Squamous cell carcinoma of the lung

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

Squamous cell carcinoma of the lung ( also known as “Squamous cell lung cancer“) is a type of non-small cell carcinoma of the lung. It is the second most commonly encountered lung cancer after lung adenocarcinoma. Squamous cell carcinoma accounts for 30-35% of all lung cancers and has a strong association with smoking. Squamous cell carcinoma of the lung may be classified according to the WHO histological classification system into 4 main types: papillary, clear cell, small cell, and basaloid. Squamous cell carcinoma of the lung arises from the epithelial cells of the lung from the central bronchi to the terminal alveoli, which are normally involved in the protection of the airways. Squamous cell carcinoma of the lung has a central location and usually appears as a hiliar or perihiliar mass. Squamous cell carcinoma of the lung is a rapidly growing cancer which may metastasize to various organs of the body. Genes involved in the pathogenesis of squamous cell carcinoma include EGFR, EML-4, KRAS, HER2, and ALK. Common causes of squamous cell carcinoma of the lung include precursor lesions, such as metaplasia or dysplasia induced by smoking, asbestos exposure, ionizing radiation, atmospheric pollution, and chronic interstitial pneumonitis. Less common causes of non-small cell lung cancer include chromium and nickel exposure, vinyl chloride exposure, and inorganic arsenic exposure. The optimal treatment management of squamous cell carcinoma of the lung will depend on several characteristics, such as pre-treatment evaluation (performance status), location, and adequate staging. Common medical treatment options for the management of squamous cell carcinoma of the lung include chemotherapy (neoadjuvant/adjuvant) and radiation therapy. Surgery is the mainstay of treatment for squamous cell carcinoma of the lung. Common surgical procedures for the treatment of squamous cell carcinoma of the lung include pulmonary lobectomy, pneumonectomy, lung resection with lobectomy, or lung resection with pneumonectomy with or without lymph node dissection. The preferred surgical procedure is thoracotomy with removal of the entire lung or lobe (lobectomy) along with regional lymph nodes and contiguous structures. Prognosis of squamous cell carcinoma of the lung is generally regarded as poor, with the average survival rate ranging from 16% to 49%.

In 1929, Fritz Lickint, a German physican, first described the association between smoking and squamous cell carcinoma of the lung.

Squamous cell carcinoma of the lung may be classified according to the WHO histological classification system into 4 main types: papillary, clear cell, small cell, and basaloid.

Squamous cell carcinoma of the lung arises from the epithelial cells from the central bronchi to the terminal alveoli, which are normally involved in the protection of the airways. The pathological irritation caused by cigarette smoke causes the mucus-secreting ciliated pseudostratified columnar respiratory epithelial cells that line the airways to be replaced by stratified squamous epithelium. Squamous cell carcinoma of the lung has a central location and usually appears as a hiliar or perihiliar mass. Squamous cell carcinoma of the lung is a rapidly growing cancer which may metastasize to various organs of the body. Genes involved in the pathogenesis of squamous cell carcinoma include several oncogenes, such as EGFR, EML-4, KRAS, HER2, and ALK. On gross pathology, findings include central necrosis, cavitation, and invasion of peribronchial soft tissue. On microscopic histopathological analysis squamous cell carcinoma of the lung demonstrate large polygonal malignant cells containing keratin and intercellular bridges. On inmunohistochemistry, findings associated with squamous cell carcinoma of the lung include the presence of p53 and high-molecular weight keratins for squamous cell carcinoma. Other squamous immunomarkers include CK5/6, CEA, 34BE12, TTF-1, and CK7.

Common causes of squamous cell carcinoma of the lung include precursor lesions, such as metaplasia or dysplasia induced by smoking, asbestos exposure, ionizing radiation, atmospheric pollution, and chronic interstitial pneumonitis. Less common causes of non-small cell lung cancer include chromium and nickel exposure, vinyl chloride exposure, and inorganic arsenic exposure.

Squamous cell carcinoma must be differentiated from other diseases that cause chronic cough, weight loss, hemoptysis, and dyspnea among adults such as tuberculosis, pulmonary fungal disease, and secondary metastases.

Squamous cell carcinoma of the lung accounts for 30% to 35% of all lung cancers and is the second most commonly encountered lung cancer after lung adenocarcinoma.Squamous cell carcinoma of the lung accounts for approximately 27% of all cancer deaths. The incidence of lung squamous cell carcinoma increases with age; the median age at diagnosis is approximately 70 years (usually ranging from 65 to 74 years). Males are more commonly affected with squamous cell carcinoma of the lung than females. The male to female ratio is approximately 1.8 to 1. Squamous cell carcinoma of the lung usually affects black individuals more frequently. Black race is associated with a higher incidence of squamous cell carcinoma compared with White race.

Common risk factors in the development of squamous cell carcinoma of the lung include smoking, family history of lung cancer, high levels of air pollution, radiation therapy to the chest, radon gas, asbestos, occupational exposure to chemical carcinogens, and previous lung disease.

According to the U.S. Preventive Services Task Force (USPSTF), screening for lung cancer by low-dose computed tomography is recommended every year among smokers who are between 55 to 80 years old and who have history of smoke 30 pack-years or more and either continue to smoke or have quit within the past 15 years (grade B recommendation).

If left untreated, squamous cell carcinoma of the lung progression occurs slowly and is then followed by local invasion to lymph nodes and distant metastasis. Squamous cell carcinoma of the lung is a locally aggressive tumor, which commonly occurs among adult patients between 65 to 74 years. Common sites of metastasis include liver, adrenal gland, bone, and brain. Complications of squamous cell carcinoma of the lung include development of pneumonia, pleural effusion, metastasis, and Horner’s syndrome. The 5-year survival rate of patients with squamous cell carcinoma of the lung depends on the stage at diagnosis. Prognosis is generally regarded as poor, and the average survival rate ranges from 16% to 49%. Features associated with worse prognosis are the presence of genetic and histologic factors (such as presence of necrosis), performance status, tumor size, presence of lymphatic invasion, invasion to the pulmonary artery, presence of satellite lesions, and presence of regional or distant metastases. The 5-year recurrence rate of squamous cell carcinoma of the lung is approximately 24%.

According to the American Joint Committee on Cancer (AJCC) staging system, there are 4 stages squamous cell carcinoma of the lung, based on 3 factors: tumor size, lymph node invasion, and metastasis. Each stage is assigned a letter and a number that designate T for tumor size, N for node invasion, and M for metastasis.

Computed tomography is the method of choice for the diagnosis of squamous cell carcinoma of the lung. On CT, findings of squamous cell carcinoma of the lung will depend on the location of the tumor, characteristic findings include: ground-glass opacity, rounded or spiculated mass, local nodal involvement, intraluminar obstruction, and lobar collapse.

The hallmark of squamous cell carcinoma of the lung is chronic cough, weight loss, and hemoptysis. A positive history of smoking may be suggestive of squamous cell carcinoma of the lung. Symptoms related to squamous cell carcinoma of the lung will vary depending on the size and location of the tumor. Common symptoms of squamous cell carcinoma of the lung may also include shortness of breath, fatigue, and chest pain. Less common symptoms of squamous cell carcinoma of the lung include bone pain, fatigue, dizziness, dysphagia, and numbness in the extremities.

