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Journal of Cancer Research and Therapeutics, Vol. 7, No. 2, April-June, 2011, pp. 128-134 Review Article Role of positron emission tomography computed tomography in carcinoma lung evaluation S Padma, P Shanmuga Sundaram, Shamily George Department of Nuclear Medicine and PET CT, Amrita Institute of Medical Sciences, Cochin -41, Kerala, India Code Number: cr11031 PMID: 21768697 Abstract Lung cancer has graduated from merely a reportable disease of 1912 to being the most common cause of cancer death in developed countries in recent years. The annual number of lung cancer deaths is greater than the combined cancer deaths from breast, colon and prostate. Its association with tobacco has been proved and is related to the type, amount of tobacco used, the age at initiation and duration of use. Significant advances have been made in the diagnosis and management of lung cancer over the past decade. The primary treatment of lung cancer is surgery and the best chance for a complete cure comes from the total resection of localized disease. Once nodal or distant metastases have developed, primary surgical intervention is ruled out and patient is considered for adjuvant chemotherapy with or without radiation therapy. Accurate staging and delineation of disease extent is therefore critical in the treatment planning of lung carcinoma patients. 18 F fluoro deoxy glucose (FDG) positron emission tomography (PET) has been proven to be a valuable noninvasive imaging modality in the evaluation of patients with known or suspected lung cancer and its integration with computed tomography (CT) has changed the face of PET imaging in many ways. This article will review the current role of FDG PET CT in the evaluation of pulmonary nodules, diagnosis, staging and restaging of non-small-cell lung carcinoma (NSCLC), role of PET in small cell lung Carcinoma (Ca), pleural disease and will also discuss its potential future applications.Keywords: Carcinoma lung, 18 F fluoro deoxy glucose, positron emission tomography computed tomography, staging and metastatic workup Introduction Incidental detection of solitary pulmonary nodules (SPNs) is common, approximately 150,000 per year, may be higher if proper cancer screening programs are in place. SPNs are mostly detected on chest X-ray and chest computed tomography (CT). SPN is defined as an opacity in the lung parenchyma measuring up to 3 cm with no associated mediastinal adenopathy or atelectasis. Lesions measuring greater than 3 cm are classified as masses. More than 75% of the patients with SPNs are asymptomatic at the time of detection. [1] Lung cancer is the most common cancer in the US with more than 600000 deaths per year reported worldwide. This rate is expected to rise in the next two decades. [2] In Kerala, according to the Rural Cancer Registry 1993-97, lung cancer is listed as the leading cause of cancer with age-adjusted incidence of 19.4% in males and 2.9% in females. Evaluation of Pulmonary Nodules Since the advent of multidetector CT, the term ′solitary′ is disappearing from SPN because a chest X-ray-detected SPN is actually one of the many CT-detected nodules, although most of them are less than 1 cm in size. Some of the specific CT criteria, [2] such as smooth, well-defined or lobulated borders, intranodular (central) calcification, fat within nodules, easily differentiate benign nodules from malignant ones. Other patterns like popcorn or chondroid calcifications, with intranodular fat are characteristic of hamartomas. Apart from the known CT criteria for malignancy (like spiculated margin of nodule, a hazy and indistinct margin, endobronchial extension, pulmonary vein extension and focal retraction of the adjacent pleura) malignant lesions also masquerade as benign lesions by exhibiting air bronchograms which are invariably associated with pneumonia. Similarly, bronchoalveolar cell carcinoma and pulmonary lymphoma can appear as benign lesions. However, a large number of SPNs are indeterminate on CT and demand further evaluation to rule out malignancy. The most commonly performed investigations are 18 F fluoro deoxy glucose positron emission tomography (FDG PET) and contrast-enhanced dynamic CT (dCT). FDG uptake is used as a measure to characterize SPNs as benign or malignant, further enhanced by a semi-quantitative index called standardized uptake value (SUV). SUV proves to be a good yardstick to characterize and prognosticate lesions. False-positive FDG uptake is seen in trauma, various inflammatory and infective etiologies like tuberculosis, aspergillosis, histoplasmosis and sarcoidosis. False positive FDG uptake can be further evaluated by performing an additional dual time point imaging. Significant FDG washout from lesion points to a more benign etiology. Investigations Although there are clinical features that make malignancy more likely (i.e. nodule size increasing or stable over a two-year time period, age more than 40 years, smoking, prior cancer history, occupational exposure to carcinogen