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Perivascular epithelioid cell tumors (PEComas) are mesenchymal neoplasms with immunoreactivity for both melanocytic and smooth muscle markers. PEComas occur at multiple sites, and malignant PEComas can undergo metastasis, recurrence and aggressive clinical courses. Although the lung is a common metastatic site of PEComas, they usually appear as multiple nodules but rarely become cystic or cavitary. Here, we describe a female patient whose lungs manifested multiple cystic, cavity-like and nodular metastases 3 years after the resection of uterine tumors tentatively diagnosed as epithelioid smooth muscle tumors with uncertain malignant potential. This patient's subsequent pneumothorax necessitated video-assisted thoracoscopic surgery, and examination of her resected lung specimens eventually led to correcting the diagnosis, i.e., to a PEComa harboring tuberous sclerosis complex 1 ( TSC1 ) loss-of-heterozygosity that originated in the uterus and then metastasized to the lungs. The administration of a gonadotropin-releasing hormone analogue later stabilized her clinical course. To the best of our knowledge, the present case is the first in the literature that associates PEComas with a TSC1 abnormality. Additionally, the pulmonary manifestations, including imaging appearance and pneumothorax, somewhat resembled those of lymphangioleiomyomatosis, a representative disease belonging to the PEComa family. Although PEComas are rare, clinicians, radiologists and pathologists should become aware of this disease entity, especially in the combined clinical setting of multiple cystic, cavity-like, nodular lesions on computed tomography of the chest and a past history of the tumor in the female reproductive system. [ABSTRACT FROM AUTHOR]

Summary: A 41-year-old woman carrying a germline tuberous sclerosis complex 2 (TSC2) mutation, whose regular medical follow-up for tuberous sclerosis complex and tuberous sclerosis complex–associated lymphangioleiomyomatosis had continued for 2 years, had uterine angiosarcoma concomitant with uterine lymphangioleiomyomatosis. Immunohistochemically, the uterine angiosarcoma cells showed an extremely skewed lymphatic differentiation; they were diffusely immunopositive for CD31 but negative for other vascular endothelial markers including factor VIII and CD34 yet strongly immunopositive for lymphatic endothelial markers including D2-40 and Prox-1. Loss of heterozygosity analysis demonstrated that not only lymphangioleiomyomatosis and renal angiomyolipoma but also the uterine angiosarcoma had loss of heterozygosity on TSC2. Furthermore, direct sequencing revealed a TP53 mutation in the uterine angiosarcoma. Collectively, the findings suggest that combined dysfunction of the p53 and TSC2 tumor suppressor proteins may contribute to the development of uterine angiosarcoma in this rare clinical setting. [Copyright &y& Elsevier]

Summary: Oncocytic mucoepidermoid carcinoma is a very rare variant of mucoepidermoid carcinoma, composed predominantly of oncocytic cells. Most previously reported cases described the difficulty in histologic differentiation from other oncocytic tumors. Here we report a case of oncocytic mucoepidermoid carcinoma of parotid gland diagnosed by the detection of CRTC1-MAML2 fusion. A 53-year-old man had a left superficial parotidectomy conducted for 3-cm-sized mass. The resected tumor was composed almost exclusively of oncocytic tumor cells. With detailed histologic evaluation, scarce vacuolated tumor cells, suggestive of mucous cell of mucoepidermoid carcinoma, and one focus of tumor embolism in a vein were found, suggesting the possibility of oncocytic mucoepidermoid carcinoma. Immunohistochemically, oncocytic cells were diffusely positive for p63. Reverse transcriptase polymerase chain reaction and direct sequencing revealed CRTC1-MAML2 translocation of this tumor. To our knowledge, this report describes the first case of oncocytic mucoepidermoid carcinoma confirmed with CRTC1-MAML2 fusion. Identification of this fusion gene may help in distinguishing oncocytic mucoepidermoid carcinoma from its mimics. [ABSTRACT FROM AUTHOR]

We report a 17-year-old male with a histopathologic diagnosis of lymphangioleiomyomatosis after surgery for a pneumothorax. In general, lymphangioleiomyomatosis has been considered a female-specific disease. However, there are a few lymphangioleiomyomatosis cases reported in males, and our patient is the youngest case reported. Spontaneous pneumothorax occurs most commonly in males in their late teens and early twenties. Histopathologic diagnosis cannot always be performed in young males with pneumothorax. However, simple diagnosis should be avoided, and lymphangioleiomyomatosis should be considered as an underlying disease. This remarkable case provides new and valuable clinical insights into young male pneumothorax. [ABSTRACT FROM AUTHOR]

