TY - JOUR
T1 - SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas
T2 - A multicenter interobserver variation analysis using virtual microscopy: A Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T)
AU - Papathomas, Thomas G.
AU - Oudijk, Lindsey
AU - Persu, Alexandre
AU - Gill, Anthony J.
AU - Van Nederveen, Francien
AU - Tischler, Arthur S.
AU - Tissier, Frédérique
AU - Volante, Marco
AU - Matias-Guiu, Xavier
AU - Smid, Marcel
AU - Favier, Judith
AU - Rapizzi, Elena
AU - Libe, Rosella
AU - Currás-Freixes, Maria
AU - Aydin, Selda
AU - Huynh, Thanh
AU - Lichtenauer, Urs
AU - Van Berkel, Anouk
AU - Canu, Letizia
AU - Domingues, Rita
AU - Clifton-Bligh, Roderick J.
AU - Bialas, Magdalena
AU - Vikkula, Miikka
AU - Baretton, Gustavo
AU - Papotti, Mauro
AU - Nesi, Gabriella
AU - Badoual, Cécile
AU - Pacak, Karel
AU - Eisenhofer, Graeme
AU - Timmers, Henri J.
AU - Beuschlein, Felix
AU - Bertherat, Jérôme
AU - Mannelli, Massimo
AU - Robledo, Mercedes
AU - Gimenez-Roqueplo, Anne Paule
AU - Dinjens, Winand N.M.
AU - Korpershoek, Esther
AU - De Krijger, Ronald R.
N1 - Funding Information:
This study was supported by the Seventh Frame-work Programme (FP7/2007–2013) under grant agreement no. 259735 (ENS@T-Cancer). Genetic analysis of the Belgian subset was partly supported by the Fonds de la Recherche Scientifique Médicale (FRSM) convention number 3.4.587.08 F (to AP). AP, SA, and MV acknowledge the contribution of N Lannoy, A Mendola, and L Evenepoel (Clin. Univ. St-Luc/UCL) for genetic analysis and F Severino (Clin. Univ. St-Luc) for maintenance of the database. Besides Professor A Mourin (Clin. Univ. St-Luc/ UCL), they are also grateful to all pathologists who contributed tumor samples: Professors M Delos and B Weynand and Drs M-C Nollevaux and C Fervaille (Cl. Un. De Mont-Godinne, UCL); Drs N Detrembleur, N Blétard, and I Scagnol (CHU Sart-Tilman, Ulg); Drs E Laterre and G Beniuga (IPG Gosselies); Professor H De Raeve and Dr W Jeuris (OLV, Aalst); Dr V Duwel (Ziekenhuis KLINA); Drs A Janssen and S Talpe (Clniques du Sud-Luxembourg, Arlon); Drs C Robrechts and J Bekaert (Imelda Ziekenhuis); Dr R Duttmann (CHU Brugmann); Dr N de Saint-Aubain (Institut Bordet); and Drs R Achten and K Wouters (Jessa Ziekenhuis). MM, ER, LC, and GN acknowledge the contribution of Dr T Ercolino for the genetic analysis of the Italian (Florence) samples. GE and GB acknowledge the contribution of Drs C Pamporaki, R Därr, S Richter, and J Brütting for data collection of the German (Dresden) samples. We thank J Shukla (Erasmus MC Cancer Institute) for her valuable technical assistance as well as Drs M Versasky and M Gomez Morales (Hospital Universitario San Cecilio) for providing one SDHD-mutated HNPGL sample.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84930178967
U2 - 10.1038/modpathol.2015.41
DO - 10.1038/modpathol.2015.41
M3 - Article
C2 - 25720320
AN - SCOPUS:84930178967
SN - 0893-3952
VL - 28
SP - 807
EP - 821
JO - Modern Pathology
JF - Modern Pathology
IS - 6
ER -