and presence of hemoptysis), an accurate and preferred noninvasive method is vital to differentiate malignant from non-malignant SPNs. Multidetector CT assesses the pulmonary nodule for size, calcification, border regularity, density and cavitation. A variety of tissue sampling techniques are available like fibreoptic bronchoscopy and biopsy, percutaneous needle aspiration or needle biopsy, video-assisted thoracoscopy and thoracotomy biopsy. When the risk of invasiveness is correlated with increased certainty of the yield of biopsy, bronchoscopy was found to be the least and thoracotomy the most. [4] FDG PET CT Imaging FDG PET CT has proved to be quite sensitive for the detection and evaluation of pulmonary nodules. Interpretation can be performed in two ways-qualitative and quantitative. In qualitative interpretation, FDG uptake in the nodule is compared with the blood pool background - nodules with uptake greater than that of the blood pool background are considered malignant and those with less uptake, benign. Quantitative assessment is done using SUV expressed generally as g/ml, a semi-quantitative measure of FDG uptake. The most widely used cutoff for the differentiation of benign and malignant nodules is an SUV of 2.5. When qualitative criteria are applied, FDG PET is approximately 95% sensitive and 80% specific for malignancy and with quantitative criteria, sensitivity decreases to 81% and specificity increases to 87%. [5],[6],[7] Limitations of FDG PET CT There can be certain false-positive and false-negative causes of FDG uptake in SPNs, which one needs to be aware. False-positive causes of FDG uptake are predominantly of inflammatory origin, [8] like tuberculosis, aspergillosis and histoplasmosis. These lesions can be intensely hypermetabolic and indistinguishable from lung Ca on PET imaging. [9],[10] Non-infectious granulomas may also be metabolically active, including sarcoidosis and Wegener′s granulomatosis. [11] False-negative results for malignant SPNs [12] are largely due to two causes - small size and or well-differentiated malignancies. Lesions less than 0.5 cm in diameter may be falsely negative because of resolution limits of the PET scanner and partial volume effects. [13],[14] Small lesions less than two times the resolution of the imaging system, will not have all radioactive counts recovered, so their apparent SUV will be lower than their true radioactivity concentration. [15] It has been shown that SUV significantly correlates with tumor doubling time, [15] thus those tumors that are falsely negative are likely to be slow-growing and hence a delay in diagnosis may be less important in this group. Well-differentiated malignancies may show little increase in FDG uptake compared with the normal surrounding tissues and thus may be falsely negative, especially carcinoids, well-differentiated adenocarcinomas and bronchoalveolar cell carcinomas. [16],[17] Studies have shown that different subtypes of bronchoalveolar cell carcinoma show various rates of metabolic activity. Focal or pure bronchoalveolar cell carcinoma appears as a peripheral nodule or localized ground-glass attenuation and may show false-negative results on FDG PET while the multifocal types appear as ground-glass opacities or as multiple nodules and are FDG-avid. [18],[19] Reported sensitivity of FDG PET for such low metabolically active lung carcinomas are as low as 50%. [19] Respiratory movements during PET CT acquisition also is another potential source of false negativity especially for lower lobe SPNs. Respiratory movements produce image misregistration there by falsely lower SUVs. Respiratory gating is a useful technique to correct respiratory motion artifacts of 1-3 cm during PET imaging, thus improving accuracy. [20] Dual time point PET imaging Another potentially important PET technique, useful in differentiating benign from malignant nodule, is dual time-point PET imaging. [21] This is particularly indicated for patients whose nodules exhibit an SUV of around 2 to 2.5 g/ml. Here FDG uptake in the lung nodule is measured at two different time intervals, usually 1 h and 2-3 h after injection. FDG uptake in malignant nodules tends to increase in the delayed imaging while uptake in benign nodules remains the same or decreases in intensity over time. Dynamic Contrast CT (dCT) Newer CT advancements like dCT measures nodule vascularity and determine peak enhancement of lung nodule in 3-mm-thin sections at 1, 2, 3 and 4 min. Enhancing nodules are assumed to be malignant. [22] For nodules that are X-ray, CT-wise indeterminate, a negative dCT at a threshold of 10 HU (Hounsfield units) virtually rules out malignancy, however, a positive study is less definitive. This technique has a sensitivity of 98%, specificity of 58% and an overall accuracy of 77%. [23] Integrated PET CT is more sensitive than dCT with similar specificity and also with greater accuracy. [24] PET CT provides improved or similar nodule resolution, faster scanning time and CT visualization of SPN, which is important