Lung Cancer

Classification and General CharacteristicsTop

Lung cancer remains the leading cause of cancer-related mortality worldwide. While cigarette smoking is the primary risk factor, environmental, occupational, and genetic factors also play significant roles. Lung cancer is broadly classified into two main categories: non–small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC). NSCLC is further divided into three main subtypes: adenocarcinoma, squamous cell carcinoma, and large-cell carcinoma.

1. NSCLCs (80%-85%):

1) Adenocarcinoma (~40%-50%) is the most common type of NSCLC, typically arising from the small airways or peripheral lung regions. Tumor testing for driver variants (eg, EGFR, KRAS, ALK, BRAF, ROS1, NTRK, RET) is essential, as targeted therapies significantly improve outcomes.

2) Squamous cell carcinoma (SCC) (~30%) is strongly linked to smoking and is more common in men. It frequently causes bronchial narrowing, atelectasis, and inflammatory lung changes. The classic appearance is that of a thick-walled mass with necrotic or cavitary center.

3) Large cell carcinoma (LCC) is difficult to define, as the tumor represents a malignant epithelial neoplasm lacking glandular, squamous, or neuroendocrine differentiation. Natural history is traditionally similar to that of adenocarcinoma in terms of propensity for spread.

2. Small cell lung carcinoma (SCLC) (<10%) is a poorly defined malignant epithelial neoplasm lacking glandular, squamous, or neuroendocrine differentiation. Its behavior resembles adenocarcinoma, with a similar spread pattern.

3. Rare lung neoplasms (<5%): This group includes carcinoid tumors, adenosquamous carcinoma, sarcoma, salivary gland tumors (eg, mucoepidermoid carcinoma, adenocystic carcinoma), and rare mesenchymal, embryonic, or lymphatic tumors

Clinical FeaturesTop

Lung cancer is often asymptomatic in early stages, leading to delayed diagnosis. Symptoms can be systemic, local, metastatic, or paraneoplastic.

1. Systemic symptoms include progressive weight loss, weakness, and low-grade fever (usually late-stage findings).

2. Symptoms related to local growth: Cough (different than many patients’ chronic cough; the most common), shortness of breath, chest pain, hemoptysis, recurrent or nonresolving pneumonia; superior vena cava syndrome (when there is massive mediastinal involvement), pleural pain (when there is pleural involvement), shoulder pain and Horner syndrome, arrhythmias (with pericardial and heart infiltration), hoarseness (as a result of recurrent laryngeal nerve paralysis), dysphagia (as a result of secondary esophageal compression or massive upper mediastinal involvement) in advanced disease.

3. Symptoms related to metastases: Enlargement of supraclavicular, cervical, or axillary lymph nodes; bone pain (or soreness), pathologic fractures or compression symptoms; in CNS metastases: headache, focal neurologic symptoms and other neurologic manifestations (eg, seizures, balance disorders), behavioral changes and personality disorders; in liver metastases: hepatomegaly, epigastric pain, nausea, jaundice.

4. Paraneoplastic syndromes:

1) Endocrine: Cushing syndrome (SCLC), syndrome of inappropriate antidiuresis (SIAD; SCLC), carcinoid syndrome, hypercalcemia (SCC), and other.

2) Neuromuscular: Peripheral neuropathies (SCLC), encephalopathies, degeneration of the cerebellar cortex, Lambert-Eaton myasthenic syndrome (SCLC), polymyositis.

3) Cutaneous: Dark keratosis, dermatomyositis, systemic lupus erythematosus (SLE), systemic scleroderma.

4) Bone: Hypertrophic osteoarthritis, finger clubbing.

5) Vascular: Migratory superficial thrombophlebitis, nonbacterial thrombotic endocarditis.

6) Hematologic: Anemia, disseminated intravascular coagulation (DIC).

Diagnosis and StagingTop

Diagnostic Tests

1. Imaging studies:

1) Chest radiography (posteroanterior and lateral projection) has lower sensitivity than computed tomography (CT) imaging. It detects nodules/masses in the lung parenchyma, atelectasis, enlargement of hilar or mediastinal lymph nodes, pleural cavity fluid, unilateral diaphragmatic elevation, and lesions indicating direct infiltration or bone metastasis. A normal chest radiography does not exclude lung cancer.

