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Journal of Clinical Oncology, Vol 22, No 10 (May 15), 2004: pp. 1949-1956 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.10.160 Diagnosis of Deep Septic Thrombophlebitis in Cancer Patients by Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography Scanning: A Preliminary ReportFrom the University of Arkansas for Medical Sciences, Myeloma Institute for Research and Therapy and Department of Radiology, Little Rock, AR; Department of Breast Surgical Oncology, The M.D. Anderson Cancer Center, Houston, TX; Department of Infectious Diseases, Lebanese University, Beirut, Lebanon; and Department of Vascular Surgery, Hospital Profesor Alejandro Posadas, Buenos Aires, Argentina. Address reprint requests to Elias J. Anaissie, MD, Supportive Care, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, 4301 W Markham, #776, Little Rock, AR 72205; e-mail: anaissieeliasj{at}uams.edu
PURPOSE: To determine the role of the fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scan in the diagnosis and management of deep septic thrombophlebitis (STP). PATIENTS AND METHODS: We conducted a prospective observational evaluation of FDG-PET in patients with cancer and suspected STP. Retrospective evaluation of patients with cancer and deep venous thrombosis (DVT) who underwent FDG-PET and extremity duplex scan (DS) was also performed. RESULTS: Strong venous uptake was observed in FDG-PET of nine STP episodes versus 0 of 27 DVT episodes (P < .001). FDG-PET identified central vein STP in five patients, whereas DS and venography were negative in five and two of these patients, respectively. FDG-PET diagnosis of STP resulted in therapeutic changes in all patients. In four patients, follow-up FDG-PET confirmed resolution. CONCLUSION: In cancer patients, FDG-PET identifies STP even in areas not optimally visualized by DS or venography, distinguishes STP from DVT, and leads to significant therapeutic changes.
Deep venous thrombosis (DVT) is a common and serious complication in some cancer patients, including those with multiple myeloma.1-4 The increased risk for DVT in these patients is thought to be related to an impaired fibrinolytic system with increased levels of proinflammatory cytokines (interleukins 1 and 6, and tumor necrosis factor beta),1,2 the presence of central venous line (CVL), and antineoplastic chemotherapy.3,4 Septic thrombophlebitis of the deep veins (STP) also can occur in cancer patients.5 This infection may cause relapsing bacteremia and can be difficult to recognize because of the lack of accepted diagnostic criteria, the inability of duplex scan (DS) to distinguish bland from infected DVT, and the false-negative results of DS and venography, particularly in central veins.6-10 These difficulties are further compounded in severely immunosuppressed patients who may not exhibit the usual manifestations of infection,11,12 and who may have more than one likely source of relapsing bacteremia. Thus, STP may result in poor outcome including relapsing infection, delay in treatment of the underlying malignancy, and even death.5,13,14 Differentiating DVT from STP is thus critical. However, no diagnostic test can distinguish between these two clinical entities. Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning is a diagnostic modality that relies on the accumulation of FDG in metabolically active cells such as malignant and inflammatory cells,15,16 and may be able to identify STP on the basis of the severe inflammation present in this condition5 compared with the mild or absent inflammation in DVT.17-19 The purpose of this study was to determine the role of FDG-PET scan in the diagnosis and management of STP.
In April 2002, after a diagnosis supported by FDG-PET that identified the index case with STP (episode 1, Table 1; Fig 1), we conducted a prospective observational evaluation of FDG-PET in all patients with suspected STP from April 2002 through April 2003 (STP group). We also performed a retrospective analysis from August 2001 through January 2003 of all patients with a hematologic malignancy who had undergone FDG-PET for staging of their disease and an extremity color flow duplex sonography (DS) for clinically suspected acute or chronic DVT (acute and chronic DVT group, respectively). Patients with acute DVT were included if the FDG-PET scan was performed within 2 weeks (–7 to +7 days) of the development of DVT, with signs and symptoms and DS documentation.
