Pietro Muto • Maria Luisa De Rimini • Cinzia Landolfi • Abdul Jalil Nordin
Lung cancer continues to rank first in mortality statistics in many areas of the world. Although there has been a decrease in the overall lung cancer burden in the United States and the rest of the world, reflecting the success of preventive strategies, it remains a critical public health problem in much of the developed world. The epidemiology of lung cancer consistently reinforces a major theme: Lung cancer is a consequence of the widespread addiction to cigarette smoking throughout the world, although there has been some success recently in reduction of exposure to occupational carcinogens in developed countries.
Lung cancer is the leading cause of cancer deaths in the United States, with an estimated 222,520 new cases and 157,300 deaths expected to be reported in 2010—approximately 28% of all cancer deaths.1. Although tobacco smoking is widely known as a causative agent, there are other causes as well, some acting synergistically to increase risk. For example, the radioactive gas radon in indoor environments is now considered as the second leading cause of lung cancer in the United States. The list of human occupational causes of lung cancer includes arsenic, asbestos, chromates, chloromethyl ethers, nickel, polycyclic aromatic hydrocarbons, radon progeny, and other agents.2 For many of the worker groups exposed to these agents, there are substantial increments in risk. The risk of developing lung cancer increases with increased exposure to asbestos either directly, as a carcinogen, or through indirect mechanisms, such as causing chronic inflammation that has been linked to cancer.3 Cigarette smoking may increase the lung cancer risk associated with asbestos exposure by enhancing the retention of asbestos fibers.4
“Traditional” epidemiologic approaches have conclusively established the carcinogenicity of tobacco smoke, and molecular epidemiology has characterized the sequence of molecular and cellular changes as a nonmalignant cell becomes malignant. Genetic factors have been identified that may determine susceptibility to tobacco smoke. Lung cancer is now also a major women’s health issue. As a result of historical cigarette smoking patterns, the epidemic of lung cancer started later in women than in men. The rate of lung cancer among women has substantially increased over the past two decades and is only now starting to plateau.
The prevalence of the various histologic subtypes of non–small cell lung cancer (NSCLC) has changed in recent decades.5 The histologic characteristics of lung cancer in developed countries, including the United States, have also changed in the past few decades such that the frequency of adenocarcinoma has risen and that of squamous cell carcinoma has declined. According to Surveillance, Epidemiology, and End Results Program data collected from 2002 to 2006, adenocarcinoma accounts for 43% of NSCLC, squamous cell carcinoma accounts for 23%, and the remaining 34%, other unspecified subtypes.6 In contrast, the database used for the original tumor, node, metastasis (TNM) staging manual contained 1,712 cases of NSCLC, of which 30% (521 cases) were adenocarcinoma and 58% (996 cases) were squamous cell carcinoma; the majority of these patients were men. Differences in tobacco smoking habits (filters, light tobacco cigarettes, profound inhalation) seem to favor the development of distal bronchiolar and alveolar carcinogenesis at the expense of proximal squamous cell carcinoma.7 Adenocarcinoma is the most prevalent form of lung cancer in younger men (<50 years) and in women of all ages, in never-smokers, and in former smokers.
Lung neuroendocrine tumors (NETs) present as well-differentiated tumors in 80% to 90% of cases. They rarely metastasize (5% to 20%). Less frequently, they present as atypical forms with poorer prognosis (5-year survival of 44% to 78% versus 87% to 89% for typical forms).8
The majority of lung cancers usually present as a peripheral lung nodule or mass; 80% are NSCLC; the remaining 20% are small cell lung cancer (SCLC).5 The new World Health Organization (WHO) classification of lung tumors is summarized in Tables 12.1 and 12.2.
WORLD HEALTH ORGANIZATION/INTERNATIONAL ASSOCIATION FOR THE STUDY OF LUNG CANCER CLASSIFICATION OF LUNG CANCER
2011 INTERNATIONAL LUNG ADENOCARCINOMA HISTOPATHOLOGIC CLASSIFICATION (BRONCHOALVEOLAR CARCINOMA)a
An international tumor classification system for lung cancer is necessary for consistency in applying treatment protocols. The WHO/International Association for the Study of Lung Cancer (WHO/IASLC) classification is based on the histologic appearance on light microscopy.9,10 In considering therapeutic approaches, lung cancer is generally divided into SCLC and NSCLC.11 To minimize the number of unclassified lesions, immunohistochemistry and electron microscopy findings are also used in the system to classify or subclassify lung tumors from surgical or needle biopsy.
Atypical adenomatous hyperplasia (AAH) has been regarded as a precursor of adenocarcinoma, mainly based on the fact that it is often found near or within the same adenocarcinoma site. AAH is also a known precursor for nonmucinous bronchoalveolar carcinoma (BAC). It is not present, however, in every patient with adenocarcinoma. It is found in 2% of young individuals without cancer and in up to 23% in those with cancer. AAH is defined as an atypical proliferation of minimally atypical cuboidal cell type II pneumocytes, measuring <5 mm. Lesions can be further defined as mild, moderate, or severe dysplasia on the basis of severity according to the thickness, anisocytosis, and pleomorphism, with little maturation and abnormally oriented nuclei. Further changes involving full thickness are seen in carcinoma in situ. Atypical alveolar hyperplasia and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia are associated with changes in the bronchoalveolar epithelium.
As stated, adenocarcinoma is the most common form of lung cancer.12–15 Histologically, this tumor is highly heterogeneous with a mixed pattern leading to difficulty in classification. Adenocarcinoma of mixed type with a predominantly bronchoalveolar pattern is categorized as BAC. Nonmucinous-type BAC usually presents as a solitary nodule. Clinically, it has a good prognosis, whereas mucinous-type BAC tends to spread and form satellite tumors with consolidation and a poor clinical prognosis.
There are several variants of adenocarcinoma in the new WHO/IASLC classification system, including well-differentiated fetal adenocarcinoma, colloid carcinoma, mucinous cystadenocarcinoma, signet ring adenocarcinoma, and clear cell adenocarcinoma. Eighty-five percent of primary lung adenocarcinomas express thyroid transcription factor 1, which is an adverse prognostic marker for the likelihood of metastases.
NETs have several histologic subtypes, from low grade, typical carcinoid to intermediate atypical carcinoid, to high-grade large cell neuroendocrine carcinoma and small cell lung carcinoma. These subclassifications have a strong prognostic significance in terms of survival. The diagnosis of neuroendocrine carcinoma requires at least one specific immunohistochemical marker.16,17 The category of SCLC is limited to tumors with pure SCLC histology. Any tumor mass with at least 10% of SCLC is called SCLC combined. Although the TNM descriptors are not commonly used in clinical practice to stage SCLC, the current (seventh) edition of the TNM staging system suggests its use for NSCLC as well as SCLC, because increasing stage correlates with decreased survival times in patients with either tumor.18 SCLC is distinct from the more common NSCLC because of its rapid doubling time, high growth fraction, early development of widespread metastases, and dramatic initial response to chemotherapy and radiation.19 Despite high initial frequency of responses to therapy, most patients die of recurrent disease.
Large cell carcinoma and NETs include other rare tumor types such as lymphoepithelioma-like carcinoma, clear cell carcinoma, and large cell carcinoma with rhabdoid phenotype. Basaloid carcinoma is a variant of large cell carcinoma presenting with relatively small cells, forming a lobular pattern with a high rate of mitosis. It is also known as giant cell carcinoma and clear cell carcinoma. NSCLC and basaloid carcinomas may display neuroendocrine histochemical markers. Apart from morphologic appearance, the presence of cytokeratins can differentiate basaloid tumors from large cell neuroendocrine carcinoma.
Carcinoma with pleomorphic or sarcomatous elements is poorly differentiated NSCLC containing sarcoma or sarcoma-like elements. They are rare tumors, and their classification depends on the presence of cytokeratin expression.
TNM-7 STAGING SYSTEM
The seventh edition of TNM classification on cancer staging by the joint committee of the American Joint Committee on Cancer (AJCC) and International Union Against Cancer (UICC) has made recommendations for the classification of NSCLC, SCLC, and carcinoid tumors of the lungs.20 Sarcomas and other rare tumors are not included. The T-stage has been redefined in this edition (Table 12.3). Findings with a diameter smaller than 30 mm are defined radiologically as nodules, whereas those with a diameter greater than 30 mm are defined as masses. Both pose challenges for the diagnosis of lung cancer. No changes have been made to the N-stage classification, but the M-stage has also been redefined.
SUMMARY OF CHANGES IN THE SEVENTH TNM CLASSIFICATION
On computed tomography (CT) examination, lymph nodes measuring 1 cm or more in the short axis are considered significant in size and suspicious for metastatic disease, although the predictive accuracy of this criterion is limited. Two lymph node maps are currently in use: The Naruke map, which is used by the Japanese Lung Cancer Society, and the Mountain–Dresler—American Thoracic Society map.21,22 To reconcile the differences between these two systems, existing nodal stations have been grouped into six anatomic zones: Upper, aortopulmonary, subcarinal; lower, hilar, and peripheral. The hilar and peripheral zones represent N1 disease, and the upper, aortopulmonary, subcarinal, and lower zones represent N2 disease. Lymph nodes on the side opposite the primary tumor, and all significantly large lymph nodes in the ipsilateral or contralateral supraclavicular or scalene regions, are considered stage N3 disease. In recent years, nodal skip metastases, particularly the presence of N2 disease in the absence of N1 disease, are thought to occur most frequently in the presence of upper lobe tumors and are reported to have a more favorable outcome.23,24
Nearly one-half of newly diagnosed lung cancers already have metastasized to the lung, brain, liver, adrenal gland, and osseous structures. Any metastatic disease is automatically designated stage IV disease and, with a few exceptions, is surgically unresectable. Because of differences in prognosis, the M category is now subcategorized into intrathoracic metastasis (M1a) and disseminated disease involving extrathoracic spread (M1b), with the former having a better prognosis.25 Stage M1a disease includes malignant pleural effusions, pleural dissemination, pericardial disease, and pulmonary nodules in the contralateral lung. Stage M1b disease involves spread to the liver, adrenal gland, brain, bone, and other locations away from the chest. Malignant pericardial and pleural diseases are now considered to be metastatic (M1a) disease, rather than stage T4 disease.26
In patients with low T-stage tumors and N0 disease, skip metastases are reported as synchronous cerebral metastases.24
USING RADIOTRACERS TO IMAGE LUNG CARCINOMAS
Historically, a fair number of nonspecific tracers have been used in nuclear medicine to image lung cancer of all types. 67Gallium (Ga) is taken up by more than 90% of lung cancers but is of limited value in lesion characterization because it does not distinguish malignant pulmonary masses from benign inflammatory processes. 201Thallium chloride (TlCl), a cardiac potassium analog imaging agent, has been used to investigate lung lesions, with similar nonspecificity. Since the late 1980s, when technetium-99m-labeled methoxyisobutyl isonitrile (99mTc-MIBI) was introduced as a myocardial imaging agent, there have been many descriptions of 99mTc-MIBI uptake in tumors, including lung and breast adenocarcinoma, lymphoma, mediastinal and pulmonary metastases from thyroid cancer, peripheral soft tissue and bone sarcomas, as well as undifferentiated mesenchymal tumors.27 99mTc-MIBI accumulates within mitochondria and the cytoplasm of cells on the basis of transmembrane electrical potentials. Since malignant tumors maintain a more negative transmembrane potential because of their increased metabolic requirements, there is an increased accumulation of MIBI in malignant tumors. Initially, it was thought that 99mTc-MIBI uptake, like that of 201thallium (Tl), is a reflection of blood flow, viability, and tumor mitochondrial activity. In cell cultures, P-glycoprotein (Pgp), a 170-kDa cytoplasmic membrane protein encoded by the MDR (multiple drug resistance) gene, has been identified. This protein results in decreased cytotoxic drug (anthracyclines, vinca alkaloids, epipodophyllotoxins, colchicine, and actinomycin D) accumulation. It also recognizes 99mTc-MIBI, with its lipophilic cationic properties, as a suitable transport substrate. It is now known that 99mTc-MIBI is excluded from the cytosol against its concentration gradient via the Pgp mechanism. Piwnica-Worms et al. have reported that 201Tl is not recognized as a substrate by Pgp. Decreased uptake of 99mTc-MIBI on scintigraphy is important from the clinical point of view.28 Imaging Pgp expression by scintigraphy with 99mTc-MIBI is an example of functional imaging. This information is in combination with the fact that a patient will fail to respond to chemotherapy after the first cycle (such failure is observed in 15% of patients with SCLC).29 This implies the presence of Pgp-mediated MDR in the tumor that limits 99mTc-MIBI concentration by acting as an efflux pump. The absence of 99mTc-MIBI uptake on scintigraphy may have an impact on the selection of the therapy, necessitating a more aggressive protocol or the augmentation of response by involving radiotherapy. In summary, 99mTc-MIBI scintigraphy may be utilized to monitor “acquired” drug resistance induced by chemotherapy. However, 99mTc-MIBI uptake in a tumor in the absence of MDR1 expression does not necessarily indicate that a cancer is sensitive to drugs associated with the MDR phenotype because there are various other mechanisms for resistance to multiple drugs, for example, changes in the activity of enzymes such as glutathione S-transferase (which is involved in glutathione detoxification) or alterations in topoisomerase II. Resistance also can be induced by overexpression of multidrug resistance-associated protein (MRP 190 kDa) in multidrug-resistant cell lines derived from SCLCs, but a direct interaction between MRP and drugs or 99mTc-MIBI as a substrate has not been demonstrated.30 Prospective studies are being conducted to determine the significance of scintigraphic imaging of Pgp expression in tumors to predict the response to therapy.
