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Nuclear Medicine |
1 From the School of Medicine, University of Milano-Bicocca, Milan, Italy (S.S., R.M., C. Mangioni, C. Messa, F.F.); IBFM-CNR, Institute for Molecular Bioimaging and Physiology, Milan, Italy (S.S., C. Messa, F.F.); Departments of Diagnostic Radiology (S.S.), Gynecology and Obstetrics (A.B., A.P., M.C., C. Mangioni), and Pathology (P.P.), H S. Gerardo Monza, Milan, Italy; and Department of Nuclear Medicine, Institute H S. Raffaele, Via Olgettina 60, 20132 Milan, Italy (M.P., C. Messa, F.F.). Received October 20, 2004; revision requested December 23; revision received January 26, 2005; accepted February 24. Address correspondence to F.F. (e-mail: fazio.ferruccio{at}hsr.it).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Materials and Methods: The study was institutional review board approved, and all patients gave informed consent. Forty-seven consecutive women aged 29–71 years with clinical stage IA or IB cervical carcinoma were included in the study. All 47 patients were scheduled for radical hysterectomy with pelvic lymph node dissection. Before surgery, all patients underwent fluorine 18 fluorodeoxyglucose (FDG) PET/CT. PET/CT findings were interpreted by two readers in consensus and then compared with histopathologic results. At histopathologic examination, the dissected lymph nodes were classified as nonmetastatic or metastatic.
Results: Fifteen (32%) patients had metastatic lymph nodes at histopathologic examination, and 32 (68%) had no histopathologically confirmed nodal metastasis. Of the total 1081 lymph nodes histopathologically sampled, 18 were found to be positive for malignant cells. The overall node-based sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of PET/CT were 72% (13 of 18), 99.7% (1060 of 1063), 81% (13 of 16), 99.5% (1060 of 1065), and 99.3% (1073 of 1081), respectively. Corresponding values for PET/CT-based diagnosis of lymph nodes larger than 0.5 cm in diameter were 100% (13 of 13), 99.6% (675 of 678), 81% (13 of 16), 100% (675 of 675), and 99.6% (688 of 691), respectively. The overall patient-based sensitivity, specificity, PPV, NPV, and accuracy of PET/CT were 73% (11 of 15), 97% (31 of 32), 92% (11 of 12), 89% (31 of 35), and 89% (42 of 47), respectively.
Conclusion: PET/CT proved to be valuable for lymph node staging in patients with early-stage cervical cancer, with short-axis diameter greater than 0.5 cm being the size threshold for accurate depiction of metastatic nodes.
© RSNA, 2005
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Computed tomography (CT) and magnetic resonance (MR) imaging are the imaging modalities used most often to noninvasively define the status of regional lymph nodes (13–24). The identification of metastatic lymph nodes with both CT and MR imaging is based on measurements of node size, with greater than 1 cm short-axis diameter being the most accepted criterion for the diagnosis of cancer involvement (13–18). However, the limitations of this size-based characterization system are well known: Metastases in normal-sized lymph nodes can be missed and reactive lymph node enlargement cannot be reliably differentiated from cancer infiltration at either CT or MR imaging (19–24). Therefore, the detection of lymph node metastasis with use of morphologic imaging modalities remains difficult.
In contrast to CT and MR imaging, positron emission tomography (PET) with the radiolabeled glucose analogue fluorine 18 fluorodeoxyglucose (FDG) is a functional method based on the increased glucose metabolism of malignant tumors. Because FDG PET can reveal the biochemical differences between normal and malignant tissues, it has been shown to be effective in the identification of different primary and metastatic tumor types (25). Although FDG PET yields limited information on the exact anatomic location of the lesion detected, it has proved to be of value for the noninvasive assessment of metastatic lymph node disease. Investigators in previous studies (26–30) have evaluated the role of FDG PET in the detection of lymph node metastasis in patients with cervical cancer mainly by comparing imaging findings with surgical or clinical follow-up findings. Histopathologic correlation has been available in only a few studies.
