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squamous cell carcinoma of the skin (SCCS)

Malignant tumor of epithelial keratinocytes in skin & mucous membrane. Etiology: 1) ultraviolet radiation 2) ionizing radiation 3) sun exposure in both childhood & adult life increases risk [7] 4) trivalent arsenic* a) Fowler's solution used as a tonic & in the treatment of psoriasis b) ingestion of arsenic - may be present in the drinking water 5) betel nut? 6) human papilloma virus (anogenital area & periungual skin) - HPV- 16, 18, 31, 33, 35, 45 7) immunosuppression 8) pharmaceuticals a) topical nitrogen mustard for treatment of mycosis fungoides b) tyrosine kinase inhibitors [2] c) hydroxyurea d) voriconazole e) HCTZ [15] 9) oral PUVA photochemotherapy 10) discoid lupus erythematosus (rare) 11) industrial carcinogens* a) polycyclic aromatic hydrocarbons b) nitrosoureas 12) chronic inflammation* [4] * the atypical chemokine receptor D6 suppresses development of chemically-induced skin tumors Epidemiology: 1) 12/100,000 white males, 7/100,000 white females, 1/100,000 blacks in continental USA 2) 62/100,000 whites in Hawaii 3) white with poor tanning capacity at risk 4) age > 55 years in USA, 20s & 30s in Australia 5) incidence 4/100,000 USA age < 40 [3] 6) males > females, but more frequently on legs of females 7) more common in sunbelt 8) penile SCC accounts for 20% of SCC in developing countries, but only 1% in USA 9) oral mucosa SCC high in India, southeast Asia, & Puerto Rico, & low in Japan, Israel & Scandinavia 10) more common in persons working outdoors 11) industrial workers exposed to carcinogens a) polycyclic aromatic hydrocarbons b) nitrosoureas 12) most common type of skin cancer in immunosupressed patients after solid organ transplant [2] - incidence of SCCS is 25 times higher in organ transplant patients taking long-term immunosuppressive agents Pathology: 1) squamous cell carcinoma generally develops from a precancerous lesion or carcinoma in situ 2) precursors to SCC a) actinic & arsenical keratosis b) Bowen's disease & bowenoid papulosis c) erythroplasia of Queyrat d) leukoplakia 3) highly differentiated SCC a) keratinization within or on the surface of the tumor b) various grades of anaplasia 4) poorly differentiated SCC a) no sign of keratinization b) anaplasia with multiple mitoses 5) squamous cell carcinoma of the lips a) develops from leukoplakia or actinic cheilitis b) found on lower lip in 90 of cases 6) SCCS tend to retain their surface scale - as SCCS accumulates a large amount of scale, it is called a cutaneous horn Invasive squamous cell carcinoma: (also see Bowen's disease & erythroplasia of Queyrat) * histopathology images [12] Immunohistochemistry: - CK1: + - CK10: + - high molecular weight keratins: + - Ber-EP4: - - bcl-2: - mostly Genetics: - associated with defects in PTCH1 - overexpression of kallikrein-8 Clinical manifestations: 1) slowly evolving, isolated keratotic or eroded papule or plaque that persists