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Original Research |
1 Department of Radiology, Dokkyo University School of Medicine, 880
Kita-kobayashi, Mibu, Shimotuka-gun, Tochigi 321-0293, Japan.
2 PET Center, Dokkyo Medical University Hospital, Mibu, Japan.
3 Department of Radiology, Kobe University Graduate School of Medicine, Kobe,
Japan.
4 Department of Obstetrics and Gynecology, Dokkyo University School of Medicine,
Mibu, Japan.
Received October 31, 2007;
accepted after revision December 31, 2007.
Address correspondence to K. Kitajima
(kitajima{at}med.kobe-u.ac.jp).
Abstract
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SUBJECTS AND METHODS. Forty patients with clinical stages IA to IIIC underwent radical hysterectomy, including pelvic lymphadenectomy with or without paraaortic lymphadenectomy, after FDG PET/CT. Lymphadenectomy involved removing all visible lymph nodes in the surgical fields. PET/CT findings were interpreted by two experienced radiologists in consensus and compared with histopathologic results. The criterion for malignancy on PET/CT images was increased radiotracer uptake by a lymph node independent of node size.
RESULTS. In total, 62 pathologically positive nodes were found in 10 patients and 60 of 62 dissected metastatic nodes were identified on the CT component. The overall node-based sensitivity, specificity, and accuracy of PET/CT for detecting nodal metastases were 53.3% (32/60), 99.6% (1,419/1,424), and 97.8% (1,451/1,484), respectively. The sensitivity for detecting metastatic lesions 4 mm or less in diameter was 16.7% (4/24), that for lesions between 5 and 9 mm was 66.7% (14/21), and that for lesions 10 mm or larger was 93.3% (14/15). The overall patient-based sensitivity, specificity, and accuracy were 50% (5/10), 86.7% (26/30), and 77.5% (31/40), respectively.
CONCLUSION. Integrated FDG PET/CT is superior to conventional imaging techniques, but it is only moderately sensitive in predicting lymph node metastasis preoperatively in patients with endometrial cancer. Even PET/CT should not replace lymphadenectomy.
Keywords: endometrial cancer • FDG PET/CT • lymph node metastasis • oncologic imaging • PET/CT • women's imaging
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Lymph node metastasis is an important prognostic factor, and the survival rates of patients with metastases to the nodes are significantly lower than those of patients without nodal metastases [7]. The depth of myometrial invasion is an important factor in predicting lymph nodal metastasis, and the incidence of lymph node metastasis increases from 3% with superficial myometrial invasion (stage IB) to more than 40% with deep myometrial invasion (stage IC) [3, 4].
Surgical lymph node assessment is the reference standard for the diagnosis of lymph node metastasis [8]. However, surgical lymphadenectomy is specialized and increases the time and cost of diagnosis, with an increased risk of immediate and delayed complications to the patient. If we were able to determine preoperatively whether metastases to lymph nodes were present, we would be able to prevent unnecessary lymphadenectomy and tailor the extent of surgery. Therefore, a noninvasive technique that accurately identifies lymph node metastasis would be beneficial.
CT and MRI are widely used to assess lymph nodes in patients with malignant tumors including endometrial cancer. Although the identification of metastatic lymph nodes by both CT and MRI is based on measurements of node size, with a short-axis diameter of greater than 10 or 8 mm being the most accepted criterion for the diagnosis of nodal involvement, these morphologic imaging techniques have very low sensitivity; the sensitivity rate for detecting lymph node metastasis in endometrial cancer is between 18% and 66%, and the specificity rate is between 73% and 99% [9-14]. The limitations of this size-based characterization system are well known: Metastasis in normal-sized lymph nodes can be missed, and reactive lymph node enlargement cannot be reliably differentiated from cancer infiltration.
In contrast to these morphologic imaging techniques, PET with 18F-FDG is a functional method based on the increased glucose metabolism of malignant tumors. It has been used successfully to assess a large variety of primary tumors and metastases, detect recurrence, determine prognosis, and monitor tumor therapy. However, PET lacks anatomic information, and precise localization of any suspicious lesions may be difficult. PET is also impaired by the presence of increased uptake in physiologic, nonpathologic, or inflammatory states [15, 16]. Recently, integrated PET/CT, in which a full-ring detector clinical PET scanner and MDCT scanner are combined, was introduced to clinical practice. This new system makes it possible to acquire both metabolic and anatomic imaging data with a single device during a single diagnostic session, and it provides precise anatomic localization of suspicious areas of increased FDG uptake [17, 18]. If there is a high index of suspicion by PET, the CT component of integrated PET/CT can be used to differentiate pathologic uptake of FDG by lymph nodes from physiologic uptake by vessels, the bowel, or the ureter.
