Occult cancer and unprovoked venous thromboembolism: What’s their relationship?

Occult cancers are generally advanced or metastatic tumors with unknown primary origin. In some cases, they are suspected of unexplained symptoms or abnormal laboratory findings that other causes cannot explain.

Unprovoked venous thromboembolism (VTE) is a thrombotic event that develops spontaneously without an obvious trigger, such as surgery, trauma, or prolonged immobilization.

Occult cancer and unprovoked VTE may be linked. A systematic review of 34 studies showed that up to 10% of patients with unprovoked VTE have a cancer diagnosis within 1 year (compared to only 2.6% of patients with provoked events) [1]. A recent review reported occult cancers being diagnosed in approximately 5% of unprovoked VTE cases [2]. In contrast, analyzing data from 528,693 cancer cases of the California Cancer Registry, one study showed that 0.11% of cancer diagnoses (596 cases) were preceded within 1 year by a diagnosis of unprovoked VTE [3].

Finally, a cohort study showed that 17% of patients with recurrent VTE also had a newly diagnosed cancer within 2 years of follow-up, while the same was true only for 4.5% of patients with no VTE recurrence [4].

While a clear association between cancer and unprovoked VTE exists, it is still unclear if an earlier diagnosis through extensive screening after an unprovoked VTE event might be of any clinical benefit.

Extensive screening vs. limited screening

Extensive screening uses abdomen and pelvis CTs to look for occult cancer. A multicenter, open-label, randomized controlled trial compared the extensive screening strategy to limited screening (which includes typical cervical, breast, and prostate cancer testing and simple blood tests with chest radiography) to test which strategy is the best for occult cancer screening [5].

Results showed that routine CT abdomen and pelvis screening did not provide any clinical benefit compared to limited screening: the cancer detection rates, time to cancer detection, and overall mortality were comparable within the two groups [5].

A recent review collected randomized control trials and systematic reviews on the matter. The results indicate that extensive screening with CT, CT + FOBT, or 18F-FDG PET/CT can lead to an earlier diagnosis but, unfortunately, has no apparent effects on the progression of the disease or the number of cancer-related death [6].

Another randomized controlled trial compared extensive testing (with ultrasound, CT) and tests chosen by the physicians within 2 years of follow-up. Results indicate that extensive screening reduced the time for diagnosis and the cancer stage at diagnosis. Still, no differences in cancer-related mortality were found at the end of the follow-up period [7].

Overall, these studies indicate that extensive screening can lead to an earlier diagnosis of occult cancer with no effects on prognosis or survival. This needs to be taken into account when evaluating the screening strategy for occult cancer because additional screening carries some extra costs and risks, such as exposure to radiation, procedures, and potential increase of unnecessary stress or anxiety for the patient. In fact, some studies found that extensive screening was paired with increased false positive testing, which might lead to further exams like biopsy or interval imaging and cause psychological distress to the patients [6].

Guidelines

A recent update of the National Institute of Health guidelines recommends routine screening with history, physical exams, and laboratory testing to investigate the presence of occult cancer after unprovoked VTE. The guidelines did not recommend further investigations for cancer in people with unprovoked DVT or PE in the absence of other clinically relevant signs or symptoms [8].

Similarly, the International Society on Thrombosis and Haemostasis guidelines recommended limited cancer screening in first unprovoked VTE, including a thorough medical history and physical examination, laboratory evaluation, and chest X-ray in addition to recommended age- and gender-specific cancer screening [9].

Scoring systems for occult cancer in patients with unprovoked VTE

The RIETE cancer score was developed to retrospectively evaluate a number of factors to assess cancer risk in patients with unprovoked VTE. The factors considered by the score as high risk for occult malignancy are male gender, age above 70 years, chronic lung disease, anemia, elevated platelet count, prior VTE, and recent surgery [6].

The effectiveness of the score is still under debate, though. While one study showed that the RIETE score could catch occult cancer in 11.8% of patients cataloged as at high risk, another study found no significant association between a high RIETE score and a cancer diagnosis. Also, the score seems to have low predictive ability in women [10].

There is conflicting evidence regarding the difference in risk for occult cancer after unprovoked VTE for men and women. A systematic review suggested a similar prevalence at 12 months for men and women, 5% and 5.7%, respectively [11]. These results are in agreement with another study that compared limited vs. extensive screening strategies for occult cancer [12]. Although, in other studies, men were found to have a higher risk of occult cancer detection after unprovoked VTE compared to women, 8.7% vs. 3.8 respectively [13].

Other risk factors suggested for occult cancer after unprovoked VTE are: the use of estrogens, comorbidities, chronic lung disease, and active smokers.

Conclusion

In patients with unprovoked VTE, limited screening is recommended to screen for underlying cancer. Screening may involve a thorough medical history, physical exam, laboratory tests, and chest radiography. Extensive screening, while reducing the time for a diagnosis, seems not to benefit prognosis and survival.

References

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