18F-FDG PET And PET/CT
Traditionally, imaging modalities such as CT and positron emission tomography (PET) have been applied sequentially in the diagnosis, staging of disease, and monitoring the effects of therapy. Nevertheless, the use of separately acquired CT and 18F-fluorodeoxyglucose (18F-FDG) PET interferes with lesion characterization. Since their introduction in 2001, PET/CT systems have gained wide acceptance primarily because of their inherent ability to combine functional and structural information about the underlying disease state of the patient in a single imaging session. The combined imaging technique has the advantage of shorter total imaging time, which reduces patient anxiety and image blurring because of patient motion. PET/CT systems have replaced dedicated PET systems as the imaging modality of choice for the diagnostic evaluation of oncology patients in general. The use of the glucose analog, 18F-FDG, reports cellular processes in tumors such as glucose metabolism with precise anatomical localization when acquired on a PET/CT instrument. The extensive implementation of 18F-FDG PET/CT has allowed more accurate detection of both nodal and distant forms of metastatic disease.31 Other PET radiopharmaceuticals also show remarkable potential in management of patients with malignant tumors.
18F-FDG is a glucose analog in which the oxygen atom at carbon number 2 is replaced by the radionuclide fluorine-18. 18F-FDG enters cells and is then phosphorylated to glucose-6-phosphate by mitochondrial enzymes that are increased in rapidly growing malignant tumors. Metabolism beyond the fluorodeoxyglucose-6-phosphate step does not occur because the altered molecule is an unsatisfactory substrate for the enzymatic processes beyond that point.
In addition to imaging the relative glucose metabolism and localizing it to anatomic structures, PET/CT has the additional advantage of attenuation correction of the PET signal (Fig. 12.1A and B), rendering PET/CT capable of quantitative imaging. The new integrated system is capable in delivering higher quality images with improved resolution.
FIGURE 12.1. Coronal, sagittal, and axial views (LEFT TO RIGHT) of PET images in grayscale showing uncorrected images (top row ) and attenuation-corrected images (bottom row ). These demonstrate poor resolution of the nonattenuation-corrected image (A) and improved resolution and normalization of the attenuation-corrected image (B) using CT parameters. (Images courtesy of Pusat Pengimejan Diagnostik Nuklear, Universiti Putra Malaysia, Serdang, Malaysia.)
The widely recommended protocol for a PET study is the intravenous injection of 370 to 740 MBq (10 to 20 mCi) of 18F-FDG (for an adult patient) after obtaining a fasting blood sugar to confirm that the blood glucose level is at an acceptable level to proceed. Specific recommendations, precautions, and potential sources of error for PET or PET/CT scans are provided in Tables 12.4 and 12.5. Prior to intravenous administration of the radiotracer, the weight of the patient should also be recorded. These essential parameters are important for the accurate calculation of the standardized uptake value (SUV), a recognized method to semi-quantify the tumor glucose metabolic rate. PET/CT image acquisition usually starts 45-minute post injection to ensure good FDG uptake and distribution in the body. Image acquisition starts with a low-dose CT scanogram to plan the study. For patients being evaluated for potential or proven lung malignancy, this is followed by a CT scan examination from base of skull to thigh. Subsequently, PET study will commence. PET images are acquired in two-dimensional (2D) or three-dimensional (3D) mode with 2 to 3 minutes per bed position ending with 5 to 7 bed positions, depending on the dose administered and size of the patient. Tall patients may require more time to complete the base of skull and thigh protocol as compared with shorter individuals. This recommended technique is adopted with minor variation from one institution to another depending on camera specification and workload.
Implication of 18F-FDG PET/CT for the Radiation Dose
The eyes to thigh protocol during PET/CT examinations incurs an increased patient exposure compared with an individual CT or PET examination. Recent advances in CT equipment provide high-resolution imaging of smaller anatomical structures but resulting in higher radiation dose delivered to the patients. Increasing concern over radiation dose has been addressed by vendors through technical improvement of x-ray tubes.
The average effective patient dose from whole-body 18F-FDG PET/CT examinations is approximately 25 mSv regardless of the acquisition protocol used. Although whole-body PET/CT scanning has improved accuracy in clinical staging and treatment monitoring of patients with lung cancer, the technique is also accompanied by substantial radiation dose and theoretical cancer risk. “Diagnostic” CT performed during a PET/CT study ultimately gives the same result as a “diagnostic” CT performed alone. Importantly, avoiding duplication of studies also reduces the overall radiation exposure. In the evaluation of patients known to have cancer, although cancer risks from radiation may be of less significance, the information is still of interest and relevant to patients.32
Normal Distribution of FDG in PET/CT
A patient who has fasted overnight will demonstrate a low-level background activity throughout the body, with intense physiologic FDG uptake in the brain as well as activity in urine and the urinary collecting system and bladder. Depending upon the duration of fasting and other metabolic factors, the left ventricular myocardial may or may not be visualized, independently of coronary artery disease comorbidity. The liver and the spleen will demonstrate intermediate-intensity uptake (see Fig. 12.1B). Aside from qualitative interpretation of the 18F-FDG distribution in a whole-body PET/CT study, the intensity of 18F-FDG uptake can be quantified as the SUV. The SUV is a parameter that corrects absolute radioactivity per gram of tissue for the amount of radioactivity administered, radioactive decay, and the size of the individual.
To a certain extent, this semiquantitative scale of 18F-FDG accumulation in tissue helps distinguish between benign and malignant lesions and the degree of aggressiveness of tumors using the maximum standardized uptake value (SUVmax). In general, a cutoff SUV of around 2.5 is useful to separate benign from malignant processes, but some malignant tumors can have an SUV of less than 2.5 whereas active inflammatory processes have SUVs higher than 2.5. During qualitative or visual interpretation of an 18F-FDG PET/CT study, the pitfalls and physiologic uptake must be considered to avoid false-positive interpretations. Despite an overall high sensitivity of 18F-FDG PET/CT to detect tumor sites, some malignancies do not vigorously accumulate 18F-FDG (i.e., BAC or carcinoid tumors). False-positive lesions (i.e., granulomatous diseases such as tuberculosis, fungal infections, or sarcoid-like lesions) may create problems for an inexperienced interpreter (Fig. 12.2).
18FDG PET/CT: IMAGE INTERPRETATION: POTENTIAL SOURCES OF ERRORa
FIGURE 12.2. A 56-year-old woman whom presentation was suspicious for a recurrent ovarian carcinoma (hairline) underwent 18F-FDG positron emission tomography (PET)–computed tomography (CT). FDG PET (coronal) revealed incidental findings of faint FDG uptake of a benign sarcoid-like lesion in the hilar regions mimicking metastatic lymph nodes (arrows ). (Image courtesy of Peter MacCallum Cancer Centre, Melbourne, Australia.)
Small pulmonary lesions may have a low 18F-FDG SUV, which does not reflect the glucose metabolism because of partial volume artifact.33,34 For a small volume of pulmonary nodules, qualitative analysis of the lesion might be more reliable, perhaps by comparison to the mediastinal blood pool (Fig. 12.3).35,36
Standardized Uptake Value in Lung Carcinoma
The use of Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria to assess a lesion has many limitations. The established assessment of lung nodules with conventional imaging techniques is based on size and morphologic changes, which do not assess intracellular metabolic changes that are important to identify malignant cells or determining the response to treatment. It should be revised to include assessment of intrinsic metabolic changes.37,38 Other limitations of structural imaging in NSCLC are well known. Tumors may be obscured by atelectasis and, after radiotherapy, may be indistinguishable from radiation pneumonitis.39 In addition, lymph nodes larger than 1 cm are denoted as containing tumor based on CT imaging without reference to the metabolic characteristics that precede morphologic changes. 18F-FDG SUV exhibits a change in cellular metabolism earlier than change in tumor size and is complementary to the high-resolution structural imaging data available from CT or magnetic resonance imaging (MRI).40
FIGURE 12.3. Reconstructed axial images in (BOTTOM LEFT and moving clockwise) positron emission tomography (PET), computed tomography (CT), fused PET/CT (in lung window setting), and multiplanar image projection (MIP) demonstrating an irregular mass with high FDG uptake in the right lung. Two subcentimeter nodules are seen in the anterior segment (black arrow ), which are non-FDG avid. Poor spatial resolution of PET camera can lead to false-negative interpretation of small lesions below the camera’s resolution. (Images courtesy of Pusat Pengimejan Diagnostik Nuklear, Universiti Putra Malaysia, Serdang, Malaysia.)
In a meta-analysis of 13 studies in patients with NSCLC, Berghmans et al.41 reported that the primary tumor SUV measurement was found to have a prognostic value. 18F-FDG SUV PET is useful in the initial assessment of lung nodules and masses and in the assessment of treatment response.
Assessment of the metabolic response by 18FDG PET, however, has no clear guidelines, but it can be assessed by qualitative or semiquantitative methods.42,43 MacManus et al.44 have recommended a scheme based on the visual interpretation of a tumor response on 18F-FDG PET.
A complete metabolic response is defined as a return of 18F-FDG SUV in previously documented lesions to a level of equivalent to or lower than the activity in normal tissue. Partial metabolic response constitutes a significant reduction in 18F-FDG PET uptake in tumor sites on visual analysis (Fig. 12.4). Progressive metabolic disease is determined by an increase in the extent of metabolic abnormality suggestive of the tumor growth, or evidence of new sites of disease, whereas stable metabolic disease is defined as lack of change.
The SUV, despite being a unitless metric, is the preferred parameter to assess therapeutic response. The SUV is determined by dividing the measured radioactivity in tissue by the total activity administered to the patient’s weight after synchronization of correction factors. High 18F-FDG uptake denotes an increase in the utilization rate of glucose (MRGlu). SUVmax has been shown to be more accurate than SUVmean and tumor volume–corrected SUV. Regardless of the methodology used, a reduction in 18F-FDG uptake in lesions implies a favorable response to treatment. The utility of 18F-FDG PET has been influenced by the observation that resolution of metabolic activity has a good prognosis. Nevertheless, the exact timing for a repeat 18F-FDG PET/CT scan is important as the early changes of the lesion posttreatment are crucial in determining the efficacy of treatment instituted. An evolving new guideline looking at the metabolic changes as a yardstick for posttreatment evaluation of a solid tumor has been suggested (i.e., PET response evaluation of a solid tumor). However, additional work is necessary before this new criterion is accepted.45 RECIST, however, has the potential to characterize tumor cell metabolism and is basically different from that based solely on anatomic imaging.
In 73 patients, evaluated with both PET and diagnostic CT scans, before and at a median interval of 70 days after treatment, an early, posttreatment 18F-FDG PET scan is a better predictor of survival than CT response, stage, or pretreatment performance status.46 In a prospective study of 105 patients with NSCLC, 18F-FDG PET scanning changed or influenced management decisions in 70 patients (67%) with NSCLC (Fig. 12.5).
