TNM staging has a very important role in managing patients with lung cancer. Treatment options as well as prognosis vary for the different stages of disease. Tumor (T) staging is better accessed by either CT or MRI as these techniques offer better resolution and anatomical details. T status depends on tumor size, location, and relationship to nearby structures. Five-year survival rates have been reported to differ in relationship to the tumor size—77% in T1a (≤2 cm), 71% in T1b (2–3 cm), 58% in T2a (3–5 cm), 49% in T2b (5–7 cm), and 35% in T3 tumors (>7 cm) [13]. Data are now available showing the importance of [¹⁸F]FDG imaging in TNM staging [15–18]. [¹⁸F]FDG imaging also has a significant role in assessing involvement of the pleura. Pleural fluid cytology can be falsely negative in 30–40% of patients [19]. On the other hand, [¹⁸F]FDG imaging has a sensitivity of 89–95%, specificity of 67–94%, and accuracy of 91–92% for the detection of malignant pleural involvement [20, 21].

Loco-regional lymph node spread represents an important factor in lung cancer management, especially in the absence of distant metastases. Patients with either negative or positive N1 (bronchopulmonary or hilar) nodes are considered for lung resection without further testing. Mediastinal lymph node positive [ipsilateral (N2) or contralateral (N3)] patients are usually referred to confirmation biopsy either by mediastinoscopy, endoscopic ultrasound (EUS), or endobronchial ultrasound (EBUS). If positive on further tests, management is changed from surgery alone to a combined approach of surgery with chemo/radiotherapy or combined chemo/­radiotherapy without surgery. [¹⁸F]FDG imaging has an established high accuracy for nodal staging. NICE [22] suggested that [¹⁸F]FDG-negative or a chain of [¹⁸F]FDG-positive nodes would not necessarily need confirmation by other diagnostic testing.

In the UK the management of N2 disease varies. Most patients are regarded as not suitable for radical surgery alone and neoadjuvant chemotherapy can be considered in a trial setting. Depending on the nodal station, some patients are better served with radical radiotherapy. In other countries combined modality management is recommended for N2 disease. Proven N3 disease patients are usually not considered for radical treatment procedures. As indicated in the 7th edition TNM classification, patients with single N1 disease have a 5-year survival of 48% as compared to 35% in patients with multiple N1, 34% for single N2, and 20% in patients with multiple N2 nodes [23].

In addition to T and N staging, [¹⁸F]FDG PET-CT imaging is useful for M staging where M0  =  no metastasis and M1  =  distant metastases. The presence of distant metastases usually changes patient management drastically with stage 4 patients typically treated symptomatically and for palliation. Patients with good performance status (e.g., Zubrod/ECOG 0–2) are offered palliative chemotherapy, radiotherapy, and/or active supportive care. The 5-year survival rates in patients with involvement of ipsilateral nodes, pleural effusion, contralateral nodes, and distant metastases are 16%, 6%, 3% and 1%, respectively [23].

These data have lead to changes in lung cancer stage grouping in 2009 (Tables 13.4 and 13.5). The major changes include stage T2 large size was upgraded from IB to IIA, and small T2 N1 was downgraded from IIB to IIA. According to this new TNM staging, the 5-year survival rates for NSCLC are 73% for stage IA, 58% IB, 46% IIA, 36% IIB, 24% IIIA, 9% IIIB, and 13% for stage IV [24].

The same TNM classification is also suggested for SCLC. The 5-year survival rates for small cell lung cancer (SCLC) are 38% for stage IA, 21% IB, 38% IIA, 18% IIB, 13% IIIA, 9% IIIB, and 1% for stage IV [25] (Fig. 13.1).

Selection of the appropriate therapeutic approach requires measurement of tumor size and local extent (T stage) of the lesion. CT is an excellent tool for this purpose. The size of the lesion is easily measured and its edges can be identified in most cases. However, the presence of atelectasis or consolidation distal to the tumor can complicate the identification of tumor margins. In the case of an intra-luminal lesion, CT can be useful in identifying its proximal part, put another marker, such as the extent of hypermetabolism is required to define the distal extent of the lesion. When the suspected lesion is surrounded by lung parenchyma thin-section CT is crucial to determine whether the tumor invades the pleura [26]. In the presence of pleural invasion the surgical approach cannot be modified. CT or MRI can be used to detect chest wall invasion but are not helpful in distinguishing chest wall invasion from fibrous adhesions. Reliable diagnosis of chest wall invasion can be made in the presence of rib destruction or of an obvious chest wall mass [27, 28]. The problem remains unresolved in the presence of contiguity of the tumor with the parietal pleura or of pleural thickening. The accuracy of CT for diagnosis of chest wall invasion is 39–87% [29–33]. Although MRI has superior soft tissue contrast resolution compared to CT, its sensitivity of 63–90% and specificity of 84–86% for diagnosis of chest wall invasion is low and similar to CT [31, 32]. Respiratory dynamic MRI may potentially improve the accuracy of this modality [33]. MRI is superior to CT in the evaluation of chest wall involvement by superior sulcus or Pancoast tumors which almost invariably invade the extrathoracic soft tissue (subclavian vessels, brachial plexus, and vertebrae) [32, 34]. Brachial plexus involvement and tumor extension into the spinal canal are contraindications to surgical resection, unlike vertebral body invasion. Invasion of the subclavian vessels, the ­common carotid or the vertebral artery represents a relative contraindication to surgery. These vessels may need to be ligated and CT and MRI can reveal significant atherosclerotic disease of the contralateral vessels, in which case the resection and ligation may not be feasible [35].

