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.     

Pulmonary hypertension attributable to neoplastic emboli: An autopsy study of 20 cases and a review of literature

Twenty cases of pulmonary hypertension attributable to neoplastic emboli were the subject of this retrospective autopsy study (1951–1990) at the Mayo Clinic. Fourteen patients were women, and ages ranged from 18 to 82 years (mean 49). In three patients, tumor was clinically occult, and in only one case was the diagnosis of neoplastic pulmonary hypertension considered clinically. The mean interval between diagnosis of malignancy and development of respiratory symptoms was 14 months, but the mean interval between respiratory symptoms and death was only one month. At autopsy, the three most common primary sites for neoplasm were breast (40%), stomach (15%), and lung (10%). All 20 cases revealed subacute changes of pulmonary hypertension, either with medial hypertrophy of muscular pulmonary arteries (70%) or with right ventricular hypertrophy (45%) or dilatation (40%). However, three subgroups were identified based on microscopic and gross features: (i) 6 patients with predominantly neoplastic microemboli, (ii) 10 patients with mixed neoplastic and thrombotic microemboli, and (iii) 4 cases with both neoplastic microemboli and large, fatal tumor emboli (primary tumors in kidney, femur, cervix, and thyroid). In conclusion, neoplastic pulmonary hypertension is most commonly associated with carcinoma of the breast, accounting for the observed female preponderance. It is generally associated with a rapid clinical course once respiratory symptoms develop, and large, fatal, acute neoplastic emboli account for a substantial number of deaths (20% in the present series).     

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.     

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.     

Pulmonary arterial dissections and ruptures: to be considered in patients with pulmonary arterial hypertension presenting with cardiogenic shock or sudden death

Four unusual cases of sudden death due to pulmonary arterial hypertension complicated by dissection and/or rupture of the main pulmonary artery are reported. The patients, 3 males and 1 female, ranged from 17 to 77 years old. Each had chronic pulmonary arterial hypertension, marked pulmonary arterial dilation and degenerative medial changes of the large elastic pulmonary arteries. The first patient had a partial thickness tear of the main pulmonary artery with local dissection without external rupture and died of shock. The other three patients died after external rupture of the main pulmonary artery, based on a full thickness tear in one case, a small dissection in another and extensive dissection in the third. In the setting of pulmonary arterial hypertension, dissection, rupture, or dissection and rupture of the pulmonary artery should be considered in the differential diagnosis when patients present in cardiogenic shock or with sudden death.     

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia

BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension.     

经胸超声心动图在肺动脉栓塞诊断中的应用价值

目的:探讨经胸超声心动图(TTE)对肺动脉栓塞(PE)的诊断价值.方法:回顾性分析21例经 CT肺动脉造影检查确诊为 PE患者的经胸超声心动图表现.结果:本组21例,经胸超声心动图大致正常者6例;直接检出主肺动脉及左、右肺动脉近段血栓8例;间接征象提示右心负荷过重15例(包括8例直接检出血栓者),均有右心扩大的表现,其中右室内径(30.7±5.4)mm,右房内径(59.4±6.6)mm.彩色多普勒观察到三尖瓣返流16例,检测其返流速度估测出肺动脉收缩压增高15例,收缩压均高于40 mmHg.结论:经胸超声心动图对中央型肺栓塞具有较高的诊断价值,它可以显示血栓发生的部位.对周围型(肺段及远端分支)肺栓塞虽然不能直接做出诊断,但根据右心扩大、三尖瓣返流及肺动脉高压等间接征象,可为肺动脉栓塞的诊断提供佐证,为临床诊断提供帮助.     

The ultrastructure of plexogenic pulmonary arteriopathy

The lungs from 16 cases of plexogenic pulmonary arteriopathy obtained at heart-lung transplantation, half of which had primary pulmonary hypertension, were examined by electron microscopy. From these the probable pathogenesis of pulmonary arterial intimal fibrosis in plexogenic pulmonary arteriopathy was deduced. The earliest detectable change was migration of smooth muscle cells from the media, through the internal elastic lamina into the intima. These cells collected beneath the endothelium and lost many of their myofilaments to become myofibroblasts. They were associated with ground substance but scanty collagen fibrils. As the quantity of interstitial collagen increased, the myofibroblasts reverted to a muscular structure, became elongated, and assumed a regular, circumferential orientation. This later stage coincided with the development of plexiform lesions. At both early and later stages, the muscular pulmonary arteries were contracted but not markedly so, and muscular evaginations were not seen. On the other hand, the cellular intimal proliferations developed early and were occlusive. This suggests that occlusion of small pulmonary arterial vessels by myofibroblasts may be at least as important as vasoconstriction in the early elevation of the pulmonary vascular resistance in primary pulmonary hypertension.     

