|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2003 American Society for Clinical Oncology F-18 Fluorodeoxyglucose Positron Emission Tomography in the Evaluation of Distant Metastases From Renal Cell CarcinomaFrom the Departments of Internal Medicine, Nuclear Medicine, Thoracic and Cardiovascular Surgery, and Biostatistics and Epidemiology, and Glickman Urological Institute and Cleveland Clinic Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH. Address reprint requests to Ronald M. Bukowski, MD, Department of Hematology and Oncology, Desk R 33, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, e-mail: bukowsr{at}ccf.org.
Purpose: We conducted a study to evaluate the role of F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in the detection of distant metastases from renal cell carcinoma (RCC). Materials and Methods: Twenty-four patients with histologically proven clear-cell RCC undergoing surgical evaluation for possible resection of recurrent disease were investigated. All patients had suspected distant metastases based on conventional anatomic imaging techniques (computed tomography and magnetic resonance imaging). A total of 36 distant metastatic sites were identified. Pathology for all sites was obtained by biopsy or after surgical resection. Results: Histologically documented distant metastases from RCC were present in 33 sites (21 patients). Overall sensitivity, specificity, and positive predictive value of FDG-PET for the detection of distant metastases from RCC was 63.6% (21 of 33), 100% (three of three), and 100% (21 of 21), respectively. The mean size of distant metastases in patients with true-positive FDG-PET was 2.2 cm (95% CI, 1.7 to 2.6 cm) compared with 1.0 cm in patients with false-negative FDG-PET (95% CI, 0.7 to 1.4 cm; P = .001). Conclusion: FDG-PET is not a sensitive imaging modality for the evaluation of metastatic RCC and may not adequately characterize small metastatic lesions. However, positive FDG-PET is predictive for the presence of RCC in lesions imaged, may complement anatomic radiologic imaging modalities, and may alleviate the need for a biopsy in selected situations. A negative FDG-PET, however does not rule out active malignancy.
F-18 FLUORODEOXYGLUCOSE (FDG) positron emission tomography (PET) has been increasingly used in oncology as studies define and establish the role of this modality in imaging cancer. FDG-PET imaging of cancer is based on the observation that many malignant tumors are characterized by accelerated glucose use compared with surrounding normal tissues.1,2 The enhanced glucose metabolism in tumor cells has been attributed to impaired aerobic glycolysis resulting in increased need for glucose for adenosine triphosphate production, which enhances the uptake and subsequent phosphorylation of both glucose and FDG via the membrane glucose-transporter system. The intermediate metabolite FDG-6-phosphate, unlike glucose-6-phosphate, cannot be metabolized further and remains trapped in the cell. Coincident detection of 511-kV photons generated by positron decay (collision and annihilation of positrons emitted by the radiopharmaceutical with electrons from surrounding tissues) characterizes the distribution of FDG in the body and its accumulation in any specific area. In comparison to conventional anatomic imaging modalities, the ability to noninvasively characterize in vivo metabolic reactions makes FDG-PET particularly attractive in oncology. PET has been applied for the diagnosis, staging, and follow-up and for monitoring response to therapy for several cancers.3,4 Stage and presence of distant metastases at diagnosis are independently predictive of poor survival in patients with renal cell carcinoma (RCC).5–7 Moreover, accurate staging is important for deciding therapy and determining prognosis for patients with RCC. Histologic evaluation is the gold standard for confirming presence of malignancy in sites of suspected disease. Computed tomography (CT) is the imaging modality currently used to stage and detect distant metastases in patients with RCC. The overall accuracy of CT scan for staging RCC ranges from 61% to 91%.8–10 Subcentimeter pulmonary nodules are frequently seen in patients with suspected advanced disease; however, they may be nonmalignant and represent granulomas or other benign structures. Improving the diagnostic yield of these investigations while precluding the need for obtaining a tissue diagnosis would have obvious implications in management. FDG-PET has been shown to complement conventional anatomic imaging modalities in staging and detecting distant disease for many cancer sites.11–16 The role of FDG-PET in the staging and detection of distant metastases from RCC has not been clearly established. We studied the role of FDG-PET in the evaluation of distant metastases from RCC.