Physical examination findings of squamous cell carcinoma of the lung will depend on the location of the tumor. Non-small cell lung cancer with central location may cause crackling sounds, focal wheezing, voice hoarseness, and tachypnea. Peripheral location can present with pleurisy findings, such as reduced chest expansion. Common physical examination of patients with squamous cell carcinoma of the lung include crackling or bubbling noises, decreased/absent breath sounds, whispered pectoriloquy, and tachypnea.

Laboratory findings associated with squamous cell carcinoma of the lung include elevation of LDH or serum tumor markers. Routine laboratory studies for squamous cell carcinoma of the lung include complete blood count, electrolytes, calcium, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, creatinine, albumin, and lactate dehydrogenase.

On chest X ray, characteristic findings of squamous cell carcinoma of the lung include rounded or spiculated mass, bulky hilum (representing the tumor and local nodal involvement) and lobar collapse.

Computed tomography is the imaging modality of choice for the diagnosis of squamous cell carcinoma of the lung. On chest CT, findings of squamous cell carcinoma of the lung will depend on the location of the tumor, characteristic findings include ground-glass opacity, rounded or spiculated mass, local nodal involvement, intraluminar obstruction, and lobar collapse.

On MRI, the diagnosis of squamous cell carcinoma of the lung requires pleural effusion assessment, as well as guidance for biopsy to detect either a peripheral or mediastinal mass.

On endobronchial and endoscopic ultrasound, characteristic findings of non-small cell lung cancer include: enlarged lymph nodes and local invasion to adjacent bronchial structures and mediastinum. Endobronchial ultrasound is a first-line diagnostic modality for mediastinal staging.

Other imaging findings of squamous cell carcinoma of the lung include: PET/CT and pulmonary angiography.

Other diagnostic modalities for squamous cell carcinoma of the lung include thoracotomy, bronchoscopy, mediastinoscopy, and transthoracic percutaneous fine needle aspiration. Common biopsy findings associated with squamous cell carcinoma of the lung include prominent nucleoli, eosinophilic cytoplasm, and intracellular bridges. Different types of lung tissue biopsy include bronchoscopy biopsy, open biopsy, and video-assisted thoracoscopic surgery.

Biopsy findings associated with squamous cell carcinoma of the lung include prominent nucleoli, eosinophilic cytoplasm, and intracellular bridges. Different sub-types of lung tissue biopsy for squamous cell carcinoma of the lung include needle biopsy, open biopsy, and video-assisted thoracoscopic surgery.

The optimal treatment management of squamous cell carcinoma of the lung will depend on several characteristics, such as pre-treatment evaluation (performance status), location, and adequate staging. Common medical treatment options for the management of squamous cell carcinoma of the lung include chemotherapy (neoadjuvant/adjuvant) and radiation therapy.

Combination chemotherapy regimens using platinum-based chemotherapy and specific-inhibitors is the treatment of choice for the management of patients with squamous cell carcinoma of the lung. Chemotherapy may be required depending on the histological subtype of the squamous cell carcinoma of the lung, molecular testing (presence of genetic mutations), and staging. In the majority of cases, the predominant treatment of choice for squamous cell carcinoma of the lung is either neoadjuvant chemotherapy or adjuvant chemotherapy, which is either followed or preceded by surgical resection. Commonly used chemotherapeutic agents include cisplatin, erlotinib, paclitaxel, docetaxel, carboplatin, etoposide or vinorelbine.

Radiation therapy is recommended as palliative care either among patients who are diagnosed at an advanced stage of squamous cell carcinoma of the lung or among symptomatic patients with local involvement (pain, vocal cord paralysis, and hemoptysis). Curative radiation therapy may be indicated in patients who are not suitable for surgery with early stage squamous cell carcinoma of the lung. The main goal of radiation therapy for squamous cell carcinoma of the lung is maximum tumor control with minimal tissue toxicity. There are 2 main types of radiation therapy for squamous cell carcinoma of the lung: external beam radiation therapy and brachytherapy (internal radiation therapy).

Surgery is the mainstay of treatment for squamous cell carcinoma of the lung. Common surgical procedures for the treatment of squamous cell carcinoma of the lung include pulmonary lobectomy, pneumonectomy, lung resection with lobectomy, lung resection with pneumonectomy with or without lymph node dissection. The preferred surgical procedure is thoracotomy with removal of the entire lung or lobe (lobectomy) along with regional lymph nodes and contiguous structures. Common complications of squamous cell carcinoma of the lung surgery, include: atelectasis, nosocomial pneumonia, prolonged mechanical ventilation, respiratory failure, bronchospasm, pulmonary embolism.

Primary preventive measures of squamous cell carcinoma of the lung include avoidance of smoking, smoking exposure, exposure to asbestos, and other high risk occupational jobs.

Secondary prevention of squamous cell carcinoma of the lung depends on the stage of squamous cell carcinoma of the lung at diagnosis. Secondary prevention routine follow-up using chest CT imaging along with periodic evaluation of alert signs in second-hand smokers or active smokers.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shanshan Cen, M.D. [2] Maria Fernanda Villarreal, M.D. [3]

In 1929, Fritz Lickint, a German physican, first described the association between smoking and squamous cell carcinoma of the lung.

• In 1879, Harting and Hesse, two German physicians, first described the association between lung cancer and working in mines.
• In 1929, Fritz Lickint a German physican first described the association between smoking and squamous cell carcinoma of the lung.
• In 1950, “The British Doctors Study” was the first solid epidemiological evidence of the link between lung cancer and smoking.^[1]
• In 1966, the first preventive measures against lung cancer were implemented, warning labels first appear on cigarette packs “Caution: Cigarette Smoking May Be Hazardous to Your Health“.^[2]
• In 1982, Geoffrey Cooper, an American pathologist, first used the NIH 3T3 focus assay to identify the activated K-RAS oncogene in lung cancer cell lines.^[3]
• In 1986, the association between second-hand smoking and squamous cell carcinoma of the lung was established.^[2]
• In 1987, researchers first established that epidermal growth factor receptor (EGFR) plays an important role in the growth and spread of squamous cell carcinoma of the lung.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Trusha Tank, M.D.[2]

Squamous cell carcinoma of the lung may be classified according to the WHO histological classification system into 4 main types: Keratinizing squamous cell carcinoma, nonkeratinizing squamous cell carcinoma, basaloid squamous cell carcinoma and preinvasive lesion.

