[Tuberous sclerosis complex-associated multifocal micronodular pneumocyte hyperplasia: a clinicopathological features and TSC1/TSC2 gene mutation analysis of eight cases].

Objective: To investigate the clinicopathological features of tuberous sclerosis complex (TSC)-associated multifocal micronodular pneumocyte hyperplasia (MMPH) and the mutation status of TSC1/TSC2 genes. Methods: A retrospective analysis was conducted on 8 MMPH cases diagnosed at Shanghai Pulmonary Hospital Affiliated to Tongji University from September 2020 to August 2024. Clinical information and imaging findings of these cases were collected. Histopathological analysis and next-generation sequencing (NGS) were performed. Results: Among the 8 patients, there were 4 males and 4 females, aged 44 (36, 50) years old. None of them had a definite family history of TSC. Only 1 patient presented with respiratory symptoms at the time of consultation. Four patients had TSC-related cutaneous lesions. Two had shagreen patches, 1 had hypomelanotic macules, and 1 had hypomelanotic macules combined with fibrous plaques on the scalp and angiofibromas. Three patients themselves or their first-degree relatives had a history of epilepsy. Five patients themselves or their first-degree relatives had liver/kidney cysts or a surgical history of renal angiomyolipoma. Computerized tomography scans showed multiple ground-glass nodules in both lungs, with an average diameter of 10.5 (8.5, 11.0) mm. Six cases were diagnosed via surgical resection, and 2 via transbronchial cryobiopsy. Intraoperative frozen sections of the 6 surgically resected cases were all misdiagnosed as early-stage lung adenocarcinoma (including adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive non-mucinous adenocarcinoma), but the diagnosis was corrected to MMPH postoperatively. One of these 6 cases was concurrent with a benign perivascular epithelioid cell tumor (PEComa). Microscopically, MMPH was characterized by multifocal proliferation of type Ⅱ alveolar epithelial cells, which showed bland cellular morphology without atypia or invasive growth. For the case concurrent with PEComa, clear epithelioid cells were observed growing in nests or sheets. Immunohistochemically, the proliferative epithelial cells were positive for TTF-1 and showed low expression of Ki-67. PEComa cells were positive for Melan A and MiTF. NGS showed that TSC1 mutations were detected in 6 cases, TSC2 mutation in 1 case (which also had a concurrent class Ⅲ missense mutation of BRAF G466E), and no mutation in 1 case, with an overall mutation detection ratio is 7/8. No other lung cancer-related driver-gene variations were found in any case. Follow-up data were available for 8 patients. During the follow-up, 1 patient developed scattered thin-walled lucencies in both lungs, but no pathological examination was performed. All patients had a favorable overall survival status, follow-up time was 14.0(9.5,47.0) months. Conclusions: MMPH is a rare, benign TSC-associated pulmonary lesion, often presenting as multiple ground-glass nodules in both lungs. It can be easily misdiagnosed as early-stage lung adenocarcinoma. The diagnosis requires a comprehensive judgment based on clinical data, imaging findings, histopathology, and TSC1/TSC2 gene mutation results.