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

CC BY 4.0 · Indian J Med Paediatr Oncol 2023; 44(02): 181-193

DOI: DOI: 10.1055/s-0042-1759572

Author : Aparna Irodi,Ashu Seith Bhalla,Leena Robinson Vimala,Taruna Yadav,Subathra Adithan,Harish Bhujade,Parang Sanghavi,Alok Kale,Mandeep Garg,Abhishek Mahajan,Yvette Kirubha Jaykar David Livingstone,Sudha Kiran Das,Geethi M. H.,Balukrishna Sasidharan,Balamugesh Thangakunam,Simon Pavamani,Rajesh Isiah,Anjana Joel,Tameem Ahmad Bhat

Abstract

Globally and in India, lung cancer is one of the leading malignancies in terms of incidence and mortality. Smoking and environmental pollution are the common risk factors for developing lung cancer. Traditionally, lung cancer is divided into small cell and nonsmall cell types, with nonsmall cell carcinomas including squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.

In this review article, we describe the imaging recommendations and findings in the diagnosis, staging, and management of lung cancer, including the imaging of treatment-related complications.

Keywords

cancer - imaging - lung - recommendations


Publication History

Article published online:
24 January 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

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Abstract

Globally and in India, lung cancer is one of the leading malignancies in terms of incidence and mortality. Smoking and environmental pollution are the common risk factors for developing lung cancer. Traditionally, lung cancer is divided into small cell and nonsmall cell types, with nonsmall cell carcinomas including squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.

In this review article, we describe the imaging recommendations and findings in the diagnosis, staging, and management of lung cancer, including the imaging of treatment-related complications.

Keywords

cancer - imaging - lung - recommendations

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.

Risk Factors

Smoking (80–90%) and environmental pollution are the leading risk factors for lung cancer in India.[2] Exposure to carcinogens in genetically susceptible individuals may cause 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 o b s e r v e d 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.[4] Although 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.[6]

On 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.

Indian Radiological and Imaging Association Guidelines for Imaging in Lung Cancer[10]

18F-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]


Table 1

ACR appropriateness criteria for imaging in lung cancer

Abbreviations: ACR, American College of Radiology; CECT, contrast-enhanced computed tomography; 18F-FDG PET-CT, flourine-18 fluorodeoxyglucose positron emission tomography-computed tomography; NCCT, noncontrast computed tomography; MRI, magnetic resonance imaging; NSCLC, nonsmall cell lung cancer.

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] [8] [9] once lung cancer is detected, a whole body 18F-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] [9] Histology 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.[12] Sampling 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.[13]

Additional 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.[7]

If 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 5-year survival rate can be significantly improved.[15] National Comprehensive Cancer Network (NCCN) was the first major organization to develop lung cancer screening using low-dose 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%.[16] The 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.[18]

The 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.[19] The 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.[20] A 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.[21]

The 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]

CT thorax

CECT is preferred. NCCT can be done if contrast cannot be administered for any reason

18F-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)
Table 2

Eligibility criteria for lung cancer screening by various specialty societies

Abbreviations: ACCP, American College of Chest Physicians; ACS, American Cancer Society; ALA, American Lung Association; ASCO, American Society of Clinical Oncology; ATS, American Thoracic Society; ESR, The European Society of Radiology; NCCN, National Comprehensive Cancer Network; USPSFT - U.S. Preventive Services Task Force.

Proposed protocol for LDCT in lung cancer screening is provided in [Table 3].

Organization

Patient age/symptoms

Smoking history (pack-years)

Other factors

ACCP, ASCO, ATS, ACS, and ALS

55–74, asymptomatic

≥ 30

Less than 15 years since smoking cessation

NCCN

55–74, asymptomatic or ≥ 50 asymptomatic

≥ 30

≥20

Less than 15 years since smoking cessation or one or more additional risk factors like pulmonary disease, family history of lung cancer, personal cancer history, radon exposure

ESR

55–80 years

At least 30 pack-years

Current smoker or exsmoker who has quit smoking within the last 15 years

USPSFT

55–80 asymptomatic

≥ 30

Less than 15 years since smoking cessation
Table 3

LDCT protocol

Abbreviation: LDCT, low-dose computed tomography.

