Diagnostic Applications of Nuclear Medicine: Lung and Mediastinal Tumors
While CT and MRI provide high-resolution anatomic assessment of lung and mediastinal malignancies, [18F]FDG imaging is superior in differentiating benign from malignant lymphadenopathy and in the detection of distant metastases. Pre-therapy assessment with [18F]FDG can provide important prognostic information. In addition [18F]FDG PET/CT can eliminate about half of futile thoracotomies and is therefore recommended for staging of lung and mediastinal tumors. [18F]FDG imaging is also indicated in the diagnosis of recurrent disease and in monitoring treatment. [18F]FDG PET/CT has been introduced for radiation planning, enabling refining treatment volumes to allow increased dose in target volume and reduced toxicity to nontarget tissues. Although [18F]FDG is the most widely used tracer in oncology, other PET tracers are evaluated with specific clinical and research goals and may have a future role in the management of lung malignancies.
KeywordsLung cancer [18F]FDG imaging in lung cancer Lung and mediastinal tumor imaging Staging of lung and mediastinal tumors
American Joint Committee on Cancer
X-ray computed tomography
CT texture analysis
Clinical tumor volume
Gene encoding for a member of the cytochrome P450 superfamily of enzymes
2-(4-Isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (macrocyclic coupling agent to label compounds of biological interest with metal radionuclides)
Eastern Cooperative Oncology Group
Epidermal growth factor receptor; the mutated form EGFRvIII plays a prominent role in tumorigenesis and proangiogenic signaling
- GST mu
Gene encoding for the mu class of glutathione S-transferase
Gross tumor volume
Human immunodeficiency virus
High-resolution computed tomography
Left lower lobe
Metastasis status according to the AJCC/UICC TNM staging system
Multi-detector computed tomography
Minimum intensity projections
Maximum intensity projection
Malignant pleural mesothelioma
Magnetic resonance imaging
Metabolic tumor volume
Lymph node status according to the AJCC/UICC TNM staging system
National lung screening trial
2-(4,7-Bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7-triazonan-1-yl)acetic acid, a bifunctional chelating agent for metal radionuclides
Negative predictive values
Non-small cell lung cancers
Positron emission tomography
Positron emission tomography/Computed tomography
Positron emission tomography/Magnetic resonance imaging
Progression free survival
Positive predictive values
Planning target organ volume
Response evaluation criteria in solid tumors
Right lower lobe
Right middle lobe
Receiver operator curve
Right upper lobe
Small-cell lung cancer
Solitary pulmonary nodule
Somatostatin receptor scintigraphy
Standardized uptake value
Increment in standardized uptake value in dual-phase acquisition
Standardized uptake value at point of maximum
Tumor status according to the AJCC/UICC TNM staging system
Total lesion glycolysis
AJCC/UICC staging system based on parameters “T” (tumor status), “N” (lymph node status), and “M” (distant metastasis status)
Union Internationale Contre le Cancer (International Union Against Cancer)
World Health Organization
Lung cancer is the leading cause of cancer death accounting for 29% of all cancer deaths in the USA . It is estimated that in 2012, there were 58.7 new cases per 100,000 and 47.2 deaths per 100,000 per year from this disease in men and women . Approximately 6.6% of men and women will be diagnosed with lung cancer at some point during their lifetime, based on 2010–2012 data . Non-small cell lung cancers (NSCLC) are responsible for 85% of lung cancers. Major histologic types of NSCLC include squamous cell carcinoma (which typically arises in the bronchus), adenocarcinoma (originating in the periphery of the lung), and large-cell undifferentiated carcinoma. Small-cell lung carcinoma (SCLC) accounts for 15% of lung malignancies and typically arises centrally in association with a bronchus . In the USA, adenocarcinoma is the most common histologic type of lung cancer, accounting for more than 40% of lung cancers, and has the worst prognosis among NSCLCs.
About 90% of lung cancer cases occur between the ages of 40 and 80, with a peak incidence in the fifth and sixth decades. Only 2% of cases are detected before the age of 40. At the time of diagnosis, 16% of patients have localized disease, 22% have regional spread, and approximately 57% have distant metastases.
Environmental and Genetic Factors
While approximately 10–15% of smokers develop lung cancer, cigarette smoking is linked to the majority of lung cancers in more than eight out of ten cases (86%). About 15% of lung cancers occur in nonsmokers, but many of these patients have been exposed to secondhand smoke. The amount of smoking as well as the duration of being a smoker is directly correlated to the risk of developing lung cancer. Starting smoking at a young age is more harmful. Stopping smoking reduces the risk of lung cancer. Passive smoking increases the risk of lung cancer, but to a much lesser extent.
Additional factors which increase cancer risk include exposure to asbestos, radon gas, hydrocarbons, and metals such as chromium, nickel, and inorganic arsenic.
It is estimated that 8–14% of lung cancers are due to inherited factors. Relatives of lung cancer patients have a 2.4 times increased risk in developing lung cancers due to combination of genes.
Underlying Molecular Biology Changes
Lung cancer may arise from differentiated or undifferentiated cells, from either the central (SCLC and squamous cell carcinoma) or the peripheral (adenocarcinoma) airway compartment. The interaction between inhaled carcinogens and the epithelium of upper and lower airways leads to the formation of DNA adducts: pieces of DNA covalently bound to a cancer-causing chemical. In 2004, a locus on chromosome 6q23–25 was reported as conferring familial lung cancer susceptibility by family members affected by cancer .
The evidence for activated or inactivated carcinogens found in tobacco smoke is strongest in CYP1A1 polymorphisms and GST mu null .
Histological types depend on causative factors as well as cell origin. Smoking is linked with small cell, squamous cell, and adenocarcinoma. Nonsmokers usually develop adenocarcinoma. Lung cancers unrelated and related to smoking have different mutation profiles.
There are several signaling pathways in lung cancer. The main signaling pathways that may provide roadmaps for therapy include growth-promoting pathways (epidermal growth factor receptor/Ras/phosphatidylinositol 3-kinase), growth inhibitory pathways (p53/Rb/P14ARF, STK11), apoptotic pathways (Bcl-2/Bax/Fas/FasL), DNA repair, and immortalization genes .
Staging and Prognostic Stratification
Only 15% of all lung cancer cases are diagnosed at an early stage, with a 5-year survival rate higher than 50%. Most of lung cancer cases are diagnosed at an advanced stage with distant metastases and a 5-year survival rate of about 4%. The overall 5-year survival rate for lung cancer is 17.4% . Therefore, prognosis mainly depends on staging at the time of diagnosis.
AJCC anatomic stage and prognostic groups for lung carcinoma
The AJCC definition of TNM for lung
Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy
No evidence of primary tumor
Carcinoma in situ
Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)
Tumor 2 cm or less in greatest dimension
Tumor more than 2 cm but 3 cm or less in greatest dimension
Tumor more than 3 cm but 7 cm or less or tumor with any of the following features (T2 tumors with these features are classified T2a if 5 cm or less)
Involves main bronchus, 2 cm or more distal to the carina
Invades visceral pleura (PL1 or PL2)
Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung
Tumor more than 3 cm but 5 cm or less in greatest dimension
Tumor more than 5 cm but 7 cm or less in greatest dimension
Tumor more than 7 cm or one that directly invades any of the following: parietal pleural (PL3), chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumor in the main bronchus less than 2 cm distal to the carinaa but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe
Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, separate tumor nodule(s) in a different ipsilateral lobe
Regional lymph nodes (N)
Regional lymph nodes cannot be assessed
No regional lymph node metastases
Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension
Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)
Distant metastasis (M)
No distant metastasis
Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural (or pericardial) effusionb
Although tumor stage is the main prognostic indicator, there are several additional factors affecting prognosis, including tumor histology, molecular genetics, comorbidity, socioeconomic background, age, gender, tumor heterogeneity, textural analysis, and standard uptake value (SUV) measured intensity of [18F]FDG uptake [5, 6, 7, 8, 9, 10, 11, 12]. In 554 patients with post-surgical follow-up, squamous cell carcinoma had the most favorable outcome and anaplastic small cell the least favorable . However, in the subgroup of tumors <4 cm confined to the lung, SCLC had the highest percentage of 5-year survivors. In larger tumors, or in those with spread to the neighboring structures or lymph nodes, squamous cell was significantly more favorable. Histology did not affect survival in stage IV disease .
In a population-based cohort study in 5,683 first-time diagnosed lung cancer patients, the most common comorbid conditions included chronic pulmonary disease (52.5%), diabetes (15.7%), and congestive heart failure (12.9%). The presence of comorbid conditions was associated with worse survival . Socioeconomic differences in survival are partly explained by social inequality in staging, treatment, and the presence of comorbidities .
