressive variant of melanoma, with 4 of 7 patients in Conley et al's seminal description dying of metastatic disease. As more experience has been gained with DM, a somewhat different picture has emerged, and it appears less aggressive than was originally thought. In fact, stage I and II DM appear to have a generally better five year survival rate than comparable conventional melanomas. The local recurrence rate of DM does appear to be significantly higher than that of conventional melanoma, presumably due to its growth pattern, and varies from approximately 10-50%, in contrast to the less than 5% local recurrence rate seen with conventional melanoma. Neurotropism is associated with a higher rate of local recurrence, and can also lead to localized neuropathies and as a portal for brain invasion. DM appears to be less likely to involve regional lymph nodes than conventional melanomas, but has a comparable rate of visceral metastasis. Metastatic DM may assume a more epithelioid morphology. Prognostic factors predictive of a worse outcome across various studies include tumor depth (Clark's level V, Breslow depth >4mm), high mitotic rate (>4/mm2), narrow margins of excision (<1 cm), ulceration, location on the head and neck, increased cellularity and prior misdiagnosis. Surgery is the mainstay of DM therapy. As narrow margins are associated with an increased risk of local recurrence, a minimum of 1 cm margins are required and when possible 2 cm margins may be preferable. Adjuvant radiation therapy may play a role in managing recurrent lesion or inoperable tumors. References Conley J, Lattes R, Orr W. Desmoplastic malignant melanoma (a rare variant of spindle cell melanoma). Cancer 28: 914-936, 1971. Reed RJ. Leonard DD. Neurotropic melanoma. A variant of DM. Am J Surg Pathol. 3:301-11, 1979. Reiman HM. Goellner JR. Woods JE. Mixter RC. Desmoplastic melanoma of the head and neck. Cancer. 60:2269-74, 1987. Egbert B. 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