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.[27] Some of the imaging features may help to differentiate lung malignancy from benign lung lesions that are given in [Table 4].

kV

120

mAs

50

Pitch

1.2

Slice thickness

1 mm

Slice interval

0.5 mm

Scan region

Thoracic inlet to costophrenic angles

Respiration

Suspended end-inspiration

Reconstructions

Lung (e.g., B70) and soft tissue (e.g., B35)

reconstructions and window setting

Effective radiation dose

< 1>

Table 4

CT features in favor of benign and malignant lung nodule

Abbreviations: CT, computed tomography; FDG, fluorodeoxyglucose; HU, Hounsfield unit; PET, positron emission tomography; SUV, standardized uptake value.

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.[28]

Other 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 CT-guided 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.[29] As 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 18F-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%.[30] A 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.[31] Invasive 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]).[32] All aspects towards staging should be carefully looked for in the imaging.

Imaging features

Benign

Malignant

Comments

Size[23] [24]

Less than 1 cm

More than 3 cm

Average of two orthogonal measurements is taken

Smaller lesions can also be malignant

Margins[23] [25]

Sharp, smooth, or well-defined

Spiculated, irregular, ill-defined, “pleural tail”

20%-of malignant nodules may show smooth and well-defined margins

Internal morphology

Density[26] [27]

Pure ground glass density nodules <5>

- Pure ground glass density nodule 6–30 mm could represent adenocarcinoma in situ

- Part-solid nodule with solid component < 5 mm could represent minimally invasive adenocarcinoma

- Part-solid nodule with solid component > 5 mm could represent invasive adenocarcinoma lepidic predominant adenocarcinoma

- Solid nodules or consolidation could represent mucinous adenocarcinoma in situ, invasive mucinous adenocarcinoma

Based on density nodules can be solid or subsolid. Subsolid nodules can be pure ground glass density or part-solid

Calcifications

Diffuse, central, popcorn, laminated

Amorphous, punctate

Fat[28]

Presence of fat (−40 to −120 HU) favors benign lesion like hamartoma

Fat is usually absent in malignancy

Cavitation

Smooth, thin walls. Usually less than 4 mm

wall thickness

Thick, irregular walls. Usually more than 16 mm wall thickness

Growth rate[29]

More than 400 days or very short in infections

Doubling time 20 to 400 days (average 240)

The serial volumes instead of diameters and computer-aided doubling of volume of small nodules have been proposed to be an accurate way to evaluate growth

Small and large cell cancers may show a

faster growth

Contrast enhancement[30]

Less than 15 HU

More than 20 HU

Larger malignant lesions tend to show more heterogeneous contrast enhancement due to presence of necrosis within the lesion

Metabolism[31]

Less than 2.5 SUV

More than 2.5 SUV

Note that infective and inflammatory conditions also can show high SUV. PET can help in guiding biopsy to the areas with increased FDG avidity

|  Figure 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.

| Figure 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.

| Figure 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 (18F-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.



Table 5

AJCC TNM 8th staging of lung cancer

Abbreviation: AJCC TNM, American Joint Committee on Cancer Tumor, Node, and Metastasis.

T staging

N staging

M staging

T0—No primary tumor

Tis—Carcinoma in situ

T1—Tumor < 3 cm (T1mi—minimally invasive adenocarcinoma; T1a—Superficial spreading tumor in central airways)

 T1a—Tumor < 1 cm

 T1b—Tumor > 1 cm but < 2 cm

 T1c—Tumor > 2 cm but < 3 cm

T2—Tumor >3 cm but < 5 cm or tumor involving visceral pleura/main bronchus (not carina)/atelectasis up to hilum

 T2a—Tumor > 3 cm but < 4 cm

 T2b—Tumor > 4 cm but < 5 cm

T3—Tumor > 5 cm but < 7 cm or invading chest wall, pericardium, phrenic nerve; or separate tumor nodule(s) in the same lobe

T4—Tumor > 7 cm or tumor invading mediastinum/diaphragm/hear/great vessels/recurrent laryngeal nerve/carina/trachea/esophagus/spine or tumor nodule(s) in a different lobe in same lung

N0—No regional node metastasis

N1—Metastasis in ipsilateral pulmonary or hilar nodes

N2—Metastasis in ipsilateral mediastinal or subcarinal nodes N3—Metastasis in contralateral mediastinal, hilar, or supraclavicular nodes

M0—No distant metastasis

M1a—Malignant pleural or pericardial effusion or pleural or pericardial nodules or separate tumor nodule(s) in the contralateral lung M1b—Single extrathoracic metastasis

M1c—Multiple extrathoracic metastases (in 1 or >1 organ)
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.

