British Journal of Radiology (2004) 77, 1000-1006
© 2004 British Institute of Radiology
doi: 10.1259/bjr/69059431
In search of an unknown primary tumour presenting with extracervical metastases: the diagnostic performance of FDG-PET
U Joshi, MD
1
J J M van der Hoeven, MD
1,3
E F I Comans, MD, PhD
1
G J Herder, MD
1
G J J Teule, MD, PhD
1 and
O S Hoekstra, MD, PhD
1,2
Departments of 1 Nuclear Medicine and PET Research and 2 Clinical Epidemiology and Biostatistics, VU University Medical Centre, Amsterdam and 3 Department of Internal Medicine, Amstelveen Hospital, Amstelveen, The Netherlands
Correspondence: Otto S Hoekstra, Department of Nuclear Medicine and PET Research, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands
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Abstract
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A retrospective study was carried out to determine the performance of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with unknown primary tumours presenting with metastases external to the neck. All patients referred to an academic PET centre (July, 1997 to December, 2000) presenting with an extracervical metastasis and no prior systemic therapy were eligible. The minimum follow-up period was 11 months. From 63 eligible cases, known metastases were FDG avid in all but one neuroendocrine process. PET scans were retrospectively classified as positive for a primary tumour (n=29), i.e. revealing at least one anatomical site suspected to be the primary tumour. This was confirmed in 16, either by histology (n=10) or radiological and clinical follow-up (n=6). There were four false positive cases. In nine patients, the primary tumour was never confirmed. Of the remaining 33 negative PET scans the primary tumour was clinically not found in 18. Follow-up and additional pathology investigations demonstrated the primary tumour in 15. A survey on clinical usefulness of PET (response rate 83%) suggested that PET positively contributed to diagnostic understanding in 29 of 52 evaluable cases. Applied late in the diagnostic trajectory, approximately four patients need to be scanned by PET in order to find one primary tumour. However, in addition to direct demonstration of unknown primaries, there appears to be a positive effect on the diagnostic work-up of these patients of a similar magnitude.
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Introduction
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An unknown primary tumour is defined as a biopsy-proven malignancy from unidentified anatomical origin following diagnostic evaluation [1]. Investigation often comprises a complete history, thorough physical examination, a blood chemistry profile, chest radiography, abdominopelvic CT and mammography in women [1–4]. If these tests do not disclose the primary tumour, a myriad of diagnostic tests are available to the clinician. The estimated incidence of unknown primary tumours is 2–7% of all cancers [1, 3, 5–7]. In The Netherlands, the observed incidence is 2500 per year [8].
The medical oncologist must be certain that tumours that are potentially curable when metastatic have been ruled out, such as lymphomas and germ cell tumours in addition to tumours that may have a good response to therapy such as breast cancer, ovarian cancer, prostate cancer and small cell lung cancer. The identification of a primary tumour may offer the possibility of a more specific and efficacious treatment than if the patient is treated with a general regimen for tumours of unknown primary origin. The dilemma for the oncologist is how much investigation is appropriate. For example, an extensive endoscopic procedure is expensive and may put the patient at risk for complications of this procedure. Therefore the oncologist needs tools that give a high probability of finding the primary tumour with a minimum of discomfort for the patient.
Positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) is an attractive tool for this indication since most malignancies are FDG avid, its biodistribution is favourable and the whole body is scanned in a single session with minimal patient discomfort. Whereas several studies have indicated that FDG-PET is useful to locate primaries within the head and neck region [9–14], very few data are available on its usefulness in extracervical metastases. After exclusion of melanoma patients, who are considered to be a separate subset [1–4], accumulated data from the four studies [15–18] providing a specific evaluation of the yield of PET in extracervical metastases consists of 48 patients with an overall approximate aggregated yield of 50%. Rades et al [19] have also evaluated the value of PET in cancer of unknown primary. However, it was not possible with the available data in the article to calculate the yield in the subset of patients presenting with extracervical metastases. Therefore, the aim of the present study was to examine the diagnostic performance of FDG-PET scanning after a negative clinical work-up in patients presenting with extracervical metastases from an unknown primary tumour.
