Dilute Intralesional 5-Fluorouracil for the Treatment of Squamous Cell Carcinomas and Keratoacanthomas: A Case Series.

BACKGROUND: Intralesional 5-fluorouracil (5-FU) is a promising, yet sparsely studied alternative to surgical treatment for nonmelanoma skin cancer (NMSC).1 Previous studies of intralesional 5-FU have reported concentrations ranging from 30 to 50 mg/mL. To the best of our knowledge, this case series represents the first reported use of intralesional 5-FU 10.0 mg/mL and 16.7 mg/mL for NMSC. METHODS: A retrospective chart review identified 11 patients who received intralesional 5-FU 10.0 mg/mL and 16.7 mg/mL for 40 cutaneous squamous cell carcinomas and 10 keratoacanthomas. We describe the characteristics of these patients and calculate the clinical clearance rate of dilute intralesional 5-FU therapy for NMSC at our institution. RESULTS: Dilute intralesional 5-FU successfully treated 96% (48/50) of the study lesions, providing complete clinical clearance in 82% (9/11) of patients across a mean follow-up time of 21.7 months. All patients tolerated their treatments well with no reported adverse effects or local recurrences. DISCUSSION: The use of more dilute preparations of intralesional 5-FU for NMSC may be a means of reducing cumulative dose and dose-dependent adverse reactions while maintaining clinical clearance. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.5058.

To treat or not to treat: PD-L1 inhibitor-induced keratoacanthoma and squamous cell carcinoma.

Keratoacanthoma (KA) and squamous cell carcinoma (SCC) are rare side effects of programmed cell death ligand-1 (PD-L1) inhibitors that can disrupt therapy. There is no consensus on optimal treatment. We investigated the management strategy and factors influencing pathophysiology. An institutional cancer registry and literature search were used for this retrospective study. Only PD-L1-induced KA and SCC cases were included. Pathology specimens were stained with immune markers and management strategies were analyzed. Four cases were identified at our institution. Immunohistochemistry of atypical keratinocytes revealed PD-1/PD-L1 positivity, high p53, and low bcl-2 for all cases with differential expression of CD44 and beta-catenin for KA versus SCC. Nivolumab was continued or temporarily held with complete resolution. In addition, a literature search identified 30 additional cases of KA/SCC after PDL-1 inhibitor use. The most common treatment was excision/destruction followed by topical and/or intralesional corticosteroids. Therapy was definitely withheld in 22% of KA patients and in 9% of SCC cases. The expression of PD-L1 by atypical keratinocytes helps to explain the effects of nivolumab on the development of cutaneous neoplasms. The expression of immune markers provides mechanistic insights into pathophysiology. Management may be achieved with conservative therapy and without treatment interruption.

Eruptive keratoacanthomas associated with dupilumab therapy.

We would like to present the case of eruptive keratoacanthomas associated with dupilumab therapy, which occurred in an 85-year-old woman receiving biologic therapy for the treatment of atopic dermatitis. With the increasing prevalence of Dupilumab usage, this is an important potential complication of which clinicians should be aware.

Sorafenib-related generalized eruptive keratoacanthomas (Grzybowski syndrome): a case report.

BACKGROUND: Sorafenib is an oral multikinase inhibitor that targets Raf serine/threonine receptor tyrosine kinases and inhibits tumor cell growth and angiogenesis. Cutaneous toxicities of sorafenib are common, including cutaneous eruptions (such as truncal erythema and seborrheic-dermatitis-like changes) and hand-foot syndrome. Keratoacanthomas and squamous cell carcinomas have been reported previously; however, we report a case of multiple eruptive keratoacanthomas in the form of Grzybowski syndrome after initiation of sorafenib. CASE PRESENTATION: We report a 63-year-old Caucasian male who developed multiple cutaneous eruptive keratoacanthomas after starting sorafenib 400 mg twice daily. He had a known history of hepatitis-C-related cirrhosis and hepatocellular carcinoma, and previously had actinic keratosis and skin squamous cell carcinoma excision. Approximately two and a half months after starting sorafenib, the patient initially developed two lesions, one on each forearm, and after excision, these lesions demonstrated histological features of squamous cell carcinoma. One month later, the patient presented with approximately 48 new skin lesions of varying size on the back, bilateral upper limbs, and face requiring excisional biopsy of a large number of these lesions. Histopathology showed eruptive invasive keratoacanthomas (Grzybowski syndrome). Sorafenib was temporarily stopped and subsequently restarted at a lower dose. Acitretin 25 mg daily was commenced after few weeks, and no further keratoacanthomas developed during his treatment. CONCLUSIONS: We report a unique case of sorafenib-associated Grzybowski syndrome. Temporary interruption and dose reduction of sorafenib and use of acitretin appeared to prevent further development of keratoacanthomas.

