Squamous-cell carcinoma of the lung

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Squamous-cell carcinoma of the lung
Squamous cell carcinoma (3922611335).jpg
A squamous-cell lung carcinoma developing in the bronchius
Specialty Oncology

Squamous-cell carcinoma (SCC) of the lung is a histologic type of non-small-cell lung carcinoma (NSCLC). It is the second most prevalent type of lung cancer after lung adenocarcinoma and it originates in the bronchi. 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, more than any other form of NSCLC. [1]

Non-small-cell lung carcinoma type of tumour

Non-small-cell lung carcinoma (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 small cell carcinoma. When possible, they are primarily treated by surgical resection with curative intent, although chemotherapy has been used increasingly both pre-operatively and post-operatively.

Lung cancer cancer in the lung

Lung cancer, also known as lung carcinoma, is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung. This growth can spread beyond the lung by the process of metastasis into nearby tissue or other parts of the body. Most cancers that start in the lung, known as primary lung cancers, are carcinomas. The two main types are small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC). The most common symptoms are coughing, weight loss, shortness of breath, and chest pains.

Adenocarcinoma of the lung non-small cell lung carcinoma that derives from epithelial cells of glandular origin

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 distinguish it from small cell lung cancer which has a different behavior and prognosis. Lung adenocarcinoma is further classified into several subtypes and variants. The signs and symptoms of this specific type of lung cancer are similar to other forms of lung cancer, and patients most commonly complain of persistent cough and shortness of breath. Adenocarcinoma is more common in patients with a history of cigarette smoking, and is the most common form of lung cancer in younger women and Asian populations. The pathophysiology of adenocarcinoma is complicated, but generally follows a histologic progression from cells found in healthy lungs to distinctly dysmorphic, or irregular, cells. There are several distinct molecular and genetic pathways that contribute to this progression. Like many lung cancers, adenocarcinoma of the lung is often advanced by the time of diagnosis. Once a lesion or tumor is identified with various imaging modalities, such as computed tomography (CT) or X-ray, a biopsy is required to confirm the diagnosis. Treatment of this lung cancer is based upon the specific subtype and the extent of spread from the primary tumor. Surgical resection, chemotherapy, radiotherapy, targeted therapy and immunotherapy are used in attempt to eradicate the cancerous cells based upon these factors.


Signs and symptoms

Squamous-cell lung carcinoma share most of the signs and symptoms with other forms of lung cancer. These include worsening cough, including hemoptysis, chest pain, shortness of breath and weight loss. Symptoms may result from local invasion or compression of adjacent thoracic structures such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing change in voice, or compression involving the superior vena cava causing facial edema. Distant metastases may also cause pain and show symptoms related to other organs. [1]

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, and certain cardiovascular conditions. Hemoptysis is considered massive at 300 mL. In such cases, there are always severe injuries. The primary danger comes from choking, rather than blood loss.

Shortness of breath, also known as dyspnea, is the feeling that one cannot breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity", and recommends evaluating dyspnea by assessing the intensity of the distinct sensations, the degree of distress involved, and its burden or impact on activities of daily living. Distinct sensations include effort/work, chest tightness, and air hunger.

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. People with dysphagia are sometimes unaware of having it.


Risk factors

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]

Tobacco smoking practice of burning tobacco and inhaling the resulting smoke

Tobacco smoking is the practice of smoking tobacco and inhaling tobacco smoke. The practice is believed to have begun as early as 5000–3000 BC in Mesoamerica and South America. Tobacco was introduced to Eurasia in the late 17th century by European colonists, where it followed common trade routes. The practice encountered criticism from its first import into the Western world onwards but embedded itself in certain strata of a number of societies before becoming widespread upon the introduction of automated cigarette-rolling apparatus.

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 investigations into risk factors for major chronic diseases ever conducted. The Nurses' Health Studies have led to many insights on health and well-being, including cancer prevention, cardiovascular disease, and type 2 diabetes. They have include clinicians, epidemiologists, and statisticians at the Channing Laboratory, Harvard Medical School, Harvard School of Public Health, and several Harvard-affiliated hospitals, including Brigham and Women's Hospital, Dana–Farber Cancer Institute, Children's Hospital Boston, and Beth Israel Deaconess Medical Center.



