Introduction

Over the past decades, pulmonary embolism and cancer have become increasingly associated with their impact on patient outcomes, hence making their relationship a subject of great interest. As these two conditions are ranked among the leading causes of morbidity and mortality worldwide, their relationship now emerges as an urgent learning agenda for today's clinicians. Pulmonary embolism (PE) is a life-threatening condition associated with obstruction of pulmonary arteries by blood clots. A study revealed that cancer patients are more prone to PE due to their hypercoagulable state, body characteristics, tumour-related factors, and treatments such as chemotherapy and surgery.¹ Second, PE may potentially indicate an undetected or recurring cancer. Therefore, a deeper understanding of the relationship between embolic events and cancer would be crucial for risk assessment, early detection, and treatment for individuals at risk.

Background data regarding pulmonary embolism and cancer

Evidence has shown that Non-Small Cell Lung Cancer (NSCLC) patients are at an increased risk of developing Venous Thromboembolism (VTE), which includes Deep Vein Thrombosis (DVT) and PE.² It has been demonstrated in several studies that the disposition of embolic events involving neoplasia and cancer is a two-way relationship. Recently, a study has shown that via DVT and PE, VTE risk is actually decreased in adult females receiving testosterone therapy. This shows the potential protective effects of testosterone against these cardiovascular disorders, as has been maintained by Pranjal Agrawal et al. (2024).³ Recently, a retrospective chart review amongst NSCLC patients examined the association of VTE with Immune Checkpoint Inhibitors (ICI) plus chemotherapy and found no significant difference between chemotherapy alone versus ICI plus chemotherapy. Also, there were lower odds for death in the ICI plus chemotherapy group, reflecting the multifaceted nature of cancer treatment modalities regarding VTE risk.⁴ These results demonstrate the complexity of PE in cancer and demand continuity in the research on mechanisms that drive associations between them.

Cancer and pulmonary embolism

There has been deep-seated literature since the 19^th century linking malignancy to the risk of thrombosis, with VTE as one of the common manifestations of this link. However, the results from recent research shed light on the association between cancer and PE, thus underlining the importance of the grave implications of this relationship. Recent studies have investigated specific types of malignancies that may pose unique effects on the development of PE. Particularly of interest, one study using data in the NIS database showed that rates of VTE co-diagnosis differed among different types of cancers, with cancer of the thyroid showing a 3.3% burden of VTE.⁵ This would suggest that thyroid cancer may be at an increased risk for VTE than the general population. This study shows a more nuanced link between non-infectious respiratory disorders and sepsis with the addition of Mendelian randomisation analysis data, offering additional details on potential preventive and therapeutic care. Given the multifaceted nature of the intricate relationship between PE and cancer, it is clear that risk assessment, diagnosis, and therapy must be highly customised in such a complicated medical scenario.

Epidemiology of pulmonary embolism in cancer patients

This intersection between cancer and PE is a clinically challenging problem, according to recent studies elucidating PE epidemiology in cancer patients. For instance, one of the studies conducted to compare the different generations of Epidermal Growth Factor Receptor - Tyrosine Kinase Inhibitors (EGFR-TKIs) reported increased VTE that encompasses deep venous thromboembolism and PE among elderly non-small cell lung cancer patients receiving third-generation EGFR-TKIs.⁶ Also, demographic differences and comorbidities affecting hospitalisation in female breast cancer survivors with PE revealed another influence on outcomes by Cannabis Use Disorder (CUD).⁷ Similar findings argue for personalised approaches to PE monitoring and management in cancer patients individualised by risk factors including age and treatment regimens, and associated with substance use disorders. By using these advances in clinical practice, healthcare professionals are given a far superior position from which to navigate the complex two-way interplay between cancer and embolic events, allowing for the best possible results for patients. 

Mechanisms of the association between cancer and pulmonary embolism

Recent advances in thrombosis and hemostasis shed light on the complex relationship between cancer and PE. While cancer is now an extremely well-defined risk factor for VTE, including PE, the underlying mechanisms are complex and multifactorial. Indeed, one-fifth of all VTE cases are heralded by thrombotic events, according to the literature.⁸ The literature points out that this reflects the huge burden of malignancy on thrombotic events. However, a review of pathogenic pathways by which cancer promotes VTE stated, "In deep-vein thrombosis, an enhanced understanding of non-tumor-related risk factors and biomarkers is needed".⁸ The potential role of DNA methylation in unprovoked VTE, particularly in molecular mechanisms mediating PE and cancer interconnections, might provide further insight into the interactions between genetic and environmental factors in cancer-associated thrombotic events.⁸ With time, this thorough research will unravel the complex relationships that will eventually lead to a correlation between PE and cancer, paving the way for targeted interventions and customised risk assessment techniques in clinical settings.

Hypercoagulability in cancer

The complex interaction between cancer and hypercoagulability marks a severe clinical concern, specifically in patients with tumours in the spine who are receiving treatment, or those infected with SARS-CoV-2 (COVID-19). Hence, the reviews of studies on the co-existence of cancer and hypercoagulability indicate a multifactorial association and are modified according to factors like age, comorbidities like diabetes and dyslipidemia, serum albumin, and history of VTE. 

Research revealed that hypercoagulability is hard to deal with. This factor particularly affects intraoperative interventions like tranexamic acid.⁹ In a similar context to the study about COVID-19 patients, it has also been established that these patients are confronted with heightened risks of arterial thrombotic events and their effects on mortality.¹⁰ Cumulatively, each of these above findings plays its role in underlining the degree to which an ideal balance has to be maintained while dealing with cases of hypercoagulability in patients diagnosed with cancer and, as in the case of COVID-19, individual-centric risk profiling and management tools become all the more crucial to avoid certain death or other undesirable outcomes.

Summary

In short, PE and cancer are multi-advanced and still remain a topic of wide speculation. Every piece of research conducted in this field undoubtedly proves that patients with malignant diseases are more susceptible to developing embolic events. However, how such cancers contribute to the development of PE has yet to be adequately explained. This is the case for certain types of cancer cells that firmly can induce developments in a hypercoagulable state, thus leading to pulmonary embolisms. Further research is needed to complete the understanding of the interaction of cancer progression with embolic events. Additionally, there are very few studies about the effects of different modalities in the treatment of cancer on the risk for pulmonary embolism. Therefore, further studies will be helpful in clarifying the mechanisms and possible approaches to preventing and managing pulmonary embolism in cancer patients. Generally, improved knowledge on the relationship between cancer and embolic events can help to improve the current outcome of individuals affected by these conditions and at the same time, help people achieve a better quality of life.¹¹

Summary of associating cancer with embolic events

Previous studies have already shown a strong association between cancer and embolic events. Pulmonary embolism is most strongly associated with cancer. One established risk factor for the onset of venous thromboembolism is cancer and a large number of patients present with cancer-associated pulmonary embolism. The mechanisms are multifactorial and involve the development of an altered hypercoagulable state that occurs due to the release of procoagulant factors from tumour cells and inflammatory cytokine production within the tumour microenvironment. Also, cancer treatment options such as chemotherapy and surgery can increase the chances of developing embolic events further in such patients. As a result, embolic events should always be suspected by the clinician while managing a patient of cancer who would present with such symptoms, and have known risk factors for embolic events or are receiving active cancer treatment. Timely identification and suitable management are critical for improving results and decreasing mortality in a high-risk population.