Brain Advance Access originally published online on September 10, 2004
Brain 2004 127(10):2331-2338; doi:10.1093/brain/awh247
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Brain Vol. 127 No. 10 © Guarantors of Brain 2004; all rights reserved
FDG-PET improves tumour detection in patients with paraneoplastic neurological syndromes
1 Neurology B, Hôpital Pierre Wertheimer, Université Claude Bernard, 2 CREATIS, CERMEP, 3 Department of Neurology, Hôpital Bellevue, Saint-Etienne, 4 Department of Thoracic Surgery, 5 Department of Pneumology and 6 Department of Radiology, Hôpital Cardiologique, Lyon, France
Correspondence to: Dr J. Honnorat, Neurologie B, Hôpital Neurologique, 59 Bd Pinel, 69677 Bron, France E-mail: jerome.honnorat{at}chu-lyon.fr
Received December 24, 2003. Revised April 5, 2004. Second revision on June 2, 2004. Accepted June 4, 2004.
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Summary |
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To determine the usefulness of [18F]fluorodeoxyglucose (FDG) whole body FDG-PET in the diagnosis of tumours in patients with paraneoplastic neurological syndromes (PNS), we prospectively studied 20 patients with paraneoplastic antibodies in whom conventional imaging gave negative or inconclusive results for the presence of tumour. All 20 patients had neurological manifestations compatible with PNS and well-characterized paraneoplastic antibodies (12 anti-Hu, one anti-Hu and anti-CV2, one anti-CV2, four anti-Yo, one anti-Ri and one anti-amphiphysin). The mean delay between the onset of neurological symptoms and FDG-PET was 10 months (range 1–54). In these 20 patients, abnormal uptake was demonstrated in 18 patients, with some patients having abnormal signal in several areas. We observed abnormal uptake in the mediastinum (13 cases), lung (two cases), breast (two cases), parotid gland (one case), or the cervical, supraclavicular or axillary lymph nodes (seven cases). Following FDG-PET, the histological diagnosis of the tumour was made in 14 patients (small cell lung carcinoma in eight cases, breast adenocarcinoma in two, lung adenocarcinoma in two, axillary metastasis of ovary carcinoma in one, and malignant thymoma in one). Two other patients with abnormal FDG uptake showed radiological evidence of lung cancer, but a histological diagnosis could not be obtained. In two other patients, initial FDG-PET showed abnormal FDG uptake that was not confirmed a few months later by repeat FDG-PET. In the two patients with negative FDG-PET, peritoneal carcinomatosis was diagnosed in one and no tumour was found in the other. In our series, the sensitivity of FDG-PET for tumour detection was >83% demonstrating a clear role of this technique in the management of patients with PNS. However, in our series, the specificity of FDG uptake was only 25% due to unexplained abnormal FDG uptake in three patients and in abnormal FDG uptake due to a benign tumour in one patient. Over the study period, we saw 73 other patients with PNS and paraneoplastic antibodies. A tumour was demonstrated in 71 out of 73 by conventional techniques. Since false-positive and false-negative results are possible with FDG-PET and in most patients with PNS, the tumour is demonstrated by conventional techniques, we believe that FDG-PET should be reserved, at the moment, for patients with well-defined PNS antibodies when conventional imaging fails to identify a tumour or when lesions are difficult to biopsy.
Key Words: paraneoplastic neurological syndromes; paraneoplastic antibodies; whole body PET-scan; cancer
Abbreviations: FDG-PET = [18F]fluorodeoxyglucose-PET; PNS = paraneoplastic neurological syndromes; SCLC = small cell lung carcinoma
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Introduction |
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Tumour detection is frequently difficult in patients with paraneoplastic neurological syndromes (PNS), most of whom have either small tumours or tumours limited to metastatic lymph nodes (Dalmau et al., 1992
; Luchinetti et al., 1998). Chest CT scan or MRI is commonly used, but, in 50–60% of cases, no tumour can be identified at the initial evaluation (Luchinetti et al., 1998), probably because the tumour is too small to be detected by these methods (Chartran-Lefebvre et al., 1998). When investigations are negative, they should be repeated every 6 months (Molinuevo et al., 1998). However, it is important to detect the tumour as soon as possible, since early treatment of the cancer is probably the only chance to stabilize the PNS, which are frequently the main cause of death (Mason et al., 1997; Keime-Guibert et al., 1999; Graus et al., 2001). In contrast to CT scan and MRI, which rely on anatomical and morphological criteria, [18F]fluorodeoxyglucose-PET (FDG-PET) depends on the metabolic characteristics of the studied tissue. As glycolysis is increased in malignancies, FDG-PET appears to be a useful tool for detecting small tumours, and has recently emerged as a practical, cost-effective imaging method in patients with a variety of tumours, in particular lung cancer (Coates and Skehan, 1999; Pieterman et al., 2000), colorectal cancer (Akhurst and Larson, 1999) and lymphoma (Moog et al., 1997). Some studies have underlined the value of FDG-PET in the diagnosis of occult tumour in patients with suspected PNS (Shinohara et al., 1998; Antoine et al., 2000; Rees et al., 2001). However, the sensitivity and specificity of this technique in PNS patients have not been clearly established. To determine the usefulness of FDG-PET in the diagnosis of tumours in patients with PNS, we prospectively studied 20 patients with paraneoplastic antibodies in whom conventional imaging gave negative or inconclusive results for the presence of a tumour.