The 2-week period was chosen because the significant inflammatory changes in acute DVT resolve within this timeframe of the initial event.20,21 This inclusion criterion would enable us to optimize the likelihood of documenting FDG-PET uptake in acute DVT (ie, reducing false-negative FDG-PET). Although chronic DVT can persist for several months or longer,22 the process is unstable and undergoes transformation over time.20 Therefore, evaluating chronic DVT in a more stable condition, and optimizing the comparison between the findings of FDG-PET and DS, is important. Episodes of chronic DVT were included if the FDG-PET scan was performed within 1 week before or 2 weeks after DS diagnosis of chronic DVT. The study was conducted at the Myeloma Institute for Research and Therapy at the University of Arkansas for Medical Sciences (Little Rock, AR), and was approved by the Institutional Review Board.
Definitions
Patient Groups
FDG-PET Imaging
Vascular Ultrasonography
Patient Data
Statistical Methods
We identified a total of 36 thrombotic episodes in 27 patients with a hematologic malignancy who underwent FDG-PET and extremity DS. Eight of these patients had more than one episode of thrombosis, either STP or acute and/or chronic DVT. Eight patients had nine episodes of STP (Table 1; Fig 2), whereas acute and chronic DVT accounted for 27 episodes in 20 patients (11 episodes in nine patients, and 16 episodes in 13 patients, respectively; Fig 2; Table 2). We could not detect significant differences in patient characteristics between the STP and the acute and chronic DVT groups with regard to age, sex, status of malignancy, type and site of CVL, site of thrombosis, and parameters of inflammation (CRP) and immunity (absolute neutrophil and lymphocyte counts) at the time of FDG-PET and DS (Table 2).
FDG-PET revealed abnormal radioisotope uptake in all nine episodes of STP (range of standardized uptake value, 3.8 to 21.4) with 100% sensitivity, specificity, and positive and negative predictive value. In contrast, no uptake could be detected among the 11 acute (of which eight were extensive) and the 16 chronic DVT episodes (P < .001). The time between testing with DS and PET was within 24 hours (two patients), 3 days (two patients), and 6 days (three patients). One patient had positive FDG-PET 19 days before DS was performed. Of note, upper-extremity DS examination was normal in the four episodes of STP involving central thoracic veins, and venography performed in two of these four episodes failed to detect a thrombus (Table 1). The FDG-PET abnormal uptake was still observed in STP even when the test was performed several days after the initial severe inflammation, as assessed by clinical and laboratory parameters. The mean time from FDG-PET to peak CRP was 4 days (range, –40 to +27 days). Four patients with STP (episodes 2, 6, 7, and 8) were neutropenic (< 1,000 neutrophils/µL) at the time their FDG-PET showed abnormal increased uptake in the infected vein (Table 1). Despite CVL removal and 2 to 3 weeks of antibiotic therapy, three of eight patients with STP (episodes 4, 5, and 6) experienced a relapse of bacteremia (same organism, same susceptibility) after chemotherapy-associated neutropenia. The FDG-PET diagnosis of STP resulted in significant therapeutic changes in all patients: venectomy (one patient), CVL removal (four patients), and longer (4 to 6 weeks) antibiotic therapy (all patients). All episodes of STP ultimately resolved with prolonged antibiotic therapy (Table 1). Follow-up FDG-PET in five patients (episodes 1 to 4, 6, and 9) showed complete resolution of previously noted abnormal uptake. The remanding three patients (episodes 5, 7, and 8) did not have a follow-up FDG-PET but their clinical and laboratory evaluation was consistent with resolution of this infection. Two of the three patients who had experienced relapse after receiving a short antibiotic course (episodes 4, 5, and 6) underwent a repeat FDG-PET. The FDG-PET after a longer course of antibiotics revealed resolution of the previously noted abnormal uptake.
