Answer: Biphenotypic Sinonasal Sarcoma

Histology: The tumor consists of a hypercellular proliferation of spindled cells that entraps submucosal glands. The tumor cells grow in a herringbone fascicular pattern. The tumor is focally positive for both S100 and actin.

Discussion: Lewis, et al. recently described a group of low-grade spindle cell sarcomas arising exclusively in the sinonasal tract and named them “low-grade sinonasal sarcoma with neural and myogenic differentiation.” The same group subsequently renamed the entity biphenotypic sinonasal sarcoma (BSNS). Thirty-six cases of BSNS have been reported. They typically arise in the superior aspects of the nasal cavity and ethmoid sinuses of women (M:F ratio is 1:3) ranging in age from 24 to 85 (mean, 52).

Histologically, BSNS is a poorly circumscribed and unencapsulated, uniformly hypercellular proliferation of intersecting fascicles. A “herringbone” fascicular pattern is commonly seen, and “staghorn” vessels are also common. The tumor cell nuclei are elongated, uniform, and hypochromatic. A feature that is diagnostically quite useful is the frequent presence of hyperplastic respiratory surface epithelium extending downward and entrapped by the spindle cell tumor. BSNS is histologically low-grade, lacking high mitotic rates and necrosis. By immunohistochemistry, BSNS characteristically expresses smooth muscle actin, calponin, and S100. BSNS is sometimes also focally positive for desmin, EMA, and cytokeratins. Almost all examples of BSNS harbor rearrangements of PAX3, and the most frequent translocation partner is MAML3. PAX3-MAML3 appears to be specific for BSNS. Huang, et al. recently described a subset of BSNS cases with the same PAX3-NCOA1 fusions that can be seen in alveolar rhabdomyosarcoma. Interestingly, these PAX3-NCOA1 tumors often harbor focal rhabdomyoblastic differentiation, with rare strap cells and myogenin immunoreactivity.

BSNS has only recently been recognized as a distinct entity, and it was likely misdiagnosed as several different neoplasms in the past. Its S100 positivity may suggest a nerve sheath tumor like schwannoma or malignant peripheral nerve sheath tumor. Certainly schwannomas of the sinonasal tract are unencapsulated and can be very hypercellular. However, while BSNS is S100 positive, it is generally not as diffusely immunoreactive as schwannoma, where essentially every cell is strongly positive. In addition, the presence of smooth muscle differentiation argues against schwannoma, and unlike schwannoma, BSNS has been consistently negative for SOX-10. Malignant peripheral nerve sheath tumor may, like BSNS, show aberrant muscle (i.e., malignant Triton tumor) or epithelial differentiation. However, malignant peripheral nerve sheath tumor is generally much higher grade than BSNS, with necrosis and considerable nuclear pleomorphism. It is likely that examples in the literature diagnosed as “low-grade” malignant Triton tumor are, in fact, BSNS. Given the focal cytokeratin immunostaining and uniform nuclear features, a monophasic synovial sarcoma is another diagnostic consideration. However, all cases of BSNS have been negative for synovial sarcoma fusion transcripts. Finally, the staghorn vasculature raises the possibility of glomangiopericytoma or solitary fibrous tumor. The spindled cells and S100 positivity of BSNS argues against glomangiopericytoma which is more epithelioid and S100 negative. In addition, BSNS lacks the characteristic ropey collagen and variable cellularity of solitary fibrous tumor, which is also S100-negative. Finally, the presence of the PAX3 rearrangement characteristic of BSNS is not found in any of the other diagnostic considerations.
Clinically, BSNS behaves relatively indolently. Almost half of patients with BSNS have experience local recurrences, but none of the tumors have metastasized, and none of the patients have died of their disease.

References
1. Lewis JT, Oliveira AM, Nascimento AG, et al. Low-grade sinonasal sarcoma with neural and myogenic features: a clinicopathologic analysis of 28 cases. Am J Surg Pathol. 2012;36:517-525.
2. Wang X, Bledsoe KL, Graham RP, et al. Recurrent PAX3-MAML3 fusion in biphenotypic sinonasal sarcoma. Nat Genet. 2014;46:666-668.
3. Huang SC, Ghossein RA, Bishop JA, et al. Novel PAX3-NCOA1 Fusions in Biphenotypic Sinonasal Sarcoma with Focal Rhabdomyoblastic Differentiation. American Journal of Surgical Pathology. 2015;In press.