for months - pink scaly indurated plaques, papules or nodules that can ulcerate & bleed or become crusty - describes as thin, scaling, chronic asymptomatic plaque on sun-exposed skin [18] 2) highly differentiated SCC a) firm or hard on palpation - may be tender to palpation b) indurated papule, plaque or nodule c) hyperkeratosis d) erosion or ulceration may crust in center e) margins may be elevated f) erythematous, yellow or flesh-colored g) lesions generally isolated, but may be multiple h) distribution: sun-exposed areas 1] face (cheeks, nose, lips) 2] tips of ears 3] periauricular areas, neck 4] scalp in bald men 5] dorsal aspect of hands & forearms 6] trunk 7] shins in females 8] in black patients, most frequently occurs on legs & in non-sun-exposed areas [2] i) evidence of chronic sun exposure 1] dermatoheliosis 2] telangiectasia 3] freckling 4] xeroderma 5] hypopigmented macules j) generally does not itch K) regional lymphadenopathy may accompany metastases 3) poorly differentiated SCC a) fleshy & granulomatous erosive papules & nodules & papillomatous vegetations b) ulceration with a necrotic base & soft, fleshy margin c) hemorrhagic, crusting d) generally isolated, but may be multiple especially on genitalia e) lymphadenopathy due to metastases more common than with differentiated SCC b) soft on palpation 4) squamous cell carcinoma of the lip * images [9,10,11,12] Special laboratory: - skin biopsy (shave biopsy of lesion) Differential diagnosis: 1) nummular eczema 2) psoriasis 3) Paget's disease of the breast 4) basal cell carcinoma: does not present as hyperkeratotic lesion 5) keratoacanthoma Complications: - risk of metastasis 2-5% Management: 1) surgery a) excision with primary closure, skin flaps or grafting b) microscopically controlled surgery on face or in difficult sites (Mohs surgery) c) small lesions may be treated with electrodessication & curettage [4] d) most lesions require surgical excision [4] 2) radiation therapy if surgery is not feasible 3) pembrolizumab (Keytruda) monotherapy for locally advanced SCCS not amenable to surgery or radiation therapy (images) [16] 4) prognosis a) 90% remission after therapy b) tumors induced by ionizing radiation or arsenic, occurring in the bed of a burn scar or on the genitalia are more likely to metastasize (up to 20%) c) patients with SCC secondary to arsenic ingestion may also have SCC of the lung & bladder d) lesions arising from solar (actinic) keratosis have lowest metastatic potential e) SCC of the skin has an overall metastatic rate of 3-4% 5) prevention: a) sunscreen, protective clothing b) cryotherapy of actinic keratoses c) celecoxib may reduce incidence of both cutaneous SCC & basal cell carcinoma (BCC) [5] d) nicotinamide 500 mg BID lowers risk of cutaneous SCC in high-risk patients by 25% [8] - benefit lost when nicotinamide discontinued e) topical fluorouracil 5% BID for 2-4 weeks in high-risk patients reduces need for surgery by 75% over the year after treatment [13]

