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

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.

doi:10.1016/j.humpath.2009.12.005

« Previous Next »Human Pathology
Volume 41, Issue 6 , Pages 805-814, June 2010

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

Anthony J. Gill, FRCPA
- Department of Anatomical Pathology, Royal North Shore Hospital, Sydney 2065, Australia
- University of Sydney, Sydney 2006, Australia
- Corresponding author. Department of Anatomical Pathology, Royal North Shore Hospital, Pacific Highway, St Leonards, NSW 2065, Australia.
- Dr Gill and Dr Benn contributed equally to this work.
Diana E. Benn, PhD
- Cancer Genetics, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney 2065, Australia
- Dr Gill and Dr Benn contributed equally to this work.
Angela Chou, FRCPA
- Department of Anatomical Pathology, Royal North Shore Hospital, Sydney 2065, Australia
Adele Clarkson, BSc
- Department of Anatomical Pathology, Royal North Shore Hospital, Sydney 2065, Australia
Anita Muljono, FRCPA
- Anatomical Pathology, Douglas Hanly Moir Pathology, Sydney 2113, Australia
Goswin Y. Meyer-Rochow, FRACS
- Cancer Genetics, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney 2065, Australia
- Department of Surgery, Waikato Clinical School, Faculty of Medical and Health Sciences, University of Auckland 3240, New Zealand
Anne Louise Richardson, BSc
- Cancer Genetics, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney 2065, Australia
Stan B. Sidhu, PhD
- Cancer Genetics, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney 2065, Australia
- University of Sydney, Department of Endocrine Surgery, Royal North Shore Hospital, Sydney 2065, Australia
Bruce G. Robinson, MD
- Cancer Genetics, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney 2065, Australia
Roderick J. Clifton-Bligh, PhD
- Cancer Genetics, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney 2065, Australia

Received 9 November 2009; received in revised form 1 December 2009; accepted 2 December 2009. published online 18 March 2010.

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.