Pulmonary tumor thrombotic microangiopathy

Pulmonary tumor thrombotic microangiopathy (PTTM) is characterized by widespread fibrocellular intimal proliferation of the small pulmonary arteries and arterioles in patients with metastatic Carcinoma. Microscopic pulmonary tumor emboll have frequently occurred in patients with malignant tumors; however, few cases of PTTM have been reported. A rare case of a patient with gastric adenocarcinoma who presented with acute dyspnea and lethal respiratory failure is described. Histologically, diffuse fibromuscular intimal thickening cauring luminal stenosis and obstruction but containing rather few cancer cells was observed in the small pulmonary arteries and arterioles. These findings were consistent with PTTM. Atthough PTTM is a rare phenomenon, PTTM should be considered in the differential diagnosis of acute dyspnea or pulmonary hypertension in patients with carcinoma.     

Pulmonary tumor thrombotic microangiopathy associated with extramammary Paget's disease: An autopsy case report

Pulmonary tumor thrombotic microangiopathy (PTTM) is histologically characterized by micro tumor cell embolism and intimal fibrocellular proliferation of pulmonary arteries or arterioles. We report a secondary case of PTTM associated with extramammary Paget's disease (EMPD). The patient was a 72‐year‐old man with exertional dyspnea. Clinical examinations found he had pulmonary hypertension and multiple osteolytic lesions of vertebra. Cytological analysis of pulmonary wedge artery sample detected malignant cells and he was dead before treatment was started. Multiple tumor embolisms (>17) were identified in pulmonary arteries or arterioles at autopsy, consistent with PTTM. Metastatic nodules were found in liver and lymph node. Furthermore, disseminated carcinomatosis of the bone marrow (DCBM) was seen. Immunostaining results pointed out that tumor cells possessed mammary gland phenotype. He had 4‐years history of EMPD in the left axilla without recurrence, and immunohistochemistry results were the same as the autopsy specimen. Thus, we diagnosed the primary site of PTTM to be EMPD. Our case highlights the usefulness of the recent proposed classification of PTTM, potential association between PTTM and DCBM, and the necessity for long‐term follow‐up in EMPD. EMPD can rarely cause PTTM to manifest as a paraneoplastic syndrome.     

Pulmonary tumor thrombotic microangiopathy showing aggressive course after transurethral resection of urinary bladder: an autopsy case report

A 77-year-old man developed pulmonary tumor thrombotic microangiopathy (PTTM) 2 days after undergoing transurethral resection for urothelial carcinoma (G3) of the urinary bladder and died of respiratory failure 6 days later. Histological findings demonstrated marked intimal fibrocellular proliferation, fibrin thrombi, and both cancer cells and fibrin thrombi in the arteries of the lungs, findings consistent with PTTM. Prominent stenosis in arteries smaller than 300 ??m was also seen. The Ki-67 labeling index of primary and metastasized cancer cells was 62.4 % and 70.2 %, respectively. The membranes of metastasized cancer cells expressed E-cadherin, similar to membranes in the urinary bladder. An aggressive PTTM course is affected by intimal fibrocellular proliferation and the high cell proliferation of cancer cells. Furthermore, prominent stenosis in small arteries and membranous staining of E-cadherin of metastasized cells suggest that cancer cells formed clusters by maintaining adhesion molecules and migrated into the arteries of the lungs, where they easily caused damage to the endothelium of small arteries, in contrast to dispersed cancer cells.     

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.     