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Methods |
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Patients
Twenty patients with suspected PNS were prospectively studied using FDG-PET between January 1999 and July 2002. Only patients positive for well-characterized paraneoplastic antibodies (anti-Hu, anti-Yo, anti-Ri, anti-CV2 or anti-amphiphysin), detected by conventional techniques (Honnorat et al., 1996
), were included in the study. All 20 patients had been investigated previously for an underlying malignancy by conventional radiography, CT scanning, ultrasound, mammography and bronchoscopy (where appropriate). These conventional imaging studies gave negative (14 cases) or inconclusive (six cases) results for the presence of tumour. The data for three of the 20 patients (patients 1, 2 and 15) have already been reported (Antoine et al., 2000). Other the same time period, the sera and clinical data of 73 other patients with PNS and paraneoplastic antibodies (42 anti-Hu, seven anti-Yo, 14 anti-CV2, four anti-Ri, three anti-Tr, three anti-amphiphysin) were referred to our laboratory. A tumour was demonstrated in 71 out of 73 patients by conventional techniques. The two patients without a cancer diagnosis had anti-Hu antibodies and died suddenly a few weeks after the diagnosis of PNS.
PET-scan
FDG-PET was performed using 210 MBq of 18FDG and a Siemens EXACT-HR+ tomograph (CERMEP, Lyon, France). The patients were scanned from the pelvis to the chin, starting 60 min after injection of tracer. The transverse, coronal and sagittal planes were reconstructed. Patients with positive PET scans were subsequently re-imaged using CT scans and, when appropriate, underwent biopsy or resection.
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Results |
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There were 12 men and eight women with a mean age of 62 years (range 49–78 years). All 20 patients had neurological manifestations indicative of PNS (Tables 1 and 2) and well-characterized paraneoplastic antibodies (12 anti-Hu, one anti-Hu and anti-CV2, one anti-CV2, four anti-Yo, one anti-Ri and one anti-amphiphysin). The predominant neurological presentations were subacute sensory neuropathy (10 cases, 50%) and subacute paraneoplastic cerebellar degeneration (six cases, 30%). Four patients had a previous history of a treated cancer [ovary carcinoma (patients 6 and 19), breast carcinoma (patient 7) and vocal cord carcinoma (patient 9)]. The mean interval between the onset of neurological symptoms and FDG-PET was 10 months (range 1–54).
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Abnormal FDG uptake was demonstrated in 18 cases (90%) sometimes in more than one area (Tables 1 and 2): in the mediastinum (13 cases, 72.2%), lung (two cases, 11.8%), breast (two cases, 11.8%), parotid gland (one case, 5.9%), or cervical, supraclavicular or axillary lymph nodes (seven cases, 41.2%). Following FDG-PET, the histological diagnosis of the tumour was made in 14 patients (70%). The diagnosis was small cell lung carcinoma (SCLC) in eight cases, breast adenocarcinoma in two, lung adenocarcinoma in two, axillary metastasis of ovarian carcinoma in one, and malignant thymoma in one.
