Case 4 -

Desmoplastic (Neurotropic) Malignant Melanoma. Omar Sangueza

Clinical History: The patient is a 55-year-old male with an infiltrating lesion above the tip of the nose. Diagnosis: Desmoplastic (Neurotropic) Malignant Melanoma. The main feature of these unusual neoplasms is their resemblance to various fibrous proliferations including reactive fibrosis, fibromatosis or fibrosarcoma. They are notorious for their propensity for local recurrence and aggressive behavior. Desmoplastic malignant melanoma (DMM) most commonly affects sun-exposed areas such as the head, neck, upper trunk and upper limbs, although cases of this entity have been reported in other areas of the body including anogenital area, acral regions, conjunctiva and oral mucosa. [1, 2] In general, it affects individuals older than 50 years, although cases in patients as young as 13 years-old have been reported. DMM in sun damaged skin are usually preceded by melanomas in-situ or invasive melanomas, but there are also a number of cases where no previous melanoma is detected (de-novo DMM). Patients with DMM present with deeply infiltrating nodules that in some cases may simulate sclerosing basal cell or squamous cell carcinomas. In other cases they present as ill defined plaque-like lesions with a hard consistency resembling scars. In a few cases symptoms of peripheral nerve impairment such as nerve palsies are present. Presence of pigment is variable and in a good number of cases is absent. Microscopically, DMM present as large, poorly circumscribed neoplasms of variable size, that occasionally extends into the subcutaneous tissue, fascia and nerves. In some cases, patchy infiltrates of lymphocytes are seen throughout the neoplasm. The presence of these lymphocytic infiltrates is a very helpful clue for the diagnosis of DMM. Neoplastic cells within the dermis show different degrees of atypia. In some cases the cells are deceptively bland, masking the true nature of this neoplasm. In those cases the neoplasm may resemble a scar or a fibromatosis. In other cases the neoplastic cells adopt a storiform pattern, reminiscent of a dermatofibrosarcoma protuberans or fibrosarcoma; in others the neoplastic cells have a neural appearance suggesting the possibility of a neurofibroma or a malignant peripheral nerve sheath tumor. The range of mitotic figures is variable, from a few to numerous. Melanin is present in only a few cases. Multinucleated cells may be present. [3] The presence of heterologous elements such as osteoid and bone occasionally has been reported. Areas containing atypical melanocytes in the epidermis may be present, however, in a good number of cases there is no evidence of melanoma. In these cases clinicopathologic correlation as well as the use of immunohistochemical stains is mandatory in order to make this diagnosis. Another helpful feature in DMM is the presence of nerve involvement. Infiltration of the perineurium and endoneurium is seen in most cases with the neoplastic cells wrapping around nerves. Immunohistochemically, most cases of DMM stain positive for S-100 protein, a feature that is extremely helpful especially in cases where there is no intraepidermal component. Vimentin has also been reported to be positive in most cases of DMM; however, this marker stains a wide range of other spindle cell neoplasms, thus it is not specific for DMM. HMB-45 positivity is more specific for melanoma than S-100 protein but tends to be less sensitive, especially among spindle cell variants. Indeed, most cases of desmoplastic melanoma do not show immunoexpression for HMB-45. [4, 5] Melan-A, the product of the MART-1 gene, is a component of the premelanosomal membrane, and probably a more sensitive immunohistochemical marker than HMB-45. The finding of melanosomes by ultrastructural examination is also a helpful clue for the diagnosis of melanoma; however, as with HMB-45 positivity, melanosomes may not be obvious and their absence does not necessarily exclude the diagnosis of melanoma. Other neural marker which is very helpful in these cases is nerve growth factor (P75) which is very reliable. The differential diagnosis of DMM includes several benign and malignant spindle cell neoplasm including fibromatosis, scar, leiomyosarcoma, atypical fibroxanthoma (AFX) and malignant peripheral nerve sheath tumors (MPNST). A major pitfall is the absence of recognizable atypia in the neoplastic cells; in these cases it is difficult to differentiate DMM from fibromatosis or scar tissue. Other helpful clues for the diagnosis of DMM are the presence of atypical melanocytes in the epidermis, involvement of nerves, the presence of patchy infiltrates of lymphocytes and positivity of the neoplastic cells for the S-100 protein. Leiomyosarcomas and AFX are usually S-100 negative and there is no evidence of clusters of atypical melanocytes in the epidermis in these neoplasms. In addition, AFX may show large, pleomorphic cells, some of which are multinucleated with foamy cytoplasm. MPNST can be virtually identical to DMM. As a matter of fact, some of the reported cases of cutaneous MPNST may indeed be DMM and vice versa. As a practical point, the treatment for both neoplasms is the same. In general, DMM appear to have a more favorable prognosis compared with classical melanomas of similar depth. It also seems that the outcome of these neoplasms is improving, due to early recognition and adequate treatment. Nevertheless, these lesions are potentially fatal and not uncommonly lead to systemic metastasis and death. Several prognostic factors have been implicated in the development of local recurrence and metastasis in DMM. These include margins of excision of less than 1 cm, head and neck localization, and depth of extension. Patients with neoplasms deeper than 4 mm. in thickness have an increased recurrence rate. Ulceration is also a predictor of bad outcome. Jain S, Allen PW. Desmoplastic malignant melanoma and its variants: a study of 45 cases. Am J Surg Pathol 1989;13:358-373. Kilpatrick SE, White WL, Browne JD. Desmoplastic malignant melanoma of the oral mucosa: an underrecognized diagnostic pitfall. Cancer 1996;78:383-389. Egbert B, Kempson R, Sagebiel R. Desmoplastic malignant melanoma: a clinicopathologic study of 25 cases. Cancer 1988;62:2033-2041. Carlson JA, Dickersin GR, Sober AJ, Barnhill RL. Desmoplastic neurotropic melanoma: a clinicopathologic analysis of 28 cases. Cancer 1995;75:478-494. Anstey A, Cerio R, Ramnarain N, et al. Desmoplastic malignant melanoma. An immunocytochemical study of 25 cases. Am J Dermatopathol 1994;16:14-22.