The World Health Organization (WHO) classifies tumors of the lungs as follows:^[1][2]

WHO Classification of Lung Tumors
Histological type	Subtype
Epithelial tumors
Squamous cell carcinoma	Keratinizing squamous cell carcinoma Nonkeratinizing squamous cell carcinoma Basaloid squamous cell carcinoma Preinvasive lesion Squamous cell carcinoma in situ

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Trusha Tank, M.D.[2],Maria Fernanda Villarreal, M.D. [3]

Squamous cell carcinoma of the lung arises from the epithelial cells of the lung of the central bronchi to terminal alveoli, which are normally involved in the protection of the airways. The pathological irritation caused by cigarette smoke causes the mucus-secreting ciliated pseudostratified columnar respiratory epithelial cells that line the airways to be replaced by stratified squamous epithelium. Squamous cell carcinoma of the lung has a central location and usually appears as a hiliar or perihiliar mass. Squamous cell carcinoma of the lung is a rapidly growing cancer which may metastasize to various organs of the body. Genes involved in the pathogenesis of squamous cell carcinoma include several oncogenes, such as: EGFR, EML-4, KRAS, HER2, and ALK. On gross pathology, findings include central necrosis, cavitation, and invasion of peribronchial soft tissue. On microscopic histopathological analysis squamous cell carcinoma of the lung demonstrate large polygonal malignant cells containing keratin and intercellular bridges. On immunohistochemistry, findings associated with squamous cell carcinoma of the lung include the presence of p53 and high-molecular weight keratins for squamous cell carcinoma. Other squamous immunomarkers, include: CK5/6, CEA, 34BE12, TTF-1, and CK7.

• Lung cancer pathogenesis can be understood with the help of following hypothesis.^[1][2][3]
• Familial lung cancer:
  • 6q23–25 locus has been identified as a susceptibility gene for familial lung cancer.

• Multistep tumorigenesis:
  • Tumors of organs such as skin, lung and colon are developed through a process called multistep tumorigenesis.
  • As with other epithelial malignancies, lung cancers are believed to arise from preneoplastic or precursor lesions in the respiratory mucosa.
  • Multistep tumorigenesis is development of tumor through a series of progressive pathologic events such as preneoplastic or precursor lesions with corresponding genetic and epigenetic aberrations.
  • Hyperplasia, squamous metaplasia, squamous dysplasia, and carcinoma in situ (CIS) comprise changes in the large airways that precede or accompany invasive squamous cell carcinoma of the lung.^[4]
  • Multistep tumorigenesis explains pathogenesis of centrally located squamous cell carcinoma of the lung very well but fails to explain pathogenesis of large cell lung carcinomas, lung adenocarcinomas, and small cell lung cancer.

• Accumulation of molecular abnormalities:
  • Another theory for pathogenesis of lung cancer is the accumulation of molecular abnormalities beyond a certain threshold point, rather than the sequence of alterations.
  • There are no known preneoplastic lesions for the most common type of neuroendocrine lung tumors, small cell carcinoma of the lung,
  • Atypical adenomatous hyperplasia (AAH) is the only sequence of morphologic change identified leading to the development of invasive adenocarcinoma of the lung.
• Pathogenesis of lung cancer is thought to be result of both due to stepwise, sequence-specific and multistage molecular pathogenesis and due to accumulation and combination of genetic and epigenetic abnormalities.

• Preneoplastic lung lesions frequently extend throughout the respiratory epithelium, indicating a field effect in which much of the respiratory epithelium has been mutagenized, presumably from exposure to tobacco-related carcinogens.^[5][6][7]
• Epithelial cells lining the entire respiratory tract that have been exposed to smoking show molecular alterations that may signify the onset of lung cancers, a paradigm known as the “airway field of injury”.
• Premalignant airway fields in the molecular pathogenesis of lung cancer:
  • Smoking induces widespread molecular alterations, such as gene expression changes in exposed epithelia throughout the respiratory tract.
  • The airway field of injury can be seen in smokers with or without lung cancer and is highly relevant for the identification of markers for minimally invasive and early detection of lung cancer.
  • The adjacent airway field of carcinoma represents the field in normal appearing airways adjacent to lung tumors.
  • It has been suggested that in this adjacent field of tumor, there is closer molecular genealogy between lung cancers and airways that are in closest proximity to the tumors compared with airways that are more distant from the tumors.
  • The progression of the molecular airway field of injury to preneoplasia and lung malignancy is still not clear.
  • Molecular changes involved in the development of the airway field of injury and changes mediating progression of this field to lung preneoplasia may help the identification of early markers for lung cancer detection and chemoprevention.

• Squamous cell carcinoma of the lung arises from bronchial epithelial cell damage (usually related with active smoking).
• Basal cells in the large airways exhibit pluripotent capacity following cigarette smoke exposure.
• These pluripotent basal cells give rise to metaplastic and dysplastic squamous cells, which in turn function as precursors of squamous cell carcinomas.
• The squamous metaplasia is then followed by epithelial dysplasia, which consists of an expansion of immature cells with a corresponding decrease in the number and location of mature cells.
• Dysplasia is often indicative of an early neoplastic process in squamous cell carcinoma of the lung.
• Squamous cell carcinoma of the lung has a central location and usually appears as a hiliar or peri-hilar mass.
• Squamous cell carcinoma of the lung is a rapidly growing cancer which may metastasize to various organs of the body.
• Basaloid lung cell carcinoma is the most aggressive subtype of squamous cell carcinoma of the lung.

• Development of squamous cell carcinoma of the lung is the result of multiple genetic mutations.^[8]
• Genetic mutations play an important role in the treatment selection for squamous cell carcinoma of the lung.
• Squamous cell carcinoma of the lung is a diploid or hyperdiploid aneuploid neoplasm with mean chromosome numbers in the triploid range.^[9]
• In squamous cell carcinoma of the lung, there is a multitude of alterations with amplifications of the telomeric 3q region.
• Gain of 3q24-qter is present in the majority of squamous cell carcinomas of the lung.
• Disruption of normal p53 gene is frequent in squamous cell carcinoma of the lung.
• Genes involved in the pathogenesis of squamous cell carcinoma include the following:^[9]
  • EGFR
    • 84% of squamous cell carcinomas of the lung are positive for EGFR
  • EML-4
  • ALK
  • KRAS
    • 30% of squamous cell carcinomas of the lung are positive for KRAS
  • HER2
    • Rare in squamous cell carcinomas of the lung

• Conditions associated with squamous cell carcinoma of the lung include:^[9]

• Pancoast tumor
• Horner’s syndrome

• On gross pathology, findings associated with squamous cell carcinoma of the lung include:^[10]

• Lung mas that is usually centrally located
• Invasion of peribronchial soft-tissue, lymph nodes, and lung parenchyma
• Large mass causing compression of pulmonary artery and vein
• Central cavitation

• On microscopic pathology, findings associated with squamous cell carcinoma of the lung include:^[10]
  • Central nucleus
  • Dense appearing cytoplasm, usually eosinophilic
  • Small nucleolus
  • Intracellular bridges (classic feature)
• The IASLC/ATS/ERS lung adenocarcinoma histologic classification system was proposed in the Journal of Thoracic Oncology in 2011.^[11]
  • Keratinizing squamous cell carcinoma:
    • Tumor budding, single cell invasion, and large nuclei.
    • Tumor budding, or the presence of small tumor nests.
    • A large nucleus was defined as a diameter greater than that of four small lymphocytes.
  • Nonkeratinizing squamous cell carcinoma
  • Basaloid squamous cell carcinoma
  • Preinvasive lesion
  • Squamous cell carcinoma in situ

