*From the Division of Allergy, Pulmonary, Immunology, Critical Care and Sleep, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX.
Correspondence to: Gulshan Sharma, MBBS, MPH, Assistant Professor, Allergy, Pulmonary, Immunology, Critical Care, and Sleep Division, 301 University Blvd, JSA-5.112, UTMB, Galveston, TX 77555-0561; e-mail: firstname.lastname@example.org
A 39-year-old man presented to the emergency department with a complaint of progressive dyspnea and intermittent chest pain over several months. His medical history was unremarkable except for a recent workup for epigastric discomfort and early satiety. Results of esophagogastroduodenoscopy, gastric mucosal biopsies, and testing for Helicobacter pylori were negative. The patient also had intermittent episodes of chest pain for which he underwent dobutamine stress echocardiography. Pertinent findings included mild dilation of the right ventricle and right ventricular systolic pressures of 35 to 40 mm Hg. The patient also admitted to daily marijuana use for the past 20 years. In addition to his other symptoms, he reported an approximate 20-pound weight loss over the past year.
On examination, the patient was afebrile and in no apparent distress, with an oxygen saturation of 88% on room air. He was tachycardic without appreciable murmurs. He had normal breath sounds throughout with good air exchange. His laboratory studies revealed a hemoglobin of 11.5 g/dL and a D-dimer > 4.0 μg/mL (normal < 0.41). An arterial blood gas obtained on room air demonstrated a pH of 7.43, Pco2 of 38 mm Hg, and Po2 of 58 mm Hg. On the chest radiograph at hospital admission, the lung fields were clear with mild pulmonary artery prominence. Chest CT (Fig 1
) revealed extensive tiny pulmonary nodules distributed to all lobes in a symmetric and centrilobular pattern with mild bilateral adenopathy.
After admission to the general medicine ward, bronchoscopy with BAL and transbronchial biopsy was performed. BAL fluid was macrophage predominant with negative cultures. Transbronchial biopsy findings were unremarkable. Approximately 48 h after initial presentation, the patient had a cardiopulmonary arrest and was unable to be resuscitated. An autopsy slide representing the pulmonary microvasculature is shown below (Fig 2
Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare entity that is almost always a postmortem diagnosis. It is characterized by fibrocellular intimal proliferation of small pulmonary arteries and arterioles in patients with metastatic carcinoma. The term was first coined in 1990 to describe morphologic findings in a large series of consecutive autopsy cases. Of 3,300 consecutive autopsies during a 4-year period, 21 of 630 cancer patients had PTTM diagnosed. The terminology was created to encompass the pathogenesis, morphologic features, and hemodynamic effects observed on autopsy. In the literature, PTTM has been reported to be observed in 0.9 to 3.3% of cadavers with extrathoracic malignancies. The most frequent malignancy associated with PTTM is gastric adenocarcinoma. Other malignancies associated with PTTM include breast, pancreas, liver, and choriocarcinoma.
The term PTTM should be considered different from the classic terminology of pulmonary tumor embolism. While pulmonary tumor embolism suggests the occlusion of pulmonary vessels by actual tumor cells with or without accompanying local thrombosis, the most predominant finding in PTTM is the intimal proliferation resulting in increased vascular resistance. Tumor cell emboli in PTTM not only mechanically obstruct the pulmonary vessels but also activate local and systemic coagulation systems that can then lead to thrombosis, intimal proliferation, luminal stenosis, and ultimately occlusion. There has also been some suggestion that various factors expressed by underlying carcinoma including tissue factor and vascular endothelial growth factor play an important role. While tumor emboli are often found during autopsy of patients with PTTM, it is important to understand that PTTM can be present despite the absence of actual tumor emboli. Individual tumor cells can adhere to the vascular endothelium, causing damage that in turn sets off the intimal fibrocellular proliferation. The proliferative process leads to diffuse narrowing of the pulmonary arterial system and increased vascular resistance, thus potentially resulting in severe pulmonary hypertension and development of acute or subacute cor pulmonale.
The clinical presentation of PTTM is often indistinguishable from that of pulmonary thromboembolism. The most common symptom associated with PTTM is dyspnea. The dyspnea is usually progressive, often developing over days to weeks. Other complaints can include pleuritic chest pain, cough, hemoptysis, fatigue, and weight loss. Occasionally, extensive disease can lead to acute fatal cor pulmonale. Severe manifestations include pulmonary hypertension, right-sided heart failure, and sudden death. Physical examination can reveal signs of pulmonary hypertension and right ventricular overload, but often the number and quality of symptoms far exceed physical findings.
