Lung Cancer (MORE)

LEARNING OBJECTIVES

  • Describe the 4 main types of lung cancer: etiology, pathology, staging, treatment and prognosis.

  • Distinguish small cell carcinoma from non-small cell carcinoma.

  • Outline the evidence linking smoking and lung cancer.

Non-Small Cell Lung Cancer

Squamous Cell Carcinoma

Etiology

  • Tobacco smoking - 90% of cases.

  • Occupational and environmental exposure e.g asbestos

  • Genetic factors e.g EGFR mutations

  • Chronic Inflammation - COPD

  • Infection - HPV/HIV.

Pathology

  • Found mainly in central part of the lung - the hilum or main bronchi.

  • Individual cell keratinization with abundant eosinophilic cytoplasm.

  • Pleomorphic cells with hyperchromatic nuclei

    • Stain more deeply than normal.

  • Squamous metaplasia → Dysplasia → invasive carcinoma

    • Penetrates the basement membrane and spreads to adjacent lung tissue.

  • Can spread to supraclavicular lymph nodes.

  • Prognosis depends on the histological grade, tumor size and molecular markers

    • TP53 mutations are associated with resistance to therapy.

Staging

T- Tumor (Primary Tumor Size and extent)

  • T1: Tumor <3 cm in greatest dimension, surrounded by lung or visceral pleura, without invasion into main bronchus.

  • T2: Tumor >3 cm but ≤ 5cm or involving the main bronchus with carina involvement, invading visceral pleura, or causing atelectasis/obstructive pneumonia.

  • T3: Tumor >5 cm ≤ 7cm or invading chest wall, phrenic nerve or parietal pericardium.

  • T4: Tumor >7 cm or invading mediastinum, diaphragm, heart, great vessels, trachea, esophagus or recurrent laryngeal nerve.

N- Lymph Node Involvement

  • N0: No regional lymph node involvement.

  • N1: Metastasis in ipsilateral peribornchial or hilar lymph nodes.

  • N2: Metastasis in ipsilateral mediastinal or subcarinal lymph nodes.

  • N3: Metastasis in contralateral mediastinal, contralateral hilar, or supraclavicular lymph nodes.

M - Metastasis (Distant Spread)

  • M0: No distant metastasis

  • M1: Distant Metastasis Present

SCC is staged as:

  • Stage 0 (carcinoma in situ): T1, N0, M0

  • Stage 1: T1/T2, N0 and M0

  • Stage II: T2/T3, N0/N1, M0

  • Stage III: T1-T3, N2/N3, M0

  • Stage IV: Any T, Any N, M1

Treatment

  • Depends on the stage

  • Stage I/II → Surgery and adjuvant therapy.

  • Stage III → combination of chemotherapy, radiation therapy, and sometimes surgery.

  • Stage IV → Chemotherapy, immunotherapy, and targeted therapies.

Adenocarcinoma

Pathology

  • Accounts to approximately 40% of lung cancers → especially in non-smokers and females.

  • Can be subdivided into preinvasive, minimally invasive and invasive adenocarcinoma.

  • Arises from the epithelial cells of the alveoli and terminal bronchioles.

  • Formation of glandular structures lined by columnar or cuboidal epithelial cells.

  • Mucin production, which can be identified using mucin stains.

    • Usually stain positive for cytokeratin 7 , thyroid transcription factor-1, and Napsin-A, but they stain negative for cytokeratin 20.

  • Cells with enlarged, hyperchromatic nuclei.

  • Can spread to adjacent lung parenchyma, pleural, and chest wall.

  • Early involvement of hilar and mediastinal lymph nodes.

  • Frequently metastasize to the brain, liver, bones, and adrenal glands.

Staging/Treatment

Same as squamous cell carcinoma

Large cell carcinoma

Pathology

  • Characterized by high mitotic rate and necrosis: large, bulky undifferentiated tumor cells with abundant cytoplasm.

  • Poorly differentiated carcinoma, making it difficult to diagnose accurately.

  • Due to its aggressive nature and lack of specific histological features, LCC often presents at advanced stage with poor prognosis.

  • Can occur anywhere in the lung but is more frequently found in the peripheral lung.

  • Common sites of spread include the regional lymph nodes, liver, bone, brain and adrenal glands.

Small Cell Lung Cancer

Small cell lung Cancer

Etiology

  • Rare in non-smokers

  • Mainly characterized by rapid growth, early metastasis, and poor prognosis.

  • Smoking is an important risk factor > 90% of all cases.

  • Originate for neuroendocrine Kulchitsky cells in the bronchial epithelium.

    • Kulchitsky cell are scattered specific cells which lie close to the basement membrane of the bronchi and bronchioles.

    • These cells respond to chemical or mechanical stimuli by releasing neuropeptides and neurotransmitters, implicating them as airway sensors.

  • Angiogenesis and immune evasion play a crucial role in progression.

Pathology

  • Typically arise in the central (hilar) region of the lung.

  • Soft, friable, and poorly circumscribed masses - associated with extensive necrosis and hemorrhage.

  • Small, round to oval cells with scant cytoplasm.

  • Hyperchromatic nuclei with fine granular chromatin (“salt and pepper” appearance)

  • Frequent vascular invasion and lymphatic spread.

  • Almost all cases relapse due to chemotherapy resistance.

Staging

Staged using two primary systems:

  1. Veterans Administration Lung Study Group (VALG)

  2. TNM (Tumor, Node, Metastasis) Staging system

VALG: Classifies SCLC in two stages

Limited-stage SCLC (LS-SCLC)

  • Cancer is confined to one hemithorax and can be encompassed within a single radiation field.

  • Involvement of ipsilateral (same side) hilar and mediastinal lymph nodes is allowed.

  • May include limited supraclavicular lymph node involvement.

  • No distant metastases.

  • Accounts for approximately 30-40% of SCLC cases.

Extensive-Stage SCLC (ES-SCLC)

  • Cancer has spread beyond ipsilateral hemithorax.

  • Includes distant metastases to the liver, brain, bones, adrenal glands, and contralateral lung.

  • Malignant pleural or pericardial effusion is classified as extensive-stage.

  • Accounts for approximately 60-70% of SCLC cases at diagnosis.

Treatment

Based on staging

  • LS-SCLC: chemotherapy, radiation therapy, prophylactic cranial irradiation, surgery.

  • ES-SCLC: Combination of chemotherapy and immunotherapy, radiation therapy, whole brain radiation therapy.

  • Rate of recurrence is high

Small cell carcinoma vs Non-small cell carcinoma

Smoking and Lung cancer

  • Exposure to tobacco has a great effect on the genetic instability of tumor cells.

  • Reactive oxygen species (ROS) from prolonged tobacco use cause the body to create large amounts of oxygen-free radicals, which directly cause DNA fragmentation and harm purines, pyrimidines, and deoxyribose.

Second hand smoke:

  • The risk of lung cancer significantly increased with the duration, intensity, and pack-year of SHS exposure.

  • Exposure to SHS increases by more than 20% the risk of lung cancer among never-smokers, providing definitive evidence of the associated between SHS exposure and lung cancer risk.