MIXED CONNECTIVE TISSUE DISEASE WITH FATAL PULMONARY HYPERTENSION

An autopsy case of mixed connective tissue disease (MCTD) with pulmonary hypertension is presented. A 34-year-old woman suffering from arthralgia, Raynaud's phenomenon, and dyspnea of 6-years duration was diagnosed as having MCTD on the basis of a high titer (1:160,000) of serum antibody to the ribonuclease-sensitve component of extractable nuclear antigen. Examination of cardiac function revealed the complication of pulmonary hypertension. Autopsy revealed concentric intimal cellular proliferation of the small arteries and arterioles of both lungs. Typical plexiform lesions of these vessels were also observed. These findings coincide with those of plexogenic pulmonary angiopathy of primary pulmonary hypertension (PPH). This is the second autopsy case of MCTD with fatal pulmonary hypertension reported and our observations suggest that some cases with PPH who had immunological abnormalities but could not be classified as cases of classical collagen disease, may have been induced by MCTD.     

Tumor embolism as a cause of an unexpected death: a case report

The primary causes of deaths for individuals with rare cancers can be difficult to diagnose clinically. Often, the symptoms implicate a variety of factors, and an autopsy is thus required to obtain the correct diagnosis. This study analyzes the death of a 45-year-old woman who reportedly died from an acute pulmonary dysfunction. The patient had been treated with antibiotics for three months for intractable pneumonia. Suspicious coin lesions detected by chest X-ray prompted a clinical clarification; however, no final diagnosis was made. The autopsy revealed a bulky thyroid tumor with venous invasion, leading to a massive pulmonary tumor embolism. Furthermore, microscopy identified the tumor as a rare pleomorphic myxoid sarcoma. Thus, the patient died of a large pulmonary tumor embolism originating from this rare sarcoma, and not of acute pulmonary dysfunction of any other means.     

Influence of hypobaric hypoxia in infancy on the subsequent development of vasoconstrictive pulmonary vascular disease in the Wistar albino rat

A group of Wistar albino rats was injected subcutaneously with monocrotaline to induce vasoconstrictive hypertensive pulmonary vascular disease characterized by medial hypertrophy of small pulmonary arteries, the appearance of muscular pulmonary arterial vessels of arteriolar dimensions (less than 20 microns) in diameter), and exudative changes in the lung parenchyma. The vascular abnormalities were quantified by measuring the percentage medial thickness of small pulmonary arteries, the number of muscular pulmonary arterial vessels below 20 microns in diameter per cm2 of lung section and by determining the smallest arterial vessels in each case showing muscularity. A second group of rats was born in a decompression chamber and kept in hypobaric hypoxia for a month of the neonatal period, developing hypoxic hypertensive pulmonary vascular disease as a consequence. The animals in this group were allowed to recover in room air for a period of 3 months and were then injected with the same dose of monocrotaline as that given to the first group. The rats previously exposed to hypoxia exhibited an exaggerated response to the alkaloid, showing in particular many more small muscular pulmonary arterial vessels which were of a smaller diameter than those found in the eupoxic rats treated with the alkaloid. The experiment demonstrates the perinatal hypoxia exaggerates the effects of agents inducing vasoconstrictive pulmonary hypertension with a shift of the segment of the pulmonary arterial tree involved to the periphery as in hypoxia. Reports of a similar phenomenon are noted as occurring in babies born at high altitude, spending their infancy there and subsequently developing primary pulmonary hypertension later in life.     