Appendiceal mucinous tumors (AMTs) are classified as low-grade appendiceal mucinous neoplasms (LAMNs) or mucinous adenocarcinomas (MACs), although their carcinogenesis is not well understood. As somatic activating mutations of GNAS are considered to be characteristic of LAMNs while TP53 mutations have been shown to be specific to MACs, MACs are unlikely to result from transformation of LAMNs. However, emerging evidence also shows the presence of GNAS mutations in MACs. We examined 16 AMTs (11 LAMNs and 5 MACs) for genetic alterations of GNAS , KRAS , BRAF , TP53 , CTNNB1 , and TERT promoter in order to elucidate the possibility of a shared genetic background in the two tumor types. Extensive histological examination revealed the presence of a low-grade component in all cases of MAC. GNAS mutations were detected in two LAMNs and in one MAC, although the GNAS mutation in this MAC was a nonsense mutation (Q227X) expected not to be activating mutation. TP53 mutations were detected in three LAMNs; they were frequently detected in MACs. KRAS mutations were detected in three LAMNs and three MACs, and CTNNB1 mutations were detected in two LAMNs. KRAS mutation and activating mutation of GNAS occurred exclusively in AMTs. BRAF and TERT mutations were not detected. Overexpression of p53 was observed in only two MACs, and p53 immunostaining clearly discriminated the high-grade lesion from a low-grade component in one. These findings suggest that p53 overexpression plays an important role in the carcinogenesis of AMTs and that, in addition to mutations of GNAS , KRAS and TP53 alterations might be shared by AMTs, thus providing evidence for the possible progression of LAMNs to MAC. [ABSTRACT FROM AUTHOR]

Background/Aims: After treatment with heat-killed Propionibacterium acnes mice show dense hepatic granuloma formation. Such mice develop liver injury in an interleukin (IL)-18-dependent manner after challenge with a sublethal dose LPS. As previously shown, LPS-stimulated Kupffer cells secrete IL-18 depending on caspase-1 and Toll-like receptor (TLR)-4 but independently of its signal adaptor myeloid differentiation factor 88 (MyD88), suggesting importance of another signal adaptor TIR domain-containing adapter inducing IFN-β (TRIF). Nalp3 inflammasome reportedly controls caspase-1 activation. Here we investigated the roles of MyD88 and TRIF in P. acnes-induced hepatic granuloma formation and LPS-induced caspase-1 activation for IL-18 release. Methods: Mice were sequentially treated with P. acnes and LPS, and their serum IL-18 levels and liver injuries were determined by ELISA and ALT/AST measurement, respectively. Active caspase-1 in LPS-stimulated Kupffer cells was determined by Western blotting. Results: Macrophage-ablated mice lacked P. acnes-induced hepatic granuloma formation and LPS-induced serum IL-18 elevation and liver injury. Myd88 −/− Kupffer cells, but not Trif −/− cells, exhibited normal caspase-1 activation upon TLR4 engagement in vitro. Myd88 −/− mice failed to develop hepatic granulomas after P. acnes treatment and liver injury induced by LPS challenge. In contrast, Trif −/− mice normally formed the hepatic granulomas, but could not release IL-18 or develop the liver injury. Nalp3 −/− mice showed the same phenotypes of Trif −/− mice. Conclusions: Propionibacterium acnes treatment MyD88-dependently induced hepatic granuloma formation. Subsequent LPS TRIF-dependently activated caspase-1 via Nalp3 inflammasome and induced IL-18 release, eventually leading to the liver injury. [Copyright &y& Elsevier]

Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant cancer syndrome caused by a germline mutation of the folliculin (FLCN) gene. Previous studies have suggested that truncated mutant folliculin proteins generated by disease causing FLCN mutations may retain partial functionality and contribute to disease phenotype. A 38-year-old Russian man presented with a left renal tumor. He underwent a left radical nephrectomy and histological examination confirmed the diagnosis of chromophobe renal cell carcinoma. He had papulae on his face suggestive of fibrofolliculomas, and pulmonary cysts on his computed tomography of the chest. He had a family history of skin manifestations. Genetic analysis identified a genomic deletion including the putative promoter region of FLCN exon 1 in the germline, and the second hit on the remaining wild-type FLCN in the renal carcinoma cells, which is expected to cause the complete lack of folliculin protein. Immunohistochemistry with the use of anti-folliculin antibody showed no antibody-binding on chromophobe renal carcinoma cells. These findings suggest that the decreased FLCN expression itself without producing mutated folliculin proteins can be at risk for developing clinical manifestations of BHDS: fibrofolliculomas, lung cysts, and tumorigenesis in the kidneys. This sheds light on the pathogenesis of BHDS and the role of FLCN as a tumor suppressor gene. [ABSTRACT FROM AUTHOR]