especially in smaller lesions. Non-Small-Cell Lung Cancer NSCLC accounts for about 80% of all lung cancers. The major histological subtypes of NSCLC are squamous cell carcinoma, adenocarcinoma and large-cell carcinoma, although more than one histological form may be seen within the same tumor. Surgical resection represents the best chance for cure. Staging is critical for planning appropriate treatment and prognostication. [25] Tumor Staging The extent of the primary tumor determines therapeutic management. Imaging is done to assess the size of the tumor and the extent of pleural, chest wall or mediastinal invasion [Figure - 1] and [Figure - 2]. CT and magnetic resonance imaging (MRI) are useful for confirming gross chest wall and mediastinal invasion. [26] But they are inaccurate in differentiating between anatomic contiguity and subtle invasion. FDG PET alone has a limited role in T staging due to inaccurate assessment of tumor size. Integrated PET CT scanners with coregistration of PET and CT improve staging by clearly demarcating involvement of chest wall, diaphragm, mediastinal pleura or pericardium, or main bronchus (T3 staging). [27] Similarly, it is useful to determine the involvement of mediastinal, vertebral and vital structures, such as the great vessels, trachea, esophagus, or heart (T4 staging). FDG PET is also used to evaluate additional pulmonary nodules in the same lobe/ipsilateral lung having primary lung cancer, and determine the likelihood of malignancy in these nodules. CT is rarely able to differentiate between reactive and malignant pleural effusions whereas FDG PET has a definitive role in that. [28],[29] Malignant pleural effusion shows FDG uptake (stage M1a). MRI is useful in assessing cardiac invasion and pancoast tumor. [30] FDG PET CT is specially indicated for superior sulcus tumors which are potential candidates for surgical resection. It also has a role in guiding biopsy in patients with disease recurrence. Nodal Staging In NSCLC patients, loco-regional lymph node involvement is associated with poorer survival and dictates the therapeutic choices in the absence of distant metastasis. Metastases to lymph node (i.e. N1-N3 disease) alters the stage and prognosis of patient [Figure - 3]. Node-negative or patients with only intrapulmonary or hilar nodes (N0/N1) undergo direct resection alone while those with N2 staging i.e. ipsilateral mediastinal lymph nodes, need platinum-based chemotherapy combined with surgery or concurrent or sequential radical radiotherapy. [31] Patients with contralateral mediastinal lymph nodes N3 need non-surgical combined modality treatment. Presence of nodal metastasis N1-N3 is associated with poorer survival than in patients with no nodal disease (N0). [32] Intrathoracic nodal staging includes invasive and noninvasive techniques. Invasive techniques most typically are mediastinoscopy, video-assisted thoracic surgery (VATS), endoscopic sonography and thoracotomy. Mediastinoscopy is best used for the evaluation of Level 2, 4, and 7 lymph node stations. VATS can be used for multiple stations, depending on the approach, and is commonly used for Level 5, 6, and 10 stations. [32] Endoscopic sonography with transbronchial needle aspiration can be used for Level 4-9 stations. All nodal groups can be reached by thoracotomy and potentially by CT-guided percutaneous needle biopsy. The drawbacks are sampling errors and coverage. Although surveillance biopsies are usually obtained from multiple nodal stations, certain specific sites of disease can be missed and a single port of entry for mediastinoscopy may be insufficient. [33] Nodes at the aortopulmonary window cannot be sampled as they are unapproachable Noninvasive assessment of lymph nodes can be easily performed with CT plus PET. Regardless of the threshold size of the lymph node chosen, CT findings in isolation cannot be taken as clear evidence of malignant involvement. CT thorax is an inappropriate investigation for staging the mediastinum, reasons being any node more than or equal to 1 cm in short axis will be called abnormal and can suggest metastasis. Sub-centimeter-sized lymph nodes harboring tumor may be wrongly interpreted as normal when size is considered to be the sole criterion. Lymph nodes may also be enlarged due to inflammatory lung disease or Congestive cardiac failure (CCF). [34],[35],[36] Not all enlarged nodes are necessarily involved with tumor cells. CT shows variable sensitivity and specificity for mediastinal nodal involvement, i.e. false-negative results of 7-39% and false-positive results of 20-45% have been reported. Fifteen percent of patients with clinical Stage I disease may have micrometastases in normal-size lymph nodes. [37] Size alone cannot be an exclusion criterion and proof is needed by biopsy or resection that a node is indeed malignant or benign. FDG PET CT aims to fulfill all the shortcomings of invasive sampling by mediastinoscopy and transbronchial needle biopsy. PET CT has a major role in preoperative noninvasive evaluation of mediastinal and