• Findings associated with squamous cell carcinoma of the lung include:^[12]
• Presence of p63 and high-molecular weight keratins for squamous cell carcinoma.
• Other squamous immunomarkers include CK5/6, CEA, 34BE12, TTF-1, and CK7.
• Differentiation of squamous cell carcinoma of the lung from adenocarcinoma on biopsy is vital as response to cytotoxic and biological agents will greatly differ.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shanshan Cen, M.D. [2] Maria Fernanda Villarreal, M.D. [3]

Common causes of squamous cell carcinoma of the lung include precursor lesions, such as metaplasia or dysplasia induced by smoking, asbestos exposure, ionizing radiation, atmospheric pollution, and chronic interstitial pneumonitis. Less common causes of non-small cell lung cancer include chromium and nickel exposure, vinyl chloride exposure, and inorganic arsenic exposure.

• Common causes of squamous cell carcinoma of the lung include precursor lesions, such as metaplasia or dysplasia.
• Precursor lesions of non-small cell lung cancer include:^{[1][2][3][4][5]}

• Smoking(active/passive)
• Asbestos exposure
• Chronic interstitial pneumonitis
• Ionizing radiation
• Atmospheric pollution

• Less common causes of squamous cell carcinoma of the lung include:^[1][6][7][8]
  • Inorganic arsenic exposure
  • Chromium, nickel exposure
  • Vinyl chloride exposure
  • Radon exposure
  • Halogen ether exposure
  • Radiation exposure

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Squamous cell carcinoma of the lung must be differentiated from other diseases that cause chronic cough, weight loss, hemoptysis, and dyspnea among adults such as pulmonary tuberculosis, sarcoidosis, pneumonia, pulmonary fungal infection, and secondary metastases.

