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Nuclear Medicine |
1 From the Departments of Nuclear Medicine (M.J.R., S.H., M.M., E.M., T.M.K.), Diagnostic Radiology (C.E.B.), Gynecology and Obstetrics (D.V.), and the Institute of Pathology (C.I.), University Hospital of Freiburg, Germany. Received February 22, 2000; revision requested April 8; revision received July 25; accepted August 29. Address correspondence to M.J.R., Department of Nuclear Medicine, University Hospital of Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany (e-mail: michael.reinhardt@meb.uni-bonn.de).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Before radical hysterectomy and pelvic lymphadenectomy in 35 patients with International Federation of Gynecology and Obstetrics stage IB or II cervical cancer, abdominal FDG-PET and MR imaging were performed. Malignancy criteria were a lymph node diameter of 1 cm or more at MR imaging and a focally increased FDG uptake at PET. The findings of FDG-PET and MR imaging were compared with histologic findings.
RESULTS: Histologic examination revealed pN0-stage cancer in 24 patients and pN1-stage cancer in 11 patients. On a patient basis, node staging resulted in sensitivities of 0.91 with FDG-PET and 0.73 with MR imaging and specificities of 1.00 with FDG-PET and 0.83 with MR imaging. The positive predictive value (PPV) of FDG-PET was 1.00 and that of MR imaging, 0.67 (not significant). The metastatic involvement of lymph node sites was identified at FDG-PET with a PPV of 0.90; at MR imaging, 0.64 (P < .05, Fisher exact test).
CONCLUSION: Metabolic imaging with FDG-PET is an alternative to morphologic MR imaging for detecting metastatic lymph nodes in patients with cervical cancer.
Index terms: Lymphatic system, MR, 80.121411, 994.33 • Lymphatic system, neoplasms, 994.33 • Positron emission tomography (PET), 80.12163 • Uterine neoplasms, 859.322, 859.324, 859.329
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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The overall survival rates of patients treated with radical hysterectomy and pelvic lymphadenectomy decrease from 85%–90% with stage IB (tumor confined to the cervix) to 65% with stage II (tumor extends beyond the cervix but not onto the pelvic wall) disease (3). This decrease may be due in part to the increasing incidence of pelvic and paraaortic lymph node metastasis observed with increase in stage (3). Investigators in several studies (4–7) have found that a subset of patients with clinical stage IB and lymph node metastasis have reduced survival rates of 45%–55%. Even with stages IIA and IIB, the survival rate is correlated with the number of pelvic lymph nodes involved (8–10). Many clinicians perform lymphangiography, computed tomography (CT), or magnetic resonance (MR) imaging to evaluate regional nodes, but the accuracy of these studies is compromised because they fail to depict small metastases, and patients with bulky necrotic tumors often have enlarged reactive lymph nodes (3). The FigO states that findings of examinations such as lymphangiography are of value in planning therapy, but because these examinations are not yet generally available and the interpretation of results is variable, they should not be the basis for changing the clinical stage.
A recent meta-analysis of 38 studies that fulfilled stringent inclusion criteria (11) showed just a trend toward higher Q* values for MR imaging (0.85) and CT (0.85) than for lymphangiography (0.74), which did not reach the level of significance. Q* corresponds to the point on the summary receiver operating characteristic curves at which sensitivity and specificity are equal. It was concluded that the noninvasive detection of nodal disease remains a difficult task. However, identification of a sensitive and specific imaging modality would be a useful adjunct to the clinical evaluation of cervical cancer, because it might improve individual therapy planning.
