Lung Cancer: Overview

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Lung Cancer: Overview

Lung cancer remains the leading cause of cancer-related death in the United States, accounting for nearly 25% of all cancer fatalities. Approximately 80–90% of cases are attributable to tobacco smoking, making it the most significant preventable risk factor. Other contributors include occupational exposures (asbestos, arsenic, chromium, nickel, silica), radon exposure, chronic pulmonary diseases, prior radiation therapy, and a positive family history.

The peak incidence occurs between 65 and 75 years of age, with men historically having higher rates, though this gap is narrowing due to increased smoking prevalence in women. Adenocarcinoma is now the most common subtype, particularly among nonsmokers and women.

Classification

Lung cancer is broadly categorized into two major groups:

1. Non-Small Cell Lung Cancer (NSCLC) – ~85% of cases

  • Histological subtypes:

    • Adenocarcinoma

      • Most common primary lung cancer.

      • Peripheral location; more common in women and nonsmokers.

      • Associated with EGFR, ALK, and KRAS mutations.

      • May present with hypertrophic osteoarthropathy (digital clubbing).

      • Growth patterns: lepidic, acinar, papillary, solid, mucinous, or mixed.

    • Squamous Cell Carcinoma

      • Central location, often arising from a hilar bronchus.

      • Strongly associated with smoking.

      • May produce PTHrP → hypercalcemia.

      • Histology: keratin pearls, intercellular bridges, cavitation.

    • Large Cell Carcinoma

      • Peripheral, poorly differentiated, aggressive.

      • Early metastasis and poor response to chemotherapy.

      • Histology: large polygonal cells without specific differentiation.

2. Small Cell Lung Cancer (SCLC) – 10–15% of cases

  • Central origin, typically in smokers; very rare in nonsmokers.

  • Highly aggressive with rapid growth and early metastasis.

  • Arises from neuroendocrine Kulchitsky cells.

  • Commonly associated with paraneoplastic syndromes:

    • SIADH, Cushing syndrome, Lambert-Eaton myasthenic syndrome.

  • Immunohistochemistry: Chromogranin A, Synaptophysin, Neuron-specific enolase, CD56.

Other Rare Subtypes

  • Large cell neuroendocrine carcinoma – high-grade, poor prognosis.

  • Typical and atypical carcinoid tumors – indolent, low metastatic potential; most common primary lung cancer in children/adolescents.

Clinical Features

Early Disease

  • Often asymptomatic, detected incidentally on imaging.

  • Solitary pulmonary nodules are frequently the first clue.

Pulmonary Symptoms

  • Cough, hemoptysis, dyspnea, wheezing, chest pain.

  • Postobstructive pneumonia and atelectasis may occur.

Extrapulmonary Symptoms

  • Constitutional: weight loss, fatigue, fever.

  • Tumor compression:


    • Superior vena cava syndrome → facial/neck swelling, distended veins.

    • Recurrent laryngeal nerve involvement → hoarseness.

    • Phrenic nerve paralysis → diaphragmatic elevation.

  • Pleural effusions (usually unilateral).

Metastatic Disease (“BLAB”)

  • Brain – headaches, seizures, focal deficits.

  • Liver – hepatomegaly, jaundice, ascites.

  • Adrenal – usually asymptomatic.

  • Bones – pain, hypercalcemia, elevated alkaline phosphatase.

Paraneoplastic Syndromes

  • NSCLC: hypercalcemia (SCC), gynecomastia, hypertrophic osteoarthropathy.

  • SCLC: SIADH, Cushing syndrome, Lambert-Eaton myasthenic syndrome, peripheral neuropathies.

Diagnosis

Screening

  • Annual low-dose CT scan recommended for:

    • Age 50–80 years with ≥20 pack-year smoking history.

    • Discontinue if life expectancy is limited or patient declines surgery.

Imaging

  • Chest X-ray: initial screening, but 10–20% of lung cancers are radiographically occult.


  • CT chest: thin-slice imaging for nodules or suspicious lesions.


  • PET-CT: highly sensitive for mediastinal and extrathoracic metastases.

  • MRI brain: preferred for CNS metastases.


Tissue Diagnosis

  • Bronchoscopy: central lesions.


  • CT-guided biopsy: peripheral lesions.

  • Pleural fluid cytology: effusions.

  • Molecular testing in NSCLC: EGFR, ALK, ROS1, BRAF, PD-L1 for targeted therapy guidance.

Staging

  • NSCLC: AJCC TNM system, stages I–IV.

  • SCLC: Limited vs. Extensive disease, with TNM sometimes applied.

Management

NSCLC

  • Curative: Early-stage (I–IIA) – surgical resection ± adjuvant chemotherapy; stereotactic radiotherapy if inoperable.

  • Intermediate-stage (IIB–IIIC): Surgery + chemo, or chemoradiotherapy if unresectable.

  • Advanced-stage (IVA–IVB): Palliative therapy; targeted therapy if actionable mutations; immunotherapy ± chemotherapy.

SCLC

  • Limited-stage: Chemoradiotherapy, possible surgical resection in select T1-2 N0 cases, prophylactic cranial irradiation.

  • Extensive-stage: Palliative chemotherapy ± immunotherapy, CNS surveillance or prophylactic cranial irradiation.

Surgical Options

  • Sublobar resection: small, peripheral tumors; preserves lung function.

  • Lobectomy: standard for most resectable NSCLC.

  • Pneumonectomy: for central or hilar involvement; high morbidity.

Chemotherapy

  • Standard regimens: platinum-based combinations (e.g., cisplatin + etoposide).

Targeted Therapy

  • EGFR TKI (osimertinib), ALK inhibitors (alectinib), ROS1 inhibitors (crizotinib), BRAF/MEK inhibitors.

Immunotherapy

  • PD-1/PD-L1 inhibitors (pembrolizumab, atezolizumab, durvalumab) for NSCLC or extensive SCLC.

Radiotherapy

  • Curative for inoperable early-stage NSCLC or limited-stage SCLC.

  • Palliative: bone metastases, brain metastases, SVC syndrome, hemoptysis.

Solitary Pulmonary Nodules (SPN)

  • Definition: Single lesion ≤30 mm, fully within lung parenchyma.

  • Malignancy risk factors: age >60, smoking, prior cancer, irregular/spiculated margins, upper-lobe location, subsolid density.

  • Management: risk-stratified based on nodule size, imaging characteristics, and patient factors (CHEST/Fleischner guidelines).

Prognosis

  • Overall 5-year survival ~20%.

  • NSCLC: Early stages (I–IIA) – 5-year survival 60–70%; locally advanced – 25–40%.

  • SCLC: Limited-stage – 5-year survival 16%; extensive-stage – 3%.

Prevention

  • Smoking cessation dramatically reduces risk over time:

    • 50% reduction after 5–10 years.

    • Risk approaches that of never-smokers after 15–20 years.

  • Low-dose CT screening for high-risk populations reduces mortality by up to 20%.

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