Nodularity of the pleura or pleural thickening associated with enhancement on CT is consistent with metastatic involvement. Thin-section CT is more sensitive in diagnosing pleural involvement [36].

In patients with bronchogenic carcinoma, CT allows accurate differentiation of potentially resectable T1–T3 lesions from unresectable T4 tumors. Mediastinal invasion cannot always be diagnosed on CT. MRI has inherent advantages including the fact that the delineation of mediastinal and hilar vessels does not require the administration of intravenous contrast medium. Increased soft-tissue characterization by MRI may be helpful in differentiating the tumor from other processes. However, MRI is costly and time consuming and its spatial resolution is inferior to that provided by CT. Although neither MRI nor CT are capable of demonstrating minimal invasion of either the mediastinal pleura or mediastinal fat, significant obliteration of fat planes or compression or encasement of vessels in the mediastinum appear to be better demonstrated by MRI than CT [3].

The most widely used diagnostic criterion of nodal metastases is a measurement of lymph node size (short axis diameter). Other characteristics, such as shape, density, or contour do not determine nodal involvement. However, lymph node enlargement may also be due to reactive hyperplasia, and metastatic nodes are not necessarily enlarged. In a meta-analysis, CT had a sensitivity of 57%, a specificity of 82%, and positive and negative predictive values (PPV and NPV) of only 56% and 83%, respectively, for mediastinal staging [37]. CT findings can exclude more than 40% of patients from potentially curative surgery and, on the other hand, another almost 20% of patients will undergo unnecessary or non-curative surgery based on CT. CT should be seen as a tool pin-pointing to suspicious enlarged nodes for histological confirmation. MRI is not sensitive for assessment of calcifications and is therefore not routinely used in the evaluation of lymph nodes. CT and MRI have a similar accuracy for detection of mediastinal node metastases (N2 or N3) with a sensitivity of 52% and 48%, and specificity of 69% and 64%, respectively [32, 38, 39].

Although in patients with early stage NSCLC the incidence of occult distant metastases is <1% [40], most clinicians prefer to conduct a metastatic survey in all patients [41]. The adrenals are currently evaluated by chest CT extended below the diaphragm, considering any adrenal mass with an attenuation value of <10 Hounsfield units on non-enhanced CT consistent with an adenoma [42]. If an adrenal lesion remains indeterminate on a non-enhanced CT, MRI can be helpful [42]. The liver is often included in the chest CT. If a suspicious lesion is detected dedicated CT, US, or MRI are required for its further characterization. Contrast-enhanced CT is the most commonly performed procedure in search of brain metastases in spite of the fact that MRI with contrast injection has a greater sensitivity than CT [43].

After treatment lung cancer is usually followed-up by serial CT scans at 3, 6, and 12 months after completion of therapy and once a year thereafter. For patients receiving chemotherapy assessment of treatment effectiveness is crucial. CT is the method of choice for measuring lesions before and after treatment according to response evaluation criteria in solid tumors (RECIST) [44]. In patients treated with radiotherapy, CT can reveal post-radiation pneumonitis and fibrosis and monitor tumor recurrence. In patients with nonspecific CT findings suspicious for recurrent cancer, sometimes difficult to differentiate from fibrosis, MRI can be helpful [45]. Posttreatment fibrosis has low signal intensity on both T1- and T2-weighted images, whereas tumors show relatively increased intensity on T2-weighted sequences [45]. However, inflammation secondary to radiation therapy may also lead to high signal intensity on T2-weighted sequences, similar to retained secretion within traction bronchiectasis and therefore the differentiation of these two entities is not always possible.

