The World Health Organization cites lung cancer as the leading cause of cancer-related deaths worldwide. Lung cancer is second in the list of newly diagnosed cancers, surpassing colon, prostate, skin, and stomach cancers, with an estimated 2.21 million cases in 2020, only surpassed by breast cancer with 2.26 million cases in the same year. The first recorded incidence of lung cancer was discovered in the 1500s when miners from a small region in Germany became ill. These workers were exposed to high levels of arsenic and radon gases in the mines, commonly known as “death pits.” Many years later, approximately 60% of these miners developed a disease locals commonly called bergkrankheit, or “mountain disease,” and ultimately perished. Several years later, after World War I, lung cancer became more prominent when soldiers returning home from the war developed symptoms of chronic bronchitis. One primary reason behind this increase was the availability of cigarettes given to soldiers in the trenches to relieve the stresses of war. However, it was not until 1950 when an article in The British Medical Journal reported a link between lung cancer and cigarette smoking. In 1964, a report from the U.S. Surgeon General showcased the dangers of cigarette smoking, linking lung cancer directly to this recreational activity.
INCIDENCE, ETIOLOGY, AND EPIDEMIOLOGY
More than 500,000 Americans are living with lung cancer today, most over the age of 65. The American Cancer Society estimated that approximately 235,760 new lung cancer cases would be diagnosed in 2021, and about 131,880 would die of the disease in the same year. Unfortunately, early detection of the disease seldom occurs because the early stages of lung cancer are most often asymptomatic. Early detection and diagnosis are essential for treatment options and survival. The 5-y survival rate for lung cancer is approximately 18%; more than half of those diagnosed with lung cancer will die within 1 y of their diagnosis.
Over time, the rate of lung cancer in women has increased, while the disease peaked for men in 1984. Compared with other cancers, lung cancer kills more women than breast and ovarian cancer combined. Some believe that the rise in women’s lung cancer is due to hormones and hormone replacement therapy; environmental and genetic factors may also be to blame—additional research and data are necessary before making a conclusive decision.
Prognosis is poor. Lung cancer symptoms can be very general and are often overlooked or ignored by patients; thus, lung cancer is usually found in advanced stages. Based on the stigma associated with lung cancer, patients may be reluctant to seek medical care or treatment.
Lung cancer symptoms vary with the disease’s extent and may include whole-body systemic disease at diagnosis. Common lung cancer symptoms include shortness of breath, chest pain, chronic cough, difficulty swallowing, hoarseness, fatigue, and coughing up blood.
Patients may be asymptomatic, and lung cancer diagnosis is often an incidental finding. Recent radiology examinations unrelated to lung disease are often where discoveries of suspicious pulmonary nodules are made by CT, chest radiographs, or an 82Rb PET myocardial perfusion study. The lung is also a common site for other malignant cancers to metastasize, including breast, colorectal, kidney, head and neck, testicular, bone, soft tissue sarcoma, melanoma, and thyroid.
One hundred fifty years ago, lung cancer was not today’s systemic disease. The popularity and steady increase in cigarette smoking are the most significant risk factors for lung cancer. Approximately 85% of all lung cancer patients are current or former smokers, who outrank their fellow nonsmokers 10 to 1 in their chances to develop this disease. There is a long delay of about 30 y before the exposure progresses into lung cancer for patients who smoke. According to experts, it is not ultimately the smoke that causes lung cancer, but rather the tar that is the primary carcinogenic agent in cigarette smoke. To address this issue, cigarette companies changed the cigarette’s design in the 1950s to a low-tar, low-nicotine cigarette. Unfortunately, these changes have resulted in consumers using methods to promote deeper inhalation and longer retention of smoke, causing increased carcinogens to enter the lung. Although smoking is the leading risk factor for developing lung cancer, many people have developed this disease who have never smoked. Other risk factors include secondhand smoke. Evidence supports an increased risk of 24% for those who live with a smoker or have occupational and environmental exposure such as to radon, asbestos, and air pollution. The U.S. Environmental Protection Agency (EPA) links exposure to radon as the second leading cause of lung cancer. Preexisting conditions, including a history of other lung diseases such as chronic obstructive pulmonary disease (COPD) and HIV, also increase a person’s risk of developing lung cancer. Above all, smoking cessation will be the most critical measure and carries the most clinical significance in the fight against lung cancer. An additional consideration is the increasing popularity of e-cigarettes and how they will play a role in pulmonary disease. Lung cancer will continue to be a global epidemic, and efforts to combat this epidemic require further investigation.
