Imaging Recommendations for Diagnosis, Staging, and Management of Lung Cancer

Smoking (80 – 90%) and environmental pollution are the leading risk factors for


Introduction Epidemiology
Globally, lung cancer is one of the leading malignancies in terms of incidence and mortality.It is the second most common malignancy in both the genders. 1 In India, lung cancer is one of the leading malignancies in men and fifth most common cancer in women.Its incidence varies between numerous regions of India.The projected incidence of lung cancer in men in India in 2020 was 9.9 per 100,000 people.activation of oncogenes and/or inactivation of tumor suppressor genes, resulting in neoplastic proliferation of cells.

Etiopathogenesis
Traditionally, lung cancer is classified into small cell lung cancer (SCLC) and nonsmall cell lung cancer (NSCLC) types, with nonsmall cell carcinomas including squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.There is an increasing incidence of NSCLC in women and nonsmokers.Following the worldwide trend, some studies in India are also reporting adenocarcinoma to be the most common pathological type in recent times, unlike squamous cell carcinoma that was more common previously. 2 However, other studies report no such change and still consider squamous cell carcinoma as the most common histopathological type. 3

Clinical Presentation
Most patients with lung cancer in India are men (up to 82.9%); this disease is more commonly observed in the age range of 46 to 70 years, with a mean age of 58 years.The most commonly reported symptoms include cough, loss of weight and appetite, dyspnea, fatigue, chest pain, and hemoptysis.Patients may also present with paraneoplastic syndromes.Examination findings include digital clubbing, lymphadenopathy, superior vena cava obstruction, and neurological deficits in metastatic disease. 4Although in countries which have adopted lung cancer screening could potentially be detecting lung cancers at an earlier stage, 44 to 47.6% of patients with lung cancer in India present at an advanced stage with metastatic disease. 2 Imaging plays an important role not only in the initial workup of patients with lung cancer but also in their regular follow-ups.It is also important to be aware of the changing profile of imaging appearances in patients with utilization of newer cancer treatments like immunotherapy. 5

Imaging Referral Guidelines
General practitioners and other primary healthcare providers should refer a patient for a chest radiograph (CXR) when there are symptoms and signs suggestive of lung cancer like hemoptysis, loss of weight and appetite, persistent cough or dyspnea, chest pain, and abnormal chest signs.If the CXR is abnormal or if there is high index of clinical suspicion, even if CXR is normal, patient should be referred for a computed tomographic (CT) scan and to a specialist. 6n CXR, lung cancer may present as a nodule, irregular mass, nonresolving consolidation, lobar collapse, effusion, hilar or mediastinal enlargement.But, usually when these are observed on CXR, the disease stage is advanced.In early stages, CXR may be appear to be normal.
AJCC, NCCN Guidelines for Imaging in Lung Cancer [7][8][9] The first imaging test to be performed in a suspected case of lung cancer is CXR.Contrast-enhanced CT (CECT) of chest and upper abdomen (including adrenal glands) is recommended for further evaluation. 18F-FDG PET-CT (positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrating CT) is indicated in patients with no signs of metastatic spread on CT who are candidates for curative intent treatments.
Contrast-enhanced magnetic resonance imaging (MRI) of brain (or CECT of brain, if MRI not available) is recommended in patients with NSCLCs (stages Ib and higher) and small cell carcinomas (any stage) even if there are no relevant symptoms.
Contrast-enhanced MRI of thoracic inlet, spine, and brachial plexus is indicated to check for Pancoast tumor for the sake of local tumor extension assessment.F-FDG PET-CT scan is the most accurate investigation method for the staging of lung cancer.If a PET scan is not available, then a CECT scan of thorax, abdomen, pelvis, and whole-body bone scan needs to be done.

American College of Radiology Appropriateness
Criteria for Imaging in Lung Cancer (►Table 1) 11 Ultrasound (US) of the abdomen may help in the evaluation of liver lesions that are observed to be ambiguous on CT scans.
According to most of the above-mentioned guidelines, 7-9 once lung cancer is detected, a whole body 18 F-FDG PET-CT scan would be the ideal modality to initially stage the disease.Gadolinium-enhanced MRI brain is recommended in all patients with SCLC or NSCLC except those with peripheral stage I (T1abc, N0).If PET-CT and MRI brain scans are not available, then CECT scan of the brain, thorax, abdomen, pelvis, and bone is recommended to be done for stage evaluation.

