Katsuya Chinen

Pulmonary tumor thrombotic microangiopathy caused by a gastric carcinoma expressing vascular endothelial growth factor and tissue factor

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare clinicopathological entity causing severe pulmonary hypertension. Its histological features include widespread tumor emboli along with fibrocellular intimal proliferation and thrombus formation in the small arteries and arterioles of the lungs. The result is occlusion or stenosis of the pulmonary vasculature, but the detailed pathogenesis has yet to be clarified in spite of the serious clinical manifestations. Herein is described the case of a 62‐year‐old man with a gastric adenocarcinoma who died of sudden cardiopulmonary arrest. The autopsy revealed advanced cancer disease as well as findings of PTTM, which seemed to be the cause of his unexpected death. The carcinoma cells were immunohistochemically positive for vascular endothelial growth factor (VEGF) and also for tissue factor (TF). There is another report suggesting that TF might play an important role in the pathogenesis of PTTM. Also, VEGF has been reported to be involved in a variety of forms of pulmonary hypertension and to be upregulated by TF. These findings suggest that VEGF and TF may be involved in the pathogenesis of PTTM. The present PTTM case, in which the tumor cells demonstrate the coexpression of VEGF and TF, is important in facilitating understanding of the lethal disorder in the future.

Pulmonary tumor thrombotic microangiopathy in patients with gastric carcinoma: an analysis of 6 autopsy cases and review of the literature.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare clinicopathological entity causing severe pulmonary hypertension (PH). Its histological features include widespread tumor emboli of the small arteries and arterioles of the lung, associated with thrombus formation and fibrocellular and fibromuscular intimal proliferation. Although PTTM has drawn increased attention as a fatal complication of gastric carcinoma (GC), comprehensive studies are still lacking. In order to clarify clinical and pathological features of GC-induced PTTM, recent autopsy cases were analyzed with a review of the literature. Of 36 autopsy cases with GC, 6 (16.7%) were affected by PTTM. Four were male and 2 female, with a mean age of 72.7 years. Three patients presented with PTTM-related clinical manifestations and died of PTTM. They showed clear morphological evidence of PH. The other 3 patients had PTTM as an incidental finding irrespective of clinical manifestations or PH. No patient was diagnosed antemortem as PTTM. All PTTM cases were associated with advanced GC, with a histology of adenocarcinoma of poorly differentiated type (n=4) or signet-ring cell type (n=2). Expression of tissue factor and vascular endothelial growth factor was confirmed immunohistochemically in tumor cells in all cases. The results were all in line with previous studies. In addition, the current study revealed vascular lesions characteristic of PTTM morphology to be present exclusively in the lung. In conclusion, our study shows a 16.7% incidence of PTTM in GC patients, with half of them developing PH and dying of PTTM, confirming a clinical significance as a non-negligible lethal complication of GC. In addition to many known clinicopathological characteristics of PTTM, the current study pointed to some PTTM issues requiring clarification, including the pathogenesis of the exclusive pulmonary distribution of vascular lesions of PTTM. Since details remain to be elucidated, interdisciplinary research is a high priority with a close collaboration between pathologists and clinicians in order to overcome this lethal condition.

Cardiac involvement by malignant lymphoma: a clinicopathologic study of 25 autopsy cases based on the WHO classification

As cardiac involvement by malignant lymphoma (ML) is relatively uncommon and antemortem diagnosis is difficult, details of this condition remain to be elucidated. To clarify clinicopathologic features of cardiac lymphoma (CL), 25 autopsy cases were studied. Each was rediagnosed according to the World Health Organization (WHO) classification, and clinicopathologic characteristics were investigated by tumor phenotype. The study subjects were 13 males and 12 females with a mean age of 53.4 years. All cases were secondary CL and were not diagnosed as CL before death; 14 cases (56%) were of B-cell and 11 (44%) of T-cell (including natural killer cell) phenotype. Nasal and nasal-type natural killer/T-cell lymphomas (NKTLs) accounted for five (20%). Cardiac manifestation was evident in eight (32%), with hematogenous infiltration as the most common pattern of tumor spread. Some B-cell CLs (n=3) were complicated by cardiac tamponade and heart failure (HF), and T-cell CLs (n=5), including three nasal NKTLs, also featured arrhythmia and sudden death. The incidence of T-cell phenotype was significantly elevated for CLs (p<0.05), especially for CLs with cardiac manifestation (p<0.01), compared with that for MLs in general. Our results indicate that T-cell lymphomas, compared with B-cell lymphomas, invade the heart more frequently and aggressively and are associated with a variety of cardiac manifestations. Where cardiac involvement is suspected, aggressive diagnostic procedures are warranted, especially with MLs having a T-cell phenotype. In cases of nasal NKTL, particular attention is necessary.