Twenty-four patients with histologically proven RCC undergoing surgical evaluation for suspected recurrent disease at a distant metastatic site were identified. Their disease was initially assessed by conventional anatomic imaging techniques (CT or magnetic resonance imaging [MRI]). In addition, FDG scintigraphy for the evaluation of distant metastases was performed. Medical record of these 24 patients was reviewed retrospectively. The study was approved by the local institutional review board and was conducted in accordance with institutional review board guidelines.
Thirty-six possible distant metastatic sites were evaluated in these 24 patients (lung, n = 19; mediastinal lymph nodes, n = 10; brain, n = 2; chest wall, n = 2; bone, n = 1; para-aortic lymph nodes, n = 1; and contralateral adrenal gland, n = 1). Pathology for all sites was subsequently obtained by biopsy or surgical resection of the identified lesion (Table 1
Patient characteristics, sites of suspected distant metastases, and results of FDG-PET and histologic review of specimens from each site are listed in Tables 1  and 2 . All patients had undergone prior total (21 patients) or partial (three patients) nephrectomy. All patients had clear-cell carcinoma. Median time interval between initial CT/MRI and PET was 10.5 days (range, 0 to 42 days). After PET scintigraphy, surgery or biopsy was performed at a median of 27.5 days (range, 1 to 69 days).
All PET scans were performed using a Siemens ECAT EXACT HR+ PET scanner (Siemens/CTI, Knoxville, TN). This system provides two-dimensional and three-dimensional acquisition and reconstruction and simultaneously acquires images in 63 planes with a thickness of 2.4 mm over a 15.5 cm axial field-of-view. The intrinsic resolution of the system is 4.5 mm full width of half maximum at the center, and the axial resolution is 5 to 6 mm full width of half maximum. All patients underwent whole-body PET imaging after an overnight fast. Emission scans were obtained 45 to 60 minutes after intravenous administration of an average of 395.9 MBq of FDG (range, 300 to 643 MBq). The initial radiologic investigation that identified the area of suspected metastases was a CT scan, except for two patients who underwent cranial MRI scans to evaluate brain metastases. All CT and MRI scans were performed with intravenous contrast. PET images and CT/MRI scans were initially interpreted by experienced nuclear medicine and radiology staff physicians, respectively, who were aware of the patient’s clinical history and prior radiologic studies. PET scans were reviewed again by two nuclear medicine physicians (J.L.U. and M.H.K.) who were blinded to patient history and results of previous CT/MRI and PET readings. There was no discordance between the initial and repeat PET readings. PET scans were scored as positive or negative for each site of suspected distant metastases identified by CT/MRI scan.
We calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FDG-PET for the detection of distant metastases from RCC. Sensitivity and specificity were calculated as the proportion of patients with or without metastatic disease at surgery who had a positive or negative PET scan, respectively. PPV and NPV were calculated as the proportion of patients with a positive or negative PET scan who had or did not have metastatic disease at surgery, respectively. The
Histologic review of specimens obtained from sites of suspected distant metastases revealed metastatic RCC in 33 sites (21 patients), whereas no tumor was detected in the remaining three sites (three patients). In no case did FDG-PET identify distant metastases that had not been visualized by CT/MRI. FDG uptake was significantly increased in 21 sites (63.6%; true-positive PET), whereas the remaining 12 sites (36.4%) were not metabolically hyperactive (false-negative PET). No false-positive PET scans were observed. False-negative results were seen in the following sites: lung (seven sites), mediastinal lymph nodes (two sites), chest wall (one site), brain (one site), and adrenal gland (one site). Overall sensitivity and specificity of FDG-PET for the detection of distant metastases from RCC identified initially on CT/MRI was 63.6% (21 of 33 sites; 95% CI, 45% to 80%) and 100% (three of three sites), respectively. The PPV, NPV, and accuracy of FDG-PET for the presence of distant metastases was 100%, 20%, and 66.7%, respectively (only three lesions were negative for cancer, and therefore the main focus of the study was sensitivity and PPV; specificity and NPV, however, are also reported for completeness).
