Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes

• Published in: Human pathology Vol. 41; no. 6; pp. 805 - 814
• Main Authors: Gill, Anthony J., Benn, Diana E., Chou, Angela, Clarkson, Adele, Muljono, Anita, Meyer-Rochow, Goswin Y., Richardson, Anne Louise, Sidhu, Stan B., Robinson, Bruce G., Clifton-Bligh, Roderick J.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.06.2010; Elsevier; Elsevier Limited
• Subjects: Adrenal Gland Neoplasms - genetics; Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Adult; Aged; Biological and medical sciences; Cohort Studies; Endocrinopathies; Female; Genetic Testing; Genetics; Germ-Line Mutation; Humans; Immunohistochemistry; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Membrane Proteins - genetics; Middle Aged; Mutation; Neurology; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Paraganglioma; Paraganglioma - genetics; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Pheochromocytoma; Pheochromocytoma - genetics; SDHB; Succinate Dehydrogenase - genetics; Syndrome; Tumors; Tumors of the nervous system. Phacomatoses; Young Adult; Paraganglioma; SDHB; Pheochromocytoma; Endocrinopathy; Secretory tumor; Immunohistochemistry; Nervous system diseases; Anatomic pathology; Diseases of the autonomic nervous system; Genetics; Medical screening; Syndrome
• ISSN: 0046-8177; 1532-8392; 1532-8392
• DOI: 10.1016/j.humpath.2009.12.005

Up to 30% of pheochromocytomas and paragangliomas are associated with germline RET, Von Hippel–Lindau ( VHL), neurofibromatosis type I ( NF1), and succinate dehydrogenase subunits ( SDHB, SDHC, and SDHD) mutations. Genetic testing allows familial counseling and identifies subjects at high risk of malignancy ( SDHB mutations) or significant multiorgan disease ( RET, VHL, or NF1). However, conventional genetic testing for all loci is burdensome and costly. We performed immunohistochemistry for SDHB on 58 tumors with known SDH mutation status. We defined positive as granular cytoplasmic staining (a mitochondrial pattern), weak diffuse as a cytoplasmic blush lacking definite granularity, and negative as completely absent staining in the presence of an internal positive control. All 12 SDH mutated tumors (6 SDHB, 5 SDHD, and 1 SDHC) showed weak diffuse or negative staining. Nine of 10 tumors with known mutations of VHL, RET, or NF1 showed positive staining. One VHL associated tumor showed weak diffuse staining. Of 36 tumors without germline mutations, 34 showed positive staining. One paraganglioma with no known SDH mutation but clinical features suggesting familial disease was negative, and one showed weak diffuse staining. We also performed immunohistochemistry for SDHB on 143 consecutive unselected tumors of which 21 were weak diffuse or negative. As SDH mutations are virtually always germline, we conclude that approximately 15% of all pheochromocytomas or paragangliomas are associated with germline SDH mutation and that immunohistochemistry can be used to triage genetic testing. Completely absent staining is more commonly found with SDHB mutation, whereas weak diffuse staining often occurs with SDHD mutation.