Immunohistochemical profile of the pulmonary vasculature in subjects with cirrhosis and histopathologic evidence of pulmonary vascular disease: An autopsy study.

Portopulmonary hypertension (POPH) is a complication of cirrhosis that results in right ventricular failure and death. The objective of this autopsy investigation was to compare pulmonary arterial receptors in subjects with cirrhosis and histopathologic evidence of pulmonary vascular disease (PVD) and control group subjects with cirrhosis lacking evidence of PVD. Autopsy records of 824 subjects with cirrhosis were reviewed to identify pulmonary arterial vasculopathy. Lung sections from paraffin embedded blocks were immunostained for endothelin A (ET-A), endothelin B (ET- B), estrogen α (ER-α), estrogen ß (ER-ß), and vascular endothelial growth factor (VEGF). Subjects with cirrhosis and histopathologic evidence of PVD included 27 individuals with intimal hyperplasia (93%), medial hypertrophy (96%), and plexiform lesions (78%). Immunohistochemical staining for ET-A revealed positive reactivity in 40% of the group with cirrhosis and histopathologic evidence of PVD and 13% of the control group (NS). ET-B reactivity in the pulmonary endothelium and smooth muscle was identified in all subjects with cirrhosis and histopathologic evidence of PVD and control group. VEGF reactivity was identified in the endothelium in all subjects with cirrhosis and histopathologic evidence of PVD compared with 33% of the control group (p = 0.0002). ER-ß reactivity was observed in four subjects (26.6%) with cirrhosis and histopathologic evidence of PVD while none in the control group (NS). Cirrhosis and histopathologic evidence of PVD was found in 3.3% of autopsies with the pulmonary vasculature immunohistochemical profile demonstrating endothelial and smooth muscle reactivity for endothelin, VEGF and ER-ß.

Host gene expression profiles in ferrets infected with genetically distinct henipavirus strains.

Henipavirus infection causes severe respiratory and neurological disease in humans that can be fatal. To characterize the pathogenic mechanisms of henipavirus infection in vivo, we performed experimental infections in ferrets followed by genome-wide gene expression analysis of lung and brain tissues. The Hendra, Nipah-Bangladesh, and Nipah-Malaysia strains caused severe respiratory and neurological disease with animals succumbing around 7 days post infection. Despite the presence of abundant viral shedding, animal-to-animal transmission did not occur. The host gene expression profiles of the lung tissue showed early activation of interferon responses and subsequent expression of inflammation-related genes that coincided with the clinical deterioration. Additionally, the lung tissue showed unchanged levels of lymphocyte markers and progressive downregulation of cell cycle genes and extracellular matrix components. Infection in the brain resulted in a limited breadth of the host responses, which is in accordance with the immunoprivileged status of this organ. Finally, we propose a model of the pathogenic mechanisms of henipavirus infection that integrates multiple components of the host responses.

The Evolving Classification of Pulmonary Hypertension.

CONTEXT: - An explosion of information on pulmonary hypertension has occurred during the past few decades. The perception of this disease has shifted from purely clinical to incorporate new knowledge of the underlying pathology. This transfer has occurred in light of advancements in pathophysiology, histology, and molecular medical diagnostics. OBJECTIVES: - To update readers about the evolving understanding of the etiology and pathogenesis of pulmonary hypertension and to demonstrate how pathology has shaped the current classification. DATA SOURCES: - Information presented at the 5 World Symposia on pulmonary hypertension held since 1973, with the last meeting occurring in 2013, was used in this review. CONCLUSIONS: - Pulmonary hypertension represents a heterogeneous group of disorders that are differentiated based on differences in clinical, hemodynamic, and histopathologic features. Early concepts of pulmonary hypertension were largely influenced by pharmacotherapy, hemodynamic function, and clinical presentation of the disease. The initial nomenclature for pulmonary hypertension segregated the clinical classifications from pathologic subtypes. Major restructuring of this disease classification occurred between the first and second symposia, which was the first to unite clinical and pathologic information in the categorization scheme. Additional changes were introduced in subsequent meetings, particularly between the third and fourth World Symposia meetings, when additional pathophysiologic information was gained. Discoveries in molecular diagnostics significantly progressed the understanding of idiopathic pulmonary arterial hypertension. Continued advancements in imaging modalities, mechanistic pathogenicity, and molecular biomarkers will enable physicians to define pulmonary hypertension phenotypes based on the pathobiology and allow for treatment customization.

Cellular Neurothekeoma: A Rare Tumor with a Common Clinical Presentation.

