TEACHING CASE 4

Relevant clinical history:
A 65 year old man presented with a nodule in the skin of his left arm. A biopsy was performed; at the same time, a basal cell carcinoma was removed from the patient's face.

H & E images:

Low power (fig. 1)

Medium power (fig. 2)

High power (fig. 3)

This dermal tumor is composed of cohesive nests of atypical to anaplastic cells, showing frequent mitotic figures, including some atypical mitoses. The tumor nests abut but do not involve the epidermis. Preliminary studies performed in the rerferring pathologist's laboratory suggested that the tumor was S100-positive but gp100-negative (the latter using antibody HMB-45). A paraffin block was submitted to confirm the suspicion that, despite the negative gp100 studies, this represented metastatic melanoma.

Relevant clinical history:

Focal cytokeratin positivity:

Fig.4: cytokeratins

Using broad spectrum anti-cytokeratin antibodies (AE1 + AE3, and the new clone, OSCAR), focal cytokeratin expression was detected. This is not the pattern of expression seen in carcinoma, in which uniform cytoplasmic immunostaining is the rule. While this finding neither confirms nor excludes melanoma, it raises a limited differential diagnosis, as discussed below. (After controversy in the 1980's regarding cytokeratin expression in melanomas, several studies [1,2] demonstrated definitively that most melanomas express low levels of cytokeratins; in the era of 'antigen retrieval', this feature of melanoma has been more widely accepted).

Negative melanoma markers:
To exclude melanoma with a high degree of confidence, given that absence of expression of the premelanosomal antigen gp100 (detected by the antibody HMB-45) is a characteristic of 5-10% of metastatic melanomas, we employ four separate antibodies to distinct melanoma-associated antigens. The antigens are gp-100; MART1 ('melanoma antigen recognized by T cells', also called MelanA); tyrosinase (a melanosomal protein); and microphthalmia transcription factor, the most recently described melanoma marker, which appears in early studies to manifest nearly 100% sensitivity in melanomas (3,4). All 4 melanoma-associated markers were negative in this case, however, essentially excluding that diagnosis.

The differential diagnosis of epithelioid tumors with focal cytokeratin expression includes melanoma, some poorly differentiated carcinomas, and some sarcomas, notably angiosarcoma (especially epithelioid variants), synovial sarcoma, epithelioid sarcoma, and malignant peripheral nerve sheath tumor (MPNST).

Of these tumors, angiosarcoma is argued against in this case by lack of expression of vascular markers CD31 and CD34. Epithelioid sarcoma does not enter into the histologic or clinical differential in this case. Likewise, monophasic synovial sarcoma is very unlikely in this clinical setting; of note, up to 30% of synovial sarcomas (5) show focal S-100 immunoreactivity, but uniform expression is not a feature of synovial sarcoma. By contrast, about 50% of MPNST express S-100, usually focally.

Fig. 5: S-100	The superficial epithelioid variant of MPNST, however, expresses S-100 in a much higher proportion of cells than do similar tumors in deep soft tissue (6,7), making distinction from melanoma a significant immunohistochemical diagnostic consideration.
Fig. 6: type IV coll	Both the superficial epithelioid and deep soft tissue MPNST also show a consistent pattern of Type IV collagen expression, in which individual cells appear to be surrounded by the antigen, as in this case (fig 6).
Fig. 7: p75-NTR	In addition, other markers of nerve/nerve sheath differentiation, including the nerve growth factor receptor p75-NTR, may be expressed, as was the case in this tumor (fig 7).

Like their deep soft tissue counterparts, superficial epithelioid MPNST (comprising perhaps up to 5% of MPNST) appear to arise in nerves or pre-existing neurofibromas, and they occur at younger ages and with increased frequency in individuals with neurofibromatosis. The majority of cases occur in patients 20-50 years of age. Presumably because of their circumscription and superficial location, these tumors appear to have a better prognosis than their deep-seated counterparts (5); likewise, their behavior is obviously substantially better than similarly situated melanomas.

In summary, this dermal lesion excised from the arm of a 65-year-old man represents an unusual variant of MPNST, referred to as the superficial epithelioid variant. This tumor, because of its location, histology, and immunophenotype, must be distinguished from malignant melanoma.

FINAL DIAGNOSIS: Malignant peripheral nerve sheath tumor (MPNST), superficial epithelioid type.

References:

1. Zarbo RJ, Gown AM, Nagle RB. Anomalous cytokeratin expression in malignant melanoma: one- and two-dimensional Western blot analysis and immunohistochemical survey of 100 melanomas. Mod Pathol 1990;3:494-501.
2. Miettinen M, Fransilla K. Immunohistochemical spectrum of malignant melanoma: the common presence of keratins. Lab Invest 1989;61:623-8.
3. King R, Weilbaecher KN, McGill G, Cooley E, Mihm M, Fisher DE. Microphthalmia transcription factor. A sensitive and specific melanocyte marker for melanoma diagnosis. Am J Pathol 1999;155(3):731-8
4. Chang KL, Folpe AL. Diagnostic utility of microphthalmia transcription factor in malignant melanoma and other tumors. Adv Anat Pathol 2001 Sep;8(5):273-5
5. Weiss SW, Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors, 4 ed. Mosby, Inc. St Louis, 2001. pp.1503, 1235-1241
6. Fletcher CDM, ed. Diagnostic Histopathology of Tumors, 2 ed. Harcourt Publishers Ltd. London, 2000. p.1698
7. Laskin WB, Weiss SW, Bratthauer GL. Am J Surg Pathol 1991 Dec;15(12):1136-45.
   
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