Lung cancer mortality is strongly related to age, rising sharply from 45 to 49 years, with the highest mortality rates in men older than 85 years and women 80–84 years. Mortality rates are similar between men and women until the age of 50–54 and higher in men afterward up to a ratio of 21 men:10 women above 85 years . Women had a higher incidence of adenocarcinoma and a higher incidence of stage IA disease as well as significantly better survival when compared to men (5-year survival 77.7% vs. 61.9% in adenocarcinoma and 59.3% vs. 53% in other lung tumors). No significant gender-related prognostic differences were found in non-adenocarcinoma .
Conventional Imaging Methods
Imaging plays an essential role in the detection, staging, and response assessment. CT is the modality of choice for lung cancer imaging, whereas magnetic resonance imaging (MRI) is used for resolving specific questions, i.e., chest wall or mediastinal invasion, adrenal mass characterization, or differentiation between tumor recurrence and radiation fibrosis .
Multi-detector computed tomography (MDCT) devices provide high-quality images with short acquisition times . Thin slices help avoid volume averaging and improve the display of anatomic structures. MDCT data can be reconstructed as axial, sagittal, coronal, and oblique images, as well as multi-planar reformations (MPR), maximum and minimum intensity projections (MIP or MinIP), virtual bronchoscopy, and volume rendering. Low-dose CT can detect stage I lung tumors four to six times more frequent than conventional radiology . Annual screening with low-dose CT can find lung cancers in their earliest stage, when the tumor is most easily treated. The National Lung Screening Trial (NLST) showed that screening with low-dose CT reduced the risk of death from lung cancer by 20% among persons 55–74 years of age who had a smoking history of at least 30 pack years. Recently this strategy is being adopted by several health systems [16, 17]. However, some lung cancers presenting as pulmonary nodules can be missed on CT  due to error in perception or misinterpretation. Subcentimeter nodules and low-density nodules, also known as ground-glass opacity (GGO), can be missed [19, 20].
Detection of a new solitary pulmonary nodule (SPN) in a patient with a history of lung cancer raises the possibility of recurrent disease. Features such as lesion size, location, contour, edge, and density (including the presence or absence of calcifications or fat) should be evaluated [21, 22, 23]. Unfortunately, none of these features alone establish benignity or malignancy. Specific combinations of features are more likely to be associated with either malignant or benign disease. For example, spiculated borders, ill-defined contours, the presence of bubble-like lucency, eccentric calcification, semisolid lesion, or GGOs are suggestive of malignancy, whereas a completely solid lesion with smooth and well-defined contours; total, central, or popcorn calcification; or inclusions of fat is indicative for benignity . Because of the lack of specificity, more than 20% of SPNs are classified as indeterminate or suspicious after performing CT, and further investigation is required, either a repeat CT to evaluate change in size, PET/CT, or biopsy .
Evaluation of the growth rate is based on measurements of the nodule diameters on two consecutive examinations and calculating the doubling time. It can aid in the characterization, especially of indeterminate nodules. Inter- and intra-observer reproducibility of 2D diameter measurements is low [25, 26, 27]. Automated computation of the size of an SPN on 3D reconstruction has been shown to improve the ability to assess its growth , with the exception of nodules that are abutting the chest wall or vessels, where errors can occur . Recently, the evaluation of the mass of an SPN, calculated by multiplying nodule volume and density, was proposed as a more accurate method. Mass measurements allow growth to be detected earlier and are subject to less variability [29, 30]. In solid SPNs the risk for malignancy can be evaluated by determining the degree of enhancement, which correlates with the degree of vascularity. Typically, malignant nodules enhance more than 20 HU, whereas benign nodules enhance less than 15 HU after intravenous administration of contrast media . Dynamic perfusion CT can further evaluate features including blood volume, blood flow, permeability, mean transit time, and peak enhancement that can help assess the degree of vascularity of the nodule which correlates with malignancy . Dual-energy CT has been suggested as a method of assessing the degree of enhancement with a single scan performed after the administration of contrast material and creating a virtual unenhanced image from the same dataset. Therefore, a single enhanced dual-energy CT scan allows measurement of the degree of enhancement as well as detection of calcifications. It may reduce radiation exposure to patients by avoiding baseline unenhanced scans and may also reduce measurement error due to different regions of interest during the subtraction of an unenhanced image from an enhanced one .
Once the diagnosis of lung cancer has been established, the next important work-up step is the assessment of the anatomic extent of the tumor. Staging separates patients who are candidates for surgical resection from those with inoperable disease who should be treated with chemotherapy and/or radiation. Staging is performed according to the recommendations of the International Staging System, and previously described evidence-based guidelines are used for clinical purposes  (Tables 1 and 2).
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 intraluminal lesion, CT can be useful in identifying its proximal part, but 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 . In the presence of pleural invasion, the surgical approach cannot be modified. CT or MRI can be used to detect chest wall invasion but is 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 [35, 36]. 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% [37, 38, 39, 40, 41, 42, 43, 44, 45]. 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 are low and similar to CT . Respiratory dynamic MRI may potentially improve the accuracy of this modality . 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) [48, 49, 50]. 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 [51, 52, 53].
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 [54, 55].
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. Improved 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 is 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 appears to be better demonstrated by MRI than CT [3, 54]. When using cardiac-gated T1-weighted MRI, the motion artifacts of the heart are reduced, and visualization of tumor invasion of the pericardium or heart is superior to CT . The addition of contrast material in ECG-gated or breath-hold MR angiography improves the accuracy with higher sensitivity and specificity than contrast-enhanced CT and T1-weighted MR [54, 55].
The most widely used diagnostic criterion of nodal metastases is 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 . CT findings can exclude more than 40% of patients from potentially curative surgery and, on the other hand, lead to another almost 20% of patients will undergo unnecessary or non-curative surgery. CT should be seen as a tool pinpointing 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 although novel MRI sequences, including STIR turbo spin echo (SE) and diffusion-weighted imaging (DWI), have been used to differentiate metastatic from nonmetastatic lymph nodes with a sensitivity and specificity that are superior to CT and comparable to [18F]FDG-PET/CT [54, 55].
Although in patients with early stage NSCLC the incidence of occult distant metastases is <1% , most clinicians prefer to conduct a metastatic survey in all patients . The adrenals are currently evaluated by chest CT extended below the diaphragm, considering any adrenal mass with an attenuation value of <10 HU on non-enhanced CT to be consistent with an adenoma . If an adrenal lesion remains indeterminate on a non-enhanced CT, MRI can be helpful . The liver is often included in the chest CT. If a suspicious lesion is detected, dedicated CT, US, or MRI is 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 . The utility of whole body MRI in the staging algorithm of lung cancer patients is considered, especially with advanced stage patients, due to the superiority in detecting brain metastases, determining mediastinal and chest wall invasion and lymph node metastases [60, 61].
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 best accessed by either CT or MRI as these techniques offer better resolution and anatomical details. T stage depends on tumor size, location, and relationship to nearby structures. Five-year survival rates differ in relationship to the tumor size from 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) . Data are now available showing the importance of [18F]FDG imaging in TNM staging [35, 36, 37]. [18F]FDG imaging also has a significant role in assessing involvement of the pleura. While pleural fluid cytology can be falsely negative in 30–40% of patients, [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 [38, 39].
Locoregional 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. The NICE study  suggested that [18F]FDG-negative or a chain of [18F]FDG-positive nodes would not necessarily need confirmation by other diagnostic testing.
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 seventh edition of 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 .
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 IV 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 .
Changes in lung cancer stage grouping were implemented in 2009 (Tables 1 and 2). 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% for IB, 46% IIA, 36% IIB, 24% IIIA, 9% IIIB, and 13% for stage IV .
The same TNM classification is also suggested for SCLC. The 5-year survival rates for small-cell lung cancer are 38% for stage IA, 21% for IB, 38% IIA, 18% IIB, 13% IIIA, 9% IIIB, and 1% for stage IV .
Treatment recommendations for non-small cell lung cancer
IA and B
Adjuvant therapy (chemotherapy/radiation or combination); chemoprevention
IIA and B
Same as stage I
Chemoradiotherapy, surgical resection in selected patients
Neoadjuvant combined-modality therapy to downstage primary tumor
Same as stage IIIA
Ciplatin-based chemotherapy, surgical resection if solitary metastatic lesion with resectable primary tumor
More efficacious single-agent and combination chemotherapy
Lung cancer is usually followed up by serial CT scans. For patients receiving chemotherapy, assessment of treatment effectiveness is crucial. CT is the method of choice for measuring lesions before and after treatment. The World Health Organization (WHO) criteria and the Response Evaluation Criteria in Solid Tumors (RECIST) have created guidelines for the evaluation of tumor response to therapy. These guidelines provide a standard reporting system using uni- or bidimensional evaluation of tumor size to define its response to therapy as “complete response,” “partial response,” or “progressive disease” [62, 63, 64]. In recent years the introduction of molecular-targeted therapies, immunological agents, and stereotactic radiotherapy has necessitated the use of a new approach. There is growing evidence that target therapies induce effects that differ from those related to the classic cytotoxic treatment including intratumoral hemorrhage, changes in vascularity, or cavitation. More advanced imaging techniques such as DWI, MR, and PET/CT that represent more adequately tumor biology and function are considered to evaluate response, including tumor volume, attenuation, or perfusion .
