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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