Abrevations: HPV: human papillomavirus; CEA: Carcino embryogenic antigen; TTF1: Thyroid transcription factor-1; EMA: Epithelial membrane antigen; CK: Cyto keratin; CD: Cluster differentiation; NCAM: Neural Cell Differentiation Molecule; MMP’s: Mettaloprotineases matrix ; GFAP: Glial fibrocilliary acid protein
Benign Lung Tumors[2]
Benign lung tumor			Risk/Epidemiology	Pleuripotent cells	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Papilloma[3]	Squamous cell papilloma		HPV 6 and 11 Men Median age of diagnosis is 54 years	Epithelial cells	Endobronchial	Cauliflower-like lesions Tan-white soft to semifirm protrutions	Loose fibrovascular core Stratified squamous epithelium Acanthosis Binucleate forms and perinuclear halos Koilocytosis	N/A	Well circumscribed Homogenous Non-calcified Solitary mass	N/A
	Glandular papilloma		Rare Mean age of diagnosis is 68 years	Goblet cells of respiratory epithelium	Endobronchial	White to tan endobronchial polyps that measure from 0.7-1.5 cm	Thick arborizing stromal stalks Thin-walled blood vessels Non-ciliated or ciliated epithelium	N/A	Well circumscribed Homogenous Non-calcified Solitary mass	N/A
Adenoma[4]	Alveolar adenoma		Mean age of diagnosis is 53 years Female predominance	Alveolar pneumocytes Septal mesenchyme	All lung lobes Lower lobes Hilar	0.7-6.0 cm Well demarcated smooth Lobulated, multicystic Soft to firm Pale yellow to tan cut surfaces	Non-encapsulated Multicystic masses Cuboidal cell linning Squamous metaplasia Myxoid and collagenous interstitium	Keratin CEA Surfactant protein TTF-1 Actin	Well circumscribed Homogenous Non-calcified Solitary mass	N/A
	Papillary adenoma[5]		Mean age of diagnosis is 32 years Male predominance	Bronchioloalveolar cell	No lobar predilection Involves alveolar parenchyma	Well defined Encapsulated Soft, spongy to firm mass Granular gray white/ brown 1.0- 4.0 cm	Infiltration Papillary growth pattern Fibrovascular cores Cuboidal to columnar epithelial linning Cilitated and oxyphilic cells Occasional eosinophilic intranuclear inclusions	Cytokeratin Clara cell protein TTF-1 Surfactant apoprotein CEA	Incidental finding	N/A
	Mucinous cystadenoma		No sex predilection Mean age of diagnosis is 52 years	Mucus glands of the bronchus	Central	White-pink to tan Smooth and shiny tumors Gelatinous mucoid solid core 0.7-7.5 cm	Numerous mucin-filled cystic spaces Non-dilated microacini, glands, tubules and papillae	EMA Cytokeratins CEA	Coin lesion Air-meniscus sign	N/A
Malignant Lung Tumors[6]
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Squamous cell carcinoma (SCC)[7]	Papillary		Cigarette smokers Arsenic	Epithelial cells	Central	White or grey lesions Focal carbon pigment deposits Cavitations Intraluminal polypoid masses Infiltration	Exophytic Intra-epithelial Without invasion	Keratin Cytokeratins CEA Thyroid transcription factor-1 (TTF-1)	Lobar or entire lung collapse Shift of the mediastinum to the ipsilateral side Hilar, perihilar or mediastinal masses	Liver Breast Bone
	Clear cell						Cells with clear cytoplasm
	Basaloid						Peripheral palisading of nuclei. Poor differentiation
Small cell carcinoma[8]			Smoking Radon exposure	Bronchial precursor cell	Peripheral	White-tan, soft, friable perihilar masses Extensive necrosis 5% peripheral coin lesions	Sheet-like growth Nesting Trabeculae Peripheral palisading Rosette formation High mitotic rate	CD56 Chromogranin Synaptophysin TTF-1	Hilar or perihilar masses Mediastinal lymphadenopathy Lobar collapse	Bone marrow Liver
Adenocarcinoma[9][10][11]	Acinar adenocarcinoma		Smoking	Columnar cells of bronchioles	Peripheral	Single or multiple lesions Different in size Peripheral distribution Gray-white central fibrosis Pleural puckering Anthracotic pigmentation Necrosis Cavitation Hemorrhage Lobulated or ill defined edges	Irregular-shaped glands Malignant cells: Hyperchromatic nuclei Fibroblastic stroma	Epithelial markers CEA CK7 TTF-1	Peripheral nodules under 4.0 cm in size Central location as a hilar or perihilar mass Rarely show cavitations. Hilar adenopathy Adenocarcinomas account for the majority of small peripheral cancers identified radiologically.	Aerogenous spread is characteristic Brain Bone Adrenal glands Liver Kidney Gastrointestinal Tract
	Papillary adenocarcinoma						Papillae Necrosis Surrounding invasion Cuboidal to columnar epithelial linning Mucinous or non-mucinous
	Bronchio-alveolar carcinoma	Non-mucinous					Clara cells Type II cells
		Mucinous					Low grade differentiation Composed of: Tall columnar cells Basal nuclei Pale cytoplasm resembling goblet cells Varying amounts of cytoplasmic mucin Cytologic atypia
		Mixed non-mucinous and mucinous or indeterminate					Mixed type of cells Low to high grade differentiated cells.
	Solid adenocarcinoma with mucin production	Fetal adenocarcinoma					Consists glandular elements: Tubules of glycogen-rich Non-ciliated cells Subnuclear and supranuclear glycogen vacuoles Rounded morules of polygonal cells with abundant eosinophilic and finely granular cytoplasm
		Mucinous (“colloid”) carcinoma					Dissecting pools of mucin containing neoplastic cells
		Mucinous cystadenocarcinoma					Partial fibrous tissue capsule Central cystic change with mucin pooling Neoplastic mucinous epithelium grows along alveolar walls
		Signet ring adenocarcinoma					Focal Cells with nuclei displaced to sides Components of other cells are present.
		Clear cell adenocarcinoma					Clear cells with no nuclei
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Large cell carcinoma[12]	Basaloid large cell carcinoma of the lung		Approximately 10% of lung cancers Smoking	Neuro endocrine cells Suprabasal bronchial cells	Peripheral masses Bronchi	Soft, pink-tan tumor Necrosis and occasional hemorrhage Cavitations Exophytic bronchial growth	Invasive growth pattern Peripheral palisading Small, monomorphic, cuboidal fusiform	Chromogranin Synaptophysin CD56  Cytokeratin	Large, peripheral masses	Pleura Liver Bone Brain Abdominal lymph nodes Pericardium
	Clear cell carcinoma of the lung						Clear cells
	Lymphoepithelioma-like carcinoma of the lung						Syncytial growth pattern Eosinophilic nucleoli Lymphocytic infiltration Invasive Amyloid deposition
	Large-cell lung carcinoma with rhabdoid phenotype						Eosinophilic cytoplasmic globules Small foci of adenocarcinoma Eosinophilic inclusions
	Mixed type						Mixture of: Adenocarcinoma Squamous cell carcinoma Giant cell carcinoma Spindle cell carcinoma
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Sarcomatoid carcinoma[13]	Carcinosarcoma		Accounts for only 0.3-1.3% of all lung malignancies Mean age at diagnosis is 60 years Tobacco smoking Asbestos exposure	Undifferentiated epithelial cells	Central or peripheral Upper lobes	> 5 cm Well circumscribed Grey, yellow or tan creamy, gritty, Mucoid and/or hemorrhagic with significant necrosis Sessile or pedunculated Infiltrative	Biphasic Mixture of carcinomatous and sarcomatous cells	Keratin S-100	No specific imaging features	Aggressive tumor Esophagus, jejunum, and rectum Kidney
	Spindle cell carcinoma						Only spindle shaped tumor cells Lymphoplasmacytic infiltrates	Keratin EMA Cytokeratin Vimentin CEA TTF-1
	Giant cell carcinoma						Multi- and/or mononucleated tumor giant cells
	Pleomorphic carcinoma						Poorly differentiated Mixture of spindle cells and/or giant cells Fibrous or myxoid stroma
	Pulmonary blastoma						Biphasic Mixture of epithelial and mesenchymal stroma	Keratin EMA CEA Chromogranin A
