Santi Raffaella, Rapizzi Elena, Canu Letizia, Ercolino Tonino, Baroni Gianna, Fucci Rossella, Costa Giuseppe, Mannelli Massimo, Nesi Gabriella
Division of Pathological Anatomy, University of Florence, Florence, Italy.
Department of Clinical Pathophysiology, University of Florence, Florence, Italy.
Anticancer Res. 2017 Feb;37(2):805-812. doi: 10.21873/anticanres.11381.
BACKGROUND/AIM: Germline mutations in any of the succinate dehydrogenase (SDH) genes result in destabilization of the SDH protein complex and loss of SDHB expression at immunohistochemistry. SDHA is lost together with SDHB in SDHA-mutated tumours, but its expression is retained in tumours with other SDH mutations. We investigated whether SDHA/SDHB immunohistochemistry is able to identify SDH-related tumours in a retrospective case series of phaeochromocytomas (PCCs) and paragangliomas (PGLs).
SDHA and SDHB immunostaining was performed in 13 SDH gene-mutated tumours (SDHB: n=3; SDHC: n=1; SDHD: n=9) and 16 wild-type tumours. Protein expression by western blot analysis and enzymatic activity were also assessed.
Tumours harbouring SDH gene mutations demonstrated a significant reduction in enzymatic activity and protein expression when compared to wild-type tumours. SDHB immunostaining detected 76.9% of SDH mutated PCCs/PGLs (3/3 SDHB-mutated samples; 1/1 SDHC-mutated sample; 6/9 SDHD-mutated samples). In three SDHD-related tumours with the same mutation (p.Pro81Leu), positive (n=2) or weakly diffuse (n=1) SDHB staining was observed. All wild-type PCCs/PGLs exhibited SDHB immunoreactivity, while immunostaining for SDHA was positive in 93.8% cases and weakly diffuse in one (6.2%). SDHA protein expression was preserved in all tumours with mutations.
SDHA and SDHB immunohistochemistry should be interpreted with caution, due to possible false-positive or false-negative results, and ideally in the setting of quality assurance provided by molecular testing. In SDHD mutation, weak non-specific cytoplasmic staining occurs commonly, and this pattern of staining can be difficult to interpret with certainty.
背景/目的：琥珀酸脱氢酶（SDH）基因中的任何一种发生种系突变都会导致SDH蛋白复合体不稳定，免疫组化时SDHB表达缺失。在SDHA突变的肿瘤中，SDHA与SDHB一起缺失，但其表达在其他SDH突变的肿瘤中得以保留。我们在一个嗜铬细胞瘤（PCC）和副神经节瘤（PGL）的回顾性病例系列中研究了SDHA/SDHB免疫组化是否能够识别与SDH相关的肿瘤。
对13个SDH基因突变肿瘤（SDHB：n = 3；SDHC：n = 1；SDHD：n = 9）和16个野生型肿瘤进行SDHA和SDHB免疫染色。还通过蛋白质印迹分析评估蛋白质表达，并检测酶活性。
与野生型肿瘤相比，携带SDH基因突变的肿瘤酶活性和蛋白质表达显著降低。SDHB免疫染色检测到76.9%的SDH突变型PCC/PGL（3/3个SDHB突变样本；1/1个SDHC突变样本；6/9个SDHD突变样本）。在三个具有相同突变（p.Pro81Leu）的与SDHD相关的肿瘤中，观察到SDHB染色阳性（n = 2）或弱阳性弥漫性（n = 1）。所有野生型PCC/PGL均表现出SDHB免疫反应性，而SDHA免疫染色在93.8%的病例中呈阳性，1例（6.2%）为弱阳性弥漫性。所有突变肿瘤中SDHA蛋白表达均得以保留。
由于可能出现假阳性或假阴性结果，SDHA和SDHB免疫组化应谨慎解读，理想情况下应在分子检测提供的质量保证背景下进行。在SDHD突变中，常见弱非特异性细胞质染色，这种染色模式可能难以确切解读。
