Impact of Metabolic Parameters of ¹⁸F-Fluorodeoxyglucose Positron-emission Tomography After Hepatic Resection in Patients With Intrahepatic Cholangiocarcinoma

Patients and Methods

Patient characteristics. This study enrolled 24 patients with IHCC who had undergone surgical resection at the Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Gunma University, Gunma, Japan, between April 2007 and December 2017. All patients had a confirmed pathological diagnosis of a malignancy arising from the intrahepatic cholangiocarcinoma. Patient demographic and clinical characteristics, including perioperative factors, tumor characteristics and survival were analyzed, and factors predicting overall (OS) and recurrence-free (RFS) survival were evaluated by univariate and multivariate analyses. The study protocol conformed to the ethical guidelines of the 1975 Helsinki Declaration and was approved by our Institutional Review Board (approval number: 2017-237).

¹⁸F-FDG/PET imaging. PET imaging was performed within 1 month before hepatic resection using a PET/CT scanner (Discovery STE; GE Healthcare, CA, USA) with a 700 mm field of view at Gunma University Hospital and another PET/CT scanner (Aquideo, PCA-7000B; Toshiba, Tokyo, Japan) at Hidaka Hospital. The patients fasted for at least 6 h before PET imaging. FDG PET/CT image acquisition, reconstruction, and attenuation correction were performed as previously described (10). All ¹⁸F-FDG images were interpreted by two experienced nuclear physicians (H.T. and T.Y.). The interpreting physicians were unaware of the patient's clinical history and data. Tracer uptake in the primary tumor was defined as positive if the uptake was higher than that of the normal mediastinum. Discrepant results were resolved by consensus review. For the semiquantitative analysis, functional images for the SUV were produced using attenuation-corrected transaxial images, the injected dose of ¹⁸F-FDG, the patient's body weight, and the cross-calibration factor between PET and the dose calibrator. SUV was defined as follows: SUV=radioactive concentration in the region of interest (ROI) [MBq/g]/injected dose (MBq)/patient's body weight (g). The ROI was manually drawn over the primary tumor on the SUV images. When the tumor was larger than 1 cm in diameter or the shape of the tumor was irregular or multifocal, a ROI of approximately 1 cm in diameter was drawn over the area corresponding to the maximal tracer uptake. ROI analysis was conducted by a nuclear physician with the aid of corresponding CT scans. The SUVmax in the ROI was used as a representative value for the assessment of FDG uptake in the lesion. CT scan for the purpose of initial staging was carried out with intravenous contrast medium. CT images were interpreted by the two Board-certified radiologists (T.H. and Y.T.). Syngo.via software (Siemens Medical Solutions, Erlangen, Germany) at the Gunma University Hospital on a workstation to automatically calculate the MTV and TLG. MTVs were defined as the tumor volume inside the tumor boundaries using SUV thresholds that were 60% of the tumor SUVmax. TLGs were calculated by multiplying the mean SUV by the tumor volume inside the tumor boundaries.

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Figure 2.

Overall (A) and recurrence-free (B) survival curves after hepatic resection in patients with intrahepatic cholangiocarcinoma according to MTV (metabolic tumor volume). These curves show that patients with MTV>81.2 cm³ had a significantly poorer prognosis.

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Figure 3.

Overall (A) and recurrence-free (B) survival curves after hepatic resection in patients with intrahepatic cholangiocarcinoma according to maximum standardized uptake value. These curves show that patients with SUVmax>9.6 had a significantly poorer prognosis.

Preoperative calculation of the cut-off value of the SUVmax, MTV and TLG. The receiver operating characteristics (ROC) curves of preoperative ¹⁸F-FDG/PET parameters were analyzed, and OS was predicted by comparing the area under the ROC curve (AUC). The best cut-off value was 9.6 for SUVmax (sensitivity=71.43%; specificity=99.42%; AUC=0.798), 81.2 for MTV (sensitivity=85.71%; specificity=82.35%; AUC=0.882) and 352.8 for TLG (sensitivity= 85.71%; specificity=81.27%; AUC=0.9076).

Surgical procedures. All patients underwent dynamic CT imaging preoperatively. The details of our surgical techniques and patient follow-up methods were reported previously (5). Major hepatectomy with bile duct resection was performed when bile duct invasion was suspected to have affected the first hepatic duct. Partial hepatectomy was performed for peripheral IHCC without bile duct invasion. When we considered it desirable to confirm the surgical margins, the resected specimen was sent for frozen pathology. The right and left lobes of the liver have different routes of lymphatic drainage; therefore, the technique for lymph node dissection was tailored to the location of the primary tumor. Postoperative surgical complications were recorded according to the Clavien-Dindo classification (11).

Follow-up strategy and recurrence pattern. After discharge, all patients were examined for recurrence by ultrasonography and tumor markers by CT every 3 months. When recurrence was suspected, additional examinations such as MRI or ¹⁸F-FDG/PET were performed.

Histopathological examination. All of the resected specimens were cut into serial 5- to 10-μm-thick slices and fixed in 10% formalin. The sections were stained with hematoxylin and eosin. Tumor differentiation, microvascular invasion, intrahepatic metastasis were assessed by the pathologist according to the criteria of the Liver Cancer Study Group of Japan (12). Histologically, all cases were identified as mass-forming type IHCC.

Statistical analysis. The associations of continuous and categorical variables with the relevant outcome variables were assessed using Student's t-test and the chi-square test, respectively. Patient survival was analyzed using the Kaplan–Meier method and groups compared using the log-rank test. Uni- and multivariate analyses were performed using a logistic regression model. To identify prognostic factors, some variables which were found to have independent association in univariate analysis (except MTV) were included in a multivariate Cox proportional model to analyze both OS and RFS because MTV was a confounding factor Lymph node metastasis is reportedly the most significant predictor of poor outcome in IHCC (5, 6), and therefore lymph node metastasis was included in the multivariate analysis. Statistical analyses were performed using JMP software (version 12.2.0; SAS Institute, Cary, NC, USA). Results with a p-value of less than 0.05 were considered statistically significant.