Pulmonary tumor thrombotic microangiopathy resulting from metastatic signet ring cell carcinoma of the stomach

Pulmonary tumor thrombotic microangiopathy is an unusual malignancy-related respiratory complication characterized by multiple microthrombi and intimal myofibroblast proliferation. Its clinical manifestation is subacute respiratory failure with pulmonary hypertension. Herein is reported a case of pulmonary tumor thrombotic microangiopathy associated with gastric signet ring cell carcinoma. A 51-year-old woman with gastric cancer died of subacute respiratory failure. Autopsy showed gastric signet ring cell carcinoma with diffuse metastasis of pulmonary lymphatics and pleurae; every organ examined lacked a space-occupying tumor mass. Histologically, proliferated intimal myofibroblasts obliterated most of the pulmonary vascular lumen, and a few stenosed vascular lumina contained cancer cells. In addition, pulmonary vasculature associated with intimal proliferation contained microthrombi. Most cancer cells in the stomach and pulmonary lymphatics were typical signet ring cells, whereas those in vascular lesions were cells of poorly differentiated adenocarcinoma without mucous production. Consistent with a previous report, the latter expressed vascular endothelial growth factor (VEGF) and tissue factor (TF). The proliferated intimal myofibroblasts also expressed type 2A serotonin receptor (5-HT(2A)). These findings suggest that local expression of VEGF, TF, and 5-HT(2A) may be linked to the pathogenesis of this unusual pulmonary complication.     

Mesangiolysis: an important glomerular lesion in thrombotic microangiopathy

Six cases of malignancy-associated thrombotic microangiopathy and eight cases of idiopathic microangiopathy have been studied by renal biopsy. All patients of both groups had mild to severe renal impairment and microangiopathic hemolytic anemia. The renal lesions were histopathologically identical in the two groups. The most characteristic abnormalities were glomerular mesangiolysis and glomerular and arteriolar thrombosis. Subendothelial widening, presumably due to entrapment of blood components, and the formation of capillary and arteriolar thrombi may be attributed to endothelial damage. Glomerular fibrinogen was demonstrated by immunofluorescence in a majority of cases. Immunofluorescence also showed glomerular immunoglobulin M (IgM) and Clq in a majority of cases and C3 in slightly less than half. Mesangiolysis, present in every case, resulted in coalescence of capillary lumina, but mesangiolysis is a bland process, easily overlooked. The mesangial waists of the glomerular tufts seemed to unravel and come apart, with no inflammatory reaction or fibrin deposition on the luminal surface. The presence of capillary enlargement was confirmed morphometrically as an increased proportion of glomerular sectional area. In what appeared to be a late stage of mesangiolysis, the mesangium was thickened by pale fibrillary material, producing a lobulated glomerular tuft and eventual glomerular solidification. The early stages of mesangiolysis may be reflected only in glomerular capillary ectasia, whereas the late stages produce a distinctive form of glomerular sclerosis.     

Pancytopenia in a patient with HIV: A diagnosis often missed

A 31 years old male presented with fever, dry cough, weight loss. Patient was found to be HIV positive and was started on empirical Anti-tubercular drugs (ATT). However, his symptoms persisted and he developed pancytopenia along with jaundice, and was shifted to our health care facility for further investigations. The patient has a history of travel to Bali and Thailand a few months ago. Patient was examined and relevant investigations were performed.     

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.     

Cystic tumor of the atrioventricular node: rare antemortem diagnosis

BackgroundThe cystic tumor of the atrioventricular node (TAV) is a rare, congenital cardiac tumor, typically located at the base of the atrial septum. Histologically benign, this multicystic mass is a tumor of the conduction system and is considered the smallest tumor capable of causing sudden and unexpected death. TAV has shown a predilection for women with a mean age at presentation of 38 years. The majority of cases are diagnosed incidentally at autopsy, while antemortem surgical excision is rare, with ours being the firth and sixth reported cases in the medical literature.MethodsWe present two cases, in 33- and 29-year-old women who were admitted for complaints of dyspnea, dizziness, palpitation or numbness, along with a review of the literature. One was known to have complete congenital heart block and ventricular septal defect, where an intraoperative transesophageal echocardiogram revealed a right atrial mass. The other patient had a right atrial mass visible on magnetic resonance imaging, which led to surgical resection and permanent pacemaker insertion.ResultsHistopathological examination revealed a tumor composed of cysts, some lined by squamous epithelium, and others by transitional epithelium. Irregular proliferation of glandular structures with squamoid nests within a fibrous stroma, with sebaceous-type differentiation, was also observed. A chronic inflammatory component with secondary lymphoid follicles was also noted.ConclusionThese cases are presented, along with a review of the four previously reported cases of TAV diagnosed antemortem. Awareness regarding this lesion could improve gross and microscopic characterization of TAV and increase antemortem diagnoses.     