In patients treated with radiotherapy, CT can reveal postradiation pneumonitis and fibrosis and monitor tumor recurrence. In patients with nonspecific CT findings suspicious for recurrent cancer, sometimes difficult to differentiate from fibrosis, MRI using T2-weighted images or contrast-enhanced imaging can be helpful [66, 67].
Mediastinal abnormalities are caused by a large number of processes that can involve various compartments of the mediastinum. Up to 50% of these processes are asymptomatic and discovered incidentally [68, 69]. The radiological armamentarium for evaluation of the mediastinum includes a wide variety of imaging modalities.
The standard posterior-anterior and lateral chest X-ray remains the initial diagnostic imaging tool . It can reveal widening of the mediastinum, deformation of its contours, displacement of adjacent organs, and the presence and type of calcification. However, its ability to delineate the extent of mediastinal processes and their relationship to specific anatomic structure is limited.
CT plays a crucial role in the detection and, in particular, in the characterization of mediastinal abnormalities. Due to its excellent density resolution, CT is not only able to distinguish normal structures from pathological processes in the mediastinum but it can also characterize the latter based on their attenuation pattern and to accurately determine their origin and extent [71, 72]. Following the detection of a mediastinal abnormality on chest X-rays, CT should be the next step in the diagnostic work-up. A second common indication for CT is the detection of mediastinal pathology which is clinically suspected such as a suspected thymoma in patients with myasthenia gravis, thymic carcinoid in patients with ectopic corticotropin production, or an ectopic mediastinal parathyroid adenoma in patients with hypersecretion of parathyroid hormone production . CT is also one of the main imaging modalities used for percutaneous biopsy guidance.
MRI is usually reserved for cases that need further clarification of CT findings and provides additional information regarding the nature, location, and extent of mediastinal disease. Based on its ability to distinguish between different tissues, MRI can confirm the cystic nature of a lesion that appears solid on CT. It can reveal small amounts of fat, favoring the diagnosis of fat-containing masses such as teratoma, hemangioma, or extramedullary hematopoiesis , and, in some cases, it can differentiate fibrosis from viable, recurrent tumor [71, 73]. Due to its ability to image vessels, MRI is used for the investigation of mediastinal pathology suspected to be of benign vascular origin, as well as for the assessment of invasion of a large artery or vein or their narrowing by a mediastinal tumor [74, 75]. MRI is helpful to evaluate mediastinal abnormalities, particularly in patients in whom administration of iodinated intravenous contrast medium is contraindicated. However, MRI is limited by reduced spatial resolution as compared with that of CT and by its inability to accurately detect calcifications [72, 74, 75]. In summary, CT is the modality of choice for evaluating suspected mediastinal pathology, whereas MRI is used as a problem-solving tool. Each modality has its own particular strengths; therefore CT and MRI do not compete, but are complementary in many clinical scenarios [71, 76, 77].
Differentiating malignant from benign tumors and grading of malignancy are essential for treatment planning as well as for defining patient prognosis. Unfortunately, the malignant or benign nature of a lesion cannot be confirmed using imaging criteria alone. Findings of irregular contours, necrotic or cystic component, heterogeneous enhancement, lymphadenopathy, and invasion of the great vessels are strongly suggestive of a malignant thymic tumor , whereas a unilocular, thin-walled, water-density lesion most probably represents a “true” cyst . Nevertheless, further investigations are often required, including noninvasive tests, such as diffusion-weighted single-shot echo-planar MRI [79, 80, 81] or functional and metabolic nuclear medicine procedures, or invasive tests such as percutaneous or video-assisted thoracoscopic biopsy, to obtain a definite diagnosis.
Thymomas, germ cell tumors, lymphomas, and neurogenic tumors account for the overwhelming majority of primary malignant mediastinal tumors in adults. Approximately 30–35% of thymomas, 20% of germ cell tumors, and 15% of nerve sheath tumors are invasive [68, 70, 71]. Radical excision is the standard of care for malignant thymic diseases and for lesions of neurogenic origin, whereas radiotherapy is the treatment of choice for seminoma. Non-seminomatous germ cell tumors are treated with a combination of surgery and chemotherapy, while a combination of chemo- and radiotherapy is administered in most cases of lymphoma [82, 83, 84].
Thymoma is the most common primary neoplasm located in the anterior mediastinum [85, 86]. It affects predominantly adults, with equal incidence in men and women, and is very rare in children . Up to 50% of patients with thymoma suffer from myasthenia gravis, but some may also present with other thoracic complaints or can be entirely asymptomatic [86, 87, 88].
Thymoma is usually well defined, but it can be aggressive, penetrating the capsule and extending into the mediastinal fat, pleura, pericardium, lung, and great vessels [88, 89], and it can also cross the diaphragm, reaching the retroperitoneum . Its size varies, ranging from small nodules to large masses . Invasive thymoma can send drop metastases to the ipsilateral pleura and the pericardium . Hematogenous metastases and lymphadenopathy are rare . The presence of enlarged mediastinal lymph nodes in association with a dominant anterior mediastinal mass suggests the diagnosis of lymphoma or of thymic carcinoma rather than thymoma [86, 90].
Thymoma is not always detectable on chest X-rays. Contrast-enhanced MDCT is used for precise assessment of a mediastinal mass and its local invasion, aiding in the preoperative planning. Staging of thymoma is based on the widely accepted clinicopathological classification of Masaoca et al.  as well as on the WHO histological classification .
Although thymoma typically rises in the anterior-superior mediastinum, it can occur anywhere from the thoracic inlet to the cardiophrenic angle [93, 94]. Most tumors are unilateral , spherical or ovoid, and usually encapsulated soft tissue lesions outlined by adjacent mediastinal fat . Up to 60% of thymomas demonstrate various degrees of invasion of adjacent structures  or encasement of vessels [97, 98]. While a lack of mediastinal fat obliteration does not necessarily exclude capsular penetration, when these planes are preserved, extensive invasion is unlikely . Aggressive thymoma can present with pleural involvement even at diagnosis, and in cases with circumferential lung encasement, it may be indistinguishable from malignant mesothelioma . Pleural effusion is not typical for patients with thymoma .
Thymoma can manifest heterogeneity on CT due to cystic degeneration, hemorrhage, or necrosis . Calcifications can occur, are more frequent in aggressive subtypes, and exhibit a variety of patterns ranging from curvilinear calcification of tumor capsule or fibrous septa to punctuate or coarse calcifications within the tumor itself [87, 97, 98, 99, 100].
Thymoma has no distinctive features on MRI, which only rarely provides additional important information to an optimally performed contrast-enhanced CT study . MRI can be useful in the assessment of vascular involvement in patients who cannot tolerate intravenous iodine contrast injection or for clarifying equivocal CT findings. On dynamic MRI thymomas reach peak lesion enhancement earlier than other mediastinal neoplasms, earlier for lower stage as compared to higher-stage disease [102, 103]. Chemical shift MRI is lower in thymic hyperplasia as compared to thymoma. This is of significance in particular in patients with myasthenia gravis, who present with a homogeneous enlarged thymus on CT and MRI which can at times be indistinguishable from thymoma .
On T1-weighted MR images, thymoma has a similar signal intensity to muscle, while T2-weighted images show a high signal intensity. Thymomas showing a heterogeneous pattern and cystic changes present as areas of increase signal intensity on T2-weighted images [100, 103]. Hemorrhage is identified as an area of high signal intensity on both T1- and T2-weighted or on STIR images . Tumor capsule and fibrous septa show low signal intensity on both T1- and T2-weighted images . The role of [18F]FDG-PET/CT in thymoma is unclear. The majority of these lesions have SUVs <3 and a variable appearance on [18F]FDG imaging. SUVs >5 suggest that the lesion may have a different etiology, such as lymphoma.