Clinical and Diagnostic Workup Excluding Imaging
Workup of lung carcinoma is dependent on the clinical presentation.The multipronged approach to complete diagnosis comprises three steps-histological diagnosis, staging, and functional evaluation.Additional tests are reserved for those who present with paraneoplastic syndromes.
Tests such as complete hemogram, liver function, calcium, electrolytes, blood urea nitrogen, and creatinine are performed as part of the initial assessment.
Tissue sample can be obtained via CT or endobronchoscopic-guided biopsy. 7,9Histology of the provided sample with light microscopy and immunohistochemical staining aids in the detection of subtypes of lung carcinoma.Molecular profiling serves as a biomarker to predict response to targeted therapies and immunotherapies. 12ampling of mediastinal nodes by endoscopic or endobronchial US or mediastinoscopy is recommended for histopathological analysis in all cases, with the exception of early-stage peripheral disease or if nodes are negative on PET-CT.
Variable sensitivity and specificity ranging from 77.4 to 81.3% and 79.4 to 90.1%, respectively, have been reported for PET-CT in mediastinal nodal staging in lung cancer. 13dditional diagnostic tests can be performed in patients with comorbidities or paraneoplastic symptoms; for example: a comprehensive paraneoplastic antibody panel for those with neurological syndromes, serum and urine osmolality in a suspected case of Syndrome of inappropriate antidiuretic hormone secretion, serum cortisol levels for Cushing's syndrome. 7f the patient has signs and symptoms suggestive of chronic obstructive pulmonary disease and has been scheduled for surgery or radiotherapy (RT), functional assessment with spirometry and 6-minute walk test and cardiac evaluation with electrocardiogram as well as echocardiogram is performed.Radionuclide lung perfusion scintigraphy can also be performed to measure the perfusion to the lung being resected during surgery and to predict postoperative lung function. 14

Imaging Guidelines Screening
It has been proven that if lung cancer is detected early, its 5year survival rate can be significantly improved. 15National Comprehensive Cancer Network (NCCN) was the first major organization to develop lung cancer screening using lowdose CT (LDCT).It was based on the National Lung Screening Trial which showed that LDCT screening reduced the relative risk of death from lung cancer by 20%. 16The International Early Lung Cancer Action Program showed annual CT screening allows at least 80% of lung cancer cases to be diagnosed early, that is, in clinical stage I. 17 The Nelson trial showed that 65 to 70% of cancers diagnosed in the screening arm were in stage IA and II, while 70% were in stage III/IV in the control arm. 18he Korean Lung Cancer Screening Project showed that lung cancer screening in a tuberculosis-endemic country may be less effective because of high incidence of false-positive results. 19The TALENT lung cancer screening study in Taiwan showed a high detection rate of 2.6% for early lung cancer with more than 96.5% of them being operable. 20A recent study by Parang and Bhavin showed high effectiveness of LDCT to detect or diagnose lung nodules and carcinoma in smokers even in a tuberculosis-endemic country like India. 21he American College of Radiology has developed Lung imaging Reporting and Data System to standardize the reporting and data management from LDCT examination. 22

Eligibility Criteria for Lung Cancer Screening
Various societies have proposed eligibility criteria for annual LDCT lung cancer screening that is given in ►Table 2. [23][24][25][26] Proposed protocol for LDCT in lung cancer screening is provided in ►Table 3.
Most societies recommend yearly LDCT for lung cancer screening in eligible individuals.

