Alveolar rhabdomyosarcoma may be extremely difficult to distinguish from other primitive round cell
neoplasms without ancillary immunohistochemistry and/or genetic study. Particularly in adults and in the head and neck locations, the differential diagnosis of
alveolar rhabdomyosarcoma includes
small cell carcinoma and
neuroepithelial tumors, such as
esthesioneuroblastoma. We have recently seen cases of genetically confirmed
alveolar rhabdomyosarcoma, which were misdiagnosed owing to expression of cytokeratins and neuroendocrine markers. We studied a large group of well-characterized
alveolar rhabdomyosarcomas for expression of such markers. Forty-four
alveolar rhabdomyosarcomas (18 genetically confirmed) were retrieved from our archives and immunostained for wide-spectrum
cytokeratin (OSCAR), low molecular weight
cytokeratin (
Cam5.2),
synaptophysin,
chromogranin A, and CD56 using commercially available
antibodies. Cases were scored as 'negative', 'rare' (<5% positive cells), '1+' (5-25%), '2+' (26-50%) and '3+' (>51%). The
tumors occurred in 23 males and 21 females at a mean age of 18 years (range, <1-64 years), and involved many sites. Fifty percent of cases (22 of 44) expressed wide-spectrum
cytokeratin, and scored almost equally as rare, 1+, and 2+, but rarely 3+.
Cam5.2 was positive in 52% (14 of 27). Forty-three percent of cases (16 of 37) expressed at least one of the specific neuroendocrine markers, 32% (12 of 37) expressed
synaptophysin, 22% (eight of 36) expressed
chromogranin A, and 11% expressed both. Expression of
synaptophysin and
chromogranin A was typically confined to rare cells but could be more widespread. Thirty-two percent of cases (12 of 37) expressed the wide-spectrum
cytokeratin and at least one of the neuroendocrine markers, and 8% (three of 36) expressed
cytokeratin and both neuroendocrine markers. CD56 expression was nearly ubiquitous. Aberrant expression of epithelial and neuroendocrine markers is relatively common in
alveolar rhabdomyosarcoma, occurring in 30-40% of cases. These findings have significant implications for the diagnosis of
alveolar rhabdomyosarcoma, particularly in adults and in the head and neck locations. Although expression of
cytokeratin and/or
synaptophysin alone does not necessarily indicate epithelial or neuroendocrine differentiation, coexpression of
cytokeratin and neuroendocrine markers, and in particular the presence of
chromogranin expression, suggest true epithelial and/or neuroendocrine differentiation in a subset of
alveolar rhabdomyosarcomas. CD56 is not a specific neuroendocrine marker, and should not be used in the absence of
synaptophysin/
chromogranin. These findings emphasize the need to employ a panel of markers, to include
desmin,
myogenin/MyoD1, and genetic study in the diagnosis of primitive round cell
neoplasms in all age groups and in all locations.