A single pulmonary nodule is seen as an opacity in the lung parenchyma measuring <3 cm (larger lesions are masses) without associated adenopathy or atelectasis [121]. Lung nodules can be caused by infection, inflammation, and ­neoplasms (about 80 different etiologies have been identified). CT alone, or with the addition of [¹⁸F]FDG PET-CT, allow the majority of pulmonary nodules to be categorized as benign or malignant. Lesions without spicules, with uniformly distributed dense calcification (>300 Hounsfield Units, including the center of the nodule) and which have <15 HU enhancement with contrast administration are radiographically benign. On the other hand, spiculated borders, indistinct margins, extension to pulmonary veins, focal retraction of adjacent pleura, heterogeneous composition, or enhancement of >25 HU following injection of intravenous contrast, suggest malignancy. However, even after careful assessment by CT, distinguishing a malignant from a benign lesion is difficult. Lesions <7 mm diameter have <1% likelihood of malignancy [122]. Lesions 7–20 mm have a 15% incidence of malignancy, and lesions >20 mm have an 81% likelihood of malignancy. Determining the metabolic status of lesions >0.7 cm in diameter with [¹⁸F]FDG PET-CT can determine if these lesions are malignant or benign in ∼90% of lesions. Lesions with SUV ≤2.0 have a low likelihood of malignancy, reducing the need for biopsy, lesions with SUV >4.0 are more likely malignant, and lesions between SUV 2.0 and SUV 4.0 are indeterminate. Nevertheless, an [¹⁸F]FDG-negative lesion in a patient with high clinical suspicion for malignancy (e.g., history of smoking, exposure to asbestos, older age, and/or history of non-thoracic neoplasm) still needs to be biopsied to establish the etiology of the lesion. In the presence of a low clinical suspicion in a patient who is at high risk for biopsy, follow up by further imaging is usually indicated. If patients carry a high clinical risk, biopsy, and histologic evaluation of the lesion is advisable if at all possible. While it could be argued that [¹⁸F]FDG imaging is not indicated for diagnostic purposes in patients with a high clinical suspicion (as they would need biopsy or surgery), its main role in the management of these patients is to determine if disease is localized prior to possible surgical or radiation therapy.

In a meta-analysis of 1,474 pulmonary lesions of any size, Gould et al. [123] found a sensitivity of 96.8% and specificity of 77.8% for [¹⁸F]FDG-PET to distinguish malignant from benign etiologies. In another meta-analysis including five prospective studies, Hellwig et al. [124] reported a sensitivity of 93% and specificity of 87% and PPV and NPV of 94% and 89%, respectively. The risk to miss malignancy was 11%. Yi et al. [125] showed that [¹⁸F]FDG PET/CT is more accurate than helical dynamic CT for SPN characterization and therefore, where available, should be performed as a first-line evaluation. The semiquantitative criterion of a mean SUV  ≥  2.5 has been shown prospectively to have a sensitivity of 90–100% and specificity of 69–95% for diagnosis of malignancy [126–128] (Fig. 13.2). In a prospective study in 585 patients, Bryant et al. [129] demonstrated that in ­nodules less than 2.5 cm in diameter an SUV_max of 2.5 or less was associated in 24% of cases with malignancy, as compared to lesions with an SUV_max of 2.6–4 which have an 80% chance of malignancy, and lesions with an SUV above 4.1 with a 96% probability. In spite of these data, Hashimoto et al. [130] have recently shown that in SPNs with an SUV_max  <  2.5 visual analysis performs as well as semiquantitative measurements. The probability of malignancy in a visually evident lesion was 60%, but decreased significantly in lesions with no [¹⁸F]FDG uptake.

The question of the location of the lesion is usually well answered by CT or the CT component of PET/CT. The exact location of the tumor and its anatomical relationship to important structures such as the bronchi, pleura, pulmonary veins, and thoracic aorta, as well as defining the presence of mediastinal or chest wall invasion, are important in the decision-making process for further management.

The question of the size of the lesion is also answered well by CT in most patients. However, in the presence of atelectasis distal to the tumor, the differential diagnosis between the tumor mass and the area of atelectasis may be difficult to determine on CT. The [¹⁸F]FDG study can define which portion of the lesion is associated with metabolically active tumor, providing additional valuable information for staging. Precise measurement of tumor size is required for TNM classification (Table 13.2) [121]. Subclassification according to tumor size is a factor that has an impact on prognosis (Table 13.3) [23]. In addition, since in most patients there is an interval of few days to a few weeks between the initial staging CT and the [¹⁸F]FDG study, exact measurement of the tumor size on the CT component of PET/CT study can help the clinician in determining the growth rate of the tumor.