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

Management (Response Assessment Imaging in Neoadjuvant, Adjuvant, and Palliative Settings)

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]

T/M

Subcategory

N0

N1

N2

N3

T1

T1a

IA1

IIB

IIIA

IIIB

T1b

IA2

IIB

IIIA

IIIB

T1c

IA3

IIB

IIIA

IIIB

T2

T2a

IB

IIB

IIIA

IIIB

T2b

IIA

IIB

IIIA

IIIB

T3

T3

IIB

IIIA

IIIB

IIIC

T4

T4

IIIA

IIIA

IIIB

IIIC

M1

M1a

IVA

IVA

IVA

IVA

M1b

IVA

IVA

IVA

IVA

M1c

IVB

IVB

IVB

IVB
Table 7

RECIST 1.1 criteria for tumor response assessment

Limitations of RECIST 1.1:

  • (i) RECIST 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.[36] ([Flowchart 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.

Measurable and target lesions

A maximum of 5 total target lesions (a maximum of 2 per organ) are quantitatively assessed

The lesion must be at least 10 mm in size

The sum of the longest diameters is recorded as the sum of measurable lesions (SOM)

Pathological lymph nodes with a short axis diameter of 15 mm or more can be considered as target lesions. For lymph nodes, a short axis dimension is taken for SOM

Nontarget and nonmeasurable lesions

May be recorded qualitatively

Lesions less than 10 mm; nodes between 10 and 15 mm

Nonmeasurable lesions like pleural or pericardial effusion or lymphangitis

Progressive disease (PD)

At least 20%-increase in size over the nadir (smallest measured tumor burden during the course of the disease). The minimum increase should be at least 5 mm

“Unequivocal” progression in nonmeasurable or other non-target lesions (effusions, bone lesions) is recorded as PD

Any new lesions are considered as PD

Partial response (PR)

When there is more than 30%-decrease in size from baseline

Complete response (CR)

When there is complete disappearance of the lesion and pathological lymph nodes are reduced to less than 10 mm

Stable disease (SD)

|  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.0.


Complications of Treatment

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.[37]

Acute 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.

|  Figure 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).


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.[38]

Immune-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 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] [42] Treatment generally consists of corticosteroid therapy and delaying/stopping immunotherapy. After an initial response to corticosteroids, “Pneumonitis flare” can occur even without restarting immunotherapy.[43]


Table 8

Radiological patterns in immune checkpoint inhibitor-related pneumonitis

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:

  • Acute diffuse alveolar damage (DAD)

  • Transient (simple pulmonary eosinophilia)

  • Subacute—Organizing pneumonia and hypersensitivity pneumonitis (OP and HP)

  • 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.

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.

Cryptogenic organizing pneumonia (COP) pattern

Peripherally distributed multifocal bilateral parenchyma consolidation and ground glass opacity (GGO)

This is the most common pattern

Diffuse alveolar damage pattern (DAD)(AIP/ARDS) (diffuse alveolar damage/acute interstitial pneumonia/acute respiratory distress syndrome)

Diffuse/multifocal; GGO/consolidation with lung volume loss and traction bronchiectasis

This is clinically the most serious type

NSIP (nonspecific interstitial pneumonitis) pattern

Peripherally distributed reticular opacities and GGO ± volume loss/traction bronchiectasis

These patients have relatively mild clinical manifestations

HP (hypersensitivity pneumonitis) pattern

Diffuse centrilobular nodules and GGO ± air trapping
Table 9

ASCO guidelines for follow-up of curatively treated stage I–III NSCLC and SCLC PCI. Adapted from ASCO 2019 guidelines[45]

Abbreviations: ASCO, American Society of Clinical Oncology; CT, computed tomography; FDG-PET-CT, fluorodeoxyglucose positron emission tomography-computed tomography; NSCLC, nonsmall cell lung cancer; PCI, prophylactic cranial irradiation.

