Size, Location, and Locoregional Invasion (T Descriptor)

FDG-PET is used together with CT because the integration of metabolic activity with the high-spatial resolution of CT is important for the evaluation of tumors in terms of size, location, and the degree of locoregional invasion (T descriptor) as well as for the determination of the anatomic location of regions of focally increased FDG uptake. It is important to be aware that the relatively poor spatial resolution of PET limits its utility for the evaluation of the primary tumor. However, the CT component of integrated PET–CT also has shortcomings in terms of its ability to accurately demonstrate T descriptors such as the presence of additional small lung nodules and locoregional invasion as it is often performed during respiration and with a low-radiation-dose imaging protocol, both of which can compromise image quality. Nevertheless, FDG-PET improves the detection of nodal and distant metastases and frequently alters the treatment of patients. Accordingly, this review of TNM staging will focus on the important role of PET imaging for the detection of nodal and distant metastases at the time of initial staging according to the seventh edition of the American Joint Committee on Cancer TNM staging system and will reference the proposals for the forthcoming eighth edition when applicable.

Regional Lymph Nodes (N Descriptor)

The presence and location of nodal metastasis (N descriptor) are important when determining the treatment of and prognosis for patients with NSCLC and, because these descriptors adequately predict prognosis, they will be maintained in the forthcoming eighth staging system. Lymph node maps, in which the node stations are numbered according to anatomic structures, are commonly used in an attempt to ensure uniformity when designating the clinical and pathologic extent of nodal metastases. There is no universally accepted nodal map and the International Association for the Study of Lung Cancer has proposed a new lymph node map that reconciles the differences among the currently used maps. However, while a precise and universally accepted nomenclature to describe lymph node involvement is essential for selecting appropriate therapy and assessing the outcomes of treatment, a major shortcoming of clinical staging is the use of nodal size to detect metastatic disease. Toloza et al., in a meta-analysis of 20 studies (3438 patients) that was performed to evaluate the use of CT for staging of the mediastinum, found that the use of a short-axis diameter of more than 1 cm as the threshold for the detection of nodal metastasis was associated with a pooled sensitivity of 57% and a pooled specificity of 82%.

FDG-PET is more accurate than CT for staging of the mediastinum in terms of nodal involvement, and FDG-PET is being increasingly integrated into both surgical and radiation oncology treatment strategies for patients with NSCLC ( Fig. 22.1 ). Birim et al., in a meta-analysis of 17 studies (833 patients) in which PET was compared with CT for nodal metastasis detection in patients with NSCLC, reported that the overall sensitivity and specificity of FDG-PET for detecting mediastinal lymph node metastases were 83% (range, 66–100%) and 92% (range, 81–100%), respectively, whereas those of CT were 59% (range, 20–81%) and 78% (range, 44–100%), respectively. In addition, improvement in the accuracy of nodal metastasis detection has been reported in association with the use of integrated PET–CT as compared with the use of CT ( p = 0.004) and PET ( p = 0.625) separately. However, in a recent study of 159 patients with NSCLC, the use of PET–CT for mediastinal N determination was associated with low sensitivity and accuracy. Based on the evaluation of 1001 nodal stations (723 mediastinal, 148 hilar, and 130 intrapulmonary), the sensitivity, specificity, and accuracy of PET–CT for the detection of mediastinal nodal metastasis were 45.2%, 94.5%, and 84.9%, respectively. The sensitivity of PET–CT for the detection of malignant involvement was 32.4% (12 of 37) for nodes measuring less than 10 mm and 85.3% (29 of 34) for nodes measuring 10 mm or more. Although infrequently addressed, the timing of PET–CT imaging may affect N determination. Ideally, PET imaging for the evaluation of nodal metastasis in patients being evaluated for surgical resection should be performed in close temporal relationship to the anticipated date of resection. In this regard, there may be a meaningful association between the sensitivity of PET–CT and the time from imaging to resection. Booth et al. reported that the sensitivity and accuracy of PET–CT for N2 nodal detection were 64% and 94%, respectively, when performed less than 9 weeks before pathologic sampling, compared with 0% and 81%, respectively, when performed 9 weeks or more before pathologic sampling.

A 49-year-old man with NSCLC who was being evaluated for surgical resection. (A) Axial contrast-enhanced CT showing a 2.5-cm nodule in the upper lobe of the right lung and a small node (short-axis diameter, 1 cm) in the ipsilateral mediastinum (arrow) . (B) Axial PET–CT scan showing increased FDG uptake in the nodule and in the right lower paratracheal lymph node. A biopsy was positive for nodal metastatic disease, and the patient underwent neoadjuvant chemotherapy followed by concurrent chemoradiation.

