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

Summary 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 hi...

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Published in:Human pathology 2010-06, Vol.41 (6), p.805-814
Main Authors: Gill, Anthony J., FRCPA, Benn, Diana E., PhD, Chou, Angela, FRCPA, Clarkson, Adele, BSc, Muljono, Anita, FRCPA, Meyer-Rochow, Goswin Y., FRACS, Richardson, Anne Louise, BSc, Sidhu, Stan B., PhD, Robinson, Bruce G., MD, Clifton-Bligh, Roderick J., PhD
Format: Article
Language:English
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
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Summary:Summary 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.
ISSN:0046-8177
1532-8392
DOI:10.1016/j.humpath.2009.12.005