PET/CT, in which a full-ring-detector clinical PET scanner and a multi–detector row helical CT scanner are combined, has been introduced into clinical practice (31–33). The two scanners are aligned, and anatomically coregistered images are obtained by using computer hardware. Thus, one of the key advantages of using integrated PET/CT rather than PET alone is the capability for improved anatomic localization of foci with elevated tracer uptake (34). Initial results with this combined imaging modality have been promising, and its potential in clinical cancer staging has been recognized (35–37). Thus, the purpose of our study was to prospectively determine the accuracy of PET/CT for lymph node staging in patients with early-stage cervical cancer, with histopathologic results as the reference standard.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Our FIGO protocol for preoperative staging included a detailed physical examination, abdominal and endovaginal ultrasonography, intravenous urography, and chest radiography. According to the findings of these procedures, the FIGO clinical stages of cancer in our patient population at initial diagnosis were IA1 in four patients, IB1 in 35 patients, and IB2 in the remaining eight patients. Cancer types were squamous cell carcinoma in 37 and adenocarcinoma in 10 patients. There were 25 grade 3 (poorly differentiated), 16 grade 2 (moderately differentiated), and six grade 1 (highly differentiated) tumors.
After their disease was clinically staged, all patients enrolled in the study underwent PET/CT and were subsequently scheduled for surgery. Six of the eight patients with a clinical stage IB2 tumor also underwent neoadjuvant chemotherapy before undergoing PET/CT and surgery. The time interval between PET/CT and surgical treatment was 7–16 days (mean, 12.5 days).
Integrated PET/CT Imaging
All imaging and data acquisitions were performed with a combined PET/CT in-line system (CTi/CPS Reveal-HD; CTi PET Systems, Knoxville, Tenn) that enables the acquisition of coregistered CT and PET images in the same patient during one imaging session. A PET scanner (CTi PET HRT; CTi PET Systems) and a multi–detector row helical CT scanner (Emotion Dual Slice CT; Siemens, Erlangen, Germany) were integrated in this dedicated system. The axes of the two systems were mechanically aligned so that by shifting the examination table by 60 cm the patient was moved from the CT gantry into the PET gantry. The resulting PET and CT images were coregistered by using computer hardware (with CTi/CPS Reveal-HD unit). The patients fasted for at least 6 hours before receiving 10 mCi (370 MBq) of FDG intravenously. In addition, they were orally hydrated with 500 mL of water during the FDG uptake period and were asked to empty their bladders before being positioned for PET/CT imaging.
The combined examination started 45 minutes after the FDG injection. CT data were acquired first. Unenhanced CT images were obtained by using a standardized protocol involving 140 kV, 80 mA, a tube rotation time of 0.5 second per revolution, a pitch of 6, a section thickness of 5 mm (to match the section thickness of the PET images), and an acquisition time of 22 seconds. CT images were acquired during the patient's shallow breathing, and the scanned region included the area from the head to the pelvic floor. No oral or intravenous contrast agent was administered. Immediately after CT scanning, PET imaging of a region encompassing an axial field of view identical to that used in CT scanning was performed. The acquisition time for PET was 4 minutes per table position. Because six incremental table positions were used, the PET examination lasted a total of 24 minutes. PET images were acquired during the patient's shallow breathing. Attenuation was corrected by using the CT images: The CT attenuation values (in Hounsfield units) were transformed into linear attenuation coefficients for an electromotive force of 511 KeV of radiation energy. The image reconstruction matrix was 128 x 128 with a transverse field of view of 49.7 x 49.7 cm. The PET component of the scanner had an in-plane spatial resolution of 4.7 mm.
Image Analyses
The images were prospectively evaluated by a review team whose members were aware of the results of only the initial diagnostic assessment, which included histopathologic confirmation of cervical cancer and the clinical stage of the disease, as determined on the basis of the FIGO scheme for preoperative staging. The review team interpreted the PET/CT imaging findings in consensus and consisted of a radiologic physician (S.S.) with 15 years of CT experience and a nuclear medicine physician (C. Messa) with 15 years of PET experience.
The image analyses were performed as follows: Attenuation-corrected PET images, CT images, and coregistered PET/CT images were displayed together on the monitor, and the PET/CT findings were analyzed as a single data set by both reviewers. The presence of abnormal (ie, suspicious for malignancy) FDG uptake was indicated when accumulation of the tracer was moderately to markedly increased relative to the uptake in comparable normal structures or surrounding tissues, with the exclusion of physiologic bowel and urinary activity. The PET/CT results were then reported in terms of whether abnormal FDG uptake was present. When abnormal uptake was present, its exact anatomic location was indicated on the basis of CT findings.
