Atypical BAP1 Deficient Epithelioid Spitz's Tumor

The patient has a very unusual atypical epithelioid tumor arising in a background of a compound nevus. This nodule is composed of pleomorphic atypical epithelioid melanocytes. This proliferation defies categorization as a nevus. The differential diagnosis encompasses a nevoid melanoma with spitzoid features arising in a precursor compound nevus versus a melanocytic tumor of undetermined malignant potential with features of the atypical Spitz's tumor versus an unusual variant of the epithelioid spitzoid tumor namely one showing a loss of BAP1. Given loss of BAP1 on IHC, the overall assessment is that of a combined lesion composed of an atypical BAP1-deficient epithelioid Spitz tumor and conventional melanocytic nevus.

Germline mutations in BAP1 cause a familial tumor syndrome characterized by melanocytic tumors with distinct clinical and histologic features. These neoplasms tend to harbor mutations in BRAF and show loss of BAP1 expression by immunohistochemistry. Histologically they resemble the so-called "atypical Spitz tumors". In fact, a subset of atypical Spitz tumors does harbor similar losses of BAP1 expression and concomitant BRAF mutations. These tumors are primarily located in the dermis and are composed of epithelioid melanocytes with abundant amphophilic cytoplasm and well-defined cytoplasmic borders. Nuclei are pleomorphic and contain conspicuous nucleoli. Wiesner T et al. A distinct subset of atypical Spitz tumors is characterized by BRAF mutation and loss of BAP1 expression. Am J Surg Pathol. 2012 Jun;36(6):818-30

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Slide 1: 28 year-old man with a pigmented lesion of the right arm. The excision specimen shows a predominantly dermal based proliferation.

Slide 2: The excision specimen shows a significantly atypical dermal based melanocytic tumor (right) arising in association with a more conventional benign compound nevus (left).

Slide 3: BAP1 immunostain reveals preserved staining in the compound nevus (left) as well as in the overlying epidermis with loss of staining seen in the atypical cells.

Slide 4: The tumor distorts the dermis resulting in a polypoid alteration of the dermis. The cells have a large bizarre epithelioid appearance. These cells are disposed singly and in small nests. There is considerable cell to cell heterogeneity. Many of the cells show large nuclei with a tendency toward multinucleation. A number of the cells have nuclear pseudoinclusions. The atypia is severe cytomorphologically and architecturally. The cytomorphology is somewhat spitzoid in appearance as one might encounter in an least an atypical Spitz's tumor. There are scattered mitotic figures. The mitotic rate is roughly 1 per mm2.

Slide 5: Junction between conventional compund nevus (left) and atypical epithelioid melanocytic proliferation (right).

Slide 6: These cells are disposed singly and in small nests. There is considerable cell to cell heterogeneity. Many of the cells show large nuclei with a tendency toward multinucleation. A number of the cells have nuclear pseudoinclusions. The atypia is severe cytomorphologically and architecturally. The cytomorphology is somewhat spitzoid in appearance as one might encounter in an least an atypical Spitz's tumor. The Ki-67/Melan-A stain does reveal a few of the bizarre cells within the dermis showing nuclear staining for Ki-67, although overall the proliferation index is very low. The R21 preparation shows diffuse cytoplasmic staining. There are occasional mitotically active cells that show a pan nuclear staining pattern for R21. The HMB45 stain highlights the many reactive melanocytes in the epidermis but the dermal component including the bizarre atypical epithelioid tumor is negative.