Age (
Sensitivity increased as a function of lesion size; sensitivity improved from 63.6% for all lesions to 76% (19 of 25 lesions), 83.3% (15 of 18 lesions), and 92.9% (13 of 14 lesions) for lesions more than 1.0, 1.5, and 2.0 cm in size, respectively. Patients with true-positive FDG-PET had larger metastatic lesions (mean size, 2.2 cm; 95% CI, 1.7 to 2.6 cm) compared with patients with false-negative FDG-PET (mean size, 1.0 cm; 95% CI, 0.7 to 1.4 cm; P = .001). The sensitivity and PPV of FDG-PET in detecting lung metastases from RCC was 63.2% (12 of 19) and 100% (12 of 12), respectively. The mean size of lung metastases in patients with true-positive FDG-PET was 2.0 cm (95% CI, 1.3 to 2.7 cm) compared with 0.8 cm (95% CI, 0.5 to 1.2 cm) in patients with false-negative FDG-PET (P = .01). In one patient with three sites of lung metastases, FDG-PET was read as true-positive in one site and false-negative in the remaining two sites; the sizes of corresponding metastases on CT scan were 2.5 cm, 0.5 cm, and 0.5 cm, respectively (Fig 1
Presence of distant metastases at diagnosis is a strong independent predictor of poor survival in patients with RCC. Patients with metastatic disease have a 5-year survival rate of 0% to 20%.5–7 A 5-year survival rate of 25% to 50% has been reported for patients with solitary metastases from RCC that can be completely resected.17–19 Currently available anatomic imaging techniques have limited accuracy for the detection of distant metastases. The sensitivity of CT scan for detection of lung metastases from extra-thoracic malignancies ranges from 75% to 95% and can be as low as 48% to 69% for metastases less than 6 mm in size.20,21 FDG-PET has been reported to be superior to conventional anatomic imaging modalities for detecting distant metastases from various tumor sites, such as the breast, lung, and esophagus.14–16 The overall sensitivity and specificity of FDG-PET for detection of primary RCC has been reported to range from 31% to 95% and 33% to 90%, respectively.22–25 FDG-PET has not been extensively studied for the evaluation of distant metastases from RCC. Reported studies of FDG-PET in metastatic RCC have involved few patients, and most series have compared the results of FDG-PET with clinical outcome determined by follow-up with conventional anatomic radiologic techniques; moreover, pathologic confirmation of metastatic disease, if performed, was usually combined with radiologic follow-up for reporting results. In a study reported by Ramdave et al, 25 FDG-PET identified distant metastases from RCC in six of six patients evaluated for possible metastatic disease. Presence of metastatic disease was confirmed by pathology (fine-needle aspiration cytology) in only one of these six patients. In the same study, FDG-PET detected unsuspected metastatic disease not seen on CT in two of 17 patients evaluated for primary RCC. Metastatic disease was confirmed by biopsy at laparotomy in only one of these cases. In another study by Brouwers et al,26 among 20 patients of RCC with 112 distant metastatic lesions evaluated by FDG scintigraphy and followed clinically, FDG-PET detected 69% (77 of 112) of the metastatic lesions. Of these, 32 lesions had not been detected by routine imaging modalities. The results of CT and FDG-PET for detecting distant metastases from RCC were comparable, with sensitivities of 70% and 69%, respectively. Using FDG-PET for restaging 36 patients with advanced RCC, Safaei et al27 demonstrated a sensitivity and specificity of 87% and 100%, respectively. From their cohort, 25 suspicious lesions from 20 patients were biopsied. FDG-PET accurately identified 84% (21 of 25) of the biopsied lesions. FDG-PET had an overall diagnostic accuracy of 89% for restaging residual/recurrent RCC. We observed the sensitivity and PPV of FDG-PET for the detection of distant metastases from RCC to be 63.6% and 100%, respectively. PPV, however, is in part a function of both the prevalence of metastatic disease in this population and the specificity of PET. Neither