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.     

Osteopontin expression in pulmonary tumor thrombotic microangiopathy caused by gastric carcinoma

Pulmonary tumor thrombotic microangiopathy (PTTM) is characterized by fibrocellular intimal proliferation and thrombus formation in small pulmonary arteries and arterioles in patients with metastatic carcinoma. Osteopontin (OPN) is a multifunctional cytokine and adhesive protein, and has been demonstrated to be implicated in fibrosis, neointima formation, arterial occlusion by thrombus, and tumor metastases in cooperation with platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Herein is described an autopsy case of gastric adenocarcinoma with severe pulmonary hypertension due to PTTM. Histologically, tumor cell emboli markedly induced both fibromuscular intimal thickening and thrombosis, resulting in luminal stenosis and occlusion of small pulmonary arteries and arterioles. Tumor cells, both in the PTTM lesions and primary gastric carcinoma, had positive immunoreactivity for OPN, PDGF, and VEGF. In addition, proliferating fibromuscular intimal cells also showed expression of OPN, PDGF, and VEGF. These findings suggest that OPN may be involved in fibrocellular intimal proliferation and thrombus formation in PTTM together with PDGF and VEGF. To the best of the authors' knowledge this is the first report to demonstrate the possible involvement of OPN in PTTM. It is postulated that OPN is one of the candidate molecules for the development of PTTM.     

Lemierre's syndrome: An often missed life-threatening infection

Lemierre''s syndrome is an uncommon, but fatal infection of the internal jugular vein (IJV) that is usually caused by Fusobacteirum necrophorum although a wide range of bacteria has been reported as causative agents. Typical symptoms include fever, sore throat, neck swelling, pulmonary symptoms and arthralgia; however, the diagnosis of this infection is frequently overlooked as initial manifestation might be subtle and non-specific. Definite diagnosis requires positive blood culture and radiological evidence of thrombus in the IJV. We describe a case of a patient with Lemierre''s syndrome who was initially misdiagnosed with viral upper respiratory tract infection. High index of suspicion is pivotal to the diagnosis of this infection and Lemierre''s syndrome should always be considered as a potential cause of sepsis in an otherwise healthy patient.     

Gomez-Lopez-Hernandez syndrome: an easily missed diagnosis

Gomez–Lopez-Hernandez syndrome (GLHS) is a rare syndrome comprising the triad rhombencephalosynapsis (RS), parietal alopecia, and trigeminal anesthesia. Other typical findings are skull abnormalities, craniofacial dysmorphic signs, and short stature. Intellectual impairment is typical but cases with normal cognitive functions have also been reported. Only 15 cases of GLHS have been described so far, all sporadic. We report four further patients with GLHS: one neonate, two children and a middle aged man. In all cases the diagnosis was made only in retrospect; one child died as neonate due to esophageal atresia. All patients presented RS and parietal alopecia, three intermittent head stereotypies, two had obvious trigeminal anesthesia, and one normal cognition. Alopecia and also trigeminal anesthesia can be very mild and can be easily missed. However, the dysmorphic signs including bilateral alopecia are already present in the neonatal period and are highly suggestive of GLHS. RS should be looked for in this situation. It is important to mention that neuroimaging does not allow distinguishing between isolated RS and GLHS. If RS is diagnosed the clinical signs of GLHS should be sought. The diagnosis of GLHS can only be made by the combination of the typical dysmorphic signs and neuroimaging in the neonatal period, but not prenatally.     