To date, several reports have discussed the usefulness of integrated PET/CT for detecting lymph node metastasis in uterine cervical cancer [19-21]. However, only two reports have evaluated FDG PET for detecting lymph node metastasis in endometrial cancer, and neither report evaluated PET/CT [22, 23]. The purpose of our study was to evaluate the diagnostic accuracy of integrated PET/CT in detecting nodal metastases in patients with endometrial cancer; histopathologic results were used as the reference standard.
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Thirty-four patients underwent pelvic and paraaortic lymphadenectomy. Six patients underwent only pelvic lymphadenectomy because two were preoperatively diagnosed in stage IA and four were in stage IB and nuclear grade 1. Paraaortic lymphadenectomy of these six patients was deemed unnecessary in the judgment of the gynecologic surgeon [8]. The clinical stage in terms of the FIGO criteria was IA in two cases, IB in 12, IC in four, IIA in four, IIB in six, IIIA in one, IIIB in one, and IIIC in 10. The histologic subtypes were endometrioid adenocarcinoma in 37 cases, serous papillary carcinoma in one, clear cell carcinoma in one, and adenosquamous cell carcinoma in one. The nuclear grade of the 37 endometrioid adenocarcinomas was G1 in 14 cases, G2 in 15, and G3 in eight. The time interval between PET/CT and surgical treatment was 5-16 days (mean, 12 days).
FDG PET/CT Study
Whole-body imaging was performed with a combined PET/CT scanner (Biograph
Sensation 16, Siemens Medical Solutions). Whole-body CT and PET covered a
region ranging from the meatus of the ear to the mid thigh. The technical
parameters of the 16-MDCT scanner were a gantry rotation speed of 0.5 second,
a table speed of 24 mm per gantry rotation, 120 kVp, 40 mA, and 2.5-mm slice
thickness; patients were given no specific breath-holding instructions.
Neither oral nor IV contrast agent was administered at CT. The PET component
had an axial view of 16.2 cm per bed position with an interslice spacing of
3.75 mm in one bed position; it provided an image with six or seven bed
positions. The transaxial field of view and pixel size of the PET images
reconstructed for fusion were 58.5 cm and 4.57 mm, respectively, with a matrix
size of 128 x 128 and 4.5-mm spatial resolution.
Patients were asked to drink 1,000 mL of water 1 hour before image acquisition and to then void just before image acquisition began to avoid urinary tract-associated artifacts. Urinary bladder catheterization was not used. After at least 4 hours of fasting, patients received an IV injection of FDG at 4.0 MBq/kg of body weight. Blood glucose levels were checked in all patients before FDG injection, and no patients had blood glucose levels greater than 160 mg/dL.
Approximately 50 minutes after FDG injection, immediately after CT, a whole-body emission PET scan was obtained with 3-minute acquisition per bed position using a 3D acquisition mode. Attenuation-corrected PET images were reconstructed with an ordered-subset expectation maximization iterative reconstruction algorithm (eight subsets, three iterations). PET, CT, and fused PET/CT images were generated for review on a computer workstation (Virtual Place version 3.0035, AZE).
Image Analysis
PET/CT images were prospectively pre operatively interpreted in consensus
by two experienced radiologists (readers A and B with 3 and 5 years of
experience in PET/CT, respectively) who had knowledge of neither the clinical
data nor other imaging results. The presence of abnormal FDG uptake was
indicated when accumulation of the radiotracer was moderately to markedly
increased relative to the uptake in comparable normal structures or
surrounding tissue, with the exclusion of physiologic bowel and urinary
activity. The classification of lymph nodes on PET/CT images as
cancer-positive was based on the presence of focally increased FDG uptake on
the PET images in a location that corresponded to the lymph node chains on the
CT images. All lymph nodes identified on the CT portion of PET/CT were also
recorded.
Lymph nodes were graded as malignant or benign on the basis of functional criteria independent of node size. Lymph nodes with increased radiotracer uptake were deemed positive for metastatic spread even if they were smaller than 1 cm in short-axis diameter. Conversely, lymph nodes with no detectable radiotracer uptake were deemed negative for metastatic spread even if they were larger than 1 cm in short-axis diameter. This method of PET/CT image analysis was derived from the results of previous studies of uterine cervical cancer and lung cancer [19, 24, 25]. Semiquantitative analysis to determine a standard up take value (SUV) of FDG in the nodal lesions was not performed in our series because the calculation of SUV may be of little help in characterizing lymph node lesions [26].
Surgical Procedures
Surgery, including total abdominal hysterectomy, bilateral
salpingo-oophorectomy, and pelvic lymphadenectomy with or without paraaortic
lymphadenectomy, and peritoneal cytology tests was performed by two
experienced gynecologic oncologists with knowledge of the PET/CT results.
