Portal de Periódicos da CAPES

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)

2015; Elsevier BV; Volume: 28; Issue: 6 Linguagem: Inglês

10.1038/modpathol.2015.41

1530-0285

Thomas Papathomas, Lindsey Oudijk, Alexandre Persu, Anthony J. Gill, Francien van Nederveen, Arthur S. Tischler, Frédérique Tissier, Marco Volante, Xavier Matías‐Guiu, Marcel Smid, Judith Favier, Elena Rapizzi, Rossella Libé, María Currás-Freixes, Selda Aydın, Thanh Huynh, Urs Lichtenauer, Anouk van Berkel, Letizia Canu, Rita Domingues, Roderick Clifton‐Bligh, Magdalena Białas, Miikka Vikkula, Gustavo Baretton, Mauro Papotti, Gabriella Nesi, Cécile Badoual, Karel Pacák, Graeme Eisenhofer, Henri Timmers, Felix Beuschlein, Jérôme Bertherat, Massimo Mannelli, Mercedes Robledo, Anne‐Paule Gimenez‐Roqueplo, Winand N.M. Dinjens, Esther Korpershoek, Ronald R. de Krijger,

Ovarian cancer diagnosis and treatment

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.