Author Affiliations: Nanfang PET Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China (Wang SB, Wu HB, Wang QS, Zhou WL and Tian Y); Department of Radiology, First People's Hospital of Yunnan Province, Kunming 650000, China (Wang SB, Ji YH and Lv L)

Corresponding Author: Quan-Shi Wang, MD, PhD, Professor, Nanfang PET Center, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China (Tel/Fax: +86-20-61642127; Email: wqslph@163.net)

 

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(15)60392-7

Published online July 2, 2015.

 

 

Contributors: WSB proposed the study. WSB and WHB performed research and wrote the first draft. WQS, ZWL and TY collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. WQS is the guarantor.

Funding: None.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: The various origins of obstructive jaundice make the diagnosis of the disease difficult. This study was undertaken to evaluate the role of ¹⁸F-FDG PET/CT in differentiating malignant from benign origins of obstructive jaundice and to quantify the added value of ¹⁸F-FDG PET/CT over conventional imaging (enhanced CT and/or MRI).

 

METHODS: Eighty-five patients with obstructive jaundice who underwent ¹⁸F-FDG PET/CT within 2 weeks after enhanced CT and/or MRI were reviewed retrospectively. All ¹⁸F-FDG PET/CT images were independently evaluated by 2 nuclear medicine physicians who were unaware of other imaging data; differences were resolved by consensus of the physicians. All conventional imaging interpretations, according to the medical records, were reviewed by 2 radiologists to determine the potential value. Final diagnoses were based on histological or surgical findings.

 

RESULTS: Sixty-six patients were diagnosed with malignancies, and 19 patients with benign lesions. The maximum standardized uptake values for malignant and benign lesions causing biliary obstruction were 8.2±4.4 and 4.0±5.0, respectively (P<0.05). The sensitivity, specificity, and overall accuracy for differentiating malignant from benign origins with ¹⁸F-FDG PET/CT were 86.4% (57/66), 73.7% (14/19), and 83.5% (71/85), respectively. ¹⁸F-FDG PET/CT in conjunction with conventional imaging changed the sensitivity, specificity, and overall accuracy of conventional imaging alone from 75.8% (50/66) to 95.5% (63/66) (P<0.05), 68.4% (13/19) to 57.9% (11/19) (P>0.05), and 74.1% (63/85) to 87.1% (74/85) (P<0.05), respectively.

 

CONCLUSIONS: ¹⁸F-FDG PET/CT is of great value in differentiating malignant from benign origins of obstructive jaundice and is a useful adjuvant to conventional imaging. ¹⁸F-FDG PET/CT should be recommended for further etiological clarification.

 

(Hepatobiliary Pancreat Dis Int 2015;14:516-522)

 

KEY WORDS: obstructive jaundice; fluorodeoxyglucose; positron emission tomography/computed tomography; computed tomography; magnetic resonance imaging

Obstructive jaundice is secondary to the complete or incomplete obstruction of the bile outflow tract, with clinical symptoms manifesting as yellow skin and sclera, itching, dark urine, and clay-colored stools.^[1] The disease often exhibits an acute onset and rapid progression and can lead to severe impairments of liver and kidney functions and coagulation disorders, with high morbidity and mortality rates.^{[2, 3]}

 

The various origins of obstructive jaundice make the diagnosis of the disease difficult. Malignant origins commonly include biliary, pancreatic, and other tumors that involve the bile duct; benign origins commonly include bile duct stones and pancreato-biliary inflammation.^[1] These diseases often reinforce each other and interconvert throughout development. Multiple diseases are often associated and easily result in missed diagnoses and misdiagnoses.^[4-6] Additionally, some rare origins, such as lymphoma and xanthogranulomatous cholecystitis,^{[7, 8]} also increase the difficulty of the diagnosis.

 

The clinical treatment decisions for obstructive jaundice vary greatly and mainly depend on whether the origin is a malignant or benign lesion. Treatment methods include minimally invasive interventions, palliative jaundice treatments, radical surgery, radiotherapy, and chemotherapy. Different methods of treatment may greatly affect the prognosis of the patient.^{[4-6, 9, 10]} For patients with early-stage tumors, the ideal time for a radical cure may be missed because of missed or incorrect diagnoses, leading to reduced patient survival. Conversely, the misdiagnosis of a benign lesion as malignant, leading to unnecessary surgical treatment, is also undesirable because such surgeries (e.g., pancreaticoduodenectomy) often cause significant trauma with many complications^{[9, 10]} and reduce the patient's quality of life while unnecessarily increasing the financial burden. Therefore, the early identification of malignant or benign obstructive jaundice is essential to the decision-making process and prognosis evaluation.

