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Thinking about seborrheic keratoses: A rare event


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By Warren R. Heymann, MD
June 9, 2017

Seborrheic Keratoses
Clinical images of squamous cell carcinoma arising in seborrheic keratosis (SCC-SK). A, Invasive SCC-SK on forehead of a man aged 69 years. B, In situ SCC-SK from a pigmented keratosis on the back of a man aged 73 years. C, In situ SCC-SK from a large, irregular, pigmented keratosis on the leg of a man aged 70 years.
Credit: JAAD


Can you envision a practice free of seborrheic keratoses (SKs)? How many times a day do you encounter a panicky patient convinced that they have a melanoma, when it is just an SK? How often do patients complain that their SKs are getting larger and they don’t want to wind up looking like their grandmother? How frequently do you reassure patients that their irritated SKs will only rarely demonstrate a malignancy on biopsy? How many discussions have you had with patients explaining that Medicare (and other insurers) considers these cosmetic, and if they want them removed, they need to pay out of pocket? I find it ironic that I spend half my life talking about SKs and never thinking about them. Dermatologists report that they diagnose SKs in an average of 155 patients a month (1). Maybe I’m an outlier, or perhaps it’s my imagination, but I think I see 155 patients with SKs per week.

Intellectually I know that SKs are composed of living keratinocytes — yet somehow I think of them (mistakenly) as inert lesions. The fact that SKs are alive means that there is always malignant potential, as rare as that might be. The etiology of SKs is unknown, although there have been recent developments offering clues to their pathogenesis. The tyrosine kinase receptor FGF receptor-3 (FGFR3) and the transcription factor forkhead box N1 (FOXN1) are highly expressed in SKs (2). SKs frequently have acquired oncogenic mutations in the receptor tyrosine kinase/phosphatidylinositol 3-kinase/Akt signaling cascade; they are sensitive to inhibition by ATP-competitive Akt inhibitors (3).
 
The rate of malignant change within SKs is probably around 1% — including Bowen disease (BD), squamous cell carcinoma (SCC), keratoacanthoma (KA), basal cell carcinoma, and melanoma. There have been debates as to whether cancers are collision tumors with, or actually derived from SKs. Ultraviolet light may be pathogenic, but so can human papillomavirus (HPV), as demonstrated by PCR in 5 of 17 cases of SKs with Bowenoid changes (4).

Immunosuppression may play an important role in the malignant transformation of SKs. Conic et al reviewed 162 cases of SCC-SK and compared them to a control group of patients with SKs who were matched by age, sex, and location of lesion from the same time period (n=162). They demonstrated that SCC-SK had the classic histopathologic features of SK, such as hyperkeratosis, parakeratosis, papillomatosis, and pseudohorn cysts. The areas of SCC were characterized by areas of squamous dysplasia (100%), hypogranulosis (79.6%), solar elastosis (80.9%), and brown pigmentation (59.9%). Patients with a history of immunosuppression had an increased risk for developing SCC-SK (19% versus 3%; P <.01), particularly when inhibition was transplant-associated (10% versus 0%; P<.01). HPV studies were not performed. The authors concluded that SCC-SK occurs more often in elderly men with a history of immunosuppression associated with organ transplants. (5)
 
According to Jackson et al, “On average, dermatologists treat 43% of their SK patients to remove lesions. Cryosurgery is the most common removal method. Other commonly employed removal methods include shave excision, electrodessication, curettage or a combination of these. While these procedures can be used to remove SK lesions effectively, each has potential drawbacks and careful patient selection is required to optimize cosmetic results particularly in skin of color patients and patients with thick or numerous lesions. While there is great interest from both patients and providers in a topical non-invasive treatment for SK, no effective topical therapeutic agent has been developed, and this remains an area of unmet need.” (1) Certainly, a shave excision with histologic confirmation makes sense if there is any clinical suspicion for malignancy, and perhaps should be de rigueur when removing such lesions in immunosuppressed hosts. Importantly, Jim DelRosso reminds us not to fall into the trap of performing a cursory exam in patients with multiple SKs – it would be easy to miss a melanoma under such circumstances (6).

One day there will be a truly effective topical medication for SKs. Patients would love it, and rightfully so. That alone could solve the manpower shortage of dermatologists. I will miss those  waxy, rough, stuck-on papules, though. It’s gratifying to reassure worried patients. When I was a dermatology resident, one of my wonderful chief residents, Alan Schliftman, said “Warren, I guarantee you, you will kiss every SK that comes into your office!” He was right — SKs and I have been good friends for nearly four decades. Earlier this year Aclaris Therapeutics* announced the submission of a New Drug Application to the FDA of a 40% hydrogen peroxide solution indicated for SKs (meant to be applied in the office). One day a novel treatment that prevents SK development will be forthcoming — it will then be time to say a bittersweet good-bye to our keratotic compatriots.

1. Jackson JM, et al. Current understanding of seborrheic keratosis: Prevalence, etiology, clinical presentation, diagnosis, management. J Drugs Dermatol 2015; 14: 1119-25.
2. Mandinova A, et al. A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans. J Clin Invest 2009; 119: 3127-37.
3. Neel VA, et al. Sustained Akt activity is required to maintain cell viability in seborrheic keratosis, a benign epithelial tumor. J Invest Dermatol 2016; 136: 696-705.
4. Wu Y-H, et al. Seborrheic keratosis with Bowenoid transformation: The immunohistochemical features and its association with human papillomavirus infection. Am J Dermatopathol 2015; 37: 462-8.
5. Conic RZ, et al. The role of immunosuppression in squamous cell carcinomas arising in seborrheic keratosis. J Am Acad Dermatol 2017; 76: 1146-50.
6. Del Rosso JQ. A closer look at seborrheic keratoses: Patient persepectives, clinical relevance, medical necessity, and implications for management. J Clin Aesthet Dermatol 2017; 10: 16-25.


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