Tumoural emboli syndromes case series: diagnostic dilemma in patients with cancer and pulmonary hypertension

Learning points.

• Patients diagnosed with cancer and pulmonary hypertension with lung perfusion defects should be evaluated for evidence of tumoural emboli syndrome.

• Diagnostic assessment should include cytology of pulmonary artery blood sample obtained during right heart catheterization to find evidence of tumour cell embolization, and/or fluorodeoxyglucose-positron emission tomography to look for evidence of pulmonary metastasis in the areas of lung perfusion defects.

Introduction

Tumoural emboli syndromes (TES) are rare but important causes of pulmonary hypertension (PH) in patients with cancer, with reports ranging from 3% to 26% in patients with solid organ tumours at autopsy.¹ They range from macroscopic tumoural emboli causing acute right ventricular failure to microscopic tumoural emboli driving progressive pulmonary vasculopathy, as in pulmonary tumour thrombotic microangiopathy (PTTM).^2,3 They can mimic other pulmonary vascular diseases such as chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary veno-occlusive disease, presenting with pre-capillary PH on right heart catheterization (RHC) and mismatched perfusion defects on ventilation-perfusion (V/Q) scan.⁴

Here, we present three cases from a single institution to underscore the key diagnostic challenges for TES. These cases were selected to illustrate the diversity of TES and highlight various clinical presentations and haemodynamic findings.

Summary figure

Case 1

A 64-year-old Caucasian man with relapsed pancreatic adenocarcinoma and stable metastases to lungs and retroperitoneum on gemcitabine presented with worsening dyspnoea on exertion and hypoxia. A year ago, bilateral lower lobe pulmonary emboli (PE) had been incidentally detected on chest computed tomography (CT) and treated with apixaban. Despite adherence, he was hospitalized 6 months later with worsening dyspnoea, hypoxaemia, and chest pain.

CT pulmonary angiography (CTPA) revealed bilateral PE with increased clot burden and right ventricular (RV) strain, with no parenchymal abnormalities or pleural disease to suggest gemcitabine toxicity. His anticoagulation was switched to enoxaparin.

Two months later, he returned with tachycardia and hypoxia, requiring high-flow nasal cannula oxygen. Troponin T level was normal, but N-terminal pro-b-type natriuretic peptide (NT-proBNP) was increased at 12 011 pg/mL. Repeat CTPA showed extensive segmental and subsegmental bilateral PE with new filling defects, mosaic attenuation of the lung parenchyma and RV enlargement and hypertrophy, suggestive of CTEPH. Transthoracic echocardiogram (TTE) confirmed RV enlargement and dysfunction consistent with PH. RHC was deferred in the setting of new on chronic PE noted on CTPA.

Haematology consultants recommended increasing enoxaparin dose by 30%, with mechanical thrombectomy deferred in favour of transfer to a specialized CTEPH centre for consideration of pulmonary thromboendarterectomy. Unfortunately, he died a few days later from sudden cardiac arrest. Autopsy revealed large thrombus burden in the main pulmonary artery, extending to the segmental level. Microscopic examination showed pulmonary emboli in both arteries and veins with tumour cells embedded in the thrombi consistent with neoplastic thrombi. No signs of vessel remodelling were seen to support diagnosis of CTEPH or PTTM.

Case 2

A 46-year-old man with metastatic HER-2 positive gastric adenocarcinoma with focal signet ring cell features presented with progressive shortness of breath on exertion, cough, and multiple syncopal episodes. He first received treatment with FOLFOX (fluorouracil, oxaliplatin, leucovorin calcium), trastuzumab deruxtecan, and pembrolizumab, and was placed on maintenance therapy with trastuzumab deruxtecan, but unfortunately, his cancer progressed.

His labs were notable for mildly elevated troponin T of 72 ng/mL, and significantly elevated NT-proBNP of 1780 pg/mL. CTPA showed interlobular septal thickening and subtle ground glass opacities along the bronchovascular bundles, suspicious for infection or drug toxicity but no evidence of PE. TTE showed evidence of severe RV dysfunction with elevated RV systolic pressure (RVSP) of 78 mm Hg.

RHC confirmed severe pre-capillary PH with pulmonary artery pressures of 81/37 mmHg (mean 52 mmHg), a pulmonary capillary wedge pressure (PCWP) of 15 mmHg, cardiac output (CO) of 4.27 L/min, cardiac index (CI) of 2.33 L/min/m², and pulmonary vascular resistance (PVR) of 12.2 Wood units. Based on NT-proBNP and WHO class IV symptoms alone, he was deemed high risk per REVEAL Lite 2.0 score.