Another approach to the noninvasive detection of nodal disease is functional imaging with positron emission tomography (PET) by using 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG). Investigators in previous studies have found FDG-PET to be useful for depicting squamous and nonsquamous histologic findings at other sites, which include the head, neck, and lung (12,13). The purpose of the present study was to compare the diagnostic accuracy of MR imaging with that of PET using FDG for detecting metastatic lymph nodes in patients with cervical cancer.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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The FigO scheme for preoperative staging included a detailed physical examination, with bimanual and rectovaginal palpation of the pelvic organs, abdominal and endovaginal ultrasonography, intravenous urography, and chest radiography. In accordance with the findings of these procedures, 21 patients had FigO stage IB disease; and 14 patients, FigO stage IIA disease. Radical surgery (class III hysterectomy and pelvic lymphadenectomy) was performed in all patients (14). This included the removal of all lymph nodes from the common, external, and internal iliac vessels and the obturator fossa nodes. The paraaortic nodes were dissected when they were thought to be suspicious for malignancy at intraoperative palpation and/or when they were enlarged at MR imaging. Because the difference between stage IIA and IIB disease is the absence (IIA) or presence (IIB) of parametrial involvement, and because surgical findings often do not agree with clinical estimates of parametrial involvement (15), eight of the 14 patients with stage IIA disease actually had stage IIB disease at histologic examination of the resected material. The tumor cell type and grading were considered for exact characterization of the study collective.
MR Imaging
MR imaging of the pelvis and abdomen was performed with a 1.5-T system (Magnetom Vision; Siemens, Erlangen, Germany). A phased-array body coil with a 50-cm transverse field of view was used. Sagittal T2- and transverse T1- and T2-weighted images were obtained. Additional coronal images were obtained in cases in which the pelvic abnormality could not be reliably assessed in transverse and sagittal planes. For T2-weighted turbo spin-echo imaging (turbo factor 15), repetition times in msec/echo times in msec were 4,500–4,700/120; and for T1-weighted spin-echo imaging, 500–600/12–15. The matrix size was 512 x 180–240 pixels. The section thickness was 7 mm for transverse and 6 mm for sagittal and coronal planes. No gadolinium-based contrast material was administered and no fat-saturated images were obtained.
PET Imaging
FDG was synthesized as reported previously (16,17). PET was performed by using a dedicated system (Ecat Exact 921; Siemens), with a 10.8-cm transverse field of view and a two-dimensional acquisition mode. Three- to 8-minute transmission scans and 9-minute emission scans were obtained. Four or five bed positions were used to cover the area from the proximal femora to the apex of the liver. Patient preparation included overnight fasting, with a blood glucose level of less than 130 mg/dL (7.2 mmol/L) before FDG injection, and continuous irrigation of the urinary bladder during PET by using a Foley catheter (Beiersdorf AG, Hamburg, Germany). Emission scanning was performed 100 minutes ± 20 after intravenous injection of 5 MBq of FDG per kilogram of body weight (370 MBq ± 50), with a minimum of 300 MBq and a maximum of 500 MBq of FDG. Images were reconstructed iteratively in transverse, coronal, and sagittal planes by means of an ordered-subset expectation-maximization algorithm and segmented photon-absorption correction (18,19).
Image Evaluation and Data Analysis
MR images were interpreted with consensus reading by three experienced investigators who did not know the results of FDG-PET (including C.E.B. and S.H.). The criterion for malignancy on MR images was a pelvic or paraaortic lymph node diameter of 1 cm or more. The process of evaluation for PET images was the same as that for MR images, but the investigators (M.J.R., T.M.K., and a third individual) were different. Focal increased FDG uptake, which could be detected in pelvic or paraaortic lymph node sites, was considered to indicate malignancy. After evaluating MR imaging and FDG-PET findings separately, morphologic and functional imaging findings were compared with histologic findings in all patients with regard to the detection of lymph node metastasis and the number of metastatic lymph node sites. Eight lymph node sites in the pelvis bilaterally covered the lymph nodes of the common, external, and internal iliac vessels and the obturator fossae lymph nodes, which are among the primary node sites and the most frequently involved in cervical cancer. Paraaortic lymph nodes were removed in 12 of 35 patients and assigned as the ninth site of lymph node metastasis. Thus, a total of 292 lymph node sites were evaluated in 35 patients.