FIGURE 12.4. Examples of discordant positron emission tomography (PET) and computed tomography (CT) results. Upper panels show pretreatment CT (LEFT) and posttreatment CT (RIGHT) images of a mediastinal lymph node, which did not regress in size on the follow-up study after 2 months. CT indicated partial response. Lower panels show corresponding PET images before and after radical chemoradiation; PET showed complete response. (Images courtesy of Pusat Pengimejan Diagnostik Nuklear, Universiti Putra Malaysia, Serdang, Malaysia.)
Because of the limitations of CT scanning, 18F-FDG PET/CT scanning may also have a role in response assessment after induction therapy prior to surgery, particularly for stage IIIA NSCLC. Choi et al.47 found that the residual metabolic rate of glucose (MRglc) as measured using FDG PET was strongly correlated with response to preoperative chemoradiotherapy in locally advanced NSCLC as assessed by pathologic examination of tumors obtained at thoracotomy. Selected patients with NSCLC have a chance for long-term survival and even cure with radical radiotherapy, provided distant metastases are absent.48 Although results have been improved by combining chemotherapy with radiotherapy, survival has remained poor.49,50
A study evaluating serial changes in the SUV during chemotherapy for NSCLC in 16 patients demonstrated that a 50% or greater reduction in the SUVmax between studies performed after 1 and 3 weeks of therapy was predictive of the survival of patients for more than 6 months, whereas patients with a less marked SUV reduction died within 6 months.51 A similar study of 15 patients receiving radiotherapy demonstrated that the peak residual 18F-FDG activity and qualitative response obtained during treatment correlated with the overall response obtained 3 months after treatment.
FIGURE 12.5. Computed tomography (CT) and positron emission tomography (PET) coronal images. A 54-year-old man had completed radiotherapy of the right lung for a recurrent non–small cell lung cancer. The images show a typical dome-shaped consolidative change in the right upper lobe with increased FDG accumulation in radiation pneumonitis. (Images courtesy of Peter MacCallum Centre, Melbourne, Australia.)
18F-FDG PET/CT may have wide application in measuring treatment response in oncology. Because prognostic information can be obtained at a relatively early time point, therapies could potentially be tailored depending on information obtained from the completeness of PET response. CT scanning alone may underestimate the activity of novel antitumor agents, and this could lead potentially to mismanagement and risk of treatment toxicity or futile surgery.
As mentioned above, the SUV is a semiquantitative method for evaluating a lesion’s metabolic rate. Its efficacy in lesion characterization, prognostication, and monitoring treatment response has been documented.52 A number of physiologic, physical, and procedural factors, however, can influence the SUV (Table 12.6). Besides dose administration, uptake time, body composition, blood glucose level, and renal function should be monitored consistently to achieve accurate results especially when comparison is made between scans and to monitor disease progression. The traditional cutoff value of SUVmax of 2.5 should be used with caution. It is known that there may be a 15% to 20% variation in the rate in the SUV in primary lung cancer among different centers and different PET/CT equipment. These differences may cause erroneous conclusions in follow-up of patients with SCLC at different centers. Ilker et al.53 reported PET/CT and mediastinoscopy and/or thoracotomy performed in 337 consecutive patients from four different centers, with a known or suspected diagnosis of NSCLC, who were found to have the optimal SUV cutoff of 2.75 in their study, with 88% accuracy. The group concluded that this value is compatible with the traditional SUV of 2.5. Thus, the SUV is valuable for comparing centers and is especially useful in the evaluation of larger nodules (>1 cm), with minimal or no value in the evaluation of smaller nodules of less than 1 cm in diameter.54 In clinical practice, it is highly recommended to adhere to strict acquisition and analysis protocols with regular quality assurance to maintain SUV reproducibility in a given patient over time.
FACTORS INFLUENCING STANDARDIZED UPTAKE VALUEa
PET/CT EVALUATION OF LUNG NODULES
18F-FDG PET and CT have been found to be promising tools to differentiate benign from malignant pulmonary nodules.16–18 More than 150,000 solitary pulmonary nodules (SPNs) are identified each year on conventional chest radiographs,13 and the number of indeterminate SPNs is becoming larger because widespread use of low-dose CT for lung cancer screening.55,56 Suspicious SPNs are biopsied to determine the diagnosis.
Malignant pulmonary nodules demonstrate higher 18F-FDG uptake in PET and PET/CT studies than benign nodules (Fig. 12.6). During qualitative assessment of pulmonary nodules, the intensity of 18F-FDG uptake should be compared with the mediastinal blood pool. The specificity of this approach to detect malignant nodules is found to be 76% as compared with using the SUV, considering 2.5 the cutoff value of the SUVmax to distinguish malignant from benign nodules57,58 or to proceed to a more invasive approach. The sensitivity and specificity of an 18F-FDG PET to characterize SPNs was found to be higher (96.8% and 77.8%) than contrast-enhanced CT, albeit well-established CT features of benign and malignant nodules have been described.
One CT criterion is the size of nodule (>1 cm in diameter). This is an inclusion criterion rather than exclusion as subcentimeter nodules have been found to demonstrate 18F-FDG avidity in PET studies. However, other benign CT features of pulmonary nodules can be exploited in excluding malignancy such as visual evidence of calcium deposits where CT value using a Hounsfield unit can suggest the nature of pulmonary nodules. The sensitivity of CT in detecting malignant nodules is 100%. The higher specificity of 18F-FDG PET (76%) than CT (26%) can ultimately lead to reduced number of biopsies and surgical interventions avoiding unnecessary, high-risk invasive procedures.
Although the functional status of lung nodule assessment in PET claims several advantages over morphologic imaging in CT, there are two limitations of 18F-FDG PET to detect malignant lung nodules. The current PET scanner technology has limited intrinsic resolution. This limitation results in false-negative results when assessing smaller nodules. Because 18F-FDG is a nonspecific tracer, nodules that originate from chronic granulomatous inflammatory and infectious conditions are well-known sources of false-positive interpretation in 18F-FDG PET and PET/CT studies. Thus, in the evaluation of pulmonary nodules, a thorough combined interpretation of results obtained during a contemporaneous PET/CT study is strongly recommended to overcome the limitations of low CT specificity and limited PET sensitivity. This can save cost and time and optimize the use of both modalities in a single seating. Detailed morphologic characterization of pulmonary nodules on CT and MR should be taken into consideration in the assessment of suspicious malignancy where nodules found with negative SUVmax or less than the blood pool are recommended for subsequent workup.
FIGURE 12.6. Reconstructed multiplanar view in coronal, sagittal, axial, and multiplanar image projection of a patient diagnosed with non–small cell lung cancer (LEFT TO RIGHT). There is a lung nodule seen in the left upper lobe. The nodule demonstrates high FDG uptake. Apart from malignant lung lesions, chronic granulomatous lesions such as active tuberculosis infection and fungal infection potentially lead to false-positive interpretation of FDG-avid lesions, mandating tissue diagnosis for confirmation. (Images courtesy of Pusat Pengimejan Diagnostik Nuklear, Universiti Putra Malaysia, Serdang, Malaysia.)
PET/CT IN EVALUATION OF LUNG MASSES
An integrated 18F-FDG PET with a CT study performed for the diagnostic investigation can provide more information in the overall staging of NSCLC than either study performed separately.12,14,15,59 18F-FDG PET/CT improves lesion localization during staging and restaging, thus improving accuracy. The “one-stop-shop” concept of PET/CT investigation allows a complete TNM staging, with a whole-body protocol adopted during the study, which covers from the eyes to the thigh. The surgical resectability decision depends on the extension of the primary malignant mass.
There are several challenges to determine tumor resectability based on initial staging with either modality alone. The tumor outline is an important consideration. Tumor masses should be differentiated from distal atelectasis, which is often seen as peritumoral opacities in CT images. These accompanying changes in lung parenchyma can overestimate the tumor size. This important information is responsible for the planning of radiotherapy where it can potentially influence the targeted radiation field. Integrated dual-imaging modality PET/CT using 18F-FDG as a biomarker has been shown to be an excellent tool to demonstrate a hypermetabolic malignant lesion from surrounding normo- to hypometabolic peritumoral atelectasis (Fig. 12.7). Thus, 18F-FDG PET/CT is helpful in planning radiotherapy portals and in reducing radiation toxicity to surrounding normal tissues.
On the other hand, a peripheral tumor mass may invade the pleura, ribs, and intercostal muscles. A mass arising from the mediastinum needs careful assessment to exclude invasion into vital structures. PET has no real advantage over CT for chest wall or mediastinal invasion. 18F-FDG PET images are limited by poor anatomical resolution, making assessment of tumor extension unreliable. Higher spatial resolution of multidetector CT scan during an integrated PET/CT study can provide useful information by delineating low-attenuation fat planes, separating the tumor mass from structures in the vicinity. Invasion may be excluded by demonstration of the preserved fat plane. Advanced T3-stage malignant vascular invasion of large arteries and veins can be demonstrated by an intraluminal filling defects on CT. These CT features are added value to PET-derived information to identify tumors suitable for surgical resection during a contemporaneous PET/CT study, including morphologic evidence of circumferential contact of mass to thoracic aorta. By optimizing information acquired from the integrated contemporaneous study, the exact demarcation of the tumor outline potentially improves T3 and T4 staging.
18F-FDG PET/CT for T Staging of Lung Cancer
CT is the predominant modality to stage patients with NSCLC. Advances in clinical staging techniques also have affected the accuracy of staging with the advent of endoscopic ultrasonography (US), endobronchial US, endoscopic US-guided fine-needle aspiration, and endobronchial US-guided transbronchial needle aspiration for the evaluation of mediastinal disease, which has made minimally invasive tumor staging possible.60 However, 18F-FDG PET and PET/CT have become more established and are widely available and cost-effective alternatives for preoperative staging.61 18F-FDG PET has assumed an integral role in the staging of NSCLC in patients who may be eligible for surgery, with pooled sensitivity and specificity values of 74% and 85%, respectively.62 Integrated PET/CT also provides better metabolic and anatomic information for tumor staging than does isolated CT and FDG PET and provides even greater accuracy.59 Results from 18F-FDG PET in lung cancer staging, a multicenter randomized trial, indicated that PET is able to depict intra- and extrathoracic metastases, findings that prevent unnecessary thoracotomy in 20% of patients.63 In this way, it better responds to the requirements of the seventh edition of the TNM classification system which includes a number of revisions, including subdivision of tumor categories on the basis of size, differentiation between local intrathoracic and distant metastatic disease, recategorization of malignant pleural or pericardial disease from stage III to stage IV, reclassification of separate tumor nodules in the same lung and lobe as the primary tumor from T4 to T3, and reclassification of separate tumor nodules in the same lung but not the same lobe as the primary tumor from M1 to T4.
FIGURE 12.7. Multiplanar reconstructed images of positron emission tomography (PET) (lower row), computed tomography (CT), and fused PET/CT (upper row) in a patient diagnosed with non–small cell lung cancer demonstrating an irregular heterogeneous mass in the left upper lobe, abutting against the posterior thoracic wall. The outline is well defined and separated from the adjacent rib. There is a “tail” connecting the mass to the mediastinum. On PET and fused PET/CT, there is no FDG uptake within the “tail” (red arrow on CT image) as compared with intense FDG uptake within the tumor mass. Peritumoral atelectasis often causes overestimation of tumor size and extension on CT images. (Images courtesy of Pusat Pengimejan Diagnostik Nuklear, Universiti Putra Malaysia, Serdang, Malaysia.)
Traditionally, the TNM staging classification has not been applied to lung NETs. Because TNM has been recently found to be useful to assess NETs, the IASLC has recommended that the TNM be applied to pulmonary NETs.64
18F-FDG PET/CT for N Staging of Lung Cancer
Accurate mediastinal staging is crucial in NSCLC. The N stage is an important determining factor for prognosis and selection of treatment. Despite poor sensitivity and specificity in identifying mediastinal metastasis, small mediastinal lymph nodes found on CT scan have been proven to harbor metastatic disease.65 Before 18F-FDG PET/CT was available, cervical mediastinoscopy using the modified Mountain–Dresler map was performed in patients with NSCLC for histopathologic evidence of malignant involvement.66
Alternatively, transbronchial, transesophageal, or transtracheal fine-needle aspiration procedures can be performed. Because the latter techniques are found to have a lower sensitivity and negative predictive value, mediastinoscopy remained the gold standard in the evaluation of N stage in patients with NSCLC, with a sensitivity rate of 90% and specificity of 100%, if nodal stations were accessible. An exception to this are patients with evidence of metastases and stage N0 where 18F-FDG PET replaced mediastinoscopy because the procedure is noninvasive and was found to give a high negative predictive value (93%) in primary mediastinal staging.67 It is generally accepted that 18F-FDG PET/CT shows higher accuracy to stage lymph nodes in NSCLC than any of CT or PET study performed alone.
