A brief refresher with useful tables, figures, and research summaries

Keratinocyte carcinomas (KCs) include basal-cell carcinomas (BCCs) and cutaneous squamous-cell carcinomas (SCCs). KCs are the most common cancers in the United States — more common than all other cancers combined. The term “nonmelanoma skin cancer” (NMSC) is still frequently used to refer to BCCs and SCCs, although this nonspecific terminology encompasses other cancers, such as Merkel cell carcinoma, dermatofibrosarcoma protuberans (DFSP), angiosarcoma, and various cancers arising from appendageal skin components. Therefore, when referring specifically to SCCs and BCCs, the term “keratinocyte carcinoma” is preferred. In this section, we provide an overview of the following topics:

• Risk Factors

• Basal-Cell Carcinomas (BCCs)

• Squamous-Cell Carcinomas (SCCs)

• Diagnosis of BCC and SCC

• Treatment

The incidence of KC increases with the following risk factors:

• age

• cumulative sun exposure

• sun-sensitive skin: light hair, blue eyes, easily sunburned

• immunosuppression (e.g., after solid-organ transplantation, immunosuppressive therapy of autoimmune disease, chronic lymphocytic leukemia): chronic immunosuppression significantly increases risk for developing cutaneous malignancies, particularly SCC (up to 65 times the risk of the general population)

The following table lists additional risk factors for BCC:

The following table lists additional risk factors for SCC:

Actinic keratoses (AKs) are precursor lesions to SCCs and found in the same phenotypic patient populations. AKs are precancerous and treated with more-conservative approaches; an estimated 1 in 100 AKs will progress to SCCs.

Actinic Keratosis

(Source: NEJM Knowledge+)

BCCs can have many different appearances. The most common forms are superficial and nodular BCCs.

Types of BCCs

(Source: Basal-Cell Carcinoma. N Engl J Med 2005.)

Key features of nodular BCC include a translucent, pink, smooth papule with slight shine, scale, and prominent vessels. The following images show the appearance of various nodular BCCs:

BCC ultimately treated with Mohs surgery.

(Photo courtesy of Anar Mikailov, MD.)

The following images of BCC are from the 1992 NEJM review article Nonmelanoma Cancers of the Skin:

Note the prominent telangiectasia in this translucent papule.

(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)

Note the pink plaque with irregular borders, telangiectasia, loss of skin markings, and small erosions.

(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)

The tumor measured 16 mm in diameter. Note the rolled border and the low level of telangiectasia relative to that in the surrounding photodamaged skin. Characterized by scar-like depression and typically more aggressive.

(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)

The lesion resembles a malignant melanoma but has rolled, translucent borders. Pigmented BCCs are commonly mistaken for melanoma or benign seborrheic keratoses.

(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)

Seemingly limited basal-cell carcinoma in a 45-year-old woman (panel A) and the defect (measuring 30 by 38 mm) resulting from surgical efforts to obtain a tumor-free tissue margin (panel B). BCC with significant subclinical extension after Mohs surgery.

(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)

SCCs can also have variable clinical presentations. Cutaneous SCCs are most commonly found on chronically sun-exposed skin, as hyperkeratotic ovoid plaques or papules. The following images show some examples of SCCs:

SCC of the Nail Bed

(Source: Squamous-Cell Carcinoma of the Nail Bed. N Engl J Med 2015.)

SCC of the Thumb

(Source: Squamous-Cell Carcinoma Resembling Pyoderma Gangrenosum. N Engl J Med 2015.)

SCC with Cutaneous Horn of the Dorsal Hand

(Source: Squamous-Cell Carcinoma Manifesting as a Cutaneous Horn. N Engl J Med 2008.)

SCC of the Scalp with Surrounding AKs

Multiple hyperkeratotic papules and plaques on the scalp and an ulcerated nodule with hemorrhagic crust on the left scalp.

(Source: VisualDx 2023.)

The following images are from the 1992 NEJM review article Nonmelanoma Cancers of the Skin:

Ulcerating SCC of the Ear

Squamous-cell carcinoma measuring 20 mm in diameter with elevated red borders and central erosion.

(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)

Well-Differentiated SCC

Well-differentiated squamous-cell carcinoma measuring 10 mm in diameter. The lesion is clinically indistinguishable from keratoacanthoma (see image below)

(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)

SCCs and AKs Due to Chronic Arsenic Toxicity

SCCs and arsenical keratoses of the palms and soles.

(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)

Keratoacanthoma Type of SCC

Keratoacanthoma measuring 10 mm in diameter with central keratin plug. The lesion is clinically indistinguishable from well-differentiated squamous-cell carcinoma (see image above). Keratoacanthoma are typically fast-growing but less invasive.

(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)

SCC of the Tongue

Commonly associated with human papillomavirus and smoking or chewing tobacco.

(Source: Cutaneous Squamous-Cell Carcinoma. N Engl J Med 2001.)

SCC of the Penis

HPV-associated SCC of the penis.

(Source: Squamous-Cell Carcinoma of the Penis with Human Papillomavirus. N Engl J Med 2016.)

SCC in Situ

An eroded and crusted plaque on the shin.

(Source: VisualDx 2023.)

Ulcerated SCC

An eroded and crusted plaque on the ankle.

(Source: VisualDx 2023.)

Skin biopsy: A diagnosis of BCC or SCC should be confirmed via skin biopsy, using either punch or shave technique. See this NEJM video of the punch biopsy procedure.

Staging of SCCs should be performed in high-risk cases. The Brigham and Women’s Hospital Tumor Staging for Cutaneous Squamous-Cell Carcinoma has been found to have better prognostic value than other criteria and includes upstaging for poorly differentiated tumors, tumor diameter ≥2 cm, perineural invasion, and invasion beyond subcutaneous fat.

• The approach to treatment of BCCs and SCCs is similar; in both cases, the goal is cure.

• In patients who are immunosuppressed (e.g., solid-organ–transplant recipients or patients with chronic lymphocytic leukemia), treatment should be managed aggressively, ideally in dedicated high-risk skin-cancer clinics.

• Surgery is associated with the highest cure rate (95%–99% at 5 years). Surgical treatment includes:

  • wide local excision

  • Mohs micrographic surgery

• Nonsurgical treatment is associated with lower long-term cure rates than surgery but is appropriate for many low-risk tumors. Nonsurgical treatment options include:

  • electrodesiccation and curettage

  • topical creams (e.g., 5-fluorouracil, imiquimod, ingenol mebutate, diclofenac)

  • cryotherapy

  • localized radiation therapy

  • laser therapy

  • intralesional methotrexate, 5-fluorouracil

  • photodynamic therapy

  • oral chemotherapy

• Patients with metastatic keratinocyte carcinomas require systemic chemotherapeutics, immunotherapies, or novel small-molecule–targeted inhibitors.

  • In the case of metastatic BCCs, vismodegib (hedgehog pathway inhibitor) and cemiplimab (anti–PD-1 monoclonal antibody immunotherapy) are approved by the U.S. Food and Drug Administration for this indication.

  • Metastatic or locally advanced cutaneous SCC management can involve adjuvant radiation therapy, sentinel lymph node biopsy, chemotherapy (e.g., cisplatin, 5-fluorouracil), epidermal growth factor–receptor inhibitors (e.g., cetuximab), and immunotherapy (e.g., nivolumab, ipilimumab, pembrolizumab, or cemiplimab). For more details on metastatic or locally advanced cutaneous SCC treatment, see the National Comprehensive Cancer Network (NCCN) guidelines.