2) Chest CT: The standard and most commonly used imaging modality; assesses tumor nature, local extension, and metastatic involvement.

3) Positron emission tomography with computed tomography (PET-CT), usually with the use of 18F-FDG (FDG-PET); permits the detection of small metastases in mediastinal lymph nodes, determination of the tumor extent within the atelectatic lesions, as well as detection of neoplastic lesions outside the chest. PET-CT improves optimal disease characterization and staging to facilitate management.

4) Magnetic resonance imaging (MRI) of the brain is routinely used in NSCLC and SCLC to assess brain metastasis, regardless of the absence of symptoms. MRI can also be useful in assessing some tumor locations, for instance, in the vicinity of or within the spine, or at the lung apex (eg, Pancoast tumor).

2. Invasive procedures:

1) Bronchoscopy and endobronchial ultrasonography (EBUS): Assessment of local advancement of endobronchial lesions, collecting specimens for microscopic examination (biopsy specimens of the bronchial wall/tumor, EBUS-guided transbronchial lung and lymph node biopsy, bronchial lavage, endobronchial brushing).

2) Transthoracic needle biopsy (TTNB): Direct sampling of lung masses using needle biopsy under direct CT guidance.

3) Other diagnostic methods:

a) Fine-needle aspiration biopsy (FNAB) of peripheral lymph nodes (eg, supraclavicular, scalene fissure).

b) Mediastinoscopy: Rarely used these days.

c) Videothoracoscopic surgery: Usually reserved for peripheral early-stage lesions with high diagnostic probability of malignancy.

3. Laboratory tests:

 1) Cytologic examination: Valuable for diagnosis and molecular analysis. It is commonly performed on transbronchial needle aspiration samples obtained during EBUS/endoscopic ultrasonography (EUS) procedures and on pleural fluid but is also applicable to sputum (rarely), bronchial lavage, and FNABs under ultrasound or CT guidance.

2) Molecular analysis:

a) Evaluation of programmed death ligand 1 (PD-L1) levels on malignant cells for immunotherapy suitability.

b) Next-generation sequencing (NGS) and immunohistochemistry identify driver variants (eg, KRAS, EGFR, ALK) for targeted therapy.

3) Liquid biopsy: Blood sample is analyzed for circulating tumor DNA (ctDNA) via NGS. The test detects driver mutations and is most valuable in adenocarcinoma cases. High-sensitivity analysis is required.

Determination of tumor markers in serum is not clinically useful.

Diagnostic Criteria

Histologic or cytologic examination of tumor material. The specific investigation used depends on the size and location of the lesion.

Differential Diagnosis

1. Peripheral tumors: Metastatic lesion, benign tumors, tuberculoma, lung abscess, fungal lesions, teratoma, hamartoma.

2. Enlarged mediastinal lymph nodes: Lymphoproliferative disorders, infection (mycobacterial, fungal), sarcoidosis (usually symmetrical involvement of the hila and mediastinal nodes), other inflammatory conditions (eg, berylliosis).

Staging

The main determinant of treatment is the precise staging of the neoplasm using the tumor, node, metastasis (TNM) framework. Always perform a chest CT scan with a contrast agent (the examination should be extended to the upper abdominal cavity). Other studies: see below.

TNM classification: Tumor (T) assesses the size, number, location, and invasion into anatomical landmarks. Node (N): Staging depends on lymph node involvement by location (hilar, mediastinal, supraclavicular) and whether ipsilateral or contralateral to the tumor. Metastasis (M) is defined by distant metastases, malignant pleural or pericardial effusion, or separate tumors in the contralateral lung.

Pathologic staging is determined by surgical resection findings. In addition, pathologic samples provide information regarding histologic grade, driver variants, and risk for recurrence, which are outside the scope of this chapter.

1. Accurate NSCLC staging requires chest CT, PET-CT, and when mediastinal lymph node staging is required, EBUS (or mediastinoscopy, mostly replaced by EBUS these days). Brain MRI (or contrast-enhanced CT if MRI is unavailable) is recommended to exclude brain metastases in NSCLC stage II or higher. TNM classification and staging of NSCLC: Table 1; Table 2.

2. SCLC: The TNM framework is used in the same fashion to stage SCLC. However, for treatment purposes a two-stage system is currently more useful, dividing presentations to limited disease (LD) and extensive disease (ED). Required examinations include CT of the chest and abdominal cavity with contrast, MRI or CT of the brain, and PET-CT:

1) LD (<30% at diagnosis): Confined to one side of the chest and regional lymph nodes, suitable for a single tolerable radiotherapy port.

