Characterizing the clinical heterogeneity of Trousseau syndrome with nonbacterial thrombotic endocarditis: a description of three cases across hematological and solid malignancies

Introduction

In 1865, the French physician Armand Trousseau reported that patients with gastric cancer are prone to lower extremity deep vein thrombosis and exhibit a tendency for spontaneous coagulation, thereby describing the association between thrombotic events and malignancy for the first time (1,2). Subsequently, various thromboembolic events associated with malignant tumors have been termed Trousseau syndrome (TS). Nonbacterial thrombotic endocarditis (NBTE) is a severe but frequently underrecognized manifestation of this syndrome.

NBTE is characterized by noninflammatory, bacteria-free, and fibrin-platelet vegetations on cardiac valves, and these friable lesions are prone to systemic embolization (3-6). Although the mechanisms underlying NBTE formation have not been extensively clarified, it is believed that NBTE is linked to endothelial injury, hypercoagulability, and the deposition of circulating immune complexes (7). TS with NBTE is most frequently associated with solid tumors, including lung, breast, pancreatic, and ovarian cancers (2,4,8,9), whereas its occurrence in hematological malignancies is rare (10). To our knowledge, only one case of NBTE associated with diffuse large B-cell lymphoma (DLBCL) has been documented in the literature (Santos et al.) (11), and there is little information available on NBTE’s clinical presentation, therapeutic approaches, or long-term outcomes in this type of hematological setting. The clinical heterogeneity of features across solid and nonsolid tumors, such as the manifestation, diagnosis, therapeutic response, and prognosis, has not been characterized in depth. A major diagnostic challenge is distinguishing NBTE from infective endocarditis (IE), especially in patients with hematological malignancies. In these cases, inflammatory mimicry is common, which makes diagnosis problematic and delays treatment.

Within this context, we report on three cases of TS with NBTE, including one case of DLBCL and two cases of solid tumors (advanced clear cell carcinoma and EGFR-mutant metastatic lung cancer). The aim of this report is to augment the scarce clinical data on DLBCL-associated NBTE; to systematically compare the core clinical, laboratory, imaging, therapeutic, and prognostic features of the three cases; to uncover the distinctive disease patterns across malignancy types; and to generate critical insights for the accurate diagnosis, differential IE exclusion, and individualized management of TS with NBTE.

Case presentation

Case 1

A 59-year-old female was admitted to hospital with a chief complaint of unexplained fever with a maximum temperature of 38.6 ℃, which had begun 3 months prior to the visit. Initial laboratory tests on admission revealed pancytopenia, elevated C-reactive protein (CRP) at 176.62 mg/L (normal range, 0–10 mg/L), and a plasma D-dimer level of 2.40 µg/mL [fibrinogen equivalent units (FEU)] [normal range, 0–0.5 µg/mL (FEU)]. Venous ultrasound during hospitalization revealed right popliteal vein thrombosis, and rivaroxaban (20 mg o.d.) therapy was initiated for anticoagulation. Positron emission tomography-computed tomography (PET-CT) revealed multiple hypermetabolic lesions in the whole-body bone marrow and spleen. Ultrasonography indicated multiple enlarged lymph nodes in the inguinal region. Bone marrow biopsy and immunohistochemistry confirmed DLBCL (germinal center B-cell origin) with bone marrow involvement (stage IV), and the cyclophosphamide, doxorubicin, vincristine, prednisone plus rituximab (R-CHOP) chemotherapy regimen was recommended. Moreover, transthoracic echocardiography (TTE) revealed a vegetation on the aortic valve (Figure 1A). Chest CT indicated left upper lobe bronchiectasis with infection, which was accompanied by an elevated procalcitonin level. The initial cardiology consultation included a high suspicion of IE based on the 3-month history of fever (maximum 38.6 ℃) and markedly elevated CRP level. Recommendations included three sets of random blood cultures; initiation of meropenem and vancomycin; and close monitoring of body temperature, complete blood count, CRP, and the serial echocardiographic changes of the vegetations. A total of five blood cultures were obtained, with only one positive result (Staphylococcus from femoral artery sampling), and contamination could not be excluded. The patient received anti-infective therapy with temporary discontinuation of rivaroxaban. Re-examination 1 month later showed a persistently elevated plasma D-dimer level [3.34 µg/mL (FEU)] and a decreased procalcitonin level (0.04 ng/mL; normal range, 0–0.05 ng/mL). TTE revealed no significant changes in the size of the vegetations. Further transesophageal echocardiography (TEE) identified filiform flutter on the surface of the aortic valve (Figure 1B) and a tiny vegetation on the posterior leaflet of the mitral valve, with no significant destruction of the aortic sinus wall or adjacent valve leaflets (Figure 1C). Given the patient’s history, repeated negative blood cultures and TEE features, a multidisciplinary consultation reconsidered the lesion to be thrombotic vegetations consistent with TS. Anticoagulation was restarted, and follow-up echocardiography 1 month later showed a significant reduction in the size of some vegetations. Complete resolution of the vegetations was confirmed after more than 6 months (Figure 1D). The patient achieved stable disease after completing eight cycles of R-CHOP.

