Aetiology

Tobacco exposure continues to be the most important cause of lung cancer, and in Europe and the US up to 90% of lung cancer is directly attributable to smoking.[11] Tobacco smoke contains multiple carcinogens including polynuclear aromatic hydrocarbons, aromatic amines, N-nitrosamines, and other organic and inorganic compounds.[12] However, because it is such a common tumour, the absolute number of patients who develop lung cancer who have never smoked is high.

Lung cancer has also been linked to radon gas, a radioactive decay product of uranium.[13][14]​​ Radon can percolate into homes from the ground underlying the homes. Radon itself is not dangerous; however, radon decays into progeny that emit alpha-particles, and these can damage DNA leading to lung cancer induction.[12] Less commonly, occupational factors, notably exposure to asbestos, play a significant part in the aetiology, and air pollution has been shown to confer some risk.[15][16]​​[17]

Pathophysiology

There are three major types of non-small cell lung cancer (NSCLC).

  • Squamous cell carcinoma: commonly involves the central airways and is thought to metastasize later in the disease course than adenocarcinoma; constitutes approximately 25% of lung cancers.[18]

  • Adenocarcinoma: tends to be located peripherally in the lung; adenocarcinoma is the most common NSCLC histology, and frequency is rising; comprises approximately 39% of lung cancers.[18][19] 

  • Large cell carcinoma: undifferentiated tumours without histological features typical of a squamous cell or adenocarcinoma and tend to arise centrally; accounts for about 8% of lung cancers.[18]

Sarcomatoid carcinoma represents a rare subset of poorly differentiated NSCLC.[20] In a proportion of cases of NSCLC it is not possible to further classify the tumour.

The classification of adenocarcinoma clarifies the terminology for pre-malignant and early invasive lesions.[21] Atypical adenomatous hyperplasia (AAH) is a pre-malignant lesion that typically measures less than 5 mm in diameter and may appear as a pure ground-glass nodule (pGGN) on computed tomography (CT) or may not be apparent on CT. AAH is a relatively common incidental finding, present in the lung tissue adjacent to resected adenocarcinomas in up to 23% of cases. A proportion of AAH lesions may evolve (often slowly) into adenocarcinoma in situ (AIS) and AIS may progress to become invasive adenocarcinoma. AIS is a pre-invasive lesion that may measure up to 30 mm in diameter and typically appears as pGGN on CT. The first stage of AIS becoming invasive adenocarcinoma is termed minimally invasive adenocarcinoma (MIA). MIA is defined as a lesion of AIS within which there is an area of invasive adenocarcinoma that measures 5 mm in diameter or less. MIA may correlate with an appearance on CT scans as a ground-glass opacity within which there is a solid area measuring less than 5 mm.

Bronchioloalveolar carcinoma (BAC) is an obsolete term but roughly corresponds to adenocarcinoma with lepidic pattern, characterised by the growth of tumour cells along the surface of alveolar walls - so-called lepidic pattern. The CT correlate is either a sub-solid nodule or consolidation. AIS and MIA when presenting as sub-solid nodules on CT have an excellent prognosis with few deaths due to lung cancer on long-term follow-up.[22][23][24]​ Lesions that show tissue invasion but also a component of lepidic spread should not be called BAC but instead are considered to be adenocarcinomas (with a lepidic component). Multi-focal lesions showing a lepidic growth pattern may occur. Some of these patients will have multiple synchronous AIS and, usually, at least one associated adenocarcinoma.[25] Some cases show mucinous adenocarcinoma (previously known as mucinous BAC) and may mimic pneumonic consolidation rather than present as a typical solitary pulmonary nodule or sub-solid nodule.[21][25]

Classification

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

Epithelial tumours

  • 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 tumour

    • Mucinous cystadenoma

    • Mucous gland adenoma

  • Precursor glandular lesions

    • Atypical adenomatous hyperplasia

    • Adenocarcinoma in situ

      • Adenocarcinoma in situ, non-mucinous

      • Adenocarcinoma in situ, mucinous

  • Adenocarcinomas

    • Minimally invasive adenocarcinoma

      • Minimally invasive adenocarcinoma, non-mucinous

      • Minimally invasive adenocarcinoma, mucinous

    • Invasive non-mucinous adenocarcinoma

      • Lepidic adenocarcinoma

      • Acinar adenocarcinoma

      • Papillary adenocarcinoma

      • Micropapillary adenocarcinoma

      • Solid adenocarcinoma

    • Invasive mucinous adenocarcinoma

      • Mixed invasive mucinous and non-mucinous 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, keratinising

      • Squamous cell carcinoma, non-keratinising

      • 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 tumours

    • NUT carcinoma

    • Thoracic SMARCA4-deficient undifferentiated tumour

  • Salivary gland-type tumours

    • Pleomorphic adenoma

    • Adenoid cystic carcinoma

    • Epithelial-myoepithelial carcinoma

    • Mucoepidermoid carcinoma

    • Hyalinising clear cell carcinoma

    • Myoepithelioma

    • Myoepithelial carcinoma

Lung neuroendocrine neoplasms

  • Precursor lesion

    • Diffuse idiopathic neuroendocrine cell hyperplasia

  • Neuroendocrine tumours

    • Carcinoid tumour, NOS/neuroendocrine tumour, NOS

      • Typical carcinoid/neuroendocrine tumour, grade 1

      • Atypical carcinoid/neuroendocrine tumour, grade 2

  • Neuroendocrine carcinomas

    • Small cell carcinoma

      • Combined small cell carcinoma

    • Large cell neuroendocrine carcinoma

      • Combined large cell neuroendocrine carcinoma

Tumours of ectopic tissues

  • Melanoma

  • Meningioma

Mesenchymal tumours specific to the lung

  • Pulmonary hamartoma

  • Chondroma

  • Diffuse lymphangiomatosis

  • Pleuropulmonary blastoma

  • Intimal sarcoma

  • Congenital peribronchial myofibroblastic tumour

  • Pulmonary myxoid sarcoma with EWSR1-CREB1 fusion

  • PEComatous tumours

    • Lymphangioleiomyomatosis

    • PEComa, benign

    • PEComa, malignant

Haematolymphoid tumours

  • 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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