Despite the superior accuracy of FDG-PET–CT over CT in terms of N determination, a limitation is the overlap in the appearance of malignant and benign lymph nodes as microscopic nodal metastases normally are not FDG-avid, whereas inflammatory lymph nodes can be FDG-avid. The use of an FDG uptake threshold such as the maximum standardized uptake value (SUV _max ) to differentiate inflammatory from metastatic nodal disease has limited utility for clinical N determination as numerous factors, including the time to imaging after FDG administration and the type of scanner and image reconstruction algorithm used, can affect the thresholds selected. We are not aware of any prospective multicenter trial that has validated an FDG uptake threshold, and visual interpretation currently tends to be more accurate than SUV quantification. When mediastinal lymph nodes are FDG-avid as determined on the basis of visual analysis or SUV, the number of false-positive results due to infectious or inflammatory etiologies is too high to allow for a confident diagnosis of nodal metastasis ( Fig. 22.2 ). In this regard, because the positive predictive value of FDG-PET is not optimal for diagnosing nodal metastasis, invasive sampling should be performed to confirm pathologically involved nodes (pN) disease when the PET and CT findings are indicative of nodal metastasis or when the CT and PET findings are incongruent. In addition, even if PET–CT is negative for mediastinal nodal metastasis, the need for histologic confirmation persists because of the low sensitivity and accuracy of PET–CT for intrathoracic nodal staging. However, it is important to emphasize that the precise role of FDG-PET with regard to invasive nodal evaluation is unclear. Although not universally accepted, the American College of Chest Physicians evidence-based practice guidelines recommend that invasive confirmation of the mediastinal nodes is not needed in patients with a peripheral clinical stage I NSCLC if PET of the mediastinum is negative. Furthermore, a meta-analysis of 10 studies (1122 patients) indicated that occult nodal metastasis is not infrequent in patients with clinical stage T1-2N0 NSCLC but that PET and CT provide a favorable negative predictive value for the detection of mediastinal metastasis (0.94 for T1 disease and 0.89 for T2 disease), suggesting a low yield from invasive clinical staging for this subgroup of patients.

A 62-year-old man with a NSCLC in the upper lobe of the left lung who was being evaluated for surgical resection. This coronal PET–CT shows increased FDG uptake in the mass in the upper lobe of the left lung (M) and a small node (short-axis diameter, 1 cm) in the left supraclavicular region (arrow) . A biopsy revealed findings consistent with reactive lymphoid hyperplasia (abundant lymphoid tissue, germinal center fragments, increased large cells, tingible body macrophages) and absence of metastatic carcinoma. The patient underwent left upper lobectomy.

In an attempt to determine the need for invasive sampling after PET and CT imaging, de Langen et al. performed a meta-analysis to evaluate the association between the size of mediastinal nodes and the probability of malignancy. The authors reported a 5% posttest probability for N2 disease in patients with a negative result on FDG-PET imaging in whom the mediastinal nodes measured 10 mm to 15 mm on CT and suggested that these patients should be treated with thoracotomy. In comparison, they reported a 21% posttest probability for N2 disease in patients with a negative result on FDG-PET imaging in whom the lymph nodes measured more than 16 mm on CT and suggested that these patients should have mediastinoscopy prior to thoracotomy. For patients with a positive result on FDG-PET, the posttest probability of malignancy was 62% when the nodes measured 10 mm to 15 mm on CT and 90% when the nodes measured more than 16 mm. Although the authors did not suggest any management strategies regarding histologic confirmation of nodal metastasis when the result on FDG-PET is positive, N2 and N3 disease should be histologically confirmed in patients who are potentially eligible for resection or adjuvant therapy.

The expanded role of nonsurgical management for patients with early-stage NSCLC and the definitive use of FDG-PET–CT to detect mediastinal nodal metastasis in high-risk patients or patients with advanced disease who are being evaluated for nonsurgical management underscore the importance of accurate nodal evaluation. In this regard, there have been attempts to improve the detection of mediastinal nodal metastasis when using FDG-PET–CT in the staging algorithm. The SUV _max of the primary tumor has been used to predict the likelihood of microscopic nodal metastatic disease and to improve the accuracy of N staging. Trister et al. reported that a high SUV for the primary tumor was an independent predictor of occult mediastinal nodal metastasis in patients with clinical stage I and II NSCLC and recommended invasive staging of the mediastinum when the SUV is more than 6. In addition, in a study of 265 patients with NSCLC, Miyasaka et al. reported that the SUV _max of the primary tumor was a significant predictor of pathologic nodal involvement, with pN1-2 disease being detected in 25 (41%) of 61 in whom the SUV _max was more than 10, compared with only 26 (12.7%) of 204 patients in whom it was less than 10 ( p < 0.0001). The detection of nodal metastasis also may be improved by the use of point spread function (PSF) reconstruction along with PET–CT scanners. PSF reconstruction recently became commercially available, and, as a result of improved image contrast and reduced image noise, may be more sensitive for the detection of small-volume nodal metastases. Lasnon et al. reported that PSF PET had higher sensitivity (97%), negative predictive value (92%), and negative likelihood ratio (0.04) than did conventional iterative reconstruction ordered subset expectation maximization PET (78%, 57%, 0.31, respectively) for nodal evaluation in patients with NSCLC. While improved sensitivity increases the likelihood of false-positive results, the authors concluded, on the basis of the significant improvements in sensitivity ( p = 0.01), negative predictive value ( p = 0.04), and low negative likelihood ratio that were observed in association with PSF reconstruction, that preoperative invasive nodal staging may be omitted in cases in which the result of PSF FDG-PET–CT is negative. A potential further advance in nodal assessment is the use of an artificial neural network (ANN). Toney and Vesselle recently reported that an ANN overcame the subjectivity associated with the interpretation of PET, outperformed an expert FDG-PET–CT reader in terms of accuracy, and differentiated malignant and benign inflammatory lymph nodes with overlapping appearances on PET–CT. The ANN used four FDG-PET–CT-derived input parameters (primary tumor SUV _max ; tumor size; node size; and FDG uptake at the N1, N2, and N3 stations) and correctly predicted the N descriptor in 99.2% of cases, compared with 72.4% for the expert reader.