HISTOPATHOLOGY
Lung cancer is classified as either non–small cell lung carcinoma (NSCLC) or small cell lung carcinoma (SCLC). NSCLC is the most common form of lung cancer. Approximately 80%–85% of all lung cancers are NSCLC, and 10%–15% are SCLC. Although both are lung cancers, they are treated differently.
NSCLC includes adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Adenocarcinoma makes up nearly 40% of all diagnosed lung cancers. It is found mainly in current and former smokers, although the disease has developed in nonsmokers. Adenocarcinoma grows slower than other lung cancers and is more commonly found in younger women and Asian populations. Adenocarcinoma of the lung originates in the glandular cells or mucous cells on the lung’s peripheral small airways, such as the alveoli. If the tumor is found in situ, a surgical lung resection may provide the patient with a favorable prognosis.
Squamous cell carcinoma originates in the squamous cells that line the bronchi of the lungs. Of all NSCLCs, squamous cell carcinoma is most often associated with a smoking history.
Although making up the lowest percentage of cases, large cell carcinoma, or undifferentiated lung cancer, spreads quickly. It predominantly originates in the lung periphery, although it may be found in any part of the lung. This tumor type grows more rapidly than other NSCLCs, making this class of tumor more challenging to treat with a less-than-favorable prognosis.
Metastases for NSCLC usually occur in the bone, liver, brain, and adrenal glands.
NSCLC uses the tumor-node-metastasis (TNM) classification developed by the International Association for the Study of Lung Cancer. Values for classification and staging are listed in Tables 1 and 2.
Classification of Lung Cancer
Staging of Lung Cancer
T in the classification refers to tumor. It describes the tumor’s size, location, growth rate, and effect on other surrounding organs. The N represents nodal involvement, and M corresponds to metastasis (proximal or distal spread of disease to other organs). Thus, lung cancer is staged 0, I, II, III, or IV. Accurate staging is critical because the more advanced the disease process, the worse the clinical prognosis (e.g., patients staged IIIB or worse are generally inoperable, and surgical resection is the best hope for cure). Figure 1 presents a case study for using the TNM method.
A case study for using the TNM method. A 64-y-old man with lung cancer in right upper lobe, stage T2a N3 M1b. (A) Axial CT image shows mass (arrow) in right upper lobe close to hilum. Prominent subcarinal lymph node (arrowhead) is seen. (B) Axial coregistered PET/CT image confirms highly 18F-FDG–avid tumor (long arrow) and presence of subcarinal nodal metastases (arrowhead) and right hilar metastases (short arrow). (C) Axial CT image at level of gastroesophageal junction shows slightly hyperdense liver lesion (arrows) in region of intrahepatic segment of inferior vena cava, being hardly appreciated. (D) Axial coregistered PET/CT image reveals intense 18F-FDG uptake of lesion (arrows), compatible with metastasis. (E) Coronal PET maximum-intensity projection image confirms nodal metastases in right hilum, mediastinum, and right supraclavicular region (arrowheads) and multiple liver metastases. Primary tumor (short arrow) is seen as well. (F and G) Axial liver acquisition volume acceleration (LAVA) (water-only) image (repetition time, 4.3 ms; echo time, 1.3 ms; flip angle, 12°) (F) and coregistered PET/LAVA image (G) show primary tumor (long arrow) in right upper lobe, nodal metastases in right hilum (short arrow), and subcarinal region (arrowhead). (H and I) Axial LAVA (water-only) image (repetition time, 4.3 ms; echo time, 1.3 ms; flip angle, 12°) (H) and coregistered PET/LAVA image (I) show liver metastasis (long arrows) with more anatomic detail. Intrahepatic segment of inferior vena cava (arrowhead) is compressed but not infiltrated. Fat plane between liver and right crus of diaphragm (short arrow) is preserved. Martin W. Huellner. TNM staging of non-small cell lung cancer: comparison of PET/MR and PET/CT. J Nucl Med. 2016;57(1):21–26.