Neurothekeomas are rare benign tumors commonly found on the head, neck, and upper extremities of women and younger individuals. They are thought to be of nerve sheath origin and usually present as painless, slow growing masses. We present a case of cellular neurothekeoma on the nasal ala of an 8-year-old girl with no previous history of trauma or piercings. Differential diagnosis, treatment options, and special considerations regarding potentially atypical characteristics are discussed.

Microscopic thymoma and parathyroid adenoma: rare combination of two distinct pathologies.

While there is an intimate anatomical and embryological relationship between the inferior parathyroid gland and thymus, concurrent pathology is rare. Three cases have been reported in the literature of a parathyroid adenoma in conjunction with a thymoma. We present a case report of a 60-year-old female with a past medical history of hypercalcemia subsequently found to have primary hyperparathyroidism. Sestamibi scan of the parathyroid revealed increased uptake in the lower left neck consistent with a parathyroid adenoma. A standard transverse neck incision was performed with exploration of the lower left thyroid pole. Further dissection was required to identify the parathyroid gland which was intimately associated with thymic tissue in the superior mediastinum. Both thymic tissue and the parathyroid gland were sent for pathology. Permanent pathology subsequently revealed a parathyroid adenoma with an incidental spindle cell thymoma. The embryological relationship of the inferior parathyroid glands and the thymus is well known as both are derived from the third branchial pouch. However, there are only 3 other previous reports of parathyroid adenoma associated with a thymoma in the current literature. Interestingly, up to 16% of parathyroid adenomas are found in the mediastinum, and the current literature states the incidence of thymoma varies from 10-42%.

Ethanol metabolism, oxidative stress, and endoplasmic reticulum stress responses in the lungs of hepatic alcohol dehydrogenase deficient deer mice after chronic ethanol feeding.

Consumption and over-consumption of alcoholic beverages are well-recognized contributors to a variety of pulmonary disorders, even in the absence of intoxication. The mechanisms by which alcohol (ethanol) may produce disease include oxidative stress and prolonged endoplasmic reticulum (ER) stress. Many aspects of these processes remain incompletely understood due to a lack of a suitable animal model. Chronic alcohol over-consumption reduces hepatic alcohol dehydrogenase (ADH), the principal canonical metabolic pathway of ethanol oxidation. We therefore modeled this situation using hepatic ADH-deficient deer mice fed 3.5% ethanol daily for 3 months. Blood ethanol concentration was 180 mg% in ethanol fed mice, compared to <1.0% in the controls. Acetaldehyde (oxidative metabolite of ethanol) was minimally, but significantly increased in ethanol-fed vs. pair-fed control mice. Total fatty acid ethyl esters (FAEEs, nonoxidative metabolites of ethanol) were 47.6 µg/g in the lungs of ethanol-fed mice as compared to 1.5 µg/g in pair-fed controls. Histological and immunohistological evaluation showed perivascular and peribronchiolar lymphocytic infiltration, and significant oxidative injury, in the lungs of ethanol-fed mice compared to pair-fed controls. Several fold increases for cytochrome P450 2E1, caspase 8 and caspase 3 found in the lungs of ethanol-fed mice as compared to pair-fed controls suggest role of oxidative stress in ethanol-induced lung injury. ER stress and unfolded protein response signaling were also significantly increased in the lungs of ethanol-fed mice. Surprisingly, no significant activation of inositol-requiring enzyme-1α and spliced XBP1 was observed indicating a lack of activation of corrective mechanisms to reinstate ER homeostasis. The data suggest that oxidative stress and prolonged ER stress, coupled with formation and accumulation of cytotoxic FAEEs may contribute to the pathogenesis of alcoholic lung disease.

Microscopic diffuse large B-cell lymphoma (DLBCL) occurring in pseudocysts: do these tumors belong to the category of DLBCL associated with chronic inflammation?

We report 2 cases of localized, microscopic diffuse large B-cell lymphoma (DLBCL) that were detected incidentally within pseudocysts. In case 1, the neoplasm was identified within a 26-cm, 860-g adrenal gland pseudocyst. In case 2, the neoplasm was detected within a 9-cm, 90-g paratesticular pseudocyst. In both cases, the neoplastic cells were large, had a nongerminal center B-cell immunophenotype, and were positive for Epstein-Barr virus (EBV)-encoded RNA detected by in situ hybridization. The most appropriate classification of these tumors using current World Health Organization classification is uncertain. The best fit seems to be DLBCL associated with chronic inflammation (DLBCL-CI), defined as DLBCL arising in the context of long-standing chronic inflammation and associated with EBV infection, with the prototype for this category being pyothorax-associated lymphoma. This term has been used by others in the literature for tumors similar to the cases reported here. However, in the 2 cases we report chronic inflammation was not a prominent feature, and the inflammatory cells that were present showed little relationship to the lymphoma cells. The findings in these cases have led us to question the role of chronic inflammation in pathogenesis. Perhaps the closed space of the pseudocyst, by preventing a cytolytic response to EBV-infected cells, results in local immunodeficiency that may be most important for pathogenesis. We also have concerns about using the term DLBCL-CI for these tumors. Perhaps the cases we report and the few other similar cases reported previously deserve their own category in a future version of the World Health Organization classification.

