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Journal of Clinical Oncology, Vol 23, No 28 (October 1), 2005: pp. 6846-6853 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.10.116 Etiology of Solitary Extrapulmonary Positron Emission Tomography and Computed Tomography Findings in Patients With Lung CancerFrom the Division of Thoracic Surgery; Division of Nuclear Medicine; Department of Pathology; Clinic and Policlinic of Oncology, University Hospital, Zurich, Switzerland; and Institute of the Human Brain, St Petersburg, Russia Address reprint requests to D. Lardinois, MD, Division of Thoracic Surgery, University Hospital, Raemistrasse 100, 8091 Zurich, Switzerland; e-mail: didier.lardinois{at}usz.ch
PURPOSE: The aim of this prospective study was to assess the incidence and the nature of solitary extrapulmonary [18F] fluorodeoxyglucose (FDG) accumulations in patients with non–small-cell lung cancer (NSCLC) staged with integrated positron emission tomography and computed tomography (PET/CT) and to evaluate the impact on management. PATIENTS AND METHODS: A total of 350 patients with NSCLC underwent whole-body PET/CT imaging. All solitary extrapulmonary FDG accumulations were evaluated by histopathology, further imaging, or clinical follow-up. RESULTS: PET/CT imaging revealed extrapulmonary lesions in 110 patients. In 72 patients (21%), solitary lesions were present. A diagnosis was obtained in 69 of these patients, including 37 (54%) with solitary metastases and 32 (46%) with lesions unrelated to the lung primary. Histopathologic examinations of these 32 lesions revealed a second clinically unsuspected malignancy or a recurrence of a previous diagnosed carcinoma in six patients (19%) and a benign tumor or inflammatory lesion in 26 patients (81%). The six malignancies consisted of carcinoma of the breast in two patients, and carcinoma of the orbit, esophagus, prostate, and non-Hodgkin's lymphoma in one patient each. Benign tumors and inflammatory lesions included eight colon adenomas, four Warthin's tumors, one granuloma of the lower jaw, one adenoma of the thyroid gland, one compensatory muscle activity due to vocal chord palsy, two occurrences of arthritis, three occurrences of reflux esophagitis, two occurrences of pancreatitis, two occurrences of diverticulitis, one hemorrhoidal inflammation, and one rib fracture. CONCLUSION: Solitary extrapulmonary FDG accumulations in patients with newly diagnosed lung cancer should be analyzed critically for correct staging and optimal therapy, given that up to half of the lesions may represent unrelated malignancies or benign disease.
For patients with early non–small-cell lung cancer (NSCLC; stages I and II) and selected patients with locally advanced disease (stage IIIA), complete surgical resection provides the best chance for cure.1 Distant metastases are found in nearly 40% of patients with newly diagnosed NSCLC by conventional staging.1 Because the incidence of metastatic disease in lung cancer is high, accurate tumor staging is an essential and a critical step for the choice of the optimal therapeutic strategy.2,3 The introduction of positron emission tomography (PET) with [18F] fluorodeoxyglucose (FDG) has modified the diagnostic approach for patients with NSCLC.3-5 Whole-body PET detects unexpected extrathoracic metastases in 10% to 20% of patients with NSCLC, and changes therapeutic management in approximately 20% of these patients.6-11 Recently, integrated PET and computed tomography (PET/CT) has been introduced. Integrated PET/CT enables the direct correlation of FDG-accumulating lesions with morphologic structures. It has been shown that integrated PET/CT improves T staging and N staging of NSCLC in comparison with the other imaging methods.12-14 However, the clinical significance of a single focal abnormality on PET remains often unclear, given that FDG accumulation is not specific for malignant tissue. Tissues such as myocardium, intestine, muscle, lymphatic tissue, and inflammatory lesions also show FDG accumulation.15-18 Although disseminated neoplasms have the characteristic pattern of multiple foci of FDG accumulation, less advanced metastatic disease may be difficult to distinguish from benign disease. PET or PET/CT with a solitary extrathoracic abnormality can be particularly problematic. FDG accumulation may reflect additional pathology unrelated to the lung cancer for which the patient was originally referred. The aim of this study was to assess the incidence and the nature of solitary extrapulmonary FDG accumulations in patients with NSCLC staged with whole-body integrated PET/CT. In addition, the influence of these additional findings on the clinical management of these patients was investigated.
