Squamous-cell carcinoma (SCC) of the lung is a histologic type of

non-small-cell lung carcinoma Non-small-cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to s ...

(NSCLC). It is the second most prevalent type of

lung cancer Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung. Lung carcinomas derive from transformed, mali ...

after

lung adenocarcinoma Adenocarcinoma of the lung is the most common type of lung cancer, and like other forms of lung cancer, it is characterized by distinct cellular and molecular features. It is classified as one of several non-small cell lung cancers (NSCLC), to di ...

and it originates in the

bronchi A bronchus is a passage or airway in the lower respiratory tract that conducts air into the lungs. The first or primary bronchi pronounced (BRAN-KAI) to branch from the trachea at the carina are the right main bronchus and the left main bronchus. ...

. Its tumor cells are characterized by a squamous appearance, similar to the one observed in epidermal cells. Squamous-cell carcinoma of the lung is strongly associated with

tobacco smoking Tobacco smoking is the practice of burning tobacco and ingesting the resulting smoke. The smoke may be inhaled, as is done with cigarettes, or simply released from the mouth, as is generally done with pipes and cigars. The practice is beli ...

, more than any other forms of NSCLC.

Signs and symptoms

Squamous-cell lung carcinoma share most of the signs and symptoms with other forms of

. These include worsening cough, including

hemoptysis Hemoptysis is the coughing up of blood or blood-stained mucus from the bronchi, larynx, trachea, or lungs. In other words, it is the airway bleeding. This can occur with lung cancer, infections such as tuberculosis, bronchitis, or pneumonia, a ...

, chest pain,

shortness of breath Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing di ...

and weight loss. Symptoms may result from local invasion or compression of adjacent thoracic structures such as compression involving the esophagus causing

dysphagia Dysphagia is difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, in some contexts it is classified as a condition in its own right. It may be a sensation that suggests difficulty in the passage of solids or liq ...

, compression involving the laryngeal nerves causing change in voice, or compression involving the superior vena cava causing facial

edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels tight, the area ma ...

. Distant metastases may also cause pain and show symptoms related to other organs.

Causes

Risk factors

Squamous-cell carcinoma of the lung is closely correlated with a history of

, more so than most other types of

. According to the

Nurses' Health Study The Nurses Health Study is a series of prospective studies that examine epidemiology and the long-term effects of nutrition, hormones, environment, and nurses' work-life on health and disease development. The studies have been among the largest in ...

, the

relative risk The relative risk (RR) or risk ratio is the ratio of the probability of an outcome in an exposed group to the probability of an outcome in an unexposed group. Together with risk difference and odds ratio, relative risk measures the association be ...

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. 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.

Mechanism

Pathogenesis

It most often arises centrally in larger

, 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 Cavitation is a phenomenon in which the static pressure of a liquid reduces to below the liquid's vapour pressure, leading to the formation of small vapor-filled cavities in the liquid. When subjected to higher pressure, these cavities, ca ...

. A squamous-cell carcinoma is often preceded for years by squamous-cell

metaplasia Metaplasia ( gr, "change in form") is the transformation of one differentiated cell type to another differentiated cell type. The change from one type of cell to another may be part of a normal maturation process, or caused by some sort of abno ...

dysplasia Dysplasia is any of various types of abnormal growth or development of cells (microscopic scale) or organs ( macroscopic scale), and the abnormal histology or anatomical structure(s) resulting from such growth. Dysplasias on a mainly microscopi ...

in the respiratory epithelium of the bronchi, which later transforms to

carcinoma in situ Carcinoma ''in situ'' (CIS) is a group of abnormal cells. While they are a form of neoplasm, there is disagreement over whether CIS should be classified as cancer. This controversy also depends on the exact CIS in question (i.e. cervical, skin, bre ...

. 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.

Gene mutations and copy number alterations

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. Inactivating mutations in lung SCC affect many

tumor suppressor genes A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...

such as

TP53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often ...

(mutated in 81% of cases), MLL2 (20%),

CDKN2A CDKN2A, also known as cyclin-dependent kinase inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. It is ubiquitously expressed in many tissues and cell types. The gene codes for two proteins, including the INK4 family ...

(15%),

KEAP1 Kelch-like ECH-associated protein 1 is a protein that in humans is encoded by the ''Keap1'' gene. Structure Keap1 has four discrete protein domains. The N-terminal Broad complex, Tramtrack and Bric-à-Brac (BTB) domain contains the Cys151 res ...

(12%) and PTEN (8%). Recurrent loss-of-function mutations have been observed also in

NOTCH1 Neurogenic locus notch homolog protein 1 (Notch 1) is a protein encoded in humans by the ''NOTCH1'' gene. Notch 1 is a single-pass transmembrane receptor. Function This gene encodes a member of the Notch family. Members of this Type 1 trans ...

(8%), suggesting a tumor suppressive role in lung SCC for this gene, that has also been implicated as an oncogene in haematological cancers. On the other hand, recurrent gain-of-function mutations have been found in

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

s such as PIK3CA (16%) and

NFE2L2 Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the ''NFE2L2'' gene. NRF2 is a basic leucine zipper (bZIP) protein that may regul ...

(15%). Common oncogene copy number amplifications have been found in SOX2,

PDGFRA PDGFRA, i.e. platelet-derived growth factor receptor A, also termed PDGFRα, i.e. platelet-derived growth factor receptor α, or CD140a i.e. Cluster of Differentiation 140a, is a receptor located on the surface of a wide range of cell types. This re ...

