Yi, Eunhee S.

Context.— Pulmonary hypertension (PHT) is a complication of pulmonary Langerhans cell histiocytosis (PLCH); however, the pathogenesis remains largely unknown. Few studies have evaluated histopathologic changes in pulmonary arteries (PAs) of patients with PLCH; systematic quantification of arterial remodeling has yet to be undertaken. Objective.— To quantify the extent of arterial remodeling among patients with PLCH through morphometry and to correlate these results with pertinent clinical parameters. Design.— Patients with PLCH were identified from institutional files (1995–2015) along with age-, sex-, and smoking status–matched controls. Morphometric analysis of intimal and medial thickness of small to medium PAs was performed in patients with PLCH (within PLCH lesions [lesional] and away from PLCH lesions [nonlesional]) and controls. Paired measures were compared with Wilcoxon signed rank tests. Results.— Twenty-five patients with PLCH (14 men: median age, 46 years; interquartile range, 37–55 years) and 25 controls were included. The lesional arteries of patients with PLCH demonstrated thicker PA intima and media than controls (P < .001 and P < .001, respectively), as did PLCH nonlesional arteries compared to controls (P < .001 and P < .001, respectively). The PA intima and media were thicker within the PLCH lesions than nonlesional arteries (P = .02 and P = .002, respectively). Patients with PLCH-related PHT had a worse prognosis than those without PHT (P = .04; hazard ratio, 4.5 [1.1, 22.2]). Echocardiography parameters including right atrial size (P = .007), estimated right atrial pressure (P = .01), and right ventricular systolic pressure (P = .01) were inversely associated with survival. Conclusions.— Our findings suggest that factors other than direct vascular obstruction or inflammatory cell infiltration contribute, at least in part, to the vascular remodeling in PLCH.

Context.— Air space invasion or aerogenous spread of lung adenocarcinoma is a relatively new concept and has been implicated as a potential prognostic factor as well as has been added as an exclusion point in the diagnosis of minimally invasive adenocarcinoma. Potential role for Ki-67 immunostaining as a diagnostic and prognostic marker in pulmonary carcinoid tumors has been suggested in the literature, given the significant interobserver variability and the difficulty in predicting their clinical behavior. Objective.— To review the concept of air space invasion in lung adenocarcinoma and the current controversies regarding the role of Ki-67 immunostaining on pulmonary carcinoid tumors Data Sources.— PubMed search of English literature. Conclusions.— Pathologists need to recognize air space invasion with a critical evaluation to differentiate it from artifacts that are commonly seen in sections. Currently, Ki-67 immunostaining is not recommended for routine use in the diagnosis of pulmonary carcinoid tumors or for predicting their prognosis, except for the differential diagnosis from small cell carcinomas or large cell neuroendocrine carcinomas in small biopsy specimens with crush artifacts.

Abstract Acute eosinophilic pneumonia (AEP) is an uncommon acute respiratory illness of varying severity that includes presentation as acute respiratory distress syndrome with fatal outcome. AEP may be idiopathic, but identifiable causes include smoking and other inhalational exposures, medications, and infections. The pathogenesis of AEP is poorly understood but likely varies depending on the underlying cause. Airway epithelial injury, endothelial injury, and release of IL-33 are early events that subsequently promote eosinophil recruitment to the lung; eosinophilic infiltration and degranulation appear to mediate subsequent lung inflammation and associated clinical manifestations. Crucial for the diagnosis are the demonstration of pulmonary eosinophilia in the BAL fluid and the exclusion of other disease processes that can present with acute pulmonary infiltrates. Although peripheral blood eosinophilia at initial presentation may be a clue in suggesting the diagnosis of AEP, it may be absent or delayed, especially in smoking-related AEP. Optimal management of AEP depends on the recognition and elimination of the underlying cause when identifiable. The cessation of the exposure to the inciting agent (e.g., smoking), and glucocorticoids represent the mainstay of treating AEP of noninfectious origin. If AEP is recognized and treated in a timely manner, the prognosis is generally excellent, with prompt and complete clinical recovery, even in those patients manifesting acute respiratory failure.

Distinguishing reactive mesothelial proliferation from malignant mesothelioma (MM) can be difficult, particularly on small biopsies. In this scenario, a diagnosis of atypical mesothelial proliferation might be rendered. However, the distinction between a reactive process and MM is important for prognosis and treatment. Recently, loss of BRCA1-associated protein 1 (BAP1) expression and/or homozygous deletion of CDKN2A were identified in some MM, but not in reactive mesothelial proliferations. We studied 34 cases of atypical mesothelial proliferation from our institutional files (1993 to 2016) for BAP1 expression, deletion of CDKN2A, and clinical outcome. Fifteen of 34 patients (44%) were subsequently diagnosed with MM. BAP1 expression was lost in 6 of these 15 (40%) patients. Ten of 15 (67%) patients died of disease within a median time of 18.2 months. BAP1 expression was also lost in 1 case of probable MM. In this case atypical mesothelial proliferation was identified in the pleura during a lobectomy procedure for lung adenocarcinoma. Follow-up of 57.0 months was remarkable for visceral and parietal pleural thickening with continued unilateral effusion identified on imaging studies but no subsequent definitive diagnosis of MM. CDKN2A studies by fluorescence in situ hybridization (performed in 31 cases) found no homozygous deletion of that gene in any case. In conclusion, loss of BAP1 expression in atypical mesothelial proliferation helps to predict MM and is a useful adjunct test in these cases. Homozygous deletion of CDKN2A in mesothelial cell proliferations did not prove to be useful to predict MM in cases of atypical mesothelial proliferation.

