Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan.
Mod Pathol. 2010 Sep;23(9):1251-60. doi: 10.1038/modpathol.2010.114. Epub 2010 Jun 4.
Multifocal micronodular pneumocyte hyperplasia is a rare pulmonary manifestation of tuberous sclerosis complex (TSC) that is a tumor suppressor gene disorder characterized by many hamartomas. A purported mechanism of hamartomatous proliferation in TSC is constitutive activation of the mammalian target of rapamycin (mTOR) signaling pathway dysregulated by a functional loss of TSC genes. Although multifocal micronodular pneumocyte hyperplasia develops locally as self-limited, benign lesions, it is morphologically similar to the preinvasive lesion of pneumocytes that characterize atypical adenomatous hyperplasia or bronchioloalveolar carcinoma. Frequently both conditions include a loss of heterozygosity on TSC. The goal of this study was to determine whether multifocal micronodular pneumocyte hyperplasia is neoplastic. Loss of heterozygosity on TSC genes and immunohistochemistry for mTOR-related proteins (phospho-mTOR, phospho-p70S6K, phospho-S6, and phospho-Akt) were analyzed in 42 lesions: 16 multifocal micronodular pneumocyte hyperplasia (7 patients with TSC, 1 TSC not confirmed), 14 atypical adenomatous hyperplasia, and 12 bronchioloalveolar carcinoma (9 and 12 patients, respectively). The results showed that at least one of two multifocal micronodular pneumocyte hyperplasia lesions from each patient had loss of heterozygosity on TSC1 or TSC2 (15 or 50%) and were frequently immunopositive for phospho-mTOR (88%), phospho-p70S6K (100%), and phospho-S6 (100%) but not phospho-Akt (14%), an upstream regulatory protein of mTOR. Loss of heterozygosity of TSC was found in the preinvasive lesions of pneumocytes, equal to or less than multifocal micronodular pneumocyte hyperplasia. In contrast, phospho-Akt was expressed in the preinvasive lesions of pneumocytes more frequently than multifocal micronodular pneumocyte hyperplasia, but the other mTOR-related proteins were less frequently expressed in the former than in the latter. These outcomes suggest that functional loss of TSCs and consequent hyperphosphorylation of mTOR-related proteins in multifocal micronodular pneumocyte hyperplasia may cause its benign neoplastic proliferation of pneumocytes.
结节性肺细胞增生症是一种罕见的肺结节性硬化症（TSC）的肺部表现，它是一种肿瘤抑制基因紊乱，其特征是存在许多错构瘤。在 TSC 中，错构瘤增生的一种假定机制是哺乳动物雷帕霉素靶蛋白（mTOR）信号通路的组成性激活，该通路由 TSC 基因的功能丧失引起失调。尽管结节性肺细胞增生症局部呈自限性、良性病变，但在形态上与肺细胞的癌前病变相似，这些病变表现为非典型腺瘤样增生或细支气管肺泡癌。通常情况下，这两种情况都包括 TSC 的杂合性缺失。本研究的目的是确定结节性肺细胞增生症是否具有肿瘤性。在 42 个病变中分析了 TSC 基因的杂合性缺失和与 mTOR 相关蛋白（磷酸化 mTOR、磷酸化 p70S6K、磷酸化 S6 和磷酸化 Akt）的免疫组化：16 个结节性肺细胞增生症（7 例 TSC，1 例 TSC 未确诊）、14 个非典型腺瘤样增生和 12 个细支气管肺泡癌（分别为 9 例和 12 例）。结果表明，每个患者的至少两个结节性肺细胞增生症病变中的一个存在 TSC1 或 TSC2 的杂合性缺失（15%或 50%），并且经常对磷酸化 mTOR（88%）、磷酸化 p70S6K（100%）和磷酸化 S6（100%）呈免疫阳性，但对 mTOR 的上游调节蛋白磷酸化 Akt（14%）呈阴性。在肺细胞的癌前病变中发现了 TSC 的杂合性缺失，与结节性肺细胞增生症相等或小于结节性肺细胞增生症。相比之下，磷酸化 Akt 在肺细胞的癌前病变中比结节性肺细胞增生症更频繁地表达，但其他 mTOR 相关蛋白在前者中的表达频率低于后者。这些结果表明，结节性肺细胞增生症中 TSCs 的功能丧失和随之而来的 mTOR 相关蛋白的过度磷酸化可能导致其良性肺细胞的肿瘤性增殖。
