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Diagnostic and prognostic value of F-18 FDG PET/CT in patients with carcinoma of unknown primary

OBJECTIVE Carcinoma of unknown primary (CUP) is inability to detect primary tumor despite all imaging methods with a biopsy-proven tumor metastasis. In the present study, we aimed to investigate the diagnostic and prognostic value of F-18 fluorodeoxyglucose (F-18 FDG) positron emission tomography/computed tomography (PET/CT) in patients with CUP. METHODS The patients with a diagnosis of CUP between November 2009 and January 2020 were evaluated retrospectively. A total of 155 patients (96 men and 59 women) were included in the study. Survival rates of the patients were evaluated by Kaplan–Meier and log-rank statistical analysis. RESULTS The correctly determined primary tumor by F-18 FDG PET/CT was found in 64 patients (41%) (true positive). F-18 FDG PET CT results were negative (false negative) in determining primary tumor localization in 14 (9%) patients whose had local disease. Of the 155 patients, 66 (42.5%) had true-negative results and 11 (7%) had false-positive results. The sensitivity of 82%, specificity of 86%, and accuracy of 84% were calculated. The SUVmax value of the malignant lesion was on average 8.9 (range 3.6–26.1). Kaplan–Meier analysis revealed that the 1-year survival rates were 37.3% in regional disease and 16% in extensive disease (log-rank test, p=0.021). CONCLUSION F-18 FDG PET/CT is a useful method in the detection of primary tumor in patients with CUP. F-18 FDG PET/CT can be helpful the evaluation of the prognosis by showing the extent of the disease.

able subtypes. Determining the location of the primary tumor increases the probability of tumor-specific treatment, thus helping to prolong the survival [5,6]. Fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography/CT (F-18 FDG PET/CT) imaging is used routinely in the diagnosis, staging, restaging, and follow-up in malignancies [7]. F-18 FDG PET/CT is valuable imaging modality to detect the primary lesion in 25-80% of patients whose cannot be visualized by conventional imaging methods. F-18 FDG PET/CT detects a primary tumor site in 41% of patients with extracervical metastases (24-63%) [8]. CT and MRI can show only anatomical abnormalities and abnormal contrast enhancements. However, F-18 FDG PET/ CT also to gather information about metabolic status of the tumor. As stated in the previous studies, F-18 FDG PET/CT is a useful imaging method for finding the primary site with high precision [9]. On the other hand, some authors indicate that there is no superiority of F-18 FDG PET/CT to radiological methods in terms of primary site detection of CUP [10].
In the present study, we investigated the diagnostic and prognostic value of F-18 FDG PET/CT in patient with CUP who were referred to us with various metastases or clinical suspicion of malignancy.

Patients
In this retrospective study, patients with a diagnosis of CUP on F-18 FDG PET/CT imaging between November 2009 to January 2020 were evaluated. The study was approved by the SBU Samsun Training and Research Hospital Local Ethics Committee (protocol number: GOKA/2021/3/9).
Patients whose medical records were lacking or who had chemotherapy before F-18 FDG PET/CT imaging were excluded from the study. Finally, 155 patients (96 men and 59 women, age range 18-86 years, mean SD 57±14) were included in the study. In all patients, appropriate conventional diagnostic imaging procedures including ultrasound, MRI, and/or CT had been performed without identification of the primary tumor. One hundred and twenty-five of 155 patients had histopathologically proven metastatic disease with unknown primary origin. Thirty out of 155 patients were recorded as clinical suspicion of malignancy with their medical history (significant weight loss, unknown fever, increased tumor marker, etc.). The clinical characteristics of the patients are shown in Table 1. The histopathological data were accepted as the gold standard.