Differential Diagnosis Between Lung Cancer and Lymphoma
Although lymph node abnormalities depicted by CT are nonspecific, the patterns of thoracic lymphadenopathy can provide important clues in the differential diagnosis of their potential etiology. Nodal metastatic spread of lung cancer always follows a similar pathway. Tumors in the right lung involve initially almost exclusively ipsilateral mediastinal nodes, while left lung tumors have a higher propensity for contralateral spread . Involvement of distal nodes may occur even when proximal nodes are spared. Nearly 30% of lung cancer patients have metastases to mediastinal lymph nodes without lobar or hilar lymph nodes being involved . Lack of vessel invasion by enlarged lymph nodes may help in differentiating lymphoma from metastatic lung cancer .
Lymphoma is characterized by predominantly mediastinal nodal involvement. When present, hilar node involvement is usually asymmetric and accompanied by mediastinal disease . Lymphoma tends to expand along or around, rather than invade adjacent structures.
Hodgkin’s disease (HD) has a predilection for thoracic involvement found in up to 85% of patients, especially in the pre-vascular and paratracheal regions . As a rule multiple sites show lymphomatous involvement although at times enlargement of a single nodal group can be encountered, usually indicating a nodular sclerosing histologic subtype . HD typically spreads contiguously, involving adjacent lymph nodes, and only rarely skips nodal groups as described for lung cancer [109, 110]. HD also has a tendency to cause thymic involvement in association with mediastinal lymph node enlargement .
Thoracic disease is less common in non-Hodgkin’s lymphoma (NHL) and is found in up to 50% of cases . The pattern of nodal involvement is also somewhat different from other types of malignancy. Single-site lymph node enlargement is much more common in patients with NHL and occurs mainly in posterior or superior mediastinal or anterior diaphragmatic nodes . Hilar node involvement is less common than for HD or lung cancer. Extranodal disease is frequently present and may involve the lungs, pleura, pericardium, and chest wall .
Approximately 70% of patients with sarcoidosis present with a characteristic radiologic pattern including hilar and mediastinal lymphadenopathy with or without concomitant parenchymal abnormalities [114, 115, 116]. However, in up to one third of cases, radiological findings are nonspecific. The most frequent presentation is that of right paratracheal and bilateral hilar lymphadenopathy. The aortopulmonary, subcarinal, and retroazygous lymph nodes may be enlarged as well . The posterior mediastinum is less commonly involved. Isolated lymphadenopathy in the anterior or posterior mediastinal compartments as well as unilateral hilar disease is more suggestive of lymphoma, metastatic lung cancer, or a granulomatous or infectious process rather than sarcoidosis. Lymph node calcification (occasionally with an eggshell pattern) can be found in up 25% of cases .
Parenchymal sarcoid can show a variety of radiographic patterns, including fine nodular, reticulo-nodular, or acinar lesions (poorly marginated, small to large nodules, or coalescent opacities), and only rarely focal lesions. Acinar opacities or interstitial granulomas may coalesce to give the appearance of the alveolar form of sarcoidosis, and an air bronchogram may be detected . High-resolution CT (HRCT) findings include areas of ground-glass attenuation, subpleural, or perivascular nodules, which appear as beading and irregular thickening of bronchovascular bundles and thickening of interlobular septa. The nodules, corresponding to coalescent interstitial granulomas, have irregular margins. The foci of ground-glass attenuation may represent areas of active alveolitis or diffuse microscopic interstitial granulomas [119, 120, 121, 122, 123]. Patients older than 50 years of age have a higher prevalence of solitary and multiple mass-like opacities in the lung at presentation . In the presence of cavitation of parenchymal lesions, which occurs in less than 1% of patients with sarcoid, tuberculosis and fungal infections should be ruled out.
Radiographic findings of thoracic histoplasmosis depend primarily on the clinical type of presentation and on the immune status of the host. A solitary pulmonary nodule is common in patients with an asymptomatic primary infection. The size of such nodules varies from a few millimeters to several centimeters. Most have well-defined margins and central, laminar, or diffuse calcification patterns. In some cases these nodules are slow growing, and in such cases histoplasmosis may be difficult to distinguish from malignancy.
Adenopathy is frequently seen in addition to parenchymal lung abnormalities, often with calcifications. The differential diagnosis of noncalcified mediastinal adenopathy includes sarcoidosis, lymphoma, and metastases. Enlarged lymph nodes may cause significant bronchial or tracheal compression or obstruction and may lead to esophageal obstruction as well .
In more severe cases, radiographs may show widely disseminated, diffuse, fairly discrete nodular shadows throughout the lungs, with individual lesions measuring 1–10 mm diameter. This form of disease is known as miliary histoplasmosis, and appearances are similar to miliary tuberculosis . The infiltrates clear within 2–8 months; however, fibrotic lesions may calcify and persist for many years.
Lung cavitation is usually noted in patients with underlying obstructive lung disease and is similar to chronic active tuberculosis, with predominantly upper lobe disease, characterized by fibrosis, necrosis, cavitation, and granulomatous inflammation. Fibrosing mediastinitis can develop in some patients. It is important to define the extent of the fibrous mass in the mediastinum or hilum and to identify if it causes obstruction of the superior vena cava, pulmonary vessels, esophagus, trachea, or bronchi. Stippled or dense calcifications within the mass are present in most patients with fibrosing mediastinitis .
Thoracic manifestations of primary coccidioidomycosis (CM) include parenchymal disease, lymphadenopathy, and pleural effusion . Parenchymal consolidation, single or multiple, is the most common manifestation found in 75% of patients. It is segmental or subsegmental, usually unilateral and with a peri-hilar or basal distribution. It can resolve spontaneously within 1–2 weeks. Nodular lung disease is found in up to 20% of patients. The nodules are frequently well defined, simulating metastases, but may also present with ill-defined margins. They are 5–25 mm in diameter and have a parahilar and lower-lobe distribution. In approximately 20% of patients, hilar adenopathy is also present, usually unilateral and concomitant with parenchymal lesions. Mediastinal adenopathy is seen in the presence of severe and prolonged infection and is associated with a higher risk of dissemination. Pleural effusion occurs in less than 20% of patients, although pleuritic chest pain is more frequent, in 50–75% of cases .
Approximately 5% of patients may develop a persistent pulmonary disease such as pneumonia with or without adenopathy, nodules and cavities, bronchiectasis, empyema, or calcifications. Pulmonary nodules are the most common radiographic findings in persistent infection. They are, as a rule, single, well circumscribed and round, averaging 1.5–2 cm in diameter, and tend to occur in the periphery of the middle and upper lobes of the lungs, in contrast to tuberculosis, when nodules develop mainly in the anterior segment of an upper lobe. CM-related nodules can remain stable for months and eventually regress. Only rarely is slow growth observed .
Calcification is much less frequent in CM than for tuberculosis and histoplasmosis. Therefore in the evaluation of these nodules, malignancy is a primary concern for the clinician. Cavitation may develop as a result of necrosis in an area of pneumonia or may be the result of the excavation of a nodule. Usually cavities appear as a single lesion, are located in the upper lobes, and can have thin or thick walls. Thin-walled cavities have a tendency to change in size, possibly reflecting check-valve communication with the bronchial tree. A rapid change in size of a cavity suggests coccidioidal infection rather than any other granulomatous process.
Disseminated CM may occur as a complication of the primary illness, a late complication of chronic disease, or may represent the reactivation of latent disease in susceptible individuals. Dissemination has a miliary pattern that resembles tuberculosis, although with less well-defined nodules. The differential diagnoses of this pattern also include other mycotic infections, silicosis, sarcoid, and metastatic disease. Hilar and mediastinal adenopathy is almost always associated with disseminated disease .
Primary lung tuberculosis (TB) has a nonspecific imaging presentation [129, 130, 131, 132]. Common findings include segmental or lobar airspace consolidation, ipsilateral hilar and mediastinal lymphadenopathy, and/or pleural effusion.
Airspace consolidations tend to be homogeneous, with ill-defined margins, and usually occur in the lower and middle lobes and in the anterior segments of the upper lobes. Cavitation within parenchymal opacity is uncommon in primary infection. The lung opacity tends to become rounded with healing and continues to shrink until only a small nodule remains. Subsequently, the nodule may become calcified or ossified, resulting in a calcified granuloma.
Lymphadenopathy is a common manifestation of primary pulmonary TB. The presence of hilar and mediastinal lymphadenopathy helps in differentiating primary from postprimary TB where it is conspicuously absent. Lymphadenopathy may be the only manifestation of primary pulmonary TB without a concomitant parenchymal opacity. This is more common in patients with HIV infection. Adenopathy is mainly found in the ipsilateral hilar region in approximately 60% of children with primary TB, paratracheal adenopathy is found in 40%, and subcarinal lymphadenopathy in 80% of pediatric patients. In adults, lymphadenopathy is unusual in an immunocompetent host but is more frequent in blacks and Asians. Adenopathy is common in patients with an HIV infection. On contrast-enhanced CT involved lymph nodes demonstrate central hypoattenuation with peripheral rim enhancement. Sometimes the pattern of lymphadenopathy is indistinguishable from that of sarcoid or lymphoma. With an appropriate immune response or with adequate chemotherapy, enlarged necrotic lymph nodes may diminish in size and commonly calcify. Calcified lymph nodes and a granuloma represent the Ranke complex. Airway involvement is frequently present in primary TB due to bronchi compression by enlarged lymph nodes or endobronchial spread of infection, broncholithiasis, or bronchiectasis.