 

Imaging examinations play an important role in the diagnosis of obstructive jaundice. Although many imaging modalities, such as ultrasonography (US), computed tomography (CT), magnetic resonance cholangiopancreaticography (MRCP), endoscopic ultrasonography (EUS), endoscopic retrograde cholangiopancreaticography (ERCP), and percutaneous transhepatic cholangiography (PTC), have been used to facilitate the differential diagnosis of this disease, a non-invasive imaging modality with high sensitivity and specificity is not currently available.^{[11, 12]}

 

Given its advantages in both functional and anatomical imaging, ¹⁸F-FDG PET/CT has been widely applied for the detection and diagnosis of malignant tumors and has achieved positive results in determining the etiology of some difficult miscellaneous diseases.^[13-15] Although a few relevant reports have indicated that ¹⁸F-FDG PET/CT is of value in the assessment of biliary stricture,^{[16, 17]} the sample sizes were small, and the added benefit of ¹⁸F-FDG PET/CT after conventional imaging has not been evaluated in differentiating malignant from benign origins of obstructive jaundice. In the present study, we assessed the role of ¹⁸F-FDG PET/CT in the differential diagnosis of 85 patients with obstructive jaundice and quantified the added value of ¹⁸F-FDG PET/CT to conventional imaging (enhanced CT and/or MRI).

 

 

We retrospectively reviewed the clinical data of consecutive patients who had been referred to the Nanfang PET Center of Nanfang Hospital at Southern Medical University for the evaluation of obstructive jaundice from October 2005 to July 2013. Inclusion criteria were as follows: the clinical confirmation of obstructive jaundice in the patient; an ¹⁸F-FDG PET/CT performed within 2 weeks after an enhanced CT and/or MRI; and a final diagnostic result that was either pathologically diagnosed or obtained surgically and confirmed with at least 6 months of clinical follow-up.

 

A total of 85 patients met the above criteria were enrolled in this study. The characteristics of the patients are shown in Table 1.

 

All PET/CT scans were performed on a Discovery LS PET/CT Scanner (GE Healthcare, Waukesha, WI, USA) or a Biography mCT PET/CT Scanner (Siemens AG, Munich, Germany). The ¹⁸F was produced in a PET trace cyclotron (GE Company). ¹⁸F-FDG was automatically synthesized in a chemical synthesis module (Beijing PET Biotechnology Co., Ltd., China) with a radiochemical purity >95%. After fasting for more than 6 hours, the patient was intravenously injected with 5.5 MBq/kg ¹⁸F-FDG and then was instructed to lie down in a dark room for approximately 1 hour. PET and non-enhanced CT imaging were performed after emptying the urinary bladder. Scanning was performed from the middle femur to the cranial vault. The PET images were reconstructed according to the iterative ordered subset expectation maximization (OS-EM) method. The thicknesses of CT image reconstruction were 4.25 mm and 3.0 mm respectively, and the PET and CT images were individually transferred to the Xeleris and Syngo MMWP workstations to display the frame-on-frame fusion images.

 

All PET/CT images were individually evaluated by 2 nuclear medicine physicians who did not know the laboratory test results and other imaging information. If disagreements occurred, consesus were reached after consultation. For the semiquantitative analysis, a region of interest (ROI) was drawn along the maximum margin of the lesion on the PET image, and the standardized uptake value (SUVmax) was measured. For those patients with negative PET scans, the ROI was drawn along the margin of the lesion displayed on the non-enhanced CT image and copied to the corresponding region on the transverse PET image. For the visual analysis of PET/CT, the non-enhanced CT scan was assessed to determine the exact location of the lesion. The PET result was considered malignant if a lesion causing biliary obstruction exhibited focally high FDG uptake compared with the adjacent normal tissue, but it was considered benign if a lesion causing biliary obstruction exhibited low FDG uptake or diffuse high FDG uptake compared with the adjacent normal tissue.

 

All interpretations from conventional imaging, including enhanced CT and/or MRI, were obtained from the database of the Nanfang Hospital and were reviewed by 2 radiologists. Both PET/CT interpretations and conventional imaging interpretations were divided into true-positive, false-negative, false-positive, and true-negative.

