Elsevier

The Lancet Oncology

Volume 13, Issue 10, October 2012, Pages e418-e426
The Lancet Oncology

Review
Squamous-cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy

https://doi.org/10.1016/S1470-2045(12)70291-7Get rights and content

Summary

Squamous-cell carcinomas of the lung (SQCLCs) are defined by unique clinicopathological and molecular characteristics that have evolved substantially over time. Historically, these neoplasms were the most common subtype of non-small-cell lung cancers and were regarded as central tumours with high molecular complexity without targetable genetic abnormalities. Today, the incidence of SQCLCs is surpassed by adenocarcinomas of the lung with a shift towards peripheral squamous tumours. Differential responses to cytotoxic and biological treatments have reshaped our approach to standard therapies. Additionally, evidence of unique biology has emerged with the discovery of SOX2 amplification, NFE2L2 and KEAP1 mutations, PI3K pathway changes, FGFR1 amplification, and DDR2 mutations. These discoveries have ushered in a new era of targeted therapeutic agents for patients with this disease. This Review draws attention to the distinct clinical and pathological characteristics of SQCLCs, summarises present experience with existing cytotoxic and targeted therapies, and discusses emerging treatments based on new insights into the biology of this disease.

Introduction

Our understanding of the molecular mechanisms that underlie the development of non-small-cell lung cancer (NSCLC) has taken great strides during the past decade. Although these discoveries continue to reshape the landscape of clinical care, the benefit to patients has largely favoured those with adenocarcinomas of the lung. Driver events can now be identified in most adenocarcinomas of the lung and approved targeted therapies (erlotinib, gefitinib, and crizotinib) are applicable to at least a third of patients.1 Squamous-cell lung cancers (SQCLCs) have long been regarded as tumours without readily targetable molecular abnormalities. Recent studies, however, have uncovered new SQCLC-associated genetic changes that are both actionable (amenable to targeting with an investigational agent) and present in a substantial proportion of tumours.

Section snippets

Epidemiology and clinical features

Squamous-cell carcinomas account for 20–30% of NSCLCs.2 Of the major histological subtypes of NSCLCs, SQCLCs are associated most strongly with cigarette smoking. SQCLC was the most common subtype of NSCLC during much of the past century, with diagnoses made largely in symptomatic patients with centrally located tumours. A decrease in the proportion of SQCLCs relative to adenocarcinomas of the lung was first noted in the 1960s and 1970s.3, 4 This shift in prevalence has been ascribed to several

Pathology

Histologically, well differentiated SQCLCs are characterised by keratinisation, intercellular bridges, and pearl formation (figure 1). Tumour cells tend to be large with abundant dense cytoplasm, irregular hyperchromatic nuclei, and small nucleoli.8 In poorly differentiated tumours, these features can be present only focally. Diagnosis in these cases, particularly in small biopsies, is often challenging. Cytological specimens (such as fine needle aspirates or bronchial brushings) can be

Cytotoxic therapy

Whereas previous therapeutic paradigms for NSCLCs paid little attention to histology, it is now clear that treatment decisions should take into account differential responses and toxicities with standard therapies. The standard of care in advanced NSCLC is to give four to six cycles of a platinum doublet in the first-line setting for patients without activating mutations in EGFR or rearrangements of ALK. In 2008, a large, randomised non-inferiority phase 3 trial by Scagliotti and colleagues15

The carcinogenic sequence

These differences in response to therapy suggest that the biology of SQCLC is substantially different from that of adenocarcinoma of the lung. The advent of more extensive molecular characterisation methods has allowed us to probe deeper into the molecular heterogeneity of SQCLCs. The sequence of pathological changes that occur during the development of SQCLC has been quite well defined. Progressive exposure to cigarette smoke induces subtle, albeit pervasive, changes in the morphology of

EGFR and KRAS mutations and EML4-ALK rearrangements

Success in targeted therapy for lung cancer has largely hinged on the discovery of targetable driver mutations that are present in a substantial proportion of individuals. In adenocarcinoma of the lung, small molecule inhibition of activated EGFR and EML4-ALK has resulted in unprecedented improvements in response rates and progression-free survival. Understandably, efforts were directed towards searching for these genetic changes in SQCLC, yielding somewhat conflicting results. Although several

FGFR1 amplification

The fibroblast growth factor receptor (FGFR) is a transmembrane receptor tyrosine kinase that participates in the regulation of embryonal development, cell proliferation, differentiation, and angiogenesis. The FGFR family has four members and binds up to 22 FGF ligands. Increased signalling through the pathway has been shown to enhance the growth of NSCLC cell lines.69 Furthermore, high serum concentrations and increased tumour expression of ligands have been identified as adverse prognostic

Conclusion

The advent of methods for next generation genomic analysis has led to a rapid accumulation of data that offer tantalising glimpses of a molecular diversity in SQCLC that rivals that seen in adenocarcinoma of the lung (figure 3). Events that are amenable to currently available targeted therapies in the PI3K pathway (20–30%), FGFR1 (20%), and DDR2 (4%) appear to occur in close to half of SQCLC tumours (figure 4). DDR2 mutations and FGFR1 amplifications lead to increased downstream signalling of

Search strategy and selection criteria

Data for this Review were identified via searches of PubMed using the search terms “squamous cell carcinoma”, “lung cancer”, “mutation”, “amplification”, “gene expression”, “chemotherapy”, “bevacizumab”, and “cetuximab”. References from relevant articles identified were incorporated. Only articles published in English from Jan 1, 1986, up to April 1, 2012, were included.

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