Lymphadenectomy involved removing all visible lymph nodes in the surgical
fields. In all 40 patients, the pelvic lymph nodes dissected included the
common iliac, external iliac, internal iliac, and obturator fossa nodes on
both sides. In the 34 patients who also underwent paraaortic lymphadenectomy,
the dissection included removal of the nodal tissue over the distal vena cava
from the level of the left renal vein to the mid right common iliac artery and
removal of the nodal tissue between the aorta and the left ureter from the
left renal vein to the mid left common iliac artery.
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Histopathologic Evaluation
The surgical specimens were histopathologically evaluated using whole-mount
specimen and standard histomorphometric techniques. All lymph nodes were
sliced, routinely processed, stained with H and E, and examined
microscopically by one experienced pathologist who was blinded to the imaging
results. The length measurements of lymph nodes with positive or negative
findings were re corded using a centimeter scale.
Statistical Analysis
We performed node-based and patient-based analyses based on the consensus
verdict in general. Sensitivity, specificity, and accuracy were calculated
using standard statistical formulas. The Mann-Whitney test was applied to the
size of metastatic lymph nodes detected or missed by PET/CT. The Student's
t test was used for comparison of the SUV indexes of primary tumors
with or without lymph node metastases. A p value of < 0.05 was
regarded as statistically significant.
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The five lymph nodes with a false-positive diagnosis by PET/CT were 7, 7, 8, 9, and 9 mm and showed reactive changes (follicular hyperplasia in three nodes and sinusoidal hyperplasia with inflammatory granulation tissue in two) at histopathologic examination. The sensitivity, specificity, and accuracy on the basis of analysis of pelvic lymph nodes alone were 54.8%, 99.8%, and 98.3%, respectively; the same figures on the basis of analysis of paraaortic lymph nodes alone were 51.7%, 99.4%, and 96.8%, respectively (Table 1).
The short-axis diameter of the 60 metastatic lymph nodes ranged from 2 to 13 mm (mean, 6.3 mm). Twenty-four metastatic lymph nodes had a short-axis diameter of 4 mm or less, 21 were between 5 and 9 mm, and 15 were 10 mm or larger. In metastatic lymph nodes with a short-axis diameter of 4 mm or less, PET had a detection sensitivity of 16.7% (Figs. 3A, 3B and 3C). With a diameter of between 5 and 9 mm, the sensitivity was 66.7%, and with a diameter of 10 mm or greater it was 93.3% (Table 2). The mean short-axis diameter of metastatic lymph nodes detected by PET/CT was 8.4 ± 3.0 mm (range, 2-13 mm) and that of the missed nodes was 4.1 ± 2.0 mm (range, 2-10 mm), respectively (p = 3.04 x 10-7, Mann-Whitney test).
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Patient-Based Analysis
At histopathologic examination, 10 (25%) of the 40 patients had one or more
lymph nodes with metastases and 30 (75%) had no nodal metastases. PET/CT was
true-positive for nodal metastases in five of 10 patients with lymph node
metastasis and true-negative in 26 of 30 patients without lymph node
metastasis. Thus, the sensitivity, specificity, and accuracy on a
patient-based analysis were 50.0%, 86.7%, and 77.5%, respectively
(Table 1).
Evaluation of the Primary Uterine Lesion
The SUV of the primary uterine lesions ranged between 2.0 and 25.6, with a
mean value of 11.2. The mean SUVs (± SD) of primary uterine lesions
with and without lymph node metastases were 12.9 ± 4.8 (range,
2.4-18.2) and 10.6 ± 6.7 (2.0-25.6), respectively (p = 0.329,
Student's t test).
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To our knowledge, our current study is the first node-specific surgical-histopathologic FDG PET/CT analysis of the detection of pelvic and paraaortic lymph node metastasis in patients with endometrial cancer. Although PET/CT detected 18 of 45 metastatic lymph nodes (40%) 9 mm or less in short-axis diameter that had been missed by CT and MRI, PET/CT could not detect the remaining 27 metastatic nodes (60%). The sensitivity for detecting metastatic nodes 4 mm or smaller was 16.7% and that for metastatic nodes between 5 and 9 mm was 66.7%.
Although PET/CT was superior to conventional imaging techniques for detecting lymph node metastasis, it still had limitations in detecting microscopic metastases. Furthermore, in this study, enlarged nodes (i.e., > 1 cm) on CT were considered negative if they were not FDG-avid on PET. This may reduce the overall sensitivity of the PET/CT on this series as compared with the possibility that enlarged nodes > 1 cm on CT should be diagnosed as lymph node metastasis regardless of FDG accumulation.