Thus, the diagnosis of cancer-positive lymph node on PET/CT images was based on the presence of focal increased FDG uptake on PET images, in a location that corresponded to lymph node chains on CT images. At PET/CT, lymph nodes with increased tracer uptake were deemed positive for metastatic spread, even when they were smaller than 1 cm in short-axis diameter. Conversely, lymph nodes with no detectable tracer uptake were deemed negative for metastatic spread, even when they were larger than 1 cm in short-axis diameter. This method of PET/CT image analysis was derived from previous studies, in which this combined imaging technique was used for lymph node staging in lung cancer (35,36).
At PET/CT, eight lymph node sites in the pelvis were considered: The lymph nodes of the common, external, and internal iliac vessels and the obturator fossa lymph nodes, which are among the most frequently involved lymph nodes in cervical cancer, were assessed bilaterally. All data sets were analyzed at a workstation (Systrium Technologies, Minneapolis, Minn) capable of providing multiplanar reformations and any appropriate window and level settings. Semiquantitative analysis to determine a standardized value of FDG uptake in the nodal lesions was not performed, because it has been shown that the calculation of standardized uptake values may be of little help in characterizing lymph node lesions (26).
Surgical Procedure
Surgery—specifically, Wertheim or type II Piver-Rutledge radical hysterectomy with bilateral pelvic lymphadenectomy—was performed in all patients, regardless of the PET/CT imaging results. In all patients, the dissected pelvic lymph nodes included the common iliac, external iliac, internal iliac, and obturator fossa nodes on both sides. The surgical procedure was performed in a gynecologic oncology unit by two dedicated surgeons (A.P., M.C.) with more than 20 years of experience.
Nodal Matching between PET/CT and Histopathologic Findings
To ensure that the lymph nodes analyzed by the pathologist (P.P.) were those that were previously assessed with PET/CT, we carefully verified that the surgically resected specimens corresponded to each of the eight pelvic lymph node sites evaluated at PET/CT. Then, each surgical specimen, which was labeled by site and side, was sectioned in the same transverse plane that was used at PET/CT so that the nodes detected at PET/CT could be matched to the nodes detected at histopathologic examination. The tissue sections were numbered sequentially from their distal to proximal ends, and a careful search for lymph nodes was made by the pathologist. The pathologist matched each lymph node found at tissue dissection to a corresponding node that was visible on the PET/CT images by studying (a) the position of the node in relation to the adjacent soft tissue, (b) the shape of the node, and (c) the size of the node. In this way, it was possible to correlate individual pelvic lymph nodes that were visible at PET/CT with histopathologic findings and to ensure that in the true-positive cases, the positive nodes detected at PET/CT corresponded to the nodes histopathologically determined to be positive.
Histopathologic Evaluation
The surgical specimens were histopathologically evaluated by using whole-mount specimen and standard histomorphometric techniques (8,10). All lymph nodes were sliced, routinely processed, and stained with hematoxylin-eosin before being examined microscopically. The pathologist, who was blinded to the imaging results, reported the lymph nodes to be normal, reactive (follicular or sinusoidal hyperplasia), or malignant. In all patients, the histopathologic findings were interpreted by a pathologist (P.P.) who had 14 years of experience in gynecologic oncology. Any metastases identified were typed to ensure that they were from the primary cancer of the uterine cervix. If a lymph node showed concomitant cancer infiltration and reactive changes, it was classified as malignant for the purposes of data analysis. The length measurements of lymph nodes with positive or negative findings were recorded by using a centimeter scale.
Statistical Analyses
For the purposes of statistical analysis, a true-positive lymph node was one that was seen on PET/CT images and confirmed to be positive for cancer infiltration at histopathologic examination. A false-positive lymph node was one that was seen on PET/CT images but found to be negative for cancer infiltration at histopathologic examination. A true-negative lymph node was one found to be negative for cancer at both PET/CT and histopathologic analysis. A false-negative lymph node was one that was missed at PET/CT but found to be positive for cancer involvement at histopathologic examination.
The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PET/CT for depicting metastatic lymph nodes were calculated on per-node and per-patient bases, in relation to the findings at histopathologic examination, which was considered the reference standard. Accuracy was reported in terms of the proportion of correctly classified nodes and patients. Ninety-five percent confidence intervals for patient-based sensitivity and specificity were calculated by using the Wilson approach (38). Statistical analyses were performed by using SAS, version 8.02, software (SAS Institute, Cary, NC).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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The macroscopic lengths of both the lymph nodes containing metastatic deposits and those negative for cancer involvement were measured. The short-axis diameters of the positive and negative nodes ranged from 0.3 to 2.8 cm (mean, 1.2 cm) and from 0.2 to 1.9 cm (mean, 0.6 cm), respectively.