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Carcinoid tumor[14]	Typical carcinoid Atypical carcinoid		Most common in males Mean age of diagnosis 45	Neuroendocrine cells of lung	Typical carcinoids are throughout the lungs Atypical carcinoid is more commonly peripheral	Firm, well demarcated, tan to yellow tumors	Uniform polygonal cells Nuclear atypia Pleomorphism The most common patterns are the organoid and trabecular Highly vascularized fibrovascular stroma Focal necrosis	Cytokeratin Chromogranin Synaptophysin CD57 CD56 S-100 protein	Well defined pulmonary nodules Calcifications is often seen. Intense contrast enhancement	Liver Bone
Salivary gland tumors[15]	Mucoepidermoid carcinoma		Most patients presents in the third and fourth decade Constitutes of less than 1% tumor No association with cigarette smoking or other risk factors	Primitive cells of tracheobronchial origin	Bronchial glands	Ranging in size from 0.5-6 cm Soft, polypoid, and pink-tan in colour High-grade lesions are infiltrative	Exophytic endobronchial growth Surface epithelium lacking changes of in-situ carcinoma Absence of individual cell keratinization Transitional areas to low grade mucoepidermoid carcinoma	GFAP	Well-circumscribed oval or lobulated mass Calcifications Post-obstructive pneumonic infiltrates	Rare Liver Bones Adrenal gland Brain
	Adenoid cystic carcinoma		Constitutes less than 1% of all lung tumors Most commonly seen in fourth and fifth decades of life	Primitive cells of tracheobronchial origin	Trachea	Gray-white or tan polypoid lesions Size ranges from 1–4 cm Infiltrative margins	Invades other cell layers Heterogeneous cellularity Cribriform pattern Perineural invasion	Immunoperoxidase Cytokeratin Vimentin Actin Calponin S-100 protein p53 GFAP	Well circumscribed Nodule	Liver Brain Bone Spleen Kidney Adrenal glands
	Epithelial-myoepithelial carcinoma		Age ranges from 33 to 71 years No association with smoking	Myoepithelial cells	Endobronchial	Solid to gelatinous in texture White to gray in colour	Myoepithelial cells Dual layer of cells lining ducts Low mitotic activity	MNF116 EMA SMA and S-100	Reflects airway obstruction	Breast
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Preinvasive lesions[16]	Squamous carcinoma in situ		Most commonly seen in fifth or sixth decades Mostly seen in women	Basal cells of squamous epithelium	Bronchi	Focal or multi-focal plaque-like greyish lesions Nonspecific erythema Even nodular or polypoid lesions	Goblet cell hyperplasia Basal cell hyperplasia Squamous dysplasia Angiogenic squamous dysplasia Micropapillomatosis	EGFR HER2/neu p53 MCM2 Ki-67 Cytokeratin 5/6 Bcl-2 VEGF Folate binding protein p16	Cauliflower like Mosaic pattern	Liver Brain Bone Spleen
	Atypical adenomatous hyperplasia			Surfactant apoprotein Clara cell specific 10kDd protein	Pleura Upper lobes	Multiple grey to yellow foci 1mm to 10mm in size	Intranuclear inclusions Clara cells and type II pneumocytes Thickened alveolar walls Discontinuous lining of cells Moderate atypia Pseudopapillae	CEA MMPs E-cadherin ß-catenin CD44v6 TTF-1 TP53	Typically not visualized on radiographs Small non-solid nodules Ground-glass opacity
	Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia			Pulmonary neuroendocrine cells	Endobronchial	Early lesions are: Small, gray-white nodules Resembling ‘miliary bodies’ Larger carcinoid tumors are: Firm Homogeneous Well-defined Grey or yellow-white masses	Nodular aggregates Fibrosis due to proliferation Invade locally Fibrous stroma aggregates to form ‘tumorlets’. Carcinoids are tumorlets >5cm.	Keratin CEA	Mosaic pattern of air trapping Sometimes with nodules Thickened bronchial and bronchiolar walls
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Mesenchymal tumors[17]	Epithelioid haemangioendothelioma / Angiosarcoma		Caucasian 80% are women	Endothelial cells	Intravascular	0.3-2.0 cm circumscribed mass Gray-white or gray-tan firm tissue Yellow flecks Central calcifications Cut surface has a cartilaginous consistency	Round to oval-shaped nodules Central sclerosis Hypocellular zone Peripheral cellular zone Calcifications Intranuclear cytoplasmic inclusions	CD31 CD34 Factor VIII (von Willebrand factor) Cytokeratin	Multiple Bilateral Small nodules 1-2 cm in size Can mimic pulmonary Langerhans’ cell histiocytosis. Calcifications	Liver Bone Soft tissue
	Pleuropulmonary blastoma		Most common in children Median age of diagnosis is 2 years	Thoracic splanchnopleural mesenchyme	Pleura Lung	Purely cystic Thin-walled Rarely solid Firm to gelatinous Upto 15 cm	Type I Purely cystic Lined by respiratory type epithelium Underneath malignant cells Type II Partial or complete overgrowth of the septal stroma Type III Mixed cells	Vimentin S-100 protein	Unilateral Localized airfilled cysts Septal thickening or an intracystic mass	Brain Spinal cord Skeletal system Eyes Pancreas
	Chondroma		Young women	Chondrocytes Cartilaginous cells	Peripheral lesions in lung Primary lesion seen in Stomach Bone Paraganglia	Peripheral Solid lesions Calcified	Capsulated lobules Hypocellular Features of malignancy are absent	N/A	Multiple Well circumscribed lesions “Pop-corn” calcifications	Benign in nature
	Congenital peribronchial myofibroblastic tumor		Rare Sporadic Complicated by Polyhydramnios Non-immune hydrops fetalis	Spindle cells	Along the bronchi	5-10 cm Well-circumscribed Non-encapsulated Smooth or multinodular surface The cut surface has a tann-grey to yellow-tan fleshy appearance Hemorrhage Necrosis	Fascicles of spindle cells Bronchial invasion Peribronchial distribution Cystic foci of hemorrhage	Vimentin	Well circumscribed Opaque hemithorax Heterogeneous mass	Rare
	Diffuse pulmonary lymphangiomatosis		Children Young adults of both sexes	Smooth muscle cells of lymphatic vessels	Along the lymphatic distribution	Prominence of the bronchovascular bundles along Pleura Interlobular pulmonary septa Mediastinum	Anastomosing endothelial-lined cells along lymphatic routes Spindle cells Intra alveolar siderophages	Vimentin	Increased interstitial markings Thickening of the: Interlobular septa Fissures Central airways Pleura	Skin Bone
	Inflammatory myofibroblastic tumor		Previous viral infections HHV8 Children	Myofibroblastic cells	Localized to bronchi	Solitary Round rubbery masses Yellowish-gray discoloration Average size of 3.0 cm Non-encapculated Calcifications No local invasion	Mixture of spindle cells Fibroblastic Myofibroblastic Arranged in fascicles Cytologic atypia Touton type giant cells Plasma cells Lymphoid follicles	Vimentin Actin p80	Solitary mass Regular borders Spiculated appearance Accompanied by Post-obstructive pneumonia Atelectasis	Rare
	Pulmonary artery sarcoma		Mean age of diagnosis is 49.3 years Commonly misdiagnosed as pulmonary embolism	Mesenchymal cells of the intima Primitive cells of the bulbus cordi in the trunk of pulmonary artery	Pulmonary trunk most commonly involving: Right pulmonary artery Left pulmonary artery Pulmonary valve Right ventricular outflow tract	Mucoid or gelatinous clots filling vascular lumens The cut surface may show Firm fibrotic areas Bony/gritty or chondromyxoid foci Hemorrhage and necrosis are common in high-grade tumors	Spindle cells in A myxoid background Collagenized stroma Recanalized thrombi	Vimentin Osteopontin Factor VIII CD31 CD34	Findings overlap with those of chronic thromboembolic disease Decreased vascularity Heterogeneous soft tissue density Smooth vascular tapering	Lung parenchyma Mediastinum
	Pulmonary vein sarcoma		Most common in women Mean age of diagnosis is 49	Smooth muscle	Pulmonary vein	Fleshy-tan tumor Can occlude the lumen of the involved vessel 3.0- 20.0 cm Invasion of wall of the vein	Smooth muscle differentiation Moderate to highly cellular spindle cell neoplasms Epithelioid morphology	Vimentin Desmin Actin Keratin		N/A