Parenchymal abnormalities of postprimary TB show a wide spectrum of findings , including patchy or confluent airspace opacities in the apical and posterior segments of the upper lobes and the superior segments of the lower lobes; cavities with a thick outer wall and a smooth inner contour and air-fluid levels ; tuberculomas appearing as discrete, sometimes calcified, nodules, typically within the upper lobes; and widespread ill-defined acinar shadows manifesting endobronchial spread, military (hematogenous) spread, appearing as circumscribed nodules less than 1–2 mm in diameter located diffusely throughout both lungs. In contrast to primary TB, lymphadenopathy is notably absent in patients with postprimary disease, with the exception of patients with HIV/AIDS infection. Bronchiectasis may occur as well, as a consequence of fibrosis. Pleural involvement is more common in postprimary TB than in primary infection, including empyema or empyema necessitans.
PET and PET/CT for Evaluation of Lung Cancer
[18F]FDG PET/CT has been used extensively in the differential diagnosis and characterization of single pulmonary lesions. While the overall performance of [18F]FDG imaging for diagnosis of pulmonary malignancy is good, there are pitfalls and limitations that can lead to potential false-positive and false-negative findings. Inflammatory lesions such as sarcoid or tuberculosis can take up [18F]FDG. While the pattern and, at times, intensity of uptake may be helpful to appropriately identify the etiology of the lesions, biopsy may be necessary to make a definitive diagnosis. False negatives may be due to small-size lesions or to the histological subtype of well-differentiated malignancies such as bronchioloalveolar carcinoma (BAC) or carcinoid , as well as sub-solid nodules, particularly GGOs, which often exhibit low glucose utilization rates and low-level metabolic activity and have therefore low or absent [18F]FDG uptake. These are slow-growing tumors with less proliferative potential and longer mean doubling times as compared to NSCLC. The sensitivity of [18F]FDG imaging for BAC is only around 50% . On the other hand, multifocal BAC appearing as multiple nodules or GGOs is detected with a high sensitivity by [18F]FDG imaging studies . Indolent behavior, small size, and paucity of malignant cells all contribute to poor FDG avidity of sub-solid nodules . Well-differentiated adenocarcinomas manifesting as GGOs can be falsely negative on [18F]FDG PET/CT, whereas benign GGOs can be falsely positive [20, 138]. However, [18F]FDG PET/CT is warranted in GGOs with a mixed solid component, more likely of being high-grade invasive tumors.
In spite of the abovementioned limitations, [18F]FDG PET/CT has been reported to change management in 25–52% of patients with NSCLC and has a major role in reducing the number of futile thoracotomies [20, 139, 140]. Pretreatment [18F]FDG PET/CT provides prognostic information. Pillot et al. have summarized the literature assessing the relationship between the SUV of the tumor and outcome , suggesting that the SUV is a powerful surrogate marker for outcome in NSCLC. Recently, Goodgame et al. retrospectively analyzed 136 patients with stage I NSCLC. Thirty-two patients had recurrence during a median follow-up of 46 months. In multivariate analysis a preoperative SUVmax of 5.5 or higher was an independent predictor of relapse and death in this group of patients . Tann et al. conducted a retrospective study in 51 patients with stage I lung cancer, comparing [18F]FDG PET/CT results to growth rates and tumor doubling times obtained from pretreatment chest CT examinations performed more than 25 days apart, and found that rapid, moderate, and slow doubling times correlated with SUV measurements . Im et al. performed a meta-analysis of 13 studies and 1581 patients assessing the prognostic value of the volumetric parameters of [18F]FDG PET/CT in patients with lung cancer . Both the metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were significant prognostic parameters in NSCLC. Patients with high MTV or high TLG had a poorer prognosis . Recently it has been demonstrated in 102 NSCLC patients significantly higher [18F]FDG uptake compared to EGFR and wild-type profiles . If these preliminary results will be proven in large prospective trials, a single pretreatment [18F]FDG PET/CT study may predict in future the rate of tumor growth and be used in an individualized approach to therapy.
Since most lung lesions are hypermetabolic (with the exception of low-grade BAC, carcinoid, and sub-solid nodules, as stated above), [18F]FDG PET/CT imaging can provide important information for the management of patients with lung lesions. [18F]FDG PET/CT is recommended as a component of initial evaluation in T1–T3 disease. [18F]FDG imaging findings can play a pivotal role in determining whether a patient with T1 disease is resectable or whether patients with more advanced disease have metastases that may require specific therapy. In addition to defining whether pulmonary nodules represent lung cancer, [18F]FDG PET/CT can determine the number and location of hypermetabolic lesions in the chest and elsewhere and define tumor response to therapy.
A baseline study in a patient with histologic evidence of lung cancer should evaluate the lung parenchyma, bronchus, lymph nodes (in the chest, neck, and abdomen), chest wall, pleura, liver, adrenal glands, and bone for hypermetabolic foci to stage the disease and address the question about the potential roles of surgery, radiotherapy, and chemotherapy in patient management.
Serial scans are helpful for surveillance, to detect recurrence, especially in patients with no clinical evidence of disease, and to determine the effectiveness of therapy, by detecting changes in lesion size and SUV, as well as detecting new lesions.
Characterization of the Solitary Pulmonary Nodule
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. 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, allows 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 suggests 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 . 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 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. 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 are 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.  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.  reported a sensitivity of 93%, specificity of 87%, and PPV and NPV of 94% and 89%, respectively. The risk to miss malignancy was 11%. Cai et al.  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 [149, 150] (Fig. 1). In a prospective study in 585 patients, Bryant et al.  demonstrated that in nodules less than 2.5 cm in diameter, an SUVmax of 2.5 or less was associated in 24% of cases with malignancy, as compared to lesions with an SUVmax 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.  have recently shown that in SPNs with an SUVmax <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 location of the lesion is usually determined 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 size of the lesion is also determined by CT in most cases. However, in the presence of atelectasis distal to the tumor, the differential diagnosis between the tumor mass and the adjacent 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 1). Subclassification according to tumor size is a factor that has an impact on prognosis (Table 2). 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.
Solitary Pulmonary Nodule (SPN)
SPN is defined as any nodule up to 3 cm in diameter. The majority of SPNs (60–70%) are benign in etiology. Lung cancer, however, is found 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 [134, 144].
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 . 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 . In nodules 5–10 mm in diameter, Bastarikka et al.  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.
Over 40% of SPNs are granulomas, including mycobacterial infection or histoplasmosis. The average SUVmax 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 . [18F]FDG PET/CT has a promising role for evaluation of TB in high-risk immunocompromised patients with cancer [156, 157]. In an area with endemic histoplasmosis, inflammatory lesions were difficult to separate from NSCLC (mean SUVmax 3.2 in benign lesions vs. 8.5 in neoplastic lesions with significant overlap between groups) .
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) . In cancer patients with biopsy-proven sarcoidosis, early metabolic response to systemic steroid treatment can help in the final differential diagnosis when both coexist . Other inflammatory conditions such as pneumonia, pyogenic abscess, aspergillosis, Wegener’s granulomatosis, and anthracosis may also need to be differentiated from lung cancer. In a patient with 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 [161, 162]. Using an SUV cutoff 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 . Chen et al. have assessed the increment in SUV (SUVinc) from dual-phase [18F]FDG PET in 187 consecutive patients with NSCLC and showed 3-year progression free survival (PFS) and overall survival of 61.6% and 87.8% in patients with SUVinc ≤1, compared to 21.1% and 46.2% in patients with SUVinc >1. The authors conclude that SUVinc is a promising prognostic factor in NSCLC . Of note, however, active granulomas, a frequent cause for false-positive [18F]FDG studies, may also demonstrate the same increase in tracer uptake over time .
[18F]FDG Imaging for Preoperative Staging of NSCLC
Accurate staging of NSCLC provides important prognostic information and determines the best treatment approach. Surgical resection is indicated for early stages of NSCLC and in N1 or N2 disease (ipsilateral mediastinal nodes), unless lymph node metastases are bulky, multilevel, or non-resectable. In N3 disease (contralateral mediastinal, scalene, or supraclavicular nodal metastases) as well as in patients with metastatic spread surgery is not indicated.
