Szalai, Fatime

Aims Lymphangioleiomyomatosis (LAM) is a PEComa that primarily affects premenopausal women and is associated with the cystic destruction of the lung. Although smooth muscle and melanocytic markers can be helpful, histologic diagnosis of LAM remains challenging, especially in small biopsies. Glycoprotein non‐metastatic melanoma protein B (GPNMB) expression has recently been identified as a highly specific and sensitive immunohistochemical marker for PEComas. Nevertheless, only a few LAM cases have been studied so far. The aim of this study was to assess the utility of GPNMB immunohistochemistry as an ancillary marker in a larger cohort of LAM samples. Methods and results Immunohistochemistry for GPNMB was performed on cases of LAM ( N = 15), potential differential diagnostic mimics ( N = 30) and normal lung tissue ( N = 2). Immunohistochemistry was assessed using the H‐score method; an H‐score above 100 was considered ‘high’. All LAM cases showed strong cytoplasmic expression, with cell membrane accentuation in some areas. In contrast, differential diagnostic mimics were either negative or only weakly positive. Normal lung parenchyma was negative for GPNMB; however, weak‐to‐moderate expression was seen in alveolar macrophages in both the normal and diseased lung tissues in most cases. Considering only ‘high’ positivity, GPNMB immunohistochemistry showed 100% sensitivity and specificity for the diagnosis of LAM in our cohort. Conclusions Based on its 100% sensitivity and specificity, GPNMB appears to be a highly valuable immunohistochemical marker for the diagnosis of pulmonary LAM. Besides its diagnostic value, the membrane positivity of GPNMB on LAM cells may predict a response to glembatumumab vedotin, an antibody‐drug conjugate targeting GPNMB.

Lung carcinoma is one of the most common cancer types for both men and women. Despite recent breakthroughs in targeted therapy and immunotherapy, it is characterized by a high metastatic rate, which can significantly affect quality of life and prognosis. Rictor (encoded by the RICTOR gene) is known as a scaffold protein for the multiprotein complex mTORC2. Among its diverse roles in regulating essential cellular functions, mTORC2 also facilitates epithelial–mesenchymal transition and metastasis formation. Amplification of the RICTOR gene and subsequent overexpression of the Rictor protein can result in the activation of mTORC2, which promotes cell survival and migration. Based on recent studies, RICTOR amplification or Rictor overexpression can serve as a marker for mTORC2 activation, which in turn provides a promising druggable target. Although selective inhibitors of Rictor and the Rictor-mTOR association are only in a preclinical phase, they seem to be potent novel approaches to reduce tumor cell migration and metastasis formation. Here, we summarize recent advances that support an important role for Rictor and mTORC2 as potential therapeutic targets in the treatment of lung cancer. This is a traditional (narrative) review based on Pubmed and Google Scholar searches for the following keywords: Rictor, RICTOR amplification, mTORC2, Rictor complexes, lung cancer, metastasis, progression, mTOR inhibitors.