[¹⁸F]FDG imaging has an established role in the evaluation of SPNs to differentiate benign from malignant lesions. An SPN is usually defined as any nodule up to 3 cm in diameter [121]. The majority of SPNs (60–70%) are benign in etiology. Lung cancer, however, is the etiology in 20–30% of SPNs. [¹⁸F]FDG imaging is a better predictor of malignancy in SPN than a combination of clinical and morphologic conventional imaging criteria [114, 131].

False-negative [¹⁸F]FDG PET/CT (no uptake in a ­malignant SPN) is found in less than 5% of nodules 0.6–3 cm in diameter [20]. In the NY-ELCAP study, 378 nodules less than 5 mm in diameter were all nonmalignant on histopathology, therefore suggesting the need for further follow up only in nodules that are 5 mm in diameter or larger [132]. In nodules 5–10 mm in diameter, Bastarikka et al. [133] report a sensitivity of 69%, which increased to 95% in nodules of greater than 10 mm for the detection of malignancy by [¹⁸F]FDG imaging. The authors also noted that uptake decreased when the size of the nodule was less than twice the system resolution (7–8 mm), and therefore different criteria may need to be applied for nodules less than 15 mm in diameter.

False-negative [¹⁸F]FDG imaging results are usually due to the small size (less than 1 cm) of the SPN or a lesion histology indicating BAC or carcinoid. In a series of 36 patients with bronchoalveolar cell carcinoma, 18 patients (50%) had SUV_max  ≤  2.5 [134].

As for NSCLC, tumor [¹⁸F]FDG avidity on PET predicts mortality in patients with BAC [134]. In NSCLC patients, an SUV_max of the primary tumor >7 [135] and >10 [136] had an independent prognostic impact. Few other series also found that the SUV_max was an independent predictor of disease free and overall survival [137, 138]. Ahuja et al. [136] found that the median survival decreased with increasing mean SUV levels in 155 patients with NSCLC. In a retrospective study in 100 patients, Downey et al. [139] showed that the 2-year survival rates were 68% for patients with an SUV_max above 9 and 96% in patients with SUV_max below nine. In patients with NSCLC, Cerfolio et al. [140] found the SUV_max to be an independent predictor of tumor aggressiveness, and a more accurate predictor of tumor recurrence and survival as compared to TNM staging.

Over 40% of SPNs are granulomas, including mycobacterial infection or histoplasmosis. The average SUV_max was 5.05 in patients with pulmonary mycobacterial infections (lesions >2 cm). Therapy resulted in a reduction of [¹⁸F]FDG uptake to near negligible levels [141]. [¹⁸F]FDG PET/CT has a promising role for evaluation of TB in high-risk immunocompromised patients with cancer [142]. In an area with endemic histoplasmosis, inflammatory lesions were difficult to separate from non-small cell lung cancer (mean SUV_max 3.2 in benign lesions and 8.5 in neoplastic lesions with significant overlap between groups [143]).

Nodal involvement with sarcoidosis can also be a confounding factor in evaluating the performance of [¹⁸F]FDG imaging in SPNs. In one series, 95% of patients with sarcoidosis had pulmonary nodal uptake (SUV 8.6) and 66% of patients had parenchymal uptake (SUV 4.7) [144]. In cancer patients with biopsy-proven sarcoidosis early metabolic response to systemic steroid treatment can help in the final differential diagnosis between cancer and sarcoid when both coexist [145]. Other inflammatory conditions such as ­pneumonia, pyogenic abscess, aspergillosis, Wegener’s granulomatosis, and anthracosis may also need to be differentiated from lung cancer. In an [¹⁸F]FDG-avid SPN and low clinical suspicion of malignancy, further investigation is indicated to determine the cause of tracer uptake.

Dual-phase [¹⁸F]FDG studies at 1 and 2 h after tracer injection have been suggested to increase the sensitivity and specificity of [¹⁸F]FDG imaging [146, 147]. Using an SUV cut-off of 2.5 and a 10% increase in SUV as a threshold of malignancy, Matthies et al. showed an improvement in sensitivity from 89 to 100%, associated however with a deterioration in specificity from 94 to 89% in single- and dual-phase PET studies, respectively, possibly due to differences in glucose-6 phosphatase and hexokinase levels within benign and malignant cells [146]. However, active granulomas, a frequent cause for false-positive [¹⁸F]FDG avidity, may also demonstrate the same increase in tracer uptake over time [131].

[¹⁸F]FDG PET-CT imaging can identify incidental lesions or entities such as inflammatory processes. However, it may be difficult to distinguish inflammation secondary to radiation therapy or recent interventional procedures from disease persistence or recurrence, especially if serial [¹⁸F]FDG scans are used for surveillance.

Accurate staging of NSCLC provides important prognostic information and determines the best treatment approach.