NCCN Surveillance Guidelines

NCCN guidelines are described in [Tables 10] (NSCLC) and [11] (SCLC).[7] [9]

ASCO 2019, lung cancer surveillance guidelines after definitive curative-intent therapy (stage I–III)

NSCLC

SCLC

Imaging modality

1. Frequency of imaging

Every 6 months for 2 years

Every 6 months for 2 years

Chest CT including adrenals ± contrast (contrast preferred)

Annually after 2 years

Annually after 2 years

Low-dose screening chest CT

2. Role of brain MRI

No

First 2 years—every 3 months during first year and every 6 months during second year in patients with or without PCI

3. Role of circulating biomarkers or FDG-PET-CT

No

No

4. Any patient factors precluding surveillance?

May 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 10

NCCN surveillance guidelines: nonsmall cell lung cancer, Version 3.2020

Abbreviations: FDG, fluorodeoxyglucose; H&P, history and physical; NCCN, National Comprehensive Cancer Network; PET-CT, positron emission tomography-computed tomography; RT, radiotherapy.

1—Timing of CT scans within Guidelines parameters is a clinical decision. 2—Previous areas treated with RT may show FDG avidity till 2 years; so, histologic confirmation of apparent “recurrent” disease is mandatory. Adapted from NCCN Guideline: Non-Small Cell Lung Cancer. Version 3.2020 (2).

Stage

Primary treatment

Imaging modality

Frequency of imaging

I–II

Surgery ± chemotherapy

H&P and chest CT ± contrast

Every 6 months for 2–3 years

Low dose noncontrast chest CT

Annually after 2–3 years

I–II or III or IV (oligometastatic with all sites treated with definitive intent)

Primary treatment included RT

H&P and chest CT1 ± contrast

Every 3–6 months for 3 years, then

H&P and chest CT1 ± contrast

Every 6 months for 2 years, then

H&P and a low dose noncontrast CT chest

annually

Any residual or new radiographic abnormalities

More frequent imaging may be required

Any stage

Chemotherapy ± RT—any residual or new radiographic abnormalities—more frequent imaging may be required.

PET/CT or brain MRI

Not routinely indicated. PET-CT may be useful where CT scan shows a mass to differentiate between malignancy versus radiation fibrosis, atelectasis, or other benign conditions2

Smoking cessation

Smoking cessation advice, counselling, and pharmacotherapy

Long term follow-up—cancer survivorship care

Cancer surveillance as above, immunizations, health monitoring, counselling for health promotion, and wellness
Table 11

NCCN surveillance guidelines: SCLC, Version 2.2022

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.

Principles of Management

Multiple international guidelines for treatment of lung cancer exist, that is, NCCN and NICE.[9] [46] Surgery, 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.[47] [Flowchart 2] highlights the main points in this complex management algorithm.

Frequency and modality of imaging

H&P, blood work as clinically indicated. Chest CT ± abdomen/pelvis - Every 2–6 months (more frequently) for 2 years and less frequently thereafter

Brain MRI (preferred) or brain CT with contrast

Every 3–4 months during 1st year for all patients and then every 6 months during 2nd year, regardless of the PCI status

New pulmonary nodule

Workup for a potential new primary lesion should be initiated

FDG-PET-CT

Not recommended for routine follow-up

Smoking cessation intervention

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

| Flowchart 2:Highlights of principles of management of lung cancer. FDG PET, flourine-18 fluorodeoxyglucose positron emission tomography; NSCLC, nonsmall cell lung cancer; SBRT, stereotactic body radiotherapy; EGFR, epidermal growth factor receptor.

|  Flowchart 3:Summary of recommendations in workup and follow-up of patients with lung cancer. CXR, chest X-ray; LDCT, low-dose computed tomography; EBUS, endobronchial ultrasound; ECG, electrocardiogram; 18F-FDG PET-CT, flourine-18 fluorodeoxyglucose positron emission tomography computed tomography.


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]

Table 12

NCCN recommendations for treatment and follow-up of loco-regional recurrence found on surveillance imaging

Abbreviations: MRI, magnetic resonance imaging; NCCN, National Comprehensive Cancer Network; PET-CT, positron emission tomography-computed tomography; SVC, superior vena cava.