With regard to diagnostic studies, arterial blood gas analysis usually reveals a respiratory alkalosis with hypoxemia. Given the activation of the coagulation system and release of inflammatory cytokines, laboratory findings consistent with consumptive coagulopathy can be observed. Chest radiography is usually unremarkable, although findings of cardiac enlargement and prominent pulmonary arteries can occasionally be seen. Potential CT scan findings of the chest include dilated and beaded peripheral pulmonary arteries, peripheral wedge-shaped opacities, diffuse thickening of the interlobular septa, enlarged central arteries, and a tree-in-bud pattern. Ventilation-perfusion radionuclide scanning is usually unrewarding given the diffuse involvement of the vasculature but can show multiple peripheral subsegmental perfusion defects without ventilatory abnormalities. This finding is often referred to as the segmental contour pattern. Echocardiography can demonstrate right-sided chamber enlargement and evidence of pulmonary hypertension.
Diagnosis of PTTM requires a high index of clinical suspicion. The cause of the patient’s findings is rarely elucidated prior to death. Most commonly, patients receive a misdiagnosis of pulmonary thromboembolism or primary pulmonary hypertension. Although the great majority of PTTM cases are only diagnosed during autopsy, the “gold standard” for antemortem identification of this disease entity is either via open or video-assisted thoracoscopic lung biopsy.
Treatment for PTTM has not been extensively studied because the overwhelming majority of cases have been diagnosed after death. Therapy directed at the underlying malignancy could potentially mitigate the overall process leading to the respiratory symptoms. Pulmonary tumor emboli and PTTM arising from choriocarcinoma have been successfully treated with chemotherapy. The use of corticosteroids and anticoagulation has not been shown to be of benefit. Overall prognosis is poor, with the majority of patients dying within weeks of the first onset of symptoms.
Given the findings of diffuse pulmonary nodules in the case of our patient, initial consideration was given to infectious diseases caused by fungal and mycobacterial organisms. Other etiologies considered included hypersensitivity pneumonitis and vasculitides. Much lower on the differential was metastatic disease because the patient had no history of cancer nor an obvious source of new malignancy especially with prior negative GI workup.
Autopsy revealed that the patient had underlying metastatic signet-ring cell gastric adenocarcinoma. Gross examination of the stomach demonstrated widened mucosal folds and extensive thickening of the wall consistent with linitis plastica appearance. On microscopic evaluation, the neoplastic cells were mostly confined to the lamina propria and submucosa with evidence of lymphovascular invasion. Histopathologic examination of the pulmonary microvasculature including arterioles and capillaries revealed extensive involvement by microthrombi at different stages of organization leading to the diagnosis of pulmonary tumor thrombotic microangiopathy (Fig 2). Special stains revealed scattered neoplastic cells admixed with only a small proportion of microthrombi focally.
Reflecting back on the history of our patient, it seems apparent that his initial GI symptoms were likely secondary to his underlying gastric cancer. Unfortunately, given the diffuse-type gastric adenocarcinoma, there is less mucosal involvement of the neoplastic cells, thus making diagnosis by esophagogastroduodenoscopy more difficult. By the time he presented to the hospital, his underlying malignancy was far advanced, with subsequent development of PTTM leading to respiratory failure and rapid demise.
PTTM is a relatively rare entity characterized by fibrocellular intimal proliferation of small pulmonary arteries and arterioles in patients with metastatic carcinoma that can lead to pulmonary hypertension, right-sided heart failure, and sudden death.
PTTM can be differentiated from pulmonary tumor emboli by the activation of the coagulation system and the presence of marked intimal proliferation in the smaller pulmonary arteries.
PTTM should be considered in the differential diagnosis of patients with known malignancy presenting with unexplained dyspnea or pulmonary hypertension.
The diagnosis of PTTM is commonly made during autopsy. Antemortem diagnosis of PTTM can be made by the “gold standard” of lung biopsy in the appropriate clinical setting.
Overall prognosis of PTTM is poor, so the main focus of diagnosis should be to refrain from overly aggressive intervention rather than attempting to reverse the process. In certain malignancies, chemotherapeutic options can be considered for potential improvement in symptoms.
The authors have no financial relationships with any commercial entity that may have an interest in the content of this article.
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