Transitional cell carcinoma manifesting as acute cor pulmonale: cause of microscopic tumor Embolism.

ABSTRACT: Acute cor pulmonale is an uncommon manifestation of microscopic pulmonary tumor embolism. We describe the case of an 84-year-old man with a history of transitional cell carcinoma (TCC) of the urinary bladder who had acute cor pulmonale and died within a few hours after the onset of dyspnea. Autopsy showed that the right ventricle was dilated without hypertrophy. Microscopic examination of the lung showed that the small arteries, arterioles, and capillaries were filled with micrometastases of TCC. Microscopic pulmonary tumor embolism has rarely been reported with TCC, and to the best of our knowledge, such a fulminant course has not been previously described in the English language.

MICROSCOPIC PULMONARY TUMOR embolism is the presence of multiple aggregates of tumor cells in the small pulmonary arteries, arterioles, and septal capillaries. (1) This phenomenon may manifest as subacute cor pulmonale, which has been described in patients with various malignancies, including carcinoma of the breast, stomach, pancreas, liver, and prostate (1); however, such a manifestation has rarely been reported in patients with transitional cell carcinoma (TCC) of the bladder. We describe a patient with TCC of the bladder who had acute cor pulmonale due to microscopic pulmonary tumor embolism and died within a few hours. Acute cor pulmonale is an uncommon manifestation of microscopic tumor embolism. (2) We believe such an acute and fulminant manifestation of microscopic tumor embolism due to TCC has not been previously described in the English language.

CASE REPORT

An 84-year-old man was admitted for intravenous hydration for dehydration due to diarrhea. The patient had had radical prostatocystectomy for TCC of the urinary bladder 8 months earlier and had a urostomy. He also had a history of diabetes mellitus, hypothyroidism, and chronic renal insufficiency. Physical examination was unremarkable. The patient had sudden onset of shortness of breath within the next 24 hours. Vital signs included a pulse rate of 106/mm, respiratory rate of 26/mm, and blood pressure of 94/54 mm Hg. The lungs were clear to auscultation. Arterial blood gas measurements showed a pH of 7.44, [PCO.sub.2] of 20 mm Hg, and [PO.sub.2] of 62 mm Hg on room air. The chest radiograph was normal, and an electrocardiogram showed a new right bundle branch block. The patient was transferred to the intensive care unit, and mechanical ventilation was initiated for worsening shortness of breath. Bedside ultrasonography of the lower extremities did not reveal any evidence of deep venous thrombosis. A 2-dimensi onal echocardiogram showed severe right ventricular dilation with compression of the left ventricle. The patient subsequently died.

An autopsy showed no evidence of deep venous thrombosis or pulmonary embolism. Microscopic evaluation of the lung showed extensive tumor emboli of high-grade TCC involving small arteries, arterioles, and capillaries (Figs 1 and 2). The right ventricle was dilated without hypertrophy. Extensive metastasis of high-grade TCC was in retroperitoneal, pelvic, para-aortic, and mesenteric lymph nodes and in the liver, kidneys, adrenal glands, small intestine, stomach, and brain.

DISCUSSION

Our patient had acute cor pulmonale due to tumor cell microemboli to the small pulmonary blood vessels. The lung parenchyma, lymphatic system, and major pulmonary arteries were normal. Although metastatic lesions commonly involve lung parenchyma, isolated involvement of the small pulmonary blood vessels with tumor microemboli resulting in cor pulmonale is rare. Autopsy studies have shown that microscopic tumor emboli can be found in 2% to 44% of patients with known malignancies. (3-5) Despite this, pulmonary symptoms develop in few patients. (3,5) This has been attributed to destruction of the majority of tumor cells in the vessel lumen by secondary thrombus formation and their subsequent organization. (6) These tumor cells usually are unable to invade the vessel wall, (3,4,6) and the presence of tumor cells in the small vessels may not even be regarded as metastasis. (4,6)

Four basic types of tumor involvement of the pulmonary vasculature have been described (3): (1) large tumor emboli occluding either the main pulmonary arteries or the large segmental branches, (2) generalized lymphatic involvement, (3) pure microscopic tumor emboli involving the small vessels and sometimes isolated involvement of alveolar capillaries, (7-9) and (4) a combination of these three manifestations. Microscopic tumor embolism may manifest as cor pulmonale or pulmonary infarction. (4,5) Most patients have subacute cor pulmonale with onset of symptoms over a few weeks, and acute cor pulmonale is a rare manifestation. (2) Theories such as occlusion of the lumen of the blood vessels by tumor cells or obliterative endarteritis and vasoconstriction associated with microemboli have been proposed to explain the pathogenesis of subacute cor pulmonale. (3) Saphir (6) described intimal thickening resembling pulmonary atherosclerosis in the small pulmonary vessels of patients who had microscopic tumor embolism, von Herbay et al (10) described 21 patients who had tumor emboli to pulmonary vasculature that resulted in fibrocellular intimal proliferation and subsequent obstruction of small vessels in association with secondary thrombosis. They called this entity "pulmonary tumor thrombotic microangiopathy" instead of using the term "obliterative endarteritis" (since no true vasculitis exists) and attributed increased pulmonary vascular resistance to this phenomenon.