MR and PET images were classified on the basis of histologic findings as true-positive, true-negative, false-positive, or false-negative. Sensitivity, specificity, positive predictive value (PPV), negative predictive value, and accuracy were calculated on a patient and lymph node site basis. Statistical proportions were compared by performing the Fisher exact test (20).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Tomographic studies with CT and MR imaging are frequently performed for noninvasive detection of metastatic cancer in the pelvic lymph nodes (11). However, one limitation of these techniques must be considered: It is impossible to differentiate metastatic nodes from nonmetastatic hyperplastic nodes of similar size. In the presented study, 16 (41%) of 39 enlarged lymph nodes did not contain metastasis. Although there have been several MR imaging studies in which different relaxation times or special contrast media enhancement was used to differentiate metastatic from hyperplastic nodes (26–29), the only CT and MR imaging criterion that is generally accepted in the evaluation of pelvic node metastases is the size of the node (29). Size criteria of 1–2 cm have been reported in the literature (11). In the past decade, a 1-cm diameter has become the preferred criterion (30), as either the maximum or minimum transverse diameter (31). By using this criterion, the reported sensitivity of MR imaging was 0.38–0.89, whereas the specificity was 0.78–0.99 (11,30–32). These results could not be further improved, even by means of a circular polarized phased-array body coil and contrast material enhancement (32). By using a similar technique in the current study, the MR imaging sensitivity of 0.73 and specificity of 0.83 on a patient basis were in the upper range reported in the literature (11,30–32). These results were obtained without administering gadolinium-based contrast material or performing fat-saturated sequences. Even before surgery in patients with gastric cancer, T2-weighted fast spin-echo sequences without gadolinium enhancement have been useful in the detection of regional lymph node metastases (33).
However, MR imaging resolution is better than it seems, according to the statistical values. Six of nine false-negative lymph nodes were seen at MR imaging in the current study but were not rated as abnormal because they were less than 1 cm in diameter. Only three micrometastases were not identified at MR imaging.
Investigators in two recent studies that involved the comparison of FDG-PET with CT (34) and surgical staging (35) for detecting lymph node metastasis in patients with cervical cancer have suggested a possible role of functional imaging for this purpose. Sugawara et al (34) reported a 0.86 sensitivity of FDG-PET for pelvic and paraaortic lymph node metastasis, as compared with a 0.57 sensitivity of CT in a study of 21 patients with cervical cancer of stages IB to IVA. Rose et al (35) reported a sensitivity and specificity of 0.75 and 0.92, respectively, for FDG-PET in depicting paraaortic lymph node metastasis in a study of 32 patients with cervical cancer of stages IIB to IVA before surgical staging lymphadenectomy. These authors observed a higher sensitivity of FDG-PET for pelvic (1.00) than for paraaortic (0.75) lymph node metastases. In the presented series of patients, most false-negative nodes were observed in the pelvis (Table 2). In the study by Rose et al (35), this difference was most likely due to the patients with more advanced stages of disease, whereas in the present study, we focused on patients with early-stage cervical cancer.
The limitations of whole-body FDG-PET studies concern the anatomic and spatial resolution, which is lower than that with either CT or MR imaging. To improve the anatomic resolution of whole-body PET, a combination of FDG and fluoride in the same study has been suggested (36). Whether this two-in-one approach should be applied to PET in patients with cervical cancer remains to be studied. Although the spatial resolution of PET is lower than that of CT and MR imaging, the differentiation capability for malignant lesions at FDG-PET is not compromised by using morphologic size criteria. Even malignant lesions less than 1 cm in diameter that manifest as high FDG uptake can be differentiated from nonmalignant tissue at PET. Thus, FDG-PET depicted as metastatic three of six lymph nodes that were not abnormally enlarged on MR images. However, micrometastasis may be missed on FDG-PET images as well.
