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Pulmonary tumor thrombotic microangiopathy (PTTM) is known as a rare and severe cancer-related pulmonary complication. Nowadays, fewer than 80 cases have been reported in the literature and very few cases have been diagnosed antemortem. We describe an autopsy case of PTTM associated with cancer of unknown origin. A 56-year-old male patient came to our attention due to a 2-day history of dyspnea. Analysis of the clinical context in combination with laboratory and imaging tests led us to suspect acute pulmonary thromboembolism. However, the computed tomography pulmonary angiogram was negative for thromboembolism; on the contrary it revealed multiple lymphadenopathy. Microscopic pulmonary tumor embolism was suspected and a lymph node biopsy was planned. However, the patient's condition progressively worsened; death occurred 3 days after admission. After autopsy, histologically extensive neoplastic emboli involved the small pulmonary arteries and arterioles, often admixed with fibrin thrombi. The involved and noninvolved arteries also demonstrated fibrocellular intimal proliferation causing marked luminal stenosis and occlusion. These pathological features were characteristic of PTTM, which should be distinguished from microscopic tumor embolism and should be considered in the differential diagnosis of acute/subacute cor pulmonale and pulmonary hypertension in cancer as well as in noncancer patients. We propose a review of the literature and an algorithm to improve PTTM antemortem diagnosis.