Squamous cell carcinoma of the skin pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2], Raviteja Guddeti, M.B.B.S. [3]

Squamous cell carcinoma (SCC) is type of non-melanoma skin cancer. The cancer arises as a result of uncontrolled growth of the squamous cells in the epidermis of the skin. Unlike it’s counter part, the basal cell carcinoma which also belongs to the group of non-melanoma cancer, squamous cell carcinoma is rapid growing and invasive. SCCs may occur on all areas of the body including the mucous membranes and genitals, but are most common in areas frequently exposed to the sun, such as the rim of the ear, lower lip, face, bald scalp, neck, hands, arms and legs. Wrinkling, changes in pigmentation, and loss of elasticity of the skin are often the telltale signs of sun damage.

• Malignant transformation of normal epidermal keratinocytes is the hallmark of squamous cell carcinoma of the skin.
• One critical pathogenic event is the development of apoptotic resistance through functional loss of TP53, a well-studied tumor suppressor gene.
  • TP53 mutations are seen in over 90% of skin cancers diagnosed in the United States, as well as in most precursor skin lesions, suggesting that loss of TP53 is an early event in the development of cSCC.^[1]
• UVR causes deoxyribonucleic acid (DNA) damage through the creation of pyrimidine dimers, a process known to result in the genetic mutation of TP53.
• Upon subsequent UVR exposure, keratinocytes undergo clonal expansion, acquiring further genetic defects, ultimately leading to invasive cutaneous squamous cell carcinoma.
• Many other genetic abnormalities are believed to contribute to the pathogenesis of squamous cell carcinoma of the skin, including mutations of BCL2 and RAS.
• Likewise, alterations in intracellular signal transduction pathways, including the epidermal growth factor receptor (EGFR) and cyclooxygenase (COX), have been shown to play a role in the development of squamous cell carcinoma of the skin.
• Squamous cell carcinoma in situ (CIS), sometimes referred to as Bowen disease, is a precursor to invasive cSCC. Characteristics of this lesion include nuclear atypia, frequent mitoses, cellular pleomorphism, and dyskeratosis, parakeratosis, and hyperkeratosis.
• p53 is mutated commonly in Actinic keratosis, demonstrating that dysplastic lesions have acquired the initial genetic mutations prior to becoming cutaneous squamous cell carcinoma.^[2][3][4]
• The mechanism leading to genomic instability in keratinocytes likely results from UVB-induced inactivation of p53, since approximately 58% of cutaneous squamous cell carcinoma harbor UVB signature mutations such as CC→TT and C→T transitions.^[5]
• Aberrant activation of EGFR and Fyn, a Src-family tyrosine kinase (SFK), are seen in human cutaneous squamous cell carcinoma.
• Kinases downregulate p53 mRNA and protein levels through a c-Jun–dependent mechanism revealing another mechanism for controlling p53 function^[6]
• Amplification and activating mutations of the Ras oncogene have been found in squamous cell carcinoma and actnic keratosis
• Ras is an upstream activator of the Raf/Mek/Erk1/Erk2 kinase pathway, and activating mutations in Ras can promote cutaneous squamous cell carcinoma.^[7]
• Expression of β1-integrins and their ligands correlates with tumor progression in human skin.
• Ras family members of proto-oncogenes transduce cellular growth and proliferation signals downstream of cell membrane–bound receptor tyrosine kinases (RTKs). Ras can be activated by gene amplification, activating mutations, or overexpression of upstream RTKs. Aberrant Ras activation promotes several key tumorigenic phenotypes including mitogenesis, resistance to apoptosis, drug resistance.^[8]

Squamous cell carcinoma is a potentially invasive cancer that arises from the surface epithelium.The development of squamous cell carcinoma is frequently a multistep process. Early lesions tend to be either actinic keratoses, with atypia of the basal keratinocytic layer of the epidermis or squamous cell carcinoma in situ, in which keratinocytic atypia spans the full thickness epidermis.

These precursors are frequently present adjacent to invasive squamous cell carcinomas which invade the dermis as nests, islands, or cords squamous cells with or occasionally as individual cells. Several grading schemes have been developed for squamous cell carcinoma and incorporate the extent of keratinization (a form of differentiation) and nuclear atypia. A widely used scheme divides tumors into well, moderately, or poorly differentiated.

Although poorly differentiated tumors tend to behave more aggressively, well-differentiated tumors can also give rise to metastasis and result in death. Several histological variants of squamous cell carcinoma have been documented, including verrucous, spindle cell and pseudovascular.

• Large lesions require a thorough sample that will adequately assess the entirety of the lesion.
• Findings Histopathological evaluation is important in determining the next step in the grade and treatment of the cancer. The neoplastic cells may demonstrate varying degrees of squamous differentiation and atypia uncder the microscope.

• The most conspicuous finding under a microscope are keratin pearls(well formed desmosome attachments and intracytoplasmic bundles of keratin tonofilaments).
• SCC can be graded up to grade 3.
  • Well differentiated: nuclei which are more normal, abundant cytoplasm & extracellular keratin pearls
  • Poorly differentiated: High degree of nuclear atypia, greater nuclear:cytoplasmic ratio and less keratinization. Due to poor differentiation it may mimic mesenchymal tumors. Poorly differentiated carcinoma has a higher rate of metastasis and high rates of invasion into surrounding tissues.
  • Moderately differentiated: Has an appearance that is midway between poorly differentiated and well differentiated.
  • Squamous cell carcinoma in situ – has full thick atypia of squamous cells (including surfaces) without invasion through the basement membrane.

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