In the 10 patients with a demonstrated lung carcinoma (eight SCLC and two adenocarcinoma), the diagnosis was made by mediastinoscopy or thoracotomy in five patients and by cytology during a second fibreoptic bronchoscopy in one case (patient 2). For the other four patients, in addition to abnormal mediastinal uptake, FDG-PET showed an easily biopsied metastatic lymph node that was not found by clinical examination [supraclavicular in three cases (patients 5, 10 and 12) and cervical in one (patient 7)] (see Fig. 1 for example). We retrospectively reviewed all the chest CT scans, performed a few days before FDG-PET, of the 10 patients with lung cancer. In eight, small (0.5–1 cm) mediastinal lymph nodes, which were noted as not significant by the radiologists, were present (Fig. 2). In the other two cases (patients 10 and 14), abnormal 1.5 cm mediastinal lymph nodes were known to be present for 1 year and cancer was suspected, but mediastinoscopy performed 1 year previously was negative. In patient 14, FDG-PET showed mediastinal FDG uptake, which led to the diagnosis of adenocarcinoma after surgical exploration. In patient 10, FDG-PET detected both mediastinal and supraclavicular lymph node uptake; the supraclavicular lymph node had not been detected by clinical examination, but surgical exploration of the supraclavicular area led to the diagnosis of SCLC lymph node metastasis.
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In patient 11, an abnormal anterior mediastinal mass was detected by CT scan. FDG-PET of this patient demonstrated only weak uptake suggesting an abnormal posterior mediastinal lymph node; no abnormal uptake was observed in the anterior part of the mediastinum. A malignant thymoma (type AB) was diagnosed by surgical exploration, but lymph nodes did not contain tumour cells, and no other tumour was detected during follow-up.
In the two patients with breast carcinoma (patients 4 and 13), although FDG-PET was clearly positive (Fig. 3), mammography, breast echography and MRI repeated after FDG-PET were negative. However, in both cases, surgical breast exploration revealed an intra-ductal breast adenocarcinoma of <1 cm. In case 13, three axillary lymph node metastases were also found, one of which was detected by FDG-PET.
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Patient 6 had been treated for a stage IV ovarian carcinoma 12 months before the onset of paraneoplastic cerebellar ataxia at which time she was considered to be in complete tumour remission. FDG-PET showed abnormal FDG uptake in right axillary and thoracic lymph nodes. Surgical exploration of the right axillary area led to the diagnosis of metastatic ovarian carcinoma.
The four patients who had abnormal FDG uptake, but no confirmed tumour, are described in Table 2. Patient 18 developed sensory neuronopathy, limbic encephalitis and gastro-intestinal motor dysfunction. Although no tumour was detected, because a paraneoplastic syndrome was strongly suspected and anti-Hu antibodies were positive, the patient received three courses of chemotherapy (Cisplatinium and Etoposide) 54 months before FDG-PET. Low levels of FDG uptake in the mediastinum were observed, but surgical exploration was not performed because a chest CT scan showed only a few small (0.5–1 cm) mediastinal lymph nodes and neurological symptoms were not evolving. Twelve months after FDG-PET, a repeat chest CT scan showed that the mediastinal lymph nodes had greatly increased in size. This led to mediastinoscopy that resulted in the diagnosis of SCLC. In patient 16, repetitive chest CT scans demonstrated the increasing size of mediastinal lymph nodes suggesting the presence of a lung cancer (Fig. 4). This patient developed encephalomyelitis and died suddenly; no autopsy was performed. In the other two cases, only slightly abnormal FDG-PET uptake was observed. Patient 15 showed low mediastinal uptake without chest CT scan abnormalities. Repeat FDG-PET performed 15 months later showed no abnormal FDG uptake. However, 39 months after the initial FDG-PET and 50 months after the onset of neurological symptoms, a pancreatic adenocarcinoma was detected. Patient 17 also had abnormal FDG uptake in the left parotid and in the peripheral part of the left lung (Fig. 5). As no abnormalities were detected by chest CT scan, the left parotid was surgically explored and a cystadenolymphoma was diagnosed. A second FDG-PET performed 7 months later was normal. The patient died suddenly 1 month after the second FDG-PET and no autopsy was performed.
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Two cases showed no abnormal FDG uptake (Table 2). Patient 19 had limbic encephalitis, gastro-intestinal motor dysfunction and anti-Ri antibodies; no tumour was found during follow-up (17 months). Patient 20 had been treated for a stage IV ovarian carcinoma (bilateral ovarian carcinoma with fallopian tube extension and peritoneal carcinomatosis) 18 months before the onset of paraneoplastic cerebellar ataxia. At the time of neurological symptom development, the patient was considered to be in complete remission. FDG-PET showed bilateral hydronephrosis, which was attributed to previous abdominal surgical exploration; however, peritoneal carcinomatosis was detected by surgical exploration 10 months later.
