Thoracic nuclear protein in testis (NUT) carcinoma: expanded pathological spectrum with expression of thyroid transcription factor-1 and neuroendocrine markers.

AIMS: Nuclear protein in testis (NUT) carcinoma, an aggressive tumour driven by NUTM1 rearrangements, often involves the lung/mediastinum and shows squamous differentiation. We encountered an index patient with a thoracic NUT carcinoma diagnosed by molecular testing, showing extensive pleural involvement and diffuse thyroid transcription factor-1 (TTF-1) expression, initially suggestive of lung adenocarcinoma with pseudomesotheliomatous growth. We thus gathered an institutional series of thoracic NUT carcinomas to examine their pathological spectrum. METHODS AND RESULTS: We searched for thoracic NUT carcinomas in our surgical pathology files and in 2289 consecutive patients with primary thoracic tumours investigated with RNA-based assays. We performed NUT immunohistochemistry on 425 additional lung adenocarcinomas. Collectively, we identified six patients (five men and one woman; age 31-80 years; four never-smokers) with thoracic NUT carcinomas confirmed by molecular testing (including five with positive NUT immunohistochemistry). They died at 2.3-12.9 months (median, 2.8 months) after presentation. Two patients were diagnosed by histopathological assessment, and the remaining four (including the index patient) were diagnosed by molecular testing. Analysis of the index case revealed expression of multiple neuroendocrine markers and TTF-1; no ultrastructural evidence of neuroendocrine differentiation was noted. No additional NUT-positive cases were found by immunohistochemical screening. CONCLUSIONS: Although NUT carcinoma classically shows squamous differentiation, it can rarely express TTF-1 (even diffusely) and/or multiple neuroendocrine markers. This immunophenotypic spectrum may lead to diagnostic confusion with pulmonary adenocarcinoma, neuroendocrine tumour, and others. To circumvent this pitfall, NUT immunohistochemistry and/or NUTM1 molecular testing should be considered in primitive-appearing tumours, regardless of their immunophenotypic features.

Malignant mesothelioma following repeated exposures to cosmetic talc: A case series of 75 patients.

BACKGROUND: Asbestos is the primary known cause of malignant mesothelioma. Some cosmetic talc products have been shown to contain asbestos. Recently, repeated exposures to cosmetic talc have been implicated as a cause of mesothelioma. METHODS: Seventy-five individuals (64 females; 11 males) with malignant mesothelioma, whose only known exposure to asbestos was repeated exposures to cosmetic talcum powders, were reviewed in medical-legal consultation. Out of the 75 cases, 11 were examined for asbestiform fibers. RESULTS: All subjects had pathologically confirmed malignant mesothelioma. The mean age at diagnosis was 61 ± 17 years. The mean latency from exposure to diagnosis was 50 ± 13 years. The mean exposure duration was 33 ± 16 years. Four mesotheliomas (5%) occurred in individuals working as barbers/cosmetologists, or in a family member who swept the barber shop. Twelve (16%) occurred in individuals less than 45 years old (10 females; 2 males). Forty-eight mesotheliomas were pleural (40 females; 8 males), 23 were peritoneal (21 females; 2 males). Two presented with concomitant pleural and peritoneal disease. There was one pericardial, and one testicular mesothelioma. The majority (51) were of the epithelioid histological subtype, followed by 13 biphasic, 8 sarcomatoid, 2 lymphohistiocytoid, and 1 poorly differentiated. Of the 11 individuals whose nontumorous tissues were analyzed for the presence of asbestiform fibers, all showed the presence of anthophyllite and/or tremolite asbestos. CONCLUSIONS: Mesotheliomas can develop following exposures to cosmetic talcum powders. These appear to be attributable to the presence of anthophyllite and tremolite contaminants in cosmetic talcum powder.

Multiple calcifying fibrous pseudotumors of the pleura: ultrastructural analysis provides insight on mechanism of dissemination.

Calcifying fibrous pseudotumor (CFP) is a rare, benign soft tissue tumor that may uncommonly arise in the pleura. These tumors can show multifocal dissemination across the pleural surface, but the mechanism underlying this dissemination is unclear. Review of previously reported cases of pleural CFP demonstrates a strong predilection for basal and diaphragmatic pleural surfaces, and a significantly higher rate of multifocality compared with other locations. We present a 59-year-old male with multiple CFP of the pleura. Reactive-appearing adhesions spanning the pleural surfaces were present, and by electron microscopy, were involved by tumor. We suggest this is the likely mode of dissemination across the pleural surfaces.

Malignant mesothelioma in Lynch syndrome: A report of two cases and a review of the literature.