Distant Metastasis

Distant metastases (M descriptor) are common in patients with NSCLC at the time of presentation and are currently subclassified into M1a metastases (additional nodules in the contralateral lung, malignant pleural effusion, pleural nodule[s], pericardial nodule[s]) and M1b (extrathoracic) metastases. The forthcoming eighth edition proposals for the M descriptor maintain the M1a descriptor but the M1b will now be assigned to cases with a single extrathoracic metastasis, and M1c to those with multiple extrathoracic metastases in one or more organs.

Although FDG-PET–CT can be useful in the evaluation of the intrathoracic and extrathoracic metastases, the role of FDG-PET in detecting M disease is not clearly defined. For instance, patients with early clinical stage (T1 N0) NSCLC have a low incidence of occult metastasis; thus extensive evaluation for metastasis in these patients may not be warranted. Viney et al. performed a randomized controlled trial to determine the appropriate role of FDG-PET in the clinical treatment of patients who have early stage NSCLC. In that study, 183 patients with early-stage lung cancer (>90% of who had T1 2N0 involvement) were assigned to conventional workup (92 patients) or to conventional workup and PET (91 patients). Compared with conventional staging, PET confirmed staging in 61 patients, staged the tumors as benign in two patients, and upstaged the tumors in 22 patients, including 11 patients with N2 nodal metastatic disease and two patients with pleural metastasis. Distant metastases were rarely detected with PET (2 of 91 patients; <5%). Overall, the results of PET could have resulted in a change in treatment for 26% of the patients, with the avoidance of thoracotomy in 11 of 91 patients and with 13 of 91 potentially receiving neoadjuvant chemotherapy or chemoradiation therapy. However, because the general policy of the participating surgeons was to operate on patients with apparently completely resectable stage IIIA disease without any further evaluation, PET resulted in further investigation or other management changes in only 12 patients (14%).

In patients with more advanced disease, whole-body FDG-PET–CT has a greater impact on the accuracy of staging as well as on management. The American College of Surgeons Oncology Group reported that PET had a sensitivity, specificity, positive predictive value, and negative predictive value of 83%, 90%, 36%, and 99%, respectively, for M1 disease. Whole-body PET imaging stages intrathoracic and extrathoracic disease in a single study and detects occult extrathoracic metastases in up to 24% of patients who are selected for curative resection ( Fig. 22.3 ). The incidence of detection of occult metastases has been reported to increase as the T and N descriptors increase (from 7.5% in early-stage disease to 24% in advanced disease). In two studies with a relatively high proportion of patients with more advanced lung cancers that were considered to be resectable on the basis of standard clinical staging, PET imaging prevented nontherapeutic surgery in one of five patients. A more recent prospective study, similar to the PLUS multicenter randomized trial conducted by van Tinteren et al. but evaluating PET–CT rather than dedicated PET, demonstrated that 52 (63%) of 83 patients in the PET–CT group underwent surgery, with 13 (25%) of 52 thoracotomies being futile. By contrast, in the conventional staging group, 73 (80%) of 91 patients underwent thoracotomy, with 38 (52%) of 73 thoracotomies being futile.

A 53-year-old man with NSCLC who was being evaluated for surgical resection. (A) Axial contrast-enhanced CT showing a spiculated mass in the upper lobe of the right lung. Note the diffuse emphysematous lung disease. (B) Whole-body maximum intensity projection PET showing increased uptake of FDG in the mass. Note the absence of nodal and distant metastasis. Whole-body PET stages intrathoracic and extrathoracic disease in a single study.