To estimate the sensitivity and the specificity of FDG-PET in detecting tumours in patients with PNS who were tumour-negative by classical radiological methods, we considered as true positives all cases in which abnormal FDG uptake led to the diagnosis of a tumour in the expected area, i.e. 15 of the 20 patients. Guided by the FDG-PET results, we demonstrated a tumour in 13 patients (all patients of Table 1, except patient 11). We also considered patients 16 and 18 as true positives. In patient 16, although a tumour was not demonstrated, the evolution of the chest CT scan was highly suggestive of lung cancer and in patient 18 an SCLC was demonstrated 12 months after FDG-PET. Patient 17 was considered a false-positive, since, although the FDG-PET was positive, a tumour was not demonstrated. Patient 20 was considered a false-negative, since the FDG-PET was negative, but the patient developed peritoneal carcinomatosis. Patient 19 was considered a true-negative, since the FDG-PET was negative and no tumour was found during the follow-up. Two patients (patients 11 and 15) were considered as both false-positive and false-negative. Patient 11 was false-negative since the malignant thymoma diagnosed by surgical exploration did not take up FDG. This patient was also false-positive since FDG-PET detected weak uptake by a posterior mediastinal lymph node which contained no tumour cells and no other mediastinal tumour was detected during follow-up. Patient 15 was false-positive since the FDG-PET detected mediastinal uptake, but no tumour was demonstrated in this area during the follow-up period. This patient was also false-negative for the pancreatic cancer which was not detected by the second FDG-PET. Thus, the sensitivity of FDG-PET to detect tumours was estimated to be 83.33% (15 out of 18) and the specificity 25% (one out of four). Positive and negative predictive values were 83.33% (15 out of 18) and 25% (one out of four), respectively.
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Discussion |
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We prospectively studied the value of FDG-PET in 20 patients with suspected PNS and well-characterized paraneoplastic antibodies in whom no tumour was detected by classical radiological methods. We found that FDG-PET facilitated the detection of the tumour in 70% of cases. This percentage is significantly higher than that of 33% found in a recent retrospective study of nine patients with PNS and paraneoplastic antibodies, in whom only three tumours were found after FDG-PET (Rees et al., 2001
). Furthermore, this percentage increases to 80% if we take into account patients 16 and 18, who probably had lung cancer at the time of FDG-PET. This high percentage may be explained by the fact that all the patients underwent a multi-disciplinary evaluation by a medical team that included neurologists, radiologists, pulmonologists, surgeons and pathologists with extensive experience in PNS.
Although the majority of these patients had anti-Hu antibodies (13 out of 20), FDG-PET also helped to detect the tumour in patients with other PNS antibodies, except the one patient with anti-Ri antibodies; given the fact that there was only one such patient, we cannot draw any conclusions about this negative result. In the 13 patients with anti-Hu antibodies, we identified the tumour in 69% of cases, and this percentage increased to 85% if patients 16 and 18 were included. Interestingly, over the study period, we saw 55 patients with anti-Hu antibodies, 13 of whom underwent FDG-PET. A tumour was detected in all but three (one in the FDG-PET group and two in the non-FDG-PET group), resulting in a failure to detect a tumour using a combination of classical radiological techniques or FDG-PET in only 5.5% of patients, compared with 16.5% when using only standard radiological methods in a study of 200 patients with anti-Hu antibodies (Graus et al., 2001). As lung cancer and particularly SCLC are the most frequent tumours observed in anti-Hu patients, our results suggest that FDG-PET is especially helpful in characterizing small thoracic tumours and particularly mediastinal lymph nodes. The problem is probably different with thymoma. In patient 11, the malignant thymoma diagnosed by surgical exploration did not take up FDG, although an anterior abnormal mass was detected by CT scan. Other authors have already demonstrated that thymic FDG uptake does not correlate with malignant evolution (Wittram et al., 2003).