All consecutive patients referred for surgery for NSCLC between July 2001 and March 2004 were included in the study after having given written informed consent in accordance with the ethical guidelines of the hospital Institutional Review Board. Our institution is a teaching and tertiary-care hospital and a major referral site for patients with cancer. Thoracic surgeons at the facility have been evaluating PET in various studies for preoperative assessment of disease stage since 1994. All patients underwent conventional staging based on a review of the medical history, physical findings, and results of blood tests, bronchoscopy, and contrast-enhanced CT of the chest and upper abdomen. All underwent integrated whole-body PET/CT independent of suggestion of metastatic disease after conventional staging. All PET/CT images were prospectively analyzed by at least one board-certified nuclear medicine physician, one board-certified radiologist, and one board-certified thoracic surgeon. All reviewers have more than 3 years of experience in PET/CT reading. Pathologic radiotracer uptake was identified as FDG accumulation comparable to or higher than that of the physiologic FDG uptake of the cerebral cortex. Focal increased FDG uptake in the renal pelvis, ureter, urinary bladder, and myocardium were considered physiologic. The readers did not try to classify the solitary extrathoracic abnormalities as benign or malignant lesions and no standard uptake value threshold was considered to discriminate these lesions. However, there was a wide consensus among the three reviewers in differentiating physiologic and pathologic FDF accumulation. All patients with evidence of advanced disease after clinical staging and PET/CT staging, patients with multiple focal abnormalities on PET/CT suggesting metastatic extension, and patients with N3- or bulky N2-disease were excluded from additional analysis. In all patients with a single focal extrapulmonary abnormality, an additional evaluation was performed. The standard of reference for the evaluation of the PET/CT findings was preferably biopsy, if available, or follow-up including clinical or laboratory testing, or other imaging such as magnetic resonance imaging.
Integrated PET/CT
Three hundred fifty patients (236 men, 114 women; mean age, 68 years; age range, 36 to 84 years) with proven NSCLC were enrolled onto the study. Histologic analysis revealed adenocarcinoma in 189 patients, squamous cell carcinoma in 120 patients, and large-cell carcinoma in 41 patients. Integrated whole-body PET/CT revealed extrapulmonary focal abnormalities in 110 of 350 (31%) patients. Of these patients, 31 (9%) had multifocal extrapulmonary PET/CT findings and seven (2%) had the combination of a solitary or multifocal extrapulmonary abnormality with an extended mediastinal ipsilateral and contralateral lymph node involvement, suggesting an advanced stage IIIB or IV disease. Solitary extrapulmonary lesions were observed in 72 (21%) of 350 patients. The final diagnosis of solitary extrapulmonary focal abnormality was obtained in 69 (96%) of these 72 patients. Three patients, including two patients with an increased FDG accumulation in the thyroid and one with an increased FDG accumulation in the esophagus, died before additional evaluation of the solitary extrapulmonary focal abnormality could be performed, and no autopsy could be obtained. Of 69 patients with a solitary extrapulmonary PET/CT finding, metastases were diagnosed in 37 patients (54%; 11% of all patients included) either histopathologically (49%), by an other imaging modality (40%), or by clinical follow-up (11%). Clinical T stage and clinical N stage were T1, T2, T3, or T4 in eight (22%), 17 (46%), nine (24%), and three (8%) patients, respectively, and N0, N1, or N2 in 12 (32%), eight (22%), and 17 (46%) patients, respectively. The 37 metastases were localized in bone, brain, liver, adrenal, and abdominal lymph-nodes in 15 (41%), seven (19%), seven (19%), six (16%), and two (5%) patients, respectively. Twenty-two patients (60%) had an adenocarcinoma, nine patients (24%) had a squamous cell carcinoma, and six patients (16%) had a large-cell carcinoma. In the other 32 of 69 (46%; 9% of all patients included) patients with a solitary extrapulmonary PET/CT finding, FDG accumulation corresponded to a lesion that was not related to the primary lung cancer. The location of these lesions was in the GI tract in 17 patients (54%); the parotid gland in four patients (13%); a joint in two patients (6%); the breast in two patients (6%); and thyroid gland, orbit, lower jaw at the level of the first molar tooth, larynx, axillary lymph node, rib, and prostate in one patient each (3%). Clinical T stage and clinical N stage were T1, T2, T3, or T4 in nine (28%), 18 (56%), three (10%), and two (6%) patients, respectively, and N0, N1, or N2 in 16 (50%), five (16%), and 11 (34%) patients, respectively (Table 1).