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Materials and methods
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Patients
From the FDG-PET scans performed from July 1997 to December 2000, patients presenting with metastases associated with unknown primary tumours were identified using the diagnostic coding system applied in our institution [20]. Within this period, referrals for this indication were accepted only if the indicated standard work-up procedures had been done, according to the referring clinician. Inclusion criteria consisted of the presence of a definable suspect metastatic tumour for which the primary tumour was unknown (i.e. patients presenting with only paraneoplastic phenomena were not included). In addition, the presenting site of the suspected metastasis had to be exterior to the neck region. Patients presenting with cervical metastases are often found to have primary tumours limited to the head and neck region. For the purposes of this study and for comparison with other similar studies in the literature, supraclavicular lymph nodes were considered to be exterior to the neck and as such, patients presenting with a supraclavicular lymph node metastasis were included in our study. Finally, the patients had undergone no prior systemic anticancer treatment.
The initial search for unknown primary tumours revealed a total of 101 cases. Four patients were excluded because they presented with paraneoplastic phenomena without an identifiable tumour mass. An additional 27 patients were excluded because they presented with a (suspected) metastasis in the neck region. Finally, seven patients were excluded because they had already undergone systemic therapy. The resultant eligible group consisted of 63 cases. The medical records of these patients were then searched to obtain information on the final diagnosis and compared with the PET result. Patients were followed until death or for a minimum period of 11 months.
We used serial questionnaires in an attempt to evaluate the impact of PET results on the diagnostic understanding of the referring clinician and their perception of the effect on patient management. For this purpose, questionnaires were sent prior to the PET scan, approximately 1 month after the scan, and about 6 months later. Details of the third questionnaire that specifically evaluates the impact on diagnostic understanding and therapy choice can be found in Table 1
. Further details regarding the questionnaires have been published elsewhere [21, 22].
PET scan
PET scans were performed on a Siemens ECAT EXACT HR+ scanner (Siemens, Erlangen, Germany), involving a whole body acquisition in two-dimensional (2D) mode with emission scans of 5 min to 7 min per bed position starting approximately 1 h after intravenous administration of 370 MBq of FDG. Patients had fasted a minimum of 6 h prior to FDG administration and their serum glucose was <10 mmol l–1. The value of attenuation correction is controversial [23] and our routine whole body FDG-PET protocol does not include transmission scanning.
PET scan result classification
Based on the actual PET scan report sent to the referring clinicians, two nuclear medicine physicians who were blinded for clinical outcome retrospectively classified PET scan results into two categories:
- Positive: the original report mentioned at least one anatomical site suspected to be the primary tumour.
- Negative: the original report mentioned no evidence of a primary tumour, with only definite metastatic sites demonstrating FDG uptake.
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Results
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Patient characteristics
The study group comprised 63 cases and 62 patients (one patient underwent two PET scans); their mean age was 57 years (standard deviation (SD) 12 years) and 52% were females. A summary of pre-PET pathology can be found in Table 2. Most (87%) had no prior history of malignancy. Eight patients had previously diagnosed primary tumours (including lung, colon, bladder, brain, cutaneous melanoma and basal cell carcinoma); in none of them was the pathological classification of the current presentation compatible with this original primary. PET was typically requested after an extensive clinical work-up (median duration 3 months) had been fruitless; 81% had undergone at least one CT scan. 35 (56%) of the cases were referred from a tertiary academic hospital centre, all but one from within our institution, and 27 from community hospitals. Referring medical specialists included oncologists (n=20, 32%), internists (n=16, 25%), pulmonologists (n=13, 21%), oncological/general surgeons (n=9, 14%), urologists (n=2, 3%), neurologists (n=2, 3%) and a neurosurgeon. Patients were followed until death or for a minimum of 11 months. The median follow-up in non-deceased patients was 28 months (range 11–51 months). On the last date of follow-up (April 2002), 37% of the patients were still alive. The median follow-up in patients in whom a primary tumour was not found was 29 months (range 17–51 months) in non-deceased patients versus 5 months (range 1–37 months) in deceased ones.
Presenting site(s) and histology
The largest group of patients (n=17, 27%) presented with lymph node metastases (12 of whom with at least one peripheral involved nodal station (Table 2
) followed by metastases in liver (n=7, 11%), lung (n=6, 10%), pleura (n=6, 10%), bone (n=6, 10%), brain (n=4, 6%), skin (n=4, 6%) and other soft tissue sites (n=6, 10%). Seven patients (11%) presented with a combination of the above-described categories. In 59 (94%), the metastases had been pathologically confirmed. In the others, the metastatic sites were either not readily accessible for biopsy or considered pathognomonic radiologically (brain metastases, multiple pulmonary metastases on chest CT). The most common histological classification was adenocarcinoma (n=40, 64%) followed by large cell carcinoma (n=7, 11%). Only two patients had squamous cell cancer.
PET scan results
The known metastases were FDG avid in all but one patient with bone metastases of a neuroendocrine tumour. In addition, previously unknown metastatic lesions were seen on the PET scan in 27 (43%) of the cases.
