When Venous Thrombosis May Hide an Underlying Cancer

Since Armand Trousseau’s 1865 discovery of the close association between “recurrent thrombophlebitis” and cancer, scientific research has sought to determine how high the risk of an occult malignancy is when a VTE event occurs.

Recent studies, conducted mainly in Europe and the United States, have shown that approximately 5% of patients with unprovoked VTE receive a cancer diagnosis within the following year, most of which are identified in the first months after the VTE diagnosis (1).

This risk is higher than that of the general population but is not the same for every patient: it depends on age, comorbidities (such as chronic lung disease), smoking habits, and other factors that are still under investigation (2,3).

It should be noted that venous thromboses occurring in “atypical” sites, such as abdominal veins, require separate consideration because they present different risk factors and a stronger association with certain malignant or hematologic conditions.

Should all patients with unprovoked VTE undergo extensive cancer screening?

Over the past two decades, numerous studies have addressed this question but have failed to demonstrate a true clinical benefit from extensive diagnostic testing—such as routine CT scans or PET scans—performed in all patients presenting with VTE (4,5,6,7,8).

Therefore, according to ISTH recommendations, evaluation should be limited to symptoms, personal and family history, physical examination, routine blood tests, urinalysis, age‑ and sex‑appropriate cancer screening (PSA, fecal occult blood test, mammography, Pap test), and chest X‑ray (9). The same document, however, emphasizes the need for further diagnostic work‑up in cases of recurrent unprovoked VTE, especially if recurrence occurs during anticoagulant therapy (9). Particular attention should also be given to unusually extensive thromboses, such as those involving both limbs.

No specific recommendation is provided regarding abdominal ultrasound, a non‑invasive test that has often been grouped together with CT scans under the umbrella of “extended evaluation,” creating some confusion. Few studies have specifically assessed the usefulness of this procedure (10). In practice, in Italy and other European countries, abdominal ultrasound is generally performed, especially when a cancer risk factor—such as age—is present.

The Thai Study

A study presented at ISTH 2026 and published in Blood Global Hematology drew attention to the ever-simmering question: are we certain that performing more extensive testing—such as thoracic and/or abdominal CT scans—in all patients with unprovoked VTE does not allow earlier detection of more cancers and thus improve survival?

Researchers at Phramongkutklao Hospital in Bangkok retrospectively analyzed 215 patients with unprovoked VTE seen between 2021 and 2024 and followed for approximately two years (11).

Consistent with recent European and North American data, the study found that 6.3% of patients received a cancer diagnosis within one year of the thrombotic event. However, the most frequent malignancies differed: lymphoma (21% of cases) was the most common, followed by cholangiocarcinoma (15%), a biliary tract cancer far more prevalent in Southeast Asia than in Western countries, where cancers most often associated with VTE include lung, pancreatic, ovarian, liver, gastrointestinal cancers, leukemias, and lymphomas (2,12).

The study compared patients who underwent an aggressive screening strategy—thoracic and/or abdominal CT or abdominal ultrasound—with those who received “limited screening,” consisting of a complete clinical evaluation, basic blood tests, and age‑ and sex‑appropriate cancer screening. Abdominal ultrasound, although considered part of extended screening, was performed in only nine patients.

Cancer diagnosis was nearly five times more frequent in the extended‑screening group compared with the limited‑screening group (11.3% vs. 2.6%) and occurred earlier (on average 1.5 months after VTE diagnosis vs. 17 months). However, earlier detection did not translate into improved two‑year survival (83.5% vs. 88.3%).

Surprising? Not entirely, considering the observational and retrospective nature of the study: since patients were not randomized to extended or limited screening, but clinicians simply followed their usual practice, the study likely reflects clinicians’ ability to identify—based on initial clinical evaluation and routine tests—those patients most likely to harbor an occult malignancy and to direct them toward more extensive testing.

The Dutch Study

Similar conclusions were reached by a real‑world Dutch study recently published in the Journal of Thrombosis and Haemostasis (13), which evaluated the performance of the diagnostic strategy commonly used in the Netherlands for lower‑limb venous thrombosis (both deep and superficial), based on national guidelines (14), with encouraging results.

This approach initially includes only a detailed and standardized clinical history, physical examination, and routine laboratory tests (complete blood count, creatinine, liver tests, C‑reactive protein, D‑dimer). Based on these initial findings and clinical suspicion, physicians proceed with further diagnostic testing. Follow‑up is crucial: all patients were reassessed after six weeks and, if a suspicion of cancer aroused, additional tests were performed.

Researchers analyzed 258 patients with deep vein thrombosis (DVT), 179 with superficial venous thrombosis (SVT), and 848 controls (patients with suspected but unconfirmed thrombosis). More than half of DVT patients (57.8%), a minority of SVT patients (18.4%), and about 9.2% of controls underwent further diagnostic evaluation for suspected cancer.

Within 12 months, cancer was diagnosed in 6.2% of DVT patients, 2.2% of SVT patients, and 2.3% of controls. Overall, the procedure was effective in 98% of cases at identifying patients who did not require extended screening. Only 2 of 109 DVT patients (1.8%) and 2 of 147 SVT patients (1.4%) who were not referred for further testing were later found to have cancer within the following year.

Implications for Clinical Practice

Both studies converge on the conclusion that, as guidelines indicate, extended screening should not be performed routinely but reserved for patients with suspicious clinical signs or additional risk factors, tailoring diagnostic tests to the clinical suspicion.

However, the authors of both studies agree that this approach is not optimal and that it is necessary to identify additional risk factors or laboratory tests capable of rapidly and effectively discriminating who should undergo in-depth diagnostic testing.

Risk Factors for Occult Cancer in Unprovoked VTE

Risk factors such as age over 70, anemia or elevated platelet count on routine blood tests, chronic lung disease, or bleeding events during follow‑up have been identified from the large RIETE registry and summarized in a risk score (CAVE score), which has shown clinical usefulness particularly when negative (a very low score correlates with a low probability of occult cancer) (2).

A large Canadian cohort identified additional risk factors: age over 60, smoking, and previous provoked VTE (3). A risk score (SOME score) was developed but did not perform well enough for routine clinical use (15).

Are There Blood Tests Useful for Detecting Occult Cancer?

It goes without saying that research in this field is fervent and the first data on the possible use of the so-called “liquid biopsy” have already been published and provide interesting perspectives (16). However, clinical applicability will not be immediate and, since these are decidedly specialized and high-cost laboratory tests, perhaps they will not even be accessible in all contexts.

Several studies have examined coagulation tests, which are elevated both in cancer and thrombosis and may provide useful clues (17). Proteomic tests analyzing numerous plasma proteins associated with cancer have shown promise, but these remain complex tests available mainly in research laboratories (18).

Among routine tests, D‑dimer is the most studied. Several studies have shown that markedly elevated D‑dimer levels at VTE diagnosis (e.g., 10 times the upper limit of normal) may raise suspicion of underlying malignancy (17,19,20). However, research is ongoing, and D‑dimer must always be interpreted within the clinical context (high levels do not necessarily indicate cancer). Machine learning may help by developing predictive models integrating multiple risk factors (21).

And What About Superficial Venous Thrombosis (SVT)?

In the following video, Dr. Davide Santagata discusses recent research on cancer incidence in patients with SVT and its clinical implications, presented at ISTH 2026.

Bibliography

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