What are keratoacanthomatous lesions of the legs in mature women?
Dec. 11, 2017
I have an increasing number of patients asking me questions about proliferating keratoacanthoma-like lesions on their shins. “Why am I getting these? Are they cancer? Why do more of them appear after surgery?”
All are very legitimate questions. Perhaps we are beginning to get some answers.
This topic was addressed previously in DI&I (Getting a Leg Up on Squamous Cell Carcinomas of the Keratoacanthoma Type; October 8, 2016) commenting on the article by Wu et al, who reported a retrospective case series on seven elderly Caucasian women (mean age 79 ± 3.7 years) with actinically damaged skin and a long-standing history of widespread pruritus and prurigo nodules. All patients had histologically confirmed keratoacanthomas, or squamous cell carcinomas with the clinical appearance of a keratoacanthoma, that developed within the field of prurigo nodules. All seven patients had a clinical response to acitretin with a decrease in the number of lesions. Four patients had an associated eczematous dermatitis and were also treated with cyclosporine with improvement in pruritus and prurigo nodules and no increase in keratoacanthomas. The authors concluded with the belief that there is a distinct subset of elderly individuals with extensive actinic damage who are predisposed to developing both prurigo nodules and keratoacanthomas (1).
Based on my clinical experience, I am absolutely convinced this phenomenon is real — and reasonably common.
Keratoacanthomas (KAs) display different clinical presentations: 1) Solitary lesions may present as classical, giant, or expanding centrifugum types; 2) Multiple KAs include the familial Ferguson-Smith type, generalized eruptive Grzybowksi variant associated with malignancies, and the Witten-Zak type (which combines features of the prior multiple KA variants). Multiple KAs may be observed in the Muir-Torre syndrome.
KAs may be triggered by immunosuppression (inherited, acquired or iatrogenic), electromagnetic radiation (UVA, UVB, UVC, and X-rays, including megavoltage radiation), trauma/Koebnerization (post surgical, tattoos), chemical (tar), drugs (BRAF inhibitors, Hedgehog pathway inhibitors), and foreign bodies (tattoos, fillers). (2)
The p53 gene contains homozygous mutations in approximately 50-60% of human cancers. About 90% of these mutations encode missense mutant proteins that produce a protein with a reduced capacity to bind to a specific DNA sequence that regulates the p53 transcriptional pathway. (3) Underlying genetic mechanisms that lead to the development of cutaneous squamous cell carcinoma are poorly understood. A study of targeted sequencing of 48 clinically relevant genes was performed on DNA extracted from formalin-fixed and paraffin-embedded high-risk primary head and neck cutaneous squamous cell carcinomas (SCCs). Associations of somatic mutations with clinicopathologic characteristics were evaluated and compared with those described in the literature for metastatic disease. Alterations in 44 cancer-associated genes were identified. TP53 was mutated in 100% of cases. (4)
Ko et al sequenced TP53 in 30 SCCs from 6 women who had multiple SCCs on their legs during a 21-month time frame. Histopathologic analysis showed that 16 of the 30 lesions did not have prominent cytologic atypia and were distinguished by having expanded follicle-like structures composed of large, glassy, eosinophilic keratinocytes; these lesions resembled keratoacanthoma and were categorized as keratoacanthoma-like squamous proliferations (KASPs). The 14 remaining tumors had more prominent cytologic atypia and remained classified as SCCs. Twenty of 30 tumors (including the KASPs) from the 6 different patients lacked detectable TP53 mutations. Ten of the 14 tumors that remained classified as SCC had detectable TP53 mutations. The authors concluded by suggesting that because some cutaneous squamous proliferations on the legs of women with multiple lesions lack prominent cytologic atypia as well as TP53 mutations, they might be more akin to KAs than SCCs, or might represent a reactive phenomenon. (5)
I am pleased that in their discussion, Ko et al stated that the term “keratoacanthoma-like squamous proliferation” was used to clarify the nature of the disorder, not to create new nomenclature. (Thank goodness — it’s already hard enough to explain the difference between a KA and a SCC to patients!). I could not tell from article, but assume that at least some patients had both lesions – KASPs and SCCs. I also speculate that there were no clinically distinguishing features between these two, as all were originally diagnosed (histologically) as SCCs. This is a crucial point that should be addressed in future studies — even if KASPs are reactive lesions, are there any clinical or non-invasive clues to distinguish them from SCCs? Even if staining for TP53 proves to be the distinguishing factor, it is completely impractical to biopsy and sequence every lesion.
The following are my current thoughts and approach the elderly woman with prurigo/KA-like lesions on the legs: 1) These patients should be listed as a separate “species” in the “genus” keratoacanthoma; 2) I biopsy one or two lesions to rule out prurigo nodularis, or other disorders such as hypertrophic lichen planus or inflamed seborrheic keratoses; 3) if the lesions are SCCs of the KA type, I carefully explain that although these may be cancerous, it is probable that they are reactive to prior injury. This distinction enables me to encourage use of acitretin, rather than surgery. 4) Depending on the response (or tolerability) to acitretin, residual lesions may be biopsied, or treated with the variety of options typically used for KAs, ranging from surgery (including Mohs), to topical (5 fluorouracil, etc.), to intralesional (methotrexate); 5) With continued study, we will know exactly what these lesions are, leading to better treatment and prevention.
1. Wu TP, et al. Keratoacanthomas arising in association with prurigo nodules in pruritic, actinically damaged skin. J Am Acad Dermatol 2013; 69: 426-30.
2. Kwiek B, Schwartz RA. Keratoacanthoma (KA): An update and review. J Am Acad Dermatol 2016: 74: 1220-33.
3. Baugh EH, et al. Why are there hotspot mutations in the TP53 gene in human cancers? Cell Death Differ 2017; Nov 3 [Epub ahead of print]
4. Zilberg C, et al. Analysis of clinically relevant somatic mutations in high-risk head and neck cutaneous squamous cell carcinoma. Mod Pathol 2017 Oct 6 [Epub ahead of print]
5. Ko CJ, et al. Squamous proliferations on the legs of women: Qualitative examination of histopathology, TP53 sequencing, and implications for diagnosis in a series of 30 cases. J Am Acad Dermatol 2017; 77: 1126-32.
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