According to the American Cancer Society, SCLC makes up roughly 10%–15% of all lung cancers. SCLC is usually found among active or former cigarette smokers and is classified as limited or extensive. At initial diagnosis, most SCLC patients have metastases to other areas of the body. These tumors begin in the bronchi, where exposure to smoke occurs. SCLC is fast growing and more aggressive than NSCLC. Limited disease is classified as a lesion confined to one side of the chest, mediastinal involvement, or metastasis to supraclavicular lymph nodes. Extensive disease involves metastases to multiple areas in the chest or lungs and malignant pleural effusions. In end-stage disease, tumor cells are found in the brain, liver, adrenal glands, and bone. Although accurate tumor staging may increase survival and improve the patient’s quality of life, the diagnosis of SCLC is associated with significant morbidity rates. SCLC is unique because these cancer cells are very sensitive to chemotherapy and radiation; however, promising early results are usually short-lived. The high recurrence rate associated with SCLC makes successful treatment difficult. Early detection can lead to a successful surgery and removal of SCLC if the patient presents with node-negative disease. SCLC does not use the TNM classification due to its rapid growth, latency in finding, and poor prognosis.
It is important to recognize two additional types of lung cancers: mesothelioma and carcinoid tumors of the lung.
Mesothelioma is a rare lung cancer that accounts for approximately 5% of all lung cancers. Mesothelioma affects the pleura, or the lining surrounding the lungs. Research has shown a positive correlation between mesothelioma and asbestos exposure. Most patients diagnosed with mesothelioma worked in manufacturing or the military, where they inhaled asbestos particles. Lung neuroendocrine tumors (NETs) are carcinoids of the lung originating from cells that only produce and secrete somatostatin. They are slow growing and make up less than 5% of all lung cancers. Although NETs can originate in any organ, the lung is second to gastric and pancreatic and accounts for 25% of all NETs. Lung NETs are divided into atypical and typical classifications. Atypical NETs exhibit higher levels of somatostatin receptors, grow faster, and are more likely to spread outside the lung. Typical carcinoid tumors grow more slowly and rarely spread beyond the lungs.
CONVENTIONAL DIAGNOSTIC PROCEDURES
Diagnostic procedures to rule out or stage lung cancer include sputum cytology, bronchoscopy, imaging studies (chest radiograph, CT, MRI, PET, and bone scan), and tissue biopsy (fine needle, core, etc.).
Sputum cytology is a diagnostic test to microscopically assess sputum (mucus coughed up from the lung) for abnormal cells, including lung cancer cells. Most of these cells originate from the central airways. With traditional cytopathological classification, results may vary between pathologists, creating a lack of sensitivity and reproducibility. Combined with bronchoscopy and CT, the sensitivity of sputum cytology increased from 47% to 71% for all lung cancer types and 100% for SCLC when located within the central airway. Using a flexible, lighted tube, bronchoscopy allows the visualization of the airways, including the trachea and bronchial tree. Efforts to improve the sensitivity of this screening exam have been explored using ultrasound to enhance visualization of identified areas of concern.
Chest radiographs, CT, or MRI can detect structural anomalies associated with suspected lung cancers. However, these modalities cannot determine whether the findings are benign or malignant with a high degree of accuracy. A nodule that is <10 mm may be detectable on CT scan but not on a chest radiograph, and a solid nodule that measures >4 cm is often associated with malignancy. Benign lesions are notably stable in appearance and show no changes over a 2-y period. Benign nodules also exhibit smooth margins and diffuse calcification and typically share the same characteristics as granulomas. The Fleischner Society Guidelines 2017, which incorporate the opinions of a multidisciplinary, international group of thoracic radiologists, pulmonologists, surgeons, pathologists, and other specialists on the management and follow-up of solid nodules, can serve as an excellent resource for interpreting physicians with incidental findings on imaging studies.
PET/CT is the modality of choice when assessing a lung nodule’s metabolic activity to determine if the nodule is benign or cancerous. It is also used to determine the extent of disease and is often used in follow-up imaging after a nodule is detected on a chest radiograph, CT, or MRI.
Radiography
The role of chest radiographs in diagnosing lung cancer is minimal. Although a chest radiograph may be ordered when a patient has symptoms including cough, shortness of breath, and chest pain, the chest radiograph only offers a two-dimensional (2D) image of the lungs. Even in an era of dual-energy subtraction chest radiography, which can enhance detection and characterization of pulmonary nodules, advanced diagnostic imaging, including CT and MRI, is required to provide a 3-dimensional assessment of any structural anomaly (Fig. 2).
