Non small cell lung cancer pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

Overview

Non-small cell lung cancer arises from the epithelial cells of the lung of the alveoli to the terminal bronchioles, which are normally involved in the protection of the airways. Non-small cell lung cancer is an invasive and rapidly growing cancer which may metastasize to different organs of the body. Genes involved in the pathogenesis of non-small cell lung cancer include EGFR, KRAS, HER2, BRAF, and ALK. Findings on gross pathology depends on the histological subtypes of non-small cell lung cancer. On microscopic histopathological analysis non-small cell lung cancer usually demonstrates large cells with abundant cytoplasm and no stippled chromatin.

Pathogenesis

The pathogenesis of non-small cell lung cancer depends on the type of histological subtype of lung cancer; Lung adenocarcinoma, lung large cell carcinoma, and squamous cell lung carcinoma.

• Non-small cell lung cancer arises from the epithelial cells of the lung of the central bronchi to the terminal alveoli, which are normally involved in the protection of the airways.
• Lung adenocarcinoma arises from the bronchial mucosal glands of the lung (main, lobar, segmental bronchi, or lung parenchyma), which are normally involved in decreasing bacterial growth in the epithelial cells of the lung.
• Lung adenocarcinoma usually occurs in a peripheral location within the lung. In the majority of the patients, cancer arises from precursor lesions, such as pre-existing scars or inflammation (chronic infections).
• Lung adenocarcinoma can also result from multiple genetic mutations. For more information about lung adenocarcinoma pathogenesis, see here
• Squamous lung cell carcinoma arises from bronchial epithelial cell damage (related to active smoking). Squamous cell carcinoma usually occurs in a central location within the lung. For more information about squamous lung cell carcinoma pathogenesis, see here
• Large cell carcinoma of the lung arises from large polygonal and anaplastic cells, hard to differentiate from other types of non small cell lung cancer. Large cell carcinoma usually occurs in a peripheral location within the lung.For more information about large cell carcinoma pathogenesis, see here
• The genetic pathogenesis of non-small cell lung cancer is due to the amplification of oncogenes and inactivation of tumor suppressor genes.
• Non-small cell lung cancer is an invasive and rapidly growing cancer which may metastasize to different organs of the body.

Genetics

Development of non-small cell lung cancer is the result of multiple genetic mutations. Genetic mutations also play an important role in the treatment selection for non small cell lung cancer.

• The table below describes the genes involved in the pathogenesis of non small cell lung cancer.

Genes	Presence in non small cell-lung cancers
EGFR	EGFR mutations are present in approximately 10% to 15% of all non-small cell lung cancers
KRAS	Mutations are present in approximately 30% of pulmonary adenocarcinomas Mutations are present in approximately 5% of pulmonary squamous cell carcinomas Associated with carcinomas with mucinous histology
ALK	Mutations are present in approximately 5% of all non-small cell lung cancers
HER2	Mutations are present in approximately 4% of adenocarcinomas
BRAF	Mutations are present in less than 2% of adenocarcinomas
ROS-1	Mutations are present in less than 2% of adenocarcinomas

Associated Conditions

• Other conditions associated with non-small cell lung cancer, include:
• Genetic conditions

• Li–Fraumeni syndrome
• Noonan syndrome

• Infections

• Human papillomavirus (HPV) infection
• Pulmonary tuberculosis

Gross Pathology

• On gross pathology, findings will depend on the histological subtype of non-small cell lung cancer.
• Lung adenocarcinoma gross pathology findings, include:

• Spherical tumor with well-defined borders
• Homogeneous gray-white cut surface
• Involvement of the thoracic wall
• Usually found in the peripheral lung

• Large cell lung cancer gross pathology findings, include:

• Well-defined borders
• Resemblance to gross findings in adenocarcinoma
• No signs of anthracosis
• Involvement of the thoracic wall

• Squamous cell lung cancer gross pathology findings, include:

• Lung mass
• Usually centrally located
• Associated with a large airway
• Usually have a central cavitation

Microscopic Pathology

On microscopic pathology, findings will depend on the histological type of non-small cell lung cancer.

• Lung adenocarcinoma microscopic pathology findings, include:

• Nuclear atypia
• Eccentrically placed nuclei
• Abundant cytoplasm with mucin vacuoles
• Often conspicuous nucleoli
• Lack of intercellular bridges.
• Different patterns, include: acinar, lepidic, micropapillary, papillary, and solid.

• Large cell lung cancer microscopic pathology findings, include:

• Large polygonal cells and anaplastic cells
• No squamous or glandular differentiation
• Moderately abundant cytoplasm
• Vesicular nuclei, prominent nucleoli

• Squamous cell lung cancer microscopic pathology findings include:

• Central nucleus
• Dense appearing cytoplasm, usually eosinophilic
• Small nucleolus
• Intracellular bridges (classic feature)

On immunohistochemistry, the findings depend on the histological type of non-small cell lung cancer.

• Common immunohistochemistry markers used for non-small cell carcinoma subtyping, include:

• TTF-1 for adenocarcinoma
• p63 and high-molecular-weight keratins for squamous cell carcinoma
• Lack of staining with neuroendocrine markers (chromogranin A, synaptophysin, and CD56)

References

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