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]

The Cancer Genome Atlas (TCGA) is a project, begun in 2005, to catalogue genetic mutations responsible for cancer, using genome sequencing and bioinformatics. TCGA applies high-throughput genome analysis techniques to improve our ability to diagnose, treat, and prevent cancer through a better understanding of the genetic basis of this disease.

Somatic evolution is the accumulation of mutations and epimutations in somatic cells during a lifetime, and the effects of those mutations and epimutations on the fitness of those cells. This evolutionary process has first been shown by the studies of Bert Vogelstein in colon cancer. Somatic evolution is important in the process of aging as well as the development of some diseases, including cancer.

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. [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%).

A tumor suppressor gene, or antioncogene, is a gene that protects a cell from one step on the path to cancer. When this gene mutates to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes. The loss of these genes may be even more important than proto-oncogene/oncogene activation for the formation of many kinds of human cancer cells. Tumor suppressor genes can be grouped into categories including caretaker genes, gatekeeper genes, and landscaper genes; the classification schemes are evolving as medicine advances, learning from fields including molecular biology, genetics, and epigenetics.

p53 protein-coding gene in the species Homo sapiens

Tumor protein p53, also known as p53, cellular tumor antigen p53, phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53 (TRP53), is any isoform of a protein encoded by homologous genes in various organisms, such as TP53 (humans) and Trp53 (mice). This homolog is crucial in multicellular organisms, where it prevents cancer formation, thus, functions as a tumor suppressor. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene.

KMT2D protein-coding gene in the species Homo sapiens

Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono-methyltransferase. It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A, KMT2B, KMT2C, KMT2F, and KMT2G. KMT2D is a large protein over 5,500 amino acids in size and is widely expressed in adult tissues. The protein co-localizes with lineage determining transcription factors on transcriptional enhancers and is essential for cell differentiation and embryonic development. It also plays critical roles in regulating cell fate transition, metabolism, and tumor suppression. Mutations in KMT2D have been associated with Kabuki Syndrome, congenital heart disease, and various forms of cancer.

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]

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. [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.

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. [6]


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.

In carcinoma in situ, atypical cells may be identified by cytologic smear test of sputum, bronchoalveolar lavage or samples from endobronchial brushings. However, squamous-cell carcinoma in situ is asymptomatic and undetectable on X-ray radiographs.

Eventually, it becomes symptomatic, usually when the tumor mass begins to obstruct the lumen of a major bronchus, often producing distal atelectasis and infection. Simultaneously, the lesion invades into the surrounding pulmonary substance. On histopathology, these tumors range from well differentiated, showing keratin pearls and cell junctions, to anaplastic, with only minimal residual squamous-cell features. [7]


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]


Treatment of lung squamous-cell carcinoma depends on many factors including stage, resectability, performance status 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 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 or carboplatin is used as the platinum backbone. [9]

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. [10]

Immunotherapy is showing promising results for NSCLC, and anti-PD-1 agent nivolumab has been approved by the US Food and Drug Administration (FDA) for lung SCC.


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. [11] 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. [9]

As much as 91% of lung SCC has been found to be attributable to cigarette smoking. Incidence is greater in men than in women. [10]

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Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.

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Adenocarcinoma in situ of the lung lung cancer that derives from the distal bronchioles or alveoli that initially exhibit a specific non-invasive growth pattern

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Large-cell carcinoma (LCC) is a heterogeneous group of undifferentiated malignant neoplasms that lack the cytologic and architectural features of small cell carcinoma and glandular or squamous differentiation. LCC is categorized as a type of NSCLC which originates from epithelial cells of the lung.

Combined small-cell lung carcinoma

Combined small cell lung carcinoma is a form of multiphasic lung cancer that is diagnosed by a pathologist when a malignant tumor arising from transformed cells originating in lung tissue contains a component of small cell lung carcinoma (SCLC) admixed with one components of non-small cell lung carcinoma (NSCLC).

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Basaloid squamous cell carcinoma (Bas-SqCC) is an uncommon histological variant of lung cancer composed of cells exhibiting cytological and tissue architectural features of both squamous cell lung carcinoma and basal cell carcinoma.

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