Is thrombosis of retinal veins a marker of occult cancer?

Although thrombosis of the retinal veins (either central or branch retinal vein thrombosis) is usually perceived as a rare entity, its prevalence in the general population (4-6/1000) does indeed exceed that (1-2/1000) reported for venous thromboembolism (VTE)¹. Retinal veins thrombosis (RVT) does not share the same risk factors that are commonly associated with VTE disorders, such as malignancy, immobilization due to medical or surgical illnesses, trauma, hormonal therapy or pregnancy, nor does it prevail in carriers of thrombophilia². As its incidence increases with age, and is commonly associated with risk factors of atherosclerosis, such as blood hypertension, diabetes mellitus or hyperlipemia, RVT is likely to develop as a result of stiffness in adjacent arteriosclerotic arteries leading to turbulence and retinal thrombus formation^[3]. Not surprisingly, therefore, an increase in RVT incidence has never been reported in association with malignant diseases, including those in the most advanced stages^1-3.

Although an association of RVT with an underlying cancer is unlikely, no investigation has formally tested whether and to what extent the development of RVT predicts the risk of malignancies. Accordingly, it is uncertain whether patients with RVT should receive a workup for an occult cancer in an attempt to ultimately improve its prognosis, in analogy with the common practice in patients with unprovoked VTE.

In order to investigate the risk of occult cancer in patients with RVT, a nationwide population-based cohort study on all patients diagnosed with RVT between 1994 and 2013 in Denmark was performed⁴. The occurrence of cancer of any type, as registered in the Danish Cancer Registry and the National Pathology Registry, was recorded within 6 months, between 6 and 12 months, and 5 years following RVT diagnosis, and compared with that of matched control individuals without RVT. Among 9589 patients with RVT, the authors observed 1514 cancer cases. The risk of any cancer was 1.2% within 6 months and 28.8% after 5 years. In comparison to control individuals without RVT, the standardized incidence ratio of cancer was 1.20 (95% CI 0.99-1.44) within 6 months, 1.15 (95% CI 0.94-1.39) between 6 and 12 months, and 1.08 (95% CI 1.03‐1.14) after 5 years. Stratification by age, gender, calendar year, and Charlson Comorbidity Index score did not change overall cancer risk estimates.

Although a similar study, conducted in Denmark in a shorter period in a smaller sample of patients, arrived at slightly different results, after adjusting for confounders the risk of cancer after 5 years (1.15; 95% CI 1.05-1.27) overlaps that which was found in the previous study.

In conclusion, the absolute cancer risk following a RVT is low and only slightly increased compared to the general population, nor does this ratio increase over years. Accordingly, an extensive diagnostic workup for cancer does not appear warranted for these patients. These findings suggest that different underlying mechanisms are involved in the pathophysiology of venous thrombosis at different vascular sites. In particular, RVT is likely to be regarded as a marker of arterial vascular disorders rather than a clinically important marker of occult cancer.

References

1. Li JQ, Terheyden JH, Welchowski T, Schmid M, Letow J, Wolpers C, Holz FG, Finger RP. Prevalence of retinal vein occlusion in Europe: a systematic review and meta-analysis. Ophthalmologica 2018 [Epub ahead of print].
2. Jaulim A, Ahmed B, Khanam T, Chatziralli IP. Branch retinal vein occlusion: epidemiology, pathogenesis, risk factors, clinical features, diagnosis, and complications. An update of the literature. Retina 2013;33(5):901‐910.
3. Li J, Paulus YM, Shuai Y, Fang W, Liu Q, Yuan S. New developments in the classification, pathogenesis, risk factors, natural history, and treatment of branch retinal vein occlusion. J Ophthalmol 2017;2017:4936924.
4. Hansen AT, Veres K, Prandoni P, Adelborg K, Sørensen HT. Retinal vein thrombosis and risk of occult cancer: A nationwide cohort study. Cancer Med 2018;7(11):5789-5795.
5. Toft-Petersen AP, Muttuvelu DV, Heegaard S, Torp-Pedersen C. Correlation between retinal vein occlusion and cancer – a nationwide Danish cohort study. Acta Ophthalmol 2018;96(8):800-803.