Laboratory of Pathology, National Cancer Institute, Bethesda, 20892, USA.
Am J Surg Pathol. 2011 Nov;35(11):1712-21. doi: 10.1097/PAS.0b013e3182260752.
Most gastrointestinal stromal tumors (GISTs) are driven by KIT or PDGFRA-activating mutations, but a small subset is associated with loss of function of the succinate dehydrogenase (SDH) complex of mitochondrial inner membrane proteins. This occurs by germline mutations of the SDH subunit genes and hitherto unknown mechanisms. SDH-deficient GISTs especially include pediatric GISTs and those associated with Carney triad (CT) or Carney-Stratakis syndromes (CSSs); the latter 2 also include paraganglioma as a component. SDH-deficient GISTs were identified in this study on the basis of immunohistochemical loss of succinate dehydrogenase subunit B (SDHB), which signals functional loss of the SDH complex. We found 66 SDH-deficient GISTs among 756 gastric GISTs, with an estimated frequency of 7.5% of unselected cases. Nearly, all gastric GISTs in patients <20 years, and a substantial percentage of those in patients <40 years, but only rare GISTs in older adults were SDH deficient. There was a female predominance of over 2:1. Two patients each had either pulmonary chondroma or paraganglioma (CT), but none of the examined cases had SDH germline mutations (CSS) or somatic KIT/PDGFRA or BRAF mutations. SDH-deficient GISTs were often multiple and typically showed plexiform muscularis propria involvement and epithelioid hypercellular morphology. They were consistently KIT-positive and DOG1/Ano 1-positive and almost always smooth muscle actin negative. Tumor size and mitotic activity varied, and the tumors were somewhat unpredictable with low mitotic rates developing metastases. Gastric recurrences occurred in 11 patients, and peritoneal and liver metastases occurred in 8 and 10 patients, respectively. Lymph node metastases were detected in 5 patients, but lymphovascular invasion was present in >50% of cases studied; these 2 were not related to adverse outcome. Seven patients died of disease, but many had long survivals, even with peritoneal or liver metastases. All 378 nongastric GISTs and 34 gastric non-GIST mesenchymal tumors were SDHB positive. SDH-deficient GISTs constitute a small subgroup of gastric GISTs; they usually occur in children and young adults, often have a chronic course similar to that of pediatric and CT GISTs, and have potential association with paraganglioma, necessitating long-term follow-up.
大多数胃肠道间质瘤（GISTs）是由 KIT 或 PDGFRA 激活突变驱动的，但一小部分与线粒体内膜蛋白琥珀酸脱氢酶（SDH）复合物的功能丧失有关。这种情况是由 SDH 亚基基因突变和迄今未知的机制引起的。SDH 缺陷型 GIST 特别包括儿科 GIST 和与卡尼三联征（CT）或卡尼-斯特拉塔克斯综合征（CSS）相关的 GIST；后两者还包括副神经节瘤作为一个组成部分。本研究基于琥珀酸脱氢酶亚基 B（SDHB）的免疫组化缺失，即 SDH 复合物功能丧失的信号，鉴定了 SDH 缺陷型 GIST。我们在 756 例胃 GIST 中发现了 66 例 SDH 缺陷型 GIST，未选择病例的估计频率为 7.5%。几乎所有<20 岁的胃 GIST 患者和相当比例<40 岁的患者，只有少数老年患者的 GIST 存在 SDH 缺陷。女性患病率超过 2:1。两名患者各有肺软骨瘤或副神经节瘤（CT），但未发现检查病例存在 SDH 种系突变（CSS）或体细胞 KIT/PDGFRA 或 BRAF 突变。SDH 缺陷型 GIST 通常是多灶性的，通常表现为丛状固有肌层受累和上皮样细胞丰富的形态。它们始终是 KIT 阳性和 DOG1/Ano 1 阳性，几乎总是平滑肌肌动蛋白阴性。肿瘤大小和有丝分裂活性不同，肿瘤有些不可预测，低有丝分裂率发生转移。11 例患者出现胃复发，8 例和 10 例患者出现腹膜和肝转移，5 例患者出现淋巴结转移，但研究中超过 50%的病例存在淋巴管血管侵犯；这两者与不良预后无关。7 例患者死于疾病，但许多患者存活时间较长，即使出现腹膜或肝转移。378 例非胃 GIST 和 34 例胃非 GIST 间叶肿瘤均为 SDHB 阳性。SDH 缺陷型 GIST 构成胃 GIST 的一个小亚群；它们通常发生在儿童和年轻人中，通常具有与儿科和 CT GIST 相似的慢性病程，并且可能与副神经节瘤有关，需要长期随访。
