Thoracic 18F-FDG PETCT RAD Magazine, 41, 482, 13-16 Dr Allanah arker Specialist registrar radiology Dr Nagmi Qureshi Consultant cardiothoracic radiologist Papworth Hospital, Cambridge email: allanahbarker@nhs.net Introduction Positron emission tomography computed tomography (PETCT) is a hybrid imaging modality that provides both anatomical CT and functional PET information in a single study. In clinical practice the most widely used PET imaging tracer is the glucose analogue labelled positron emitter 18 F-Fluorodeoxyglucose (18F-FDG). FDG accumulates in cells that demonstrate increased glucose metabolism typically seen in malignant cells. Since its introduction in the 1990s, 18F-FDG PETCT has proven to be a valuable tool for diagnosis and staging of lung cancer. This article provides an overview of the current indications for thoracic PETCT and highlights potential limitations and pitfalls in image acquisition and interpretation. What are the indications for PETCT in thoracic practice? Staging of non-small cell lung cancer (NSCLC) Lung carcinoma is the leading cause of cancer-related death in the western world. In the UK there are over 39,000 new diagnoses of lung cancer per annum, accounting for 35,000 deaths. The majority of patients present with advanced disease and this, in part, accounts for the low long-term survival rate for lung cancer in the UK currently 5.5%. 1 The National Institute of Clinical Excellence (NICE) guidelines recommend that all patients suitable for treatment with curative intent by surgery, radical radiotherapy or chemoradiotherapy are staged using 18F-FDG PETCT. The main role for 18F-FDG PETCT in lung cancer staging is as a complementary tool alongside existing imaging and endoscopic modalities, which include contrast-enhanced CT, endobronchial ultrasound (EUS) and endoscopic ultrasound (EUS). 1 Accurate lung cancer staging using the seventh edition tumour (T), node (N), metastasis (M), classification system is essential because the detection of locally advanced or distant metastatic disease will influence treatment selection and is the main determinant of prognosis in NSCLC. 2 PETCT is particularly useful at detecting occult nodal and extra-thoracic metastasis not evident on the staging contrast enhanced CT (figure 1). A systematic review found that 18F-FDG PET detected 11%-20% more distant metastases than other imaging methods, resulting in a management change in 9%-64% of patients and reducing the incidence of futile thoracotomies from 41% to 21%. 3 The superior anatomic detail of helical CT means the T stage, tumour size and extent of tumour invasion is best assessed by contrast enhanced CT. PETCT plays a limited role in T staging due to its lower spatial resolution. However, it can complement CT by helping assess tumour extent and differentiating metabolically active primary tumour from distal collapse, which may be important for radiotherapy treatment planning. According to the current NICE guidelines, 18F-FDG PETCT is the preferred first test after CT in patients with mediastinal nodes <1cm short axis with low probability of mediastinal spread as well as nodes that measure 1-2cm on CT (intermediate probability of mediastinal spread) where there is curative intent. PETCT is not indicated for patients with high probability of mediastinal or distant metastatic disease. In this situation biopsy of the metastatic disease is recommended. 1 Reported sensitivity and specificities of 18F-FDG PETCT for metastatic lymph node staging range from 83%-100% and 78%-92% respectively, compared with 59%-61% and 79% respectively for CT alone. 4,5 Nevertheless, false negatives can occur due to micro-metastatic disease and false positives in patients with pulmonary fibrosis, vasculitis, infection/inflammation and granulomatous disease. Sarcoid-like reaction that corresponds to the presence of non-caseating granulomas in patients with solid malignancy is an increasingly recognised entity where there is avid FDG tracer uptake that can mimic nodal metastasis and can lead to over-staging (figure 2). Similarly, avid nodal FDG uptake is seen in patients with previous inhalational lung disease due to anthracotic pigment deposition in lymph nodes. In these situations, nodal sampling by mediastinoscopy or EUS is essential for accurate mediastinal staging. Therefore, current NICE guidelines recommend that mediastinal nodal sampling should be performed for all PET positive nodes, PET negative nodes that measure >1cm in short axis or for central tumours with positive hilar nodes on PETCT. Normal sized mediastinal nodes that show no tracer uptake on PETCT do not require further sampling. 1 Solitary pulmonary nodules Solitary pulmonary nodules (SPN) are defined as a discrete well-defined intra-parenchymal lesion <3cm in size. Current NICE guidelines suggest that 18F-FDG PETCT should be considered for all indeterminate SPNs identified on CT in patients of good performance status, especially where biopsy is considered technically difficult, where there is a significant risk of pneumothorax, or previous biopsy attempts have proved non-diagnostic. 