Highlight key points
• Carcinoma of unknown primary (CUP) is a biopsy-proven tumor metastasis with unidentified primary site despite all routine imaging methods clinical work-up.
• Whole-body F-18 FDG PET/CT is also useful in the detection of additional solid organ metastasis and to determine the extent of metastatic disease. Identification of additional metastasis may provide more effective treatment and prolonged survival in some cases.
•   ) were calculated. Primary tumor assessment on the PET images was performed by the detection of focally increased glucose (F-18 FDG) metabolism with a SUV max ≥2.5. Malignancy diagnosis is not only based on increased F-18 FDG findings but also these lesions were also accepted as malignant by evaluating of patients' medical history, physical examination findings, laboratory parameters, and the correlation with the non-diagnostic CT images which were concurrently obtained with a PET study. The rate of primary tumor detection was given with the PET/CT and histopathological results together ( Table 2).

Data Analysis
The histopathologically confirmed primary site of malignancy was accepted as true-positive (TP) only. The finding which was not confirmed histopathologically was regarded as false-positive (FP) diagnosis. The multiple hypermetabolic lesions may be found. However, they could not have been differentiated neither in F-18 FDG PET/CT nor in histopathology. In this situation, they were classified as true negative (TN). When the site of primary was not identified by F-18 FDG PET/CT but proved in histopathologic examination, it was regarded as false negative (FN).

Statistical Analysis
We compared the 1-year survival of CUP patients with multiple metastatic diseases and those with local disease.

RESULTS
One hundred and fifty-five patients with CUP aged 18-86 years (mean ±SD: 57±14) were included in the study. Ninety-six were male and 59 were female. One hundred and twenty-five of 155 patients had histopathologically proven metastatic disease with unknown primary site. F-18 FDG PET/CT was able to detect a biopsy-proven primary tumor in 49 of 125 patients: Lung (n: 25), colon (n: 4), breast (n: 4), pancreas (n: 3), ovary (n: 2), nasopharynx (n: 2), and the others (n: 10). F-18 FDG PET/CT identified focal FDG uptake indicative of a primary tumor in nine of 125 which were not confirmed histopathologically. Primary tumor was not detected during the follow-up five of 125 patients with negative F-18 FDG PET/CT. Thirty out of 155 patients were recorded as clinical suspicion of malignancy with their medical history and laboratory examinations (profound weight loss, unknown fever, increased tumor marker, etc.). F-18 FDG PET/CT was able to detect a biopsy-proven primary tumor in 15 of 30 those patients including six non-small-cell lung cancers, four diffuse large B-cell lymphomas, three invasive ductal cancers, one small-cell lung cancer, and one gastric adenocarcinoma. Primary tumor was not detected in four of 30 patients in   TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP   Table 3 TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP  TP   Table 3

TP Results
Primary tumors were correctly detected in 64 of 155 patients by F-18 FDG PET/CT whole-body imaging (44 males and 20 females). The 64 patients were aged between 24 and 79 years (Fig. 1). Primary tumors were confirmed histopathologically. The lung carcinoma was the most common detected tumor in our patients and all the primary tumor diagnosis are shown in Table 3.

FP Results
F-18 FDG PET/CT identified focal FDG uptake indicative of a primary tumor in 11 patients (Fig. 1). However, positive results of F-18 FDG PET/CT were not confirmed histologically or identified during the follow-up (Table 4).

TN Results
Primary tumors could not be detected during the follow-up in 66 patients with F-18 FDG PET/CT (Fig. 1).

FN Results
Primary tumor was not detected during the follow-up of 14 patients with negative F-18 FDG PET/CT (Table 5).

Diagnostic Values of F-18 FDG PET/CT in CUP
The sensitivity, specificity, and accuracy of F-18 FDG PET/CT in the detection of primary tumor site were 82%, 86%, and 84%, respectively. The median SUV max of the lesions with maximum uptake in patients with remaining malignant lesions on F-18 FDG PET/CT was 8.9 (range, 3.6-26.1). The 1-year survival rates were 37.3% in locoregional disease, 16% in the multiple metastatic disease on F-18 FDG PET/CT by Kaplan-Meier analysis (log-rank test, p=0.021) (Fig. 2). 2). Histopathological evaluation of the patient for whom we recommended histopathological examination for thyroid cancer was reported as a benign nodule.