2) ED: Lesions extend beyond the LD area.

TreatmentTop

The treatment modality is decided upon on a case-by-case basis by a multidisciplinary team comprising specialists in medical oncology, thoracic surgery, oncologic radiotherapy, and imaging diagnostics. All smokers should receive antismoking advice and help to overcome the addiction (see Nicotine Addiction).

Treatment of Non–Small Cell Lung Carcinoma

The treatment method depends primarily on the stage of the cancer, patient’s performance status, and pretreatment assessment. Other important factors include age and molecular and histologic characteristics of the tumor. Treatment modalities include surgery, chemotherapy, radiotherapy, immunotherapy, and targeted therapy. Overview of treatment modalities: Table 2.

Pretreatment assessment includes pulmonary function tests (PFTs), functional tests such as the 6-minute walk test or the stair climb test, and oxygen oximetry. If uncertainty remains, additional tests such as cardiopulmonary exercise testing and arterial blood gas measurements at rest and during exercise may be performed.

1. Surgical treatment: Complete resection of the tumor with clean margins, performed via videothoracoscopy, open thoracotomy, or robotic surgery, is the preferred treatment for stages I, II, and selected cases of stage IIIA NSCLC. In stage I, surgery alone is often sufficient. In stage II and higher, a multimodal approach is typically employed, incorporating surgery, chemotherapy, immunotherapy, and radiotherapy. The extent of resection may include pneumonectomy, bilobectomy, lobectomy, segmentectomy (all of the above are anatomic resections), or wedge resection. The choice of the procedure depends on the stage of the disease (resectability), tumor’s anatomic location, and patient’s overall cardiopulmonary function and performance status (operability). Complete regional lymph node resection remains the standard of care, ensuring accurate staging and enhancing curative outcomes.

2. Immunotherapy: Immune checkpoint inhibitors (ICIs) have revolutionized lung cancer treatment and improved outcomes. Programmed death receptor 1 (PD-1), PD-L1, and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors are the primary ICIs used, with newer ones in development. Their main mechanism is enhancing the body’s immune response to cancer and blocking the tumor’s ability to evade it. ICIs are often combined with chemotherapy, but they can also be used as monotherapy.

3. Chemotherapy: Typically platinum-based combination therapy is used. Common combinations include cisplatin or carboplatin with one of the following: gemcitabine, docetaxel, etoposide, paclitaxel, vinorelbine, pemetrexed, or irinotecan. In most regimens, immunotherapy is added to chemotherapy, as this combination has been shown in multiple trials to be superior to chemotherapy alone.

4. Radiotherapy:

1) External beam radiotherapy (EBRT): The most common type of radiotherapy, often combined with chemotherapy or immunotherapy. Recent advances, including 3D CT imaging, radiation intensity adjustment, and proton beam therapy, have improved accuracy and reduced damage to adjacent healthy tissues.

2) Stereotactic body radiation therapy (SBRT): Used to treat small lung nodules (≤5 cm) in patients who are not suitable for surgery.

3) Brachytherapy (internal radiotherapy): Delivers radiotherapy directly inside or near the tumor. Used in patients with endobronchial involvement to relieve symptoms, particularly in advanced disease with airway obstruction or recurrent hemoptysis.

5. Targeted therapy: Molecular analysis of tumor tissue, cytology, or ctDNA from blood (liquid biopsy) can identify oncogenic driver variants with specific therapies, improving prognosis and survival. Treatable sequence variations include EGFR, ALK, ROS1, RET, NTRK, HER-2, MET, KRAS, and BRAF, which are most commonly found in patients with adenocarcinoma.

6. Presurgical and postsurgical therapies:

1) Neoadjuvant therapy: Administered before surgery to reduce tumor volume, target micrometastases, and improve surgical outcomes, in the form of chemotherapy, radiation therapy, immunotherapy, or targeted therapy. This area is evolving rapidly. The most common regimens used nowadays are combined chemoradiation with or without immunotherapy.

2) Adjuvant therapy: Given after surgery to eliminate residual tumor cells or micrometastases and prevent recurrence. Similar to neoadjuvant therapy, it may involve chemotherapy, immunotherapy, radiotherapy, targeted therapy, or a combination of these.

