**3. VTE and occult cancer**

Thrombosis can be the first manifestation of malignancy. Patients who present with idiopathic or unprovoked DVT are more likely to be diagnosed with cancer during followup than patients with secondary DVT. In pooled analyses of cohort studies, the odds ratio for subsequent cancer in patients presenting with idiopathic VTE compared with patients with secondary VTE is 4.8 (156). About 10% of patients with idiopathic VTE were diagnosed with subsequent cancers over the next 5–10 years. More than 75% of these cases were reported within the first year after the diagnosis of DVT (157).

Prins et al studied (158) the incidence of newly diagnosed malignancy in patients with unexplained venous thromboembolism during the first year after a thromboembolic event in comparison to controls (odds ratio, 3.9-36). The authors used extensive screening with computed tomography, endoscopy and tumor markers and stated that they identify most of these undetected malignancies. However, the authors continued, approximately half of these can also be identified based on a simple clinical evaluation.

Monreal et al (159) reported on retrospective analysis of our 5-year experience with a series of 674 consecutive otherwise healthy patients, and a more restricted battery of diagnostic tests including: abdominal CT-scan; carcinoembryonic levels, and prostate-specific antigen levels. The authors reported that cancer was more commonly found in patients with idiopathic VTE: 13/105 patients (12%) versus 10/569 patients (2%); p <0.01; O.R.: 7.9 (95% CI: 3.14-20.09). During the same period of time they diagnosed VTE in 147 patients with previously known cancer. When overall considered, VTE was the first sign of malignancy in most patients with prostatic and pancreatic carcinoma. However, most patients with breast, lung, uterine and brain cancers developed VTE as a terminal event of the disease (159).

Piccioli et al (160) also concurred with Monreal et al (159) that the diagnosis of venous thrombosis although may help to uncover previously occult carcinoma by prompting a complete physical examination, chest roentgenography, and mammography, extensive cancer screening with computed tomography to neck, chest, abdomen and pelvis or magnetic resonance imaging has not been shown to be cost effective for patients with venous thrombosis.

Pathophysiology and Clinical Aspects of 86 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

exemestane, are being used in place of tamoxifen for long-term prophylaxis after initial therapy of breast cancer. Exemestane is the generic name for the brand-name drug Aromasin and works by binding irreversibly to the body's aromastase enzyme, which is responsible for producing estrogen. Many breast cancer cells depend on estrogen to grow and multiply quickly. Once the aromatase inhibitor binds to the aromastase enzyme, the bound aromatase enzyme can no longer produce estrogen. This drug caused lack of estrogen "starves" estrogen- dependent breast cancer cells, preventing them from multiplying. Coombes et al, in a trial in which 4742 breast cancer patients were randomized to continue tamoxifen or to switch to exemestane. Those receiving exemestane experienced improvement in disease-free survival (154-155) The adjusted hazard ratio was 0.67 (95% CI 0.56 to 0.82, P<0.001) and the rate of thromboembolic events was almost halved in those receiving exemestane as compared with tamoxifen (1.3%

Thrombosis can be the first manifestation of malignancy. Patients who present with idiopathic or unprovoked DVT are more likely to be diagnosed with cancer during followup than patients with secondary DVT. In pooled analyses of cohort studies, the odds ratio for subsequent cancer in patients presenting with idiopathic VTE compared with patients with secondary VTE is 4.8 (156). About 10% of patients with idiopathic VTE were diagnosed with subsequent cancers over the next 5–10 years. More than 75% of these cases were

Prins et al studied (158) the incidence of newly diagnosed malignancy in patients with unexplained venous thromboembolism during the first year after a thromboembolic event in comparison to controls (odds ratio, 3.9-36). The authors used extensive screening with computed tomography, endoscopy and tumor markers and stated that they identify most of these undetected malignancies. However, the authors continued, approximately half of

Monreal et al (159) reported on retrospective analysis of our 5-year experience with a series of 674 consecutive otherwise healthy patients, and a more restricted battery of diagnostic tests including: abdominal CT-scan; carcinoembryonic levels, and prostate-specific antigen levels. The authors reported that cancer was more commonly found in patients with idiopathic VTE: 13/105 patients (12%) versus 10/569 patients (2%); p <0.01; O.R.: 7.9 (95% CI: 3.14-20.09). During the same period of time they diagnosed VTE in 147 patients with previously known cancer. When overall considered, VTE was the first sign of malignancy in most patients with prostatic and pancreatic carcinoma. However, most patients with breast, lung, uterine and brain cancers developed VTE as a terminal event of the disease (159).