DISCUSSION
The subject of this study is patients with cancer of unknown primary (CUP) who referred our clinic with various site lesions suspected of cancer metastasis or clinical suspicion. Our results demonstrated that F-18 FDG PET/CT has beneficial role in detecting of primary site of tumor and additional metastasis. F-18 FDG PET/CT can also contribute to the evaluation of the prognosis. Nowadays, CT and MR are routinely used imaging methods in the detection and follow-up of tumors. The main advantage of these methods is the cross-sectional images of the whole body which is also especially important in patients with CUP. However, the detection of only structural abnormalities and pathological contrast enhancements are the main limitations of CT and MRI. In some cases, tumor cannot be detected such as very small lesions or non-enhancing lesions. One of the main characteristics of primary tumor is too small to be detected in many patients with CUP [1,11]. In addition, metabolic changes can occur without accompanying anatomical pathologies and cannot be showed by conventional imaging modalities. Therefore, CT and MRI may be insufficient and limited to the detection of CUP with low sensitivity [12].
The reasons why the most primary tumors cannot be detected in CUP are still unclear. There are some suggestions that spontaneous disappearance (angiogenetic) after metastasis, destruction of the primary tumor by immune system-related causes, so tiny tumor to detect by imaging methods or the necrotic tumor on the intestinal wall is removed through the gastrointestinal tract [1,11].
FDG is a very suitable radiotracer for PET imaging due to increase in glucose metabolism in most cancer types (Warburg effect) [13]. F-18 FDG PET/CT modality can identify abnormal metabolic properties of the structures.
It was recently reported that F-18 FDG PET/CT is superior to CT and MRI imaging in the detection of CUP. In one study, while CT alone was demonstrated to identify the primary site only in 8 patients (18%), on the other hand, F-18 FDG PET/CT was able to detect the primary site in 15 patients (33%) [14]. In our study, F-18 FDG PET/CT detected primary tumors in 64 of 155 patients (41.2%).
In the study of Han et al. [12], sensitivity, specificity, and accuracy of F-18 FDG PET/CT were noted as 91.5%, 85.2%, and 88.3%, respectively. These results were lower in a study of Cengiz et al. [15] as 84%, 78%, and 82%. In our study, we detected the sensitivity, specificity rates, and accuracy of F-18 FDG PET/CT of primary tumor that 82%, 86%, and 84%, respectively. F-18 FDG PET/CT whole-body imaging is not only could detect the primary site but also present the extent of metastatic disease. Accordingly, F-18 FDG PET/CT prevents further imaging and invasive procedures and provides to start faster suitable therapy [16].
Lung, nasopharynx, oropharyngeal, and pancreatic cancer were declared to be most common primary tumors in patients with CUP [15]. Autopsy studies also showed that lung and pancreatic cancer are also the most common primary tumor [17]. In our study, the most common sites for primary tumors were lung (51%), lymphoma (12.5%), and colon (7.8%). In addition, we were able to localize carcinoma of ovarian, nasopharyngeal, oropharyngeal, breast (invasive and epidermoid), gastric, pancreatic, renal cell, and extramedullary acute myeloid leukemia and malign melanoma.
The most often reported locations of false-positive results in F-18 FDG PET/CT imaging were the lung and the oropharynx (15%) [18]. The cause of that may be FDG uptake in benign conditions with increased glycolysis or high physiological FDG uptake. Unlikely in our study, two out of the 11 false-positive results were detected in the lung. However, the thyroid was the most common site in five patients of false-positive results. FDG uptake in thyroid carcinomas as well as thyroiditis, follicular adenomas, or nodular goiters may be the cause of this result [19]. Other false-positive results occurred in the abdomen. We supported that the combination of functional and anatomical imaging (positron emission tomography and computerized tomography scans) should reduce the rate of false-positive diagnosis.