He was promptly transferred for evaluation at a local PH centre, where lung scintigraphy SPECT-CT showed peripheral mismatched defects leading to a differential diagnosis of CTEPH, pulmonary veno-occlusive disease, and PTTM. Intravenous prostacyclin was initiated and initially improved symptoms but was stopped due to side effects, and he was discharged with macitentan alone. A few days later he re-presented with hypoxia, recurrent syncope, and chest discomfort. Repeat CTPA showed diffuse reticulonodular opacities concerning for lymphangitic carcinomatosis and no PE.

A few hours later, he developed pulseless electrical activity cardiac arrest and passed away. The family declined autopsy; however, PTTM was thought to be the most likely diagnosis.

Case 3

A 65-year-old Caucasian man with metastatic renal cell carcinoma on cabozantinib and nivolumab presented to the emergency room with three months of worsening shortness of breath and exertional dyspnoea. Initial evaluation revealed mildly elevated troponin T at 107 ng/mL and severely elevated NT-proBNP at 2123 pg/mL. TTE indicated mild pulmonary hypertension with RVSP of 45 mm Hg, but a moderately enlarged and severely dysfunctional RV.

RHC revealed moderate pre-capillary PH with right atrial pressure of 6 mmHg, pulmonary artery pressures of 43/23 mmHg (mean 32 mmHg), pulmonary artery wedge pressure of 7 mm Hg, CO by thermodilution of 3.08 L/min, CI of 1.82 L/min/m², and PVR of 8.12 Wood units. A pulmonary artery catheter blood sample demonstrated rare clusters of atypical cells that were positive for PAX8 immunohistochemistry, confirming tumour emboli consistent with renal cell carcinoma (Figure 1).

Figure 1.

Lung scintigraphy SPECT-CT of patient in Case 2 showed patchy perfusion defects. The blood sample from the right pulmonary artery obtained via the Swan Ganz catheter underwent preparation with Papanicolaou stain. This revealed clumps of atypical cells with strong positivity for PAX8, consistent with renal cell carcinoma.

Management included re-initiation of cancer therapy with levatinib, continued anticoagulation for new-onset atrial fibrillation, and addition of sildenafil. NT-proBNP levels initially improved to 1171 ng/mL. However, lenvatinib was discontinued due to progressive QTc prolongation. He developed worsening dyspnoea and repeat chest CT demonstrated new findings concerning for lymphangitic carcinomatosis. Due to progression of malignancy with limited therapy options, he was transitioned to hospice care and passed away a few weeks later.

Discussion

PH secondary to TES includes a wide spectrum of diseases, ranging from macroscopic tumour emboli causing acute RV failure and shock to more insidious microvascular disease from smaller emboli and/or microangiopathy.⁵ During evaluation, they may have several signs of CTEPH, a rare complication of thrombotic ‘bland’ PE, including mismatched perfusion defects on ventilation perfusion scan, as well as findings of recurrent pulmonary emboli.^2–4,6 In some cases, there is rapid progression of PH severity due to growth factors secreted by the cancer leading to pulmonary vascular wall fibromuscular hyperplasia—a condition known as PTTM.^7–9 Each of these cases highlight the challenges in differentiating tumour from bland thromboembolic disease in patients with cancer. Overall, the distinction is complicated by the elevated thromboembolic risk in this population. Chemotherapy is a recognized independent risk factor, especially cisplatin-based regimens, asparaginase, and combined thalidomide/lenalidomide and steroid regimens.¹⁰ Paraneoplastic thromboembolism can be seen, such as Trousseau syndrome, defined by migratory and recurrent venous or arterial thromboses, especially with aggressive malignancies such as pancreatic, lung, and gastrointestinal tumours.¹¹ Radiation therapy can also induce a prothrombotic environment.¹⁰ Notably, the 2022 ESC/ERS Guidelines for the diagnosis and treatment of PH do not include the wide spectrum of TES as a cause of pulmonary hypertension or propose a suggested diagnostic strategy.¹²

These cases emphasize different clinical and haemodynamic presentations. In Case 1, strict adherence to guideline-recommended 3-month anti-coagulation prior to perfusion imaging delayed identification of tumour emboli and chemotherapy, with focus on treatment of presumed bland PE and CTEPH.¹² In Case 2, the patient had findings consistent with lymphangitic carcinomatosis on chest CT, prompting consideration of PTTM. RHC showed severe pre-capillary PH, and his clinical course rapidly declined, consistent with prior case reports of PTTM.^3,13 In Case 3, diagnostic workup was expanded to include cytology during RHC, which revealed intravascular tumour cells in the pulmonary circulation. Our prior case report also demonstrates a role of fluorodeoxyglucose-positron emission tomography (FDG-PET) in confirming suspected diagnoses, particularly with negative pulmonary artery sample cytology.¹³ Together, the rapidly declining clinical course of these cases highlights the importance of expedited evaluation with additional modalities to differentiate tumour from bland thromboembolic disease, which could be emphasized in future iterations of PH guidelines.