, EGFR,

FGFR1 Fibroblast growth factor receptor 1 (FGFR1), also known as basic fibroblast growth factor receptor 1, fms-related tyrosine kinase-2 / Pfeiffer syndrome, and CD331, is a receptor tyrosine kinase whose ligands are specific members of the fibroblast ...

and CCND1. Deletions were observed in tumor suppressors such as CDKN2A, PTEN and NF1. 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.

Somatically altered pathways

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. 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 Receptor tyrosine kinases (RTKs) are the high- affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kin ...

pathway are also common but not as widespread as for the adenocarcinoma type.

RNA expression profiles

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.

Diagnosis

Early squamous-cell carcinoma of the lung (generally as squamous-cell carcinoma in situ) is asymptomatic and may only appear as an

incidental imaging finding In medical or research imaging, an incidental imaging finding (also called an incidentaloma) is an unanticipated finding which is not related to the original diagnostic inquiry. As with other types of incidental medical findings, they may represen ...

on CT scan or

magnetic resonance imaging Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...

as a

lung nodule A lung nodule or pulmonary nodule is a relatively small focal density in the lung. A solitary pulmonary nodule (SPN) or coin lesion, is a mass in the lung smaller than three centimeters in diameter. A pulmonary micronodule has a diameter of less ...

. Eventually, it becomes symptomatic, usually when the tumor mass begins to obstruct the lumen of a major bronchus, often producing distal

atelectasis Atelectasis is the collapse or closure of a lung resulting in reduced or absent gas exchange. It is usually unilateral, affecting part or all of one lung. It is a condition where the alveoli are deflated down to little or no volume, as distinct ...

and

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable di ...

Cytopathology Cytopathology (from Greek , ''kytos'', "a hollow"; , ''pathos'', "fate, harm"; and , '' -logia'') is a branch of pathology that studies and diagnoses diseases on the cellular level. The discipline was founded by George Nicolas Papanicolaou in ...

may detect atypical cells from cytologic smear test of sputum,

bronchoalveolar lavage Bronchoalveolar lavage (BAL) (also known as bronchoalveolar washing) is a diagnostic method of the lower respiratory system in which a bronchoscope is passed through the mouth or nose into an appropriate airway in the lungs, with a measured amoun ...

, or samples from endobronchial brushings.

Histopathology Histopathology (compound of three Greek words: ''histos'' "tissue", πάθος ''pathos'' "suffering", and -λογία '' -logia'' "study of") refers to the microscopic examination of tissue in order to study the manifestations of disease. Sp ...

requires at least a

lung biopsy A lung biopsy is an interventional procedure performed to diagnose lung pathology by obtaining a small piece of lung which is examined under a microscope. Beyond microscopic examination for cellular morphology and architecture, special stains and ...

. On such exams, these tumors range from well differentiated, showing keratin pearls and

cell junction Cell junctions (or intercellular bridges) are a class of cellular structures consisting of multiprotein complexes that provide contact or adhesion between neighboring cells or between a cell and the extracellular matrix in animals. They also main ...

s, to

anaplastic Anaplasia (from grc, ἀνά ''ana'', "backward" + πλάσις ''plasis'', "formation") is a condition of cells with poor cellular differentiation, losing the morphological characteristics of mature cells and their orientation with respect to e ...

, with only minimal residual squamous-cell features.Entire section, if not else specified, is taken from

Classification

The 2015 WHO classification of lung tumors divided squamous cell lung carcinomas into 3 categories: keratinizing, non-keratinizing and basaloid. Keratinizing SCC harbor features of

keratin Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. Alpha-keratin (α-keratin) is a type of keratin found in vertebrates. It is the key structural material making up Scale (anatomy), scales, hair, Nail ...

ization; 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.

Treatment

Treatment of lung squamous-cell carcinoma depends on many factors including

stage Stage or stages may refer to: Acting * Stage (theatre), a space for the performance of theatrical productions * Theatre, a branch of the performing arts, often referred to as "the stage" * ''The Stage'', a weekly British theatre newspaper * Sta ...

, resectability,

performance status In medicine (oncology and other fields), performance status is an attempt to quantify cancer patients' general well-being and activities of daily life. This measure is used to determine whether they can receive chemotherapy, whether dose adjustment ...

and genomic alterations acquired by the individual tumor. Therapy of early-stage SCC mimics that of other histologic types of NSCLC. Early stage (I, II and IIIA) lung SCC are typically resected surgically, and cytotoxic

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...

and/or radiation may be used as an adjuvant therapy following surgery. On the other hand, advanced, metastatic or recurrent lung SCC are given first-line systemic therapy with a palliative (i.e., noncurative) intent consisting of cytotoxic chemotherapy, most commonly a platinum-based doublet. Either

cisplatin Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, ...

carboplatin Carboplatin, sold under the trade name Paraplatin among others, is a chemotherapy medication used to treat a number of forms of cancer. This includes ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. It is used ...

is used as the platinum backbone. Development of targeted therapies has been less rapid for lung SCC with respect to adenocarcinoma, as ALK rearrangements and EGFR mutations targetable with receptor tyrosine kinase inhibitors are much less frequent in the former compared to the latter.

Immunotherapy Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...

is showing promising results for NSCLC, and anti-PD-1 agent

nivolumab Nivolumab, sold under the brand name Opdivo, is a medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urotheli ...

has been approved by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) for lung SCC.

Epidemiology

Lung squamous-cell carcinoma is the second most common histologic type of lung cancer after adenocarcinoma, reaching 22.6% of all lung cancer cases as of 2012. The relative incidence of the former has been steadily decreasing in favor of the latter due to the decreasing smoking rates in the last few years. As much as 91% of lung SCC has been found to be attributable to cigarette smoking. Incidence is greater in men than in women.

References

{{Respiratory neoplasia Lung cancer