Accuracy of FDG PET/CT in discovering the primary site of the patients with histologically proven tumor metastasis (n = 74)
When the results of the other group (the patients with CSM) were excluded, the final values that were found were as follows: TP=32, TN=30, FP=7, FN=6. Accordingly, the calculated sensitivity, specificity, PPV, and NPV values were 84, 81, 82 and 83%, respectively.
FDG PET/CT performance in patients with clinical suspicion of malignancy (n=16)
Among 16 patients with CSM, FDG PET/CT revealed a solitary organ involvement in seven patients and multiple organ involvement in eight patients. Of these, eight of 14 primaries were correctly identified (TP and TN), whereas six were missing (FN). Primary malignancies were missing in two patients and were falsely diagnosed in another, and these lesions were regarded as being both FP and FN findings. In one patient, there were multiple generalized skeletal system lesions, which were diagnosed as metastatic lesions histologically. The result of FDG PET/CT was regarded as TN for this patient, because the primary could not be found by the gold standard either. There was one normal FDG PET/CT study considered as FN, because this patient was later diagnosed as having chronic lymphocytic leukemia (CLL). Although the number of these patients was not sufficient for individual statistics, calculated sensitivity, specificity, PPV, and NPV values were 47, 33, 78 and 11%, respectively (TP=7, TN=1, FP=2, FN=8).
Survival analysis (n=90)
According to our findings, the identification of the primary site did not change life expectancy in this clinical setting (log rank, Mantel–Cox), because there was no statistical difference between the mean survival times of the patients for whom primaries were reached (PR) and the RPU patients (P = 0.232). In our patient population, the ratios of PR and RUP patients were 59% (53 of 90) and 41% (37 of 90), respectively. The death rate was 32% (17 of 53) for the group of PR and 43% (16 of 37) for the group of RPU. The mean survival times were 17.75±2.21 months for the patients of PR and 16.31±1.95 months for RPU patients When the patients were evaluated on the basis of the extension of disease on FDG PET/CT, their mean survival time with disseminated disease was significantly shorter than that of patients with single or no lesion (13.44±1.61, 20.98±2.0 and 26.67±2.73 months, respectively, P=0.014).
Considering the group including RPU patients, the mean survival time of the patients with multiple system involvement on PET/CT was significantly shorter than that of the patients with single or no lesion (13.95±1.69 and 20.69±2.33, 26.67±2.73, respectively; P=0.041) (Fig. 1). According to the PET/CT findings, 51% (19 of 37) of these patients revealed generalized disease with multiple organ involvement, 40.5% (15 of 37) had single organ involvement, and 8% (three of 37) were normal. Among RPU patients, 43% (16 of 37) of the patients (12 of 19 generalized disease, three of 15 single organ involvement, one of three normal) died with a mean survival time of 17.75±2.21 months (mean±SE). In the surviving group, 33% (7 of 21) of the patients revealed generalized disease with multiple organ involvement, 57% (12 of 21) had single organ involvement, and 10% (2 of 21) were normal. The mean survival time of these patients was 16.31±1.95 months.
Follow-up data of patients with remained primary unknown
Among 21 surviving patients during follow-up, two patients had normal findings on FDG PET/CT, whereas 19 patients showed pathological findings. Two of the normal patients were female and metastatic lesions were detected from the axillary lymph node in one and T12 vertebra in the other (histopathological diagnoses were metastatic adenocarcinoma and malign epithelial tumor, respectively). These two patients have been alive without any symptom for 26 and 19 months, respectively.
Among 19 patients with pathological findings, 12 had single and seven had multiple organ involvement. Four solitary lesions were evaluated as suspicious for malignancy (SUVmax=3–3.5). Of these, one patient has been alive for 26 months without any symptoms and there were no findings from various diagnostic tests. One patient has been alive for 25 months with bone metastasis detected in the last year with magnetic resonance imaging (MRI) from the thoracic vertebra. The other two patients have been relatively newly diagnosed and have been followed for 8 and 3 months.