Pulmonary tumor thrombotic microangiopathy caused by an ovarian cancer expressing tissue factor and vascular endothelial growth factor

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare clinicopathologic entity causing severe pulmonary hypertension, right-side heart failure, and sudden death. Its histologic features include widespread tumor emboli of the small arteries and arterioles of the lung, associated with thrombus formation and fibrocellular and fibromuscular intimal proliferation. The most frequent causative neoplasm for PTTM is gastric cancer, but lesions in other organs, including the ovary, have been occasionally identified as primary causes. Detailed molecular mechanisms underlying PTTM remain unclear, but some studies have suggested that tissue factor (TF) and vascular endothelial growth factor (VEGF) expressed by tumor cells may be involved in the pathogenesis for cases of gastric cancer. However, little is known about these molecules in PTTM caused by neoplasms of non-gastric origin. Here, we report the autopsy findings of a 42-year-old woman with ovarian cancer showing positive immunoreactivity for both TF and VEGF who died suddenly of PTTM. The present case provides support for the conclusion that these factors may be involved in the pathogenesis of PTTM, independent of the causal neoplasm.

A case of mucin hypersecreting intraductal papillary carcinomas occurring simultaneously in liver and pancreas

Intraductal papillary mucinous tumor of the pancreas (IPMT) is accepted as a distinct disease entity. Its unique features are attributable primarily to excessive amounts of mucin secreted by the tumor. In contrast, a mucin hypersecreting bile-duct tumor is rare. A subgroup of bile-duct tumors, which clinically and histopathologically resemble IPMT, has been described. This type of tumor excretes excessive mucin that fills the biliary tree and results in segmental dilatation of the intrahepatic bile ducts. Histopathologically, the tumor frequently exhibits intraductal spreading and/or intraductal papillary projections ofmucinproducing columnar epithelium with variable cellular atypia. Based on these characteristic homologies with IPMT, it has been proposed that such papillary mucinous tumors of the intrahepatic bile duct be called intraductal papillary neoplasmof the liver (IPNL). Because thepancreas and the bile duct develop embryonically from the same primordium, such tumors can occur in either of these tissues. However, the simultaneous occurrence of IPNL and IPMT is extremely rare. To our knowledge, only two cases of IPNL associated with IPMTare reported. In neither case was the liver or the pancreatic tumor malignant. Herein, a case is presented of concurrent IPMTand IPNL, both were malignant.

Nasal natural killer cell/T-cell lymphoma showing cellular morphology mimicking normal lymphocytes.

We report the autopsy case of a 34-year-old Japanese man with a nasal natural killer (NK)-cell/T-cell lymphoma. The patient developed the disease at 32 years of age, and a biopsy of the nasopharynx revealed pleomorphic lymphoma cell proliferation. Radiotherapy was performed, but the patient eventually died of respiratory failure. After radiotherapy, no histologic evidence of malignancy was obtained with biopsy materials featuring lymphocytic infiltration. Autopsy studies, including in situ hybridization for Epstein-Barr virus-encoded RNA, revealed generalized infiltration of normal lymphocyte-like, UCHL-1-positive, and Epstein-Barr virus-encoded RNA-positive lymphoma cells. Monoclonal proliferation of the Epstein-Barr virus-carrying cells was verified by means of Southern blot analysis. Retrospectively, we concluded that the normal lymphocyte-like presentation of the lymphoma cells, probably influenced by radiotherapy, prevented pathologists from recognizing the lymphoma. The utility of in situ hybridization for Epstein-Barr virus-encoded RNA in identification of tumor cells is emphasized with respect to the present case.

Severe Pulmonary Hypertension Caused by Smoldering Plasma Cell Myeloma: An Autopsy Case of POEMS Syndrome

The POEMS syndrome (coined to refer to polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) is a rare variant of plasma cell disorders with multiple systemic manifestations. Recently, pulmonary hypertension (PH) has become established as a complication, but pathological studies of this condition are scarce and the detailed pathogenesis remains to be elucidated. We present herein a case of a 49-year-old woman who was diagnosed as having idiopathic PH and was treated in accordance. However, she eventually died of respiratory failure and an autopsy revealed the presence of smoldering plasma cell myeloma and multiple organomegaly in addition to severe PH. The latter was attributed to stenosis and occlusion of the arterioles of the lungs due to marked plasma cell proliferation, quite different from the histology of idiopathic PH. From these findings, together with the clinical details, we concluded that the patients PH was a complication of the POEMS syndrome. This case showed a unique pulmonary vascular pathology featuring plasma cell proliferation and it provides clues towards understanding the pathogenesis with this background.