Although CT can accurately detect tumor size and infiltration of adjacent structures, [18F]FDG PET/CT predicts T stage in 82% of cases as compared to 68% and 76% for stand-alone CT and visually co-registered separately performed PET and CT, respectively [33, 34, 35, 36, 163, 164, 165, 166]. [18F]FDG PET/CT may improve accuracy for detection of tumor invasion of the chest wall . Changes in the therapeutic management due to PET/CT occur mainly in T3 and T4 tumors . [18F]FDG PET/CT has also an advantage in the assessment of tumor spread to the pleura. Pleural thickening and pleural nodularity can be detected on CT and MRI, but may also be encountered in benign disorders. However, [18F]FDG PET/CT has a high PPV and NPV in the assessment of malignant pleural effusion . In contrast to CT, [18F]FDG PET/CT can help differentiate between tumor (usually avid) and peri-tumoral atelectasis (usually non-avid) and therefore has an impact on planning of surgical procedure or radiation therapy. The accurate information on tumor extent provided by [18F]FDG PET/CT has been shown to cause changes in planning the radiation field in 30–40% of patients [167, 168].
Based on the criterion that a node of ≥10 mm in the short axis diameter is metastatic, the sensitivity of CT has been reported in the range of 52–69% and the specificity between 69% and 82% . Normal-size lymph nodes on CT have micrometastases in 15% of cases , while 30–40% of enlarged lymph nodes have no tumor cells . [18F]FDG imaging, on the other hand, has a sensitivity ranging between 79% and 85%, specificity of 89–92% , and a NPV above 90%  for the detection of metastatic mediastinal lymphadenopathy. False-negative results can occur in cases of micrometastases and false-positive findings in cases of inflammation. The PPV of [18F]FDG imaging for evaluating the mediastinum ranges from 45% to 93% [174, 175]. Mediastinoscopy is therefore the standard of care for mediastinal staging. In cases of [18F]FDG-positive mediastinal nodes, the study can further direct biopsy. Antoch et al.  assessed 27 NSCLC patients comparing CT and [18F]FDG PET/CT with histopathology. PET/CT classified the tumor stage correctly in 26 patients, compared to 19 with CT. The accuracy for regional lymph node staging was 93% with PET/CT and 63% with CT. PET/CT also detected 17 distant metastases in four patients, compared to 14 metastases in four patients with CT . Shim et al. prospectively recruited 106 patients with NSCLC who underwent tumor resection and lymph node dissection after [18F]FDG PET/CT and CT. PET/CT correctly staged 86% of the primary tumors as compared to 79% by CT. PET/CT was more sensitive and more specific (85% vs. 70% and 84% vs. 69%, respectively) than CT for diagnosis of malignant regional nodes, with more false-positive findings and false-negative findings on CT .
18F-Fluoride-PET/CT was also assessed for the detection of bone metastases in NSCLC. In a prospective study  of 103 patients with lung cancer, receiver operator curve (ROC) analysis showed that the performance of 18F-fluoride PET was better than that of the conventional BS. In 1,000 NSCLC patients with confirmed bone metastases, PET/CT had a better sensitivity (98.3% vs. 95.1%) and specificity (98.7% vs. 98.4%) as compared to planar BS . Recently Kruger et al.  have correlated the findings on [18F]FDG PET/CT to BS and 18F-Fluoride studies in 126 patients with NSCLC including 34 patients with osteolytic metastatic bone lesions. [18F]FDG PET/CT was superior to planar BS in the detection of these skeletal lesions, also leading to changes in patient management. 18F-Fluoride detected more metastatic foci and was at least as sensitive as [18F]FDG PET/CT .
[18F]FDG imaging is less useful in the detection of brain metastases, due to high physiologic glucose utilization in normal brain tissue. [18F]FDG PET/CT has an advantage in depicting unsuspected pancreatic metastases from lung cancer, particularly those that are not detected by CT alone . Finally, [18F]FDG imaging can also diagnose a synchronous second primary tumor, mainly of colorectal origin, detecting incidentalomas, unsuspected foci of increased tracer uptake in the gastrointestinal tract .
Value of [18F]FDG PET/CT in Patient Management
Fisher et al.  assessed the clinical effect of [18F]FDG PET/CT on preoperative staging of NSCLC, comparing 98 patients who had PET/CT to 91 patients who had conventional staging. The primary end point was defined as the number of futile thoracotomies. There were 21/60 futile thoracotomies in the [18F]FDG PET/CT group compared to 38/73 in the conventional imaging group. The number of justified thoracotomies and survival of patients were similar in the two groups. Therefore the use of [18F]FDG PET/CT reduced the number of total and specifically of futile thoracotomies in these patients . Similar findings were also reported by others, who have assessed the cost-effectiveness of lung cancer staging with [18F]FDG PET/CT . In a randomized prospective study, 188 patients had either conventional imaging including CT or had both conventional workup and [18F]FDG imaging . Patients who performed [18F]FDG studies had a 51% reduction in unnecessary thoracotomies. Subedi et al.  assessed the clinical impact of [18F]FDG PET/CT in 161 patients with suspected lung cancer. In this study the addition of PET/CT to the conventional evaluation of lung cancer excluded the presence of malignancy in 10% of patients with no uptake in the suspected lung lesion and revealed occult metastases in 16% of patients. [18F]FDG PET/CT was a better predictor for T staging (64% vs. 58%) and N staging (78% vs. 65%) and influenced management decisions in 41% of patients, leading to a decrease in the number of thoracotomies performed for non-resectable disease .
[18F]FDG Imaging for Radiation Treatment Planning in NSCLC
NSCLC patients with newly diagnosed stage IIIA or IIIB disease as well as patients with limited disease who are not suitable for surgery are candidates for radiation therapy . It has been shown that [18F]FDG imaging has a significant impact on defining the target volume in patients with lung cancer prior to radiation therapy . Nestle et al. have reviewed the results in 661 patients with lung cancer in 18 trials that compared target volumes, gross tumor volume (GTV), clinical tumor volume (CTV), and planning target organ volume (PTV) using CT alone and [18F]FDG PET/CT. All trials showed significant changes in target volumes when [18F]FDG PET/CT was added due to better diagnosis of lymph node involvement and optimized differentiation between tumor and adjacent atelectasis . In the past, due to diagnostic uncertainties, target volumes in lung cancer patients included large portions of unaffected tissue. High doses of irradiation were delivered with a high risk of irradiating normal lung and adjacent tissues. Due to the high NPV for the detection of mediastinal lymph nodes (>90%) and the delineation of the metabolically active tumor volume, [18F]FDG PET/CT can influence the definition of the GTV for radiotherapy planning. The GTV can be reduced when [18F]FDG-negative nodes or areas of atelectasis are excluded from the radiation treatment field or enlarged when previously unsuspected [18F]FDG-avid nodes are detected. This can lead to a change in the GTV or dose to be delivered in up to two thirds of cases [192, 193, 194, 195, 196, 197, 198]. For example, omission of extensive nodal irradiation in patients with N2 disease with lower burden of nodal invasion resulted in a significant reduction of doses given to the lung, esophagus, heart, and spinal cord . However, because of a false-positive rate that may reach 30%, depending on the patient population, ideally, pathological confirmation of [18F]FDG-positive nodes should be obtained by mediastinoscopy or endoscopic ultrasound-guided fine-needle aspiration . Importantly, the addition of [18F]FDG imaging to CT reduces the inter-observer variability in definition of the GTV for NSCLC [199, 200, 201, 202, 203, 204].
There are no large clinical trials assessing long-term consequences of [18F]FDG-induced changes in the treatment plan. Isolated cases of nodal failure  and out-of-field recurrence  were reported. Large prospective trials of patient outcome are needed to assess the clinical impact of this strategy.
Is Radical Therapy Suitable for the Patient?
The outcome of the combined anatomic and metabolic data available from [18F]FDG PET/CT imaging guides clinicians in the selection of the most suitable treatment modality. For example, an 80-year old patient with a single isolated [18F]FDG-positive N2 node adjacent to a left upper lobe tumor would benefit more from radical radiotherapy rather than from neoadjuvant treatment followed by radical surgery.
[18F]FDG imaging can also help in planning the surgical approach with respect to the extent of resection, by identifying [18F]FDG-positive lesions in the mediastinum, chest wall invasion, peribronchial infiltration, or vascular invasion. [18F]FDG imaging is also increasingly used for radiation treatment planning. It can help in decreasing the risk of radiation-related side effects such as pneumonitis and esophagitis by accurate definition of the tumor volume.
