A brief refresher with useful tables, figures, and research summaries
Keratinocyte carcinomas (KCs) include cutaneous squamous-cell carcinomas (SCCs) and basal-cell carcinomas (BCCs). Keratinocyte carcinomas 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 appendageal cancers. Therefore, when referring specifically to SCCs and BCCs, the term “keratinocyte carcinoma” is preferred.
The incidence of KC increases with the following factors:
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 in the general population)
The following table lists risk factors for development of BCCs:
|Risk Factors for the Development of Basal-Cell|
|Blond or red hair|
Blue or green eyes
Light skin color
Bazex–Dupré–Christol syndrome (Bazex’s syndrome)†
Nevoid basal-cell carcinoma syndrome (Gorlin’s syndrome)‡
Recipients of solid-organ transplants
The following table lists risk factors for development of SCCs:
|Risk Factors for the Development|
of Cutaneous Squamous-Cell Carcinoma
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.
Basal-cell carcinomas (BCCs) can have many different appearances. The most common forms are superficial and nodular BCCs.
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:
The following images of BCC are from a 1992 NEJM review article Nonmelanoma Cancers of the Skin:
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.
Seemingly Limited Basal-Cell Carinoma in a 45-Year-Old Woman (Panel A) and the Defect (Measuring 30 by 38mm) Resulting from Surgical Efforts to Obtain a Tumor-free Tissue Margin (Panel B). BCC with significant subclinical extension after Mohs surgery. BCC with significant subclinical extension after Mohs surgery.
(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)
Additional images of BCCs can be found here.
Squamous-cell carcinomas (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:
The following images are from a 1992 NEJM review article Nonmelanoma Cancers of the Skin:
Well-Differentiated Squamous-Cell Carcinoma Measuring 10 mm in Diameter. The lesion is clinically indistinguishable from keratoacanthoma (see image below).
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.
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, depth of tumor invasion ≥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. Patients who are immunosuppressed (e.g., solid-organ–transplant recipients or patients with chronic lymphocytic leukemia) 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
Nonsurgical treatment is associated with lower long-term cure rates than surgery in some cases, although it is appropriate for many cases of low-risk keratinocyte carcinomas. Nonsurgical treatment options include:
electrodesiccation and curettage
topical creams (e.g., 5-fluorouracil, imiquimod, ingenol mebutate, diclofenac)
localized radiation therapy
intralesional methotrexate, 5-fluorouracil
Metastatic keratinocyte carcinomas require systemic chemotherapeutics, immunotherapies, or novel small-molecule–targeted inhibitors. In the case of metastatic BCCs, vismodegib (hedgehog pathway inhibitor) is FDA approved 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). For more details see the National Comprehensive Cancer Network (NCCN) guidelines.
Landmark clinical trials and other important studies
Jansen MHE et al. N Engl J Med 2019.
In this comparison of 5% fluorouracil cream, 5% imiquimod cream, MAL-PDT, and 0.015% ingenol mebutate gel for treatment of actinic keratosis, 5% fluorouracil cream was the most effective.
Jambusaria-Pahlajani A et al. JAMA Dermatol 2013.
This single center study proposed a new staging schema for cutaneous SCCs (now referred to as the BWH staging). Subsequent studies confirmed superior prognostication of this new staging system, compared to the AJCC.
Chen AC et al. N Engl J Med 2015.
This Phase 3 trial showed that 500mg twice daily of vitamin B3 (nicotinamide) decreased rates of new SCCs but not BCCs. Subsequently, many dermatologic and oncologic groups recommend nicotinamide for patients with pre-existing high density of precancerous actinic keratoses, and/or prior keratinocyte carcinomas.
Von Hoff DD et al. N Engl J Med 2009.
This was a Phase 1 clinical trial of vismodegib, a hedgehog pathway inhibitor that showed excellent efficacy in metastatic and locally advanced BCC. Vismodegib is now FDA approved for advanced BCC and basal cell nevus syndrome.
Bath-Hextall F et al. Lancet Oncol 2014.
This study showed that at 3-year follow up, superficial BCCs treated with surgery led to 98% successful treatment vs. 84% for topical imiquimod cream, affirming surgery as the preferred option, though also showing reasonable success with topical therapy.
The best overviews of the literature on this topic
Nehal KS. N Engl J Med 2018.
This article reviews the epidemiology, risk factors, staging, management, and prevention of keratinocyte carcinomas.
Preston D and Stern R. N Engl J Med 1992.
This article reviews the epidemiology, recognition, treatment, and prevention of basal-cell and squamous-cell carcinomas.
Alam M and Ratner D. N Engl J Med 2001.
Nonmelanoma skin cancer is the most common cancer in the United States, with over 1.3 million cases expected to occur in the year 2001. Approximately 80 percent of nonmelanoma skin cancers are basal-cell carcinomas, and 20 percent are squamous-cell carcinomas.
The current guidelines from the major specialty associations in the field
Eisen DB et al. American Academy of Dermatology 2021.
National Comprehensive Cancer Network 2021.
National Comprehensive Cancer Network 2021.