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1 Department of Obstetrics and Gynecology, Fukui Medical University
Matsuoka-Cho, Yoshida-Gun, Fukui-ken 910-1103, Japan.
2 Department of Radiology, Fukui Medical University Matsuoka-Cho, Yoshida-Gun,
Fukui-ken 910-1103, Japan.
3 Departments of Neurosurgery and the Biomedical Imaging Research Center, Fukui
Medical University Matsuoka-Cho, Yoshida-Gun, Fukui-ken 910-1103, Japan.
Received March 31, 2003;
accepted after revision July 23, 2003.
Address correspondence to Y. Yoshida
(yyoshida{at}fmsrsa.fukui-med.ac.jp).
Abstract
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SUBJECTS AND METHODS. Fifteen patients who were thought to have ovarian cancer on the basis of the results of physical examination, sonography findings, and level of serum cancer antigen 125 were enrolled over an 11-month period. After screening, patients underwent two imaging examinations—abdominopelvic CT and whole-body FDG PET— within 2 weeks before surgery. Also before surgery, staging accuracy was assessed separately using CT with or without FDG PET (which was based on modifications of the International Federation of Gynecology and Obstetrics [FIGO] criteria). The results of the histology and surgery findings were used to assess the accuracy of the scanning findings.
RESULTS. Staging revealed stage III disease in seven patients (IIIC, n = 6; IIIB, n = 1), stage II in three (IIC, n = 2; IIB, n = 1), and stage I in five (IC, n = 3; IA, n = 2), according to the FIGO criteria. Although CT staging correlated with postoperative staging in eight (53%) of 15 patients, consensus evaluation of CT with FDG PET staging improved correlation with postoperative staging in 13 (87%) of 15 patients.
CONCLUSION. The addition of FDG PET to CT increases accuracy in staging of ovarian cancer.
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Accurate staging of patients with ovarian cancer before treatment is important to determine the appropriate therapy for those who will potentially benefit from intervention. The detection and staging of ovarian cancer have posed considerable challenges for cross-sectional imaging. The accuracy of CT in staging of ovarian cancer has been reported to range from 60% to 80% [6, 7].
In the past decade, positron emission tomography (PET) with the radiotracer FDG has emerged as a promising oncologic imaging tool [8]. The addition of FDG PET to cross-sectional imaging can improve the accuracy of staging in patients with lung cancer [9]. However, whether FDG PET is useful to detect the spread of cancer and to help determine the staging of ovarian cancer in the preoperative assessment is unknown. Thus, we compared the accuracy of staging using CT with and without the addition of FDG PET. Our specific goal was to determine whether the addition of FDG PET to CT is advantageous in the detection of tumor spread.
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Patients who met the criteria and agreed to participate in this study underwent two imaging examinations (abdominopelvic CT and whole-body FDG PET) within 2 weeks before full pelvic and abdominal surgery. Before surgery, the results of diagnostic imaging were evaluated for each patient (CT with or without FDG PET) by the reviewers who comprised one nuclear medicine specialist, one radiologist, and two other gynecologic oncologists who had experience with these methods and no knowledge of patient identity at the time of evaluation. The results of the histology and surgery were used to assess the accuracy of the scanning findings.
Patients
Fifteen patients were enrolled over an 11-month period between September 1,
2001, and July 31, 2002, at Fukui Medical University, Fukui, Japan. Patient
exclusion criteria included unwillingness to give informed medical consent or
ineligibility for full pelvic–abdominal surgery or surgical exploration.
Overall contraindications included pregnancy or having undergone
pelvic–abdominal surgery within 6 months of study entry. The study was
approved by the ethics committee of Fukui Medical University, and written
informed consent was obtained from each patient before the study.
Screening for Ovarian Cancer
To screen for ovarian cancer, two experienced gynecologic oncologists
evaluated sonographic findings, physical examinations (including pelvic
examination), and level of serum CA 125 (> 35 U/mL was considered to
indicate possible malignancy)
[2].
For sonography and Doppler sonography, transvaginal sonography was performed using a unit equipped with a 7.5-MHz transducer head (530 Combision, Toshiba, Tokyo, Japan). The criterion for suspicion of malignancy in the ovary on transvaginal sonography was a pattern suggestive of malignancy as described in the evidence-based medicine guidelines of 2001 [10]. In brief, malignant tumors may have a tumor wall or septa greater than 3 mm in thickness, have papillary growths inside the cyst (or cysts), be multicystic, and have a complex structure with solid and cystic components. In addition, Doppler sonography was used to evaluate the arterial flow of the detected complex and solid components of the ovaries. A pulsatility index and resistive index were calculated, with the thresholds for malignancy being a pulsatility index of less than 1.0 and a resistive index of less than 0.4 [6].