Chest radiograph showing mass in right mid zone. Sandip Basu. 18-F FDG PET/CT imaging features of IgG4-related pulmonary inflammatory pseudotumor at initial diagnosis and during early treatment monitoring. J Nucl Med Technol. 2016;44(3):207–209.
CT
In recent decades, significant efforts have been made to screen patients with a heavy smoking history for lung cancer using low-dose CT scans. The purpose of the low-dose CT scan is to detect lung cancer as a single nodule before becoming a whole-body systemic disease. A low-dose CT scan without contrast may provide sufficient quality to detect lung abnormalities using 90% less ionizing radiation than a standard CT scan. If incidental findings are identified on the low-dose CT scan, a full-dose, IV-contrast CT can be performed to more clearly define the abnormality. Although only a small percentage of lung nodules identified on CT are malignant, evaluating the mass’s metabolic activity using other imaging modalities, such as PET (if the nodule is large enough), should be considered before biopsy (Fig. 3).
Contrast-enhanced CT of chest showing heterogeneously enhancing mass with calcification in right middle lobe. Sandip Basu. 18-F FDG PET/CT imaging features of IgG4-related pulmonary inflammatory pseudotumor at initial diagnosis and during early treatment monitoring. J Nucl Med Technol. 2016;44(3):207–209.
MRI
MRI plays an important role when advanced lung cancer is suspected or there is a high probability of brain or spinal cord involvement. New advancements in PET/MR imaging could pave the way for simultaneous evaluation of a lung tumor’s metabolic rate and determining the extent of disease.
Tissue Biopsy
When imaging confirms the presence of a nodule, a tissue sample or biopsy is the only definitive way to differentiate benign versus malignant cells and remains the “gold standard” for diagnosing cancer. A needle biopsy is a minimally invasive procedure that extracts cells from a lung mass for microscopic evaluation. Biopsies are routine procedures performed in a hospital or outpatient setting. This procedure can accurately distinguish adenocarcinoma from squamous cell carcinoma or other cancer cells; however, a guided biopsy is recommended for safety. Guided needle placement using an imaging modality such as CT or ultrasound improves accuracy and retrieves the most promising cells from a lung mass. A misplaced needle can cause a false-negative biopsy or a medical emergency, such as a pneumothorax.
Molecular characteristics of pathological samples from a biopsy can help predict a patient’s prognostic outcome. Biological markers and immunohistochemistry can determine mutations such as the p53 tumor suppressor gene or Ki-67 antibody, which correlate with cellular proliferation. Both overexpressed and elevated markers suggest a poor patient prognosis. Samples containing IgG4 immunoglobulin are consistent with inflammatory cells and are known as pseudotumors, which can mimic lung malignancy (Fig. 4).
Patient with lung adenocarcinoma in right lower lobe, as depicted by arrow. (A) CT scan. (B) 4′-[methyl-11C] thiothymidine PET. (C) 18F-FDG PET. (D) Ki-67 immunohistochemistry. B and C depict radioactivity accumulation in lung lesions. D shows positive nuclei (colored brown) with estimated proliferation rate of 81%. Ryogo Minamimoto. 4′-[Methyl-11C]-thiothymidine PET/CT for proliferation imaging in non-small cell lung cancer. J Nucl Med. 2012;53(2):199–206.
INDICATIONS FOR IMAGING
PET/CT is indicated for the morphological and functional characterization of pulmonary nodules or masses, for TNM staging of the mediastinum and screening for metastases not detected by CT alone, for radiotherapy planning, and for restaging lung cancer patients following treatment.