In eight patients, including two with single and six with multiple organ involvement, FDG PET/CT examination was again performed to monitor the disease (Table 5). One patient underwent FDG PET/CT to clear some symptoms and a bone metastasis was missed, which was reached by MRI later. All the others were studied to search for the response to therapy. A complete response was achieved in three patients, of whom one relapsed 6 months later from the last normal FDG PET/CT examination. In the other four patients, of whom two had progressive disease and two had stable disease, chemotherapy regimes were modified.
In this study, including 90 patients suffering from the CUP syndrome, 18F-FDG PET/CT was able to identify 39 sites among 53 primaries confirmed by the gold standard. Our primary detection rate of 43% seems comparable with the report by Seve et al. , in which the 10 previous reports were reviewed showing detection rates ranging from 24 to 63%. As found in this review, the most common localization site of the primary tumor was the lung, with a ratio of 43%, with disseminated findings on FDG PET/CT in our study.
All but one lung primary were correctly identified with their metastases by FDG PET/CT. There were three patients in whom the FDG PET/CT directed the diagnosis of the primaries to the incorrect organs. All of them had disseminated disease on PET/CT and the incorrect organs that were suggested as the primaries were liver, lung, and colon. The correct localization sites were discovered to be lung, bone marrow (CLL), and ovarium, respectively.
Among the other 11 patients with FN results, the FDG distribution in the whole body was exclusively within normal limits in two patients, one with CLL and the other with myeloproliferative disease. The other types of malignancy missed on FDG PET/CT images were prostatic cancer, neurofibroma, testicular cancer, cutaneous epidermoid cancer, multiple myeloma, low-grade NHL, and papillary thyroid cancer. There were two patients in this group for whom the primaries were diagnosed by the gold standard as prostatic cancer in one and testicular cancer in the other. They had multiple hypermetabolic lymphoid masses in all the lymphoid compartments over the whole body from inguinal to the cervical region without any sign with regard to the other organs. When we retrospectively re-analyzed these organs of the primary sites, we could not find any pathological uptake except physiological FDG distribution.
In a fairly large series by Fencl et al. , overall sensitivity and specificity values in detecting the primary site were reported as 62 and 82%, respectively. When they divided the whole population into two groups as patients with HPM and CSM, the sensitivity and specificity were calculated as 54.5 and 75% for the first group and 76 and 86%, respectively, for the second group. In our study, although most of the patients had been studied by previous conventional imaging methods, some patients were initially studied with FDG PET/CT. For this reason, the overall sensitivity calculated in our study (74%) was rather higher than that found by Fencl et al. The overall specificity (78%) was found to be comparable. In contrast with their results, when the same calculations were carried out with regard to patients with HPM only, the sensitivity and specificity were relatively increased to 84 and 81%, respectively. As the ratio of the tumor types that could be easily missed by FDG PET/CT was rather higher in the group of patients with CSM in our study (Table 1) the value of a negative finding in this group was significantly lower (10%).
In the meta-analysis by Seve et al.  from 10 earlier reports, the sensitivity and specificity were calculated as 92 and 82%, respectively. Although the specificity values are comparable, the sensitivity is higher than that in our study. The reviewers of the meta-analysis commented that patients that were included in the PET studies were selected and did not reflect the overall population of patients with CUP, because 91% of the meta-analysis patients had only a single metastatic site, whereas the rate in the literature ranged from 29 to 43%. In accordance with this observation, the ratio of patients with single-site metastasis among all the groups (35%) was found to be within these limits in our study.
FDG PET/CT has also been shown to be useful for detecting second primary cancers . In our series, a second primary cancer was confirmed in one patient when we were searching for the primary tumor with HPM in the adrenal gland. In this patient, not only did we locate the primary tumor in the lung, but, after FDG PET/CT imaging, we identified a second primary tumor in the colon. The second primary could be proved in only one patient, because an invasive application, such as biopsy, was not accepted by most of the patients in whom a primary site had already been reached and who had generalized disease.