CT
CT examination was performed using a helical CT scanner (HiSpeed Advantage,
General Electric Yokogawa Medical Systems, Tokyo, Japan). According to the
standard imaging protocol at our hospital, both unenhanced and
contrast-enhanced scanning were performed. For contrast-enhanced imaging, IV
administration of 100 mL of contrast material via a power injector at a rate
of 1 mL/sec was performed. The scanning field extended from the upper end of
the dome of the diaphragm to the pubic symphysis.
At our university, ovarian cancer is surgically staged primarily on the basis of 16 specific sites, which are referred to by Forstner et al. [11] and are important for ovarian cancer staging in accordance with the modified recommendations of FIGO criteria (Appendix 1) documented at laparotomy. These 16 specific sites include the ovary, uterus, pelvic sidewall, sigmoid colon, urinary bladder, cul-de-sac, peritoneum of the anterior abdomen, diaphragm, omentum, mesentery, serous membrane of the small bowel, liver surface, pelvic and paraaortic lymph nodes, liver, and lung. Liver and lung metastases were determined by cytologically positive pleural fluid from fine-needle aspiration. Concerning staging, Table 1 shows the importance of the existence of tumors inside the pelvis (stages I and II), although Table 2 emphasizes the importance of the existence of tumors outside the pelvis (stages III and IV).
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The criteria for the spread of cancer as determined by CT were modified from those described by Forstner et al. [11]. In brief, tumor presence was defined as unilateral or bilateral. Uterine invasion was diagnosed by means of localized distortion of the uterine contour and irregular interface between tumor and myometrium. Invasion of the sigmoid colon or urinary bladder was diagnosed when there was subtle nodule linear contrast enhancement. Pelvic sidewall invasion was diagnosed when the tumor was less than 3 mm away from the pelvic sidewall or when iliac vessels were surrounded or distorted by the tumor. Peritoneal implants were diagnosed when nodular or plaquelike lesions were seen adjacent to or projecting from these peritoneal surfaces. Omental involvement was diagnosed when there was an infiltrative (feathery pattern), nodular, or cakelike appearance of soft tissue in the omentum. Detected abdominal and pelvic lymph nodes were considered malignant when the diameter of the short axis exceeded 1 cm, irrespective of location. Metastases to the hepatic parenchyma were evaluated using established CT criteria [12]. CT images were interpreted by consensus of the reviewers.
PET
All subjects underwent PET using an Advance scanner (General Electric
Medical Systems, Milwaukee, WI), which permits simultaneous acquisition of 35
image slices with interslice spacing of 4.25 mm. Performance tests showed
intrinsic resolution of 4.6–5.7 and 4.0–5.3 mm in the transaxial
and axial directions, respectively. FDG was produced using a small cyclotron
(OSCAR3, Oxford Instruments, Oxford, UK)
[13] and an automated
synthesis system (NKK, Tokyo, Japan). After the patients had fasted for at
least 12 hr before radiotracer administration, approximately 370 MBq of FDG
was injected IV. Whole-body emission scanning was started 40–60 min
after FDG administration, and PET data were acquired for 12–14 min with
six or seven bed positions. A transmission scan was obtained using a
germanium-68–gallium-68 rod source for attenuation correction after the
emission scan at the same bed positions as the emission scan. The PET data
were reconstructed using the iterative reconstruction algorithm and segmented
attenuation correction (IRA/SAC) method and resliced into transaxial, coronal,
and sagittal sections with the gray scale in the standardized uptake values
[14].
PET findings for the transaxial, coronal, and sagittal sections were interpreted by the reviewers. If regions of FDG accumulation were manifest on the FDG PET images, the site of each region was evaluated. Estimation of lesions on the FDG PET images was based on correlation with CT. Hypermetabolic lesions, which were more intense than physiologic liver uptake and could not be attributed to structures such as the bladder, ureters, or gastrointestinal tract (which physiologically accumulate FDG), were considered positive for malignancy. In cases of visually equivalent standardized uptake values between the tumor and the liver, regions of interest were drawn on the tumor and liver, and then the standardized uptake values were compared. Furthermore, peritoneal seeding was considered present when FDG uptake was prominent on the peritoneal lining and the surfaces of solid organs.