Cor pulmonale can also be caused by lymphangitic carcinomatosis. The possible mechanisms that can result in increased pulmonary artery pressure have been described as (1) pressure effects on the pulmonary vessels from the adjacent cancer-laden lymphatic vessels, (2) connective tissue proliferation in the adjacent pulmonary arterioles, and (3) direct contact invasion of the blood vessels. (11) In fact, the term subacute cor pulmonale was coined for the first time in 1927 to describe right ventricular failure of subacute onset (2 weeks to 2 months) in patients with small vessel or lymphatic involvement by a malignancy, (11) since these patients had a subacute course of events unlike the acute manifestation of pulmonary thromboembolism or the insidious onset of symptoms in chronic cor pulmonale. Although clinical manifestation of microscopic tumor embolism and lymphangitic carcinomatosis is similar, cor pulmonale and hemorrhagic infarcts are seen more commonly in microscopic tumor embolism. (5) Respiratory distr ess as the mechanism of death is significantly more frequent in cases with arterial involvement by tumor emboli. (5)

Subacute cor pulmonale has been well-described in association with microscopic tumor embolism with and without lymphatic involvement, (1,12-14) the most common primary tumors being carcinomas of the breast, stomach, and liver and choriocarcinomas. (1,12-14) Even in patients with known malignancy, the diagnosis of tumor embolism is frequently missed. Patients with microscopic tumor embolism have clear lung fields on lung radiographs as compared with the interstitial pattern of lymphangitic carcinomatosis, (1) and ventilation-perfusion scan may show multiple subsegmental peripheral perfusion defects described as "segmental contour pattern." (15) Angiography generally does not show any evidence of embolism. (1,12) A pulmonary artery catheter may also be used to collect blood from the pulmonary port for cytologic analysis to aid in the diagnosis. (16) Tissue biopsy is probably the best way to establish the diagnosis.

Although autopsy studies have shown a high rate of metastasis of TCC of the urinary bladder, such metastasis is infrequently diagnosed clinically. (17) Tumor microembolism from TCC has been rarely reported. Fitzpatrick et al (18) reported three cases of TCC that involved small vessels of the lung, all with dyspnea and pulmonary infiltrates on chest radiographs. Two of the patients died, with diagnosis established at autopsy. The third patient had transbronchial biopsy and received chemotherapy after the diagnosis was established. This patient responded well to chemotherapy, had resolution of radiographic abnormalities, and was able to resume activities of daily living.

Our patient had a sudden onset of symptoms. Acute cor pulmonale development over a few hours is an extremely rare manifestation of microscopic tumor embolism, (2) and few similar cases have been reported. (27,19-22) Three previously described patients had breast cancer, while the others had pancreatic, carcinoid, and occult malignancy, respectively. Our patient became short of breath, hypoxemic, and hypotensive over a few hours, and the clinical picture closely mimicked massive pulmonary embolism. This presented a difficult clinical scenario, since there was little time for any diagnostic workup. Microscopic tumor embolism should be considered in any patient with known malignancy who has acute cor pulmonale.

References

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(11.) Brill IC, Robertson TD: Subacute cor pulmonale. Arch Intern Med 1927; 60:1043-1057

(12.) King MB, Harmon KR: Unusual forms of pulmonary embolism. Clin Chest Med 1994; 15:561-580

(13.) Kupari M, Laitinen L, Hekali P, et al: Cor pulmonale due to tumor cell embolization. Acta Med Scand 1981; 210:507-510

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(15.) Sostman HD, Brown M, Toole A, et al: Perfusion scan in pulmonary vascular/lymphangitic carcinomatosis: the segmental contour pattern. AJR Am F Roenlgenol 1981; 137:1072-1074

(16.) Masson RJ, Krikorian J, Luke P, et al: Pulmonary microvascular cytology in the diagnosis of lymphangitic carcinomatosis. N Engl J Med 1989; 321:71-76

(17.) Goldman SM, Fajardo AA, Naraval RC, et al: Metastatic transitional cell carcinoma from the bladder: radiographic manifestations. AJR AM J Roentgenol 1979; 132:419-425

(18.) Fitzpatrick TM, Covelli HD, Tenholder MF: The acute and insidious onset of pulmonary metastatic transitional cell carcinoma. Chest 1991; 99:498-500

(19.) Pfeifer EA, Bjornsson J, Hanzlick R: Case of the month. Arch intern Med 1998; 158:14

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(21.) Domanski MJ, Cunnion RE, Fernicola DJ, et al: Fatal cor pulmonale caused by extensive tumor emboli in the small pulmonary arteries without emboli in the major pulmonary arteries or metastases in the pulmonary parenchyma. Am J Cardiol 1993; 72:233-234

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KEY POINTS

* Microscopic pulmonary tumor embolism can present as pulmonary infarction or subacute cor pulmonale.

* This case describes a patient who had acute cor pulmonale due to microscopic tumor embolism from transitional cell carcinoma of the urinary bladder.

* The patient's clinical presentation mimicked massive pulmonary embolism.