The widespread use of FDG-PET has changed the imaging algorithm that is used to detect metastases to specific organ sites, particularly the osseous skeleton, the adrenal glands, and extrathoracic lymph nodes. In this regard, FDG-PET–CT is particularly effective for detecting bone metastasis. A meta-analysis of 17 studies demonstrated that the pooled sensitivity and specificity for the detection of bone metastasis were 92% and 98%, respectively, for FDG-PET–CT, compared with 86% and 88%, respectively, for bone scintigraphy. As a result, FDG-PET–CT has to a large extent replaced 99mTc-methylene-diphosphonate (MDP) bone scintigraphy for the evaluation of possible bone metastasis in patients with NSCLC ( Fig. 22.4 ). Specifically, 99mTc-MDP bone scintigraphy now has no additional utility for patients with NSCLC if FDG-PET is performed as part of the staging algorithm. In fact, discordant findings of skeletal metastasis between 99mTc-MDP scintigraphy and FDG-PET–CT have been reported to occur in 20% of patients with NSCLC. This discordance is in large part due to the ability of FDG-PET to detect early bone metastasis and the failure of 99mTc-MDP scintigraphy to detect early neoplastic infiltration of bone marrow. FDG-PET–CT is also useful for detecting adrenal metastasis and for distinguishing benign from malignant adrenal masses that are detected with CT. A meta-analysis of 21 studies (1391 lesions), including five studies that specifically focused on patients with lung cancer, demonstrated that FDG-PET had a combined sensitivity and specificity of 94% and 82%, respectively, for the detection of adrenal metastasis in patients with lung cancer. Similar to the assessment of bone metastasis, FDG-PET has changed the imaging algorithm used to evaluate an indeterminate adrenal mass detected with CT and is now often used as the definitive imaging modality rather than magnetic resonance imaging (MRI), particularly when the adrenal mass is small ( Fig. 22.5 ). In fact, adrenal masses can be characterized with use of FDG-PET, and subsequent imaging is usually unnecessary. If an adrenal mass in a patient with potentially resectable NSCLC has normal FDG uptake on PET, curative resection should be considered without further evaluation. If an adrenal mass has increased FDG uptake, biopsy should be performed to confirm metastatic disease. FDG-PET–CT has limitations in the evaluation of liver and brain metastases. Specifically, because of the high background uptake of FDG by normal brain tissue, the ability to detect brain metastasis is not optimal. MRI is the current standard of care for patients with NSCLC who are undergoing evaluation of possible brain metastases, and FDG-PET–CT lacks the sensitivity and specificity to replace this diagnostic test. Similarly, FDG-PET–CT has a limited role in the detection of hepatic metastases. Although FDG-PET–CT has a high specificity for the detection of occult hepatic metastases, it has a low sensitivity, and, accordingly, FDG-PET is not routinely used for this purpose.

A 46-year-old woman with NSCLC in the upper lobe of the left lung who presented with shoulder pain. (A) Axial contrast-enhanced CT showing a spiculated nodule in the upper lobe of the left lung. (B) Coronal PET–CT showing increased uptake of FDG in the nodule in the upper lobe of the left lung and in the coracoid process of the scapula (arrow) , which was suspicious for metastasis. Biopsy confirmed metastatic disease, and the patient was treated palliatively.

A 70-year-old woman with NSCLC of the upper lobe of the right lung and an adrenal mass. (A) Posteroanterior radiograph of the chest, showing a mass in the upper lobe of the right lung. Note the presence of an implantable cardioverter defibrillator. (B) Whole-body PET maximum intensity projection image showing increased FDG uptake in the mass in the right lung and the right adrenal mass (arrow) . Asterisk indicates normal renal excretion of FDG in a calyx. (C) Axial PET–CT showing increased uptake of FDG in the right adrenal mass (arrow) , which was suspicious for metastasis. A biopsy confirmed metastatic disease.

Whole-body FDG-PET imaging improves the accuracy of staging in patients with NSCLC. However, focal increased uptake of FDG in extrathoracic lesions that are unrelated to the primary NSCLC can mimic distant metastasis. Accordingly, all extrathoracic FDG-avid lesions that potentially would alter patient management should be further imaged or biopsied to confirm the diagnosis of distant metastasis. The rationale for this management approach is supported by the results of a prospective study that was performed to assess the incidence and diagnosis of a single site of extrapulmonary accumulation of FDG in patients with newly diagnosed NSCLC. Of the 350 patients in the study group, 72 had solitary FDG-avid lesions. Sixty-nine of these patients underwent biopsy of the lesion; of these, 37 (54%) had a solitary metastasis, whereas 32 (46%) had a lesion that was unrelated to the NSCLC, such as a benign tumor or inflammatory lesion (26 patients) or a clinically unsuspected second malignancy or recurrence of a previously diagnosed carcinoma (6 patients).