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.
ReviewSquamous-cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy
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
References (78)
Pathology of lung cancer
Clin Chest Med
(2011)- et al.
Striking changes in smoking behaviour and lung cancer incidence by histological type in south-east Netherlands, 1960–1991
Eur J Cancer
(1995) - et al.
Clinicopathologic features of peripheral squamous cell carcinoma of the lung
Ann Thorac Surg
(2004) Management of Pancoast tumours
Lancet Oncol
(2006)- et al.
Subtyping of non-small cell lung carcinoma: a comparison of small biopsy and cytology specimens
J Thorac Oncol
(2011) - et al.
Immunohistochemical algorithm for differentiation of lung adenocarcinoma and squamous cell carcinoma based on large series of whole-tissue sections with validation in small specimens
Mod Pathol
(2011) - et al.
p40 (DeltaNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma
Mod Pathol
(2012) - et al.
BRIDGE: an open-label phase II trial evaluating the safety of bevacizumab + carboplatin/paclitaxel as first-line treatment for patients with advanced, previously untreated, squamous non-small cell lung cancer
J Thorac Oncol
(2011) - et al.
Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial
Lancet
(2009) - et al.
EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study
Lancet Oncol
(2012)
SOX2 gene amplification and protein overexpression are associated with better outcome in squamous cell lung cancer
Mod Pathol
Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin
J Pathol
ALK-rearranged lung cancer: adenosquamous lung cancer masquerading as pure squamous carcinoma
J Thorac Oncol
PIK3CA mutation status in Japanese lung cancer patients
Lung Cancer
PTEN mutations and relationship to EGFR, ERBB2, KRAS, and TP53 mutations in non-small cell lung cancers
Lung Cancer
Prognostic impact of fibroblast growth factor 2 in non-small cell lung cancer: coexpression with VEGFR-3 and PDGF-B predicts poor survival
J Thorac Oncol
Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib
Eur J Pharmacol
Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: the NCI's Lung Cancer Mutation Consortium (LCMC)
Proc Am Soc Clin Oncol
A population-based study of lung cancer incidence trends by histologic type, 1974–81
J Natl Cancer Inst
Clinicopathologic characteristics of peripheral squamous cell carcinoma of the lung
Am J Surg Pathol
World Health Organization classification of tumors. Pathology and genetics of tumours of the lung, pleura, thymus and heart
Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing
Semin Respir Crit Care Med
Abnormalities of epidermal growth factor receptor in lung squamous-cell carcinomas, adenosquamous carcinomas, and large-cell carcinomas: tyrosine kinase domain mutations are not rare in tumors with an adenocarcinoma component
Cancer
Comprehensive histologic analysis of ALK-rearranged lung carcinomas
Am J Surg Pathol
Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer
J Clin Oncol
First-line chemotherapy for non-small-cell lung cancer: is there a superior regimen based on histology?
J Clin Oncol
Results of a randomized, phase III trial of nab-paclitaxel and carboplatin compared with cremophor-based paclitaxel and carboplatin as first-line therapy in advanced non-small cell lung cancer
J Clin Oncol
Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer
J Clin Oncol
Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer
N Engl J Med
Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil
J Clin Oncol
Retrospective evaluation of the clinical and radiographic risk factors associated with severe pulmonary hemorrhage in first-line advanced, unresectable non-small-cell lung cancer treated with carboplatin and paclitaxel plus bevacizumab
J Clin Oncol
Expression of tumor-derived vascular endothelial growth factor and its receptors is associated with outcome in early squamous cell carcinoma of the lung
J Clin Oncol
Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis
J Clin Oncol
A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications
Cancer Res
Genetics of preneoplasia: lessons from lung cancer
Curr Mol Med
High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints
Cancer Res
Lung squamous cell carcinoma mRNA expression subtypes are reproducible, clinically important, and correspond to normal cell types
Clin Cancer Res
Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma
Oncogene
The molecular biology of head and neck cancer
Nat Rev Cancer
Cited by (163)
Immunochemotherapy Disrupts Peripherally Located Lung Squamous Cell Carcinoma Resulting in Pleuritis: A Report of Two Cases, Case Report
2022, JTO Clinical and Research Reportsα7-Nicotinic acetylcholine receptor antagonist QND7 suppresses non-small cell lung cancer cell proliferation and migration via inhibition of Akt/mTOR signaling
2020, Biochemical and Biophysical Research CommunicationsCitation Excerpt :The α7-nAChR has been reported to play an important mechanism in the nicotine-mediated oncogenic process [4,5]. Several studies showed that α7-nAChR was strongly up-regulated in smoker patients with SCLC and non-smoker patients with NSCLC [24–26]. Lung cancer pathogenesis via this receptor was progressively enhanced by both nicotine- and autocrine oncogenic factor-dependent activations [8,9].
Expression and Purification of FGFR1-Fc Fusion Protein and Its Effects on Human Lung Squamous Carcinoma
2024, Applied Biochemistry and BiotechnologyA cuproptosis-associated long non-coding RNA signature for the prognosis and immunotherapy of lung squamous cell carcinoma
2023, Biomolecules and Biomedicine