Diagnosis
As most of the cases with lung carcinoma present with advanced stages, diagnosis is usually not difficult by utilizing both modalities: CXR and CECT thorax.However, one-third of lung carcinoma cases have a solitary pulmonary nodule that may be difficult to differentiate from a benign nodule. 27ome of the imaging features may help to differentiate lung malignancy from benign lung lesions that are given in ►Table 4.
The Fleischner Society has formulated the guidelines for the assessment of an incidentally detected lung nodule based on appearance, growth rate, patient age, and history of smoking. 28ther features to be assessed on CT scans include invasion/ infiltration into surrounding structures like intercostal muscles and mediastinum, presence of lymphangitis (irregular nodular septal thickening adjacent to the tumor mass), adenopathy, erosion of ribs or vertebrae, and distant metastases.Central mass lesions may show either encasement and occlusion of segmental or lobar bronchus/endobronchial component or encasement of adjacent vessels.The imaging signs indicating invasion are tumor-mediastinal/pleural contact of more than 3 cm length, absence of the fat plane between the mass and mediastinum, thickening of the pleura, increased density of the extra-pleural fat adjacent to the tumor, angle of contact of tumor being more than 90 degrees with the aorta.Short-axis dimension more than 10 mm is generally considered to be indicative of abnormal mediastinal or hilar lymph node.Malignant nodes can be necrotic, but infections like tuberculosis also can show necrotic nodes.

Sampling of Lung Lesions
Tissue sampling is required during these scenarios: new or growing solitary mass, multiple nodules without known malignancy, and biopsy or re-biopsy of malignancy for targeted therapy.Various methods for sampling of lung nodule are available that include fiberoptic bronchoscopy, endobronchial ultrasound (EBUS) guided sampling, transthoracic needle biopsy, and video-assisted thoracoscopic surgery. 18F-FDG PET-CT helps to locate the site of biopsy, especially in larger tumor masses, where biopsy should be done from FDG-avid areas.For central lesions, bronchoscopic or EBUS-guided approach is preferred.Transthoracic US or CTguided approach may be used depending upon the location and ease of access to the lung lesion.Coaxial system should be used to take multiple samples and to increase yield and safety. 29As per the recent advances in molecular targeted therapy in lung cancers, larger sample volume is needed for necessary molecular testing.Therefore, core biopsy is preferred over fine needle aspirations.Abnormalities detected by 18 F-FDG PET scan have to be confirmed radiologically or pathologically.CT staging alone is not adequate for nodal involvement, as CT-based criteria of short axis dimension of more than 10 mm size of the lymph nodes has been shown to have a sensitivity of 55%, and specificity of 81%. 30A higher sensitivity of 83% and specificity of 92% are reported when high FDG uptake on PET is taken as a criterion for diagnosing nodal metastasis. 31Invasive sampling of suspicious nodes is recommended using EUS/EBUS/mediastinoscopy/ CT guidance.If pleural of pericardial effusion is present, US-guided thoracocentesis or pericardiocentesis is undertaken.Thoracoscopy can be performed when repeated pleural fluid analysis (at least 3 times) is inconclusive.

Staging
The aim of imaging with CT (►Figs. 1 and 2) and PET-CT (►Fig. 3)scans is that to assign appropriate clinical staging of lung cancer.Eighth edition American Joint Committee on Cancer Tumor, Node, and Metastasis (AJCC TNM) staging for lung cancer was implemented in 2018 (►Tables 5 and 6). 32ll aspects towards staging should be carefully looked for in the imaging.
Combined approach using TNM and veterans administration classification of SCLCs into 33 : a) Limited (where disease is confined to a single hemithorax and adjacent nodes which can be safe to include in an RT field) and b) Extensive stage (extends beyond the hemithorax including malignant pleural or pericardial effusion) is used to make treatment decisions

Tumor Response Assessment
The major attribute of RECIST 1.1 that is widely used for tumor response assessment is given in ►Table 7. 34,35 Limitations of RECIST 1.1: 1 is based on anatomical unidimensional measurement.The appropriateness of moving to three-dimensional volumetric measurement or functional measurement using PET/MRI scan was considered but not incorporated, due to insufficient standardization and evidence.(ii) RECIST 1.1 also does not contemplate morphological changes such as tumor cavitation.
(iii) Interreader variability can be present in reporting new lesions and non-target lesions (iv) RECIST 1.1 does not consider pseudoprogression.