Malignant mesothelioma is a rare and aggressive cancer most typically associated with prior asbestos exposure. The nature of the relationship between asbestos exposure and hereditary familial syndromes predisposing to malignancy has not been determined. We report two Lynch syndrome patients with paraoccupational asbestos exposure who developed diffuse malignant mesothelioma of the pleura or peritoneum. Interestingly, one showed a separate focus of pleural well-differentiated papillary mesothelioma. It is likely that Lynch syndrome patients are at increased risk for the development of mesothelioma in the setting of exposure to asbestos, even at what is generally considered to be low levels. In the presence of a documented history of low-level asbestos exposure, patients with genetic predisposition disorders (including Lynch syndrome) should be considered to have an independent risk factor modifying the effects of asbestos exposure.

A Conserved Distal Lung Regenerative Pathway in Acute Lung Injury.

Improved tools have led to a burgeoning understanding of lung regeneration in mice, but it is not yet known how these insights may be relevant to acute lung injury in humans. We report in detail two cases of fulminant idiopathic acute lung injury requiring extracorporeal membrane oxygenation in previously healthy young adults with acute respiratory distress syndrome, one of whom required lung transplantation. Biopsy specimens showed diffuse alveolar injury with a striking paucity of alveolar epithelial regeneration, rare hyaline membranes, and diffuse contiguous airspace lining by macrophages. This novel constellation was termed diffuse alveolar injury with delayed epithelization. In addition, mirroring data from murine models of lung injury/regeneration, peribronchiolar basaloid pods (previously described as squamous metaplasia) and ciliated bronchiolarization were identified in these patients and in 39% of 57 historical cases with diffuse alveolar damage. These findings demonstrate a common and clinically relevant human disease correlate for murine models of severe acute lung injury. Evidence suggests that peribronchiolar basaloid pods and bronchiolarization are related spatially and temporally and likely represent overlapping sequential stages of the response to severe distal airway injury.

Fibroma-like PEComa: A Tuberous Sclerosis Complex-related Lesion.

Perivascular epithelioid cell tumor (PEComa), mesenchymal tumors morphologically characterized by epithelioid cells, coexpress melanocytic and muscle markers. Herein, we describe a heretofore-undescribed tuberous sclerosis complex (TSC)-related neoplasm, morphologically resembling a soft tissue fibroma-like lesion, but showing an immunophenotype resembling PEComa. We identified 3 soft tissue fibroma-like lesions in individuals with TSC. We also evaluated 6 TSC-related periungual fibroma as well as a range of non-TSC fibroma-like lesions (n=19). Immunohistochemistry for HMB-45, desmin, smooth muscle actin, TFE3, and S100 was performed on the TSC-related fibromas. Periungual fibromas and non-TSC fibroma-like lesions were also stained for HMB-45. All 3 TSC patients were female, ranging in age from 4 to 51 years (mean, 26.7 y). Two tumors were located in extremities and 1 on the chest wall. The tumors showed elongated to stellate spindle-shape cells, prominent collagenous background, and lacked mitotic activity and cytologic atypia. Immunohistochemically, all 3 tumors were positive for HMB-45; smooth muscle actin or desmin was positive in both tumors tested. TFE3 was negative. All patients were alive with no evidence of disease with median follow-up of 55 months (range, 6 to 131 mo). Non-TSC fibroma-like lesions and oral and periungual fibromas were negative for HMB-45. Fibroma-like PEComa, a newly recognized soft tissue tumor with a strong association with TSC, mimics soft tissue fibroma but shows reactivity with melanocytic markers.

Diffuse peritoneal mesothelioma: A case series of 62 patients including paraoccupational exposures to chrysotile asbestos.

BACKGROUND: Diffuse peritoneal malignant mesothelioma (DPM) is caused by exposure to asbestos. The medical literature has linked DPM primarily to high levels of asbestos exposure, in particular amosite. Controversy persists as to whether chrysotile is capable of causing DPM, especially when exposures are paraoccupational. METHODS: Sixty-two subjects (51 men, 11 women) with DPM were reviewed in medical-legal consultation with deposition and product identification evidence. RESULTS: All had pathologically confirmed DPM. Most were exposed to both amphibole and chrysotile, but chrysotile alone was documented in 14/62 (26%) cases. A total of 7/14 (50%) cases of the paraoccupational exposures were to chrysotile alone. Women were younger than men as were those with paraoccupational versus those with occupational exposure. The mean duration of exposure for all cases was 17.9 ± 10 years and latency from time of first exposure was 45.9 + 11.6 years. CONCLUSIONS: DPM occurs with both occupational and paraoccupational exposures to asbestos and may be seen in paraoccupational exposures to chrysotile asbestos.

Pulmonary adenocarcinoma with epidermal growth factor receptor-mutations in asbestos exposed non-smokers: A case series.