quantity could be reliably estimated in the present study; therefore, the 100% PPV must be viewed cautiously and may not be generalizable to other studies. Nevertheless, although we did not find FDG-PET to be a highly sensitive test for detecting metastatic RCC, the high PPV indicates that it might find an application in the evaluation of patients with metastatic lesions that cannot be accurately characterized by anatomic radiologic imaging techniques. For example, we observed FDG-PET to be more sensitive for imaging larger lesions (sensitivity was 83.3% for lesions > 1.5 cm and 92.9% for lesions > 2.0 cm in size). Again, true-positive lesions were larger in size (mean size, 2.2 cm) compared with false-negative lesions (mean size, 1.0 cm). Therefore, FDG-PET may be useful as an imaging modality complementary to CT in the evaluation of distant metastases from RCC, especially for lesions greater than 1.5 cm in size. In patients with metastatic RCC identified by anatomic radiologic imaging techniques, a positive FDG-PET, particularly for large lesions (> 1.5 cm), could obviate the need for pathologic confirmation of disease. However, FDG-PET may not accurately characterize small lesions (< 1.0 cm). Depending on the clinical scenario, biopsy is needed to evaluate for the presence of metastatic RCC in such lesions, especially if the FDG-PET is negative. Although our study was not designed to compare FDG-PET with conventional anatomic imaging techniques, CT/MRI accurately identified 33 (91.6%) of 36 suspected distant metastases initially detected by these modalities. CT also correctly detected seven lung lesions less than 1.3 cm in size that were missed by FDG-PET. Because of our study design, we could not determine whether patients with true-positive FDG-PET had more aggressive tumors and poorer outcome compared with those with false-negative FDG-PET. There is increasing evidence to suggest that FDG-PET may provide important prognostic information, and reduction or resolution of FDG uptake in the tumor is an early indicator of response at a clinical or subclinical level.28 FDG accumulation depends on the rate of transport through the cell membrane and has been shown to be mediated by a family of glucose transporters (GLUT). Significantly elevated expression of GLUT-1 is considered to be a factor contributing to the increased accumulation of FDG in malignant tumors and has been shown to be correlated with tumor invasiveness and poor survival in various cancer sites.29–34 The role of GLUT-1 expression in RCC is still evolving. Miyauchi et al24 observed primary RCC well visualized by FDG-PET to have higher GLUT-1 expression, higher grade, and larger size than poorly imaged tumors. However, other investigators have reported no correlation between GLUT-1 immunoreactivity and tumor grade or FDG-PET positivity.22,35 We did not examine the expression of GLUT-1 in resected tumor specimens. Whether tumor size correlates with GLUT-1 expression and overall outcome in metastatic RCC is a potential area for further investigation. Our study has the inherent limitations of a retrospective study. However, blinding the reader interpreting the PET scans to patient data should have diminished significantly potential bias in PET reporting. Comparison of the roles of anatomic imaging techniques and FDG-PET in RCC patients was not possible given the retrospective nature of our study. Overall, FDG-PET scintigraphy is not a very sensitive imaging modality for the evaluation of metastatic RCC and may not adequately characterize small metastatic lesions. However, positive FDG-PET is predictive for the presence of RCC in lesions imaged, may complement anatomic radiologic imaging modalities, and may alleviate the need for a biopsy in selected situations. A negative FDG-PET, however, does not rule out active malignancy. The role of FDG-PET in other histologic types of RCC and for staging patients with RCC needs to be further explored and validated in clinical trials.
The authors indicated no potential conflicts of interest.
