Immunohistochemical distinction of paragangliomas from epithelial neuroendocrine tumors—gangliocytic duodenal and cauda equina paragangliomas align with epithelial neuroendocrine tumors

• Published in: Human pathology Vol. 103; pp. 72 - 82
• Main Authors: Mamilla, Divya, Manukyan, Irena, Fetsch, Patricia A., Pacak, Karel, Miettinen, Markku
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2020; Elsevier Limited
• Subjects: Adult; Aged; Biomarkers, Tumor - analysis; Bladder; Carcinoma, Neuroendocrine - diagnosis; Cauda Equina - pathology; Cauda equina paraganglioma; Duodenal Neoplasms - diagnosis; Female; Gangliocytic paraganglioma; GATA3; Humans; Immunohistochemistry; Keratin; Keratins; Male; Middle Aged; Neck; Neuroendocrine tumor; Neuroendocrine tumors; Paraganglioma; Paraganglioma - diagnosis; Peripheral Nervous System Neoplasms - diagnosis; Proteins; Thorax; Thyroid gland; Transcription factors; Tyrosine hydroxylase; Keratins; Gangliocytic paraganglioma; Paraganglioma; Cauda equina paraganglioma; Tyrosine hydroxylase; GATA3; Neuroendocrine tumor
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2020.07.010

Distinction of paraganglioma (PGL) from epithelial neuroendocrine tumors (NETs) can be difficult as they can mimic each other by nested architecture and expression of neuroendocrine markers. In this study, we examined differential diagnostic markers in 262 PGLs (142 adrenal pheochromocytomas and 120 extra-adrenal PGLs), 9 duodenal gangliocytic PGLs and 3 cauda equina PGLs, and 286 NETs (81 GI, 78 pancreatic, 42 thoracic, 37 medullary thyroid carcinomas, and 48 high-grade NETs including 32 small cell carcinomas of lung). While keratin expression was nearly uniform in NETs with the exception of few tumors, extensive keratin expression was seen in only one PGL (<1%) and focal expression in 5% PGLs. GATA3 was present in >90% of PGLs but only in 2% of NETs, usually focally. Tyrosine hydroxylase (TH) was expressed in >90% of adrenal, abdominal, and thoracic PGLs but only in 37% of head and neck PGLs, reflecting their variable catecholamine synthesis. Focal or occasional extensive TH-expression was detected in 10% of NETs. CDX2 was a helpful discriminator seen in 28% of pancreatic and most GI NETs but in no PGLs. SOX10 detected sustentacular cells in 85% of PGLs and 7% of NETs, whereas GFAP detected sustentacular cells mainly in PGLs of neck and was absent in NETs. Duodenal gangliocytic PGLs (n = 9) and all cauda equina PGLs (n = 3) expressed keratins, lacked GATA3, showed no or minimal TH expression as some NETs, and contained SOX10 and S100 protein-positive spindle cells negative for GFAP. Ganglion-like epithelioid cells were keratin-positive and negative for TH and SOX10 differing from true ganglion cells. We conclude that duodenal gangliocytic and cauda equina PGLs have a NET-like immunoprofile and differ from ordinary PGLs. NETs can be distinguished from PGLs by their expression of keratins and general lack of GATA3, TH, and GFAP-positive sustentacular cells, and sometimes by expression of CDX2 or TTF1. •Keratins, GATA3, CDX2, TTF1, and tyrosine hydroxylase distinguish PGLs from NETs.•Gangliocytic PGL and cauda equina paraganglioma have NET-like immunoprofiles.•SOX10 is superior to S100 protein to evaluate sustentacular cells.•Occasional pancreatic NETs mimic paragangliomas by their antigenic patterns.