Figure 1 TTE and TEE findings illustrating the presence and subsequent resolution of valvular vegetations in this patient. Parasternal long-axis view from TTE showed a vegetation adhering to the AV (arrow)(A). The AV long-axis view from the midesophageal position via TEE showed AV vegetation, an additional filiform flutter on the AV surface (arrow)(B) and a tiny mitral valve vegetation on the posterior leaflet (arrow). The upper arrow indicates the tiny mitral valve vegetation and the lower arrow indicates the AV vegetation (C). The TTE showed that the AV and mitral valve vegetations had completely disappeared 6 months after restarting anticoagulation therapy (D). AO, aorta; AV, aortic valve; LA, left atrium; LV, left ventricle; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.

Case 2

A 38-year-old female complained of right ankle joint pain. Further imaging incidentally revealed bilateral lower extremity venous thrombosis (Figure 2A), and filling defects in pulmonary artery branches (Figure 2B) were apparent on computed tomography angiography (CTA). An inferior vena cava (IVC) filter was placed (Figure 2C), and the patient was administered rivaroxaban (20 mg o.d.) to prevent severe pulmonary embolism. One week postoperatively, she was readmitted to hospital with abdominal pain. Abdominal ultrasound detected a solid mass around the left iliac vessels. On admission, TTE identified a fresh vegetation on the posterior leaflet of the mitral valve with moderate-to-severe regurgitation (Figure 3A,3B). Subsequently, the patient developed sudden aphasia and right-sided motor dysfunction, and cranial CT revealed a fresh lamellar infarction in the left parietal lobe. Abdominal CTA further found partial thrombosis of the splenic and renal veins (Figure 3C,3D) and a mass measuring approximately 38 mm × 29 mm adjacent to the left iliac vessels (Figure 3E). Laboratory tests confirmed prolonged prothrombin time (PT) (21.3 s; normal range, 11–14.5 s), elevated prothrombin time ratio (PT-R) (1.66; normal range, 0.8–1.25), a markedly increased plasma D-dimer level [18.94 µg/mL (FEU)], and elevated tumor marker expression [including carbohydrate antigen 125 (CA125)]. PET-CT strongly suggested a gynecologic malignancy with T3N1M0 stage. Given the presence of multiple arteriovenous thromboses, hypercoagulability, a lack of fever, normal inflammatory indicators, negative blood cultures, and elevated tumor markers, IE was ruled out and a diagnosis of TS with NBTE was made. Pathological examination later confirmed advanced clear cell carcinoma. A few days later, the patient died due to severe disease progression.

Figure 2 Imaging findings of femoral vein, pulmonary artery and IVC thrombotic lesions. Venous ultrasound revealed femoral vein thrombosis (A). Pulmonary CTA showed filling defect of the pulmonary artery branches (arrow) (B). Abdominal CTA showed IVC thrombosis (arrow) with an IVC filter (C). CTA, computed tomography angiography; FV, femoral vein; IVC, inferior vena cava.

