| Literature DB >> 25720320 |
Thomas G Papathomas1, Lindsey Oudijk2, Alexandre Persu3, Anthony J Gill4, Francien van Nederveen5, Arthur S Tischler6, Frédérique Tissier7, Marco Volante8, Xavier Matias-Guiu9, Marcel Smid10, Judith Favier11, Elena Rapizzi12, Rosella Libe13, Maria Currás-Freixes14, Selda Aydin15, Thanh Huynh16, Urs Lichtenauer17, Anouk van Berkel18, Letizia Canu12, Rita Domingues19, Roderick J Clifton-Bligh20, Magdalena Bialas21, Miikka Vikkula22, Gustavo Baretton23, Mauro Papotti8, Gabriella Nesi24, Cécile Badoual25, Karel Pacak16, Graeme Eisenhofer26, Henri J Timmers18, Felix Beuschlein17, Jérôme Bertherat27, Massimo Mannelli28, Mercedes Robledo29, Anne-Paule Gimenez-Roqueplo11, Winand Nm Dinjens2, Esther Korpershoek2, Ronald R de Krijger30.
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.Entities:
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Year: 2015 PMID： 25720320 DOI： 10.1038/modpathol.2015.41
Source DB: PubMed Journal: Mod Pathol ISSN： 0893-3952 Impact factor: 7.842