A meta-analysis involving 570 studies found 18F-FDG PET more accurate than CT for mediastinal staging in patients with NSCLC.68–71 The sensitivity of CT is about 59% and the specificity is 79%, lower than that of 18F-FDG PET (81% and 90%, respectively). However, 18F-FDG PET is not perfect either. The study is prone to give false-negative results particularly in cases where the nodal size is below the system’s highest resolution, possible micrometastasis or close proximity of involved nodes to a large tumor mass. Therefore, negative 18F-FDG PET findings should be interpreted in the light of the patient’s pretest probability of mediastinal metastasis and whether the CT reveals enlarged mediastinal lymphadenopathy. A meta-analysis involving 14 studies showed 5% pretest probability of N2 disease for nodes measuring 15 mm or less on CT with negative FDG PET result. This group of patients is recommended for thoracotomy because the yield from mediastinoscopy is expected to be very low.72
For patients with a mediastinal node measuring 16 mm and above on CT and negative 18F-FDG PET findings, the result of pretest probability for N2 disease is 21%. Mediastinoscopy is recommended for this group of patients.15Taken together, mediastinoscopy is required in all patients without evidence of distant metastases, with a cutoff transaxial nodal diameter of 1.5 cm.
Lower accuracy of 18F-FDG PET/CT in mediastinal staging is also expected in countries with high prevalence of inflammatory lung lesions such as tuberculosis.73 In these cases, the major problem with PET/CT is inadequate specificity for mediastinal staging, although the modality is more efficient than CT. Anthracosis, follicular hyperplasia, and granulomatous inflammation are other common etiologies accounting for these false-positive lymph nodes.
Recent studies have reported that the dual-phase 18F-FDG PET/CT protocol improves the diagnostic efficacy to differentiate benign from malignant lesions.74,75 According to this end, authors assessed lesion SUV at first and delayed scan (respectively at 1 hour and 3 hours). They reported the utility of index retention SUV (RI SUV) evaluation, that is based on the SUVs values obtained for each phase, by using the following equation:
RI SUV (%) = (SUV [delayed scan] - SUV [early scan]) × 100/SUV (early scan)
18FDG PET/CT for M Staging of Lung Cancer
18F-FDG is the most commonly used tracer with a PET or PET/CT system in initial staging of lung cancer. NSCLC without distant metastases is potentially curable. The likelihood of metastases increases with higher T stage, in patients with laboratory evidence of metastatic disease and with histology of adenocarcinoma. The most common metastatic sites are the brain, bones, adrenal glands, lung, and liver. However, virtually any organ can be the site of metastatic disease.
FIGURE 12.8. Transaxial computed tomography (CT) and fused positron emission tomography (PET)–CT images in a patient diagnosed with lung cancer showing a left suprarenal mass (arrow ) with high FDG uptake in keeping with distant metastasis. (Images courtesy of Pusat Pengimejan Diagnostik Nuklear, Universiti Putra Malaysia, Serdang, Malaysia.)
In a study involving 170 patients with NSCLC, preoperative staging with 18F-FDG PET/CT and cranial imaging identified more patients with mediastinal and extrathoracic disease than conventional staging, thereby sparing more patients from stage-inappropriate surgery. In another study, 18F-FDG PET reduced the number of futile thoracotomies from 46% (using conventional workup) to 25% in clinical stage I to II tumors and from 29% to 11% in patients with clinical stage III tumors.70,76
Brain metastases are found in up to 18% of NSCLC cases, but physiologic FDG uptake in brain parenchyma can obscure abnormal 18F-FDG activity. Thus, in cases with suspected cerebral metastases, additional MRI or contrast CT is appropriate.
Adrenal metastases can occur in up to 20% of patients at presentation.71 On PET/CT imaging, finding of 18F-FDG activity higher than the liver is a sign of metastatic disease. The overall diagnostic accuracy is 92%. False-positive findings can be found in adrenal adenomas, and a false-negative result can be seen in smaller metastases (Fig. 12.8).
Bone metastases are found in 20% to 30% of patients at initial diagnosis of lung cancer, and they are usually osteolytic lesions. Planar bone scintigraphy has moderate sensitivity to detect bone metastases and often gives a false-negative result especially in the spine and pelvis. Nevertheless, the technique is better than MR to detect metastases involving the skull and the ribs. 18F-FDG PET/CT is excellent to detect osteolytic lesions but not osteoblastic metastasis (Fig. 12.9). PET using 18F-fluoride as sodium fluoride is highly sensitive to detect both types of metastatic lesions. The diagnostic accuracy of 18F-FDG PET/CT and 18F-labeled sodium fluoride to detect bone metastases in NSCLC is the best technique to detect both types of bone metastases. 18F-fluoride has higher diagnostic accuracy than 99mTc bone scintigraphy. The accuracy of 18F-FDG to detect bone metastases is 96% compared with bone scintigraphy. Thus, bone scintigraphy can be eliminated if 18FDG PET/CT is performed for staging.77
FIGURE 12.9. Reconstructed transaxial images at the level of pubic bone (top row ) and right shoulder (bottom row ) in two settings: Computed tomography (CT) (LEFT) and fused positron emission tomography (PET)–CT (RIGHT) demonstrating well-defined lytic lesions (white arrow ) corresponding with high 18F-FDG uptake. Glycolytic process is markedly raised in osteolytic bone metastases translated into high FDG uptake at these sites. Morphologic changes on CT validate the PET findings and vice versa. (Images courtesy of Pusat Pengimejan Diagnostik Nuklear, Universiti Putra Malaysia, Serdang, Malaysia.)
18F-FDG PET is an improved method in the diagnosis of malignant pleural effusion with better results, eliminating high-risk invasive thoracotomy procedures. The diagnostic accuracy of 18F-FDG PET imaging to detect pleural metastases has a high sensitivity (92% to 100%) and negative predictive value (100%) but only a specificity of 67% to 71% and a positive predictive value of 63% to 79%.78
Overall, 18F-FDG PET imaging has been found to improve staging in NSCLC, leading to major changes in the treatment plan. In a prospective study involving 24 patients with NSCLC, 18F-FDG PET imaging upstaged 8.3% of patients with sensitivity and specificity for metastatic disease of 100% and 95.5%.79
18F-FDG PET/CT in Therapy Response Assessment
Treatment options for lung cancer and lung metastases include surgical resection, external beam radiotherapy, chemotherapy, targeted therapies (such as tyrosine kinase inhibitors), and thermal ablation procedures, such as radiofrequency ablation (RFA). Radiotherapy is one of the main treatment modalities for lung cancer. For locally advanced NSCLC and for nonmetastatic SCLC, fractionated radiotherapy combined with chemotherapy is the standard option.
Approximately two-thirds of patients with SCLC have extensive disease with hematogenous metastatic disease at the time of presentation. Only chemotherapy is suitable for these patients. Patients with tumors limited to one hemithorax, regional lymph node metastases involving hilar, ipsilateral, or contralateral mediastinal and supraclavicular lymph nodes, and ipsilateral pleural effusion (regardless of positive or negative findings) are treated with chemotherapy and radiotherapy.
In locally advanced NSCLC, imaging during treatment with adequate diagnostic tools such as CT with intravenous contrast, or even better with 18F-FDG PET/CT scans, has been performed.80,81 CT imaging is the standard method for response assessment, but with the new targeted therapies and chemotherapeutic drugs, assessment of tumor volume might not reflect an adequate treatment response. Furthermore, CT-based assessment is often not sensitive for early response evaluation. Because of fibrosis, the tumor diameter might not reflect the true reduction in viable tumor volume. Therefore, functional imaging is viewed as a suitable method to assess tumor response, frequently preceding morphologic changes seen on CT imaging.82
Assessment of the therapeutic response in NSCLC is primarily based on changes in the measured dimensions of lesions identified on CT. These changes are graded on the basis of definitions detailed in RECIST,38 which are modifications of earlier WHO response criteria.83 Both include definitions for a complete response, a partial response, stable disease, and progressive disease, which are based on the percentage change in lesion dimensions.
Response assessment with CT is especially unreliable in lung cancer because of the inaccuracy of initial lymph node staging. For the primary tumor, the confounding effects of atelectasis and of radiation pneumonitis and subsequent fibrosis compromise the definition of the dimensions of the primary lesion before and after treatment, respectively. Some of these limitations are compensated for by the use of serial CT during treatment. Further regression at a later time point is generally accepted as evidence of a therapeutic benefit, whereas an increase in size represents progression. However, some cancers have a very low doubling rate and therefore may not demonstrate appreciable enlargement for months and even years, whereas many aggressive cancers may grow in weeks. These circumstances confound the optimal timing of follow-up imaging and potentially lead to residual disease being unrecognized until it is too late for salvage therapy. Conversely, slow regression in lesion size after treatment may lead to the mistaken belief that there has been a poor response and prolong treatment or even to substitute more aggressive therapy.
18F-FDG PET/CT imaging is increasingly used for response assessment in lung cancer.84 Several reports have documented changes in 18F-FDG uptake.85 18F-FDG PET/CT has significantly higher accuracy than CT or stand-alone 18F-FDG PET to assess response. 18F-FDG uptake in the primary tumor is predictive of long-term survival and is a better predictor of therapeutic response than the volume change as measured with CT scans. SUVmax is a reproducible parameter and has therefore become the preferred parameter to assess the therapeutic response. One of the concerns regarding the use of the SUVmax as a parameter for response assessment is that it ignores changes in the distribution of a tracer within a lesion and in the extent of metabolic abnormality.
The optimal timing of 18FDG PET/CT scanning during a course of radiotherapy or concurrent chemotherapy has not been established. The earlier during treatment that scans are obtained, the more likely a change in therapy can be considered. When 18F-FDG PET scans are performed late during therapy, the 18F-FDG PET scans may be falsely positive because of radiation-induced inflammation, rendering it difficult to determine whether the treatment was effective. If 18F-FDG PET imaging is delayed and the tumor progresses, an opportunity to modify treatment has been lost.86
In contrast to NSCLC, SCLC generally responds very quickly to concurrent chemoradiotherapy. In a prospective study, van Loon et al.87 showed that both early CT and 18F-FDG PET response were predictive of survival. Residual 18F-FDG uptake after radiotherapy treatment is correlated with worse outcome.
Hypofractionated treatment schedules used in stereotactic body radiotherapy, with fractional doses ranging from 7.5 to 20 Gy, may lead to a false-positive finding on the posttreatment 18F-FDG PET scan.
In a pilot study involving 15 patients receiving induction chemotherapy or radiotherapy,88 seven patients with persistently elevated 18F-FDG uptake in the mediastinum developed early systemic disease and died, whereas seven of the eight patients with negative mediastinal 18F-FDG PET results remained free of extracerebral relapse. Even with the small number of patients studied, it was observed that patients with 18F-FDG PET downstaging had significantly longer cumulative survival than patients with a persistent mediastinal nodal abnormality, whereas a partial response on CT was not predictive of outcome.