 

The data were expressed as means±standard deviations. Quantitative data were compared using Student's t test, and qualitative data were compared using the Chi-square test or Fisher's exact test. All of the statistical analyses were performed using MedCalc, Version 9.6.2.0 (MedCalc Software, Ostend, Belgium). A P value less than 0.05 was considered statistically significant.

 

 

Seventeen of origins causing biliary obstruction were found in the 85 patients (Table 2). Of the 66 patients with malignancy, 54 were subjected to pathological diagnoses (surgery in 32 patients, ERCP biopsy in 5, brush cytology in 8, EUS biopsy in 6, and PTC brush cytology in 3); 12 underwent surgery indicating that the tumor could not be resected, and no biopsy was done to avoid postoperative complications and tumor spread, including 11 patients with tumors (8 patients with pancreatic head carcinoma and 3 with ampullary carcinoma) involving the major blood vessel and 1 patient with hilar cholangiocarcinoma extending to the bilateral intrahepatic bile duct. Among the 19 patients with benign lesions, 13 were subjected to pathological diagnoses (surgery in 6 patients, ERCP biopsy in 4, and EUS biopsy in 3), and 6 underwent surgery showing no mass at the level of biliary obstruction. No biopsy was done in these patients including 4 patients with bile duct stones and 2 with bile duct stricture. These diagnoses were confirmed by at least 6 months of clinical follow-up.

 

The SUVmax values were 8.2±4.4 (1.2-23.2) and 4.0±5.0 (1.1-22.3), respectively for malignant and benign lesions causing biliary obstruction (P<0.05).

 

Visual analysis showed that ¹⁸F-FDG PET/CT was true-positive in 57 (86.4%) of 66 patients and false-negative in 9 (13.6%) patients. Low FDG uptake was seen in 7 of the false-negative patients: 1 patient with pancreatic head cancer, 1 with ampullary carcinoma, 1 with common bile duct cancer, 1 with hilar cholangiocarcinoma, 1 with intrahepatic cholangiocarcinoma, 1 with pancreatic head cancer associated with pancreatitis showed diffuse high FDG uptake in the pancreas and was interpreted as only pancreatitis, and 1 with duodenal cancer associated with pancreatitis showed diffuse high FDG uptake in the pancreas that masked the tumor FDG uptake and was considered to be only pancreatitis.

 

¹⁸F-FDG PET/CT was true-negative in 14 (73.7%) of 19 patients and false-positive in 5 (26.3%) patients. Among these false-positive patients, 1 had multiple common bile duct stones associated with adenomyomatosis of the gallbladder presented as an obvious thickening of the gallbladder wall with high FDG uptake and was misdiagnosed as gallbladder carcinoma and multiple common bile duct stones; 1 had autoimmune pancreatitis showing focal high FDG uptake in the pancreatic head, which was considered as pancreatic head cancer; 1 had xanthogranulomatous cholecystitis associated with intrahepatic cholangitis showing focal high FDG uptake in the gallbladder wall and liver tissue around the bile duct, which was considered gallbladder carcinoma with hepatic metastasis; 1 had pancreatitis associated with pancreatic head abscess showing focal high FDG uptake, which was misdiagnosed as pancreatic cancer associated with pancreatitis; and 1 had common bile duct stricture associated with post-ERCP pancreatitis showing focal FDG uptake, which was considered as pancreatic cancer.

 

Overall, the sensitivity, specificity and overall accuracy for differentiating malignant from benign origins with ¹⁸F-FDG PET/CT were 86.4% (57/66), 73.7% (14/19) and 83.5% (71/85), respectively.

 

Altogether 111 conventional imaging studies (74 enhanced CT and 37 MRI) were carried out to evaluate obstructive jaundice in 2 weeks preceding each PET/CT study, including 26 patients with both enhanced CT and MRI, 48 with enhanced CT alone, and 11 with enhanced MRI alone. In addition, MRCP was performed together with enhanced MRI in 11 patients.

