Aberrant expression of epithelial and neuroendocrine markers in alveolar rhabdomyosarcoma: a potentially serious diagnostic pitfall

Abstract

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' (o5% positive cells), '1 þ ' (5-25%), '2 þ ' (26-50%) and '3 þ ' (451%). The tumors occurred in 23 males and 21 females at a mean age of 18 years (range, o1-64 years), and involved many sites. Fifty percent of cases (22 of 44) expressed wide-spectrum cytokeratin, and scored almost equally as rare, 1 þ , and 2 þ , but rarely 3 þ . 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.

Aberrant intermediate filament and synaptophysin expression is a frequent event in malignant melanoma: an immunohistochemical study of 73 cases

“…40 Aberrant chromogranin A exception is exceptional, seen only in very rare alveolar rhabdomyosarcomas 5 and angiosarcomas. 40 Synaptophysin expression has been reported previously in o10 melanomas, 9,10,34,41 including 1 case with overt ganglioneuromatous differentiation 34 and 2 cases showing actual neuroendocrine differentiation, in the form of chromogranin A co-expression and ultrastructurally confirmed dense core granules.…”

“…1 Welldescribed examples of this phenomenon include keratin expression in angiosarcoma, 2 leiomyosarcoma, 3 and Ewing sarcoma, 4 and synaptophysin expression in alveolar rhabdomyosarcoma. 5 It is less widely appreciated that melanomas too may show aberrant expression of various immunohistochemical markers, with a relatively small number of reports, of melanomas showing expression of intermediate filaments other than vimentin (e.g., keratins, desmin, neurofilament protein, and glial fibrillary acidic protein) [6][7][8] and/or neuroendocrine markers. [9][10][11] Over the past several years, we have seen in consultation a significant number of melanomas in which aberrant expression of intermediate filaments and/or neuroendocrine markers obscured the correct diagnosis, and prompted consideration of various non-melanocytic neoplasms, including carcinoma, rhabdomyosarcoma, neural neoplasms, and various neuroendocrine tumors.…”

Ewing’s Family of Tumors of the Sinonasal Tract and Maxillary Bone

“…The histologic and immunophenotypic diversity of EFTs, including occasional keratin and neuroendocrine marker positivity [11], makes the diagnosis of this entity quite challenging particularly in small biopsies. Compounding this difficulty is the fact that other non-epithelial or neuroendocrine tumors, such as alveolar rhabdomyosarcoma, have recently been reported to occasionally stain with keratins and/or synaptophysin [12]. Herein, we describe the clinicopathologic features, immunohistochemical profile and molecular characteristics of a series of 14 cases of sinonasal tract EFT and review the literature to determine the prognostic implications of the diagnosis in this location.…”

Small round blue cell tumors of the sinonasal tract: a differential diagnosis approach

“…a Pituitary hormones and/or pituitary transcription factors, but may include or peptides and hormones (ADH, oxytocin). Based on data aggregate in part from Bahrami et al, 36 Bell et al, 51 Bishop et al, 74 Bourne et al, 143 Chapman-Fredricks et al, 88 Folpe et al, 151 Hafezi et al, 150 Hicks et al, 30 Nikitakis et al, 166 Thompson et al, 7 Thompson et al, 124 Thompson et al, 159 and Wooff et al 57 …”

“…A characteristic plasmacytoidrhabdoid appearance, with eccentric, eosinophilic cytoplasm strongly suggests ribbon or strap-type Figure 5a and b), with Myo-D1 and muscle-specific actin less frequently positive; smooth muscle actin is only detected in about 10% of cases. 30 Co-expression of CD56, synaptophysin (Figure 5c), cytokeratins (up to 10%; Figure 5d), EMA, NSE, and CD99, 30,[36][37][38] must be taken into account in differential diagnosis, especially when choosing a panel of immunohistochemistry studies to perform. A FISH breakapart probe for FOXO1 (13q14) may help to confirm the commonly identified fusion with PAX3 or PAX7 genes in alveolar rhabdomyosarcoma.…”