IN-DEPTH REVIEW Eruptive Keratoacanthoma in a 59-year-old Female with Chronic Kidney Disease: A Case Report and Review of Treatment Approaches

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Multiple KA syndromes may be familial or sporadic and are classified into different subtypes based on specific disease criteria and characteristics.A correct diagnosis of multiple KA syndrome provides medical treatment options other than surgical methods used for conventional solitary KAs and well-differentiated SCCs and provides an opportunity to avoid surgical overtreatment of lesions.
We report the case of a 59-year-old Caucasian female who presented with a 5year history of disseminated skin lesion development on her upper and lower extremities, sparing the trunk, head, and neck associated with extreme pruritus (Figure 1).Her medical history was significant for a 4-year history of stage 4 chronic kidney disease as well as a 36-year history of type 2 diabetes mellitus.Analysis of peripheral blood and serum biochemistry revealed a hemoglobin A1c of 5.8%, estimated Glomerular Filtration Rate (eGFR) of 22, creatinine of 2.37, and BUN of 37. Her social history consisted of 10+ pack years of tobacco use and 10+ years of daily alcohol consumption.The patient's family history was noncontributory.Biopsies and excisions were taken for diagnostic and curative reasons.Histopathology of the submitted specimens revealed two prurigo nodules on deep shave saucerizations (Figure 2), three welldifferentiated SCCs on deep shave saucerizations, KA-type SCCs on two excisions (Figure 3), and well-differentiated invasive SCC on three excisions (Figure 4).All specimens were examined by dermatopathologists.Features of perforating diseases, such as collagen or elastic fiber degeneration and expulsion through the epidermis, were not seen in the submitted specimens.In light of the abundance of her lesions, further diagnostic workup was initiated to determine her risk of metastasis.One of the well-differentiated SCCs was sent for molecular testing via DecisionDx-SCC.Results of the test determined the patient to be in a Class 1 category, which is associated with a low risk of metastasis within a 3-year period.Given the diffuse nature of her lesions, oral Acitretin 25mg once daily was initiated.After three months of therapy, new lesions ceased to develop, and existing lesions decreased in size.However, the patient reported significant levels of pruritus and xerosis associated with Acitretin, which led to the patient discontinuing Acitretin.Going forward, our plan is to begin intralesional triamcinolone acetonide injections once every four weeks in an attempt to alleviate pruritus associated with her lesions and potentially reduce the possibility of overlapping reactive epithelial changes leading to prurigo nodularis-like lesions.The patient may also benefit from Unna boot applications to help protect the lesions from manual trauma due to pruritus, also leading to reactive prurigo nodularis-like changes.Unna boots may be combined with topical 5fluorouracil each week for a 4-6-week period to target the patient's hyperplastic epithelial neoplasms (prurigo nodules, KAs, welldifferentiated SCC).The patient will continue to be carefully observed on a regular basis to monitor for development of high-grade squamous cell carcinomas with higher morbidity potential, requiring more aggressive surgical treatment.
KAs may present as solitary or multiple lesions; multiple KAs can be further divided into the Ferguson-Smith and Grzybowski's eruptive KA syndromes. 8Ferguson-Smith syndrome is an autosomal dominant variant of multiple KA syndrome seen predominantly in individuals of Scottish descent. 6These patients present during adolescence with multiple KAs that tend to spontaneously regress, resulting in the formation of an atrophic scar.The other form of multiple KA syndrome, Grzybowski's eruptive KA (GEKA), was first described by Gzrybowski in 1950 and published under the title "A Case of Peculiar Generalized Epithelial Tumors of the Skin". 9This particular variant of multiple KA syndrome is sporadic and characterized by some (see below) as an abrupt or progressive development of hundreds to thousands of small 0.5cm to 1cm KAs during the fifth to seventh decade of life on the torse and extremities, sometimes involving the palms, soles, genitals, and mucous membranes of the lips and eyelids. 10spite continued reports of new GEKA cases since its discovery in 1950, the medical community has failed to establish a definitive set of diagnostic criteria for the condition. 9ofal et al. have proposed the following as potential criteria for GEKA diagnosis: generalized eruption of multiple welldemarcated papules with some having a keratotic center, lack of family history, onset in adulthood (most often fifth to seventh decade), and severe and persistent pruritus.Variable features include the presence of mucosal lesions, masked facies, and ectropion.Some of our patient's presentation, such as histological findings of KAs, late onset of presentation during the fifth decade of life, lack of family history, and severe pruritus all point to a diagnosis of GEKA.Other characteristics of our patient favor the diagnosis of Eruptive Squamous Atypia (ESA), given her lesions were confined to her extremities, accessible to picking and koebnerization, and some lesions not meeting diagnostic criteria for KAs and showing features of prurigo nodules and well-differentiated SCCs. 11In real-life clinical settings, many patients present with overlap features of entities with multiple generalized KAs, and this contributes to the difficulty in the literature to consistently define GEKA.Therefore, we propose our patient may have overlapping features of GEKA and ESA.The distinction may only be of DISCUSSION academic interest as the treatment approaches are similar.