Interactions

disease interactions

Related

dermatoheliosis (photoaging, skin aging) squamous cell

Specific

erythroplasia of Queyrat Marjolin's ulcer squamous cell carcinoma (SCC) of the anus squamous cell carcinoma in situ (Bowen's disease) squamous cell carcinoma of the nail bed

General

skin cancer squamous cell carcinoma (SCC)

References

  1. Color Atlas and Synopsis of Clinical Dermatology, Common and Serious Diseases, 3rd ed, Fitzpatrick et al, McGraw Hill, NY, 1997, pg 222-227
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 15, 16, 17, 19. American College of Physicians, Philadelphia 1998, 2009, 2012, 2015, 2022 - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  3. Christenson LJ, Borrowman TA, Vachon CM, Tollefson MM, Otley CC, Weaver AL, Roenigk RK. Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years. JAMA. 2005 Aug 10;294(6):681-90. PMID: 16091570
  4. Nibbs RJ, Gilchrist DS, King V, Ferra A, Forrow S, Hunter KD, Graham GJ. The atypical chemokine receptor D6 suppresses the development of chemically induced skin tumors. J Clin Invest. 2007 Jul 2;117(7):1884-1892. PMID: 17607362
  5. Elmets CA et al Chemoprevention of nonmelanoma skin cancer with celecoxib: A randomized, double-blind, placebo-controlled trial. J Natl Cancer Inst. 2010 Dec 15;102(24):1835-44. PMID: 21115882 http://dx.doi.org/10.1093/jnci/djq442 - Meyskens FL Jr and McLaren CE. Chemoprevention, risk reduction, therapeutic prevention, or preventive therapy? J Natl Cancer Inst. 2010 Dec 15;102(24):1815-7. PMID: 21115881 http://dx.doi.org/10.1093/jnci/djq466
  6. Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol. 1992 Jun;26(6):976-90. PMID: 1607418
  7. Wu S et al. Long-term ultraviolet flux, other potential risk factors, and skin cancer risk: A cohort study. Cancer Epidemiol Biomarkers Prev 2014 Jun; 23:1080 PMID: 24876226 http://cebp.aacrjournals.org/content/23/6/1080
  8. Chen AC, Martin AJ, Choy B et al A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention. N Engl J Med 2015; 373:1618-1626. October 22, 2015 PMID: 26488693 http://www.nejm.org/doi/full/10.1056/NEJMoa1506197
  9. Squamous cell carcinoma (image) American Academy of Dermatology https://www.aad.org/public/diseases/skin-cancer/squamous-cell-carcinoma - Squamous cell carcinoma (SCC) (image) Skin Cancer Foundation http://www.skincancer.org/skin-cancer-information/squamous-cell-carcinoma
  10. Alam M, Ratner D. (images) Cutaneous squamous-cell carcinoma. N Engl J Med. 2001 Mar 29;344(13):975-83. PMID: 11274625
  11. DermNet NZ (images) Squamous cell carcinoma of the skin http://www.dermnetnz.org/lesions/squamous-cell-carcinoma.html
  12. Monroe MM, Meyers AD (images) Medscape: Cutaneous Squamous Cell Carcinoma http://emedicine.medscape.com/article/1965430-overview
  13. Harrison P 5-FU Cream Reduces Surgery in High-Risk SCC Patients Medscape. Jan 08, 2018. https://www.medscape.com/viewarticle/891047
  14. Bowser A MedPage Today. Dermatology Times. January 28, 2018 https://www.medpagetoday.com/dermatology/generaldermatology/70798 - Karia PS, Morgan FC, Califano JA, Schmults CD. Comparison of tumor classifications for cutaneous squamous cell carcinoma of the head and neck in the 7th vs 8th edition of the AJCC cancer staging manual. JAMA Dermatol 2017. Dec 20 PMID: 29261835 - Karia PS, Morgan FC, Ruiz ES, Schmults CD. Clinical and Incidental Perineural Invasion of Cutaneous Squamous Cell Carcinoma: A Systematic Review and Pooled Analysis of Outcomes Data. JAMA Dermatol. 2017 Aug 1;153(8):781-788. Review. PMID: 28678985 Free PMC Article - Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol. 2013 Jun;68(6):957-66. PMID: 23375456 - Jambusaria-Pahlajani A, Kanetsky PA, Karia PS et al. Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system. JAMA Dermatol. 2013 Apr;149(4):402-10. PMID: 23325457
  15. Pedersen SA, Gaist D, Schmidt SAJ et al Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide case-control study from Denmark. J Am Acad Dermatol. 2018 Apr;78(4):673-681.e9. Epub 2017 Dec 4. PMID: 29217346 Free Article
  16. Worcester S Latest FDA Pembrolizumab Approval Expands Label to Cutaneous SCCs. Medscape - Jul 13, 2021 https://www.medscape.com/viewarticle/954715 - Thakker S, Al-Mondhiry J Complete Resolution of Bulky Cutaneous Squamous Cell Carcinoma by Programmed Death-1 Inhibitor. Ann Intern Med Clinical cases. 2024. March 5. https://www.acpjournals.org/doi/10.7326/aimcc.2023.0570
  17. Kim JY, Kozlow JH, Mittal B, et al; Work Group. Guidelines of care for the management of cutaneous squamous cell carcinoma. J Am Acad Dermatol. 2018;78:560-78. PMID: 29331386
  18. NEJM Knowledge+ - Wysong A. Squamous-Cell Carcinoma of the Skin. N Engl J Med. 2023 Jun 15;388(24):2262-2273. PMID: 37314707 Review. No abstract available. https://www.nejm.org/doi/pdf/10.1056/NEJMra2206348