hilar lymph nodes. [38],[39] PET-guided lymph nodal biopsies are feasible and also provide more accuracy in the nodal staging. FDG PET can be falsely positive in sarcoidosis, tuberculosis and other infective etiologies and may be falsely negative in bronchoalveolar carcinoma and bronchial carcinoids. In normal-sized mediastinal lymph nodes PET has a sensitivity and specificity of 74 and 96%, respectively, for detecting metastasis. This means that if the PET is positive in these normal-sized nodes, there is almost always a lymph node metastasis with a false-negative rate of only 4%. Metastasis Staging Forty percent of the patients with NSCLC have distant metastasis at presentation. The most common sites of metastasis are adrenals, bones, liver and brain. [40] Distant metastasis groups the patient into Stage 4 NSCLC where treatment is non-surgical and primarily palliative [Figure - 4]. PET CT is useful is distinguishing benign from malignant adrenal lesions detected on CT, especially when the lesion is small (sensitivity 100% and specificity 80-100%). [41] However, as there can be false-positive findings on PET, an isolated adrenal mass with increased FDG uptake needs to be histology confirmed before surgery is denied. Bone metastasis is usually assessed by 99m Tc MDP (Methylene diphosphonate) bone scintigraphy, which has a good sensitivity (90%) but a low specificity (60%) due to false-positive findings. FDG PET CT is reported to have similar sensitivity (>90%) but with a higher specificity (>98%). [42] FDG PET CT has also been shown to detect unsuspected metastatic disease in unusual locations such as muscle, extrathoracic lymph nodes, soft tissue and pleura. It may also identify unsuspected synchronous non-pulmonary malignancy. [43],[44] Sensitivity and specificity of FDG PET to detect pleural masses and malignant pleural effusions is 95% and 67% respectively. [45] FDG PET is not suited for the detection of brain metastasis because of the low sensitivity (60%). This is due to the high glucose uptake of normal surrounding brain tissue. Hence CT and or MRI is used to evaluate brain metastasis, especially occult brain metastasis. [46] Overall, integrated FDG PET CT has improved the detection of T4 and M1 disease. Studies conclude that PET information added clinical benefit prior to, during and after surgery and also lowered total hospital expenditure mainly due to a 51% reduction in the number of futile (or unrewarding) thoracotomies. [47] SUV was an independent predictor of outcome in patients with NSCLC, regardless of stage. Monitoring Therapy Response and Detection of Recurrence Patients undergoing multimodality therapy need to undergo a proper imaging procedure to ascertain response to therapy and to re-evaluate tumor for resectability. By conventional CT, therapy response is determined by a decrease in tumor size but it is difficult to assess whether this decrease in size represents complete or partial response to therapy. CT also fails to clearly delineate treatment response in the setting of post-radiotherapy pulmonary fibrosis. MR Gadolinium contrast imaging is also not useful as it provides enhancement of both primary and surrounding fibrotic tissue. FDG PET is more sensitive in this aspect by providing metabolic rather than anatomic information. PET scanning demonstrated high sensitivity (95%) and moderate specificity (80%) for the evaluation of residual disease. [48],[49],[50] A negative PET scan or a decrease in SUV of greater than 80% was predictive of prolonged survival. In patients without metabolic response, PET CT guides the oncologist to alter the chemotherapy regimen, thereby significantly reducing the morbidity and costs resulting from ineffective therapy. False positives can occur with FDG PET study in treatment evaluation. Therapy modalities, especially external radiation can cause radiation pneumonitis or macrophage-mediated inflammation within tumor necrosis, which may be metabolically active on PET imaging. [51] Hence FDG PET should ideally be performed at least eight weeks after completion of radiotherapy when these changes resolve. [52] FDG PET as a prognostic factor The best tool for prognosis and prediction of survival of newly diagnosed patients with NSCLC is Tumour Nodal Metastases (TNM) staging and the stages determined by FDG PET were predictive of survival, whereas CT-determined staging was not. But this was only for unoperated cases, as PET provided no additional prognostic information if histological staging was available. [53] FDG uptake in NSCLC correlates well with tumor grade accounting for the low uptake in low-grade tumors like bronchoalveolar carcinoma and high uptake in high-grade lung cancers. As the intensity of FDG uptake in the tumor increases, survival decreases. Studies demonstrated that tumors with an SUVmax of ≥ 7 had a relative risk of 6.3 as compared with those with an SUVmax of ≤ 7. This increase in relative risk was found to be independent of other prognostic features. [54] Small-Cell Lung Cancer This constitutes 20% of all