A unique challenge of managing GEKA/ESA is differentiating clinical and histological features of well-differentiated SCC (that require surgical intervention) from multiple eruptive KAs and reactive hyperplasia and atypia as a result of chronic scratching and picking (that require more conservative treatment approaches).In practice, to distinguish a true neoplastic carcinoma from a low-grade generalized KA or reactive squamous proliferation, clinicians often rely on clinical features such as duration, morphology, and growth rate. 12While this information can be helpful, studies suggest that these features are extremely variable and unreliable as diagnostic criteria.Histopathology and distinctive microscopic criteria, mainly architectural silhouette of completely excised lesions and degree of epithelial atypia, have been proposed in distinguishing between KAs/reactive squamous proliferations and welldifferentiated SCCs on the other side.In spite of these suggested criteria, differentiating the two histologically continues to be a challenge due to shared silhouette, cytology, and architectural growth patterns. 13A study conducted by Criber et al. examining pathology features of 296 KA and SCC found that the criteria historically used to differentiate these lesions is unreliable. 12hey observed that the 5 most useful criteria in distinguishing between KAs (epithelial lip, sharp outline between tumor and stroma) and SCCs (ulceration within the tumor, numerous mitoses, marked pleomorphism) did not significantly increase the sensitivity and specificity of a histological diagnosis.While recent studies have shown potential in differentiating SCCs from KAs using apoptotic and cell adhesion markers, further research is necessary before such techniques can be implemented into clinical practice. 14e biopsy method has also been observed to affect the diagnosis of KA versus SCC.According to Popkin et al., biopsy specimens obtained via shave, partial punch, or piececut provide inadequate tissue for a pathologist to examine when suspecting a diagnosis of KA. 15 The downfall to these methods is the inability to consistently obtain the base or overall architectural silhouette of the lesion.This increases the possibilities of overlooking a more aggressive and invasive growth pattern.Therefore, a fusiform sample obtained via scalpel excision is regarded as the recommended technique when suspecting KA.As the majority of our patient's biopsies were obtained via shave and saucerization, we question the degree to which KAs may have been misdiagnosed as SCCs.As a result, individuals like our patient presenting with GEKA/ESA overlap features may have biopsy reports indicating both KAs and well-differentiated SCCs. 5,8 ariety of systemic and topical agents have been explored in the treatment of GEKA and ESA, but none are considered to be satisfactory.16 For singular KAs, treatment via surgical excision or other physical modalities including cryotherapy, laser ablation, and curettage have been well described.Topical agents such as 5-fluorouracil, tretinoin, imiquimod, bleomycin, and methotrexate have also been utilized.However, some of these methods pose challenging to use in GEKA and ESA due to the diffuse nature of lesions in these patients.Therefore, systemic therapy represents the most practical approach in management of GEKA and ESA.9,17 Oral retinoids such as isotretinoin and acitretin are proposed as first-line agents, although response to these medications is variable.Our patient responded well to a three-month trial of 25 mg Acitretin, where her lesions decreased in size and no new lesions were noted.However, the response to systemic retinoids in GEKA and ESA patients is incredibly variable; some patients experience minimal or no improvement following treatment. 18Because our patient became non-adherent to systemic retinoids due to side effects, treatment with intralesional triamcinolone acetonide and weekly application of an Unna boot combined with topical 5-fluorouracil cream until achieving treatment goal were discussed.Sanders et al. reported a case in which treatment with intralesional triamcinolone acetonide in a GEKA patient resulted in complete clearance of lesions and minimal scarring within 2-4 weeks.19 Compared to intralesional methotrexate and 5-fluorouracil, which are both commonly used in practice, intralesional triamcinolone acetonide holds the benefit of immediately reducing inflammation and itching in the patient.
Advocates of intralesional triamcinolone acetonide believe eruptive KAs are reactive in nature and due to low-grade cutaneous injury or inflammation. 20Supplemental weekly treatment with topical 5-fluorouracil wrapped with an Unna boot has also shown to be effective for inducing KA regression. 20,21 se of an Unna boot containing zinc oxide further reduces inflammation, promotes healing, and provides a physical barrier to prevent further trauma inflicted by the patient scratching intensely itchy lesions and thereby potentially perpetuating lesions or contributing to reactive changes such as prurigo nodules and reactive squamous hyperplasia. 20is case describes a 59-year-old female with generalized KAs, prurigo nodules, and well-differentiated SCCs on her extremities, demonstrating characteristic features of GEKA and ESA.Because KAs and welldifferentiated SCCs have similar clinical and histologic features, it is often a challenge to diagnostically distinguish the two.While three months of oral Acitretin therapy was mildly effective in our patient, adherence to treatment was inconsistent due to intolerable xerosis and worsening pruritus.Our treatment plan moving forward will include continued systemic therapy with Acitretin at a reduced dose of 12.5 mg daily, intralesional triamcinolone acetonide every four weeks, and weekly topical 5% fluorouracil covered by an Unna boot on one leg at a time for 4-6 weeks.With our patient's comorbidities of diabetes and chronic kidney disease, we plan to monitor complete blood count (CBC), renal function, blood glucose, and fasting lipid profile throughout treatment.

Figure 1 .
Figure 1.Lesions on the upper and lower extremities.