Pulmonary veno-occlusive disease. A report of four cases

Four cases of pulmonary veno-occlusive disease are described. Two patients, who were brothers, had respiratory tract infections. The third patient had chronic active hepatitis and coeliac disease suggesting an abnormality of the immune system; the fourth patient had no obvious cause but presented initially with systemic hypertension. Three of the cases had been diagnosed initially as primary pulmonary hypertension either on open lung biopsy or clinically. In all cases the pulmonary arteries were abnormal with medial hypertrophy, intimal fibrosis and, in some cases, thrombosis in elastic pulmonary arteries. These findings suggest that pulmonary veno-occlusive disease is not confined to veins and should be considered as a widespread pulmonary vascular disease. The range of aetiological factors indicate that it should not be considered as a single disease entity.     

亚段及单一段肺栓塞临床特点分析

目的 探讨亚段及单一段肺栓塞的临床特征、高危因素、治疗及预后。方法 分析我院收治的60例累及亚段及单一段肺栓塞患者的危险因素、临床表现、动脉血气分析、D-二聚体、栓塞部位,比较单一段及亚段肺栓塞的临床特征及预后。结果 60例患者中累及单一段36例,累及亚段24例。累及亚段或单一段的肺栓塞患者临床表现不典型,主要包括呼吸困难、心绞痛样胸痛、心悸、胸膜炎样胸痛、咳嗽,其中8.33%无临床症状。单一段组呼吸困难发生率为80.56%,高于亚段组的45.83%（P＜0.05）。栓塞部位累及右肺多见。60例患者中合并高血压病（48.33%）,糖尿病（18.33%）,COPD（6.67%）,脑卒中（10.00%）,肿瘤（8.33%）,心衰（11.67%）,房颤（13.33%）,高脂血症（38.33%）,冠心病（23.33%）,感染性疾病（3.33%）,手术、外伤、骨折（11.67%）,下肢静脉曲张（5.00%）,合并DVT（16.67%）。单一段组肺泡动脉氧分压差、D-二聚体阳性率均高于亚段组（P＜0.05）。结论 累及亚段或单一段的肺栓塞临床表现多样,血浆D-二聚体敏感性不高,抗凝治疗总体预后良好。     

Unilateral pleural effusion secondary to Takayasu arteritis: a case report and literature review

Takayasu arteritis (TA) is a chronic, nonspecific inflammatory disease of large and medium-sized vessels that primarily involves the aorta and its branches. TA involving the pulmonary arteries has a prevalence ranging from 14% to 86%, which can lead to pulmonary hypertension, a progressive increase in pulmonary artery pressure, and eventually death from right heart failure. The presentation of pulmonary arteritis (PA) is very nonspecific, with a reported misdiagnosis rate of up to 60% and a diagnosis time ranging from 1 month to more than 10 years. The clinical manifestation of pleural effusion is very rare in both TA and PA cases. Based on our literature review, this is the 6^th reported case of TA with pleural effusion, and the specific mechanism of TA with pleural effusion is still unclear. The characteristics of this case and the previously reported cases are summarized in this article to improve the understanding of TA and PA and reduce the misdiagnosis rate.     

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.     

Pathology of experimental pulmonary bone marrow embolism. I. Initial lesions of the rabbit lung after intravenous infusion of allogeneic bone marrow with special reference to its pathogenesis

In order to investigate the initial lesions of pulmonary bone marrow embolism and its pathogenesis, the author studied the pulmonary changes of 70 rabbits during a 24-hour period after the infusion of 500 mg of fresh allogeneic bone marrow into the marginal ear veins. After 30 minutes, leukostasis was observed in the non-embolized small arteries. After 2 hours, leukostasis increased and by 5 to 10 hours, it reached a maximum, still decreased considerably after 24 hours. In the perivascular connective tissue, edema and inflammatory cell infiltration had occurred as a result of increased vascular permeability due to leukostasis. Fifteen minutes after intravenous administration of a single shot of indomethacin (5 mg/kg), the infusion of allogeneic bone marrow was performed. Five hours after the infusion, the suppression of pulmonary vascular leukostasis and interstitial edema were observed. The effect of drugs on morphological changes, however, is extremely small in the group pre-treated with diphenhydramine hydrochloride (3 mg/kg). The author concluded that the mechanical injury of vascular endothelial cells by emboli and the accumulation of leukocytes in the pulmonary vessels may play an important role in the pathogenesis of the initial change of pulmonary bone marrow embolism. It is also suggested that the embolized bone marrow in the small arteries and vasculitis may lead to arteriosclerosis in the future.     

