Cutaneous Squamous Cell Carcinoma

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Key points

  • Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer that presents as a scaly, red, or bleeding lesion on sun-exposed areas.

  • UV exposure, fair skin, and immunosuppression increase incidence of cSCC.

  • Recurrence and metastasis are associated with tumor diameter greater than 2 cm, depth greater than 2 mm or beyond subcutaneous fat, extensive or large-caliber perineural involvement, and poor differentiation on histopathology.

  • AJCC 8 is used for TNM staging for cSCC of the head and neck.

Incidence and epidemiology

Cutaneous squamous cell carcinoma (cSCC) is the second most common nonmelanoma skin cancer. It accounts for 20% of skin cancer and results in 1 million cases in the United States each year resulting in up to 9000 estimated deaths.1, 2, 3, 4

Depending on the latitude, the incidence of cSCC ranges from 5 to 499 per 100,000 patients.5, 6, 7, 8 The lifetime risk of developing SCC is 14–20% in a non-hispanic white population in the United States.9, 10 This number continues to increase annually with

Clinical presentation

cSCC presents as a red scaly plaque, typically in sun-exposed areas. Lesions are typically solitary (Fig. 1A); however, they rarely can present as multiple “in transit” metastases (Fig. 1B).

Work-up

Diagnosis is made by a skin biopsy deep enough to allow the pathologist to comment on depth of invasion, perineural or lymphovascular invasion, differentiation, and connection to the overlying epidermis.12 Local lymph nodes and parotid when appropriate should be evaluated by clinical examination and should be sampled if clinically involved.13 The value of sentinel lymph node biopsy in cSCC without clinically apparent lymph nodes is currently unknown.14, 15, 16, 17 The patient should also be

Histopathology

On histopathology, cSCC differentiation may vary from well to poorly differentiated. Well-differentiated tumors exhibit interconnecting follicular infundibular type squamous epithelium. Mitosis may be rare or absent. Poor differentiation indicates that it is difficult to determine a keratinocyte lineage (Fig. 2).19, 20

Risk factors

The most significant risk factors resulting in cSCC include UV exposure, older age, fair skin (Fitzpatrick skin types I-III), and immunosuppression. UV (primarily UV-B) from the sun or tanning beds induces skin cancer by causing DNA damage.21, 22, 23, 24, 25 The incidence of SCC doubles with each 8° to 10° in latitude.26, 27 Skin types that burn after UV exposure (related to Fitzpatrick skin type) are predisposed to developing cSCC.28

Genetics

cSCC carries more mutations than other common malignancies, with more than four times the mutation rates in melanoma.41 Tumor protein 53 (TP53),42 cyclin-dependent kinase inhibitor 2A mutations (CDKN2A), Ras mutations, and mutations of Notch homolog 1 are involved in cSCC carcinogenesis.41, 43 Genetic mutations found to be differentially expressed in cSCC include CXCL8 (IL8), MMP1, HIF1A, ITGA6, and ITGA2.20, 44

Mortality

Although most cSCC are treated locally with no sequelae, a small subset result in tumor-specific mortality. In the United States, the annual disease-specific mortality is estimated to be 1.5% to 2% with up to 4% mortality rates reported in other countries; 5604 to 12,572 people with cSCC developed nodal metastases with an estimated 9000 deaths.2, 45 Factors associated with local recurrence and metastases are listed in Table 1.

American Joint Committee on Cancer-8

In October 2016, the American Joint Committee on Cancer (AJCC) introduced the eighth edition of its cancer staging systems.62 The AJCC-8 staging system classifies cSCC of the head and neck by local tumor burden (T), nodal status (N), and metastatic disease (M).61, 63 Stage T1 are tumors less than 2 cm. T2 are tumors 2–3.9 cm. T3 tumors are ≥4 cm or with minor bone erosion or large caliber perineural invasion or deep invasion >6 mm. T4a tumors invade to cortical bone or marrow and T4b invade the

Treatment

cSCC is stratified into low risk or high risk. Guidelines are available to help guide treatment including those by the National Comprehensive Cancer Network (NCCN)13 and the American Academy of Dermatology (AAD) guidelines (Table 2).12

There are two main types of margin analysis commonly used for surgically excised cSCC: sectional assessment used in standard excision, and complete circumferential peripheral and deep margin assessment (CCPDMA). Sectional assessment describes traditional “bread

Prevention

Photoprotective measures including sunscreen application have been shown to decrease SCC by 40%.75, 76 Other measures of prevention include those aimed at managing field cancerization (large defects of DNA damaged skin): 5-fluorouracil, imiquimod, topical retinoids, diclofenac sodium, ingenol mebutate, chemotherapy wraps, photodynamic therapy, nicotinamide and acitretin or capecitabine for very high-risk, immunosuppressed patients.12

Monitoring

A patient with at least one cSCC is at risk for additional cSCC and other for skin cancers, including basal cell carcinoma and melanoma.77, 78 The 5-year probability of another non-melanoma skin cancer (NMSC) after diagnosis of a first is 40.7%, the 10 year is 59.6%, and after more than one cSCC it is 82% and 91.2%.79 After a diagnosis of local SCC, the NCCN guidelines suggest follow-up and screening every 3 to 12 months for 2 years after initial diagnosis and then every 2 years. For regional

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