PET/CT Findings
PET/CT correctly depicted 13 of the 18 lymph nodes proved to be positive for cancer infiltration at histopathologic examination after surgical dissection (Fig 1). All 13 of these metastatic nodes had a short-axis diameter greater than 0.5 cm. All five metastatic lymph nodes that were missed with PET/CT were 0.5 cm or less in short-axis diameter and contained small deposits of viable cancer cells (micrometastasis) at histopathologic analysis. In the 15 patients with cancer-positive lymph nodes at histopathologic analysis, no false-positive nodes were seen at PET/CT. The presence of metastatic lymph nodes was correctly diagnosed with PET/CT in 11 of these 15 patients.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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In the past decade, different relaxation times and special lymphographic contrast agents—ultrasmall particles of iron oxide being the most used—have been proposed as a means of improving the accuracy of nodal staging with MR imaging (39–41). Although these techniques have yielded interesting results in both experimental and clinical settings, morphologic size remains the most important criterion that is generally accepted for lymph node assessment, even at MR imaging (39).
In contrast to CT and MR imaging, which yield morphologic information, FDG PET can noninvasively depict different primary and metastatic tumor types on the basis of the increased glucose metabolism of malignant tissue (25). Moreover, because metabolic changes may precede morphologic changes, FDG PET might be an accurate imaging modality for depicting early-stage cancerous lesions. Investigators (26–30) in studies involving the comparison of FDG PET with either CT or MR imaging for depicting lymph node metastasis in patients with cervical cancer have suggested a possible role of functional imaging for this purpose. Sugawara et al (26) reported the diagnosis of lymph node metastasis with FDG PET in patients with cervical cancer in a series of 21 cases. Their preliminary data showed FDG PET to have 86% sensitivity and 100% specificity for pelvic and paraaortic nodal metastases, with surgical or clinical follow-up findings as the reference standard. Rose et al (28) reported FDG PET to have 75% sensitivity and 92% specificity in depicting lymph node metastasis in patients with advanced cervical cancer.
Grigsby et al (29) retrospectively evaluated the results of FDG PET and CT for node staging in patients with various clinical stages of cervical cancer. Their study findings revealed that FDG PET was more effective than CT, especially in depicting abnormal lymph nodes located in the pelvic chains. The lack of pathologic correlation was a limitation of their study, however. Reinhardt et al (30) evaluated the accuracy of FDG PET and MR imaging in the diagnosis of lymph node metastasis in a series of 35 patients with cervical cancer, with histopathologic findings as the reference standard. In their work, which was focused on patients with stage IB, IIA, or IIB disease, FDG PET had an accuracy of 97%, compared with an accuracy of 80% for MR imaging, at patient-based analysis. Likewise, at lymph node site–based analysis, FDG PET proved to be superior to MR imaging for depicting nodal metastasis. In all of these previous studies (26–30), the main drawbacks of FDG PET imaging were lower spatial resolution compared with the spatial resolution of either CT or MR imaging and poor anatomic resolution, which prevents the generation of precise information about the site of the lesion depicted.
Our study results indicate that integrated PET/CT may be an effective means of evaluating the lymph node status of patients with early-stage cervical cancer. With PET/CT, the capability to differentiate malignant nodes, which manifest as foci with high FDG uptake at PET, is not compromised by the use of morphologic size criteria. Consequently, PET/CT enables one to detect and localize metastatic lymph nodes that are not enlarged (ie, smaller than 1 cm in short-axis diameter) and thus overcome the limitations of the size-based characterization used with morphologic imaging modalities. This is particularly important for patients with cervical cancer, in whom as much as 30%–50% of malignant lymph nodes have been normal-sized in previous studies with pathologic correlation (11,12).