Pulmonary thrombotic arteriopathy in patients with sickle cell disease.

BACKGROUND: Shortened life expectancy due to pulmonary hypertension (PH) is seen in 5% to 10% of patients with sickle cell disease. The principal factors suspected of causing PH are pulmonary thromboemboli (PE) and in situ arterial thrombosis. OBJECTIVE: To investigate the possible role that PE or in situ arterial thrombosis play in the development of PH in sickle cell disease. METHODS: Autopsies of 12 patients with sickle cell disease were correlated with clinical data from medical records. RESULTS: Right ventricular hypertrophy was present in 9 of 12 patients. Six patients with right ventricular hypertrophy had thrombi in large elastic pulmonary arteries. All patients with elastic artery thrombi had fresh or organized thrombi in small muscular pulmonary arteries. Hypertensive small arterial changes were present in 5 of these 6 patients. Six patients showed no thrombi in elastic arteries. Among these 6 patients, 3 had right ventricular hypertrophy and recent and organized thrombi, as well as hypertensive changes in small arteries. One of these 3 patients demonstrated plexiform-like lesions and fibrinoid necrosis of small arteries. Three patients without right ventricular hypertrophy had pneumonia or pulmonary edema with no identifiable pulmonary artery pathology. CONCLUSIONS: Arterial thrombosis with PH and cor pulmonale was regarded as the cause of death among most of these patients. Elastic artery thrombi are pulmonary thromboemboli, but pulmonary thromboemboli are always associated with widespread thrombosis of small arteries. Widespread thrombosis of small arteries alone was associated with PH in some cases. This finding suggests that pulmonary thromboemboli may be a late complication of PH and cor pulmonale and that an in situ thrombotic arteriopathy underlies the development of PH in most patients with sickle cell disease.     

Changes in the pulmonary arteries of the rat during recovery from hypoxia-induced pulmonary hypertension.

Pulmonary hypertension has been induced in rats by 2 weeks' exposure to hypoxia, equivalent to an altitude of approximately 5500 m, in a hypobaric chamber. The rats were removed from the chamber and allowed to recover for up to 8 weeks at atmospheric pressure. Precise quantitative microscopic techniques after injection of the pulmonary artery have been used to estimate the regression in the pulmonary artery of the structural changes associated with pulmonary hypertension. During recovery the degree of muscularization of the pulmonary arteries decreases by disappearance of muscle cells from the small arteries and a drop in arterial wall thickness of larger vessels. These changes do not seem to reflect pulmonary artery pressure directly, since right ventricular hypertrophy regresses at a faster rate. In hypertensive rats there is a "loss" of small arteries in the alveolar region and little filling of precapillary vessels. On recovery, some of the vessels fill, suggesting that encroachment on the lumen by muscle and endothelial cells has lessened. Even after 8 weeks' recovery, however, some arteries do not return, suggesting they have completely disappeared and that regions are left with relatively little perfusion. This reduction of vascular reserve presents without there being right ventricular hypertrophy.     

Massive pulmonary tumor microembolism from a hepatocellular carcinoma

A 48-year-old patient with known alcohol abuse and long-standing liver cirrhosis presented with spontaneous bacterial peritonitis and subsequent hepato-renal syndrome. Autopsy revealed a large hepatocellular carcinoma of the right liver lobe. Histologically, pulmonary arteries, arterioles, and capillaries were occluded by numerous tumor emboli. Small tumor emboli also covered the endocardium of the right ventricle. A review of the literature shows that macroscopic as well as microscopic pulmonary tumor embolism is often diagnosed in patients with a previously unknown malignancy. Moreover, pulmonary tumor embolism radiologically mimics pneumonia, tuberculosis, or interstitial lung disease. Therefore, an autopsy should be considered in cases of fulminant or massive pulmonary embolism to exclude tumor embolism even when the patients' history is insignificant as to this point, and in cases with known malignant tumors and respiratory symptoms to exclude tumor microembolism.