1. Kubota K: From tumor biology to clinical Pet: a review of positron emission tomography (PET) in oncology. Ann Nucl Med 15:471–486, 2001[Medline] 2. Weber WA, Schwaiger M, Avril N: Quantitative assessment of tumor metabolism using FDG-PET imaging. Nucl Med Biol 27:683–687, 2000[CrossRef][Medline] 3. Scott AM: Current status of positron emission tomography in oncology. Australas Radiol 46:154–162, 2002[CrossRef][Medline] 4. Hustinx R, Benard F, Alavi A: Whole-body FDG-PET imaging in the management of patients with cancer. Semin Nucl Med 32:35–46, 2002[CrossRef][Medline] 5. Ficarro V, Righetti R, Pilloni S, et al: Prognostic factors in patients with renal cell carcinoma: Retrospective analysis of 675 cases. Eur Urol 41:190–198, 2002[CrossRef][Medline] 6. Tsui KH, Shvarts O, Smith RB, et al: Prognostic indicators for renal cell carcinoma: A multivariate analysis of 643 patients using the revised 1997 TNM staging criteria. J Urol 163:1090–1095, 2000[CrossRef][Medline] 7. McNichols DW, Segura JW, DeWeerd JH: Renal cell carcinoma: Long-term survival and late recurrence. J Urol 126:17–23, 1981[Medline] 8. Bechtold RE, Zagoria RJ: Imaging approach to staging of renal cell carcinoma. Urol Clin North Am 24:507–522, 1997[CrossRef][Medline] 9. Levine E: Renal cell carcinoma: Clinical aspects, imaging diagnosis, and staging. Semin Roentgenol 30:128–148, 1995[CrossRef][Medline]
10. Zagoria RJ, Bechtold RE, Dyer RB: Staging of renal adenocarcinoma: Role of various imaging procedures. AJR Am J Roentgenol 164:363–370, 1995
11. Gambhir SS, Hoh CK, Phelps ME, et al: Decision tree sensitivity analysis for cost-effectiveness of FDG-PET in the staging and management of non-small-cell lung carcinoma. J Nucl Med 37:1428–1436, 1996
12. Kim K, Park SJ, Kim BT, et al: Evaluation of lymph node metastases in squamous cell carcinoma of the esophagus with positron emission tomography. Ann Thorac Surg 71:290–294, 2001 13. Kim TS, Moon WK, Lee DS, et al: Fluorodeoxyglucose positron emission tomography for detection of recurrent or metastatic breast cancer. World J Surg 25:829–834, 2001[CrossRef][Medline]
14. Luketich JD, Friedman DM, Weigel TL, et al: Evaluation of distant metastases in esophageal cancer: 100 consecutive positron emission tomography scans. Ann Thorac Surg 68:1133–1136, 1999 15. Eschmann SM, Friedel G, Paulsen F, et al: FDG-PET for staging of advanced non-small cell lung cancer prior to neoadjuvant radio-chemotherapy. Eur J Nucl Med Mol Imaging 29:804–808, 2002[CrossRef][Medline] 16. Dose J, Bleckmann C, Bachmann S, et al: Comparison of fluorodeoxyglucose positron emission tomography and "conventional diagnostic procedures" for the detection of distant metastases in breast cancer patients. Nucl Med Commun 23:857–864, 2002[CrossRef][Medline] 17. Kavolius JP, Mastorakos DP, Pavlovich C, et al: Resection of metastatic renal cell carcinoma. J Clin Oncol 16:2261–2266, 1998[Abstract] 18. Kierney PC, van Heerden JA, Segura JW, et al: Surgeon’s role in the management of solitary renal cell carcinoma metastases occurring subsequent to initial curative nephrectomy: An institutional review. Ann Surg Oncol 1:345–352, 1994[CrossRef][Medline] 19. Tongaonkar HB, Kulkarni JN, Kamat MR: Solitary metastases from renal cell carcinoma: A review. J Surg Oncol 49:45–48, 1992[Medline]
20. Margaritora S, Porziella V, D’Andrilli A, et al: Pulmonary metastases: Can accurate radiological evaluation avoid thoracotomic approach? Eur J Cardiothorac Surg 21:1111–1114, 2002