Symptoms/site of recurrence

Treatment options

Follow-up imaging (depends on initial recurrence and any newly developing symptoms)

Hemoptysis

RT/surgery/embolization

Contrast-enhanced chest CT

Contrast-enhanced MRI brain PET-CT

SVC obstruction

SVC stenting, chemoradiation

Endobronchial obstruction

Radiotherapy/stenting/laser /photodynamic therapy

Resectable local recurrence

Resection

Nodal recurrence

Chemoradiation/systemic therapy
Table 13

NCCN recommendations for the treatment of distant metastases found on surveillance imaging

Abbreviations: NCCN, National Comprehensive Cancer Network; RT, radiotherapy.

Summary of Recommendations ([Flowchart 3])

  • Initial imaging in lung cancer includes CECT thorax and 18F-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.

  • 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 occur with ICI and therapy-related toxicities in the lungs and elsewhere in the body.

Conflict of Interest

None declared.

Symptoms/site of recurrence

Treatment options

Follow-up imaging

Localized symptoms

Palliative RT

No specific imaging recommended

Diffuse brain metastases

Palliative RT

Skeletal metastases

Surgical stabilization/palliative RT/bisphosphonates

Limited metastases

Resection

Disseminated metastases

RT/ systemic therapy

References

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  2.  Mohan A, Garg A, Gupta A. et al. Clinical profile of lung cancer in North India: a 10-year analysis of 1862 patients from a tertiary care center. Lung India 2020; 37 (03) 190-197
  3.  Noronha V, Pinninti R, Patil VM, Joshi A, Prabhash K. Lung cancer in the Indian subcontinent. South Asian J Cancer 2016; 5 (03) 95-103
  4.  Mathur P, Sathishkumar K, Chaturvedi M. et al; ICMR-NCDIR-NCRP Investigator Group. Cancer statistics, 2020: report from National Cancer Registry Programme, India. JCO Glob Oncol 2020; 6: 1063-1075
  5.  Nishino M, Hatabu H, Hodi FS. Imaging of cancer immunotherapy: current approaches and future directions. Radiology 2019; 290 (01) 9-22
  6.  Del Giudice ME, Young SM, Vella ET. et al. Guideline for referral of patients with suspected lung cancer by family physicians and other primary care providers. Can Fam Physician 2014; 60 (08) 711-716 , e376–e382
  7.  Ganti AKP, Loo BWJ, Bassetti M. et al. Small cell lung cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021; 19 (12) 1441-1464
  8.  Ettinger DS, Wood DE, Aisner DL. et al. Non-small cell lung cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2022; 20 (05) 497-530
  9.  Ettinger DS, Wood DE, Aisner DL. et al. NCCN guidelines insights: non-small cell lung cancer, Version 2.2021. J Natl Compr Canc Netw 2021; 19 (03) 254-266
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  14.  Brunelli A, Kim AW, Berger KI, Addrizzo-Harris DJ. Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013; 143 (5, Suppl): e166S-e190S
  15.  American Cancer Society. Cancer facts & figures 2020. Accessed November 15, 2022, at: https://www.cancer.org/research/cancer-factsstatistics/all-cancer-facts-figures/cancer-facts-figures-2020.html
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Address for correspondence

Aparna Irodi, MD, FRCR
Department of Radiology, Christian Medical College
Vellore, Tamil Nadu 632004
India   


Publication History

Article published online:
24 January 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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|  Figure 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.

| Figure 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.

| Figure 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 (18F-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.

|  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.0.

|  Figure 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).

| Flowchart 2:Highlights of principles of management of lung cancer. FDG PET, flourine-18 fluorodeoxyglucose positron emission tomography; NSCLC, nonsmall cell lung cancer; SBRT, stereotactic body radiotherapy; EGFR, epidermal growth factor receptor.

|  Flowchart 3:Summary of recommendations in workup and follow-up of patients with lung cancer. CXR, chest X-ray; LDCT, low-dose computed tomography; EBUS, endobronchial ultrasound; ECG, electrocardiogram; 18F-FDG PET-CT, flourine-18 fluorodeoxyglucose positron emission tomography computed tomography.

