Background
Biliary tract cancers (BTCs) are rare, highly lethal carcinomas that develop from the epithelium of the gallbladder and bile duct. Because of the late clinical presentation of BTCs, only 10% of patients are eligible for curative surgery [
1,
2]. Even among those patients who have undergone curative surgery, a majority of the patients develop recurrent cancer, supporting the notoriously poor prognosis of BTCs. Nevertheless, the prompt diagnosis of recurrent BTC could allow for prompt treatment and reduce the number of unnecessary interventions [
2]. Therefore, the surveillance of BTC recurrence is important.
According to the practice guidelines for detecting BTC recurrences, a physical examination with routine laboratory tests, every 3-4 months for the first 3 years after surgery and then every 6 months until the 5th post-operative year, is recommended [
3]. Additionally, because of the high risk of recurrence, it is recommended that surveillance includes radiologic evaluation with an abdominal CT scan every 6 months for 2-3 years [
3,
4]. The role of tumor marker (CA19-9) as surveillance is not clear, but constantly rising levels often precede radiologic evidence of recurrence by a number of months [
3].
During surveillance, the definitive diagnosis of suspicious lesions on contrast-enhanced CT (ceCT) scans as recurrent cancer can only be made by pathologic confirmation. However, a valid biopsy is not always possible as the lesion of interest is often small in size and located deep adjacent to large vessels or vital structures. There are also cases in which no definite recurrent lesions are detected on ceCT following measurement of elevated tumor markers, such as CA19-9 or CEA, with or without suspicious symptoms. In these cases, recurrence status must only be determined clinically by considering the clinical context, including symptoms, laboratory findings, and CT findings.
Recently,
18F-fluorodeoxyglucose positron emission tomography integrated with computed tomography (
18F-FDG PET/CT) has been introduced and considered to be a valuable imaging tool by combining anatomic and metabolic imaging information in cancer [
5]. In particular, the usefulness of
18F-FDG PET/CT is reported in several studies for staging of breast, colorectal, lung, and head and neck cancers, cholangiocarcinomas, lymphomas, and for detecting recurrences of breast, colorectal, lung and cervical cancers [
6‐
12]. However, a study concerning the role of
18F-FDG PET/CT during surveillance of BTCs is scarce [
13]. Therefore, we conducted this study to evaluate and compare the diagnostic validity of ceCT and
18F-FDG PET/CT in the assessment of BTC recurrence after curative surgery. In addition, we searched for correlation between maximal standardized uptake value (SUV
max) in
18F-FDG PET/CT and tumor markers.
Methods
Patients
Between October 2003 and June 2008 we consecutively enrolled 50 patients with BTCs who underwent curative resection at Seoul National University Hospital and obtained a 18F-FDG PET/CT for assessment of recurrence due based on clinical suspicion. All data were collected and analyzed retrospectively.
Patients were classified as clinically suspicious for recurrent BTC and underwent 18F-FDG PET/CT scans when there is at least one of the following criteria: 1) suspicious CT findings, 2) elevated tumor markers, such as CA19-9 or CEA, 3) abnormal liver function tests, and/or 4) suspicious clinical symptoms.
Contrast enhanced CT
All CT images were obtained using a multidetector-row computed tomography (MDCT) scanner (Mx 8000, Philips Healthcare; or LightSpeed Ultra, GE Healthcare; Sensation 16, Simens Healthcare). Each patient received 90 mL of nonionic contrast material that was administered at a rate of 3.0-4.0 mL/s using a mechanical injector. For the MDCT examinations, 3- to 5-mm slice thickness, and 3- to 5-mm reconstruction interval were used. CT images were obtained during the arterial and portal venous phases.
18F-FDG PET/CT
All scans were performed with one of two PET/CT systems (Philips Gemini Dual; Best, The Netherlands [from October 2003 to the end of the study] or SIMENS Biograph TruePoint; Germany [from November 2007 to the end of the study]). After fasting for 8 hours, 5.18 MBq/kg (0.14 mCi/kg) of FDG was injected. Then, all of the subjects rested quietly for 1 hour. A whole-body 18F-FDG PET scan was performed from the skull base to the mid-thigh. The CT scan without contrast was performed immediately prior to the PET scan with a multi-detector 2-slice spiral CT scanner. For the whole-body emission scan, 9-bed positions were examined at 3 min per step. CT and PET images were reconstructed onto a 512 × 512 matrix and a 128 × 128 matrix, respectively, and integrated after attenuation correction.