IMAGING
Lung cancer was the first Centers for Medicare and Medicaid Services (CMS)–approved indication for PET scanning and is routinely used for diagnosing, staging, therapy assessment, and recurrence. PET imaging is beneficial when assessing a solitary pulmonary nodule’s metabolic activity seen on CT or chest radiograph. Lesions seen on other imaging modalities may not decisively predict if the lesion is benign or malignant. When imaging with FDG, tumor metabolism is measured using the SUV. This measurement is a quantitative predictor of glucose metabolism in tumor cells and is useful in determining tumor size, how aggressive the tumor is, and tumor metastasis. On the basis of scientific data, if the SUVmax is <2.5 or the region of interest is visibly less metabolically active than the mediastinal blood pool, then the lesion is most likely benign. If the SUVmax is >2.5 or the region of interest is more metabolically active than the mediastinal blood pool, then the lesion is most likely malignant. However, caution is advised when evaluating solitary pulmonary nodules with PET to prevent false-positive findings, because alternative clinical conditions may demonstrate metabolically active areas, including:
Granulomatous conditions
Infection (Figure 5)
Inflammation
Inflammatory pseudotumor (Figure 6)
Neurofibromas
Pulmonary fibrosis
Sarcoidosis
Transaxial CT (left), attenuation-corrected 18F-αvβ6-binding peptide PET (middle; scale: SUVmax of 5), and fused 18F-αvβ6-binding peptide PET/CT (right) images through upper lungs (top) and lower lungs (bottom), showing increased uptake and areas of bilateral patchy opacity. Cameron C. Foster. αvβ6--targeted molecular PET/CT imaging of the lungs after SARS-CoV-2 infection. J Nucl Med. 2020;61:1717–1719.
(A) Baseline PET/CT scans showing metabolically active lesion with calcification in right middle lobe. (B) Follow-up PET/CT at 6 wk after initiation of corticosteroid therapy showing decreased uptake in previously active areas. Sandip Basu. 18-F FDG PET/CT imaging features of IgG4-related pulmonary inflammatory pseudotumor at initial diagnosis and during early treatment monitoring. J Nucl Med Technol. 2016;44(3):207–209.
Additional clinical conditions that may cause false-negative FDG PET scans include bronchoalveolar cancer, scar adenocarcinoma, carcinoid tumors, neuroendocrine tumors (Fig. 7), and lesions <1 cm.
18F-FDG PET/CT maximum-intensity projection and axial fused PET/CT images showing focal-on-diffuse hypermetabolic activity in left ventricular myocardium consistent with cardiac sarcoidosis (A) and resolution of myocardial activity after immunomodulator therapy (B). William Rieter. 18F-FDG PET-CT in the clinical management of cardiac sarcoidosis: a regional academic referral center experience. J Nucl Med. 2018;59:1527.
PET-only scanners have a sensitivity of approximately 79%, specificity of 76%, and accuracy of 78%. These lower performance percentages may lead to some lung cancers being missed. PET/CT scanners have improved sensitivity of approximately 95%, specificity of 91%, and accuracy of 93%. Compared with PET-only systems, the combined technology of PET/CT drastically improves image quality. Where available, PET/CT imaging should be used for lung cancer patients.
When staging a patient using TNM criteria, nodal involvement is critical in determining the extent of disease and prognosis. Nodule size is a poor factor for determining metastatic involvement. When evaluating nodal involvement, conventional imaging modalities only use structural criteria to detect nodules, and thus have poor accuracy in determining benign versus malignant nodal disease. PET/CT has a high diagnostic accuracy in detecting nodal involvement and has shown an increased accuracy in identifying tumor invasion in the chest wall and mediastinal infiltration. Because of this, conventional imaging can be a noninvasive alternative to surgical procedures or serve as a guide to identify less invasive areas to biopsy; however, PET/CT is the modality of choice when determining nodal involvement for lung cancer.
Finally, the spread of lung cancer can differentiate treatment options. The detection of proximal or distal metastases may affect staging 27%–67% of the time and alter management 19%–52% of the time. When examining the adrenals, a difficult area to biopsy, a metabolically active lesion on FDG PET/CT is a noninvasive conclusion of metastatic spread to the adrenal glands. Compared with radiography, CT, and MRI, PET/CT is the modality of choice for detecting bone lesions in lung cancer patients. However, compared with conventional imaging, PET/CT is not recommended for assessing brain metastasis. Due to the high affinity for glucose in the brain, it is challenging to determine normal brain activity compared with brain metastasis.
When PET/CT is used for radiotherapy planning, the combined technology leads to improved tumor imaging, radiation dose targeting, and a reduced radiation dose to surrounding healthy tissue. Another advantage PET/CT brings to lung cancer patients is assessing response to therapy accurately. Due to the rapid change in lung tumors’ cellular metabolism, successful results can be detected with PET/CT even before a change in tumor size.
Mesothelioma
PET/CT in mesothelioma patients presents a characteristic uptake pattern that encircles the lung area involving the pleural lining and is more sensitive than other imaging modalities. The intensity of FDG uptake, as measured by the SUV, has prognostic implications for the patient. Patients with intense uptake on FDG imaging have a poor prognosis and shorter survival (Fig. 8).
