A 34-year-old white man with a history of smoking and “primary pulmonary hypertension” presented with upper abdominal fullness and increasing dyspnea. Physical examination showed signs of cardiac dysfunction, including sinus tachycardia, distended jugular veins, hepatomegaly, and clubbing of the fingers. Increased bilateral interstitial markings with prominent pulmonary arteries were observed on a chest radiograph. Cardiac catheterization revealed pulmonary hypertension with a mean pulmonary arterial pressure of 62 mm Hg and a pulmonary capillary pressure of 35 mm Hg (normal, 30 and 12 mm Hg, respectively). An echocardiogram showed severe left ventricular dysfunction (ejection fraction, 25%) with enlargement of the right ventricle. The ventilation-perfusion lung scan was indeterminate. A large mass was palpable in the left epigastric region. Three days after admission, the patient died of refractory arrhythmia and respiratory failure.
A limited autopsy was performed and was restricted by consent to examination of the thorax. Gross examination revealed cardiomegaly with biventricular hypertrophy (right ventricular thickness, 0.7 cm; left ventricular thickness, 1.8 cm), moderate coronary artery atherosclerosis, marked pulmonary congestion and pulmonary edema. No lung lesions were identified. However, cut sections of the lungs showed prominent pulmonary vasculature. Histologically, extensive tumor emboli involved the small pulmonary arteries and arterioles (Figure 1). Tumor emboli were often admixed with fibrin thrombi. The involved and noninvolved arteries also demonstrated intimal fibrocellular proliferation, causing marked luminal stenosis and occlusion (Figure 2). Some thrombosed vessels were organized by recanalization (Figure 3). These pathologic features were characteristic of pulmonary tumor thrombotic microangiopathy (PTTM). Immunohistochemical stains showed the tumor emboli to be strongly positive for cytokeratin 7, cytokeratin 20 (Figure 4), and carcinoembryonic antigen, which, in the absence of a primary lung cancer, suggested either a pancreatic or gastric primary. The pancreatic and gastric adenocarcinomas display the aforementioned immunophenotype in 65% and 38% of cases, respectively.1 Tumor metastasis to perihilar and paratracheal lymph nodes were also identified.
The lung is a common site for metastatic spread of malignant tumors, and tumor embolism in the lung is common, but it is not often diagnosed clinically. Although pulmonary tumor embolism is known to be associated with pulmonary hypertension secondary to thrombus formation, the tumor-related lesion of the pulmonary vessel wall, PTTM, was first described by von Herbay et al2 in 1990. PTTM is characterized by widespread fibrocellular intimal proliferation of the small pulmonary arteries and arterioles in patients with metastatic carcinoma; tumor cell emboli in PTTM may not only occlude the vessels but also activate both local and systemic coagulation systems, leading to thrombosis, fibrocellular and fibromuscular intimal proliferation, luminal stenosis, and finally occlusion. Increased resistance in the pulmonary vascular bed may lead to fatal pulmonary hypertension and acute or subacute cor pulmonale. Clinically, patients with PTTM often present with progressive dyspnea and pulmonary hypertension of unknown etiology, and develop right heart failure.
PTTM is rare and is observed during 0.9% to 3.3% of autopsies of patients with malignant tumors.2,3 Few cases are diagnosed antemortem. PTTM is usually associated with adenocarcinomas, particularly gastric adenocarcinomas and adenocarcinomas of the pancreas, breast, and liver, as well as with choriocarcinoma.3 In the case we report, the primary tumor site could not be confirmed due to the limitation on autopsy.
The presence of cytokeratin-positive carcinomatous emboli and the marked pulmonary arterial and arteriolar intimal fibrocellular proliferation distinguish PTTM from other pathologic entities that could also cause pulmonary hypertension, including paraneoplastic thromboembolism, angiotrophic lymphoma, lymphangitis carcinomatosa, epithelioid hemangioendothelioma, and intravascular bronchioloalveolar tumor of the lung.4
Treatment for PTTM has not been extensively studied, as the diagnosis is usually made postmortem. Because the arterial stenosis in PTTM is mainly caused by intimal fibrocellular proliferation, the effect of fibrinolysis is limited.
In conclusion, PTTM is a rare entity and should be considered in the differential diagnosis of pulmonary hypertension.