Data analysis and statistical methods
Two other board-certified radiologists, who were blinded to the diagnosis, independently interpreted ceCT images for the recurrence. All lesions on the ceCT were interpreted as recurrent, equivocal, or benign. The appearance of new malignant lesions in locoregional area or distant site denotes disease recurrence. For the confirmation of recurrence by ceCT, the RECIST criteria were used [
14]. When a postoperative image finding was uneventful: no locoregional recurrence and no distant metastasis, we can define a benign finding. If we cannot differentiate recurrence from benign, the lesion of interest is an equivocal finding. On statistical analysis, equivocal lesions were regarded as benign. Abnormal
18F-FDG PET/CT lesions were assessed as benign or malignant with respect to their location, patterns of uptake, and SUV
max. Recurrence in the liver remnant or operative site was categorized as locoregional recurrence. In addition, recurrences in other areas were categorized as metastases.
When evaluating findings of 18F-FDG PET/CT on ceCT as recurrences, at least one image finding of recurrence was necessary. However, benign findings on both 18F-FDG PET/CT and ceCT were necessary to interpret the lesions of interest as benign.
Either histopathologic or clinical confirmation after 18F-FDG PET/CT was considered the standard of reference. When a pathologic confirmation was possible, it was considered the standard of reference. However, when pathologic confirmation was impossible or inconclusive, we resorted to a clinical confirmation via radiologic correlation with subsequent ceCT with a minimum 3-month follow-up. Thus, no significant interval change for at least 3-months of follow-up by ceCT was required to confirm the lesion of interest as clinically benign. If there is a significant increase in size of lesion of interest, we can confirm the lesion is malignant.
The diagnostic validity of ceCT, 18F-FDG PET/CT, and the combination was evaluated by comparison with the standard of reference. Overall and site-specific sensitivity, specificity, positive predictive value, and negative predictive value were calculated. McNemar's test and Fisher's exact test were used to evaluate the efficacy of ceCT, 18F-FDG PET/CT, and the combination. Receiver operating characteristics (ROC) analysis was performed for the detection of recurrent lesions of ceCT and 18F-FDG PET/CT. All p values were two-sided in tests and p values less than or equal to 0.05 were considered to be statistically significant. All analyses were performed using Stata 9.0 software (Stata Corp, College Station, TX, USA).
Ethics
The study protocol was reviewed and approved by the Institutional Review Board of Seoul National University Hospital (IRB No: 1001-001-304). All studies were carried out according to the Declaration of Helsinki guidelines for biomedical research.
Discussion
The objective of the current study was to determine the clinical role of 18F-FDG PET/CT in the assessment of BTC recurrences when clinicians suspected recurrence during surveillance based on symptoms, laboratory findings (including tumor markers), and CT findings. Our data suggest that 18F-FDG PET/CT alone is not more sensitive or specific than ceCT in the detection of recurrent BTCs. However, these results do not reach statistical significance, probably due to the low number of patients. On the other hand, an additional 18F-FDG PET/CT on ceCT significantly improves the sensitivity in detecting recurrences.
Previous studies have evaluated the utility of
18F-FDG PET or PET/CT in BTCs [
11,
13,
16‐
18]. The study by Kim
et al enrolled 123 patients with suspected and potentially operable cholangiocarcinomas, and demonstrated that PET/CT showed no advantage over ceCT in the diagnosis of primary tumors, but was more valuable in the diagnosis of regional lymph node and distant metastases [
11]. Petrowsky
et al reported that PET/CT and ceCT provided comparable accuracy for primary cholangiocarcinoma, but PET/CT was particularly valuable in detecting unsuspected distant metastases which were not diagnosed by standard imaging in the staging of patients with gallbladder cancer and cholangiocarcinomas (12/12 in PET/CT
vs. 3/12 in ceCT;
p < 0.001) [
17]. In these studies,
18F-FDG PET or PET/CT did not have a statistically significant advantage over ceCT in the diagnosis of primary tumors, but was valuable in identifying occult distant metastases which were not detected by conventional imaging. Only Corvera
et al identified the role of
18F-FDG PET in detecting disease recurrences after resection in their analysis and reported that
18F-FDG PET was helpful to clarify recurrences with 76% of sensitivity [
16]. Thus,
18F-FDG PET was merely confirmatory because recurrences were also identified on conventional imaging.