Coronal slices of 18F-FDG PET scan of patient with mesothelioma demonstrating contiguous involvement of right pleural surface, including infiltration of oblique fissure. There is additional subcarinal, precarinal, right paratracheal, and right hilar lymph node involvement. Roslyn J. Francis. Early prediction of response to chemotherapy and survival in malignant pleural mesothelioma using a novel semiautomated 3-dimensional volume-based analysis of serial 18F-FDG PET scans. J Nucl Med. 2007;48(9):1449–1458.
Beyond FDG
Additional radiopharmaceuticals used to evaluate lung cancer are presented in Table 3.
Experimental and Preclinical Radioisotopes for Lung Imaging
68Ga-DOTATATE/DOTATOC shares the same receptors as NETs, allowing tagged tumors to be imaged with PET/CT. A positive 68Ga-DOTATATE/DOTATOC scan correlates with molecule-targeted therapies such as peptide receptor radioligand therapy (PRRT) to deliver a therapeutic dose of radiation to a specific target. Due to the promise of using 177Lu-DOTATATE in treating somatostatin receptor–positive NETs of both pancreatic and gastric cancers, studies are being conducted to show the potential effectiveness of 177Lu to treat lung NETs (Fig. 9).
Whole-body images acquired after administration of 177Lu-DOTATATE in different therapy cycles. Thomas A. Hope. NANETS/SNMMI procedure standard for somatostatin receptor-based peptide receptor radionuclide therapy with 177Lu-DOTATATE. J Nucl Med. 2019;60:937–943.
The presence of hypoxia in solid tumors is an indication of radiotherapy or chemotherapy resistance. 18F-Fluoromisonidazole (18F-FMISO) and 64Cu-ATSM are imaging agents that visualize hypoxia and help predict a patient’s response to radiation therapy. 18F-FLT is a cellular proliferation radiopharmaceutical that directly correlates with dividing cells and can be a prognostic indicator for tumors. 18F-FLT is more sensitive than 18F-FDG for evaluating treatment response. 11C-methionine has been shown to image amino acid metabolism, and 11C-choline demonstrates the metabolic rate of cells. 11C-choline has been beneficial for detecting and differentiating brain tumors and lung cancer due to its higher specificity and sensitivity than 18F-FDG.
TECHNICAL RECOMMENDATIONS
The 18F-FDG PET/CT protocol for lung cancer, including patient preparation, injection, and imaging, follows the SNMMI/EANM guidelines for oncology and will not be duplicated here.
Misregistration between the CT and PET images (Fig. 10) affects image quality. Respiration artifacts are usually to blame for misregistration artifacts. Whereas PET data are acquired over several respiratory cycles, CT may only capture one cycle. The areas most affected by respiration artifacts are the lower lungs, liver, and spleen. Hepatic lesions are commonly mistaken for lower lobe lung nodules and metabolically active lung nodules at the lung base, appearing as liver or spleen lesions. Normal breathing during both the CT and PET scan can provide fewer registration errors.
Mismatch in percentages of exhalation (EX) and inhalation (IN) between CT and PET. Tezontl Rosario. Phased versus midventilation attenuation-corrected respiration-correlated PET for patients with non-small cell lung cancer. J Nucl Med Technol. 2009;37(4):208–214.
Other technologies such as four-dimensional (4D) PET offer improved visualization of a moving tumor compared with standard imaging. The scan is performed over the lungs using information from the respiratory cycle as determined by a special belt resting on the patient’s abdomen. The breathing data are then binned and reconstructed based on the tumor’s correct position in the respiratory cycle. The gated image’s improved target-to-background ratio (Fig. 11) directly correlates with enhanced targeted therapy.
18F-FDG PET/CT of patient with hypermetabolic left lower lobe lung nodule with respiration-gated imaging (CT, PET, and fused images) (A) and non–respiration-gated imaging (CT, PET, and fused images) (B). Eric Fair. Retrospective quantitative analysis comparing respiratory gated to nonrespiratory gated 18F-FDG PET/CT imaging in patients undergoing evaluation for primary lung cancer. J Nucl Med. 2019;60:1324.