Figure 3 Imaging findings of mitral valve vegetation, splenic and renal infarction and iliac adjacent mass. On the TTE, the apical four-chamber view showed a vegetation adhering to the posterior leaflet of the mitral valve (arrow) (A). Color Doppler echocardiography revealed moderate-to-severe mitral regurgitation (B). Abdominal CTA showed splenic infarction (arrow) (C), and partial thrombosis of the renal veins (arrow) (D). Abdominal CT showed a large mass adjacent to the left iliac vessels (arrow) (E). CT, computed tomography; CTA, computed tomography angiography; LA, left atrium; LV, left ventricle; TTE, transthoracic echocardiography.

Case 3

A 60-year-old female with metastatic lung cancer was admitted to hospital due to sudden right-sided motor dysfunction and aphasia lasting 4 hours. She had been diagnosed with EGFR-mutant lung cancer (axon 19 deletion with MET amplification) 2 years prior, underwent surgical resection, and was receiving icotinib targeted therapy for recurrent disease with multiple metastases (including bilateral lung, bilateral cervical lymph node, and bone metastases). Seven months earlier, external hospital venous ultrasound had detected internal jugular vein thrombosis, and therapy with rivaroxaban (20 mg o.d.) was initiated. On admission, cranial magnetic resonance imaging (MRI) revealed extensive infarction in the left cerebral hemisphere (Figure 4A). Bedside echocardiography showed vegetations on the aortic and mitral valves (Figure 4B,4C). Laboratory tests indicated a hypercoagulable state, with a PT of 20.9 s, a PT-R of 1.57, and a plasma D-dimer level >30 µg/mL (FEU). In the absence of fever and normal CRP level, white blood cell count, and neutrophil counts, TS with NBTE was considered. Unfortunately, due to the severity of the illness, the patient declined further treatment.

Figure 4 Cranial MRI and bedside TTE findings indicated cerebral infarction and cardiac valvular vegetations. MRI revealed extensive infarction in the left cerebral hemisphere (arrow) (A). Bedside TTE showed aortic (arrow) (B) and mitral valve (arrow) (C) vegetations. AO, aorta; LA, left atrium; LV, left ventricle; MRI, magnetic resonance imaging; TTE, transthoracic echocardiography.

Ethical statement

All procedures described in this study were performed in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. The requirement for patient consent for publication of this article and accompanying images was waived by the Second Affiliated Hospital of Dalian Medical University Ethics Committee. The authors confirm that the article has been fully anonymized to preclude any potential harm to the patients or their family members.

Discussion

As the core clinical, laboratory, imaging, therapeutic, and prognostic features between hematological and solid malignancy-associated disease differ, the presentations of the three cases of TS with NBTE are summarized in Table 1 to highlight this heterogeneity. DLBCL-associated NBTE is extremely rare, with only one prior case reported by Santos et al. (11). A critical limitation of that case was the failure to implement effective antineoplastic therapy, and despite aortic valve replacement surgery being administered, the patient died due to postoperative complications, highlighting the inadequacy of surgical intervention alone in addressing the underlying paraneoplastic hypercoagulable state. In contrast, our management of the DLBCL case addressed this deficiency and demonstrated the efficacy of combined therapeutic strategies. Notably, our patient presented with early unexplained fever, elevated CRP level, and aortic valve vegetations, findings that initially mimicked IE. However, short-term anti-infective treatment resulted in no significant aggravation of valvular regurgitation or changes in vegetation size. TEE further revealed filiform flutter on the vegetation surface, a characteristic feature of thrombotic lesions, prompting the correct diagnosis of NBTE. Subsequent combined antineoplastic (R-CHOP regimen) and anticoagulant (rivaroxaban) therapy achieved complete remission, which supports the notion that targeted control of the underlying hematological malignancy can attenuate paraneoplastic hypercoagulability, thereby enhancing the efficacy of anticoagulation in resolving NBTE. This stands in stark contrast to the two cases of solid tumor in our series, where rapid disease progression, widespread metastases, and multiple thromboses were observed. Despite anticoagulant therapy, the NBTE lesions in these patients with solid tumors showed poor responsiveness, reflecting the refractory nature of hypercoagulability driven by advanced solid malignancies.