Owing to the differences in patient selection criteria and natural heterogeneity between the groups, it was not possible to make direct comparisons with previous studies. Our experience supports the finding that FDG PET/CT is a useful tool for identifying the primary tumor site in addition to the metastatic sites involved. However, the literature reveals some doubts regarding whether the diagnostic tests, including FDG PET with or without CT, make any sense in the diagnosis of CUP, which looked like a sleuth in the investigation of a sinister crime . From this perspective, we focused on the prognostic value of the test in addition to the value in identifying the primary site in our patient population. The identification of the primary site did not change life expectancy in survival analysis when the mean survival of the patients with PR and RPU was compared. However, the mean survival time of the patients with multiple lesions was found to be significantly shorter than that of patients with single/no lesion on FDG PET/CT with regard to all the study population. When the same analysis was carried out for only RPU patients, the finding did not change and suggested that sensitive staging plays an important role in determining life expectancy even in the patients with RPU. This finding was supported by the previous report by Fencl et al. , who showed a shorter life expectancy in patients with a positive FDG PET finding in comparison with patients with a negative FDG PET finding. The investigators concluded that the presence of a hypermetabolic lesion and the increase in the number of involved organs are sensitive prognostic indicators of a shorter life expectancy in patients with CUP.
In this study, FDG PET/CT was also used to monitor the chemotherapy response in some patients with RPU. Although the number of these patients was not large enough to draw a conclusion in statistical means, the test effectively showed complete remission in three patients. Among them, relapse was diagnosed in one patient during follow-up. In four patients, FDG PET/CT revealed unchanged or increased findings after chemotherapy and their therapies were modified. These findings showed that the test has a potential in therapy monitoring in patients with RPU and effectively identifies the primary sites and gives the opportunity to optimize prognosis.
According to our findings, whole-body FDG PET/CT has to be considered as a useful method in CUP syndrome. In the management of these patients, the method offers several advantages such as (i) identification of the primary tumor in nearly half of the patients, (ii) optimal staging and thereby an opportunity to give a prognosis even when the primary could not be found, and (iii) identification of chemotherapy response. The role of the test seems important, especially in monitoring the chemotherapy response considering the metastatic state in most of these patients. Our preliminary results showed that FDG PET/CT could potentially detect therapeutic efficacy. Pretherapeutic scanning could also be useful in evaluating the response after therapy, in addition to helping in the decision of the therapeutic approach according to the findings with regard to the primary site and metastatic state.
These results suggest that FDG PET/CT can be used reliably in an early phase of the diagnostic workup of the patients with CUP syndrome to optimize their management.
The authors thank all the members of the related departments from two centers for their contributions to the routine workup of nuclear medicine, medical oncology, and pathology divisions.
1. Muir C. Cancer of unknown primary site. Cancer 1995; 75:353–356.
2. Levi F, Te VC, Erler G, Randimbison L, La Vecchia C. Epidemiology of unknown primary tumors. Eur J Cancer 2002; 38:1810–1812.
3. Abbruzzese JL, Abbruzzese MC, Lenzi R, Hess KR, Raber MN. Analysis of a diagnostic strategy for patients with suspected tumors of unknown origin. J Clin Oncol 1995; 13:2094–2103.
4. Chorost MI, Lee MC, Yeoh CB, Molina M, Ghosh BC. Unknown primary. J Surg Oncol 2004; 87:191–203.
5. Le Chevalier T, Cvitkovic E, Caille P, Harvey J, Contesso G, Spielmann M, Rouesse J. Early metastatic cancer of unknown primary origin at presentation. Arch Inten Med 1988; 148:2035–2039.