This is the largest series of STP and the first description of the potential role of FDG-PET in the diagnosis of STP in a homogenous population of cancer patients cared for at the same institution. Several new findings emerged from this preliminary report. First, FDG-PET could identify STP, even when the infected vein is in an anatomic site not optimally visualized by DS or venography, or when the test is performed after improvement of the initial acute inflammation (episodes 4, 8, and 9). Second, FDG-PET might distinguish infected thrombosis (STP) from uninfected acute and chronic DVT (Table 2). Third, FDG-PET could be as useful in evaluating response (ie, resolution of abnormal FDG-PET uptake; Table 1). Fourth, along with clinical and/or laboratory findings, FDG-PET might result in therapeutic changes (Table 1). Fifth, FDG-PET could potentially lead to earlier identification and more precise location of STP than other diagnostic tools (ie, DS and computed tomography; Table 1). Finally, FDG-PET might be able to identify persistent infection, especially after immunosuppression (episodes 4, 5, and 6). Of note, FDG-PET showed abnormal uptake in the infected vein despite the presence of neutropenia (episodes 2, 6, to 8). The indium-111 WBC scan could be an alternative test in institutions that do not have a PET facility.25 Limitations of the WBC scan include delay in diagnosis (longer time interval between injection and imaging: 24 v < 1 hour for FDG-PET), cost (WBC scan is labor intensive, requiring blood sampling, WBC labeling, and subsequent imaging), and longer radiotracer half-life (67 v < 2 hours for FDG-PET).15,26 Unlike FDG-PET, WBC scan is not useful for detecting sites of involvement by the underlying cancer. In the proper clinical context, DVT by DS or venogram may be strongly suggestive of STP. However, the sensitivity and specificity of DS for upper-extremity DVT ranges between 56% to 100% and 77% to 100%, respectively, with a significant decrease in sensitivity when thrombosis involves veins beyond the proximal portion of the subclavian vein (such as innominate veins and the superior vena cava).6-8 Imaging of the central thoracic veins with venography might miss the site of obstruction in the presence of collateral channels or partial obstruction of the venous system proximal to the central thoracic veins,9,10 is fraught with observer variability (up to 30%) and technical difficulties, and is contraindicated in patients with renal failure or allergy to contrast material.27 If our results are confirmed by others, FDG-PET might become an important test in patients with suspected deep vein STP, especially when central thoracic veins are involved. Our study is limited by its retrospective design, the small number of patients, the nonsimultaneous imaging with various techniques (WBC scan and others), and the lack of blinded rereading of imaging tests. Additional testing may lower the sensitivity, specificity, and positive and negative predictive value of the FDG-PET for STP. In summary, in our small series, FDG-PET appears to be a safe, rapid, and accurate tool for diagnosing the presence, site(s), and extent of STP, including in anatomic areas not readily amenable to visualization by other methods. The test also appears to distinguish STP correctly from acute and chronic DVT. Prospective studies are needed to confirm our preliminary findings.
The authors indicated no potential conflicts of interest.
We thank Denise Shollmier, University of Arkansas for Medical Sciences (UAMS) Vascular Laboratory, and Suzanne Speaker, Janice Wojcik, and Paula Card-Higginson, Office of Grants and Scientific Publications at UAMS, for their assistance with manuscript preparation.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
3 days after appropriate intravenous antimicrobial therapy with signs and symptoms of infection, or signs and symptoms of persistent or relapsing sepsis despite appropriate antimicrobial therapy for bloodstream infection; (2) DVT as diagnosed by DS or venography (in areas amenable to good evaluation by these techniques) or surgery; and (3) no other source of primary infection in a remote site, including endocarditis. Appropriate antibiotic therapy was defined as administration of an antibiotic that is active in vitro against the offending pathogen. DVT was defined as evidence of venous thrombosis by DS, venography, or surgery, in the absence of the diagnostic criteria of STP. Thrombotic events (including STP, acute and/or chronic DVT) were considered as independent episodes if they affected different anatomic segments in the same patient. Thrombosis was considered extensive if it involved several veins of an anatomic segment and limited if it was isolated to any individual vein of a segment. 
2 test or Fisher's exact test. The Mann-Whitney U test was used to test the differences between the medians of continuous variables. We also determined sensitivity, specificity, positive predictive value, and negative predictive value for FDG-PET. P values 
.05 were considered significant. The SPSS 11.5 software package (SPSS Inc., Chicago, IL) was used for statistical analysis. 
), patient had one episode of STP (STP episode 2) and one episode of acute DVT at a different site, and is included in the STP and the acute DVT groups; (
), patient had three DVT episodes at different sites (one acute and two chronic), and is included in the acute and chronic DVT groups.