There is no confirmed value for the degree of 18F-FDGmax reduction that is a reliable prognostic indicator. In a population of patients with stage III NSCLC, a postradiotherapy SUVmax reduction of 72% or more has been reported to have better overall survival and longer disease-free survival than those showing less than 72%. Although the pretreatment SUVmax has not been associated with survival outcome, reduction in the SUVmax was associated with disease control after radiotherapy for locally advanced NSCLC, observing that the greater the decrease in the SUVmax in the lesion (primary tumors or lymph nodes) with the highest SUVmax at diagnosis, the longer the overall survival. Currently, the American College of Radiology Imaging Network 6668/RTOG 0235 trial is prospectively evaluating whether the primary tumor 18F-FDG SUVmax shortly after definitive chemoradiation can predict long-term survival in inoperable stage II or III NSCLC. Greene et al.89 proposed that a complete response after high-dose radiotherapy, or concurrent chemoradiotherapy, is defined as the complete disappearance of all evidence of malignant disease or residual radiographic abnormalities at 3 and 6 months after completion of radiotherapy, which remains stable for an additional 6 months or more. A recent Dutch study confirmed the validity of metabolic response assessment up to 6 months after radiotherapy as a surrogate of survival. Timing of the first 18F-FDG PET scan as early as 3 months after radiotherapy was reported to predict survival and obtain information helpful in identifying patients who are at high risk for recurrence and to design additional salvage treatment.90
18F-FDG PET/CT has allowed more accurate detection of both nodal and distant forms of metastatic disease. This advance has been complemented by improved methods for sampling mediastinal nodes, including endoscopic ultrasound-guided biopsy, with many such studies providing complementary information. The consequences of more sensitive detection of metastatic disease are that fewer patients are likely to undergo futile thoracotomy and that more patients will be identified as requiring aggressive locoregional or systemic treatment. Molecularly targeted therapies are now increasingly being used for cancer. Inhibitors of epithelial growth factor receptor signaling are already in widespread use, and clinical studies are in progress to evaluate tumor glucose utilization to predict treatment response following epidermal growth factor receptor kinase inhibitors.91–94
RFA of lung lesions has gained increasing acceptance as a viable alternative for the treatment of pulmonary malignancies in patients who are unable to undergo surgery or for palliation of patients’ symptoms.
Okuma et al.95 have shown a decrease in tumor 18F-FDG uptake to the background level at 1 day after RFA treatment. Inflammation, including the migration of inflammatory cells into tissue surrounding the ablation zone, is a process that takes several hours.
Dual-time-point 18F-FDG PET imaging has been suggested as a method to better differentiate between cancer and inflammatory changes.96 The underlying hypothesis is that cancer tissue is characterized by a continued increase in 18F-FDG uptake, whereas inflammatory cells show either no significant change or some tracer washout between the first and second scans.
Singnurkar,97 in his retrospective study, evaluated 68 consecutive patients with 94 lung lesions, including metastases and primary lung cancers, who underwent RFA and in whom 18F-FDG PET/CT was performed at baseline before therapy or during follow-up. 18F-FDG PET/CT may be useful to assess treatment response to RFA and to predict the likelihood of local recurrence. Pretherapy and posttherapy imaging features associated with local recurrence were identified. Among pretherapy findings, tumor size is a significant predictor of suboptimal treatment response with RFA, showing a lower recurrence-free survival in patients with tumors greater than 3 cm. However, this trend may be more a reflection of current technical limitations of RFA, rather than of tumor biology. In addition, as a factor not independent of lesion size, high pretherapy SUV has been observed as a predictor of local recurrence. Indeed, because partial-volume effects cause an underestimation of the true activity concentration in smaller lung tumors, lesions with greater size (in particular, greater than twice the resolution of the PET camera) tend to have higher SUVs.98 For these technical reasons, successful RFA is more difficult to confirm in larger lesions.
Postablation scans may reflect various patterns of 18F-FDG uptake: Diffuse, focal, heterogeneous, rim, and rim plus focal, with focal uptake either at a site of original disease or at another site. Rim uptake has been previously shown as a favorable indicator of normal postablation inflammation around the treated tumor. Other favorable uptake patterns included diffuse, heterogeneous, and rim plus focal uptake when the focal uptake did not correspond to the original tumor nodule. On this basis, the combination of rim plus focal uptake deserves further comment: A rim of 18F-FDG uptake with a superimposed hypermetabolic nodule, whose location corresponds to the original tumor nodule, indicates local recurrence, whereas superimposed focal uptake at a noncorresponding site more likely indicates heterogeneous inflammation around the ablated site.
Many experiences have been reported regarding interpretation criteria, as the capability of local tumor regrowth is likely when the reduction in SUV from baseline to follow-up study at 2 months after RFA is less than 60%. On the other hand, it seems reasonable to assume that minor reductions in SUV between the preablation and postablation scans indicate incomplete ablation of the lesion. In addition, the postablation SUV, by itself, has been hypothesized a better predictor of recurrence-free survival, in particular when persisting or increasing during follow-up. Such a pattern is suggestive of regrowth of viable tumors rather than chronic post-RFA inflammation. Response criteria such as RECIST fail in this situation because they rely solely on size in a situation in which the postablation mass is almost always larger than the original lesion. Some groups have used an arbitrary time interval of 6 months after ablation, after which any size increase is considered indicative of regrowth.99 Moreover, reliable assessment of post-RFA findings at 6 months may be too late because the opportunity for successful retreatment declines with time.
OTHER CHALLENGES OF PET/CT IMAGING IN LUNG CANCER
In lung cancer, the challenges in multimodality imaging are mainly because of motion artifact and the false-negative PET lesion of some NSCLC. The standard technique adopted by many PET users is the acquisition of the emission images during normal shallow breathing. Nevertheless, there is still a debate as to whether optimal attenuation maps are provided by obtaining CT scans during a breath-holding technique or during normal breathing.100 Respiratory motion results in inaccurate image fusion on PET/CT localization of lesions at the base of the lungs or the dome of the liver in about 2% of patients.101
Coaching patients to hold their breath at end-tidal volume during a CT examination can minimize artifacts from misregistration. Breath holding during maximum inspiration or maximum expiration is not recommended because doing so will increase the degree of misregistration artifacts. A gated respiratory system has been used to mitigate the breathing motion that blurred off the image acquisition.102 The system allows better localization of abnormalities near the borders between organs such as lung and liver, as well as for the detection of very small lesions that are “blurred” into the background activity by respiratory motion. Time-of-flight systems have increased sensitivity and may make it possible to reduce acquisition time sufficiently to improve single breath image acquisitions.103,104
In fact, in image coregistration, technical limitations are generally attributed to organ motion inducing image blurring and artifacts. These pitfalls can be improved by adoption of shallow breathing techniques during the sequential PET and CT scanning or improvement in the PET software systems. The shallow breathing techniques have been popular in practice in many PET/CT centers to reduce the artifacts generated at the diaphragm–lung interface. Nevertheless, a nondependent patient approach via 4D PET/CT technique based on product features is preferable over regulating patient breathing.
However, in 4D PET/CT image acquisition, the patient needs to be coached in order to relax in and breathe at a consistent rate. CT data are acquired first, followed by PET acquisition. The scanner acquires images at one phase of the patient’s respiratory cycle. The prospective gating creates a single volumetric image collected at a specific respiratory segment. In retrospective gating, the scanner acquires data continuously during all phases of the breathing cycle. The data are retrospectively assigned to a respiratory cycle phase and hence to the corresponding image in the respiratory cycle.
The impact of the 4D PET/CT has been shown in assessment of a small pulmonary nodule. In pulmonary lesions >1 cm, respiratory gating changed the SUVmax by 22.5%, without compromising the lesion size.105 4D PET/CT has also been used in radiotherapy planning for which the target lesion in question warrants an accurate localization for an effective treatment. Its use has facilitated the visualization of respiratory movement and reduces the tumor margins in the treatment beam.97
In the assessment of a smaller lesion, synchronized PET and CT data confer essential benefits to patients, whereby a small-volume lesion appears to be more conspicuous with profound increase in the SUVmax.106 In addition, as mentioned above, improvement in the PET detector technology such as the TOF may reduce motion artifacts and hence better characterize small lesions.107
Another challenge in 18F-FDG PET/CT imaging is the relative nonspecificity of increased glucose metabolism for malignancy. The dilemma of delineating a non–18F-FDG–avid lung tumor (i.e., BAC or carcinoids) is at times problematic when one has to differentiate between a less aggressive lesion (i.e., benign tumor) and a low-grade malignant lesion. There are also active inflammatory diseases that can have high 18F-FDG avidity where dual-time-point 18F-FDG PET imaging has been recommended to differentiate between the latter two.108,109
PET tracers that demonstrate an increased rate of cellular proliferation are likely to be particularly helpful in the setting of therapeutic monitoring because they are less likely to be taken up in inflammatory conditions. The search for proliferation markers has been active with most attention to thymidine analogs. To date, the most promising of proliferation tracer for clinical application appears to be 18F-fluorothymidine (18F-FLT).110 There is evidence that 18FLT uptake is closely correlated with cellular proliferation, with correlation between the intensity of uptake as measured by SUV with proliferation indices such as Ki-67 staining in suspected lung cancer lesions undergoing resection.111
In addition, 18FDG PET/CT uptake is related to epidermal growth factor receptor mutations, in predicting tumor response to treatment, which is a new advancement in clinical application of molecular imaging in personalized treatment delivery in patients with lung cancer.112
LABELED PEPTIDE SCINTIGRAPHY
[111Indium-DTPA-d-Phe1]-octreotide scintigraphy and 99mTc-depreotide have been used to detect and evaluate patients with known or suspected NSCLC and thoracic NETs including SCLC. High-affinity somatostatin receptors (SSTRs), in particular subtype 2 (SSTR2), have been demonstrated in vitro in a variety of human malignancies, including SCLC.113–124 Traditionally, SCLC has been hypothesized to originate from the so-called Kulchitsky normal cells with neuroendocrine characteristics found in the tracheobronchial mucosa,125 making it likely that tumor expresses SSTRs.
In some studies that explored the value of SSTR of different NETs, evidence was obtained that part of the normal immune system in the surrounding tissue and “activated” leukocytes, lymphocytes, and macrophages126 and labeled octreotide to tissue surrounding the tumor in NSCLC. Two mechanisms may be responsible for this: (1) A variety of white blood cells, but especially activated lymphocytes, shown to possess SSTRs,127,128 and (2) proliferation of neuroendocrine cells of the lung, leading to the formation of “tumorlets.”129 111In-octreotide is not specific for SCLC; it is positive for many other tumors, granulomas, and autoimmune disease involvement.130 SCLC cells possess both amine precursor uptake and decarboxylation (APUD) characteristics and represent the so-called APUD cells. The catecholamine analog meta-iodobenzylguanidine (MIBG) has a high affinity for adrenergic neurons. As this characteristic has been exploited in other APUD tumors, it has been postulated that this might be of value in scintigraphic imaging and staging of SCLC. Indeed, Nakajo et al.131 observed accumulation of iodine-131 labeled MIBG in such a tumor, but other studies failed to reproduce this result both for the primary tumor and for metastases.132
111IN-PENTETREOTIDE SOMATOSTATIN RECEPTOR SCINTIGRAPHY
111Indium pentetreotide (OctreoScan®) is [111In-DTPA-D-Phe]-octreotide, a standard somatostatin analog. The amount of pentetreotide injected per dose of OctreoScan® is 10 μg, with no clinically significant pharmacologic effect.
111IN-PENTETREOTIDE SOMATOSTATIN RECEPTOR SCINTIGRAPHY IMAGE INTERPRETATION: POTENTIAL SOURCES OF ERROR
In patients with NETs, 111In-octreotide somatostatin receptor scintigraphy (SRS) can be used to localize and staging primary tumors and to select patients for peptide receptor radionuclide therapy (Tables 12.7and 12.8), but it has low specificity and differentiation between SCLC and NSCLC is not possible. There is a correlation between SSTR expression and prognosis; patients with NETs with positive SRS have a better response to treatment with somatostatin analogs.133–136
SRS is the procedure of choice to image NETs and serves as a prognostic parameter to predict therapeutic response (surgery, radiotherapy, chemotherapy, or somatostatin analog one). SRS sensitivity depends on both lesion size and the expression of SSTR subtypes 2 and 5, and it is between 82% and 95%, higher than CT and MRI.137–139 However, in a study of 27 patients,140 helical CT appeared to be more sensitive than SRS to detect extrahepatic metastasis from NETs and to have a similar sensitivity, specificity, and accuracy in detecting primary NETs and hepatic metastasis.
Although SRS octreotide is not useful to differentiate SCLC from other lung disease, it should be included in the staging procedure of SCLC because it provides early detection of metastases, especially to the brain, in both limited disease and extensive disease. As stated previously, 60% of the patients already have extensive disease at the time of initial diagnosis. Common sites of metastatic disease include liver (22% to 28%), bone (38%), bone marrow (17% to 30%), central nervous system (8% to 15%), and retroperitoneum (11%).