21. Diederich S, Semik M, Lentschig MG, et al: Helical CT of pulmonary nodules in patients with extrathoracic malignancy: CT-surgical correlation. AJR Am J Roentgenol 172:353–360, 1999 22. Miyakita H, Tokunaga M, Onda H, et al: Significance of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for detection of renal cell carcinoma and immunohistochemical glucose transporter 1 (GLUT-1) expression in cancer. Int J Urol 9:15–18, 2002[CrossRef][Medline] 23. Bachor R, Kotzerke J, Gottfried HW, et al: Positron emission tomography in diagnosis of renal cell carcinoma. Urologe 35:146–150, 1996[Medline] 24. Miyauchi T, Brown RS, Grossman HB, et al: Correlation between visualization of primary renal cell cancer by FDG-PET and histopathological findings. J Nucl Med37:64P, 1996 (suppl, abstr 245) 25. Ramdave S, Thomas GW, Berlangieri SU, et al: Clinical role of F-18 fluorodeoxyglucose positron emission tomography for detection and management of renal cell carcinoma. J Urol 166:825–830, 2001[CrossRef][Medline] 26. Brouwers AH, Dorr U, Lang O, et al: 131I-cG250 monoclonal antibody immunoscintigraphy versus [18F] FDG-PET imaging in patients with metastatic renal cell carcinoma: A comparative study. Nucl Med Commun 23:229–236, 2002[CrossRef][Medline] 27. Safaei A, Figlin R, Hoh CK, et al: The usefulness of F-18 deoxyglucose whole-body positron emission tomography (PET) for re-staging of renal cell cancer. Clin Nephrol 57:56–62, 2002[Medline]
28. Kostakoglu L, Goldsmith SJ: 18F-FDG-PET evaluation of the response to therapy for lymphoma and for breast, lung, and colorectal carcinoma. J Nucl Med 44:224–239, 2003 29. Smith TA: The rate-limiting step for tumor [18F]fluoro-2-deoxy-D-glucose (FDG) incorporation. Nucl Med Biol 28:1–4, 2001[CrossRef][Medline]
30. Ito S, Fukusato T, Nemoto T, et al: Coexpression of glucose transporter 1 and matrix metalloproteinase-2 in human cancers. J Natl Cancer Inst 94:1080–1091, 2002 31. Younes M, Juarez D, Lechago LV, et al: Glut 1 expression in transitional cell carcinoma of the urinary bladder is associated with poor patient survival. Anticancer Res 21:575–578, 2001[Medline] 32. Younes M, Brown RW, Stephenson M, et al: Over-expression of Glut1 and Glut3 in stage I non-small cell lung carcinoma is associated with poor survival. Cancer 80:1046–1051, 1997[CrossRef][Medline] 33. Kawamura T, Kusakabe T, Sugino T, et al: Expression of glucose transporter-1 in human gastric carcinoma: Association with tumor aggressiveness, metastasis, and patient survival. Cancer 92:634–641, 2001[CrossRef][Medline] 34. Younes M, Brown RW, Mody DR, et al: GLUT1 expression in human breast carcinoma: Correlation with known prognostic markers. Anticancer Res 15:2895–2898, 1995[Medline] 35. Nagase Y, Takata K, Moriyama N, et al: Immunohistochemical localization of glucose transporters in human renal cell carcinoma. J Urol 153:798–801, 1995[CrossRef][Medline] Submitted April 8, 2003; accepted May 29, 2003.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
2 test or the t test, as appropriate, was used to detect differences between patients with true-positive and false-negative FDG-PET. Statistical analysis was done using NCSS 2000 software (NCSS Statistical Software, Kaysville, UT). A P value of less than .05 was considered to be significant. 
60 years v > 60 years; P = .69), sex (male v female; P = .58), initial Fuhrman grade (grade 1 and 2 v grade 3 and 4; P = .14), prior biologic or chemotherapy (received v not received; P = .69), survival free of distant metastases (
