Up to 10% of patients with unprovoked VTE will be subsequently diagnosed with cancer and in all patients, age-appropriate cancer screening is recommended [1
]. In selected patients, a comprehensive cancer screening strategy may be considered. Prior clinical investigations have studied the utility and cost of various screening strategies, including the incorporation of cancer biomarkers, ultrasound, and CT imaging [5
]. Nevertheless, controversy exists with regard to how extensive the assessment should be and whether it is cost-effective.
FDG-PET/CT is more sensitive than other imaging modalities for detection of malignancy [16
] and systematically evaluates the majority of the body. As a result, whole body FDG-PET/CT may be a single, comprehensive imaging strategy for the early detection of malignancy in patients with acute, unprovoked VTE. While these data represent a small, pilot study, to our knowledge this is the first prospective investigation utilizing FDG-PET/CT as a comprehensive cancer screening strategy in patients with unprovoked VTE. In our study, FDG-PET/CT was feasible and no patients with a negative FDG-PET/CT scan were diagnosed with malignancy during the follow-up period. Not unexpectedly, and likely due to its enhanced sensitivity, we found that whole body FDG-PET/CT resulted in the identification of suspicious findings requiring additional evaluations in 62.5% of our patients.
While many of these false positive findings were clinically significant, such as the identification of sites of infection or inflammatory diseases, other findings simply represented physiological variants. The necessity of further diagnostic evaluation for these false positive findings does carry potential risks as tests such as bronchoscopy or biopsy are associated with inherent procedural complications. Nevertheless, other studies utilizing colonoscopy, mammography, and CT scans as extensive cancer screening strategies in patients with unprovoked VTE have also reported that false positive test results are not uncommon [8
]. Fortunately, and also consistent with these published studies, none of our patients suffered an adverse event related to the additional diagnostic testing. We did not assess the psychological impact of false positive test results on patients, but measurement of these effects may be considered for future studies.
Although a negative FDG-PET/CT scan reduces the likelihood of occult malignancy, some cancers are poorly FDG avid and may fail to be identified by PET. These include low grade lymphomas, low grade breast cancers (such as lobular and tubular types), hepatocellular carcinoma, low grade lung cancers (such as bronchoalveolar carcinoma and carcinoid tumors), hepatocellular carcinoma, renal cell carcinoma, prostate cancer and some testicular cancers [14
]. Hematological malignancies may escape detection by PET, particularly because of great variability in the degree of metabolic activity displayed by red marrow-containing portions of the skeleton. Furthermore, with many tiny tumors (≤1–2 cm in diameter), increased metabolic activity may not be identified by FDG-PET/CT because of partial volume effects [14
To minimize the risk to patients, the CT scan performed in conjunction with the FDG-PET study was done with diagnostic exposure parameters and the inclusion of oral barium contrast medium, but was not performed with iodinated contrast. The lack of IV contrast could limit characterization of renal cysts, non-FDG avid hepatic and pancreatic masses, and some lymph nodes, particularly those in the pulmonary hila and mesentery. As such, a negative FDG-PET/CT scan in a patient with signs or symptoms strongly concerning for malignancy may not preclude further diagnostic workup or follow-up as clinically appropriate.
Finally, the initial FDG-PET/CT screening study and any follow-up CT scans do carry some risk due to the long term effects of radiation exposure. Two-thirds of the radiation dose of FDG-PET/CT is derived from the CT scan. Whole body FDG-PET, when performed with a diagnostic quality CT scan, provides a total body effective dose of radiation exposure of 19–40 rem (.19-.40 Sv), depending on the size of the patient and the number of CT detectors [14
]. This is equivalent to approximately 6–14 years of natural background radiation. Conservative epidemiological data suggested an increase in cancer risk of 5% with exposure to medical radiation sources with a 1 Sv dose [16
]. Although the risk from radiation exposure from a single FDG-PET/CT is considered low, the cumulative effects of multiple radiographic studies in a given patient may be significant and any unnecessary radiation exposure should be avoided.
The incidence of malignancy in our study (2.5%, 95% CI: 0.6%-12.9%) was slightly lower than reported in other studies utilizing various types of comprehensive cancer screening in patients with idiopathic VTE [5
]. This may be due, in part, to the younger cohort of patients in our study and the higher incidence of malignancy in older subjects [10
]. In the SOMIT trial, the average age of patients was 66 years [8
]. The average age of patients in our study was 55 years with 65% of our patients being 60 years of age or younger. Although the overall incidence of malignancy in the SOMIT trial was 13.1%, the incidence was only 4.9% in patients ≤60 years [8
The average age of subjects in the current cohort is very consistent with other cohorts of patients with unprovoked VTE that have been reported in the literature [20
]. Additionally, thrombophilia, including the factor V Leiden mutation and the prothrombin gene mutation, was identified in about 18% of subjects, consistent with published studies investigating the prevalence of thrombophilia in unprovoked VTE [8
]. The prevalence of hyperhomocysteinemia in the current cohort was about 12%, similar to other epidemiologic reports [24
As age is an important risk factor for malignancy, a comprehensive cancer screening approach may be more effective when applied to older patients with unprovoked VTE. For example, based on the data from the SOMIT trial [8
], in patients with unprovoked VTE aged >60 years, the number of patients needed to screen extensively to identify one malignancy was approximately 6. In comparison, in patients with unprovoked VTE aged 51–60, the number needed to screen increases to approximately 19 [8
]. Although the use of FDG-PET/CT in our study cohort identified only one occult malignancy, the application of whole body FDG-PET/CT as a comprehensive cancer screening strategy may have higher utility in older patients.
The estimated cost of FDG-PET/CT ($1,162) and the cost of subsequent diagnostic tests and procedures to resolve suspicious FDG-PET/CT image findings was $1,479 dollars per patient. The majority of these costs were related to the cost of the initial FDG-PET/CT (78.5%). We used 2010 Medicare figures for our cost analysis and these costs are therefore very conservative. For private insurance or self-paying patients, these costs may be substantially higher. These costs, however, might be mitigated by the use of stringent guidelines defining what incidental findings do and do not require additional diagnostic evaluation [25
]. Although published costs of cancer screening strategies in patients with idiopathic VTE vary depending on the strategy used, our costs are similar to data from the SOMIT trial [11
] and reasonable when compared to other cancer screening programs [26
The strengths of the current study include the prospective design, the long follow-up period, and the screening process for malignancy prior to acquisition of the FDG-PET/CT. The primary weakness of this study was the small number of patients included in the analysis. However, this was a pilot study designed to test the feasibility of FDG-PET/CT as an extensive cancer screening strategy in patients with unprovoked VTE and was not powered for clinical outcomes. The inclusion of 6 patients (14.6%) with a prior history of VTE may be considered a limitation. While none of these patients had a known history of thrombophilia, a possible predisposition toward thrombosis might have made occult malignancy less likely in these 6 patients. In spite of this, the single patient in whom malignancy was confirmed had a remote history of provoked DVT 15 years prior to her presentation with acute PE and enrollment into this study.