Dermatologic Look-Alikes

Actinic Keratosis

Actinic keratosis (AK; also known as solar keratosis or senile keratosis) was first described by Duhreuilh in 1896 as keratosis senilis. The lesions were first called actinic keratoses by Pinkus in 1958 to emphasize their keratotic (thickened and scaly) aspects.1,2 These lesions are generally diagnosed in individuals 45 years and older and are more common in men and light-skinned individuals in geographical areas with increased sunlight exposure such as Australia.3,4

Actinic keratosis arises from keratinocyte proliferation at the dermoepidermal junction, disturbing regular epidermal differentiation and causing hyperkeratosis.5 This abnormal keratinocyte proliferation stems from DNA mutations as a result of exposure to UV light from sunlight and artificial sources such as tanning beds and psoralen and UV-A (PUVA) therapy.3,5 The most important cause of AK is exposure to UV-B radiation from sunlight.2

Actinic keratoses are considered premalignant by many researchers, while others have classified them as small, localized squamous cell carcinoma in situ.1,2,5 Mutations of TP53 are the most common mutation seen in AKs.2-4 Generally, once the lesion reaches the depth of the deep reticular dermis or if the atypical keratinocytes extend throughout the entire epidermis, the lesion is considered to have progressed to squamous cell carcinoma (SCC).5 Conversion rate of AKs to SCC is approximately 0.25% to 1% per year. The number of SCCs that develop from AKs is considered to be approximately 60%.5

Actinic keratoses present as scaly, rough, flesh-colored or erythematous papules and patches that may be tender, itchy, or asymptomatic.2,3,6 The lesions are divided into 3 grades depending on clinical presentation. Grade I lesions are thin and easier to feel than to see; grade II AKs are readily felt and seen; and grade III AKs are thick, hypertrophic, and hyperkeratotic.5 The texture of AKs is gritty and similar to sandpaper.2,3 Some lesions may contain pigment or telangiectasias.2,3 Their size can vary from millimeters to more than 2 centimeters and occur with the greatest frequency in sun-exposed areas including the upper extremities, upper back, neck, face, and areas of the scalp with thinning or absent hair.2-4,6 Lesions on the upper extremities often have greater thickness and more hyperkeratosis than those found on the head and neck.3

Histologic analysis of AKs reveals atypical keratinocytes, loss of polarity, nuclear pleomorphism, and increased mitotic figures.2-4 Abnormal keratinocyte development can lead to alternating hyperkeratosis and parakeratosis in the stratum corneum.2,3 Keratinocytes in hair follicles and sweat glands will appear normal.3 The dermis may contain inflammatory infiltrates with plasma cells and lymphocytes as well as solar elastosis.2,3 Actinic keratoses are classified histologically as acantholytic, atrophic, bowenoid, hypertrophic, lichenoid, or proliferative. Some AKs may be confused as SCC, especially since there are no clear guidelines for differentiating between AKs and SCC.2,3 Invasive SCC will spread into the dermis, unlike AKs.4

Actinic keratoses are usually diagnosed clinically and can either spontaneously resolve, remain stable, or progress to SCC.2-4 Since it is impossible to predict which AKs may become malignant, they must be treated.3 Cryotherapy, topical fluorouracil cream, imiquimod cream, carbon dioxide lasers, chemical peels, dermabrasion, curettage and electrodessication, and photodynamic therapy are typically used for treatment of AKs.3,5

Treatment with liquid nitrogen had a 99% cure rate after 1 year in a study.5 Cryotherapy results vary with aggressiveness of application and the location and depth of the lesion. This therapy modality is most effective when treating single lesions.4-6 Side effects often include erythema and pain with possible scarring and depigmentation. Cryotherapy can be less effective in treating hyperkeratotic lesions.4,6

Topical fluorouracil treatment is most effective in treating multiple lesions located on the head and neck by triggering inflammatory processes within the lesions.3-5 The inflammatory process may cause ulceration and erosion.4 A study by Jansen et al compared the effectiveness of 5% topical fluorouracil cream with 5% imiquimod cream, methyl aminolevulinate photodynamic therapy (MAL-PDT), and 0.015% ingenol mebutate gel after 12 months.7 The differences in success rates between the 4 treatment options were significant, with fluorouracil cream having a 74.7% success rate and imiquimod, MAL-PDT, and ingenol mebutate showing 53.9%, 37.7%, and 28.9% success rates, respectively. The authors defined treatment success as a 75% or greater reduction in the number of AKs. The group randomized to receive fluorouracil treatment also reported higher rates of treatment satisfaction and in health-related quality of life.7 Curettage and electrodessication are typically only used for hyperkeratotic AKs and can cause scarring.4,6

The patient in this case was diagnosed clinically with actinic keratoses and was treated with liquid nitrogen in clinic and was also given a prescription for topical fluorouracil for treatment of numerous AKs on his scalp.

