Background

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer, arising from the malignant transformation of keratinocytes in the epidermis. It accounts for approximately 20% of all non-melanoma skin cancers. While many cases are low-risk and treatable with local therapies, cSCC has a greater potential for local tissue invasion and distant metastasis than basal cell carcinoma. The increasing incidence of cSCC globally reflects rising ultraviolet (UV) exposure, an aging population, and a growing number of immunosuppressed individuals.

Etiology and Risk Factors

The principal etiological factor in cSCC is cumulative exposure to ultraviolet radiation, particularly UVB, which induces DNA damage and mutations in tumor suppressor genes. Additional risk factors include chronic immunosuppression, such as that seen in transplant recipients or patients with HIV/AIDS, which significantly elevates both incidence and aggressiveness of disease. Environmental exposures, including arsenic and ionizing radiation, also contribute to carcinogenesis. Chronic wounds, burns, or inflammatory skin conditions can evolve into cSCC through a process known as Marjolin ulceration. Moreover, infection with certain subtypes of human papillomavirus (HPV), particularly in mucosal or periungual lesions, is implicated in some cases. Genetic conditions like xeroderma pigmentosum, which impair DNA repair, further increase susceptibility.

Clinical Features

cSCC most commonly presents as a firm, erythematous papule, plaque, or nodule with a scaly or crusted surface, often located on sun-exposed areas such as the face, ears, scalp, neck, and dorsal hands. Lesions may ulcerate, become tender, or bleed. Growth is often gradual but can be rapid in aggressive variants. High-risk lesions may exhibit perineural symptoms, such as pain, numbness, or tingling, indicating possible nerve involvement. The clinical appearance can mimic benign conditions such as actinic keratoses or keratoacanthomas, underscoring the importance of biopsy in suspicious cases.

Diagnosis

Diagnosis of cSCC relies on histopathological confirmation through skin biopsy. A punch, shave, or excisional biopsy is typically performed, depending on lesion size and location. Histologically, cSCC is characterized by atypical keratinocytes extending into the dermis with varying degrees of differentiation. Poorly differentiated tumors may lose characteristic squamous features and be more challenging to diagnose. In cases where metastasis is suspected—such as with large, deeply invasive tumors or those in high-risk anatomical locations—imaging studies like ultrasound, CT, or MRI may be indicated. Sentinel lymph node biopsy may be considered in select cases.

Management

Treatment decisions are guided by tumor size, location, depth of invasion, histologic differentiation, and patient comorbidities. Surgical excision with histologically clear margins remains the standard of care for most cases of cSCC. Mohs micrographic surgery offers the highest cure rates and maximal tissue preservation, making it the treatment of choice for high-risk or cosmetically sensitive areas. For patients who are not surgical candidates, radiation therapy may be used as primary or adjuvant treatment. In situ lesions may be managed with topical therapies such as 5-fluorouracil or imiquimod, while advanced or metastatic cSCC may require systemic therapies, including immune checkpoint inhibitors like cemiplimab.

Prognosis and Prevention

The prognosis of cSCC is generally favorable, with cure rates exceeding 90% for low-risk lesions treated appropriately. However, features such as tumor diameter >2 cm, depth >2 mm, perineural invasion, and poor differentiation are associated with increased risk of recurrence or metastasis. Preventive strategies include sun protection through regular use of broad-spectrum sunscreen, protective clothing, and avoidance of peak UV exposure. Patients with actinic keratoses or a history of cSCC should undergo regular dermatologic surveillance to detect early lesions.

Written by:

Dr Renad AlKanaan

Revised by:

Naif Alshehri, Medical Intern

References:

Dermnet

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