29 (46%, 95% CI 33–59%) of the PET scans were classified as positive for a primary tumour (Table 3). Within this group, the PET result was confirmed to be true positive in 16 cases, either by histology (n=10) or by radiological and clinical follow-up (n=6). The following primary tumours were found: lung carcinoma (n=8; in 2 the initial work-up did not include a chest CT; both had a prior malignancy of bladder and colon, respectively), breast carcinoma (n=2), colon carcinoma (n=1), gastric carcinoma (n=1), cholangiocarcinoma (n=1) renal cell carcinoma (n=1), endometrial carcinoma (n=1) and thyroid carcinoma (n=1, Figure 1).
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Figure 1. True positive FDG-PET. Patient 62: 70-year-old male with bone metastases. Besides multiple bone metastases (vertebrae, humerus, chest wall), PET revealed markedly increased uptake in the thyroid (arrow). Thyroidectomy confirmed a papillary thyroid carcinoma.
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There were four false positive cases: a breast abscess (biopsy proven); thoracotomy later confirmed the presence of a primary lung tumour (this lesion had been reported at PET but was interpreted as a metastasis of the presumed breast malignancy, Figure 2). In another patient, who presented with extensive supradiaphragmatic and infradiaphragmatic lymphadenopathy, the kidney was incorrectly interpreted as the primary; the patient was later clinically diagnosed as having prostate cancer. In the third case, the primary site was incorrectly thought to be in the lung (granuloma appearance on CT) with follow-up revealing the diagnosis of a primary breast tumour (biopsy proven) 11 months after PET. In the fourth case, the primary site was misinterpreted as being in the stomach (retrospectively likely in the left liver lobe) in a patient clinically diagnosed with cholangiocarcinoma and multiple liver metastases. In nine patients, the primary tumour was not confirmed.
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Figure 2. False positive FDG-PET. Patient 41: 48-year-old female with cerebral metastases. PET demonstrates increased uptake in the right breast (abscess, misinterpreted as the primary tumour, small arrow) as well as the right lung (primary tumour, misinterpreted as metastasis, large arrow).
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33 (52%, 95% CI 40–64%) PET scans were negative for a primary tumour, and in 18 the primary tumour was not found. In 12 patients, multiple previously unknown tumour sites were evident at PET but these were assumed to be metastases. Seven cases were solved by pathology revision (including additional immunohistochemical analyses) yielding primary cholangiocarcinoma (n=2), and mesothelioma (n=2), thymoma (n=1), recurrent oligoastrocytoma (n=1) and primary primitive neuroectodermal tumour (n=1). Follow-up revealed the primary in 8 of 33 patients: lung cancer was found in five (in four, a known lung lesion was later considered to be the primary; in another, presenting with a lower lumbar skeletal metastasis, a primary lung tumour was later diagnosed; PET had demonstrated only moderately increased uptake in the left hilar region). The sixth patient presented with what was initially thought to be three metastatic brain lesions. After debulking surgery of the largest lesion a histological diagnosis of glioblastoma multiforme was made. PET had demonstrated definite focal increased tracer activity in the largest brain lesion. In the seventh case, PET had been false negative in a patient with axillary lymph node metastasis surgically proven to have a 7 mm primary breast tumour (1 month after PET). The last patient in whom follow-up disclosed the primary tumour after a negative PET scan was the only patient to undergo two PET scans. While his second PET scan was diagnostic for a primary tumour in the left kidney, the initial scan demonstrated several other equally intense/extensive lesions from which assignment of a single site as the primary tumour was difficult.
The clinician's perspective
In 52 of 63 (83%) cases, the clinicians returned the survey questionnaires (2 of 52 lacking information on impact on management). PET had a positive impact on diagnostic understanding (DU) in 29 (DU= 4 or 5). Beyond demonstration of the primary, this retrospectively also reflected the utility of PET to point at accessible sites for biopsy (if no prior histological diagnosis had been feasible), to simplify or redirect the diagnostic thinking guided by extent and pattern of previously unknown metastases, respectively. To a greater or lesser extent, the PET result had favourably contributed to a change in management in 17 patients. This involved different systemic therapy (n=5, e.g. guided by histology obtained after PET, Figure 3), change from local to systemic therapy or vice versa (n=4, e.g. PET showing more extensive disease, or a presumed metastasis was later considered to be the primary, lacking any evidence of other tumour activity, respectively), switch from single to multimodality therapy or vice versa (n=4, e.g. in case of locally advanced breast cancer, and metastasized thyroid cancer), or to start or refrain from systemic treatment (n=3, e.g. prompted by a classifying histological diagnosis or by the extent of dissemination evident at PET, respectively), and in one patient local therapy was changed from radiotherapy to surgery. Impact of PET was estimated "negative" (therapy choice (TC)=1 or 2) in 3 patients (in 2 of them, additional tests were instigated by PET which would not have been done otherwise), and without impact (TC =3) in 20.
