Trousseau's Syndrome, a Previously Unrecognized Condition in Acute Ischemic Stroke Associated With Myocardial Injury

Abstract

Trousseau's syndrome is a well-known malignancy associated hypercoagulative state leading to venous or arterial thrombosis. The pathophysiology is however poorly understood, although multiple mechanisms are believed to be involved. We report a case of Trousseau's syndrome resulting in concomitant cerebral and myocardial microthrombosis, presenting with acute ischemic stroke and markedly elevated plasma troponin T levels suggesting myocardial injury. Without any previous medical history, the patient developed multiple cerebral infarctions and died within 11 days of admission. The patient was postmortem diagnosed with an advanced metastatic adenocarcinoma of the prostate with disseminated cerebral, pulmonary, and myocardial microthrombosis. Further analyses revealed, to the best of our knowledge for the first time in stroke patients, circulating microvesicles positive for the epithelial tumor marker CK18 and citrullinated histone H3 in thrombi, markers of the recently described cancer-associated procoagulant DNA-based neutrophil extracellular traps. We also found tissue factor, the main in vivo initiator of coagulation, both in thrombi and in metastases. Troponin elevation in acute ischemic stroke is common and has repeatedly been associated with an increased risk of mortality. The underlying pathophysiology is however not fully clarified, although a number of possible explanations have been proposed. We now suggest that unexplainable high levels of troponin in acute ischemic stroke deserve special attention in terms of possible occult malignancy.

Keywords: Trousseau; malignancy; myocardial infarction; stroke; thrombosis; troponin.

Figure 1.

Multiple widely spread cerebral infarctions developing over the course of 9 days. Acute CT scan showed a number of small infarctions. Additional CT scans day 1, day 3, and day 9 revealed several new and larger infarctions with hemorrhagic transformations on both sides.

Figure 2.

Row A: Hematoxylin and eosin staining showing disseminated focal areas of myocardial damage at different stages accompanied with widespread microvascular thrombosis in the brain, heart, and lung. Occluding thrombus in a small cerebral artery (arrow). Around it, there is a massive hemorrhagic infarction. Scale bar = 200 µm. Thrombus in a coronary artery (arrowheads). Around the artery, there are areas with acute infarction and granulocyte infiltration (arrows). Scale bar = 200 µm. Thrombus in a small pulmonary artery. Around the artery, cancer metastases are seen (arrows). Scale bar = 500 µm. Row B: Immunohistochemistry for cytokeratin 18 (CK18) staining for CK18 in metastases (dark brown) but not thrombi. Thrombus in a small cerebral artery. No CK18 immunoreactivity is detected. Scale bar = 100 µm. Thrombus in a coronary artery. No CK18 immunoreactivity is detected. Scale bar = 100 µm. Thrombus in a small pulmonary artery. Around the artery, metastases are staining strongly positive for CK18. Scale bar = 100 µm. Row C: Immunohistochemistry for tissue factor (TF) showing both metastasis and thrombi staining for TF (dark brown). Thrombus in a small cerebral artery. There is some immunoreactivity to TF in the thrombus, but also in the vessel wall (arrow) and in lipid-laden macrophages near the artery (arrowheads). Scale bar = 100 µm. Thrombus in a coronary artery, staining positive for TF. Inside the thrombus are also a number of granulocytes with blue stained nuclei. Scale bar = 50 µm. Cancer metastasis in the lung, staining strongly positive for TF. Scale bar = 100 µm. Row D: Immunohistochemistry for citrullinated histone H3 (Cit H3) showing thrombi in the brain, heart and lung staining positive for Cit H3 (dark brown). Thrombus in a small cerebral artery. Slight immunoreactivity to Cit H3 is seen. Scale bar = 100 µm. Thrombus in a coronary artery, staining strongly positive for Cit H3. Inside the thrombus are also a number of granulocytes with blue stained nuclei. Scale bar = 30 µm. Thrombus in a small pulmonary artery. There is a weaker staining of Cit H3 in the fibrin, but in some cellular matter the staining is strongly positive. Scale bar = 100 µm.

Figure 3.

Circulating microvesicles exposing cytokeratin 18 (CK18). Microvesicles were measured by flow cytometry and defined as vesicles less than 1.0 µm in size and positive for CK18 exposure in a patient with Trousseau’s syndrome (A) and a patient with stroke but without known malignancy (B).