6. Naresh KN. Do metastatic tumors fom an unknown primary reflect angiogenic incompetence of the tumor at the primary site? A hypothesis. Med Hypothesis 2002; 59:357–360.
7. Haas I, Hoffmann TK, Engers R, Ganzer U. Diagnostic strategies in cervical carcinoma of an unknown primary (CUP). Eur Arch Otorhinolaryngol 2002; 259:325–333.
8. Issing WJ, Taleban B, Tauber S. Diagnosis and management of carcinoma of unknown primary in the head and neck. Eur Arch Otorhinolaryngol 2003; 260:436–443.
9. Pavlidis N, Fizazi K. Cancer of unknown primary (CUP). Crit Rev Oncol Hematol 2005; 54:243–250.
10. Townsend DW. A combined PET/CT scanner: the choices. J Nucl Med 2001; 42:533–534.
11. Hany TF, Steinert HC, Goerres GW, Buck A, Schulthess GK. PET diagnostic accuracy: improvement with in-line PET-CT systems-initial results. Radiology 2002; 225:575–581.
12. Bar-Shalom R, Yefremov N, Guralnik L, Gaitini D, Frenkel A, Kuten A, et al. Clinical performance of PET/CT in evaluation of cancer: additional value for diagnostic imaging and patient management. J Nucl Med 2003; 44:1200–1209.
13. Gutzeit A, Antoch G, Kühl H, Egelhof T, Fischer M, Hauth E, et al. Unknown primary tumors: detection with dual-modality PET/CT-initial experience. Radiology 2005; 234:227–234.
14. Freudenberg LS, Fischer M, Antoch G, Jentzen W, Gutzeit A, Rosenbaum SJ, et al. Dual modality of 18
F-fluorodeoxyglucose-positron emission tomography/computed tomography in patients with cervical carcinoma of unknown primary. Med Princ Pract 2005; 14:155–160.
15. Ambrosini V, Nanni C, Rubello D, Moretti A, Battista G, Castellucci P, et al. 18
F-FDG PET/CT in the assessment of carcinoma of unknown primary origin. Radiol Med 2006; 111:1146–1155.
16. Pelosi E, Pennone M, Deandreis D, Douroukas A, Mancini M, Bisi G. Role of whole body positron emission tomography/computed tomography scan with 18
F-fluorodeoxyglucose in patients with biopsy proven metastases from unknown primary site. Q J Nucl Med Mol Imag 2006; 50:15–22.
17. Paul SAM, Stoeckli SJ, von Schulthess GK, Goerres GW. FDG PET and PET/CT for the detection of the primary tumour in patients with cervical non-squamous cell carcinoma metastasis of an unknown primary. Eur Arch Otorhinolaryngol 2007; 264:189–195.
18. Fencl P, Belohlavek O, Skopalova M, Jaruskova M, Kanturova I, Simonova K. Prognostic and diagnostic accuracy of [18
F]FDG-PET/CT in 190 patients with carcinoma of unknown primary. Eur J Nucl Med Mol Imag 2007; 34:1783–1792.
19. Seve P, Billotey C, Broussolle C, Dumontet C, Mackey JR. The role of 2-deoxy-2-(F-18)fluoro-D-glucose positron emission tomography in disseminated carcinoma of unknown primary site. Cancer 2007; 109:292–299.
20. Kim Sy, Roh JL, Yeo NK, Kim JS, Lee JH, Choi SH, Nam SY. Combined 18
F-fluorodeoxyglucose-positron emission tomography and computed tomography as a primary sceening method for detecting second primary cancers and distant metastases in patients with head and neck cancer. Ann Oncol 2007; 18:1698–1703.
21. Dowden S, Miller W. New look at the old management of unknown primary. J Surg Onc 2008; 98:71–72.
Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
carcinoma of an unknown primary; diagnosis; 18F-fluorodeoxyglucose positron emission tomography/computed tomography; prognosis; therapy response