Immune-Related Response Criteria
Following immunotherapy, there may be an appearance of new lesions or an increase in size of existing lesions before eventual regression and partial or complete response.This may be due to infiltration by T cells and is called "pseudoprogression."An increase in the size of lesions associated with rapid clinical decline is termed as "hyperprogression." The iRECIST criteria have been proposed for use in clinical trials for patients treated with immunotherapy. 36Flowchart 1) iRECIST has not been validated for treatment decisions.An important limitation of using iRECIST is that if the original progression was a true progression, effective salvage therapy gets delayed by several weeks.

Complications of Radiotherapy
Conformal RT is typically used for patients with advanced stage lung cancer and the treatment course is over 6 to 7 weeks.In contrast, stereotactic body radiotherapy (SBRT) is used for early-stage lung cancer; precise high dose fractions are given over a period of 2 weeks.Intensity-modulated RT (IMRT) is a technique in which radiation is delivered using multiple RT fields of varying influence; both conventional RT and SBRT can be delivered using this technique.Use of IMRT reduces the radiation delivered to the normal lung tissue around the tumor.Thus, treatment with IMRT can result in unusual patterns of pneumonitis in the patient, since radiological pneumonitis changes correlates with the shape of the RT field/plan. 37cute radiation pneumonitis (►Fig.4) can manifest as consolidation with air-bronchogram and straight borders and occurs 1 to 6 months after RT.Radiation fibrosis sets in at 6 to 12 months and stabilizes at 1 year period.Radiation fibrosis manifests as traction bronchiectasis, volume loss, kinking of airways, and pleural thickening/effusion.
Post RT changes in the lung can be FDG-avid for up to 2 years.In previously irradiated patients, treatment with immune checkpoint inhibitors (ICI) can cause RT recall pneumonitis (pneumonitis in the irradiated regions of the lung), years after completion of RT.Besides pneumonitis, pulmonary artery thrombosis, esophagitis, fistulas, cardiac disease have been reported as complications of RT.Unlike radiation fibrosis, if the lesion is progressively increasing in size in real time or after 1 year of treatment, when the margins are convex and bulging, there is opacification of previously seen bronchograms, or development of new adenopathy of pleural effusion, then recurrence or disease progression needs to be suspected. 38mune-Related Adverse Events 5,39,40 Because of their unique mechanism of action, ICI can cause toxicities in several organs in the body, which can occur earlier or later during therapy.RT recall pneumonitis, described in post RT patients on ICI, occurs in previously irradiated tissue after weeks, months, or even years of radiation therapy.
Hypophysitis, sarcoid-like granulomatosis, lymphadenopathy, pneumonitis, hepatitis, colitis, adrenalitis, and inflammation in other parts of the body have been described Flowchart 1 iRECIST criteria for follow-up of patients who are on immunotherapy.iCR, immune complete response; iPR, immune partial response; iSD, immune stable disease. in association with ICI toxicity.They must be differentiated from metastasis, infection, or progressive disease.
ICI pneumonitis is relatively rare but clinically serious with different patterns described.(►Table 8). 41,42Treatment generally consists of corticosteroid therapy and delaying/ stopping immunotherapy.After an initial response to corticosteroids, "Pneumonitis flare" can occur even without restarting immunotherapy. 43

Complications of Targeted Therapy
A recently published position paper by the Fleischner Society 44 recommends that radiological patterns be used to evaluate drug related pneumonitis which may be:

Follow-Up Surveillance Imaging Guidelines
American Society of Clinical Oncology Guidelines 45 American Society of Clinical Oncology guidelines can be used for patients with curatively treated stage I to III NSCLC and SCLC in absence of clinical symptoms of recurrence as described in ►Table 9.These guidelines apply for all patients treated with any modality including surgery, SBRT, and chemoradiation.

Principles of Management
Multiple international guidelines for treatment of lung cancer exist, that is, NCCN and NICE. 9,46Surgery, RT, and systemic therapy are used either individually or in combination.Therapy type is determined by the histological type (NSCLC or SCLC), extent of disease, and fitness of the patient for curative surgery following multidisciplinary team assessment. 47Flowchart 2 highlights the main points in this complex management algorithm.Image-guided thermal ablation treatment (IGTA) is a local ablative therapy that can be undertaken by interventional radiologist after an multidisciplinary team meeting decision is made to treat the patient with IGTA.Most often this treatment is reserved for localized disease with tumor size less than 3 cm in size and potentially operable, but other comorbidities preclude surgery.Various electromagnetic energies like radio frequency, microwave, or cryoablation are used to thermally ablate the lesion without affecting the adjacent normal lung tissue.One of the common complications of IGTA is pneumothorax.