FDG-PET seems to be less helpful in detecting extrathoracic tumours. In patient 20, bilateral hydronephrosis and a small liver nodule were suggestive of abdominal abnormalities, but we failed to detect early peritoneal carcinomatosis, probably because the size of the nodules was below the threshold of detection of the PET scan camera. Shinohara et al. (1998) described a case of peritoneal carcinomatosis detected by PET in a patient with cerebellar ataxia, anti-Yo antibodies and ovarian carcinoma, but one nodule was quite large (28 x 22 mm). In contrast, the false negative results of mammography, echography and MRI in our two patients with breast cancer detected by FDG-PET are surprising since the usefulness of FDG-PET to improve the diagnosis of breast cancer is still controversial (Goerres et al., 2003; Wahl et al., 2004). As a whole, the limited number of patients with extra-thoracic tumour in the current study makes it difficult to arrive at any conclusion on the sensitivity of FDG-PET to detect extra-thoracic tumours in PNS patients.
Another interesting result of our study is that FDG-PET helps to guide surgical exploration. In five of the 14 cases in whom we detected a tumour (36%), FDG-PET showed abnormal FDG uptake in both thoracic and extra-thoracic lymph nodes. Extra-thoracic lymph nodes were not identified by clinical investigations. A simple extra-thoracic lymph node biopsy, guided by FDG-PET results, provided a relatively simple means of achieving a tumour diagnosis. In two other cases (patients 10 and 14) who previously had positive CT scan but negative mediastinoscopy, positive FDG-PET supported surgical re-exploration that led to the tumour diagnosis. Taken together, these results indicate that FDG-PET should be proposed in patients with a suspected thoracic tumour when the CT scan is negative or shows tumours or lymph nodes that would be difficult to approach surgically.
Although our results demonstrated >83% sensitivity and a positive predictive value of abnormal FDG uptake in detecting the tumour, the finding of abnormal uptake should be interpreted with caution. In a previous study of FDG-PET in 43 patients with suspected PNS, only half of the patients with abnormal FDG uptake had a pathologically confirmed tumour (Rees et al., 2001). This study was retrospective and only 20% of the 43 patients had paraneoplastic antibodies, which could explain why the false-positive rate was higher than in our study. However, our case 17 demonstrates clearly that abnormal uptake can be due to a benign tumour or, as others have described, to an inflammatory process (Knight et al., 1996; Bomanji et al., 2001). In addition, the specificity was only one-quarter in our group of patients and should be re-evaluated in further studies with more patients.
In two of our cases (patients 15 and 17), no abnormal mediastinal uptake was seen on the second FDG-PET; this might be explained by tumour regression, as has been described in some PNS patients (Gill et al., 2003), or the abnormal uptake seen on the initial FDG-PET might have been due to an artefact. Patient 15, with anti-Hu antibodies, developed pancreatic adenocarcinoma 24 months after the second FDG-PET, which could have been a second cancer or possibly a tumour of small size missed by the FDG-PET. A lack of sensitivity probably explains why we failed to detect abnormal abdominal uptake in patient 20, despite the fact that she probably had peritoneal carcinomatosis. Taken together, our results demonstrate a negative predictive value of FDG-PET of one-quarter. Thus, a patient with a high clinical and biological index of suspicion of PNS, but a negative FDG-PET result, should still receive a thorough follow-up and further investigations for cancer as appropriate. The value of repeat FDG-PET examination in screening for a tumour in patients with an initial negative exam should be studied.
FDG-PET could also be a useful tool to investigate tumour growth in PNS patients. In our small series, tumour progression could be estimated in 12 patients with a follow-up of more than 1 year; tumour growth was observed in 10. This high percentage supports the concept suggested by others that the small size of tumours of patients with PNS is probably due to early tumour diagnosis (facilitated by the paraneoplastic neurological symptoms) rather than a clinically effective immune response (Rojas et al., 2000; Graus et al., 2001).
We conclude that there is a clear role for FDG-PET in the management of patients with PNS. This technique can facilitate early tumour detection and guide surgical exploration. However, as false-positive results are possible and could lead to dangerous surgical exploration, FDG-PET results should be interpreted with caution in patients without paraneoplastic antibodies, especially if the neurological disorder is not typical of PNS. We therefore recommend that, at the moment, this technique should be reserved for patients with well-characterized paraneoplastic antibodies when conventional imaging fails to identify a tumour or when lesions are surgically inaccessible. Further prospective studies will be necessary to define the use of FDG-PET in patients with suspected PNS without paraneoplastic antibodies.
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Acknowledgements |
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The authors wish to thank all the neurologists who provided clinical information of their patients. This study was supported in part by a grant from l'Association de Recherche contre le Cancer (ARC).
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