1 False positives and false negatives Although malignant nodules usually show increased FDG uptake there is no reproducible standardised uptake value (SUV) that can confidently differentiate between a malignant and benign lesion. False positive results can occur in certain benign conditions including granulomatous disease (T and sarcoidosis) and infective/inflammatory conditions (figure 3). False negative results can be seen in tumours that demonstrate low glucose metabolism and include lung adenocarcinomas with a lepidic or mucinous component and carcinoid tumours that show no atypia (figure 4). Although the resolution of PET is continually improving, it remains 7-8mm and false negatives can occur in small malignant nodules that demonstrate low SUV due to partial volume effect rather than reflecting the underlying nature of the nodule. 6 In these situations findings should be interpreted with caution. Lesions thought to be low risk for malignancy may be followed by interval CT and those considered high risk for malignancy could be offered biopsy. The most recent meta-analysis that included 1,008 nod-
ules from 22 eligible studies reported a pooled sensitivity of 95% (95% CI: 93%-98%) and specificity 82% (95% CI: 77%- 88%) for 18F-FDG PET in SPN characterisation. This metaanalysis included only studies using dedicated PET imaging systems, as published reports on the incremental value of integrated PETCT systems are limited. 7 Other indications for PETCT in thoracic oncology Restaging NSCLC For patients with NSCLC treated with curative intent, the five-year survival rate is around 14%. 2 Local or distant disease recurrence is common and directly related to the tumour T and N stage at the time of surgery/radiotherapy as well as to the histologic type and the extent of resection. On CT it is often difficult to differentiate post-operative scarring or post-radiotherapy pneumonitis/fibrosis from disease recurrence. 18F-FDG PETCT can be helpful in these cases and has been shown to be more sensitive and specific than chest CT for detecting disease recurrence (90% and 90% and 78% and 80%, respectively). However, because postradiation/surgical related inflammatory change can cause avid FDG uptake and simulate tumour recurrence, repeat scanning should not be performed within three months of treatment. 8 Following stereotactic radiotherapy PETCT performed at 12 months rather than three months has been shown to be most accurate for detecting local recurrence. 9 Typically focal nodular tracer uptake is more suggestive of local recurrent disease compared to curvilinear uptake that is likely to represent inflammation. Small cell lung cancer (SCLC) SCLC is more aggressive than NSCLC and has a poorer prognosis. The role of PETCT in the diagnosis and staging of SCLC is limited. The Royal College of Radiology guidelines suggest using PETCT in the staging of patients who appear, on CT, to have limited disease being considered for radical treatment. 10 Investigation of pleural disease Currently in the UK, 18F-FDG PETCT is not routinely recommended in the diagnostic work-up of patients with malignant pleural mesothelioma. However, the Royal College of Radiologists and European Society of Medical Oncology guidelines suggest it should be considered to exclude extrathoracic disease in proven mesothelioma in patients being considered for multi-modality treatment including radical surgery/decortication. In addition, in patients with pleural thickening and suspected mesothelioma where conventional imaging and biopsy have been non-diagnostic or equivocal, there is some evidence that PETCT may be useful for guiding an optimal site to biopsy. 10-12 18F-FDG PETCT is less likely to be useful in patients presenting with a pleural effusion only or with a history of previous pleurodesis. Talc pleurodesis can cause a chronic inflammatory reaction that may be FDG-avid and mimic pleural tumour deposits on PET in patients treated for pulmonary or pleural malignancy (figure 4). The characteristic high CT attenuation of talc density from matched FDG-avid curvi-linear features helps to differentiate this entity from pleural tumours. 10 Pulmonary artery sarcoma Pulmonary artery sarcoma (PAS) is an extremely rare neoplasm that is usually indistinguishable from acute or chronic thromboembolic disease of the pulmonary arteries on clinical and CT findings. The role of 18F-FDG PETCT in the diagnosis of PAS is still under investigation, although studies have suggested that moderate and high grade PAS usually demonstrate increased tracer uptake on PETCT. It should be noted that low grade myxoid PAS may not take up FDG, producing a false negative result. PETCT can also be used in assessing treatment response in high grade PAS. 13 General artifacts and normal variants One of the main problems with thoracic 18F-FDG PETCT interpretation is the presence of artifacts, normal variants and non-malignant physiological tracer uptake. In the chest, differences in breathing and timing acquisition of the PET and CT images (6-9 minutes/bed and tidal breathing for PET and around 15 seconds and deep inspiration for CT) can lead to image misregistration and potential misdiagnosis. This can be seen adjacent to the myocardium as well as around the diaphragm where hepatic metastasis may erroneously appear in the lung. Correlation with the staging CT scan is essential in this situation. Metallic objects within the body, such as stents, can also cause increased FDG uptake in adjacent tissue due to beam hardening related artifacts, potentially causing false positive results. Similarly, normal symmetrical, linear physiologic uptake in brown fat may show an asymmetrical distribution leading to potential errors in interpretation. 