Two research groups have reported the sensitivity, specificity, and accuracy of FDG PET/CT for detecting lymph node metastasis in patients with uterine cervical cancer [19, 20]. They reported mean values of 73% and 77% (sensitivity), 56% and 97% (specificity), and 68% and 89% (accuracy) in a patient-based analysis; the equivalent values were 57% and 72% (sensitivity), 93% and 99% (specificity), and 73% and 99% (accuracy) in a lesion-based analysis. Sironi et al. [19] found that PET/CT could detect all lymph nodes larger than 5 mm but could not detect any lymph node 5 mm or smaller. Choi et al. [20] revealed PET/CT was more accurate in detecting metastatic lymph nodes than unenhanced MRI using the size criterion.
The use of FDG PET for detecting nodal metastasis in endometrial cancer has been discussed in only two reports [22, 23]. Horowitz et al. [22] found that PET had 60% (3/5) sensitivity and 98% (68/69) specificity on a lymph node site basis and 67% (2/3) sensitivity and 94% (15/16) specificity on a patient basis; two false-negative PET cases were micrometastases 10 mm in size. Suzuki et al. [23] reported that PET could not identify seven metastatic lymph nodes less than 1 cm in diameter in five patients; the nodes measured < 1 mm, 1 x 2 mm, 1 x 3 mm, 2 mm, 2 x 3 mm, 3 x 4 mm, and 5 x 6 mm.
FDG PET and PET/CT are limited primarily by their inability to detect microscopic metastasis. Impaired PET and PET/CT performance is not surprising because 0.5 cm corresponds to the mean value of spatial resolution of the PET components, which is in the range of 0.4-0.6 cm. This still-limited spatial resolution of the PET component makes metastasis in small lymph nodes hardly detectable [19, 24, 25]. The imaging principle of using annihilation to produce images makes it extremely difficult to improve on the spatial resolution in use now. Future improvements more likely will be developed using novel radiotracers or robust fusion with other techniques such as CT or MRI.
In contrast to its low sensitivity, FDG PET/CT gave only five false-positive diagnoses, which were due to inflammatory node reaction, among 1,424 nonmetastatic nodes in our series; thus, the specificity in terms of node-based analyses was relatively high. This trend is similar to that described in other reports of PET and integrated PET/CT [19-23].
Although the difference in SUVs was not statistically significant in our series, primary uterine cancer with lymph node metastasis tended to have a larger SUV index than that without lymph node metastasis. The association between primary tumor FDG uptake and the presence of lymph node metastasis is controversial in several types of cancer. Some have reported that a high SUV of the primary tumor at diagnosis is associated with an increased risk of lymph node metastasis [27, 28], whereas others have found no correlation between the two factors [29].
In the past decade, enhanced MRI using a special lymphographic contrast agent—ultrasmall superparamagnetic iron oxide (USPIO)—has been proposed as a useful means of evaluating lymph node metastasis in several human malignant tumors, such as uterine cancer [13], prostate cancer [30], and breast cancer [31]. These researchers have found that USPIO allows microscopic metastatic lymph nodes to be detected and that USPIO has a high overall level of accuracy in detecting nodal metastasis.
Our study had certain limitations. First, the number of patients involved was relatively small. A larger investigation to evaluate the role of PET/CT in the detection of lymph node metastasis is warranted. Our findings reflect the accuracy of PET/CT in a selected cohort of women with endometrial cancer and not in the entire population of women with all stages of the disease. Second, oral and vascular contrast agents were not used in the CT component. Therefore, we were not able to establish the additional diagnostic value gained by integrated PET/CT with the use of such agents. It is interesting that two positive nodes and 588 negative nodes were not seen on the CT component of the PET/CT because of very small size. We should note that the calculation of sensitivity and accuracy for PET/CT for node metastasis was based on the 60 nodes imaged on CT and not on the 62 positive nodes seen on pathology. The technical parameters for CT were 120 kVp and 40 mA. Given the relatively low mA used, visualization of nodes on CT may have been reduced compared with visualization of nodes on enhanced CT using a higher mA. Third, the surgeons were guided by preoperative PET/CT findings, and this may have resulted in verification bias.
In conclusion, integrated FDG PET/CT is superior to conventional imaging techniques but is only moderately sensitive in predicting lymph node metastasis preoperatively in patients with endometrial cancer. Even PET/CT should not replace lymphadenectomy.
Acknowledgments
We thank Kennichi Kobayashi, Kouichi Asano, Kazufumi Suzuki, Kaoru Ishida,
and Tomoyuki Sakamoto for their excellent technical assistance and generous
support.
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  S. I. Lee and A. H. Russell Performance of 18F-FDG PET/CT in Endometrial Cancer Am. J. Roentgenol., November 1, 2008; 191(5): W210 - W210. [Full Text] [PDF]
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