Attenuation artifacts in the lungs may pose a problem when imaging lung cancer patients. Pacemakers, defibrillators, and cardiac catheters may make interpretation more difficult, and IV ports may show increased FDG activity. Occasionally, small doses of infiltrated FDG may cause well-defined focal uptake, which are typically small blood clots trapped in the lungs. These show up as FDG-avid areas but can generally be confirmed as blood clots when the area of interest is absent on CT.
Although FDG PET/CT is not as sensitive as MRI for detecting brain metastasis from lung cancer, evidence supports that including the entire brain for specific populations could detect brain metastases earlier in asymptomatic patients. However, the cost-to-benefit ratio should be weighed in the imaging decision due to the increased radiation exposure (Fig. 12).
Axial 18F-FDG PET image of brain demonstrates focal hypometabolism in right frontal lobe (A), corresponding to vasogenic edema on low-dose CT images (B). Subsequent axial T2-FLAIR and contrast-enhanced MR images confirm metastasis with adjacent vasogenic edema (C and D). Emily S. Nia. Incidence of brain metastases on follow-up 18F-FDG PET/CT scans of non-small cell lung cancer patients: Should we include the brain? J Nucl Med Technol. 2017;45(3):193–197.
A detailed patient history is essential to help delineate lung cancer from alternative clinical findings. Inflammation and infection from macrophages or lymphocytes utilize increased glucose and have a high glycolic rate. FDG-avid granuloma cells in sarcoidosis can be found in the lungs and the mediastinal and hilar nodes (Fig. 13). Tuberculosis (TB), a bacterial infection of the lungs, typically demonstrates increased 18F-FDG uptake. Dual time-point imaging can differentiate areas of active TB from old or inactive disease.
(A) 51-y-old man with sarcoidosis. Axial fused PET/CT images show intense 18F-FDG uptake at subcarinal nodes and left hilar lymphadenopathy. Hypermetabolic right lung nodule is also noted (arrow). (B) 65-y-old man with sarcoidosis. Axial fused PET/CT images show increased 18F-FDG uptake in right upper lobe associated with interstitial nodules having perilymphatic/peribronchovascular distribution. Increased uptake at mediastinal nodes and bilateral hilar lymphadenopathy are also noted. Panithaya Chareonthaitawee. Joint SNMMI-ASNC expert consensus document on the role of 18F-FDG PET/CT in cardiac sarcoid detection and therapy monitoring. J Nucl Med. 2017;58(8):1341–1353.
Scheduling too close following radiation therapy can cause positive FDG findings associated with radiation pneumonitis or inflammation. Therefore, PET/CT should be delayed for 3–6 mo following radiotherapy.
Understanding lung anatomy and potential areas of metastasis is critical in producing high-quality images. The carina, mediastinum, axillary nodes, and adrenals are important landmarks in lung cancer imaging. Contrast-enhanced CT in conjunction with PET/CT can be beneficial when evaluating hilar nodes, which can change the staging of lung cancers and assist clinicians in identifying specific sites for biopsy. Patients with a history of diabetes pose a higher risk for infections and inflammation in the lungs. It may be difficult for some lung cancer patients to lie flat due to O2 restrictions, pleural effusion, fluid around the lungs, or recent lung resections.
Overall, the recent PET/CT scanner improvements, including time-of-flight (TOF) technology, digital PET detectors, and PET/MRI, have improved image quality and tumor detection in lung cancer (Fig. 14).
(A and B) 18F-FDG–avid, histologically proven NSCLC in left upper lobe of 59-y-old woman on T2-weighted BLADE (balanced steady-state free-precession line acquisition with undersampling) MR image with measured maximum diameter of 3.7 cm (A) and fused 18F-FDG PET/MR image (B). (C and D) Identical tumor mass of same patient in left upper lobe on CT image with measured maximum diameter of 3.8 cm (C) and 18F-FDG PET/CT image (D). Primary tumor was correctly staged as T2a on 18F-FDG PET/MRI and 18F-FDG PET/CT. Philipp Heusch. Thoracic staging in lung cancer prospective comparison of 18F-FDG PET/MR imaging and 18F-FDG PET/CT. J Nucl Med. 2014;55(3):373–378.
Lung cancer will continue to be a global epidemic. Molecular imaging, genetic sequencing, and targeted therapy will continue to play a significant role in lung cancer detection, diagnosis, and treatment. Early detection and evaluation and knowing the extent of disease will predict the survival rate and improve the quality of life for lung cancer patients.
