Department of Pathology, University of California, San Francisco, CA, USA.
Cancer Risk Program, Hellen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
Histopathology. 2022 Aug;81(2):264-269. doi: 10.1111/his.14681. Epub 2022 May 27.
Mutations and epimutations in genes encoding the succinate dehydrogenase complex (SDHx) are associated with multiple tumour types in which identification of SDH-deficiency has significant management implications. Immunohistochemistry (IHC) for the succinate dehydrogenase B (SDHB) subunit can help to detect SDH-deficiency, which manifests as complete loss of staining in tumour cells. However, a subset of SDH-deficient tumours can show aberrant cytoplasmic SDHB-IHC staining patterns and be misinterpreted as 'retained', a diagnostic pitfall complicating interpretation. Herein, we characterise in detail aberrant SDHB-IHC staining patterns in SDH-deficient tumours.
We identified 23 tumours from patients with known germline SDHx and/or molecularly confirmed SDHx pathogenic/likely-pathogenic variants in their tumour. Of these, eight (35%) showed significant SDHB-IHC staining: one SDHA-, one SDHB-, three SDHC- and three SDHD-mutated cases. In all eight cases, closer inspection revealed differences in intensity and intracellular distribution of SDHB-IHC staining in tumour cells compared to adjacent non-neoplastic cells: non-neoplastic cells showed intense cytoplasmic coarse granular staining; tumour cells in seven of eight cases showed weak to focally strong, cytoplasmic blush to fine granular staining, in > 80% of cells. The remaining case in the initial block showed variably strong non-granular cytoplasmic staining with globular perinuclear accentuation throughout, only subtly distinct from the staining pattern of non-neoplastic cells. SDHB-IHC performed on two additional blocks in this latter case revealed significant intratumoral heterogeneity, including convincing areas of complete loss.
When evaluating SDHB-IHC, care should be taken to distinguish true retained expression from aberrant cytoplasmic expression, which may be difficult to appreciate. Sometimes this may require additional molecular testing.
琥珀酸脱氢酶复合物（SDHx）编码基因的突变和表观突变与多种肿瘤类型相关，其中 SDH 缺陷的鉴定对管理具有重要意义。琥珀酸脱氢酶 B（SDHB）亚单位的免疫组织化学（IHC）可帮助检测 SDH 缺陷，其表现为肿瘤细胞中完全丧失染色。然而，一部分 SDH 缺陷肿瘤可表现出异常的细胞质 SDHB-IHC 染色模式，并被错误地解释为“保留”，这是一种复杂的诊断陷阱，会导致解释困难。在此，我们详细描述了 SDH 缺陷肿瘤中异常的 SDHB-IHC 染色模式。
我们从患者的肿瘤中确定了 23 个已知具有种系 SDHx 和/或分子上确认的 SDHx 致病性/可能致病性变异的肿瘤。其中，8 个（35%）显示出明显的 SDHB-IHC 染色：1 个 SDHA-、1 个 SDHB-、3 个 SDHC-和 3 个 SDHD-突变病例。在所有 8 个病例中，仔细观察发现肿瘤细胞与相邻非肿瘤细胞的 SDHB-IHC 染色强度和细胞内分布存在差异：非肿瘤细胞显示出强烈的细胞质粗颗粒染色；7 例中的肿瘤细胞表现出弱至局灶性强、细胞质晕染至细颗粒染色，在>80%的细胞中。在最初的切片中，剩余的一个病例表现出不同强度的非颗粒状细胞质染色，伴有核周球状突出，与非肿瘤细胞的染色模式仅略有不同。对该病例的另外两个切片进行 SDHB-IHC 检测，显示出明显的肿瘤内异质性，包括完全丧失的有说服力的区域。
在评估 SDHB-IHC 时，应注意区分真正的保留表达和异常的细胞质表达，这可能难以识别。有时这可能需要额外的分子测试。