Unlike the aforementioned studies, the current analysis documented the complementary role of
18F-FDG PET/CT under a frequently encountered situation in the clinic in which clinicians suspected a recurrence. Of 50 patients, 36 had concordant results between ceCT and subsequent
18F-FDG PET/CT, and
18F-FDG PET/CT was 83% (30/36) consistent with the final recurrence status (Figure
2). Moreover, an additional PET/CT correctly identified six false-negative cases as recurrences which were interpreted as benign or equivocal by ceCT. This resulted in a significant increase in sensitivity (88%
vs. 94%,
p = 0.03) and suggested a complementary role of
18F-FDG PET/CT beyond ceCT when clinicians suspected a recurrence.
Of these six false-negative cases by ceCT, three were first interpreted as post-operative inflammatory changes. For the other three cases, lymph node metastasis was not confidently interpreted as a recurrence due to the insignificant size. However, the 18F-FDG PET/CT was interpreted as a recurrence in these lesions based on the high 18F-FDG uptake. From this information, five patients could receive palliative chemotherapy, whereas the other patient could not receive chemotherapy because of poor performance status. Moreover, an additional PET/CT showed no 18F-FDG uptake in five false-positive cases by ceCT, which provided decisive information to the clinicians. Among 14 patients with discordant results, 11 patients (11/14, 79%) was treated regarding to the results of PET/CT. In this context, when ceCT is inconclusive for identifying post-operative changes and the lymph nodes are of borderline size, a discernible role for 18F-FDG PET/CT is feasible.
This complementary role of
18F-FDG PET/CT during surveillance has been assessed in other cancers. Specifically, Radan
et al described patients with breast cancer and rising tumor markers in which
18F-FDG PET/CT was superior to CT for diagnosis of tumor recurrence, and led to changes in the subsequent clinical management of 51% of the patients [
19]. In addition, Guo
et al evaluated the role of
18F-FDG PET/CT in patients with possibly recurrent esophageal squamous cell carcinoma who underwent definitive treatment and displayed a remarkable sensitivity and a high specificity and accuracy at regional and distant sites for recurrent esophageal squamous cell carcinoma [
20].
Furukama
et al. evaluated the prognostic significance of FDG uptake on PET in patients with biliary tract cancer and demonstrated the SUV
max of 6.3 to be the optimal cutoff point for survival [
21]. In addition, their data showed that the SUV
max was one of the significant prognostic factors for overall survival in univariate analysis. However, our data did not show that the SUV
max was the significant prognostic factor for overall survival, probably due to the low number of patients and selection bias.
Our study had limitations other than retrospective design. First of all, the majority of recurrent cases were confirmed clinically. Our standard for non-recurrence required no significant changes in the lesion for a minimum of 3 months; however, such a criterion has not been validated and may be insufficient for confirmation. Second, the validity of 18F-FDG PET/CT may have been overestimated because the nuclear medicine physicians were aware of the findings of the corresponding ceCT. Lastly, the longer time interval between ceCT and PET/CT and the different characteristics of 3 CT scanners between the period of 2003 to 2008 might influence the results. Nevertheless, our study has significance in demonstrating the complementary role of 18F-FDG PET/CT in a commonly encountered clinical situation in which clinicians suspect BTC recurrence by elusive clinical manifestations with equivocal or inconclusive conventional imaging. Additionally, as the most modern PET/CT scanners allow for fully diagnostic ceCT scans, contrast enhanced diagnostic PET/CT could be recommended as the primary modality of choice in case of suspected recurrence.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
YGL contributed to the study design, data collection/analysis/interpretation and writing of the manuscript. DY Oh treated many of the patients and contributed to the study design, data analysis/interpretation and writing of the manuscript. SWH, EKC, JYJ, SAITYK, SW K, SWH and YJB treated many of the patients in this study. All authors read and approved the final manuscript.