 

When ¹⁸F-FDG PET/CT was compared with conventional imaging in differentiating malignant from benign origins of obstructive jaundice, 19 (28.8%) of 66 malignancies exhibited a discrepancy. ¹⁸F-FDG PET/CT was true-positive in 13 (19.7%) patients where conventional imaging was false-negative (typical cases are shown in Figs. 1-3). This number included 7 (10.6%) patients with tumors missed on conventional imaging, including common bile duct carcinoma in 2 patients, pancreatic head carcinoma in 2, ampullary cancer in 1, intrahepatic bile duct cystadenocarcinoma recurrence after operation in 1, and gastric antral cancer in 1. Six (9.1%) patients with tumors showed atypical manifestations which were falsely interpreted as benign lesions on conventional imaging, including 1 patient with gallbladder carcinoma showing mild thickening of the gallbladder wall which was falsely interpreted as cholecystitis, 2 patients with pancreatic head carcinoma showing pancreatic head swelling which was falsely interpreted as chronic mass-forming pancreatitis, 2 patients with common bile duct carcinoma showing mild thickenings of the bile duct wall which were falsely interpreted as bile duct stricture, and 1 patient with intrahepatic cholangiocarcinoma associated with tumor necrosis that was falsely interpreted as a liver abscess. ¹⁸F-FDG PET/CT was false-negative while conventional imaging was true-positive in 6 patients, and both ¹⁸F-FDG PET/CT and conventional imaging were false-negative in 3 patients (PET/CT false-negative in 9 patients mentioned above). Both ¹⁸F-FDG PET/CT and conventional imaging were true-positive in the remaining 44 patients. Therefore, ¹⁸F-FDG PET/CT in conjunction with conventional imaging increased the sensitivity of conventional imaging alone from 75.8% (50/66) to 95.5% (63/66) (P<0.05).

 

Of the 19 patients with benign lesions, 5 (26.3%) were diagnosed differently by ¹⁸F-FDG PET/CT and conventional imaging. ¹⁸F-FDG PET/CT was true-negative in 3 patients whereas conventional imaging was false-positive. The 3 patients included 1 patient with cholecystolithiasis associated with hypertrophic cholecystitis showing obvious thickening of the gallbladder wall which was misdiagnosed as gallbladder cancer, 1 patient with chronic mass-forming pancreatitis showing a pancreatic mass which was misdiagnosed as pancreatic carcinoma, and 1 patient with common bile duct stricture showing irregular thickening of the common bile duct wall which was misdiagnosed as cholangiocarcinoma by conventional imaging. ¹⁸F-FDG PET/CT was false-positive while conventional imaging was true-negative in 2 patients, and both ¹⁸F-FDG PET/CT and conventional imaging were false-positive in 3 patients (PET/CT was false-negative in the 5 patients mentioned above). Both ¹⁸F-FDG PET/CT and conventional imaging were true-negative in the remaining 11 patients. Therefore, ¹⁸F-FDG PET/CT in conjunction with conventional imaging decreased the specificity of conventional imaging alone from 68.4% (13/19) to 57.9% (11/19) (P>0.05). Overall, combined ¹⁸F-FDG PET/CT with conventional imaging increased the accuracy of conventional imaging alone from 74.1% (63/85) to 87.1% (74/85) (P<0.05).

 

 

¹⁸F-FDG PET is a noninvasive diagnostic technique utilizing biochemical metabolic differences between benign and malignant tissues. Integrated ¹⁸F-FDG PET/CT combines functional imaging and anatomic imaging and has increased diagnostic accuracy.^[13] However, the role of ¹⁸F-FDG PET/CT in differentiating malignant from benign origins of obstructive jaundice has not been fully elucidated. Studies^{[16, 17]} have shown that this technique is of importance in diagnosing biliary stricture. Wakabayashi et al^[16] reported that the sensitivity and specificity of ¹⁸F-FDG PET in diagnosing malignancy in 30 patients with biliary stricture were 90.5% and 77.8%, respectively. Nishiyama et al^[17] reported that the sensitivity, specificity and accuracy of ¹⁸F-FDG PET in the differential diagnosis of cholangiocarcinoma causing biliary stricture in 37 patients were 82.8%, 87.5% and 83.8%, respectively.

 

This study showed that the SUVmax, a semi-quantitative index of glucose uptake, was significantly different between malignant and benign lesions causing obstructive jaundice. This difference provided the basis for the PET/CT-assisted differential diagnosis in this setting. Moreover, the results of visual analysis confirmed that ¹⁸F-FDG PET/CT played a significant role in differentiating malignant from benign origins of obstructive jaundice, with a sensitivity, specificity and accuracy of 86.4%, 73.7% and 83.5%, respectively.