• The table below summarizes the findings that differentiate squamous cell carcinoma of the lung from other conditions that cause chronic cough, weight loss, hemoptysis, and dyspnea.^[18][19]

Organ system		Diseases	Clinical manifestations								Diagnosis				Other features
			Symptoms							Physical exam
			Onset	Duration	Productive cough	Hemoptysis	Weight lost	Fever	Dyspnea	Ascultation	Lab findings	Imaging	PFT	Gold standard
Respiratory	Parenchyma	Lung cancer[20][21]	Chronic	Years	+	+	+	+/−	+	Hoarseness	The following investigations may be helpful: Complete blood count (CBC) ALT, AST Calcium Alkaline phosphatase LDH Creatinine	Contrast−enhanced CT of chest and upper abdomen	Not specific	Tissue biopsy (sample should be sufficient for molecular testing)	Risk factor: Cigarette smoking Types Small cell lung cancer (SCLC) Non−small cell lung cancer (NSCLC)
		Interstitial lung disease[22][23]	Chronic	Variable	−	+	+	−	+	Wheezing Crackles or velcro rales Inspiratory high−pitched rhonchi	The following investigations may be helpful: Hepatic function test Renal function test CBC Serological testing	Nodular, reticular or both pattern in chest X−ray CT in patients with diffuse pulmonary lung disease	Reduction in FVC, RV, FRC, TLC and FEV1 on spirometry FEV1/FVC normal or increase Lung volumes Diffusion capacity (DLCO reduced)	Lung biopsy when lab, imaging, and PFT has indeterminate result	Clubbing is common in asbestosis and idiopathic pulmonary fibrosis
		Tuberculosis (TB)[24][25]	Chronic	More than 2 or 3 weeks	+	+	+	+	+	Pleural effusion Crackles Whispered pectoriloquy Decreased fremitus Rhonchi	Sputum acid−fast bacilli (AFB) smear may be positive Mycobacterial culture may be positive Molecular testing may be helpful	Reactivation of TB is observed as infiltration in the upper lobe in chest X−Ray In patients with HIV, Tb is observed as lobar infiltration, adenopathy, lung mass named tuberculoma, small fibronodular lesions, and/or pleural effusion on chest X−Ray CT can detect early nodal process	Decreased FEV1 Reduced FVC	Isolation of Mycobacterium tuberculosis from some secretion	Etiology: Mycobacterium tuberculosis Complications: Pneumothorax, bronchiectasis, pulmonary destruction and chronic pulmonary aspergillosis
Cardiac		Pulmonary hypertension[26][27]	Chronic	More than 2 years	−	+	+	−	+	Hoarseness	The following investigations may be helpful: HIV serology Antinuclear antibody (ANA) Rheumatoid factor (RF) Anti−neutrophil cytoplasmic antibody (ANCA)	Enlargement of the central pulmonary artery and right heart in chest X−Ray Pulmonary artery systolic pressure can be estimated in echocardiography	Low levels of FEV1 Decreased FVC DLCO reduced	Mean pulmonary artery pressure more than 25 mmHg at rest	Chest pain Ascites Syncope Peripherial edema
Organ system		Diseases	Clinical manifestations								Diagnosis				Other features
			Symptoms							Physical exam
			Onset	Duration	Productive cough	Hemoptysis	Weight lost	Fever	Dyspnea	Ascultation	Lab findings	Imaging	PFT	Gold standard
Autoimmune		Wegener’s disease (GPA) [28][29]	Chronic	Months	+	+	+	+	+	Hoarseness Stridor Wheezing	The following investigations may be helpful: ANCA, P−ANCA, C−ANCA BUN Creatinine Complete blood count Urinalysis Lung biopsy	Nodules, pulmonary infiltrates, reticular margins, pleural opacities and cavities in chest X−Ray Nodules, cavities and stellate−shaped peripherial pulmonary in chest CT Bronchoscopy may be helpful	Low levels of DLCO Reduce lung volumes	Tissue biopsy	Nasal crusting, sinus pain, chronic rhinosinusitis, nasal obstruction and discharge in upper airway Saddle nose deformity Purpura in lower extremities
		Microscopic polyangitis (MPA)[30]	Chronic	Variable	+	+	+	+	+	Hoarseness Stridor Wheezing	The following investigations may be helpful: ANCA positive BUN Creatinine Complete blood count Urinalysis	Cavitation, nodules, and alveolar opacities in chest X−ray Head and chest CT may be helpful Electromyography/nerve conduction study may also be helpful	Reduced lung volumes	Tissue biopsy	Nerve damage Rhinosinusitis Purpura involving lower extremities
		Churg−Strauss[31][32]	Chronic	Variable	+	+	+	+	+	Wheezing Rales Rhonchi Expiratory sounds(related to asthma)	Peripherial eosinophilia In active phase CRP and erytrocyte sedimentation rate high Elevated IgE ANCA positive	Infiltrates in chest X−Ray Ground glass opacities, tree−in−bud sign and small nodules in chest CT	Lung volumes decreased FVC reduced FEV1/FVC ratio <70%	Tissue biopsy	Asthma Eosinophilia Rhinosinusitis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shanshan Cen, M.D. [2] Maria Fernanda Villarreal, M.D. [3]

Squamous cell carcinoma of the lung accounts for 30% to 35% of all lung cancers. It is the second most commonly encountered lung cancer after lung adenocarcinoma. Squamous cell carcinoma of the lung accounts for approximately 27% of all cancer deaths. The incidence of lung squamous-cell carcinoma increases with age; the median age at diagnosis is approximately 70 years (usually ranging from 65 to 74 years). Males are more commonly affected with squamous cell carcinoma of the lung than females. The male to female ratio is approximately 1.8 to 1. Black race has a higher incidence of squamous cell lung carcinoma compared with White race.

• Squamous cell carcinoma of the lung is the second most common non-small cell lung cancer subtype in the United States.
• It accounts for 30% to 35% of all lung cancers.
• It accounts for approximately 27% of all cancer deaths.^[1]
• The overall mortality from lung cancer (NSCLC and SCLC combined) in the United States in 2018 is 47.14 per 100,000 individuals.^[2]

• The annual incidence rate of lung squamous cell carcinoma is 14.4 per 100,000 individuals.
• The relative incidence rate of squamous cell carcinoma of the lung appears to be decreasing, compared to previous years.^[1]
• The overall incidence of lung cancer (NSCLC and SCLC combined) in the United States in 2018 is 71.629 per 100,000 individuals.^[3]

• The incidence of squamous cell carcinoma of the lung increases with age; the median age at diagnosis is 70 years (usually ranging from 65 to 74 years).^[4]

• Males are more commonly affected with squamous cell carcinoma of the lung than females. The male to female ratio is approximately 1.8 to 1.

• Black race has a higher incidence of squamous cell lung carcinoma compared with White race.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shanshan Cen, M.D. [2] Maria Fernanda Villarreal, M.D. [3]

Common risk factors in the development of squamous cell carcinoma of the lung are smoking, family history of lung cancer, high levels of air pollution, radiation therapy to the chest, radon gas, asbestos, occupational exposure to chemical carcinogens, and previous lung disease.

• Common risk factors in the development of squamous cell carcinoma include:^{[1][2][3][4][5][6]}
  • Smoking
  • Second-hand smoke
  • Family history of lung cancer
  • High levels of air pollution
  • Radiation therapy to the chest
  • Radon gas
  • Asbestos
  • High levels of arsenic in drinking water
  • Occupational exposure to chemical carcinogens
  • Previous lung disease
  • Indoor burning of coal
  • Weakened immune system
    • Human immunodeficiency virus infection^[7]
  • Lupus

Smoking

• Cigarette smoking is the leading cause of squamous cell carcinoma of the lung.
• Both active and passive smoking are associated with increased risk of lung cancer.
• The risk of squamous cell carcinoma of the lung is associated with increased quantity of cigarette smoking as well as increased duration of smoking.
• There is a direct correlation between the amount of smoked cigarettes per day and the risk of lung cancer.
• The e-cigarrettes have also been associated with a significantly increased risk of lung cancer due to the presence of formaldehyde.^[8]
• In the United States, smoking is estimated to account for approximately 87% of squamous cell carcinoma of the lung cases.(90% in men and 85% in women)^[9]

Second-hand Smoke

• People exposed to second-hand smoke have an increased risk of squamous cell carcinoma of the lung.
• Second-hand smoke is a main risk factor for squamous cell carcinoma of the lung among non-smokers.^[10]

Air Pollution

• The long term exposure to air pollution can also cause squamous cell carcinoma of the lung.^[11][12]

• Emissions from automobiles, factories, and power plants are thought to pose potential risks for the development of squamous cell carcinoma of the lung.^[13]
• Individual components of outdoor air pollution, namely diesel engine exhaust, benzene, particulate matter and some polycyclic aromatic hydrocarbons (PAHs), are associated with development of squamous cell carcinoma of the lung.^[14]

Family History of Lung Cancer

• Family history of lung cancer may increase the risk of squamous cell carcinoma of the lung.^[15][16]
• First-degree relatives of individuals who have had lung cancer may have a slightly higher risk of developing lung cancer themselves.
• The increased risk among first-degree relatives could be due to a number of factors, such as shared behaviors or living in the same place where there are carcinogens.
• Studies of families with a strong history of lung cancer have found that the increased risk iis likely caused by a mutation in specific lung cancer genes.
• The risk of lung cancer in a family increases if one family member developed the disease at an early age.