Follow-Up Imaging and Management of Recurrent
Disease Including Specific Interventional and Palliative Measures ►Tables 12 and 13 highlight the salient points in follow-up and management of recurrent disease. 9

Summary of Recommendations (Flowchart 3)
• Initial imaging in lung cancer includes CECT thorax and 18 F-FDG PET-CT aiming for accurate clinical staging both locoregionally and extrathoracic metastases.
• Invasive lymph node sampling is recommended for suspicious nodes detected on CT or PET scans.occur with ICI and therapy-related toxicities in the lungs and elsewhere in the body.

Fig. 1 (
Fig. 1 (A) Axial computed tomographic (CT) thorax section in lung window shows a spiculated mass (white arrow) of longest dimension 2.8 cm in the apicoposterior segment of the left upper lobe.(B) Axial CT thorax section in mediastinal window reveals that there are no enlarged mediastinal or hilar nodes.TNM (tumor , nodes, and metastases) stage: T1cN0M0.

Fig. 3
Fig. 3 Patient with adenocarcinoma of the lung with positron emission tomography-computed tomography (PET-CT) imaging.CT thorax (A and C) and corresponding flourine-18 fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) images (B and D) demonstrate chest wall extension (thick white arrow), having standardized uptake value (SUV) of 9.4, enlarged right hilar (thin white arrow), and subcarinal node (black arrowhead) with SUV of 8.4 and 7.6, respectively.Pleural effusion with nodular pleural thickening (thin black arrow) with SUV of 6.6.Moderate amount of pleural effusion (double thin white arrows) on the left side.

Fig. 2 (
Fig. 2 (A and B) Axial computed tomographic (CT) thorax sections demonstrate central hilar mass having convex margin (white arrow) causing occlusion of right upper lobe bronchus, bronchus intermedius, right middle lobe bronchus with the resultant collapse, with mild peripheral bronchiectasis of right upper and right middle lobe having retained secretions in the peripheral bronchi (double thin white arrow).The lesion infiltrates and merges with the ipsilateral mediastinal, hilar, and subcarinal nodes.(C) The coronal CT thorax section also reveals the medial extension into the right main bronchus (black arrow).No distant metastases.TNM stage: T4N2.

Fig. 4 (
Fig. 4 (A and B) Computed tomographic (CT) thorax lung and mediastinal sections, respectively, demonstrate a lobulated mass (double thin white arrow) of 3.3 cm in the left lower lobe.No enlarged nodes.The patient underwent a left lower lobectomy.Histopathological examination revealed pleomorphic carcinoma with adenocarcinomatous component.Final stage was pT2aN2Mx.The patient had four cycles of adjuvant cisplatin and pemetrexed.(C) Post-chemotherapy and prior to radiotherapy, the CT thorax performed demonstrates no lesion in the left upper lobe.(D and E) CT thorax and corresponding flourine-18 fluorodeoxyglucose positron emission tomography images demonstrate an irregular lesion (thick white arrow) in the left upper lobe having an standardized uptake value of 4.6.As the lesion appeared after starting radiotherapy and as there was no evidence of infection clinically, radiation pneumonitis was considered the most likely diagnosis.The patient was treated with steroids and follow-up CT thorax (F) demonstrates the replacement of the irregular parenchymal lesion with small residual fibrotic changes (black arrow).
a. Acute diffuse alveolar damage (DAD) b.Transient (simple pulmonary eosinophilia) c.Subacute-Organizing pneumonia and hypersensitivity pneumonitis (OP and HP) d.Chronic-Nonspecific interstitial pneumonitis.A single drug may cause multiple radiological patterns.Epidermal growth factor receptor tyrosine kinase inhibitors therapy has been associated with all the above patterns.ALK inhibitor therapy has been associated with OP and DAD patterns.The diagnosis is made based on the occurrence of new changes in the lungs, their temporal association with the drug, and exclusion of other causes.Management of these complications is by cessation of the drug course, immunosuppressive therapy, and supportive treatment.