Operative Procedures
All patients (n = 15) underwent surgical staging within 2 weeks of
the imaging examination. Laparotomy staging involved total abdominal
hysterectomy (n = 15), bilateral salpingo-oophorectomy (n =
15), and infracolic (n = 5) or supracolic (n = 10)
omentectomy. In all patients, resection or cytoreduction or biopsy of
peritoneal implants was performed throughout the abdomen and pelvis; sites
were the small- and large-bowel surfaces and mesentery, diaphragm, liver, and
spleen. When there was no evidence of gross disease, multiple cytologic
samples were acquired from the abdominal and pelvic peritoneal surfaces. Lymph
node sampling or complete lymphadenectomy was performed in all 15 patients. At
surgery and biopsy or cytology, the presence or absence of tumor tissue at 16
specific sites was recorded. When the patient had pleural effusion or liver
metastases, aspiration biopsy was performed to prove the existence of
malignant cells.
Data Analysis
Before surgery, the images acquired using the two modalities (CT and FDG
PET) were reviewed and conclusions arrived at by consensus of the reviewers.
The accuracy of the 16 specific lesion-based assessments was determined
separately for CT with and without FDG PET. Overall staging accuracy was
assessed separately for CT with and without FDG PET based on the modified FIGO
criteria (Appendix 1). In the second session, all results were compared with
the histology and cytology findings. Sensitivity, specificity, positive and
negative predictive values, and accuracy were then calculated by the
reviewers. The reviewers had no prior knowledge of patient ages, physical
examination findings, tumor markers, or surgical or histopathology
findings.
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The performance of CT with or without FDG PET in the detection of tumor tissue inside the pelvis is summarized in Table 1. When lesion-based diagnostic accuracy inside the pelvis was compared for CT with and without FDG PET, the sensitivity improved from 72% to 76%; specificity, from 81% to 82%; accuracy, from 79% to 81%; positive predictive value, from 48% to 50%; and negative predictive, from 92% to 94%. The performance of CT with or without FDG PET in the detection of tumor tissue outside the pelvis is summarized in Table 2. When lesion-based diagnostic accuracy outside the pelvis was compared for CT with and without FDG PET, the sensitivity improved from 24% to 63%; specificity, from 95% to 98%; accuracy, from 85% to 93%; positive predictive value, from 45% to 88%; and negative predictive value, from 88% to 93%.
The overall lesion-based sensitivity improved from 46% to 68%; specificity, from 90% to 92%; accuracy, from 83% to 88%; positive predictive value, from 47% to 65%; and negative predictive value, from 90% to 93%.
Overall staging accuracy was assessed separately for CT with and without FDG PET using the modified FIGO criteria (Appendix 1). Although CT staging correlated with postoperative staging in eight (53%) of the 15 patients, consensus evaluation of CT with FDG PET staging improved correlation with postoperative staging in 13 (87%) of the 15 patients (Table 3).
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Disease was overstaged using CT in three patients. One patient had pleural effusion and slight pleural thickness on CT. FDG PET showed definite linear intense uptake only at the right subphrenic space but not at the pleural walls. Aspiration biopsy did not prove the existence of malignant cells in pleural effusion. The consensus evaluation based on CT alone was stage IV, but the addition of FDG PET to CT caused the evaluation to be changed to stage IIIC. The other two patients had heterogeneous cysts but not metastatic parenchymal liver disease. Of these two, FDG uptake in the liver was not significant in one patient. In the other patient FDG uptake was not significant within the liver, only on the liver surface (Fig. 1A, 1B, 1C). The consensus evaluation of CT was stage IV, but the addition of FDG PET to CT caused the evaluation to be changed to stages IC and IIIC, respectively. In these two patients, the consensus evaluation of CT with FDG PET resulted in correct diagnoses at clinical staging.
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In four patients, the disease was understaged when CT alone was used because of overlooked omental implants, normal-sized paraaortic (Fig. 2A, 2B) or retroperitoneal lymph nodes, and small-bowel implants, which displayed significant FDG uptake at PET in each case. In these patients, consensus evaluation of CT with FDG PET resulted in correct diagnoses at clinical staging.
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In one patient, disease was understaged when CT with FDG PET was used for staging because of missed tumor extent in the pelvic cavity. The staging was accurate for this patient who underwent CT, but FDG PET overestimated the extension of tumor to the sigmoid colon. At surgery, there were extensive adhesions between the ovarian tumor and sigmoid colon. However, on histologic examination, the resected sigmoid colon specimens showed no tumor extension to the mucosa and lumen but showed infiltration of numerous lymphocytes and histiocytes in the superficial and deep mucosa of the sigmoid colon. The reason for overestimation on FDG PET was due to the infiltrative activity of the sigmoid colon. Thus, the consensus evaluation of CT with FDG PET resulted in overestimation.