Prognostic Value of SUV
The importance of SUV measurements on the baseline [18F]FDG study is very useful in lung tumors. SUV is a good prognostic indicator as well as a good indicator of response to treatment. In NSCLC patients an SUVmax of the primary tumor >7  and >10  had an independent prognostic impact, also showing that the median survival decreased with increasing mean SUV levels. Others also showed that the SUVmax was an independent predictor of disease free and overall survival [209, 210]. In a retrospective study in 100 patients, Downey et al.  showed that the 2-year survival rates were 68% for patients with a SUVmax above 9% and 96% in patients with SUVmax below 9. In patients with NSCLC, Cerfolio et al.  found the SUVmax to be an independent predictor of tumor aggressiveness and a more accurate predictor of tumor recurrence and survival as compared to TNM staging. Total lesion glycolysis (TLG) was also found to be a significant prognostic parameter in NSCLC .
[18F]FDG Imaging for Assessment of Response to Therapy in NSCLC
Literature data thus indicate that a decrease in [18F]FDG uptake usually correlates with the pathologic response and with improved survival. It needs to be emphasized, however, that there is not yet a consensus regarding the measurement of response and the degree of reduction in SUV that is required to define a metabolic response .
[18F]FDG Imaging in the Follow-Up of Lung Cancer
After curative treatment follow-up is indicated to assure proper management of therapy-related complications or for early detection of tumor recurrence which is most likely to occur within the first 4 years with only 10% developing after 5 years or more . A meta-analysis showed no significant benefits of follow-up of lung cancer after curative treatments. A nonsignificant trend for improved survival with intensive follow-up was identified in the curative-intent treatment subgroup . The most recent guidelines published by the American College of Chest Physicians suggest that in patients who have undergone curative-intent surgical resection of NSCLC, chest CT should be performed every 6 months for the first 2 years after resection and every year thereafter . It is further recommended that in NSCLC and carcinoid treated with curative intent, the original treating physicians participate in the decision-making process during follow-up. Routine surveillance with [18F]FDG PET imaging, somatostatin receptor scintigraphy (SRS), or abdominal ultrasonography is not recommended .
[18F]FDG PET-CT imaging is helpful in the management of advanced stage lung cancer. Advances in chemotherapy and availability of second- and third-line regimens (including less toxic drugs as well as oral chemotherapy) require a marker to define when these drugs are no longer effective and a change in therapy is necessary.
Changes in lesion size on CT and SUV on serial [18F]FDG PET/CT studies provide information about the efficacy of therapy. Reduction in size and decrease in SUV suggest that therapy is effective. Increasing lesion size or failure of the SUV to decline by ≥25% after 6–8 weeks of treatment suggests failure of therapy. In patients who have a complete metabolic response, serial [18F]FDG PET/CT surveillance imaging is very useful to detect recurrence and is more sensitive than stand-alone CT.
In a retrospective study of 261 lung cancer patients with 488 follow-up [18F]FDG PET/CT studies performed ≥6 months after completion of initial treatment and followed for a median of 29.3 months, the median survival of [18F]FDG-positive and [18F]FDG-negative groups was 32.9 months and 81.6 months, respectively, with similar differences in overall survival between the groups. Age and [18F]FDG PET/CT results were the only factors associated with overall survival on multivariate analysis, regardless of the timing of the follow-up study . The same group has assessed the value of the fourth and subsequent [18F]FDG PET/CT studies performed during follow-up after completion of primary therapy in 1,171 patients. [18F]FDG PET/CT identified recurrence or metastases in 43% of studies in patients with no previous evidence of disease and ruled out recurrence or metastases in 24% of studies with prior clinical suspicion of disease with an overall change in management in 28% of patients .
[18F]FDG Imaging for Detection of NSCLC Recurrence
Early detection of recurrence can be difficult with CT. New findings can be related to tumor recurrence but can also be due to treatment. Differentiating treatment-induced fibrosis and necrosis from viable tumor may not be possible on CT [223, 224]. However, [18F]FDG imaging can differentiate recurrent or persistent tumor from scar tissue with a sensitivity of 89–98% and specificity of 87–93% [225, 226, 227]. Since the results of [18F]FDG studies performed less than 10 days after administration of chemotherapy may be misleading, it is advisable to perform the study at least 2 weeks after completion of therapy. Increased [18F]FDG uptake in recent surgical scars, due to a healing inflammatory process, usually a linear pattern decreasing in intensity over time, can be differentiated from recurrence in the surgical field which has a more focal appearance with high intensity uptake .
Small-Cell Lung Cancer (SCLC)
The advantages of [18F]FDG PET-CT in SCLC appear to be similar to NSCLC. A prospective study of patients with extensive SCLC reported a sensitivity and specificity of 79% and 100% for standard staging, 93% and 83% for [18F]FDG PET stand alone, and 93% and 100% respectively, for [18F]FDG PET/CT. [18F]FDG imaging is more accurate in nodal detection. [18F]FDG-based selective nodal irradiation for limited disease SCLC resulted in a low rate of isolated nodal failures of 3% and low percentage of acute esophagitis . These findings contradict results obtained using CT-based selective nodal irradiation, which showed isolated nodal failures in 11% of cases . The low rate of isolated nodal failures and decreased esophageal toxicity supports the use of [18F]FDG-based nodal irradiation for limited SCLC.
Response of SCLC to chemotherapy can be assessed as early as at the end of the first cycle of chemotherapy. Prognostic stratification was studied by Lee et al.  who reported that in patients with SCLC, high SUVmax was significantly related to poor prognostic factors and extensive disease. Furthermore, multivariate analysis indicated that high SUVmax was associated with poor survival outcomes compared with patients with low SUVmax (adjusted hazard ratio, 3.74). In a subgroup analysis, patients with limited disease and high SUVmax had a significantly shorter overall survival than patients with limited disease and low SUVmax (20.1 months vs. 35.3 months respectively; p = 0.02). Patients with extensive disease and high SUVmax had significantly shorter overall survival than patients with extensive disease and low SUVmax (9.5 months vs. 17.7 months, respectively; p = 0.007). These findings were replicated in progression-free survival analysis. Therefore, it was concluded that in SCLC, metabolic tumor activity assessed by [18F]FDG imaging is a significant prognostic factor and identifies subgroups of patients at higher risk of death in patients with both limited and extensive disease . [18F]FDG PET-CT also has a role in radiation treatment planning in patients with SCLC [233, 234]. In the current guidelines, [18F]FDG PET-CT is not indicated for surveillance in SCLC .
[18F]FDG and Other PET Tracers for Imaging in Neuroendocrine Tumors
[18F]FDG Imaging of Malignant Pleural Disease
[18F]FDG imaging has been used for the assessment of pleural masses and effusions. Pleural metastases of lung cancer are best diagnosed with CT, or the CT component of [18F]FDG PET/CT study, since the lesions are as a rule below the resolution of PET . In 25 patients with suspected malignant pleural effusions, Erasmus et al. found sensitivity, specificity, and PPV for [18F]FDG PET/CT of 95%, 67%, and 95%, respectively . Schaffler et al. have studied 92 patients and found a sensitivity, specificity, and PPV of 100%, 71%, and 63%, respectively .
Malignant pleural mesothelioma (MPM) is an aggressive tumor of mesothelial cell origin associated with asbestos exposure. Although it is a relatively rare neoplasm, its incidence is increasing worldwide due to widespread exposure to asbestos [245, 246]. Mesothelioma is seen more often in men (likely due to a higher incidence of exposure to asbestos) and occurs in the right hemithorax more often than the left. CT is the primary imaging modality [247, 248, 249, 250, 251]. Key findings include unilateral pleural effusion and nodular pleural and interlobar fissure thickening. Calcified pleural plaques are found in 20% of the patients, indicating previous asbestos exposure . The invasion of adjacent structures, adenopathy, and the presence of bone, pulmonary, and distant metastases can occur in advanced stages of the disease [252, 253]. MRI provides detailed information in challenging cases  and can assist in differentiating malignant from benign pleural disease as well as in the assessment of chest wall and diaphragmatic involvement . High signal intensity in relation to adjacent musculature on T2-WI, significantly enhancing on T1-WI, is suggestive of malignant disease. MRI has a 100% sensitivity and 93% specificity for detection of pleural malignancy  and is superior to CT in delineating chest wall and diaphragm invasion, thus providing a better assessment of potential resectability [254, 255]. Dynamic contrast-enhanced MRI is a promising new technique that may reflect tumor histopathology  and may predict the therapeutic efficacy of chemotherapy in patients with MPM.