7. Treatment strategies by stage:

1) Stage I: Managed with surgery as the first line or with SBRT for patients unfit for surgery.

2) Stage II: Surgery as the first-line therapy with adjuvant chemotherapy.

3) Stage III: Practice varies according to location and local guidelines. Therefore, each case should be discussed in a multidisciplinary tumor board/meeting. Some options include:

a) Stage IIIA: Surgery combined with chemoradiotherapy, either as neoadjuvant and/or adjuvant therapy. Immunotherapy and targeted therapy may also be used.

b) Stage IIIB/IIIC: Nonsurgical treatment with chemoradiation, immunotherapy, and targeted therapy if driver variants are identified.

c) Stage IV: Systemic therapy with a combination of chemotherapy, targeted therapy, and immunotherapy. Radiotherapy is used for palliative care only (eg, alleviation of pain from metastases, dyspnea, dysphagia, superior vena cava syndrome, metastatic lesions to the brain).

Treatment of Small Cell Lung Carcinoma

1. Treatment of LD: In rare cases, when the tumor involves a single small lesion with no lymph node involvement or metastatic disease, surgery may be considered. For most cases of limited-stage SCLC, surgery is not an option and concurrent chemoradiation is the treatment of choice. For patients unable to tolerate concurrent chemoradiation, chemotherapy with or without subsequent radiation therapy is recommended. Selected patients may also benefit from immunotherapy following chemoradiation. Patients typically receive prophylactic cranial irradiation as part of their treatment to prevent brain metastases. While most cases respond well to therapy, recurrence rates remain high.

2. Treatment of ED: For patients with good functional status and clinical condition, chemotherapy combined with immunotherapy (eg, atezolizumab or durvalumab) is the treatment of choice. Radiation therapy may be used for symptom relief in cases of brain, bone, or spinal cord metastases.

Treatment of a Lung Carcinoid Tumor

Lung neuroendocrine tumors (NETs) are rare, accounting for ~1% to 2% of lung malignancies. Low-grade typical carcinoids are slow-growing, well-differentiated tumors that rarely metastasize; while atypical carcinoids are intermediate-grade tumors that are more likely to progress and metastasize.

Diagnosis typically involves a CT scan with biopsy or surgery. PET imaging using somatostatin receptor-based techniques is the most sensitive for detection.

Surgery with lymph node sampling or dissection is the preferred first-line treatment. Adjuvant chemotherapy and radiotherapy may be considered based on tumor histology or lymph node involvement. For inoperable cases, somatostatin analogues are part of the therapy.

PrognosisTop

Lung cancer survival is primarily determined by disease stage, but additional factors such as cell type (NSCLC vs SCLC), actionable sequence variants, age, and comorbidities also play a significant role.

The overall 5-year relative survival rate for lung cancer is ~19.4% (16% for men and 22% for women), reflecting diagnosis at an advanced stage for most patients. Survival is notably higher for NSCLC (23%) compared with SCLC (6%), reflecting the more aggressive nature of SCLC.

NSCLC 5-year survival rates by stage as of 2015:Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness). Goldstraw P, Chansky K, Crowley J, et al; International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee, Advisory Boards, and Participating Institutions; International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee Advisory Boards and Participating Institutions. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016 Jan;11(1):39-51. doi: 10.1016/j.jtho.2015.09.009. PMID: 26762738.*The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer; Goldstraw, Peter et al.; Journal of Thoracic Oncology, Volume 11, Issue 1, 39 -51; DOI: 10.1016/j.jtho.2015.09.009

1) Stage IA: 77% to 92%.

2) Stage IB: 68%.

3) Stage IIA: 60%.

4) Stage IIB: 53%.

5) Stage IIIA: 36%.

6) Stage IIIB: 26%.

7) Stage IIIC: 13%.

8) Stage IV: 0% to 10%.

SCLC survival rates:

1) LD: Median survival is 12 to 16 months.

2) ED: Median survival is 7 to 11 months.

Despite these challenging outcomes, advances in immunotherapy and targeted therapies are continuously improving long-term survival. Additionally, lung cancer screening programs have demonstrated a significant reduction in lung cancer mortality by enabling early-stage diagnosis, providing a critical opportunity for curative treatment in high-risk populations.

TablesTop