Histopathologic correlation of these lesions revealed a second unknown and clinically unsuspected malignant tumor or a recurrence of a previous carcinoma in six patients (19%), including carcinoma of the breast in two patients, and carcinoma of the orbit, esophagus, prostate, and non-Hodgkin's lymphoma in one patient each. In two patients with synchronous lung carcinoma and breast carcinoma, the breast lesion was asymptomatic and was not observed after conventional initial staging and before PET/CT imaging. A needle biopsy confirmed the diagnosis of breast carcinoma. Both patients underwent combined surgery, consisting of lung resection, excision of the breast carcinoma, and a postoperative radiotherapy. Esophageal carcinoma was confirmed by endoscopic biopsy (Fig 1). The patient underwent an oncologic resection of lung cancer followed by an induction therapy for the esophagus carcinoma. Then the esophagus was resected and the passage reconstructed by the stomach. In one patient, a prostate carcinoma had been diagnosed 9 years ago. The patient underwent hormonal therapy after radiotherapy and the prostate-specific antigen value remained stable and low. A recurrence of the prostate carcinoma was found and radiotherapy was performed. Another patient underwent a radical operation of an orbit carcinoma followed by radiotherapy 2 years before diagnosis of lung cancer. All CT scans following the operation showed no signs of recurrence. Integrated PET/CT demonstrated a single focal FDG accumulation at the base of the orbit. Biopsy revealed recurrence of disease. The patient underwent reoperation 3 weeks after lung resection. In one patient, a non-Hodgkin's lymphoma was diagnosed 16 years before the diagnosis of lung cancer. The patient had undergone chemotherapy with complete remission. PET/CT revealed a single focal FDG accumulation in an axillary lymph node. To rule out a stage IV NSCLC, an excision of the lymph node was performed. Surprisingly, a recurrence of the lymphoma was revealed, which was treated by chemotherapy after lung resection.
In 26 (81%) patients, the solitary extrapulmonary focal FDG accumulation corresponded to a benign tumor or to an inflammation. Benign tumors included eight adenomas of the colon and four Warthin's tumors (Fig 2), and inflammatory lesions consisted of one granuloma of the lower jaw, one adenoma of the thyroid gland, one compensatory muscle activity due to vocal chord palsy, two occurrences of arthritis, three occurrences of reflux esophagitis, two occurrences of pancreatitis, two occurrences of diverticulitis, one hemorrhoid, and one rib fracture without known trauma.
The lesions of the GI tract were investigated endoscopically. All of the colon polyps were excised, revealing adenoma in all of the patients (Fig 3). In two patients, a solitary extrapulmonary finding was localized in a hip and in a shoulder joint, respectively. Magnetic resonance imaging examination showed degenerative changes. In one young patient with central lung cancer on the left side, a single focal FDG accumulation was observed in the second rib on the contralateral side (Fig 4) This finding was suggestive of bone metastasis. The patient underwent surgery because of major hemoptysis. The second rib was resected and histopathology revealed a rib fracture. A metastasis was excluded.