PET/CT IMAGING UPDATE
COVID-19
The COVID-19 pandemic has changed the way medicine is practiced around the world. According to the American Cancer Society, COVID-19 patients with cancer are at a higher risk for severe complications or death than those without cancer. Individuals with lung cancer are especially at risk for COVID-19 complications and poor prognosis.
Another challenge facing clinicians and patients is delayed screening, imaging, and follow-up care. Within a few weeks of the initial outbreak, clinicians in PET centers worldwide saw incidental findings on PET/CT. The most common presentation on CT for suspected COVID-19 infection included multifocal patchy shadows and ground-glass opacities within the posterior or peripheral lungs. Unfortunately, this pattern is common in patients who suffer from pneumonia and fungal infections and may be difficult to diagnose without a positive COVID-19 test.
In patients with COVID-19, increased FDG uptake is commonly seen within the same ground-glass opacities in the lung parenchyma seen on CT images. Given that FDG PET/CT is widely used for restaging purposes, consideration should be given when patients present with these findings (Fig. 15).
18F-FDG PET/CT in 53-y-old patient with NET of pancreas (grade 3 tumor) referred for restaging. At time of PET scan, patient was asymptomatic. Current 18F-FDG PET/CT displays new hypermetabolic area in right upper and lower lobe (SUVmax, 5.5), in topographic correlation to predominantly peripheral and subpleural ground-glass opacities with incipient partly round consolidations consistent with atypical inflammation. Later, COVID-19 infection was confirmed. Johannes Czernin. Nuclear medicine operations in the times of COVID-19: strategies, precautions, and experiences. J Nucl Med. 2020;61:626–629.
One additional finding associated with COVID-19 on FDG PET/CT is increased lymph node activity in the axilla following a recent COVID-19 immunization.
PET/CT in Immunotherapy Assessment
Few studies have been published regarding FDG PET/CT for patients undergoing immunotherapies. The basic principle of immunotherapy is to create a tumor response originating from a patient’s immune system. FDG PET/CT is currently used to predict the treatment response to therapy and watch for an inflammatory response related to a patient’s immunotherapy treatment. The immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) was recently proposed to monitor patients’ immunotherapy responses. The trend for developing new radiopharmaceuticals to image immune response is growing. The benefits are being seen in patients’ treatment plans by selecting patients who would benefit from immunotherapy, avoiding unnecessary and costly treatments. New biomarkers can be developed to identify patients who would benefit from immunotherapy using the body’s immune checkpoint pathways, such as the cell death protein PD-1 and PD-L1 and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4). 64Cu-DOTA-ipilimumab is used to visualize CTLA-4 expression in NSCLC, and 89Zr-nivolumab is used to correlate PD-1 expression tumor-infiltrated immune cells.
Patterns of tumor response to immunotherapy differ from other therapies such as chemotherapeutic and molecular agents. One phenomenon in patients undergoing immunotherapy is called pseudoprogression. Patient response to immunotherapy can occur early or be delayed. This includes the appearance of increased tumor size, SUV, or new lesions following therapy. Pseudoprogression is not due to cancer’s growth or spread, but it can be challenging for clinicians to determine. Therefore, FDG PET imaging should be performed before the patient undergoes immunotherapy. Follow-up scans are usually desired for comparison depending on the immunotherapy treatment regimen (Fig. 16).
18F-FDG PET/CT fused axial (A, D, and G), fused coronal (B, E, and H), and maximum-intensity projection (C, F, and I) images of 58-y-old man with metastatic adenocarcinoma of left lung showing 18F-FDG avidity with mediastinal lymph nodes and bilateral lung nodules on baseline PET/CT (G, H, and I). After 4 cycles of nivolumab, PET/CT (C, D, and E) showed progression by both immune RECIST and immune adaptive PERCIST; however, findings were considered immune unconfirmed progressive disease because of immunotherapy, and patient was clinically stable. After 6 cycles of nivolumab, PET/CT showed partial response by both criteria. Hence, this case highlighted pseudoprogression. Manoj Gupta. A comparative study of immune RECIST and immune adaptive PERCIST in non-small cell lung cancer patients treated with nivolumab. J Nucl Med. 2020;61(suppl 1):242.
Footnotes
↵* Reprinted from Thomas KS, Farrell MB. PET/CT in Oncology 2021: Part 2. Society of Nuclear Medicine and Molecular Imaging–Technologist Section; 2022:33–61.
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