Squamous-cell carcinoma of the lung

Squamous-cell carcinoma of the lung is closely correlated with a history of tobacco smoking, more so than most other types of lung cancer. According to the Nurses' Health Study, the relative risk of SCC is approximately 5.5, both among those with a previous duration of smoking of 1 to 20 years, and those with 20 to 30 years, compared to never-smokers.[2] The relative risk increases to approximately 16 with a previous smoking duration of 30 to 40 years, and approximately 22 with more than 40 years.[2]

It most often arises centrally in larger bronchi, and while it often metastasizes to locoregional lymph nodes (particularly the hilar nodes) early in its course, it generally disseminates outside the thorax somewhat later than other major types of lung cancer. Large tumors may undergo central necrosis, resulting in cavitation. A squamous-cell carcinoma is often preceded for years by squamous-cell metaplasia or dysplasia in the respiratory epithelium of the bronchi, which later transforms to carcinoma in situ.

Large scale studies such as The Cancer Genome Atlas (TCGA) have systematically characterized recurrent somatic alterations likely driving lung squamous-cell carcinoma initiation and development.[3][4]

Squamous-cell lung carcinoma is one of the tumor types with the highest number of mutations since smoking, the main driver of the disease, is a strong mutagenic factor.[5]

Inactivating mutations in lung SCC affect many tumor suppressor genes such as TP53 (mutated in 81% of cases), MLL2 (20%), CDKN2A (15%), KEAP1 (12%) and PTEN (8%). Recurrent loss-of-function mutations have been observed also in NOTCH1 (8%), suggesting a tumor suppressive role in lung SCC for this gene, that has also been implicated as an oncogene in haematological cancers.[3] On the other hand, recurrent gain-of-function mutations have been found in oncogenes such as PIK3CA (16%) and NFE2L2 (15%).

Common oncogene copy number amplifications have been found in SOX2, PDGFRA, EGFR, FGFR1 and CCND1. Deletions were observed in tumor suppressors such as CDKN2A, PTEN and NF1.[3]

Some alterations such as the ones affecting TP53 and CDKN2A are shared by lung SCC and the other most common type of NSCLC, lung adenocarcinoma. Conversely, the two main driver oncogenes of the latter, EGFR and KRAS, are rarely mutated in lung SCC.[4]

Many of the gene mutations and copy number alterations occur in pathways whose deregulation seems to be important for the initiation and progression of the tumor. Specifically, KEAP1 and NFE2L2 belong to the oxidative stress response pathways; alterations in these genes tend to occur in a mutually exclusive fashion, and therefore this pathway is overall altered in more than 30% of the cases.[3] Similarly, the squamous cell differentiation pathway, whose components include SOX2, TP63 and NOTCH1, is altered in 44% of the tumors.

Alterations in the receptor tyrosine kinase pathway are also common but not as widespread as for the adenocarcinoma type.

Recently, four mRNA expression subtypes (primitive, basal, secretory, and classical) were identified and validated within squamous-cell carcinoma. The primitive subtype correlates with worse patient survival. These subtypes, defined by intrinsic expression differences, provide a possible foundation for improved patient prognosis and research into individualized therapies.[6]

The 2015 WHO classification of lung tumors[8] divided squamous cell lung carcinomas into 3 categories: keratinizing, non-keratinizing and basaloid. Keratinizing SCC harbor features of keratinization; non-keratinizing SCC lack such features but show other squamous markers, such as p40 and p63; finally, basaloid SCC is a rare subset of poorly differentiated squamous cell lung carcinoma. Previous variants such as papillary, small-cell and clear-cell SCC were discarded from the current classification as these subtypes are very uncommon. There is no clear evidence of prognostic significance to the subtyping of lung squamous cell carcinoma.[8]