lung cancers and has a higher incidence in women. Small-cell lung cancer (SCLC) is associated with rapid tumor mass doubling time, high growth fraction and early development of distant metastasis. It has a poor prognosis with an average two-year survival rate of less than 10%. [55],[56] SCLC is staged according to the Veterans Administration Lung Cancer Study Group recommendations, as limited disease (LD) or extended disease (ED). [57] LD is defined as tumor confined to the hemithorax and regional lymph nodes while ED includes tumor with non-contiguous metastasis to the contralateral lung and distant metastasis. [58] Most patients with SCLC have ED at presentation. LD is localized enough to be included in a radiation port, hence treated with radiation along with chemotherapy while ED patients receive chemotherapy alone. Most patients relapse within two years despite aggressive treatment and high responsiveness to chemotherapy and radiotherapy. [59] Experience with FDG PET is more limited in SCLC, compared to NSCLC simply because of lower survival rates and lack of follow-up. PET CT is more sensitive and specific in the evaluation of the mediastinum (complex anatomy and close proximity of vasculature and nodal stations), adrenal and liver lesions by accurate localization of FDG-avid foci. PET CT can accurately establish LD by excluding extrathoracic disease and thus treat with radiotherapy along with chemo therapy. PET can accurately map the extent of thoracic disease and thus helps to delineate an appropriate radiation port. FDG PET helps to identify active tumors by their tracer avidness even if the lymph nodes are not enlarged while CT does not detect lymph nodes less than 1 cm. Radiotherapy planning PET CT has an evolving role in radiotherapy planning of lung cancer patients. It improves radiotherapy planning by providing more complete coverage of the disease and less radiation to normal tissues. Incorrect delineation of gross tumor volume, GTV (i.e. detectable tumor) from clinical target volume, CTV (i.e. tumor plus margin for microscopic extension) is a source of systemic error leading to under-treatment and can reduce the probability of tumor control. FDG PET CT provides metabolic information, and can be used to determine planned target volumes (PTVs), target coverage and critical organ dose. Studies have demonstrated change in PTV in approximately 30% of cases, either leading to smaller volumes resulting in reduction of dose exposure to healthy tissues or to larger volumes due to positive lymph nodes. It is difficult to separate tumor mass from tumor-associated atelectasis based on CT alone. PET CT has a specific role in this group in deciding PTV. [60] In a recent international atomic energy agency (IAEA) recommendation, [61] elective nodal irradiation of mediastinal nodes has been omitted from the standard radiation portals for NSCLC. The current recommendation is to treat the gross primary and involved nodes with margins. It reduces radiation treatment volumes by avoiding PET-negative mediastinal lymph nodes and hence reducing toxicity with the same radiation dose or enabling radiation-dose escalation with the same toxicity. Encouraging data are also available for SCLC. PET CT reduces inter-observer variability in tumor delineation and opens the perspective for more automated delineation in Radio Therapy (RT) planning as well as in innovative radiation delivery. "Dose-painting" radiotherapy allows for a heterogeneous delivery of radiation within the tumor volume by targeting radio-resistant areas defined by functional imaging. By defining Biological target volume (BTV) which is equal to PTV, it is possible to apply a strategy of intensity-modulated radiation therapy (IMRT) that will deliver a higher dose to these regions to give maximum benefit to the patient. Therefore rapid advances in 18 F FDG-PET CT technology and novel co-registration algorithms have created a strong interest in 18F FDG-PET/CT′s application in IMRT and image-guided radiation therapy (IGRT). Conclusion Optimized management of patients with lung cancer requires accurate delineation of the extent of disease. FDG PET CT has proven to be valuable in the evaluation of indeterminate pulmonary nodules, staging and restaging of disease in patients with known lung cancer. CT thorax alone is an inappropriate investigation for staging the mediastinum in the era of PET. PET CT is also increasingly used in therapy response monitoring and in planning radiation therapy. PET techniques continue to improve with the introduction and validation of new imaging agents like 18F-labeled Fluoro Thymidine (FLT), Fluoro Misonidazole (F MISO). It is hoped that the limitations with FDG like its false positive and negatives will be addressed with these new agents. References
Copyright 2011 - Journal of Cancer Research and Therapeutics The following images related to this document are available:Photo images[cr11031f1.jpg] [cr11031f2.jpg] [cr11031f3.jpg] [cr11031f4.jpg] |
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