Radiation Therapy to the Chest

• A history of radiation therapy to the chest (e.g. Hodgkin’s lymphoma or breast cancer) increases the risk due to the development of cellular damage and DNA mutations.^[17]

Radon Exposure

• Radon is the leading cause of lung cancer in non-smokers and the second leading cause of squamous cell carcinoma of the lung in smokers.^[18]
• Radon is a colorless, odorless, and tasteless gas that comes from the natural breakdown of uranium in rocks and soil. In the outdoors, radon gas is diluted by fresh air, so it is not usually a concern. But radon can seep into a home or building through dirt floors or cracks in basement foundations. It may reach unsafe concentrations in enclosed, poorly ventilated homes or buildings because of seepage into the basement. Breathing in radon gas can damage cells that line the lungs.
• Radon exposure increases the risk of lung cancer.
• The risk of developing squamous cell carcinoma of the lung depends on the duration and quantity of radon a person has been exposed to.

Asbestos Exposure

• Asbestos is a group of minerals that occur naturally. Asbestos has been widely used in building materials and many industries.
• Exposure to asbestos fibers in the air increases the risk of lung cancer.^[19]
• The risk of asbestos exposure is highest for individuals who work with asbestos, such as miners.
• The combination of smoking and asbestos exposure is especially hazardous.

Exposure to Other Chemical Carcinogens

• The other chemical carcinogens that can cause squamous cell carcinoma of the lung include:^{[20][21][22][23]}
• Arsenic and inorganic arsenic compounds
• Beryllium and beryllium compounds
• Cadmium and cadmium compounds
• Chemicals used in rubber manufacturing, iron and steel founding and painting
• Chloromethyl ethers and bischloromethylether
• Chromium (VI) compounds
• Cobalt–tungsten carbide
• Diesel engine exhaust
• Mustard gas
• Polycyclic aromatic hydrocarbons (PAHs)
• Radioactive ores such as uranium and plutonium
• Silica dust and crystalline silica
• Some nickel compounds
• Beta carotene supplements in heavy smokers

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shanshan Cen, M.D. [2] Maria Fernanda Villarreal, M.D. [3]

According to the U.S. Preventive Services Task Force (USPSTF), screening for lung cancer by low-dose computed tomography (LDCT) is recommended every year among smokers who are between 55 to 80 years old and who have history of smoke 30 pack-years or more and either continue to smoke or have quit within the past 15 years (grade B recommendation).

Guidelines

• According to the clinical practice guideline by the U.S. Preventive Services Task Force (USPSTF), screening for lung cancer by low-dose computed tomography (LDCT) is recommended every year among smokers and former smokers who are between 55 to 80 years old and who have smoked 30 pack-years or more and either continue to smoke or have quit within the past 15 years (grade B recommendation).^[1][2][3][4]

• According to the American College of Chest Physicians (CHEST) in 2013, screening for lung cancer by low-dose CT (LDCT) is recommended every year among smokers and former smokers who are aged between 55 and 74 years and who have smoked for 30 pack-years or more and either continue to smoke or have quit within the past 15 years.^[5]

• To view all the screening guidelines recommendations for squamous cell lung carcinoma, click here

Strategies

• Low-dose helical computed tomography:^[6]

• Benefits

• There is evidence that screening persons aged 55 to 74 years who have cigarette smoking histories of 30 or more pack-years and who, if they are former smokers, have quit within the last 15 years reduces lung cancer mortality by 20% and all-cause mortality by 6.7%.

• Harms

• The majority of of all positive low-dose helical computed tomography screening exams do not result in a lung cancer diagnosis.
• False-positive exams may result in unnecessary invasive diagnostic procedures.

• Chest x-ray and/or sputum cytology:^[7][8][9]

• Benefits

• Screening with chest x-ray and/or sputum cytology does not reduce mortality from lung cancer in the general population or in ever-smokers.

• Harms

• False positive exams
• The majority of all positive chest x-ray screening exams do not result in a true positive diagnosis of lung cancer.
• False-positive exams result in unnecessary invasive diagnostic procedures.

Over-diagnosis

• Based on current evidence, the majority of non-small cell lung cancers detected by screening chest x-ray and/or sputum cytology appear to represent over-diagnosed cancer.^[8]

• The magnitude of over-diagnosis appears to be between 5% and 25%.
• These cancers result in unnecessary diagnostic procedures and also lead to unnecessary treatment.
• Harms of diagnostic procedures and treatment occur most frequently among long-term and/or heavy smokers because of smoking-associated comorbidities that increase risk propagation.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shanshan Cen, M.D. [2] Maria Fernanda Villarreal, M.D. [3]

If left untreated, squamous cell carcinoma of the lung progression occurs slowly and is then followed by local invasion to lymph nodes and distant metastasis. Common sites of metastasis include liver, adrenal gland, bone, and brain. Complications of squamous cell carcinoma of the lung, include pneumonia, pleural effusion, metastasis, and Horner’s syndrome. The 5-year survival rate of patients with squamous cell carcinoma of the lung, depends on the stage at diagnosis. The average survival rate ranges from 49% to 16%. Prognosis is generally regarded as poor, the 5-year recurrence rate of squamous cell carcinoma of the lung is 24%.

• The majority of patients with squamous cell carcinoma of the lung are initially asymptomatic.^[1]
• The symptoms of squamous cell carcinoma of the lung usually develop in adult patients between 55 to 60 years
• Patients with squamous cell carcinoma of the lung may also experience non-specific symptoms, such as: chronic cough, hemoptysis, dyspnea, chest pain, dysphonia, dysphagia, lack of appetite, and fatigue.^[2]
• If left untreated, patients with non-small cell lung cancer may develop local invasion to lymph nodes and distant metastasis
• Common sites of metastasis include adrenal gland, bone, brain, and liver
• Patients with advanced squamous cell carcinoma of the lung may develop symptoms, such as: paresthesias, bladder dysfunction, seizures, hemiplegia, cranial nerve palsies, confusion , personality changes, skeletal pain, and pleuritic pain.^[2]

• Common complications of squamous cell carcinoma of the lung, include:^[1]

• Pneumonia
• Malignant pleural effusion
• Metastasis
• Horner’s syndrome

• The presence of metastasis is associated with a particularly poor prognosis
• The 5-year survival rate of patients with squamous cell carcinoma of the lung, depends on the stage at diagnosis
• The average survival rate ranges from 49% to 16%.^[1]
• Features associated with worse prognosis, include:

• Poorly differentiated tumor, and presence of necrosis
• DNA aneuploidy
• Poor performance status
• Presence of lymphatic invasion
• Invasion to the pulmonary artery
• Presence of satellite lesions
• Large tumor size (>3 cm)
• Presence of pulmonary symptoms
• Presence of regional or distant metastases

• Prognosis is generally regarded as poor, the 5-year recurrence rate of squamous cell carcinoma of the lung is 15%.^[1]

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