BACKGROUND: Cigarette smoke and asbestos are recognized causes of lung carcinoma and together promote carcinogenesis. Adenocarcinoma is currently the most common cause of lung cancer in the USA and it has been linked to both smoking and asbestos exposure. Mutations in the epidermal growth factor gene receptor (EGFR) occur predominantly in non-smokers with adenocarcinoma. Methods Mutations in the EGFR gene were investigated using next-generation sequencing. RESULTS: We report the presence of EGFR exon point mutations in the pulmonary adenocarcinomas of three never-smokers occupationally exposed to asbestos. CONCLUSION: The role of asbestos as a possible cause of EGFR mutagenesis requires further investigation. Am. J. Ind. Med. 60:306-309, 2017. © 2017 Wiley Periodicals, Inc.

Honeycomb Lung: Time for a Change.

The recent introduction of new US Food and Drug Administration-approved medications for the treatment of idiopathic pulmonary fibrosis/usual interstitial pneumonia raises important concerns about the accuracy of diagnosis. The term honeycomb lung, used widely by radiologists and pathologists in the diagnosis of usual interstitial pneumonia, represents a late stage of the disease and conveys no biological information. A new conception of end-stage lung disease in usual interstitial pneumonia, based on the dying back of the pulmonary acinus, is proposed, which may improve the sensitivity and specificity of the diagnosis and provide an understanding of its pathogenesis.

Pulmonary capillary hemangiomatosis: the role of invasive cardiopulmonary exercise testing.

Pulmonary capillary hemangiomatosis (PCH) is a rare form of pulmonary arterial hypertension (PAH) characterized by pulmonary capillary proliferation and pseudoinvasion of collagenous septal structures. PCH is often accompanied by veno-occlusive changes and pulmonary hypertensive arterial remodeling. The clinical and pathological diagnosis of PCH can be subtle and easily missed. Most reported cases of PCH have been associated with resting PAH. We report the cases of 3 patients who initially presented with exertional dyspnea with normal to mildly elevated resting pulmonary arterial pressures and marked intrapulmonary shunting. In all 3 patients, invasive cardiopulmonary exercise testing was suggestive of pulmonary vascular disease. Owing to abnormalities on invasive exercise testing, lung biopsies were performed; these were diagnostic of PCH, and the patients were referred for lung transplantation. We describe unique features of these 3 cases-including novel pathological findings and the presence of intrapulmonary shunting in all 3 patients-and we discuss the role of cardiopulmonary exercise testing in the evaluation of PCH.

Smoking-associated fibrosis and pulmonary asbestosis.

The diagnosis of pulmonary asbestosis is most often established based on clinical criteria and has both clinical and legal implications. Unfortunately, one of the confounding features in the diagnosis may be a history of cigarette abuse, which can produce interstitial opacities on chest imaging as well as diffusion defects on pulmonary function testing, criteria that are used in the diagnosis of pulmonary asbestosis. The objective of the present study was to evaluate the correlation of radiographically detected pulmonary fibrosis with fibrosis established histopathologically as attributable to asbestos, in a cohort referred for diagnosis of an asbestos-related malignancy in the context of litigation. We examined the slides of 186 cases with reported asbestos exposure, referred in consultation for asbestos-related malignancy and the presence of pulmonary fibrosis. Sixty-five cases had what was judged to be adequate tissue sampling for histopathologic evaluation of asbestosis as well as an existing radiologic assessment of pulmonary fibrosis by B-reader report. Of 24 cases judged to have asbestosis radiographically, which had sufficient tissue for pathologic examination, six showed asbestosis histopathologically. The remaining 18 cases (mean smoking history of 53 pack-years) showed interstitial fibrosis that was judged to be most consistent with smoking-associated pulmonary fibrosis. We conclude that the clinical diagnosis of mild asbestosis cannot be reliably distinguished from interstitial fibrosis in heavy smokers.

Bilateral lung transplantation in a patient with humoral immune deficiency: a case report with review of the literature.

Humoral immune deficiencies have been associated with noninfectious disease complications including autoimmune cytopenias and pulmonary disease. Herein we present a patient who underwent splenectomy for autoimmune cytopenias and subsequently was diagnosed with humoral immune deficiency in the context of recurrent infections. Immunoglobulin analysis prior to initiation of intravenous immunoglobulin (IVIG) therapy was notable for low age-matched serum levels of IgA (11 mg/dL), IgG2 (14 mg/L), and IgG4 (5 mg/L) with a preserved total level of IgG. Flow cytometry was remarkable for B cell maturation arrest at the IgM+/IgD+ stage. Selective screening for known primary immune deficiency-causing genetic defects was negative. The disease course was uniquely complicated by the development of pulmonary arteriovenous malformations (AVMs), ultimately requiring bilateral lung transplantation in 2012. This is a patient with humoral immune deficiency that became apparent only after splenectomy, which argues for routine immunologic evaluation prior to vaccination and splenectomy. Lung transplantation is a rare therapeutic endpoint and to our knowledge has never before been described in a patient with humoral immune deficiency for the indication of pulmonary AVMs.