The optimal management of pulmonary tumoural emboli remains unknown.^3,9 While treatment of underlying cancer ought to be the primary objective, recent case reports suggest a potential role of mechanical thrombectomy for tumour emboli.^14,15 Our prior work also demonstrated that mechanical thrombectomy for symptomatic DVT in cancer patients led to symptomatic improvement with 18% of patients having tumoural instead of bland thrombi.¹⁵ Some case reports suggest that adjunctive therapies directed at growth factors, such as imatinib, may slow pulmonary vascular remodelling.^8,13 Ultimately, pulmonary tumoural emboli syndrome is a manifestation of advanced cancer, which may drive prognosis. However, there may be select patients whose advanced cancer is responding to therapies, who may benefit from therapies targeted at PH to delay the course of clinical deterioration.¹³

Currently, no clinical trials have systematically tested PH-specific therapies for tumour emboli syndromes, but case reports suggest that PH often progress despite pulmonary vasodilators.⁵ Future studies are needed to better understand the impact of PH targeted therapies in patients with tumour emboli syndrome. Figure 2 summarizes the cases of pulmonary tumour embolism in this series, highlighting the relevant details regarding underlying malignancy as well as the pulmonary hypertension evaluation and outcomes. We propose a diagnostic strategy in the evaluation of PH in patients with metastatic cancer in Figure 3.

Figure 2.

Challenges in diagnosis and management of pulmonary tumour emboli syndrome in patients with cancer. CTPA, computed tomography pulmonary angiogram; PA, pulmonary artery; PAH, pulmonary arterial hypertension; PCWP, pulmonary capillary wedge pressure; PE, pulmonary embolism; PVR, pulmonary vascular resistance; RHC, right heart catheterization; RV, right ventricular; TTE, transthoracic echocardiogram; V/Q, ventilation perfusion scan.

Figure 3.

Proposed diagnostic algorithm for tumoural emboli syndrome. CT, computed tomography; FDG-PET, fluorodeoxyglucose-positron emission tomography; PE, pulmonary embolism; RV, right ventricular; V/Q, ventilation/perfusion.

1. Evaluation for tumoural emboli syndrome is indicated for patients with:

   1. Metastatic solid tumour with RV failure or PH out of proportion to the degree of PE burden on CTPA.

   2. Shortness of breath despite 6 weeks to 3 months of anticoagulation with no progression of PE, as evidenced by CTPA.

2. The comprehensive evaluation for tumour emboli syndrome should include:

   1. Lung perfusion imaging—whether by lung scintigraphy, pulmonary angiogram, or dual-energy CT

   2. Cytology of pulmonary artery blood sample obtained during RHC and/or

   3. FDG-PET to look for evidence of pulmonary uptake in the areas of poor perfusion not explained by known metastatic burden on CT.

Lead author biography

Hyeon-Ju R. Ali, MD, FACC is an assistant professor in the Department of Cardiology at the University of Texas MD Anderson Cancer Centre. She specializes in the care of pulmonary hypertension in patients with cancer, specifically as it relates to drug-induced toxicity, advanced metastatic cancers, and haematologic malignancies. She is the recipient of the 2022 ISHLT Early Career and Trainees Clinical Case Dilemmas Best Presentation Award as well as 2025 ACC Cardi-Oncology Best Case Poster Award. She is the principal investigator of the first international prospective registry of patients with cancer and pulmonary hypertension.

Author contributions

Hyeon-Ju R. Ali (Conceptualization [lead], Data curation [lead], Formal analysis [lead], Investigation [lead], Supervision [lead], Validation [lead], Writing—original draft [lead], Writing—review & editing [lead]), Emily Wang (Data curation [supporting], Formal analysis [supporting], Writing—original draft [supporting], Writing—review & editing [supporting]), Nicolas L. Palaskas (Supervision [supporting], Writing—review & editing [supporting]), Sandeep Sahay (Conceptualization [supporting], Supervision [supporting], Writing—review & editing [supporting]), Wendong Yu (Data curation [supporting], Validation [supporting], Writing—review & editing [supporting]), Rahul A. Sheth (Conceptualization [supporting], Writing—review & editing [supporting]), Anita Deswal (Formal analysis [supporting], Supervision [supporting], Writing—review & editing [supporting]), and Saadia A. Faiz (Conceptualization [supporting], Formal analysis [supporting], Supervision [supporting], Validation [supporting], Writing—review & editing [supporting])

Consent: All patients consented to the collection of the reported data and publication in this case series as per COPE guidelines and our institutional IRB protocol 2023-0888.

Funding

This research is supported in part by the National Institutes of Health through MD Anderson’s Cancer Centre Support Grant (CA016672).

Data availability

The data underlying this article are available in the article and will be shared on reasonable request to the corresponding author.