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A major problem in ovarian cancer is that a high proportion (75%) of patients are in advanced stages of the disease at the time of diagnosis, which results in a 5-year survival rate of only 46% [1, 15]. Primary debulking surgery is not the only treatment option for ovarian cancer, and patients with bulky nonresectable disease will not benefit from primary surgery [5, 16]. In addition, the survival benefit is small if debulking is not optimal. The results of studies regarding therapy for patients with advanced cancer of the pancreas and esophagus provide clear evidence that neoadjuvant chemotherapy before surgery enables downstaging and thus improves the operability as well as the prognosis of patients [17, 18]. The results of these studies strongly suggest the need to consider neoadjuvant chemotherapy in patients with advanced ovarian cancer [5]. Thereafter, accurate staging of patients with ovarian cancer before treatment is needed to determine appropriate treatment for those who will potentially benefit from it.
When ovarian cancer is staged using cross-sectional imaging such as CT, the distinction of stages III and IV, which contributes to treatment planning and prognosis, is important. There are two important related issues in imaging such patients. First, the most common finding to result in the assignment of stage IV disease at presentation is pleural effusion [19]. In our study, CT revealed pleural effusion and slight pleural thickness but no nodules. FDG PET showed definite intense uptake only at the right subphrenic space but not at the pleural walls. Aspiration biopsy did not prove the existence of malignant cells in the pleural effusion. The consensus evaluation of CT was stage IV, but the addition of PET to CT led to correlation with histopathologic staging. The second important distinction is the differentiation of liver-surface implants (peritoneal spread, stage III) from true intraparenchymal metastases (hematogenous spread, stage IV). In our study, CT showed suspicious intraparenchymal metastasis and did not reveal any surface implants. FDG PET scans showed no intraparenchymal uptake but revealed uptake in the node on the liver surface. The consensus evaluation of CT was stage IV, but the addition of FDG PET led to correlation with histopathologic staging. In light of these findings, FDG PET contributes to the resolution of an important issue for staging of ovarian cancer—that is, the distinction between disease stages III and IV.
One limitation of CT in the detection of metastases involves lymph node metastases. Yuan et al. [20] stated that PET can detect metastases in normal-sized lymph nodes and can verify malignant tissue in enlarged nodes. However, Nakamoto et al. [21] pointed out PET can miss a poorly localized microscopic spread of disease and lesions smaller than 1 cm. In our study, CT showed normal-sized lymph nodes in paraaortic lymph nodes smaller than 10 mm, although FDG PET scans showed definite uptake at the same lymph nodes. Operative findings proved the existence of malignant cells in the paraaortic lymph nodes. The consensus evaluation of CT was stage IC, but the addition of FDG PET to CT led to correlation with histopathologic staging (stage IIIC). This finding indicates that the detection of lymph node metastases might be improved with the addition of FDG PET to CT analysis. We believe that FDG PET can be used to accurately predict both the presence and absence of lymph node metastases.
The detection of metastases located on the small-bowel surface, mesentery, or peritoneum has been problematic. The sensitivity of the detection of peritoneal metastases with CT was previously reported to be 63–79% [22–24]. In our study, only one of three patients had regions in which FDG PET scans showed uptake in the bowel but did not have abnormal CT findings. Peritoneal implants can be detected on FDG PET only when patients have massive ascites. Therefore, a positive imaging-based diagnosis of peritoneal implantations on CT with FDG PET remains clinically more useful than a negative result.
Ovarian cancer is a peculiar disease in that the detection of peritoneal metastases is not by itself a contraindication to curative surgery, but this information is important if tumor debulking is being considered. FDG PET does not seem to provide greatly improved sensitivity for the detection of small implants but may be useful in the detection of peritoneal implants.
The principal shortcoming of the present study design was that the CT technique might have limited its accuracy. Although helical CT was used, a slice thickness of 10 mm is standard protocol at our hospital, whereas recently, helical CT with slice collimation ranging from 5 to 7 mm has become standard [25]. Therefore, this may be one of the reasons that the accuracy of staging by CT was only 53% in the present study.
The general shortcomings of FDG PET include the high financial cost of the procedure, the need for patients scheduled for PET to fast at least 4 hr (preferably 6–12 hr) before injection of FDG, and the need for patients to be well hydrated and avoid strenuous work or exercise for 24 hr before scanning. An important aspect in detecting pelvic masses is the normal presence of intense FDG activity in the ureter and bladder, due to normal FDG renal clearance, that interferes with optimal interpretation of the images [13]. However, whole-body FDG PET can detect viable cancer cells. It is useful for staging various cancers [8].
In conclusion, consensus evaluation of CT with FDG PET staging improved correlation with postoperative staging in 13 (87%) of 15 patients. Although in our study CT without FDG PET staging correlated with postoperative staging in eight (53%) of 15 patients, the addition of FDG PET to conventional imaging methods such as CT improves the accuracy in staging of ovarian cancer.
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Acknowledgments
We thank Nobuyo Matsui and Fumiko Maki for assistance with manuscript
preparation.
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