Squamous cell carcinoma of the skin pathophysiology
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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]
Overview
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.
Pathophysiology
- p53 is mutated commonly in Actinic keratosis, demonstrating that dysplastic lesions have acquired the initial genetic mutations prior to becoming cutaneous squamous cell carcinoma.[1][2][3]
- 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.[4]
- 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[5]
- 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.[6]
- 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.[7]
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.
Frequently an actinic keratosis or squamous cell carcinoma overlies the invasive component and the two are focally contiguous. Occasionally squamous tumors arise rapidly, have a crater-form morphology and spontaneously regress. These tumors are known as keratoacanthomas. Some craterform squamous lesions do not regress, but continue to invade and grow and represent invasive squamous cell carcinomas.
Microscopic Pathology
Histopathological examination confirms diagnosis and aids in the staging of the disease. Histopathology evaluates in detail the following characteristics :
- Invasion
- Differentiation
- Depth
The various types of biopsy that may be obtained includes shave, punch, and excisional biopsies. The sample may be obtained at a physician's office under local anesthesia. The type of biopsy method chosen is based upon the size of lesion.
- For smaller lesions in easy accessible region of the body, an excisional biopsy is preferred. This may be therapeutic as well as diagnostic.
- For lesions which are large and for which the cosmetic appearance may be of concern, a punch biopsy is advisable. Further treatment is based upon the results of histopathological evaluation.
- A shave biopsy is seldom recommended in cases where the lesion is suspected to be malignant.
Important principles to consider when taking a sample for biopsy.
- A full thickness biopsy should be taken to best evaluate the true depth of the lesion and extent of invasion. Depth of the lesion is an important determinant in the prognosis and staging of cancer.[8]
- The biopsy specimen should also include samples of normal tissue as a comparison.
- 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.
References
- ↑ Ortonne JP (April 2002). "From actinic keratosis to squamous cell carcinoma". Br. J. Dermatol. 146 Suppl 61: 20–3. PMID 11966728.
- ↑ Berner A (June 2005). "[Actinic keratosis and development of cutaneous squamous cell carcinoma]". Tidsskr. Nor. Laegeforen. (in Norwegian). 125 (12): 1653–4. PMID 15976832.
- ↑ Tsai KY, Tsao H (November 2004). "The genetics of skin cancer". Am J Med Genet C Semin Med Genet. 131C (1): 82–92. doi:10.1002/ajmg.c.30037. PMID 15468170.
- ↑ Borelli D, Salas J (1975). "[The use of trypan blue instead of cotton blue in mycology]". Rev. Latinoam. Microbiol. (in Spanish; Castilian). 17 (3): 185–6. PMID 52880.
- ↑ Strabala TJ, Bednarek SY, Bertoni G, Amasino RM (April 1989). "Isolation and characterization of an ipt gene from the Ti plasmid Bo542". Mol. Gen. Genet. 216 (2–3): 388–94. PMID 2747621.
- ↑ Spencer JM, Kahn SM, Jiang W, DeLeo VA, Weinstein IB (July 1995). "Activated ras genes occur in human actinic keratoses, premalignant precursors to squamous cell carcinomas". Arch Dermatol. 131 (7): 796–800. PMID 7611795.
- ↑ Khavari PA (April 2006). "Modelling cancer in human skin tissue". Nat. Rev. Cancer. 6 (4): 270–80. doi:10.1038/nrc1838. PMID 16541145.
- ↑ Brantsch KD, Meisner C, Schönfisch B, Trilling B, Wehner-Caroli J, Röcken M, et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol. Aug 2008;9(8):713-20