A case of new-onset vitiligo in a patient on tofacitinib and brief review of paradoxical presentations with other novel targeted therapies.

With recent advancements in the understanding of vitiligo pathogenesis, Janus kinase (JAK) inhibitors have emerged as a promising new treatment modality, but their effects remain incompletely elucidated. Tofacitinib, an oral JAK 1/3 inhibitor approved for the treatment of rheumatoid arthritis, has previously been shown to induce significant re-pigmentation in vitiligo. However, as with other novel targeted therapies, cutaneous adverse effects have been observed. We report a 36-year-old woman with a history of rheumatoid arthritis, refractory to multiple pharmacotherapies, who was initiated on tofacitinib and subsequently developed progressive depigmented patches consistent with new-onset vitiligo. Although definitive causation cannot be established in this case without additional studies, it is important to note that many targeted therapies have the potential to induce paradoxical effects, that is, the occurrence or exacerbation of pathologic conditions that have been shown to respond to these medications. Paradoxical findings with other targeted therapies include the occurrence of melanoma during treatment with BRAF inhibitors, keratoacanthomas with PD-1 inhibitors, vitiligo and psoriasis with TNF-alpha inhibitors, and hidradenitis suppurativa with various biologic agents. Although JAK inhibitors hold therapeutic promise in the treatment of inflammatory skin disorders, further research is warranted to more fully comprehend their effects.

Systematic review and meta-analysis of prevalence of dermatological toxicities associated with vemurafenib treatment in patients with melanoma.

BACKGROUND: Vemurafenib has been linked to dermatological adverse events in patients with melanoma, including an increased risk of rash, cutaneous squamous cell carcinoma, photosensitivity reaction and keratoacanthoma. However, there has been no systematic attempt to assess the dermatological toxicity data of vemurafenib associated with melanoma treatment. AIM: To evaluate the point prevalence of dermatological toxicities associated with vemurafenib treatment in patients with melanoma. METHODS: Searches were conducted of the electronic databases PubMed and EMBASE and of conference abstracts published by the American Society of Clinical Oncology. Eligible studies included prospective clinical trials and expanded-access programmes (i.e. outside a clinical trial) of patients with melanoma assigned to vemurafenib treatment. Outcomes included prevalence of dermatological toxicities treated with vemurafenib. Statistical analyses were performed using the R2.8.1 meta package. RESULTS: In total, 11 studies comprising 4197 patients were included in the meta-analysis. For patients assigned to vemurafenib, the overall prevalence of all-grade cutaneous squamous cell carcinoma (cSCC) was 18.00% (95% CI 12.00-26.00%), rash 45.00% (95% CI 34.00-57.00%), photosensitivity reaction (PR) 30.00% (95% CI 23.00-38.00%), keratoacanthoma (KA) 10.00% (95% CI 6.00-15.00%) and hand-foot skin reaction (HFSR) 9.00% (95% CI 4.00-20.00%), while the prevalence of high-grade events was: cSCC 16.00% (95% CI 11.00-23.00%), rash 12.00% (95% CI 3.00-38.00%), PR 4% (95% CI 2.00-8.00%) and KA 6.00% (95% CI 5.00-7.00%). CONCLUSION: The most frequent dermatological toxicities associated with vemurafenib treatment in patients with melanoma were cSCC, rash, PR and KA. These data may be useful for estimation of the efficacy and safety of the drug during clinical treatment and for reducing the prevalence of adverse reactions to vemurafenib treatment in patients with melanoma.

Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

BACKGROUND: Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC-III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAFV600 mutation-positive melanoma. METHODS: BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC-IIIA-IIIB (cohort 1) or stage IIIC (cohort 2) BRAFV600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419. FINDINGS: The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9-41·6) in cohort 2 and 30·8 months (25·5-40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6-26·5) in the vemurafenib group versus 15·4 months (11·1-35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54-1·18; log-rank p=0·26). In cohort 1 (patients with stage IIC-IIIA-IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4-not estimable) in the placebo group (HR 0·54 [95% CI 0·37-0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3-4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3-4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3-4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. INTERPRETATION: The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC-IIIA-IIIB BRAFV600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population. FUNDING: F Hoffman-La Roche Ltd.

[Keratoacanthomas on recent tattoos: Two cases]. / Kératoacanthomes sur tatouages récents : deux cas.