A microscopic adenocarcinoma of the stomach with pulmonary tumor thrombotic microangiopathy in a 17-year-old male

Pulmonary tumor thrombotic microangiopathy (PTTM), characterized by widespread fibrocellular intimal proliferation of the small pulmonary arteries and arterioles in patients with metastatic carcinomas, has been reported in only few cases. In childhood, gastrointestinal tumors represent less than 5% of pediatric neoplasms, and carcinomas within this subgroup have been very rarely described, in particular those arising in the stomach. We report on a case of a microscopic gastric signet-ring cell carcinoma identified by serial step sections through the entire stomach at autopsy. The patient was a 17-year-old high school student with severe dyspnea and marked pulmonary hypertension due to PTTM. Although the combination of PTTM with gastric cancer is very rare in childhood, it should be considered in the differential diagnosis of primary pulmonary hypertension and progressive respiratory failure, as indicated by a review of previously reported cases.     

Tumor-related thrombotic pulmonary microangiopathy: review of pathologic findings and pathophysiologic mechanisms

We report a middle-aged woman who died 2 days after presenting with dyspnea and severe pulmonary hypertension of unknown etiology. Her symptoms were highly suggestive of pulmonary embolism, but clinical evaluations for that disease yielded negative results. Autopsy revealed a Krukenberg tumor of the left ovary, representing metastatic gastric carcinoma from an occult primary lesion. Although the lungs exhibited no gross evidence of pulmonary emboli or neoplasia, microscopic examination revealed diffuse microscopic metastases in the pulmonary arterial vasculature. The pulmonary arteries exhibited fibrocellular intimal proliferation with smooth muscle colonization of the luminal neoplastic lesions and associated microthrombi. This disease entity, known as tumor-related thrombotic pulmonary microangiopathy, results in generalized microvascular obliteration and subsequent pulmonary hypertension. It is a rare condition that is distinct from ordinary pulmonary thromboembolism and primary pulmonary hypertension. Tumor-related thrombotic pulmonary microangiopathy should be considered diagnostically by the autopsy pathologist in cases of rapidly evolving pulmonary hypertension in a middle-aged or elderly individual, or respiratory failure of unknown cause, especially if there is a history of a visceral malignancy.     

Platelet-derived growth factor-A and vascular endothelial growth factor-C contribute to the development of pulmonary tumor thrombotic microangiopathy in gastric cancer

Pulmonary tumor thrombotic microangiopathy is a rare but lethal complication in cancer-bearing patients, particularly those with gastric cancer. It is characterized by cancer cell emboli with marked intimal proliferation. In the present study, we tried to elucidate the pathogenesis of pulmonary tumor thrombotic microangiopathy, notably angiogenic factors specific for cancer cells lodged in pulmonary arteries. An autopsy series of gastric cancer (51 cases) was reviewed for pulmonary tumor thrombotic microangiopathy and pulmonary tumor cell emboli without intimal proliferation. Pathological and immunohistochemical characteristics were compared between two groups. In eight cases in muscular pulmonary arteries, tumor thrombotic microangiopathy was noted, and in three cases pulmonary tumor emboli without intimal proliferation was noted. Histological features of pulmonary tumor thrombotic microangiopathy included small nests or single cancer cells accompanied by intimal proliferation, whereas in pulmonary tumor emboli large cell nests prevailed. By immunohistochemistry, in pulmonary tumor thrombotic microangiopathy, cancer cells expressed platelet-derived growth factor-A (7/8 cases) and vascular endothelial growth factor-C (8/8) more frequently than in pulmonary tumor emboli (0/3 and 1/3; P?=?0.02 and P?=?0.055, respectively). Expression of tissue factor, vascular endothelial growth factor-A and -D, osteopontin, fibroblast growth factor-2, and platelet-derived growth factor-B was similar in both groups. Platelet-derived growth factor-A and vascular endothelial growth factor-C might induce intimal proliferation in pulmonary arteries and contribute to the development of pulmonary tumor thrombotic microangiopathy.