The influence of various sites of distant metastases on survival has been analyzed in several studies, but it seems that prognosis is related more to an increase in the number of sites than to specific sites. Following this, Richardson et al.141 suggested that no further diagnostic procedures are necessary once extensive disease has been demonstrated unequivocally. This would also improve the cost-effectiveness of pretreatment evaluation. In this respect, 111In-octreotide scintigraphy has been suggested as a (single) tool to stage the patient suffering from SCLC. Nevertheless, to date, the results obtained with 111In-octreotide in the staging of SCLC are still inconclusive. In two studies with only a small number of patients, a sensitivity of 45% and 50% was found. In patients with a solitary metastasis, there is a high likelihood of understaging. The low sensitivity may be because planar techniques were used for the detection of metastases.
Li et al.142 described a sensitivity of 100% for bone marrow scintigraphy and 91% for bone scintigraphy to detect skeletal metastases. Because MRI seems to be more sensitive than bone scintigraphy to detect metastases in the spine, pelvis, and sternum, this modality might be performed in patients with NETs with a normal bone scintigram.143 In 50% of the patients with known skeletal metastases, O’Byrne et al.144 demonstrated 111In-octreotide uptake, but there was a discrepancy between findings on bone and octreotide scintigraphy. In view of the high sensitivity and low cost, it seems logical to use bone scintigraphy as the first step. With this modality, one-third of the patients with extensive disease will be correctly identified at an early stage during the initial diagnostic workup.
Limitations of SRS include the evaluation of organs with higher physiologic uptake (e.g., liver) and the detection of small lesions.145,146 SRS has other potential sources of error such as physiologic uptake in the liver, spleen, kidneys, and bowel contents secondary to biliary excretion (see Tables 12.7 and 12.8). In addition, the visualization of brain metastases may not represent expression of SSTRs but rather a disturbance of the blood–brain barrier. Octreotide is a polar substance and does not sufficiently penetrate the intact barrier to allow accumulation at possible receptors.
Single-photon emission computed tomography (SPECT)/CT combines functional and anatomical data and improves sensitivity of detection.135,147,148 Attenuation correction of SRS SPECT data by SPECT/CT further improves the sensitivity.149
99mTc-depreotide, a 99mTc-labeled somatostatin analog, depreotide, which was introduced clinically several years ago, had affinity for SSTR2 (expressed in NETs such as SCLC) but had greater affinity for SSTR3. The 99mTc depreotide false-negative rate in this study showed favorable comparison with the results of a prospective trial with FDG-PET in SPNs evaluation.130 The trial evaluated 114 patients with SPNs; the diagnosis of all these patients was subsequently confirmed by tissue analysis; the sensitivity of 99mTc-depreotide scintigraphy was 96.6% and the specificity was 73.1%.114 Malignant lesions correctly identified by 99mTc-depreotide scintigraphy (SPECT/CT) ranged from 0.8 to 6 cm. 18F-FDG PET in a previous series had failed to identify this tumor type.130 The tracer, however, is no longer available.
The PET tracers most commonly employed to assess thoracic NETs are 68Ga-DOTA-peptides (68Ga-DOTA-TOC, -NOC, -TATE) and 18F-DOPA. 18F-FDG provides valuable information in selected cases. Because well-differentiated NETs have a slow proliferation rate and low glucose consumption, FDG is not suitable to stage well-differentiated NETs but is valuable in highly proliferating undifferentiated tumors.150,151
68Ga is of great interest because of its suitable physical properties; it decays by positron emission (89%) and electron capture (11%)152–155 (Tables 12.9 and 12.10). The long half-life of 270.8 days of the parent 68Ga allows the use of the generator for up to 1 year or longer. 68Ga-DOTA-TOC is not yet available for routine clinical use. There are several 68Ga-DOTA–peptides (TOC, NOC, TATE). The most relevant difference among these compounds relies in a variable affinity to SSTRs subtypes: All can bind to sst2 and sst5, but only DOTA-NOC presents a good affinity also for sst3, and DOTA-TATE has a predominant affinity for SST receptor 2.156 SCLC (mainly primary tumors) has high expression of SST receptors and can be visualized with 68Ga-DOTA–conjugated peptide PET/CT.157,158
68Ga-DOTA–CONJUGATED PEPTIDES (DOTA-TOC, DOTA-NOC, DOTA-TATE)
68Ga-DOTA–CONJUGATED PEPTIDES (DOTA-TOC, DOTA-NOC, DOTA-TATE) IMAGE INTERPRETATION: POTENTIAL SOURCES OF ERROR
In the management of NETs, 68Ga-DOTA–conjugated peptide PET/CT is used to localize primary tumors and to stage and follow-up of patients with known disease as well as to detect residual, recurrent, or progressive disease (restaging) and to identify patients likely to respond to octreotide and SST receptor radionuclide therapy with 177Lu or 90Y-DOTA-peptides.159 68Ga-DOTA-TOC PET has a significantly higher detection rate compared with conventional SRS and diagnostic CT, with a clinical impact in a considerable number of patients, even if the combined use of PET and CT shows the highest overall accuracy.160,161
Wherever available, 68Ga-PET/CT has become a routine imaging modality to assess patients with NET lung cancer. 68Ga-DOTA-TOC PET is more accurate than 111In-DTPA-octreotide SPECT and SPECT/CT. Although the sensitivity of 111In-DTPA-pentetreotide SPECT to detect NETs in the lung approaches 100%, the use of PET combined with a diagnostic CT further improves the value of 68Ga-DOTA-TOC in these patients.
18F-DOPA is another PET tracer that is useful to detect NETs. It serves as a substrate for the synthesis of dopamine in tumors manifesting the APUD pathway.162 A potential advantage of 18F-DOPA over 68Ga-DOTA peptides is the detection of lesions with low expression of SSR as frequently observed in patients with undifferentiated tumors.
In general, 68Ga-DOTA-NOC is superior to 18F-DOPA for the detection of the primary tumor site in nonoperated cases and detects more lesions in the liver, lymph nodes, and lung.163 The greatest discordance is in the pancreas because of the high physiologic uptake of 18F-DOPA.
It is debatable whether the use of carbidopa, an inhibitor of DOPA decarboxylase, as premedication increases the sensitivity of 18F-DOPA PET for the detection of NET lesions.164
OTHER PET TRACERS
Radiolabeled methionine has been investigated extensively in cancer imaging with PET. The normal biodistribution of C-11 methionine (MET) includes relatively intense tracer accumulation in the pancreas, liver, stomach, and intestine and moderate tracer localization in the bone marrow, tonsils, and the salivary glands, which does not interfere with evaluation of tumors in the thorax. 11C-MET may have a specificity advantage over 18FDG by improving the differentiation between cancer and inflammation.
Thymidine labeled with 11C at the methyl group (methyl-11C-thymidine) makes possible PET imaging of cellular proliferation.165 Toyohara et al.166,167 developed 4′-thiothymidine labeled with 11C at the methyl group (4′-[methyl-11C]-thiothymidine [11C-4DST]) as a new candidate tracer for cell proliferation imaging, which is resistant to degradation by thymidine phosphorylase and is incorporated into DNA.
Recently, Minamimoto et al.168 studied 18 patients with NSCLC with 11C-4DST. All malignant lesions showed focal increases in uptake of 11C-4DST and 18F-FDG.169 All NSCLC specimens contained Ki-67-positive cells. 11C-4DST showed a higher correlation with cell proliferation evaluated by the Ki-67 index in NSCLC than 18F-FDG, confirming 11C-4DST PET/CT as a useful noninvasive modality to image DNA synthesis by NSCLC. 11C-4DST to evaluate lymph node metastases, however, is difficult. Relatively low accumulation of 11C-4DST results in failure to detect some lesions. This is also seen with 18F-FLT.170,171 As a result, 11C-4DST PET may be best to predict patient prognosis rather than detection or staging of cancers. Minamimoto et al.168 reported a double-tracer protocol, by obtaining 18F-FDG scans after the 11C-4DST one, for most of the patients included in their study. 18F-FLT is receiving greater interest because it is an analog of thymidine; thus, it reflects cellular proliferation and correlates better with proliferation of lung tumors than 18F-FDG.172–174
Tian et al.175 recently conducted a randomized multicenter clinical trial with dual-tracer PET/CT using 18F-FLT and 18F-FDG. Fifty-five patients in six imaging centers, using the same models of equipment and standardized protocols, were evaluated. The diagnostic accuracy to assess pulmonary nodules improved over 18FDG.
In general, the uptake of 18F-FLT by a pulmonary lesion is lower than that of 18F-FDG. The higher uptake by liver and bone marrow of vertebrae and ribs makes the detection of small lesion(s) by 18F-FLT more difficult. 18F-FLT was developed to reflect the proliferation rate of the lesions and to characterize malignant tumor growth. The current dual-tracer study was designed to prove the following assumptions: (a) 18F-FDG and 18F-FLT provide information related to different aspects of tumor biology; (b) 18F-FDG and 18F-FLT, dual tracer imaging, are complementary to each other and increase diagnostic confidence; and (c) the criteria in dual-tracer PET/CT image interpretation are objective, accurate, and easy to use. 18F-FDG PET detected more lesions than 18F-FLT, and the image quality of 18F-FDG was superior with higher SUVs. The better image quality was believed to be due primarily to its comparatively lower background and more uniform tissue distribution. However, nonspecific uptake has been noted in a number of benign lesions, especially in tuberculosis. In comparison with 18F-FDG, 18F-FLT images are “noisy.” The positive bone marrow of the thoracic cage may interfere with the evaluation of intrathoracic lesions. The uptake of 18F-FLT is lower than that of 18F-FDG, which is in accordance with other reports. For example, Buck et al. reported that 18F-FLT uptake was only 50% of 18F-FDG uptake in positive nodal metastases of NSCLC. In the study, 18F-FLT had better specificity (76.92% versus 58.97%), but the increased 18F-FLT uptake was not “related exclusively to malignant tumors.” The uptake of 18F-FLT was present to various degrees in many tuberculous and other benign lesions. This was not entirely unexpected because false-positive 18F-FLT PET had been reported.176 The mechanism of false positive is poorly understood considering, for example, that the extent of 18F-FLT accumulation in positive benign lesions did not correlate with granulomatous tissue. Similar results occurred in a case of interstitial pneumonia with a Ki-67 of 15% and inflammatory cells with a slightly increased Ki-67.
LUNG PERFUSION SCINTIGRAPHY
Although surgical resection of lung cancer remains the best therapeutic option, only one in four patients presents with a resectable disease. Prediction of postsurgical pulmonary function is crucial to limit morbidity and mortality after lung resection in patients with ventilatory obstruction, making accurate preoperative evaluation the key to successful outcome.177–181 Measurement of ventilation indices, including forced expiratory volume in 1 second (FEV1), diffusing capacity of the lungs for carbon monoxide, and maximal oxygen uptake, usually represents the first step of this evaluation process.
Spirometry-based pulmonary function tests have become the gold standard of preoperative functional assessment of lung function, but the constant need for more accurate evaluation tools led to the use of perfusion or ventilation lung scintigraphy, or both, to provide a regional assessment of lung function and thus offer the possibility of estimating postoperative pulmonary function by means of the predicted postoperative FEV1 (FEV1ppo).182,183 In particular, an FEV1 >2 L or >60% of the predicted value usually accounts for a feasible pneumonectomy, with the values lowered to >1.5 L or >40% of the predicted value for a lobectomy. These cutoff values exclude a considerable number of subjects who have a resectable disease but whose pulmonary function appears too compromised for them to successfully undergo lung resection.
LUNG PERFUSION SCINTIGRAPHY
Lung perfusion scintigraphy with Tc-labeled macroaggregates of albumin is the currently recommended protocol to estimate the FEV1ppo (Table 12.11). Preoperative and postoperative assessment by means of perfusion scan with planar acquisition (PA) and SPECT has been evaluated. It has been suggested that surgical candidates with preoperative FEV1 <60% should always undergo lung perfusion scintigraphy to achieve accurate postoperative outcome prediction with an estimated FEV1ppo >40%, indicating an acceptable surgical risk. Postoperative FEV1 estimation by perfusion SPECT demonstrates good correlation with spirometrically measured FEV1. In this study, FEV1ppo, estimated by planar scintigraphy or SPECT acquisition, was similar compared with spirometry-measured postoperative FEV1.