Table 1
ACR appropriateness criteria for imaging in lung cancer CT thorax CECT is preferred.NCCT can be done if contrast cannot be administered for any reason 18 F-FDG PET-CT PET imaging from skull base to upper thigh is recommended for evaluation of extrathoracic disease CT abdomen and pelvis To look for extrathoracic disease if PET-CT is not available Bone scan To look for skeletal metastasis if PET-CT is not available MRI brain With gadolinium in NSCLC stage II, III, or IV even in the absence of neurological symptoms Any stage of NSCLC with neurological symptoms All small cell carcinoma (irrespective of stage) CT head With contrast, only if MRI brain cannot be performed MRI thorax For superior sulcus tumors or in equivocal findings on chest CT, to better evaluate for chest wall or mediastinal infiltration MRI abdomen Chemical shift imaging of adrenal gland lesions to see if they are adenomas or metastases (may not be necessary if PET-CT is performed) Abbreviations: ACR, American College of Radiology; CECT, contrast-enhanced computed tomography; 18 F-FDG PET-CT, flourine-18 fluorodeoxyglucose positron emission tomography-computed tomography; NCCT, noncontrast computed tomography; MRI, magnetic resonance imaging; NSCLC, nonsmall cell lung cancer.

Table 2
Eligibility criteria for lung cancer screening by various specialty societies

Table 4
CT features in favor of benign and malignant lung nodule Imaging Recommendations for Diagnosis, Staging, and Management of Lung Cancer Irodi et al. 185 Abbreviations: CT, computed tomography; FDG, fluorodeoxyglucose; HU, Hounsfield unit; PET, positron emission tomography; SUV, standardized uptake value.Indian Journal of Medical and Paediatric Oncology Vol.44 No. 2/2023 © 2023.The Author(s).

Table 5
AJCC TNM 8th staging of lung cancer : AJCC TNM, American Joint Committee on Cancer Tumor, Node, and Metastasis. Abbreviation

Table 6
Stage grouping according to AJCC 8th ed TNM staging of lung cancer Abbreviation: AJCC TNM, American Joint Committee on Cancer Tumor, Node, and Metastasis.

Table 7
RECIST 1.1 criteria for tumor response assessment Partial response (PR) When there is more than 30% decrease in size from baselineComplete response (CR)When there is complete disappearance of the lesion and pathological lymph nodes are reduced to less than 10 mm Stable disease (SD)

Table 8
Radiological patterns in immune checkpoint inhibitor-related pneumonitis

Table 9
45CO guidelines for follow-up of curatively treated stage I-III NSCLC and SCLC PCI.Adapted from ASCO 2019 guidelines45May be omitted in clinically unsuitable patients or those unwilling to undergo further treatment.Age should not preclude surveillance imaging.Overall performance status, medical history, and patient preferences are to be considered.

Table 11
NCCN surveillance guidelines: SCLC, Version 2.2022 For all patients with SCLC to decrease the occurrence of second primary tumors Cancer survivorship care Cancer surveillance as above, immunizations, health monitoring, counseling for health promotion and wellness Abbreviations: FDG-PET-CT, fluorodeoxyglucose positron emission tomography-computed tomography; MRI, magnetic resonance imaging; NCCN, National Comprehensive Cancer Network; PCI, prophylactic cranial irradiation; SCLC, small cell lung cancer.Adapted from NCCN Guidelines: Small Cell Lung Cancer.Version 2.2022.
• Contrast-enhanced brain MRI scan is recommended in advanced stage NSCLCs and in all stages of SCLCs.• Different surveillance protocols are available and radiologists should be aware of pseudoprogression that can
NCCN recommendations for treatment and follow-up of loco-regional recurrence found on surveillance imaging Symptoms/site of recurrence Treatment options Follow-up imaging (depends on initial recurrence and any newly developing symptoms) Abbreviations

Table 13
NCCN recommendations for the treatment of distant metastases found on surveillance imaging Abbreviations: NCCN, National Comprehensive Cancer Network; RT, radiotherapy.