Etiology

The US Surgeon General declared in 1964 that cigarette smoking causes lung cancer in men and that increased duration and amount of cigarette use increases that risk.[3] Multiple case-control studies were cited to support this assertion.[12][13][14] Tobacco exposure continues to be the most important cause of lung cancer and approximately 90% of lung cancer is directly attributable to smoking, including virtually all cases of SCLC.[10] Tobacco smoke contains multiple carcinogens, including polynuclear aromatic hydrocarbons, aromatic amines, N-nitrosamines, and other organic and inorganic compounds.[15]

Lung cancer has also been linked to radon gas, a radioactive decay product of uranium. Radon can percolate into homes from the ground below. Radon itself is not dangerous but radon decays into progeny that emit alpha-particles, which can damage DNA and induce lung cancer.[16]

Pathophysiology

SCLC comprises approximately 15% of lung cancers and is highly associated with smoking relative to other subtypes of lung cancer.[10][11] The relative incidence of SCLC is declining, likely reflecting the decreasing percentage of smokers in the population.[17] These tumors tend to arise in the central lung with mediastinal involvement. SCLC is an aggressive malignancy. Approximately two-thirds of patients have evidence of distant metastasis at presentation (extensive stage), while one third present with limited-stage disease (confined to the ipsilateral hemithorax).[5]​​

Classification

The 2021 World Health Organization classification of lung tumors[2]

Epithelial tumors

Papillomas

  • Squamous cell papilloma, not otherwise specified (NOS)

  • Squamous cell papilloma, inverted

  • Glandular papilloma

  • Mixed squamous cell and glandular papilloma

Adenomas

  • Sclerosing pneumocytoma

  • Alveolar adenoma

  • Papillary adenoma

  • Bronchiolar adenoma/ciliated muconodular papillary tumor

  • Mucinous cystadenoma

  • Mucous gland adenoma

Precursor glandular lesions

  • Atypical adenomatous hyperplasia

  • Adenocarcinoma in situ

    • Adenocarcinoma in situ, nonmucinous

    • Adenocarcinoma in situ, mucinous

Adenocarcinomas

  • Minimally invasive adenocarcinoma

    • Minimally invasive adenocarcinoma, nonmucinous

    • Minimally invasive adenocarcinoma, mucinous

  • Invasive nonmucinous adenocarcinoma

    • Lepidic adenocarcinoma

    • Acinar adenocarcinoma

    • Papillary adenocarcinoma

    • Micropapillary adenocarcinoma

    • Solid adenocarcinoma

  • Invasive mucinous adenocarcinoma

    • Mixed invasive mucinous and nonmucinous adenocarcinoma

  • Colloid adenocarcinoma

  • Fetal adenocarcinoma

  • Adenocarcinoma, enteric type

  • Adenocarcinoma, NOS

Squamous precursor lesions

  • Squamous cell carcinoma in situ

  • Mild squamous dysplasia

  • Moderate squamous dysplasia

  • Severe squamous dysplasia

Squamous cell carcinomas

  • Squamous cell carcinoma, NOS

    • Squamous cell carcinoma, keratinizing

    • Squamous cell carcinoma, nonkeratinizing

    • Basaloid squamous cell carcinoma

  • Lymphoepithelial carcinoma

Large cell carcinomas

  • Large cell carcinoma

Adenosquamous carcinomas

  • Adenosquamous carcinoma

Sarcomatoid carcinomas

  • Pleomorphic carcinoma

    • Giant cell carcinoma

    • Spindle cell carcinoma

  • Pulmonary blastoma

  • Carcinosarcoma

Other epithelial tumors

  • NUT carcinoma

  • Thoracic SMARCA4-deficient undifferentiated tumor

Salivary gland-type tumors

  • Pleomorphic adenoma

  • Adenoid cystic carcinoma

  • Epithelial-myoepithelial carcinoma

  • Mucoepidermoid carcinoma

  • Hyalinizing clear-cell carcinoma

  • Myoepithelioma

  • Myoepithelial carcinoma

Lung neuroendocrine neoplasms

Precursor lesion

  • Diffuse idiopathic neuroendocrine cell hyperplasia

Neuroendocrine tumors

  • Carcinoid tumor, NOS/neuroendocrine tumor, NOS

    • Typical carcinoid/neuroendocrine tumor, grade 1

    • Atypical carcinoid/neuroendocrine tumor, grade 2

Neuroendocrine carcinomas

  • Small cell carcinoma

    • Combined small cell carcinoma

  • Large cell neuroendocrine carcinoma

    • Combined large cell neuroendocrine carcinoma

Tumors of ectopic tissues

  • Melanoma

  • Meningioma

Mesenchymal tumors specific to the lung

  • Pulmonary hamartoma

  • Chondroma

  • Diffuse lymphangiomatosis

  • Pleuropulmonary blastoma

  • Intimal sarcoma

  • Congenital peribronchial myofibroblastic tumor

  • Pulmonary myxoid sarcoma with EWSR1-CREB1 fusion

PEComatous tumors

  • Lymphangioleiomyomatosis

  • PEComa, benign

  • PEComa, malignant

Hematolymphoid tumors

  • MALT lymphoma

  • Diffuse large B-cell lymphoma, NOS

  • Lymphomatoid granulomatosis, NOS

    • Lymphomatoid granulomatosis, grade 1

    • Lymphomatoid granulomatosis, grade 2

    • Lymphomatoid granulomatosis, grade 3

  • Intravascular large B-cell lymphoma

  • Langerhans cell histiocytosis

  • Erdheim–Chester disease

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