No significant difference between either planar or SPECT scans was reported by Piai et al.,184 who also suggested that each of them is more effective for estimating FEV1ppo in lobectomies than in pneumonectomies. At the same time, it has been observed that integration of SPECT with CT can provide more precise anatomic information.
SPECT estimation of FEV1ppo is more accurate than planar scintigraphy. In addition, Wu and colleagues found quantitative CT scanning to be an adequate tool. It is now routinely performed during the preoperative workup for lung cancer surgery.185–187
Errors may be large with perfusion scintigraphy, and the accuracy is not improved by the combined use of ventilation scintigraphy.188 Nevertheless, patients undergoing lobectomy with a quantitative CT-predicted FEV1ppo of about 40% or less should also undergo a perfusion scintigraphy. The technique has been used extensively to predict lung function after resection and is still the simplest and most reliable method, even if it can underestimate postoperative measured FEV1 values. Conversely, CT-based methods require more postprocessing and are limited by the need for scanner calibration, the dependence of lung density on the inspiratory effort, and the x-ray beam collimation.189,190 Furthermore, Mineo et al.177 showed that, although results achieved by planar lung scintigraphy and SPECT were comparable, SPECT accounts better for spatial overlapping of the pulmonary lobes and differences in their size or perfusion and better estimates hypoperfused areas/segments in candidates for lobectomy or pneumonectomy with no additional cost.
SPECT can assess the amount of pulmonary emphysema in specific regions of the lung, without loss of accuracy by the superposition of lung tissues. Operable patients tolerate a pulmonary resection of a nonfunctional part of the lung without increased risk of respiratory failure during the postoperative period if determined to be operable by SPECT.191
Planar scintigraphy and SPECT lung perfusion scintigraphy accurately predict postoperative FEV1ppo and can therefore be considered reliable tools to establish operability of patients with lung cancer and ventilatory obstruction.
Pulmonary function can also be investigated by MRI.192
MALIGNANT PLEURAL MESOTHELIOMA
Malignant pleural mesothelioma (MPM) is the most frequent primary tumor of the pleura characterized by a poor prognosis. The pleural form is the most common of the three typical forms of the disease —pleural, peritoneal, and pericardial—in about 75% of cases. Once considered to be rare tumors, malignant mesothelioma is now seen in increasing numbers. Death rates in the United Kingdom are some of the highest in the world, at around 30 cases per million per year, similar to Australia and Belgium.193 In the United States, the annual incidence of malignant mesothelioma is approximately 2,500 to 3,000 cases.194,195
The major etiologic factor for MPM is exposure to asbestos fibers, particularly crocidolite.196 The long gestation period, up to 50 years of exposure to asbestos dust or fiber inhalation before the appearance of asbestosis symptoms, can often mean that a diffuse MPM has reached an advanced stage and spread to tissues of other organs.
Various approaches have been used in the treatment of MPM. Radiotherapy alone is generally used for palliation. Patients who undergo chemotherapy have shown limited response, without significant change in survival time.197Aggressive surgical resection (extrapleural pneumonectomy or radical pleurectomy/decortication) used alone has also yielded disappointing results, with a median survival time of less than 1 year.198 However, multimodality therapy consisting of surgery followed by chemotherapy and radiotherapy has been shown to prolong survival.
On the basis of histopathology, it is possible to distinguish three types of mesothelioma: Epithelioid, sarcomatoid, and biphasic.193,199
Epithelioid mesothelioma is the most common type of asbestos cancer. Approximately 50% to 70% of all mesothelioma cases are of this variety. The cell structure is similar to other diseases that manifest in the tissue lining. The most notable one is adenocarcinoma. Because of the similarities in cellular appearance, a misdiagnosis of epithelioid mesothelioma is very common. Diagnostic problems can be categorized into several groups. Determining whether a biopsy specimen is benign or malignant presents problems in two main areas: (1) distinguishing between reactive mesothelial hyperplasia and epithelioid mesothelioma and (2) distinguishing between reactive pleural fibrosis and sarcomatoid or desmoplastic mesothelioma. Having decided that malignancy is present, the distinction must be made between epithelioid mesothelioma and metastatic carcinoma, particularly in patients who have a history of malignancy or atypical radiology, and between sarcomatoid mesothelioma and other types of malignant connective tumors that may occasionally involve the pleura primarily.
Sarcomatoid is the least common type of mesothelioma, occurring in approximately 10% to 15% of all cases. In relation to epithelioid cancer cells, sarcomatoid cells feature a less uniform structure. Singular cells are more oval than they are cubed. In addition, the nucleus of each cell is less distinct when viewed under a microscope. Like epithelioid, sarcomatoid mesothelioma can be difficult to diagnose because other disorders exhibit similar cell structures. For example, desmoplastic sarcomatoid mesothelioma, a subtype, has a rather innocuous appearance, which may be dismissed as benign fibrous tissue. Pulmonary sarcomatoid carcinoma and sarcomatoid cancer are also frequently misdiagnosed in individuals who suffer from sarcomatoid mesothelioma. The distinction between reactive fibrosis, sarcomatoid mesothelioma, or desmoplastic mesothelioma can be very difficult and depends largely on the recognition of cellular atypia.200
Biphasic mesothelioma, occurring in 20% to 40% of all cases, is the second most prevalent form of cancer. Unlike the more distinct cell structures of epithelioid and sarcomatoid, biphasic mesothelioma exhibits a more varied structure. In fact, biphasic mesothelioma is named as such because both epithelioid and sarcomatoid cells are present. The structure of such intermingled cells can vary from one case to another. Sometimes, individual epithelioid and sarcomatoid cells mix together in true patchwork form. Other times, each type of cell assembles in larger clusters. Because of the combined nature of biphasic mesothelioma, extreme precision is again necessary in the diagnosis process.
Several factors have been shown to correlate with survival: Intrathoracic lymph node metastases, distant metastatic disease, and the initial extent of pleural involvement. Patients affected with mesotheliomas of the epithelial subtypes tend to survive longer than those with mixed or sarcomatoid subtypes.
MPM diagnosis in the early stages is often limited by unspecific symptoms, which mimic other illnesses and diseases, including allergies, some cardiac conditions, immune system failures, and persistent pneumonia of unknown etiology. Often, at onset the radiologic pattern is characterized by pleural effusion. Exudative effusion, typical of mesothelioma, is caused by the inflamed pleura. Thoracentesis can be used to extract pleural fluid for analysis. Protein-rich fluid indicates transudative effusion. Biopsy and immunohistochemistry findings plays a major role in helping to make the diagnosis, but they should be interpreted with due regard to the clinical setting and radiologic features, and with knowledge of the wide morphologic variations seen in mesothelioma.
Mesothelioma is known as a particularly aggressive cancer, with a range of development rates. Although the genetic changes that lead to the disease’s initial development can take decades, mesothelioma grows quickly and spreads to other parts of the body within a matter of months. Because it is not generally diagnosed until its later stages (usually stage III or stage IV), metastatic disease is common at the time of diagnosis. Mesothelioma progression normally affects the organs around the lungs ipsilateral to the side of the original tumor. It has shown a natural history of relentless local progression with rare hematogenous spread even in the late stages of untreated disease. Even after aggressive local control measures, locoregional recurrence is the fate of a majority of patients.
Many diagnostic modalities are used to identify patients with MPM. Surgical staging consists of bronchoscopy, mediastinoscopy, and/or laparoscopy with peritoneal lavage to rule out abdominal involvement. Before surgery, actually, there is no consensus as to which single modality should be used to confirm diagnosis prior to surgery, but it is evident that imaging plays an essential role in the evaluation of MPM. Each imaging modality, particularly CT, MRI, and nuclear imaging, has its advantages and limitations, but their combined use is crucial in determining the most appropriate treatment options for patients with MPM, allowing to select those patients who may benefit from aggressive therapy.
18F-FDG PET and PET/CT: Role in the Actual Imaging Scenario
The increasing role of nuclear imaging is because of 18F-FDG PET/CT, which plays a crucial role in the assessment of patients with known or suspected MPM. However, surgical or radiologic pleural biopsy still provides the most accurate definitive diagnosis in MPM, although it is a more invasive procedure than 18F-FDG PET/CT.
CT is the primary imaging modality used for the diagnosis and staging of MPM, with signs such as pleural effusion, diffuse pleural thickening with frequent nodularity, interlobar fissure thickening, growth typically leading to tumoral encasement of the lung, and calcified pleural plaques. However, although some findings are quite characteristic, none is pathognomonic for the disease; for example, enlarged nodes alone do not prove nodal involvement, so CT accuracy remains suboptimal.201 CT can also lead to underestimation of the extent of disease in early chest wall involvement and peritoneal studding.202,203 Despite these limitations, CT remains the imaging study of choice for initial evaluation of patients with or suspected for MPM, because it is superior to conventional chest radiography, even more in delineating the optimal site for biopsy and providing a tremendous amount of anatomic information about the stage of the disease.204–206
18F-FDG PET/CT is a useful diagnostic tool to identify and stage MPM and differentiate it from benign pleural disease. Mesothelioma, in fact, is 18F-FDG avid (Fig. 12.10), and initial studies suggested that 18F-FDG PET/CT may be useful in the assessment of prognosis and in the staging of patients with MPM.207–209
Increased 18F-FDG uptake is not uncommon in inflammatory and infectious processes, and also radiation-induced pneumonitis is a known cause of false-positive findings in PET/CT.210 The other one false-positive case can consist of an intense linear focus of uptake, extending to the right chest wall because of bronchopleural fistula with empyema. Nevertheless, MPM is a malignancy in which the prognostic information provided by 18F-FDG PET imaging could be of value. Although most MPMs are highly FDG avid, lack of tracer uptake was previously reported in the epithelial subtype.211 The excellent sensitivity of 18F-FDG PET in detecting and staging MPM, combined with the prognostic information of this method, can make this imaging modality a useful adjunct to conventional evaluation. As known, PET with coregistration of anatomic and functional imaging data (PET/CT) improves the localization of regions with increased FDG uptake and accuracy of MPM staging. It is effective for highlighting MPM metastases, which may not appear on other conventional imaging scans. By revealing the stage of the cancer, PET scans can also project survival of a patient with MPM. Because these scans help visualize a mesothelioma tumor’s volume and level of metabolic activity, theoretically it can be used to predict how quickly the cancer will spread and how positive the patient’s prognosis will likely be.
Mesothelioma staging is a crucial diagnostic step that influences the course of treatment and the patient’s prognosis. Several staging systems are in use. The IASLC and the International Mesothelioma Interest Group (IMIG) previously developed a TNM staging system that has been accepted by the UICC and the AJCC. The most widely used and most comprehensive system is the TNM system associated with the IMIG, which emphasizes the importance of local tumor invasion in determining respectability.212 Patients’ diseases are staged according to the IMIG TNM staging system by combining the information obtained from the CT and PET scans, whereas mediastinoscopy is the standard method for obtaining preoperative histologic evaluation of tumor involvement in mediastinal lymph nodes, although the nodes in the para-aortic and aortopulmonary window are inaccessible.213Further evaluation of mediastinal node involvement together with histologic verification of local tumor spread is obtainable by the surgical procedure of extrapleural pneumonectomy (EPP).
FIGURE 12.10. Axial computed tomography (CT) and axial, coronal, and sagittal FDG positron emission tomography (PET)–CT fusion images, illustrating the patterns of FDG uptake in malignant pleural mesothelioma. Pattern of intense FDG uptake corresponding to circumferential pleural thickening seen on CT. (Images courtesy of Nuclear Medicine–PET/CT Center Azienda dei Colli, Monaldi, Naples, Italy.)
Although the current AJCC/UICC staging system and the methods available for clinical staging represent advances made in the management of MPM during the past decade,214 they are imperfect. The IASLC database represents the largest, multicenter, and international database on MPM to date. Analyses not only demonstrate that the proposed TNM staging system effectively distinguishes the T and N categories but also highlight areas for potential revision in the future. Further studies to improve the accuracy of staging in MPM are warranted.