References

  1.  Thandra KC, Barsouk A, Saginala K, Aluru JS, Barsouk A. Epidemiology of lung cancer. Contemp Oncol (Pozn) 2021; 25 (01) 45-52
  2.  Mohan A, Garg A, Gupta A. et al. Clinical profile of lung cancer in North India: a 10-year analysis of 1862 patients from a tertiary care center. Lung India 2020; 37 (03) 190-197
  3.  Noronha V, Pinninti R, Patil VM, Joshi A, Prabhash K. Lung cancer in the Indian subcontinent. South Asian J Cancer 2016; 5 (03) 95-103
  4.  Mathur P, Sathishkumar K, Chaturvedi M. et al; ICMR-NCDIR-NCRP Investigator Group. Cancer statistics, 2020: report from National Cancer Registry Programme, India. JCO Glob Oncol 2020; 6: 1063-1075
  5.  Nishino M, Hatabu H, Hodi FS. Imaging of cancer immunotherapy: current approaches and future directions. Radiology 2019; 290 (01) 9-22
  6.  Del Giudice ME, Young SM, Vella ET. et al. Guideline for referral of patients with suspected lung cancer by family physicians and other primary care providers. Can Fam Physician 2014; 60 (08) 711-716 , e376–e382
  7.  Ganti AKP, Loo BWJ, Bassetti M. et al. Small cell lung cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021; 19 (12) 1441-1464
  8.  Ettinger DS, Wood DE, Aisner DL. et al. Non-small cell lung cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2022; 20 (05) 497-530
  9.  Ettinger DS, Wood DE, Aisner DL. et al. NCCN guidelines insights: non-small cell lung cancer, Version 2.2021. J Natl Compr Canc Netw 2021; 19 (03) 254-266
  10.  Accessed November 15, 2022, at: https://iria.org.in/radiology-imaging-guidelines
  11.  de Groot PM, Chung JH, Ackman JB. et al; Expert Panel on Thoracic Imaging. ACR Appropriateness Criteria® noninvasive clinical staging of primary lung cancer. J Am Coll Radiol 2019; 16 (5S): S184-S195
  12.  Melosky B, Blais N, Cheema P. et al. Standardizing biomarker testing for Canadian patients with advanced lung cancer. Curr Oncol 2018; 25 (01) 73-82
  13.  Schmidt-Hansen M, Baldwin DR, Hasler E, Zamora J, Abraira V, Roqué I Figuls M. PET-CT for assessing mediastinal lymph node involvement in patients with suspected resectable non-small cell lung cancer. Cochrane Database Syst Rev 2014; (11) CD009519 DOI: 10.1002/14651858.CD009519.pub2.
  14.  Brunelli A, Kim AW, Berger KI, Addrizzo-Harris DJ. Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013; 143 (5, Suppl): e166S-e190S
  15.  American Cancer Society. Cancer facts & figures 2020. Accessed November 15, 2022, at: https://www.cancer.org/research/cancer-factsstatistics/all-cancer-facts-figures/cancer-facts-figures-2020.html
  16.  Aberle DR, Adams AM, Berg CD. et al; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011; 365 (05) 395-409
  17.  Henschke CI, McCauley DI, Yankelevitz DF. et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999; 354 (9173): 99-105
  18.  De Koning H, Van Der Aalst C, Ten Haaf K. et al. Effects of volume CT lung cancer screening: mortality results of the NELSON randomized-controlled population-based trial. Paper presented at: 2018 World Conference on Lung Cancer. Abstract PL02.05; 2018
  19.  Kim H, Kim HY, Goo JM, Kim Y. Lung cancer CT screening and lung-RADS in a tuberculosis-endemic country: The Korean Lung Cancer Screening Project (K-LUCAS. Radiology 2020; 296 (01) 181-188
  20.  Yang P. MS16.04 National Lung Screening Program in Taiwan. IASLC 19th World Conf . Lung Cancer 2018; 13 (10, Supplement): S274-S275
  21.  Parang S, Bhavin J. LDCT screening in smokers in India-a pilot, proof-of-concept study. Indian J Radiol Imaging 2021; 31 (02) 318-322
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