In our study, the primary tumor could not be detected in 80 patients (51.6%). Primary tumors were detected histopathologically alone in 14 of 155 (9%) patients and it was considered as FN. Breast cancer was the most common cause of false-negative F-18 FDG PET/CT results (27%) [20]. It was because of the inability of F-18 FDG PET/CT to show lesions smaller than <1.0 cm and low-grade lesions with decreased or no FDG uptake. However, false-negative F-18 FDG PET/CT results of our study were prostate cancer, low-grade lymphomas, and head-and-neck cancers. Interestingly, we did not detect breast tumor in the present study. We suggest that our FN results may be due to the low signal-to-noise ra-tio, low tumor differentiation, or low spatial resolution of the PET system for the detecting small lesions.
Yapar et al. [4] showed that lymph node metastasis was localized in 30 patients of 94 patients (41%) and metastatic localization was most often detected in cervical lymph nodes in 21 (70%) of those patients. Park et al. [21] detected that lymph nodes metastasis in 11 patients with the most frequent metastatic localization was in the cervical lymph nodes in series with 20 patients. Yu et al. [7] detected lymph node metastasis in 330 of 449 patients and determined the metastatic localizations as cervical (37.6%), supraclavicular (12.9%), axillary (10.9%), mediastinal (2.7%), and retroperitoneal (2.2%), respectively. In 66 patients of 155 patients had lymph nodes metastases (42.6%) in our study group. Similarly, we found that 40 (60.6%) had cervical, 10 (15.1%) mediastinal, 9 (13.6%) axillary, 6 (9%) retroperitoneal, and 1 (2%) inguinal lymph node metastasis. Whole-body F-18 FDG PET/CT is also useful in the detection of additional solid organ metastasis and determination of the extent of metastatic disease [1]. Identification of additional metastasis may provide more effective treatment and prolonged survival in some cases. We also detected other solid organ metastases in 82 (52.9%) of 155 patients.
F-18 FDG PET/CT can detect second primary tumors [22]. We also detected second primary tumor in one patient. The primary tumor located in the lung, and additionally, we identified a second primary tumor in the colon in F-18 FDG PET/CT imaging.
High SUV max and F-18 FDG uptake pattern on PET/ CT scan are considered an important parameter for locating the primary tumor. The SUV-based quantitative analysis of the hypermetabolic lesions is very useful to make difference between benign from malignant tumors. At present, a maximum SUV of 2.5 is a widely accepted standard threshold in the diagnosis of the malignancy [23]. In our study, the SUV max of the lesion with maximum uptake in patients with remaining malignant lesions on F-18 FDG PET/CT was in the median of 8.9 (range, 3.6-26.1).
Unlike CT and MRI, F-18 FDG PET/CT provides high lesion-to-background contrast. This characteristic makes F-18 FDG PET/CT a potentially more sensitive imaging modality in detection of primary sites and metastasis [24]. On the other hand, in a prospective study, it was found that there were no significant differences between of the imaging methods of F-18 FDG PET/ CT and CT regarding sensitivity, specificity, and accuracy [10]. In this prospective study, TP primary tumor sites identified 38 (28.1%) in F-18 FDG PET/CT and 43 (31.9%) in CT. In addition, whole-body MR imaging may be alternative to F-18 FDG PET/CT. There is no potentially harmful radiotracer in MR and MR contrast agents are more preferred compared CT with iodinated contrast [25]. However, in the literature, there are not enough reports on the diagnostic competency of wholebody MRI in detecting of CUP [26].

Conclusion
Whole-body F-18 FDG PET/CT imaging is both noninvasive and sensitive modality allowing for the detection of a primary tumors and additional metastasis in patients with CUP. Hence, F-18 FDG PET/CT is also useful helping in the decision of the therapeutic approach. We suggest that F-18 FDG PET/CT is convenient wholebody imaging modality in patients with CUP for diagnostic and prognostic evaluation.