MRI can provide additional staging information. The excellent contrast resolution of MRI imaging can allow improved detection of tumor extension, especially to the chest wall and diaphragm, and better prediction of overall resectability. Anatomic and morphologic MRI features, similar to those seen on CT, are used to establish local invasion of MPM. Loss of normal fat planes, extension into mediastinal fat, and tumoral encasement of more than 50% of the circumference of a mediastinal structure are some of the MRI imaging features that suggest tumor extension. Perfusion MRI is the most promising technique for the assessment of the tumor microvasculature. In MPM, therapeutic effects of chemotherapy can be monitored with perfusion. Both CT and MRI are helpful in identifying the location and extent of the involved area.215
Although the IMIG staging system for MPM emphasizes the importance of local tumor invasion in determining respectability, these imaging techniques often fail to detect nonresectable tumor invasion in the chest wall, mediastinal structures, or the diaphragm (T4).216 A consequence of the increasing use of TNM staging is that accurate determination of the anatomic extent of disease is important in selecting patients for potentially curative resection. CT plays an important role in the assessment, diagnosis, and staging in patients who are being considered for resection. CT features can also be used to preclude surgery in patients with obviously unresectable tumors (e.g., diffuse extension of tumors into the chest wall, mediastinum, or peritoneum or distant metastasis), whereas EPP is the surgical procedure of choice for patients with resectable disease.217,218 This distinction guides the choice of treatment options and implies significant differences in survival. Although CT is the most commonly used modality for the evaluation of lymph node groups, its accuracy remains suboptimal because enlarged nodes alone do not prove nodal involvement.219 PET scans are highly effective in revealing cancerous activity in the lymph nodes, which implies a later stage of cancer in the traditional TNM staging system and the optimal therapeutic strategy considering, for example, that disease can also spread to N2 mediastinal lymph nodes, which in many centers is considered to be a sign of inoperability, or N3 glands that may be missed. The TNM system emphasizes criteria used to determine the extent of local tumor and lymph node involvement, both of which factors have been shown to be related to the overall survival rate in MPM.220
So, currently CT and PET scanning provide the most accurate information, whereas MRI does not appear to add significantly to PET/CT combined and should be used selectively. Video-assisted thoracoscopic surgery can provide some additional information about T status, transdiaphragmatic tumor invasion, and peritoneal metastases. Currently available data in solid tumors indicate that PET/CT is more sensitive and specific than either of its constituent imaging methods alone.
With locally advanced tumors, it is important to distinguish between T3 (potentially resectable) and T4 (technically unresectable) disease. This distinction guides the choice of treatment options and implies significant differences in survival. The presence of N3 nodal disease or distant metastasis also precludes surgery. Although surgical staging is often required in patients with potentially resectable lesions, CT, MRI, and PET have proved helpful in further delineating the extent of disease and can aid in choosing whether to treat MPM surgically, medically, or both, as reported in some studies221,222 regarding the use of 18FDG PET/CT in the evaluation of patients with MPM. However, it is important to note that PET alone lacks the spatial resolution to detect transdiaphragmatic extension of tumors. Some authors, for T4 disease, obtained as a result the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PET/CT, which were 67%, 93%, 86%, 82%, and 83%, respectively.223 For the purpose of evaluating the ability of PET/CT compared with conventional preoperative CT to detect inoperable stages of MPM in order to avoid futile surgery, Sørensen et al.224 demonstrated that PET/CT improves the accuracy of preoperative staging in MPM as compared with CT alone in 29% of patients (caused by either distant metastases or T4 disease). On the other hand, when comparing PET/CT with the final histologic results obtained on all patients referred to surgery and by the surgical–pathologic results from EPP by mediastinoscopy and surgical–pathologic results together, the following results were obtained: Sensitivity of 50%, specificity of 75%, positive predictive value of 50%, negative predictive value of 75%, positive likelihood ratio of 5, and negative likelihood ratio of 0.67. PET scan was found to be useful in the prediction of survival, determination of mortality risk, and detection of metastases and recurrent disease. Erasmus et al.223 in their study noted that PET/CT did not detect the metastases in some patients with pathologic N1 disease because of the presence of confluent adjacent primary tumors or absence of increased FGD uptake in the hilum and detected the metastases in only two of the eight patients with N2 disease. Although this may affect prognosis, it did not affect surgical management.
Furthermore, PET/CT inaccurately staged MPM as N3 (nonresectable) disease in three patients. In two of these patients, false-positive increased FDG uptake in the N3 nodes was attributable to inflammation on histopathologic examination. Because of the implications for management, authors advocate sampling of all FDG-avid N3 nodes in patients with MPM and also for N3 lymph nodes that are enlarged according to CT criteria and are not FDG avid, in patients considered for surgery. The authors concluded that the use of integrated PET/CT in patients with MPM increases the accuracy of the overall staging and significantly improves the PET/CT selection of patients for EPP and suggested that whole-body integrated PET/CT should be the preferred modality for staging in patients with MPM. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PET/CT in lymph node staging in patients with N2 disease have been reported as 38%, 78%, 60%, 58%, and 59%, respectively.
Flores225 observed higher SUVs in N2 disease (8.6 ± 3.4) than in N0/N1 disease (5.3 ± 2.1). The area under the receiver operating curve of the SUV was a strong predictor of N2 disease (78% ± 10%). An SUV of <4 was associated with a longer survival than an SUV of >4 (24 months versus 14 months; p < 0.04), with the latter having a hazard ratio for death of 3.3 ( p = 0.03).225
PET/CT has been demonstrated to detect extrathoracic metastases that are not suspected after routine clinical and conventional radiologic evaluation. In fact, a well-documented advantage of 18F-FDG PET over anatomic imaging modalities is its greater accuracy for the detection of systemic metastases.207,226 As shown by Erasmus and colleagues,223 18F-FDG PET/CT improves extrathoracic staging by detecting lesions missed in conventional imaging or by correctly characterizing equivocal lesions. These authors indicated that preoperative 18F-FDG PET/CT detected extrathoracic metastases not identified by conventional imaging in 24% of patients with MPM.
Gerbaudo et al.227 described that, at initial staging of MPM, metastatic failure sites were more FDG avid than primary lesions and the metabolic activity in primary lesions of patients with metastases was significantly higher than in those without metastases. These findings, later confirmed by Lee et al.,228 tend to support the hypothesis that tumors with high metastatic potential have higher energy requirements, suggesting that the observed increased glycolytic activity in primary lesions might be a necessary precondition for the acquisition of metastatic potential.229 The number of systemic sites of relapse was lower in those patients who had received more aggressive treatment. Patients with extrathoracic metastases had a significantly higher SUV in the primary pleural lesion at all stages of disease and shorter survival than those with nonmetastatic disease. The treatment process is similar to all types of mesothelioma. However, the rate of survival and expected survival time varies from one type to another. Epithelioid mesothelioma offers the best chances for survival. Individuals with this type of cancer have an expected survival rate of approximately 8.5 months. Sarcomatoid mesothelioma offers slightly reduced expectations, with a mean survival time of 7 months. Biphasic mesothelioma is the most dangerous, with diagnosed patients expected to survive 6 months.
Surgical procedures for MPM can range from a pleurectomy/decortication for those patients with early stage disease to more aggressive procedures. In most cases, surgery alone can be inadequate because of residual disease and a high rate of relapse, and is followed by chemotherapy and/or radiotherapy. Despite effective treatment, changes in tumor size can be minimal in tumors such as lymphomas, sarcomas, hepatomas, mesotheliomas, and gastrointestinal stromal tumors. PET/CT is a functional measure of tumor metabolic activity, which is potentially more sensitive in detecting change to therapy than anatomic measurements. PET/CT has been demonstrated to be useful in the prediction of response to chemotherapy in several solid tumors, with the reduction in 18F-FDG uptake often preceding radiologic changes.230 There are no formalized guidelines for the measurement of response to chemotherapy using 18F-FDG PET in solid tumors. Visual analysis is challenging, particularly in mesothelioma, because of the extent and distribution of disease.
The most common semiquantitative parameter used is the SUVmax within a tumor.231,232 Mesothelioma is poorly suited to SUVmax measurements because it is often diffuse and heterogeneous. Defining the site to apply a representative SUVmax measurement is difficult and potentially unreliable. In addition, a measure that defines change on the basis of only 1 pixel within such a complex tumor mass is likely to be an oversimplification. There is an emerging interest in volume-based measures for response assessment with PET/CT, and volume-based 18F-FDG PET tumor assessment has been performed also for other tumors.233,234 Theoretically, this technique can be particularly effective in MPM, as a predominantly contiguous tumor encasing the pleural space and defining the tumor volume manually is laborious and unreliable.
Most published methods used fixed threshold techniques. Fixed threshold techniques are poorly suited to mesothelioma because of the plaque-like tumor mass and the problems associated with differentiating tumors from adjacent normal tissue, such as chest wall, mediastinum, liver, and heart. Therefore, Francis et al.235 have developed a novel software that semiautomatically defines the 3D boundaries of the tumor on 18F-FDG PET scans. This results in a measure of the total glycolytic volume (TGV), which is a composite of tumor volume and total metabolic activity. The authors used this methodology to compare the response to one cycle of chemotherapy, as assessed by serial CT scans, with changes on serial 18F-FDG PET scans in patients with MPM. They observed the role of serial 18F-FDG PET in assessing the response to chemotherapy after one cycle. Patients with a partial response had a lower median total glycolytic volume (TGV: A volume-based measure of total glycolysis) (30% versus 71% of baseline) compared with those with stable disease. Reduction in TGV was predictive of improved survival ( p = 0.015).
We do not know what change in total lesion glycolysis is required for a response. Because the dynamic range is larger, a suggested figure of 40% for a response should be considered on the basis of the larger changes in total lesion glycolysis than SUVmax reported in mesothelioma.236 Ceresoli et al.237 evaluated response to chemotherapy using 18F-FDG PET. Responders (≥25% reduction in FDG uptake) had a longer median time to tumor progression (14 months versus 7 months; p = 0.02) and longer survival (p = 0.07) than nonresponders. In this study, serial 18F-FDG PET in mesothelioma appeared useful in predicting response and patient survival after only one cycle of chemotherapy. TGV has been demonstrated superior to SUVmax and to CT measurements in predicting survival in the patient group studied. A considerable overlap has been reported in the change in TGV values in patients respectively with partial response and those with stable disease at CT, demonstrating the limited sensitivity of the modified RECIST criteria and highlighting the difficulties of applying the principles of unidimensional response measurements to a tumor that encases the pleural cavity.235,236
In conclusion, 18F-FDG PET/CT can discriminate between malignant and benign pleural thickening with a high accuracy and a high negative predictive value. It is an accurate modality to diagnose and to estimate the extent of locoregional and distant MPM recurrence. It also carries an independent prognostic value. A significant survival difference can indeed be assumed between patients with high 18F-FDG uptake and those with low 18F-FDG uptake. Moreover, metabolic imaging has the potential to improve the care of patients receiving chemotherapy for mesothelioma by the early identification of responding patients.
18F-FDG PET/CT plays a role in the clinical staging of all patients with lung cancer because it provides a noninvasive evaluation of patients with lung cancer and an initial estimate of the whole-body tumor burden. 18F-FDG PET is currently indicated for the characterization of lung lesions, staging of patients with NSCLC, detection of distant metastases, and diagnosis of recurrent disease. Furthermore, many institutions have found significant value in 18F-FDG PET to monitor treatment. Probable or definite benign results on PET and CT are strongly correlated with a benign diagnosis, and definitely malignant results on 18F-FDG PET are strongly correlated with a malignant diagnosis.
Recently, there have been reports of the use of PET/MRI for lesion characterization and tumor staging. The results at this time justify further investigation of MRI/PET in the assessment of pulmonary lesions, especially with the broad spectrum of MRI techniques. 18F-FDG PET/CT is an established tool for routine staging and evaluation of therapy response in lung cancer. With the recent commercial availability of whole-body PET/MRI systems, the researchers sought to compare the hybrid modalities in the assessment of pulmonary lesions regarding 18F-FDG uptake and tumor staging. Currently, however, MRI has a limited role in the clinical staging of patients with NSCLC, whereas PET/CT fusion scans (the most sensitive imaging technique) should be considered as the standard of care in patients suspected or known to have malignant tumors of the lung.
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