Rotation Prep
Published April 12, 2024
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:
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:
Risk Factors for the Development of Basal-Cell Carcinoma | |
---|---|
Physical characteristics | Blond or red hair Blue or green eyes Light skin color |
Exposures | Arsenic Coal tar Ionizing radiation Smoking Tanning bed use Ultraviolet light |
Genodermatoses | Albinism Xeroderma pigmentosum Rombo syndrome* Bazex–Dupré–Christol syndrome† Nevoid basal-cell carcinoma syndrome (Gorlin syndrome)‡ |
Immunosuppression | Recipients of solid-organ transplants |
* This syndrome is an autosomal dominant disorder, characterized by basal-cell carcinoma, atrophoderma vermiculata, milia, hypotrichosis, trichoepithelioma, and peripheral vasodilatation. † This syndrome is an X-linked dominant disorder, characterized by basal-cell carcinoma, follicular atrophoderma, hypotrichosis, and localized anhidrosis. ‡ This syndrome is an autosomal dominant disorder, characterized by basal-cell carcinoma, palmoplantar pits, odontogenic keratocysts, bifid ribs, frontal bossing, and central nervous system defects. (Reference: Basal-Cell Carcinoma. N Engl J Med 2005.)
The following table lists additional risk factors for SCC:
Risk Factors for the Development of Cutaneous Squamous-Cell Carcinoma |
---|
|
(Reference: Cutaneous Squamous-Cell Carcinoma. N Engl J Med 2001.)
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.
(Source: NEJM Knowledge+)
BCCs can have many different appearances. The most common forms are superficial and nodular 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:
(Photo courtesy of Anar Mikailov, MD.)
The following images of BCC are from the 1992 NEJM review article Nonmelanoma Cancers of the Skin:
(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)
(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)
(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)
(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)
(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)
Additional images of BCCs can be found here
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:
(Source: Squamous-Cell Carcinoma of the Nail Bed. N Engl J Med 2015.)
(Source: Squamous-Cell Carcinoma Resembling Pyoderma Gangrenosum. N Engl J Med 2015.)
(Source: Squamous-Cell Carcinoma Manifesting as a Cutaneous Horn. N Engl J Med 2008.)
(Source: VisualDx 2023.)
The following images are from the 1992 NEJM review article Nonmelanoma Cancers of the Skin:
(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)
(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)
(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)
(Source: Nonmelanoma Cancers of the Skin. N Engl J Med 1992.)
(Source: Squamous-Cell Carcinoma of the Tongue. N Engl J Med 2016.)
(Source: Squamous-Cell Carcinoma of the Penis with Human Papillomavirus. N Engl J Med 2016.)
(Source: VisualDx 2023.)
(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
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.
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, methyl aminolevulinate photodynamic therapy (MAL-PDT), and 0.015% ingenol mebutate gel for treatment of actinic keratosis, 5% fluorouracil cream was the most effective.
Chen AC et al. N Engl J Med 2015.
This phase 3 trial showed that 500 mg 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.
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 versus 84% for topical imiquimod cream, affirming surgery as the preferred option, though also showing reasonable success with topical therapy.
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 Brigham and Women’s Hospital [BWH] tumor staging). Subsequent studies have confirmed superior prognostication of this new staging system, compared to the American Joint Committee on Cancer (AJCC).
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.
The best overviews of the literature on this topic
Nehal KS and Bichakjian CK. N Engl J Med 2018.
Rubin AI et al. N Engl J Med 2005.
Alam M and Ratner D. N Engl J Med 2001.
Preston DS and Stern RS. N Engl J Med 1992.
The current guidelines from the major specialty associations in the field
National Comprehensive Cancer Network 2023.
Eisen DB et al. J Am Acad of Dermatol 2021.