Piccioli et al (160) also concurred with Monreal et al (159) that the diagnosis of venous thrombosis although may help to uncover previously occult carcinoma by prompting a complete physical examination, chest roentgenography, and mammography, extensive cancer screening with computed tomography to neck, chest, abdomen and pelvis or magnetic resonance imaging has not been shown to be cost effective for patients with

reported within the first year after the diagnosis of DVT (157).

these can also be identified based on a simple clinical evaluation.

versus 2.4%, p=0.007).

venous thrombosis.

**3. VTE and occult cancer** 

In another publication, Piccioli et al (161) reported that patients with symptomatic idiopathic venous thromboembolism and apparently cancer-free have an approximate 10% incidence of subsequent cancer. In their study, apparently cancer-free patients with acute idiopathic venous thromboembolism were randomized to either the strategy of extensive screening for occult cancer or to no further testing. Patients had a 2-year follow-up period. Of the 201 patients, 99 were allocated to the extensive screening group and 102 to the control group. In 13 (13.1%) patients, the extensive screening identified occult cancer. In the extensive screening group, a single (1.0%) malignancy became apparent during follow-up, whereas in the control group a total of 10 (9.8%) malignancies became symptomatic [relative risk, 9.7 (95% CI, 1.3–36.8; P < 0.01]. Overall, malignancies identified in the extensive screening group were at an earlier stage and the mean delay to diagnosis was reduced from 11.6 to 1.0 months (P < 0.001). Cancer-related mortality during the 2 years follow-up period occurred in two (2.0%) of the 99 patients of the extensive screening group vs. four (3.9%) of the 102 control patients [absolute difference, 1.9% (95% CI,) 5.5–10.9)].

Rickles et al (162) stated that while migratory thrombophlebitis is a clear indicator of an underlying neoplasm, the risk of cancer in patients with the more typical form of VTE has been the subject of intense debate over recent years. The authors concluded that, the costeffectiveness of aggressive screening for cancer in patients with VTE remains questionable.

Nordström, M et al (163) conducted a prospective study of 366 patients in Malmo, Sweden, who had treatment after positive results on venography reported an overall incidence of deep venous thrombosis of 159 per 100 000 inhabitants per year. At the time of diagnosis of deep venous thrombosis, 71 patients (19%) had a known cancer and a further 19 (5%) developed cancer within the following year. Eight of the cancers were obvious at the time of diagnosis of the deep venous thrombosis and 11 were occult.

To date, there is very little evidence that routine cancer screening is indicated or costeffective in patients with unprovoked thrombosis. Nonetheless, it is prudent to perform a comprehensive history and physical exam and check basic blood work with relevant tumor markers, as deemed appropriate, in patients with unprovoked thrombosis because about 90% of occult cancers can be detected using this conservative approach (164-165).

At our institutions, when performing pulmonary artery CTA and CTV for unprovoked VTE, our radiologist analyzes all information produced by the imaging examination. An attentive analysis of the entire thoracic and abdominal structures on all pulmonary artery CTA and CTV examinations is routine. Careful evaluation is also made in hospitalized patients in whom thromboembolic disease is discovered incidentally. In such patients, pulmonary artery CTA and CTV is considered a cancer screening procedure with an increased likelihood of finding an occult malignancy. When the CTV examination begins at the level of the diaphragm instead of below the level of the iliac crest, it permits the detection of venous thrombosis and serves as a simultaneous screening for possible underlying malignant disease.