14 Conclusion PETCT has established itself as an invaluable complementary imaging modality for the evaluation of various thoracic conditions. Awareness of normal variants, potential false positives and negatives can significantly reduce misdiagnosis and improve diagnostic accuracy and image interpretation. References 1, Lung Cancer. NICE clinical guideline 121. April 2011. https://www.nice.org.uk/guidance/cg121. 2, Goldstraw P, Crowley J, Chansky K et al. The IASLC Lung Cancer Staging Project: Proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2007;2:706-14. 3, Fletcher J W, Djulbegovic, Soares H P et al. Recommendations on the use of 18F-FDG PET in oncology. J Nucl Med Mar 2008;49(3):480-508. 4, irim O, Kappetein A P, Stijnen T, ogers A J. Meta-analysis of positron emission tomographic and computed tomographic imaging in detecting mediastinal lymph node metastases in nonsmall cell lung cancer. Ann Thorac Surg 2005;79:375-82. 5, Gould M K, Kuschner W G, Rydzak C E et al. Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: A meta-analysis. Ann Intern Med 2003;139(11):879-92. 6, Rohren E M, Turkington T G, Coleman R E. Clinical application of PET in oncology. Radiology 2004;231:305-32. 7, Cronin P, Dwamena A, Kelly A M, Carlos R C. Solitary pulmonary nodules: Meta-analytic comparison of cross-sectional imaging modalities for diagnosis of malignancy. Radiology 2008;246:772-82. 8, ury T, Corhay J L, Duysinx et al. Value of FDG-PET in detecting residual or recurrent nonsmall cell lung cancer. Eur Respir J 1999;14(6):1376-80. 9, Hicks R J, Kalff V, MacManus M P et al. The utility of (18)F-FDG PET for suspected recurrent non-small cell lung cancer after potentially curative therapy: Impact on management and prognostic stratification. J Nucl Med 2001;42(11):1605-13. 10, Evidence-based indications for the use of PET-CT in the UK 2013. www.rcr.ac.uk/publication/evidence-based-indications-use-pet-ct-uk-2013. 11, Stahel R A, Weder W, Lievens Y, Felip E, on behalf of the ESMO Guidelines Working Group. Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 21 (Supplement 5): v126-v128, 2010. 12, Guidelines of European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignancy pleural mesothelioma. Eur Respir J 2010;35:479-95. 13, Wong H H, Gounaris I, McCormack A et al. Presentation and management of pulmonary artery sarcoma. Clin Sarcoma Res 2015;5(1):3. 14, Kligerman S, Digumarthy S. Staging of non-small cell lung cancer using integrated PET/CT. Am J Roentgenol 2009;193(5):1203-11.
A Figure 1 (A) Axial contrast enhanced CT demonstrates a solitary right upper lobe 2.8cm nodule with adjacent pleural puckering in keeping with a suspected early stage T2aN0M0 lung cancer. () 18F-FDG PETCT coronal reformats show RUL nodule tracer uptake (Max SUV 5) (yellow arrow) and incidental focal tracer uptake (Max SUV 8) (white arrow) within the left pectoralis major muscle suggestive of an occult intramuscular metastasis. This upstaged the disease to T2aN0M1b. Figure 2 Sarcoid like reaction: (A) Axial CT shows a right lower lobe biopsy proven 8mm adenocarcinoma (red arrow) and symmetrical mediastinal and hilar adenopathy (blue arrows). () PETCT showed low grade tracer uptake (Max SUV 2.5) in the primary tumour (red arrow) and avid nodal uptake (Max SUV 15). EUS confirmed the presence of benign non-caseating nodal granulomas in keeping with a sarcoid-like reaction.
C Figure 3 Organising pneumonia leading to a false positive 18F-FDG PETCT: (A) Contrast enhanced CT shows a 5cm left upper lobe mass that extends into the mediastinum concerning for a localised primary lung cancer with avid tracer uptake Max SUV 6 on 18F-FDG PETCT. () CT guided biopsy was performed to obtain histological confirmation which demonstrated organising pneumonia and no evidence of malignancy. (C) Follow-up CT performed after two months and a short course of steroids/antibiotic with complete resolution of the inflammatory mass.
Figure 4 (A) 18F-FDG PETCT shows FDG avid right talc pleurodesis induced pleural masses with corresponding high attenuation talc on CT mimicking pleural malignancy. () In addition the scan demonstrated a 1.5cm part solid left apical lesion. This showed low-grade tracer uptake Max SUV 1.5 (arrow) and was initially wrongly reported as a focal area of benign scarring. Subsequent CT guided biopsy confirmed a lepidic primary lung adenocarcinoma causing a false negative 18F-FDG PETCT finding.