The overall per-node values in our study, which were calculated regardless of lymph node size, indicate that the sensitivity of PET/CT was good although lower than the sensitivity achieved in previous works (26–29) in which only PET was used. The main cause for this discrepancy could be the fact that, unlike the results of many of the previous works, the imaging findings in our study were correlated with histopathologic findings rather than intraoperative surgical or clinical follow-up findings. Performing complete histopathologic confirmation is expected to yield more complete knowledge of microscopic disease sites compared with the level of this knowledge gained in previous studies. This complete histopathologic confirmation, in turn, results in a larger number of false-negative cases due to microscopic cancer spread. Furthermore, the patients in our series had earlier clinical stages of disease than the patients examined in the previous studies (26–30), in which PET alone and either CT or MR imaging were used. This patient selection resulted in the detection of fewer positive lymph nodes compared with the number of positive nodes detected in the other studies and accounts for the lower sensitivity achieved in our study.
The per-node results of PET/CT in our study clearly improved when accuracy rates for the detection of lymph nodes with a short-axis diameter greater than 0.5 cm were calculated. This improved PET/CT performance is not surprising, because 0.5 cm corresponds to the mean value of spatial resolution of the PET component, which is in the range of 0.4–0.6 cm. Such a still limited spatial resolution of the PET component makes the presence of metastasis in small lymph nodes hardly detectable, even at PET/CT, as confirmed by the five false-negative lymph nodes smaller than 0.5 cm in diameter reported in our series. These observations are consistent with the results of some preliminary investigations of PET/CT performed in patients with lung cancer (35,36), in which it was reported that although use of the dual modality improved the accuracy of mediastinal node staging, the spatial resolutions that are achievable with currently available PET systems are not sufficient for the depiction of microscopic nodal metastases. On the basis of previous reports on the use of PET only (28–30), the number of false-positive lymph nodes was limited in our series, and at overall node-based analysis their presence was less relevant than the presence of false-negative lymph nodes. Nevertheless, the differentiation between a malignant node and focally increased glucose metabolism caused by inflammatory node reaction remains challenging, even at PET/CT.
In terms of per-patient analysis, the accuracy in evaluating lymph node metastasis in the present study was slightly lower than the accuracies in previous series involving the use of PET only (26,30). As with the node-based results, with the patient-based results, the reasons for this difference could be related to the precise histopathologic correlation performed and the patient selection criteria adopted in our work. In a typical clinical situation, especially that to plan adequate therapy, the most relevant issue may be whether the patient has lymph node metastasis. With regard to this issue, the positive predictive value may be the most important statistical measure. In our series, the patient-based positive predictive value was high, meaning that if a patient had a positive PET/CT finding, the probability that that patient had lymph node metastasis would be high.
A limitation of the present study was the fact that oral and vascular contrast agents were not used for CT imaging. Therefore, we were not able to establish the additional diagnostic value of integrated PET/CT gained by administering such agents. Oral contrast material could be helpful for differentiating lymph nodes from normal bowel. Vascular contrast material might have limited value, however, because it has been clearly shown that metastatic and reactive lymph nodes may have similar attenuation values at contrast-enhanced CT (16,17,23). Further studies are needed to define the role of oral and vascular contrast agents in PET/CT protocols for patients with cancer.
In summary, the results of this study show that integrated PET/CT is valuable for preoperative lymph node staging in patients with early-stage cervical cancer, with greater than 0.5 cm short-axis diameter being the size threshold for accurate depiction of metastatic nodes. If the results of forthcoming studies of lymph node metastasis in cervical cancer confirm our findings, integrated PET/CT may become an alternative to CT and MR imaging for lymph node staging in patients with cancer.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: FDG = fluorine 18 fluorodeoxyglucose • FIGO = International Federation of Gynecology and Obstetrics
Authors stated no financial relationship to disclose.
Author contributions: Guarantors of integrity of entire study, S.S., A.B.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, P.P., R.M., A.P.; clinical studies, A.B., M.P., P.P., A.P., M.C., C. Mangioni, C. Messa, F.F.; statistical analysis, S.S.; and manuscript editing, all authors
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References |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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This article has been cited by other articles:
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  P. Petignat and M. Roy Diagnosis and management of cervical cancer BMJ, October 13, 2007; 335(7623): 765 - 768. [Full Text] [PDF]
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 J. Czernin, M. Allen-Auerbach, and H. R. Schelbert Improvements in Cancer Staging with PET/CT: Literature-Based Evidence as of September 2006 J. Nucl. Med., January 1, 2007; 48(1_suppl): 78S - 88S. [Abstract] [Full Text] [PDF]
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