 

The high sensitivity of PET/CT for the differential diagnosis of obstructive jaundice is primarily related to high FDG uptake in the malignancies causing biliary obstruction. The majority of malignant tumors leading to biliary obstruction, such as cholangiocellular and pancreatic cancers, have high levels of glucose transporter and hexokinase.^[18-20] glucose transporter and hexokinase promote high accumulation of FDG in tumor cells and induce cellular phosphorylation that makes tumor's FDG uptake strongly positive.^[21]

 

However, ¹⁸F-FDG PET/CT still has limitations in diagnosing the origins of obstructive jaundice. The cause is mainly related to the SUVmax overlap between malignant and benign lesions, as shown in the present study. The possible causes of false-negative results include a small number of tumors, such as infiltrating cholangiocarcinoma,^[20] that could manifest as a low FDG uptake, easily leading to false-negative interpretations. In addition, the tumor complications (such as pancreatitis) could manifest as diffuse high FDG uptake, which can sometimes conceal the tumor in the image and result in a missed diagnosis.

 

Benign inflammatory lesions may accumulate FDG and result in false-positive interpretations.^{[8, 14, 22]} Our study showed that pancreatic abscess, xanthogranulomatous cholecystitis, adenomyomatosis of the gallbladder, autoimmune pancreatitis, and post-ERCP pancreatitis manifest as focal high FDG uptake that may mimic malignant tumors and lead to false-positive diagnoses.

 

In conventional imaging modalities, CT and MRI/MRCP are very useful in determining the presence, level, extent and severity of biliary obstruction.^{[23, 24]} Although these techniques may also determine the cause of obstruction in most cases, not all cases are correctly diagnosed.^[11] A gray area may persist in conventional imaging when differentiating malignant from benign origins of obstructive jaundice, particularly when there is no evidence of a mass or stone.^[16] The coexistence of various lesions causing biliary obstruction may also result in missed diagnoses and misdiagnoses.^[4-6] Additionally, the morphological manifestations between benign and malignant lesions causing biliary obstruction overlap on conventional imaging,^[25] which may result in misdiagnoses. A prospective study by Rösch et al^[12] showed that the sensitivity and specificity in the differential diagnosis of malignant and benign biliary stricture were 77% and 63% for CT and 85% and 71% for MRCP, respectively. A review^[11] indicated that the accuracy of CT in the differential diagnosis of malignant and benign obstructive jaundice varied greatly over a range of 70%-94%. A retrospective study^[25] showed that the sensitivity, specificity and accuracy of MRCP for the differentiation of malignant from benign causes of biliary stricture were 81%, 70% and 76%, respectively.

 

By virtue of the detection of metabolic changes, ¹⁸F-FDG PET/CT provides added value to conventional imaging in various diseases.^{[26, 27]} The present study confirmed that ¹⁸F-FDG PET/CT helped to detect missed diagnoses and correct misdiagnosed cases based on conventional imaging in differentiating malignant from benign origins of obstructive jaundice. ¹⁸F-FDG PET/CT in conjunction with conventional imaging increased the sensitivity and accuracy of conventional imaging alone from 75.8% to 95.5% (P<0.05) and 74.1% to 87.1% (P<0.05), respectively, although this combined approach slightly decreased the specificity from 68.4% to 57.9% (P>0.05).

 

This study possessed some limitations. This study is a retrospective analysis of patients who underwent ¹⁸F-FDG PET/CT after conventional imaging within a defined time frame, possibly leading to selection bias. Although the standard ¹⁸F-FDG PET/CT protocol at our institution using low-dose unenhanced CT is of value, PET/CT performed with full-dose enhanced CT or PET/MRI may be more interesting in evaluating patients with obstructive jaundice. Although ¹⁸F-FDG PET/CT in conjunction with conventional imaging is of greater value in differentiating malignant from benign origins of obstructive jaundice, some cases were still misdiagnosed. New markers in PET/CT may be of value in the complementary diagnosis of obstructive jaundice. Invasive imaging modalities, such as ERCP, PTC and EUS, may carry a risk, but they combine morphological diagnosis, tissue samples and therapeutic procedures, and they should be considered as adjunct tools after noninvasive imaging techniques.

 

In conclusion, our results showed that ¹⁸F-FDG PET/CT is of clinical value for differential diagnosis of malignant and benign obstructive jaundice. To a certain extent, ¹⁸F-FDG PET/CT may compensate for the deficiencies of conventional imaging. However, given the high cost of these examinations, ¹⁸F-FDG PET/CT cannot serve as the preferred or conventional imaging method. We suggest that for the patients with obstructive jaundice of undetermined etiology or those for whom it is difficult to establish differential diagnoses using clinical, laboratory, and other imaging examinations, ¹⁸F-FDG PET/CT should be recommended for further etiological clarification.

 

 

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