CASE #2 Squamous Cell Carcinoma

The first description of squamous cell carcinoma in situ (SCCIS) was made by Bonney in 1914.8 The incidence of SCC is 356 per 100,000 White men in the US and 16 per 100,000 people in central Europe.9 Patients with a history of organ transplantation are up to 250 times more likely to develop SCC and their tumors are more likely to metastasize.9

Squamous cell carcinoma is most commonly found among older individuals in their mid-60s and is more common in White persons.10 Notable risk factors include high amounts of sun exposure, immunosuppression, and male gender (3:1 male to female ratio). Among people of color, including those of African, Asian, and Hispanic descent, cutaneous SCC is the most common skin cancer. Black patients with SCC have a higher mortality rate than non-Black patients because of delays in diagnosis and greater likelihood of occurrence of SCC in areas of prior trauma or scars, which also leads to a worse prognosis.10

Squamous cell carcinoma develops because of several different mutations in DNA. Mutations in tumor protein 53 (TP53), cyclin-dependent kinase inhibitor 2A (CDKN2A), RAS, and NOTCH1 genes are commonly implicated in the development of SCC. Of these gene mutations, TP53 is the most common cause.Tumor protein 53 mutations often arise as a base mutation where cytosine is replaced with thymine at dipyrimidine sites, which allows SCC cells to evade apoptosis and continue to grow. Cyclin-dependent kinase inhibitor 2A mutations affect regulation of the cell cycle, while RAS gene mutations lead to changes in cell cycle transduction. These mutations are primarily caused by UV light damage.10,11

Histologic and physical characteristics of SCCs are important for management and prognosis. Squamous cell carcinoma has 2 well-differentiated histologic subtypes: keratoacanthoma and verrucous carcinoma. Keratoacanthomas appear crateriform with a central keratin plug.9 Verrucous carcinomas are further differentiated into 2 subtypes: Buschke-Lowenstein, which are found in the genital and groin areas, and epithelioma cuniculatum, which are found on the bottom of the feet. Desmoplastic and adenosquamous histologic subtypes have a worse prognosis, with a higher risk for metastasis and recurrence after treatment.10,12-14

Other prognostic factors associated with a greater chance of metastasis and recurrence include a diameter of 2.0 cm or greater; a depth greater than 2 mm; perineural invasion of nerves greater than 0.1 mm; poorly differentiated tumors; previously treated or recurrent SCC; SCCs arising within chronic wounds or scars; and lesions arising in a patient with a suppressed immune system.10 Location of the SCC is another prognostic factor: SCCs on the lip and ear have the greatest risk of metastasizing than those in other locations.9,10

Diagnosis of SCC depends on clinical presentation and biopsy of the lesion. Lesions are most often found on the scalp, face, neck, dorsal hands, and forearms. They are erythematous to skin-colored papules or plaques and have varied degrees of scale. Lesions may have crust, erosions, or ulcerations. Some are cutaneous horns that contain actinic keratoses at the base that can progress to SCC. Keratoacantomas present as a rapidly enlarging papule with a central keratotic plug.15,16 keratoacanthoma and verrucous.

Dermoscopy is helpful in making a diagnosis.Vascular patterns that are present on dermoscopy are either small dotted vessels, glomerular vessels, or elongated vessels resembling hairpins. Erosions or ulcerations will appear as brown-red or black-colored surface blotches.10,15

Biopsy is needed to confirm the diagnosis of SCC.16 On biopsy, well-differentiated SCC will have atypical keratinocytes in the epidermis with disordered maturation as well as hyperkeratosis and parakeratosis. A downward proliferation of nests of keratinocytes extending into the dermis is also found. Nuclei of these keratinocytes will display varying degrees of pleomorphism and mitoses as well as prominent nucleoli. Degrees of cellular differentiation vary among tumors.15

Lesions that can mimic SCC include melanoma, where suspicious lesions should also be completely biopsied; actinic keratoses, which appear red, scaly, and inconsistent in texture compared with the surrounding skin; and basal cell carcinoma,