Rotation Prep


Published October 29, 2021

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

Keratinocyte Carcinomas 

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.

Risk Factors for KC

The incidence of KC increases with the following 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 in the general population)

The following table lists risk factors for development of BCCs: 

Risk Factors for the Development of Basal-Cell
Carcinoma 
Physical characteristics



Exposures






Genodermatoses





Immunosuppression
Blond or red hair
Blue or green eyes
Light skin color

Arsenic
Coal tar
Ionizing radiation
Smoking
Tanning–bed use
Ultraviolet light

Albinism
Xeroderma pigmentosum
Rombo syndrome*
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
  • Exposure to ultraviolet radiation

  • Ultraviolet A

  • Ultraviolet B

  • Therapy with methoxsalen and ultraviolet A radiation

  • Exposure to ionizing radiation

  • Genodermatosis

  • Oculocutaneous albinism

  • Xeroderma pigmentosum

  • Infection with human papillomavirus, especially types 6, 11, 16, and 18

  • Exposure to chemical carcinogens

  • Arsenic

  • Polycyclic aromatic hydrocarbons

  • Immunosuppression

  • Organ transplantation

  • Leukemia and lymphoma

  • Immunosuppressive medications

  • Chronically injured or diseased skin

  • Ulcers

  • Sinus tracts

  • Osteomyelitis

  • Radiation dermatitis

  • Certain chronic inflammatory disorders, such as dystrophic epidermolysis bullosa

  • Precursor lesions

  • Actinic keratoses

  • Arsenical keratoses

  • Radiation-induced keratoses

  • Bowen’s disease (squamous-cell carcinoma in situ)

  • Erythroplasia of Queyrat (squamous-cell carcinoma in situ of the penis)

Actinic Keratoses

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

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Basal-Cell Carcinomas

Basal-cell carcinomas (BCCs) can have many different appearances. The most common forms are superficial and nodular BCCs.

Types of BCCs

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Nodular BCC

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:

Biopsy-Confirmed Nodular BCC

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

Nodular BCC on the Trunk

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Note the prominent telangiectasia in this translucent papule.

Superficial Spreading BCC

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

Morpheaform BCCs

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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.

Pigmented BCC

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

BCC of the Nose

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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

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:

SCC of the Nail Bed

SCC of the Thumb

SCC with Cutaneous Horn of the Dorsal Hand

SCC of the Scalp with Surrounding AKs

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Multiple hyperkeratotic papules and plaques on the scalp and an ulcerated nodule with hemorrhagic crust on the left scalp.
(Source: VisualDx)

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

Ulcerating SCC of the Ear

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Squamous-Cell Carcinoma Measuring 20 mm in Diameter with Elevated Red Borders and Central Erosion.

Well-Differentiated SCC

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Well-Differentiated Squamous-Cell Carcinoma Measuring 10 mm in Diameter. The lesion is clinically indistinguishable from keratoacanthoma (see image below).

SCCs and AKs Due to Chronic Arsenic Toxicity

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Squamous-Cell Carcinoma and Arsenical Keratoses of the Palms and Soles

Keratoacanthoma Type of SCC

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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.

SCC of the Tongue

SCC of the Penis

SCC in Situ

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An eroded and crusted plaque on the shin.
(Source: VisualDx)

Ulcerated SCC

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An eroded and crusted plaque on the shin.
(Source: VisualDx)

Diagnosis

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.

Treatment

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

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

Nonsurgical Options

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)

  • cryotherapy

  • localized radiation therapy

  • laser therapy

  • intralesional methotrexate, 5-fluorouracil

  • photodynamic therapy

  • oral chemotherapy

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.

Research

Landmark clinical trials and other important studies

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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.

Read the NEJM Journal Watch Summary

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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.

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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.

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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.

Read the NEJM Journal Watch Summary

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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.

Reviews

The best overviews of the literature on this topic

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Nehal KS. N Engl J Med 2018.

This article reviews the epidemiology, risk factors, staging, management, and prevention of keratinocyte carcinomas.

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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.

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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.

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Rubin AI et al. N Engl J Med 2005.

According to the American Cancer Society, skin cancer is the most common cancer, accounting for about half of all cancers in the United States. More than 1 million cases of skin cancer will be diagnosed in the United States this year.

Guidelines

The current guidelines from the major specialty associations in the field

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Eisen DB et al. American Academy of Dermatology 2021.

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National Comprehensive Cancer Network 2021.

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National Comprehensive Cancer Network 2021.

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