When performing abdominal PET studies, further problems may occur. Because of the urinary excretion of FDG, radioactivity is greatest in the bladder, and some focal accumulation can be seen in the renal pelvis and along the ureter. Retrograde saline irrigation and vigorous hydration, which includes administration of furosemide, have recently been suggested to overcome this problem (37). In the current study, continuous irrigation of the bladder by using a Foley catheter and slight peroral hydration were satisfactory to differentiate metastatic and urinary FDG uptake in the pelvis. The only two false-positive foci on FDG-PET images were caused by granulomatous changes in lymph nodes that were induced by previous lymphangiography.
Physiologic FDG accumulation can, to some extent, be further seen in the bowel; this situation might complicate the differentiation of malignant foci. It cannot be denied that the interpretation of abdominal PET images requires a certain degree of experience when performed without the corresponding MR images. The application of segmented attenuation correction seems to improve image quality and made differentiation of abnormal and physiologic FDG accumulation easier (19). In our experience, on the basis of repeated discussions with colleagues from clinical departments when presenting FDG-PET images, the application of attenuation correction gains more relevance when FDG-PET images are reviewed without the corresponding MR images. However, there is a continuing discussion of the necessity of attenuation correction on PET images; to our knowledge, no final agreement has yet been reached (38).
In the present study, the results of both functional and morphologic cross-sectional imaging were compared with the intraoperative findings so that a single enlarged lymph node or hypermetabolic focus could most likely be assigned to a certain lymph node site. It has been argued that calculating statistical values on a patient basis might be correct for the wrong reason (30,31). For example, a patient might present with enlarged lymph nodes that are not metastatic at one site but have small metastases that were not detected at other sites. As the present comparison shows, this applied to both FDG-PET and MR imaging. Six of 21 metastatic lymph node sites in five patients (patients 17, 23, 31, 34, and 35) were not identified on MR (patients 23, 31, and 35) or FDG-PET (patients 17, 34, and 35) images, but the images were valued as positive for lymph node metastasis because other areas of lymph node involvement had been seen or supposed. Thus, it seems reasonable to calculate statistical values on a patient and lymph node chain basis.
However, such a differentiated approach is less practical in a typical clinical situation. Without the histologic information obtained from an extensive lymph node dissection, a rougher subdivision of pelvic nodes might be useful (31). For adequate therapy planning, two items regarding the status of lymph node metastasis may be most important: first, whether there are lymph node metastases in a patient; and second, whether these are localized in the pelvis or around the aorta; such locations would require expansion of the field of radiation. For both questions, the PPV may be the most important statistical measure. Whereas the difference in PPV between FDG-PET and MR imaging was not significant for the first question (patient basis), it became significant for the second (lymph node site basis). Here, a PPV of 0.90 for FDG-PET contrasted with that of 0.64 for MR imaging (P < .05, Fisher exact test). Thus, if there is a focal accumulation of FDG on FDG-PET images in a certain lymph node site, then the probability is high that there is in fact a lymph node metastasis and that this area should be included in the field of radiation or surgically removed. The delineation of the extent of metastatic disease gains increasing relevance when primary therapy includes irradiation of pelvic and/or paraaortic lymph nodes (39).
Because assessment of the extent of lymph node metastasis may be essential for therapy planning, patients might benefit from more frequent use of FDG-PET. Further studies are needed to show whether determination of the extent of metastatic disease with FDG-PET in patients with cervical cancer and a subsequent adaptation of the field of radiation might influence the prognosis in more advanced stages. The data presented suggest that FDG-PET is a reliable alternative to MR imaging for lymph node staging in patients with cervical cancer.
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, M.J.R., T.M.K., E.M.; study concepts and design, M.J.R.; definition of intellectual content, M.J.R., T.M.K., E.M.; literature research, M.J.R.; clinical studies, M.M., S.H., C.I., M.J.R., C.E.B., D.V.; data acquisition, D.I., S.H., M.M., M.J.R., C.E.B., D.V.; data analysis, M.J.R., C.E.B., D.V., C.I., S.H., M.M., T.M.K.; statistical analysis, M.J.R.; manuscript preparation, M.J.R., C.E.B., D.V.; manuscript editing, M.J.R.; manuscript review, all authors.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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