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Genetics and Risk Factors

 Genetics/Mutations                                                                                                                                                                                                          

  • Highly mutated cancer, with >4 times the mutational rate of melanoma.

  • p53 (#1), CDKN2A, Ras, and NOTCH1 are most common mutations. Multiple other mutations are usually concomitant.

 Medications/Therapies                                                                                                                                                                                                    

Azathioprine

  • Apart from its immunosuppressive effects, incorporation of 6-TG into DNA results in UVA photosensitivity. 18489587

BRAF inhibitors

  • Associated with squamoproliferative lesions and keratoacanthomas, possibly via MAPK pathway activation. Concurrent MEK inhibition abrogates this effect.

Cyclosporine

  • Apart from its immunosuppressive effects, CsA also contributes to skin cancer by inhibiting mitochondrial permeability that occurs in the setting of cell damage, such as by UV, in order to expire damaged cells. 19836469

Glucocorticoids

  • Case-control study in non-organ transplant recipients demonstrated OR 2.31 (CI 1.7-4.18) for SCC and oral steroids. 11531252

PUVA

  • RR=8.6 for 100-337 treatments. 9731734

TNF-inhibitors​

  • adalimumab, infliximab, etanercept, etc. 

Vismodegib

  • (8x risk) inhibition of smoothened selects for tumors that proliferate through the Ras-MAPK pathway.

Voriconazole

  • mechanism is by inducing photosensitivity.

 Comorbidities                                                                                                                                                                                                                     

Solid organ transplantation (~65-250x risk)

  • Proportional to # of immunosuppressant meds so heart and lung tend to have highest risk, then kidney, liver much lower.  

  • Prior AK history and age significantly increase the risk. (39025265)

Hematopoietic transplantation (~18x risk)

  • Notable increased risk, but generally lower than SOTRs. 26454261

Human Papillomavirus​

  • Its role is well established in SCC of the anogenital and periungal skin (types 16 and 18).

  • It is less well established as a risk factor in other cutaneous SCC, but beta HPV types 8, 9, and 15 are found.

  • The mechanism is uncertain as HPV is not transcriptionally active in these tumors, suggesting it may be involved in induction but not maintenance.

 Environmental/Lifestyle                                                                                                                                                                                                  

  • Chronic sun exposure, tanning bed usage (independent risk factor).

  • Ionizing radiation: particularly a/w aggressive SCCs with high rates of recurrence and metastasis.

  • Tobacco use

  • Arsenic: from well water, some pesticides.

  • Polycyclic aromatic hydrocarbons: tar, pitch, soot.

  • Nitrosamines

  • Alkylating agents

 Literature                                                                                                                                                                                                                             

Cutaneous squamous cell carcinoma: Incidence, risk factors, diagnosis, and staging. J Am Acad Dermatol. 2018. PMID: 29332704.

EM OPINES: Nice overview of that which is mentioned in the title, which also has a comprehensive figure on risk factors borrowed from 26762219.  FIGURE

ABSTRACT: Cutaneous squamous cell carcinoma (cSCC), a malignant proliferation of cutaneous epithelium, represents 20% to 50% of skin cancers. Although the majority of cSCCs are successfully eradicated by surgical excision, a subset of cSCC possesses features associated with a higher likelihood of recurrence, metastasis, and death. The proper identification of these aggressive cSCCs can guide additional work-up and management. In the first article in this continuing medical education series, we discuss the incidence, recurrence rates, mortality rates, and risk factors associated with cSCC and review the staging systems used to stratify patients into high- and low-risk groups. The second article in this series reviews the treatment options for cSCC, with focused attention on the management of high-stage tumors.

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