Summary Background: Pulmonary artery sarcoma (PAS) is a rare malignant neoplasm with an aggressive behavior and often difficult to distinguish from pulmonary thromboembolic disease. Aim: To assess the demographic, clinical, and radiological characteristics of PAS and clinical course. Design and Methods: We retrospectively identified and analyzed all patients with PAS seen at Mayo Clinic in Rochester, Minnesota, between January 1, 1996 and July 31, 2015. Results: Of nine patients (5 women and 4 men; median age 55 years [range, 24–74 years]), eight were diagnosed while alive with surgical (n = 6) or catheter-based endovascular biopsy (n = 2); the remaining patient was diagnosed at postmortem examination. All tumors manifested on CT as filling defect in the main, right or left pulmonary artery and were not associated with peripheral filling defects in seven patients. Seven patients were initially treated with anticoagulant therapy for presumed PE; two patients were suspected to have tumor based on constrictive or expanding effect seen on CT. Five patients died after a mean duration of 2.1 years (10 months–4.25 years) after diagnosis. Two patients are alive with recurrence and metastases of the disease 23 and 27 months after diagnosis, respectively; one remaining patient is alive and disease-free 116 months after diagnosis. Conclusions: Although PAS is associated with a poor prognosis, long-term survival is possible and can be improved by early diagnosis and prompt surgical resection. Atypical appearance on CT including central mass-like lesion without peripheral emboli and constrictive or expanding effect should raise suspicion of PAS.

Context.— The diagnosis and grading of acute cellular and antibody-mediated rejection (AMR) in lung allograft biopsies is important because rejection can lead to acute graft dysfunction and/or failure and may contribute to chronic graft failure. While acute cellular rejection is well defined histologically, no reproducible specific features of AMR are currently identified. Therefore, a combination of clinical features, serology, histopathology, and immunologic findings is suggested for the diagnosis of AMR. Objective.— To describe the perspective of members of the Pulmonary Pathology Society (PPS) on the workup of lung allograft transbronchial biopsy and the diagnosis of acute cellular rejection and AMR in lung transplant. Data Sources.— Reports by the International Society for Heart and Lung Transplantation (ISHLT), experience of members of PPS who routinely review lung allograft biopsies, and search of literature database (PubMed). Conclusions.— Acute cellular rejection should be assessed and graded according to the 2007 working formulation of the ISHLT. As currently no specific features are known for AMR in lung allografts, the triple test (clinical allograft dysfunction, donor-specific antibodies, pathologic findings) should be used for its diagnosis. C4d staining might be performed when morphologic, clinical, and/or serologic features suggestive of AMR are identified.

ABSTRACT TGF‐β plays a central role in the pathogenesis of fibroproliferative disorders. Defining the exact underlying molecular basis is therefore critical for the development of viable therapeutic strategies. Here, we show that expression of the facilitative glucose transporter 1 (GLUT1) is induced by TGF‐β in fibroblast lines and primary cells and is required for the profibrotic effects of TGF‐β. In addition, enhanced GLUT1 expression is observed in fibrotic areas of lungs of both patients with idiopathic pulmonary fibrosis and mice that are subjected to a fibrosis‐inducing bleomycin treatment. By using pharmacologic and genetic approaches, we demonstrate that up‐regulation of GLUT1 occurs via the canonical Smad2/3 pathway and requires autocrine activation of the receptor tyrosine kinases, platelet‐derived and epidermal growth factor receptors. Engagement of the common downstream effector PI3K subsequently triggers activation of the MEK and mammalian target of rapamycin complex 2, which cooperate in regulating GLUT1 expression. Of note, inhibition of GLUT1 activity and/or expression is shown to impair TGFβ–driven fibrogenic processes, including cell proliferation and production of profibrotic mediators. These findings provide new perspectives on the interrelation of metabolism and profibrotic TGF‐β signaling and present opportunities for potential therapeutic intervention.—Andrianifahanana, M., Hernandez, D. M., Yin, X., Kang, J.‐H., Jung, M.‐Y., Wang, Y., Yi, E. S., Roden, A. C., Limper, A. H., Leof, E. B. Profibrotic up‐regulation of glucose transporter 1 by TGF‐β involves activation of MEK and mammalian target of rapamycin complex 2 pathways. FASEB J. 30, 3733–3744 (2016) www.fasebj.org