Diagnostic Value of 18F-FDG PET/CT in Patients with Carcinoma of Unknown Primary

Objective: The aim of this study is to investigate the clinical role of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in patients with carcinoma of unknown primary (CUP). Methods: One hundred twenty one patients with a diagnosis of CUP who underwent whole body 18F-FDG PET/CT imaging were included in this retrospective study. The final diagnoses were confirmed either histopathologically or by clinical follow-up. Results: The 18F-FDG-PET/CT successfully detected the primary tumor in 59 out of 121 (49%) patients. The most common primary tumor as detected by 18F-FDG PET/CT was lung cancer (n=31). In a patient, two primary tumors (colon and prostate) were detected on PET/CT imaging. Bone marrow biopsy revealed prostate cancer in this patient and the colon cancer was accepted as a synchronous second primary tumor. 18F-FDG PET/CT findings were false-positive in 11 patients. 18F-FDG PET/CT could not detect any primary lesion in 51 patients, whose conventional work-up detected a primary tumor in 11 and thus considered as false-negative. The sensitivity, specificity rate and accuracy of 18F-FDG PET/CT in detection of primary tumor were identified as 84%, 78% and 82%, respectively. Conclusion: Whole body 18F-FDG PET/CT is an effective method for detecting the primary tumor in patients with CUP. In addition to detecting the primary tumor, it can also help determine disease extent and contribute to patient management.


Introduction
Carcinoma of unknown primary (CUP) refers to the presence of metastatic disease for which the site of the primary lesion remains unidentified after conventional diagnostic procedures. CUP accounts for approximately 2.3-4.2% of cancer in both men and women (1,2). The mean survival is between 3-11 months, and only 25% of patients survive over one year (3,4). Several studies have shown that survival of patients in whom the primary tumor has been detected was higher than that of patients in whom the primary tumor has remained unknown (5,6). Various radiologic methods and serum tumor markers can be used for primary tumor detection. However, the primary tumor could be detected in less than 20% of patients with CUP (1). Although spontaneous regression or immune-mediated destruction of primary tumor or the small size of a primary tumor may be an explanation, it is not yet fully understood why primary tumors remain undetected (2,7,8). Several studies reported that 18 F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) has higher sensitivity than other imaging methods for detection of the primary tumor (9,10,11). The aim of this retrospective study is to evaluate to primary tumor detection efficiency of 18 F-FDG PET/CT in patients with CUP.

Patient Population
All patients who have been referred to our department for 18 F-FDG PET/CT with a diagnosis of CUP from April 2013 to March 2016 were retrospectively evaluated. Patients who had inadequate medical records or irregular clinical followup data and who had chemotherapy before imaging were excluded. 121 patients (79 men, 42 women, age range 30-86 years, mean 63±12 years) were analyzed finally in the study. Ninety five out of 121 patients were proved to have metastases histopathologically and 26 patients had highly suspicious metastases by conventional imaging [8 patients with multiple lung metastases detected by CT, 10 patients with multiple bone metastases detected by scintigraphy and/or magnetic resonance imaging (MRI), 5 patients with multiple liver metastases by MRI and/or US, and 3 patients with brain metastases detected by MRI]. Locations of the metastatic foci that have been proven histologically were as follows; 36 in lymph nodes, (21 cervical, 6 supraclavicular, 4 axillary, 2 mediastinal, 2 inguinal, 1 retroperitoneal), 19 in liver, 13 in bone, 6 in brain, 3 in soft tissue, 1 in adrenal gland, 1 in lung, 9 patients had peritoneal implants or malignant ascites, 6 patients had malignant pleural effusion and 1 patient had malignant pericardial effusion. The study were approved by the Adnan Menderes University of Local Ethics Committee (protocol number: 2017/1043).

F-FDG PET/CT Imaging
All patients underwent 18 F-FDG PET/CT imaging after 6-8 hours of fasting. Before injection of 18 F-FDG, the medical history, weight and blood sugar level of the patients were recorded. All patients' blood sugar levels were less than 180 mg/dL prior to imaging. Oral contrast was given to all patients. After intravenous administration of 270-370 MBq of 18 F-FDG, patients rested in a quiet room. Imaging was performed after a resting period of 60 minutes with (Siemens Biograph mCT 20 Excel) PET/CT scanner. Images were acquired from the head to the feet. The CT transmission scan was acquired with 140 kVp and 110 mA and 3 mm slice thickness. PET scan was acquired at 2-4 min per bed position. 18 F-FDG PET/CT images were evaluated both visually and semi-quantitatively by two nuclear medicine physicians. Abnormal 18 F-FDG uptake (SUV max ≥2.5) with an anatomical correlation in any tissue or organ other than the metastases sites was considered as the primary site. The final results were confirmed either histopathologically or by clinical follow up including other imaging methods.