Idiopathic bronchiolitis with features of diffuse panbronchiolitis in an African-American patient with hepatitis C virus infection.

Diffuse panbronchiolitis (DPB) is an idiopathic inflammatory process involving respiratory bronchioles, largely restricted to Japanese people and associated with HLA Bw54. We report a case of idiopathic bronchiolitis with DPB features in an African American with hepatitis C virus infection, correlated with postmortem anatomic findings. The 53-year-old patient presented with shortness of breath and productive cough. Examination revealed hypercapnic respiratory failure. Lung computed tomography showed diffuse centrilobular nodules and branching linear opacities, whereas lung biopsy demonstrated diffuse peribronchiolar fibrosis and chronic inflammation with bronchiolectasis. He died 37 days postadmission. Autopsy revealed numerous bronchiolocentric nodules with bronchiolectasis and sheets of foamy macrophages in alveolar septa and spaces. This is a rare example of idiopathic bronchiolitis with features of DPB in an hepatitis C virus-infected African-American patient. Hepatitis C virus infection is known to be associated with extrahepatic pulmonary manifestations, and DPB may be one of these. Early diagnosis will allow appropriate treatment and may slow the disease progression.

Nodular mucinosis of the breast in a supernumerary nipple: case report and review of the literature.

Nodular mucinosis is an extraordinary stromal lesion of the breast. The usual clinical presentation is that of an oozing, slow-growing, soft, non-tender, lobulated mass in the subareolar region. Histologically, it is a non-encapsulated myxoid/mucinous lesion with a sparse infiltrate of spindle cells within a collagenized stroma. The histogenesis of nodular mucinosis is undetermined but the pattern of staining of the spindle cells suggests it might be of myofibroblastic origin. We herein report for the first time in the English literature a case of nodular mucinosis occurring in a supernumerary nipple. We also discuss the main differential diagnoses and review the literature of previously published cases of this entity.

Changing trends in the distribution of the histologic types of lung cancer: a review of 4,439 cases.

Lung cancer is the second most common cancer and the leading cause of cancer death in both men and women. The purpose of the study is to explore the distribution of the 4 major histologic types of lung carcinoma and the incidence of lung cancer with reference to all other sites of cancer. The clinical and histopathologic data of 4,439 patients with lung carcinoma between January 1980 and December 2003 were reviewed. Adenocarcinoma has become the most frequent histologic type in men and women (36.8% and 46.5%, respectively), followed by squamous cell carcinoma (31.6% and 25.4%, respectively). The incidence of large cell (undifferentiated) carcinoma in men and women is 18.0% and 9.9%, respectively. The incidence of small cell carcinoma in men and women is 13.7% and 18.3%, respectively. In addition, analysis of our data indicates that lung cancer rate is decreasing, relative to all other primary cancer sites. The results of this study suggest that the incidence of lung cancer has decreased in comparison with other sources of cancer in southern Texas. This observation is consistent with the current national trends. In addition, there are significant changes in the distribution of the major histologic types of lung cancer. The results of this study may portend important changes in the selection of targeted therapy and patient management.

SYT-SSX2 variant of primary pulmonary synovial sarcoma with focal expression of CD117 (c-Kit) protein and a poor clinical outcome.

Pulmonary synovial sarcoma is a rare neoplasm recently recognized as a distinct entity and characterized by t(X;18) translocation and production of at least 2 fusion genes, SYT-SSX1 and SYT-SSX2. We report a case of primary pulmonary synovial sarcoma with the SYT-SSX2 phenotype and a rapidly progressive downhill course. Previous reports have suggested that the soft tissue synovial sarcomas with SYT-SSX2 phenotype have a favorable clinical outcome. To the best of our knowledge, this is also the first report of CD117 (c-Kit) expression in a pulmonary synovial sarcoma. A 45-year-old woman presented with left chest pain and was found to have a left lower lobe tumor that was originally diagnosed as a sarcomatoid carcinoma. After the patient underwent chemotherapy and brachytherapy, the specimen from a left pneumonectomy showed a large spindle cell tumor, which was reclassified as a synovial sarcoma based on the results of immunophenotyping and molecular genetic studies. Differentiation between sarcoma and carcinosarcoma is crucial for implementing appropriate therapy. Furthermore, if the tumor expresses c-Kit, it may respond to target-based therapy.