While [18F]FDG imaging is at present under extensive investigation in patients with MPM, CT is the gold standard for response assessment in clinical trials in these patients. [18F]FDG PET-CT was also assessed for radiation therapy planning in 13 patients with inoperable MPM, showing the usefulness of target volume delineation by PET/CT as compared to CT alone, which led to reducing the GTV, CTV, and PTVI by 47%, 39%, and 40%, respectively .
[18F]FDG Imaging of Mediastinal Tumors
CT and MRI can identify mediastinal masses, show their extent, and diagnose correctly a variety of benign lesions. [18F]FDG PET/CT may be helpful in the assessment of malignant as well as some of the benign masses. Luzzi et al.  evaluated [18F]FDG PET/CT in the preoperative assessment of isolated anterior mediastinal lesions, especially for planning the operative strategy (biopsy or upfront resection), including 13 thymomas (six low grade and seven high grade), three lymphomas, and three with other primitive thymic tumors (one paraganglioma and two non-seminomatous germ cell tumors). The mean SUV of low-grade lesions was 3.3 + 0.5 compared to 13.5 + 7 in high-grade tumors (p = 0.009). The SUV in low-grade thymoma was significantly lower compared to lymphoma and to the other primitive anterior mediastinal tumors. Low SUV (less than 5) was associated with low-grade thymoma and minimal invasive thymoma. For lesions with an infiltrative pattern on CT and SUV above 5, open biopsy is mandatory to exclude mediastinal lymphomas or, in case of high-grade thymoma, to address neoadjuvant treatment . Kumar et al.  reported on a mean SUVmax of 1.1 in thymic hyperplasia. Patients with low-risk thymoma had large tumors and a mean SUVmax of 3, while patients with high-risk thymoma had small tumors with a mean SUVmax of 2.1. The mean SUVmax in the entire group of thymomas was 2.3. All thymic carcinomas were large, with a mean SUVmax of 7. The difference between the mean SUVmax of thymic hyperplasia, thymoma, and thymic carcinoma was statistically significant, but not for high- and low-risk thymoma . Sung et al. have assessed 33 patients with thymic epithelial tumors . SUVmax of high- and low-risk thymomas were both significantly lower than that of thymic carcinomas. A homogenous [18F]FDG uptake pattern was more common in thymic carcinomas, while thymomas showed heterogenous uptake . Benveniste et al. have assessed whether [18F]FDG PET/CT can assist in differentiating between early- (stage I–II) and advanced-stage (stages III and IV) thymoma before surgery, as patients with locally advanced tumors are treated with neoadjuvant chemotherapy before surgery . [18F]FDG uptake was significantly higher in patients with B3 thymoma compared to lower stages and was significantly higher in thymic carcinoma or carcinoid compared to thymoma . Thomas et al. have evaluated 56 patients with unresectable advanced-stage thymic epithelial tumors who had [18F]FDG PET/CT at baseline and after 6 weeks of treatment showing a close correlation between early response on [18F]FDG PET/CT and subsequently diagnosed response by RECIST criteria. The authors conclude that [18F]FDG PET/CT may be used for monitoring response to treatment in these patients .
Mediastinal sarcomas are rare, but can be [18F]FDG avid . The use of [18F]FDG imaging in lymphoma is extensive and is covered in a separate chapter.
PET/MRI Imaging of Lung and Thoracic Malignancies
Increasing use of PET/MRI scanners in recent years does not expose the patient to the ionizing radiation of the CT scan, and provides new functional parameters, mainly lung perfusion, ventilation, blood flow, gas exchange, and respiratory motion. However, because of the low density of lung tissue artifacts at the air-tissue interfaces and because of respiratory and heart motion, MRI of the lungs is challenging.
The feasibility of PET/MRI in lung tumors has been confirmed in a pilot study in ten patients showing a similar overall performance with PET/CT . While further recent studies showed an excellent agreement between PET/CT and PET/MRI in lung cancer patients with similar diagnostic accuracy, so far no specific advantage for PET/MRI was demonstrated [275, 276, 277]. The PET/MR protocol that has been used did not include specific brain and liver MR sequences which could have potentially improved the diagnostic value in some cases .
PET Imaging of Lung and Thoracic Malignancies with Other Tracers
While [18F]FDG is the most widely used tracer in oncology, many biological targets can be imaged with other radiolabelled ligands. Uptake of [11C]choline in tumors is an index of the rate of tumor-cell replication and has also been used to image lung cancer. Uptake of [18F]FDG and [11C]choline is similar in primary lung tumors [278, 279] but the latter can more accurately assess suspicious brain lesions, due to lower physiologic levels of tracer activity in the normal brain cortex.
Hypoxia is common in malignant tumors and influences the cell’s ability to respond to therapy. The degree of hypoxia is therefore associated with tumor progression. Hypoxia also promotes angiogenesis by increasing the expression of growth factors such as the vascular endothelial growth factor. 60Cu- or 64Cu-labelled methylthiosemicarbazone (Cu-ATSM) has been used to assess tumor hypoxia . This tracer is taken up and trapped in hypoxic cells but quickly washes out from normoxic cells. Dehdashti et al.  studied 14 patients with NSCLC before therapy with 60Cu-ATSM-PET including eight who subsequently responded and six who had disease progression . Pretreatment 60Cu-ATSM uptake was predictive of response. The tumor/muscle uptake ratio was significantly lower in responders as compared to nonresponders. In the same group of patients, there was no significant difference in the degree of [18F]FDG uptake between responders and nonresponders . 18F-fluoromisonidazole (18F-MISO) is another specific tracer for hypoxia, with slower washout from normoxic cells compared to Cu-ATSM and was used in the initial studies of in vivo mapping of tumor hypoxia. Eschmann et al.  have assessed whether 18F-MISO can predict tumor recurrence after radiation therapy in a group of patients including 14 with NSCLC. A tumor/muscle cutoff of 1.6 or a tumor/mediastinum cutoff of 2 differentiated patients with or without subsequent tumor recurrence.
Information on tumor cell proliferation can be obtained using the thymidine analog 3′-deoxy-3′-18F-fluorothymidine (18F-FLT). Thymidine incorporation into DNA is the gold standard for the assessment of proliferation, and 18F-FLT has been therefore used to assess response to therapy. 18F-FLT PET/CT in NSCLC correlated with tumor proliferation determined by Ki-67 labelling index and with tumor angiogenesis determined by tumor microvessel density (MVD) . In 68 patients with known or suspected NSCLC who had 18F-FLT PET/CT followed by surgery, 18F-FLT SUVmax correlated with Ki-67 labelling index and with MVD. Survival of patients correlated with 18F-FLT uptake and with Ki-67-labelling index, and both parameters correlated with MVD . Everitt et al. studied 20 patients with stage I–III NSCLC at baseline and at weeks 2 and 4 during radical chemoradiotherapy with both FLT and [18F]FDG PET/CT . FLT was more sensitive for early treatment response. At the study performed at week 2, there was marked partial proliferative response in almost all tumors, whereas the metabolic tumor volume on [18F]FDG PET-CT was stable or showing only a moderate response in most patients, suggesting that chemoradiotherapy affects tumor cell proliferation more rapidly than cellular metabolism . The prognostic significance of these differences is still unclear at present.
Integrin α v β 3 has a major role in angiogenesis and tumor growth. A recent pilot feasibility study in 17 lung cancer patients imaged with 18F-Al-NOTA-PRGD2 (18F-alfatide) showed that this tracer can successfully differentiate lung tumors from hamartoma but not from inflammatory changes . Zheng et al. have recently assessed another integrin imaging tracer, 68Ga-NOTA-PRGD2, in 91 patients with lung cancer and have reported sensitivity, specificity, and accuracy of 84%, 91%, and 86%, respectively, for the diagnosis of lung cancer. In addition, 68Ga-NOTA-PRGD2 was more specific than [18F]FDG PET-CT in the assessment of lymph node metastases, with positive and negative predictive values of 90% and 94% compared to 30% and 91% .
Although CT and MRI provide high-resolution anatomic assessment, [18F]FDG imaging is superior in differentiating benign from malignant mediastinal lymphadenopathy and in the detection of distant metastases. Pre-therapy [18F]FDG studies can provide important prognostic information. [18F]FDG PET/CT can eliminate about half of futile thoracotomies and is therefore recommended for staging of lung and mediastinal tumors. [18F]FDG imaging is also indicated in the diagnosis of recurrent disease and in monitoring treatment response. [18F]FDG PET/CT has been introduced for radiation planning; optimizing delineation of treatment volumes, thus increasing the dose in target volumes; and reducing toxicity to nontarget tissues. Although [18F]FDG is the most widely used tracer in oncology, other PET tracers are currently evaluated with specific clinical and mainly research goals and may have a role in future in the management of lung malignancies. PET/MRI has an overall similar performance to PET/CT in patients with lung cancer.
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