[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [General pathology](https://durgical.com/en/general-pathology/) › [Lung](https://durgical.com/en/general-pathology/areas/lung/) › Lung carcinoma: pathogenesis and precursors

# Lung carcinoma: pathogenesis and precursors

- Mechanism

Tobacco carcinogens mutate the airway lining step by step. Each type of lung cancer has its own driver genes and precursor lesions.

Updated Nov 12, 2026

## Key points

- Adenocarcinoma drivers: EGFR (more in never-smoking Asian women), ALK fusions, ROS1, RET, MET, BRAF, KRAS (smokers; almost never with EGFR).
- Squamous carcinoma: losses at 3p, 9p (CDKN2A) and 17p (TP53); TP53 mutation in most; early p53 overexpression in dysplasia.
- Small cell carcinoma: near-universal loss of TP53 and RB1.
- Precursors: squamous dysplasia and carcinoma in situ; atypical adenomatous hyperplasia (5 mm or less); adenocarcinoma in situ (3 cm or less, pure lepidic); diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH).
- Radon is the main cause of lung cancer in never-smokers in some regions; asbestos and smoking multiply each other's risk.
- Cytochrome P-450 variants that activate procarcinogens raise individual risk.

## What it is

Most lung cancers are caused by tobacco smoke, with risk rising almost linearly with pack-years; other carcinogens include radon, asbestos, arsenic, chromium, nickel, uranium and air pollution. Driver mutations accumulate stepwise in a field of exposed epithelium. Never-smokers make up a sizable share worldwide, mostly women with adenocarcinoma carrying targetable mutations such as EGFR.

## Structure

- Squamous sequence: basal cell hyperplasia, squamous metaplasia, mild to severe dysplasia, carcinoma in situ, invasive carcinoma.
- Atypical adenomatous hyperplasia: a small focus of mildly atypical pneumocytes lining slightly thickened alveolar walls.
- Adenocarcinoma in situ: atypical cells growing only along existing alveolar septa (lepidic), mucinous or non-mucinous, no invasion.
- Minimally invasive adenocarcinoma: lepidic-predominant tumour of 3 cm or less with 5 mm or less of invasion.

## Step by step

- Polycyclic hydrocarbons and nitrosamines in smoke are activated by P-450 enzymes and form DNA adducts.
- Typical smoking mutations (G to T transversions) appear in TP53, KRAS and other genes.
- Losses of 3p and 9p (CDKN2A) are among the first events, found even in normal-looking smokers' mucosa.
- Activating mutations in receptor tyrosine kinases (EGFR, ALK) drive growth signalling in many adenocarcinomas.
- TP53 and RB1 loss remove the cell-cycle brakes, especially in small cell carcinoma.
- Clones with enough complementary drivers acquire the hallmarks of cancer and invade.

## Driver alterations by type

| Type | Typical alterations | Who |
| --- | --- | --- |
| [Adenocarcinoma (smoker)](https://durgical.com/en/conditions/lung-cancer/) | KRAS, TP53, STK11 | Current or former smokers |
| [Adenocarcinoma (never-smoker)](https://durgical.com/en/conditions/lung-cancer/) | EGFR, ALK, ROS1, RET fusions | Women, East Asian ancestry |
| [Squamous cell carcinoma](https://durgical.com/en/conditions/lung-cancer/) | TP53, CDKN2A loss, 3p loss, SOX2 gain | Heavy smokers |
| [Small cell carcinoma](https://durgical.com/en/conditions/lung-cancer/) | TP53 and RB1 loss, MYC family gain | Heavy smokers |

## Markers

- EGFR
- ALK
- ROS1
- KRAS
- PD-L1

## Clinical notes

- Stopping smoking lowers risk over time but not to baseline; second-hand smoke also causes lung cancer.
- Molecular testing of non-small cell carcinoma guides targeted therapy (EGFR and ALK inhibitors) and immunotherapy.
- Low-dose CT screening of heavy smokers finds early tumours; in Colombia lung cancer is a leading cause of cancer death.

## Memory aid

Never-smokers get EGFR and ALK (targets); smokers get KRAS and TP53 (scars); small cell loses TP53 and RB1 (both brakes).

## Test yourself

Think of the answer, then tap the question to see it.

## Which two tumour suppressor genes are lost in almost all small cell carcinomas?

TP53 and RB1.

## What is adenocarcinoma in situ of the lung?

A tumour of 3 cm or less made of atypical cells growing only along pre-existing alveolar septa (lepidic pattern) without invasion.

## Which mutation is more common in lung adenocarcinoma of never-smokers, and which in smokers?

EGFR mutations in never-smokers (especially women of East Asian ancestry); KRAS mutations in smokers. They rarely occur together.

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## Connections

## Related 10

- [Tobacco: how smoking injures tissue](https://durgical.com/en/general-pathology/tobacco-how-smoking-injures-tissue/)
- [Chemical carcinogens: initiation, promotion and the table to know](https://durgical.com/en/general-pathology/chemical-carcinogens-initiation-promotion-and-the-table-to-know/)
- [Oncogenes: RAS, MYC, HER2, BCR-ABL and the table to know](https://durgical.com/en/general-pathology/oncogenes-ras-myc-her2-bcr-abl-and-the-table-to-know/)
- [Tumour suppressor genes: RB, TP53, APC, BRCA and the two-hit hypothesis](https://durgical.com/en/general-pathology/tumour-suppressor-genes-rb-tp53-apc-brca-and-the-two-hit-hypothesis/)
- [Molecular pathology: PCR, FISH, sequencing and liquid biopsy](https://durgical.com/en/general-pathology/molecular-pathology-pcr-fish-sequencing-and-liquid-biopsy/)
- [Dysplasia and carcinoma in situ](https://durgical.com/en/general-pathology/dysplasia-and-carcinoma-in-situ/)
- [Lung carcinoma: histologic types](https://durgical.com/en/general-pathology/lung-carcinoma-histologic-types/)
- [Lung carcinoma: spread and paraneoplastic syndromes](https://durgical.com/en/general-pathology/lung-carcinoma-spread-and-paraneoplastic-syndromes/)
- [Asbestos-related disease](https://durgical.com/en/general-pathology/asbestos-related-disease/)
- [Multistep carcinogenesis: the adenoma–carcinoma sequence](https://durgical.com/en/general-pathology/multistep-carcinogenesis-the-adenoma-carcinoma-sequence/)

## Related conditions 1

- [Lung cancer](https://durgical.com/en/conditions/lung-cancer/)

[← All of general pathology](https://durgical.com/en/general-pathology/)

Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.

Sources: [Non-Small Cell Lung Cancer Treatment (PDQ®)–Health Professional Version](https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq) (National Cancer Institute, 2025); [Non–Small Cell Lung Cancer](https://www.ncbi.nlm.nih.gov/books/NBK562307/) (StatPearls (NCBI Bookshelf), 2025).

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Representative model, for educational purposes only.

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Source: https://durgical.com/en/general-pathology/lung-carcinoma-pathogenesis-and-precursors/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/general-pathology/lung-carcinoma-pathogenesis-and-precursors/