Accurate staging of patients with NSCLC is needed to define surgical, multimodality, or palliative treatment. Patients who have distant metastases at the time of diagnosis cannot be cured by surgery. The data of the present study show that integrated PET/CT revealed solitary extrapulmonary lesions in 21% of patients with NSCLC. In half of these patients, lesions were not related to lung cancer but represented other malignancies or benign lesions. It has been reported that PET imaging is an excellent method for screening of distant metastases, excluding the brain.3,7,9 Whole-body PET detects occult metastases in 10% to 20% of patients with NSCLC. High sensitivity of FDG PET has been shown in the detection of adrenal metastases and bone metastases.8,19 In addition, FDG PET produces fewer false-positive results in degenerative, inflammatory, and post-traumatic bone disease compared with bone scintigraphy.20,21 The ability of PET imaging to stage both intra- and extrathoracic sites in one single examination with a better accuracy than conventional imaging has a potential impact on stage assignment and therapeutic decision making. A change in patient management has been reported in 25% to as high as 40% of patients who were clinically staged.9 However, it is well known that FDG is not tumor specific and is also taken up in benign diseases.17,18,20,22 For proper staging, management, and decision making, it is highly relevant to differentiate between malignant and benign lesions. Although extended disease and inoperability are often obvious in patients with multifocal extrapulmonary findings, the analysis of solitary extrapulmonary PET positive finding is crucial in potentially curable patients. In this study, solitary extrapulmonary lesions without clearly defined clinical symptoms were found in 72 (21%) of 350 patients with PET/CT imaging. However, it should be noted that other staging consisted only of a CT of the chest and upper abdomen in addition to the clinical examination. We could obtain a diagnosis in 69 of these patients and found a surprisingly high incidence of lesions unrelated to the primary lung tumor in 46% of the patients, whereas metastases of NSCLC were observed in 54%. It has been recommended that the diagnosis of a solitary FDG accumulation be confirmed in a classical location for metastases, given that this diagnosis determines the possibility for radical treatment. In addition, false-positive FDG results have been reported at a low rate in adrenal masses19 and acute fractures.22 In one of our patients with left central NSCLC, a solitary FDG accumulation suggestive of a metastasis was observed in the second right rib. In the corresponding CT image, a thickening of the rib was found. The patient had no history of trauma or coughing. A partial resection of the rib was performed to evaluate the indication for administration of adjuvant chemotherapy. Histology revealed a fracture of the second right rib and a metastasis could be ruled out. Our results suggest that the etiology of solitary FDG-positive extrapulmonary findings should be determined. Indeed, metastases of NSCLC have also been described rarely in spleen, axillary lymph nodes, spinal canal, and pancreas.23 In our series, we found two patients with focal pancreatic FDG uptake and one patient with a PET-positive axillary lymph node. In these patients, pancreatitis and recurrence of a non-Hodgkin's lymphoma were diagnosed and metastases were ruled out. Most GI tumors show a highly increased FDG accumulation.24-26 It is well known that FDG may also accumulate in some inflammatory and benign disorders of the GI tract.27,28 Focal colonic FDG accumulation should be systematically investigated because the lesions of the GI tract are not only reachable endoscopically,29,30 but most patients with lung cancer are also in the age group most likely to have other malignancies such as colorectal cancer. Furthermore, even if abdominal CT imaging were used, it might not reveal all of the lesions, because most adenocarcinomas and intraluminal polyps rarely exhibit abnormalities on abdominal CT images at an early stage.29,30 This is another advantage of PET/CT imaging, which can localize these lesions precisely. Because commercial PET scanners provide nominal spatial resolutions of 4.5 to 6.0 mm in the center of the axial field of view, even lesions that are less than 1 cm in diameter can be detected on the basis of an increased FDG accumulation. In this respect, a part of the solitary extrapulmonary findings may correspond to early-stage tumor manifestations, which would have been overlooked with conventional staging. In our study, two early-stage breast carcinomas and one esophageal carcinoma were diagnosed and treated with curative intention. An important issue of our study is that 19% (six of 32) of the solitary lesions that were not related to the primary lung cancer were malignant, either synchronous second carcinoma, or clinical silent recurrence of a former malignancy. The role of PET/CT to detect secondary cancers in addition to the staging of the primary lung cancer should not be underestimated. In this study, clinical T and N stage of lung cancer was comparable between the patients with solitary extrapulmonary metastases and the patients with lesions unrelated to the primary NSCLC. A limitation of this study is that four (12.5%) of 32 of the lesions were not histopathologically confirmed. However, the follow-up of these patients did not reveal any signs of a malignant disease. Furthermore, micrometastases and FDG-negative lesions with minor abnormalities in native CT could be missed. In conclusion, the findings of whole-body integrated PET/CT imaging can clearly affect therapeutic management in patients with operable NSCLC. A solitary FDG accumulation that determines the possibility for radical treatment requires a histopathologic diagnosis, not only to exclude a false-positive result or to confirm an occult extrapulmonary metastasis, but also to diagnose lesions that are not related to the primary lung tumor but influence the strategy of therapy.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Supported in part by the Jaqueline Seroussi Memorial Foundation for Cancer Research, Tel Aviv, Israel, and by the Sonnenwiese Stiftung. Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, June 4-8, 2004, New Orleans, LA. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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30. Kamel EM, Thumshirn M, Truninger K, et al: Significance of incidental 18F-FDG accumulations in the gastrointestinal tract in PET/CT: Correlation with endoscopic and histopathologic results. J Nucl Med 45:1804-1810, 2004 Submitted December 22, 2004; accepted June 7, 2005. This article has been cited by other articles:
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
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