Diagnostically, the primary challenge remains the differentiation of NBTE from IE, especially when the underlying disease is accompanied by fever, a common finding in patients with advanced or occult cancer, or when there is a concurrent febrile illness secondary to an infectious or noninfectious process (5). IE and NBTE have overlapping imaging features such as valvular vegetations but differ fundamentally in pathophysiology and clinical course. IE is characterized by destructive valvular lesions (e.g., regurgitation progression and perforation) and persistent infection, such that vegetations rarely resolve completely with anti-infective therapy alone (12). In contrast, NBTE vegetations are thrombotic in nature and nondestructive and may resolve with effective anticoagulation and tumor control. These findings are consistent with our DLBCL case, including the absence of valvular destruction, vegetation stability during short-term anti-infection, and subsequent resolution with combined anticoagulation and antineoplastic therapy. TTE should be administered with caution to avoid missed diagnoses. TEE offers superior spatial resolution as compared to TTE, enabling the detection of subtle features (e.g., filiform flutter on vegetations) that favor NBTE over IE (13). Clinically, when valvular vegetations are identified in patients with cancer, a comprehensive evaluation should include not only infection markers such as blood cultures, procalcitonin, and CRP but also coagulation parameters such as plasma D-dimer. Individuals with cancer, particularly those undergoing chemotherapy, are prone to cardiovascular endothelial injury, which predisposes them to thrombogenesis, an important pathogenic mechanism underlying NBTE that should not be overlooked in the diagnostic workup.

Prognostically, outcomes of TS with NBTE are dictated by the type and stage of the underlying malignancy (10,14). Treatable hematological malignancies, such as DLBCL managed with the R-CHOP regimen, enable the favorable resolution of NBTE. Meanwhile, advanced solid tumors, characterized by persistent hypercoagulability and end-organ damage, are associated with a poor prognosis. This heterogeneity necessitates tailored management strategies. For hematological malignancy-associated TS with NBTE, close monitoring for IE mimicry and aggressive combination of antineoplastic and anticoagulation therapy are recommended. For solid tumor-associated disease, early recognition of fulminant thrombosis and consideration of intensive anticoagulation such as low-molecular-weight heparin for refractory cases are critical (14,15).

Given the relatively small number of cases described in this report, the findings may be subject to individual bias, as the clinical characteristics and outcomes observed could be influenced by unique patient-specific factors that may not be representative of the broader population with TS with NBTE. Nonetheless, these cases remain valuable in highlighting the distinct clinical heterogeneity of TS with NBTE associated with different malignancies.

In conclusion, the DLBCL-associated TS with NBTE presents a unique clinical profile characterized by inflammatory manifestations that mimic IE but that are responsive to combined antineoplastic and anticoagulant therapy. This observation enriches the limited understanding of NBTE in patients with hematological malignancies, an exceptionally rare medical combination. In contrast, TS associated with solid tumors and uncontrolled or difficult-to-control disease is characterized by a poor prognosis. Recognizing these differences, the nuanced echocardiographic differentiation of IE from NBTE, and the integration of infection and coagulation marker assessments is crucial for the timely diagnosis and tailored management of TS combined with NBTE across oncological backgrounds.

Acknowledgments

None.

Footnote

Funding: This study was supported by the Basic Scientific Research Project of Liaoning Education Department (No. JYTMS20230585 to J.W.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1934/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Publication of this article and accompanying images was waived from patient consent according to the Second Affiliated Hospital of Dalian Medical University Ethics Committee. The authors confirm that the manuscript has been fully anonymized to preclude any potential harm to the patients or their family members.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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