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Figure 3. Multiple positive foci. Patient 11: 56-year-old male with mediastinal lymphadenopathy (biopsy difficult). PET demonstrates multiple foci of increased uptake (left pleura, possible separate focus in left lung, mediastinum, ribs, vertebrae). A rib biopsy based on PET (arrow) revealed small cell lung cancer.
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Discussion
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The yield (i.e. percentage of confirmed true-positive results) of FDG-PET scanning in patients with extracervical metastases from an unknown primary tumour in our series was 25% (16/63, 95% CI 15–38%). To our knowledge, our study population comprises the largest series reported to date of FDG-PET scans performed in patients presenting with extracervical metastases related to an unknown primary tumour.
This observed yield appears to be lower than that reported by other investigators [15–19]. One possible reason could be differences in the pre-PET diagnostic work-up. For example, in the retrospective study by Bohuslavski et al [16], only specific mention was made of chest radiography in the pre-PET diagnostic imaging work-up. However, the pre-PET diagnostic work-up appeared adequate in the prospective studies of Kole et al [16] and Lassen et al [17]. The PET scans in our patients were performed late in the diagnostic trajectory, i.e. typically after an extensive diagnostic work-up. There were, however, two patients with prior bladder and colon primary tumours who were found to have a second primary lung tumour on the FDG-PET scan. These patients had only undergone chest X-rays and abdominal CT scans because of their prior histories and clinical presentation. However, it is controversial whether chest CT is necessary in the routine work-up of unknown primary tumours [1, 24] and is not mentioned in the recommendations of Abbruzzese et al [1]. Additionally, patient sample size may play a role: in studies published so far, the number of patients with extracervical metastases (excluding melanoma metastases) has ranged from 8 to 22.
The clinicians reported a positive contribution of PET to their diagnostic understanding twice as often as the observed true positive rate for demonstration of a primary tumour. Negative PET findings and the pattern of newly discovered metastatic spread may serve to reduce the number of differential diagnoses and better histological classification may result from biopsy of a newly detected lesion. We therefore suggest that the contribution of PET to diagnostic thinking may extend beyond the number of true positive primaries directly demonstrated by PET. However, robust data can only be obtained with a randomized trial.
Even though whole body FDG-PET has several advantages over conventional imaging, there are limitations. The first is paradoxically related to its high sensitivity. In over 40% of our cases PET disclosed previously unknown lesions. In such cases, it may be difficult to differentiate metastases from a possible primary tumour. The second is related to the biodistribution of FDG. For example, FDG is excreted by the kidneys and the ability to detect renal tumours may be limited. Alternatively, FDG uptake is low in several tumours and in our study, as expected, in prostrate cancer and neuroendocrine tumours [25–27]. Finally, precise anatomical localization with PET can be difficult in comparison with cross-sectional radiological imaging. This may improve with the introduction of combination PET-CT scanners.
It was surprising to learn how often (n=7/63, 11%) histology revision of the biopsy specimen solved the diagnostic dilemma (this may have included re-biopsy and/or case presentation at a specialized panel discussion). We do not know whether histology revision was more often requested in case of a negative PET scan result. It appeared, however, that histology revision more often provided the solution in cases in which the PET scan was classified as negative. In our institution, a pathological review often occurs but is not uniformly applied. In their article, Abbruzzese et al [5] describe a review of the pathological material as the initial step in a diagnostic strategy for all patients with tumours of unknown origin referred to their institution. Following this observation, it may be advisable to suggest, at least in our institution, that all cases of unknown primary tumours with extracervical metastases undergo routine pathology revision and/or panel discussion prior to FDG-PET scanning. Accordingly, the yield of PET would have increased from 16/63 to 16/56 (29%).
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Conclusion
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When applied late in the diagnostic trajectory, approximately four patients need to be scanned by PET in order to find one primary tumour. However, in addition to direct demonstration of unknown primaries, there appears to be a positive impact of PET on the diagnostic work-up of these patients of a similar magnitude.
Received for publication July 17, 2003.
Revision received May 21, 2004.
Accepted for publication August 9, 2004.
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Abstract
Introduction
