SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: A multicenter interobserver variation analysis using virtual microscopy: A Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T)

Thomas G. Papathomas, Lindsey Oudijk, Alexandre Persu, Anthony J. Gill, Francien Van Nederveen, Arthur S. Tischler, Frédérique Tissier, Marco Volante, Xavier Matias-Guiu, Marcel Smid, Judith Favier, Elena Rapizzi, Rosella Libe, Maria Currás-Freixes, Selda Aydin, Thanh Huynh, Urs Lichtenauer, Anouk Van Berkel, Letizia Canu, Rita DominguesRoderick J. Clifton-Bligh, Magdalena Bialas, Miikka Vikkula, Gustavo Baretton, Mauro Papotti, Gabriella Nesi, Cécile Badoual, Karel Pacak, Graeme Eisenhofer, Henri J. Timmers, Felix Beuschlein, Jérôme Bertherat, Massimo Mannelli, Mercedes Robledo, Anne Paule Gimenez-Roqueplo, Winand N.M. Dinjens, Esther Korpershoek, Ronald R. De Krijger

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Abstract

Despite the established role of SDHB/SDHA immunohistochemistry as a valuable tool to identify patients at risk for familial succinate dehydrogenase-related pheochromocytoma/paraganglioma syndromes, the reproducibility of the assessment methods has not as yet been determined. The aim of this study was to investigate interobserver variability among seven expert endocrine pathologists using a web-based virtual microscopy approach in a large multicenter pheochromocytoma/paraganglioma cohort (n=351): (1) 73 SDH mutated, (2) 105 non-SDH mutated, (3) 128 samples without identified SDH-x mutations, and (4) 45 with incomplete SDH molecular genetic analysis. Substantial agreement among all the reviewers was observed either with a two-tiered classification (SDHB κ=0.7338; SDHA κ=0.6707) or a three-tiered classification approach (SDHB κ=0.6543; SDHA κ=0.7516). Consensus was achieved in 315 cases (89.74%) for SDHB immunohistochemistry and in 348 cases (99.15%) for SDHA immunohistochemistry. Among the concordant cases, 62 of 69 (∼90%) SDHB-/C-/D-/AF2-mutated cases displayed SDHB immunonegativity and SDHA immunopositivity, 3 of 4 (75%) with SDHA mutations showed loss of SDHA/SDHB protein expression, whereas 98 of 105 (93%) non-SDH-x-mutated counterparts demonstrated retention of SDHA/SDHB protein expression. Two SDHD-mutated extra-adrenal paragangliomas were scored as SDHB immunopositive, whereas 9 of 128 (7%) tumors without identified SDH-x mutations, 6 of 37 (∼16%) VHL-mutated, as well as 1 of 21 (∼5%) NF1-mutated tumors were evaluated as SDHB immunonegative. Although 14 out of those 16 SDHB-immunonegative cases were nonmetastatic, an overall significant correlation between SDHB immunonegativity and malignancy was observed (P=0.00019). We conclude that SDHB/SDHA immunohistochemistry is a reliable tool to identify patients with SDH-x mutations with an additional value in the assessment of genetic variants of unknown significance. If SDH molecular genetic analysis fails to detect a mutation in SDHB-immunonegative tumor, SDHC promoter methylation and/or VHL/NF1 testing with the use of targeted next-generation sequencing is advisable.

Original languageEnglish
Pages (from-to)807-821
Number of pages15
JournalModern Pathology
Volume28
Issue number6
DOIs
Publication statusPublished - 1 Jun 2015

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