Data Analysis and Statistical Evaluation
The final diagnosis was considered true-positive (TP) when
The sensitivity, specificity rates and accuracy of 18 F-FDG PET/CT in detection of primary tumor were identified as 84%, 78% and 82%, respectively. When 36 patients with lymph node metastases were evaluated separately, primary tumors were correctly identified in 14 out of 36 patients. In these cases, the sensitivity, specificity and accuracy were calculated as 66%, 75% and 70%, respectively. There were eleven patients in whom primary tumors were reported incorrectly by 18 F-FDG PET/CT imaging. These results were accepted as false-positive (Table 2). A falsepositive case is presented in Figure 2.
The primary tumor could not be identified in 51 (42%) patients. Forty of these patients were TN. The remaining 11 patients, 18 F-FDG PET/CT did not detect any lesion but the primary tumors were detected during clinical follow-up (mean 6.8 months, range: 2-30 months). These FN results are listed in Table 3. images showed hyper-metabolic focus in the prostate and wall-thickness on descending colon with pathologically increased 18 F-FDG uptake, which were later confirmed as prostate adenocarcinoma and colon adenocarcinoma by histopathology  Additional distant metastases were detected in 45 out of 59 (76%) patients whose primary tumors were detected correctly by 18 F-FDG PET/CT. In patients with only lymph node metastases, additional solid organ metastases were detected in 5 patients out of 36 (14%) with PET/CT imaging.

Discussion
CT and MRI have been the imaging methods of choice in clinical practice in patients with CUP. Although they detect anatomical abnormalities with pathologic contrast enhancement, small or non-enhancing lesions can be overlooked (1). 18 F-FDG PET/CT is gaining acceptance as an imaging method to be used in the management of patients with CUP. Small lesions can be detected with higher sensitivity due to its high lesion-to-background contrast. Several studies reported that 18 F-FDG PET/CT is more sensitive than CT and MRI in the imaging of CUP. In a study, Gutzeit et al. (12) have shown that CT alone indicated a primary tumor in only 8 of 45 patients (18%) while 18 F-FDG PET/CT detected the primary site in 15 of 45 patients (33%). In another study, Roh et al. (13) have reported that the sensitivity rate of 18 F-FDG PET/CT (87.5%) was significantly higher than that of CT (43.7%) for the primary tumor in patients with cervical metastases from unknown origin. In several studies, primary tumor detection rate ranged between 24.5-53% for 18 F-FDG PET/ CT in patients with CUP (11,14,15,16). Consistent with   (19,20). Lung, oropharyngeal and pancreatic cancers were reported to be most common primary tumors in patients with CUP (21). In our study, lung (52%) and colon (8%) were the most common sites for primary tumors. Colorectal cancer is the third most common cancer in women and the fourth in men in our country (22). Although there were 21 patients with cervical lymph node metastases in our study, we detected 5 head and neck tumors as true-positive. The most important limitation of 18 F-FDG PET/CT is that it's not a specific tumor imaging technique. Inflammatory lesions or benign tumors with high tracer uptake are the most common causes of false-positive results. In our study, there were eleven false-positive results related to benign tumors or inflammation. In a meta-analysis, authors reported that oropharynx and the lung are the two most common locations of false-positive 18 F-FDG PET/CT results (21). Inflammatory lesions, pulmonary infarction and emboli have been reported as etiologies for false-positive results in the lung (2,12). In this study, 3 out of the 11 false-positive results were detected in the lung. Pulmonary alveolar proteinosis, hamartoma and inflammation were the final diagnosis in these patients. PET/CT diagnosed a false-positive colon cancer in three patients. The final diagnoses were polyps in two patients and diverticulitis in one patient, that were confirmed histopathologically.
In a study, the authors concluded that if 18 F-FDG PET/CT findings are positive, a confirmatory biopsy is necessary due to false-positive results (23).
In our study, 18  Whole body 18 F-FDG PET/CT is also useful in detecting the extent of metastatic disease which may have important implications for clinical management. It is especially important in patients with initial lymph node metastases (2,24). We showed additional solid organ metastases in 5 out of 36 (14%) patients with CUP who presented with lymph node metastases on PET/CT imaging.