BACKGROUND: Increasing numbers of reports of rapidly arising, isolated or eruptive keratoacanthomas (KA) and squamous cell carcinomas (CSC) on the red part of tattoos tend to suggest a non-fortuitous link with the procedure. We report herein two different presentations of KAs on tattoos: one patient with multiple eruptive KAs on sun-exposed areas of a recent red tattoo and another with a solitary lesion on a recent tattoo. We discuss the issues related to the distinction between KAs and CSCs in this particular context. PATIENTS AND METHODS: Case No. 1: A 55-year-old heavily tattooed man presented multiple round keratotic verrucous-like lesions restricted to a red tattoo. The tattoo had been performed by a professional tattooist in summer 2016, a week before the onset of the symptoms. The patient did not protect a part of his tattoo from sun-exposure during the healing phase and lesions developed only on the sun-exposed tattooed parts. In January 2017, he consulted with about ten lesions. The histologic study by shaving of a lesion militated in favor of a CSC, KA type. The physical examination was unremarkable. He had no previous history of skin cancer. Two weeks later, most of the lesions regressed spontaneously. Based on the clinical history and progression of the lesions, a diagnosis was made of eruptive KA on a red tattoo. Residual lesions were treated by cryotherapy or excision. Case No. 2: A 72-year-old woman developed a 1-cm painful dome-shaped nodule with a central crust three weeks after tattooing. Full excision confirmed the diagnosis of KA. DISCUSSION: To date, we have found 31 case reports and series (17 men, median age: 50.5 years) of KA and CSC on tattoos. Lesions usually develop rapidly after completion of the tattoo, after between one week and several months. Exceptional cases have been described in old tattoos. Red tattoo ink is most commonly the culprit. The main difficulty lies in distinguishing between KA and CSC. Nowadays pathologists agree that a KA should be considered as a variant of CSC. Eruptive forms of KA present a peculiar situation. They may sometimes be inherited, and KA on recent traumatized areas or drug-induced have been described. Like other authors, we believe that cases of CSC on red tattoos belong rather to the KA type. The physiopathogenesis of tattoo-associated eruptive KA and CSC is not clearly understood, but could be multifactorial, involving: the trauma induced by tattooing, local inflammatory reaction, a component of the red ink, external factors such UV exposure, and a possible genetic predisposition. Rapidly arising KA and eruptive KA on top of recent (red) tattoos are not fortuitous. The lesions should be excised and the patient monitored. Additional studies on tumor specimens are warranted to identify the possible causative agents in tattoo ink that may be responsible for such reactions.

Case Report of Multiple Keratoacanthomas and Squamous Cell Carcinomas in a Patient Receiving Pembrolizumab.

PD-1 is expressed on antigen-stimulated T cells and induces a downstream signaling pathway that works by negative feedback to inhibit T cell proliferation, cytokine release, and cytotoxicity. PD-1 antibodies increase tumor cell killing peripherally and have a role in advanced melanoma treatment. We describe a case of an 84 year old female with stage 4 metastatic melanoma in a trial of the PD-1 inhibitor pembrolizumab who developed multiple keratoacanthomas after several months of treatment. While keratoacanthomas have been reported in patients taking BRAF inhibitors, no such reports exist for those on pembrolizumab, making this the first case report to point out this association for further investigative studies.

J Drugs Dermatol. 2017;16(5):513-515.

Eruptive Keratoacanthomas Associated With Pembrolizumab Therapy.

Importance: To our knowledge, there have been no previous reports of eruptive keratoacanthomas (KAs) in patients receiving pembrolizumab. Objective: To report the cases of 3 consecutive patients with pembrolizumab-induced eruptive KAs and their management. Design, Setting, and Participants: Case report study of 3 patients from 2 centers with pembrolizumab-treated cancer who all developed eruptive KAs. Interventions: All 3 patients had AK treatment with clobetasol ointment and intralesional triamcinolone; 2 patients also underwent open superficial cryosurgery. Results: Three consecutive patients with cancer, 2 men and 1 woman (median age, 83 years; range 77-91 years), experienced pembrolizumab-associated eruptive KAs. All patients presented with a sudden onset of multiple lesions on sun-exposed areas of their extremities after a median of 13 months (range, 4-18 months) of pembrolizumab therapy. On lesional biopsy, a lichenoid infiltrate was observed in the underlying dermis, predominantly composed of CD3+ T cells, scattered CD20+ B cells, and relatively few PD-1+ (programmed cell death 1-positive) T cells, an immunophenotypic pattern also observed in other cases of anti-PD-1-induced lichenoid dermatitis. Patients were treated with clobetasol ointment and intralesional triamcinolone, alone or in combination with open superficial cryosurgery. All KAs resolved in all patients, and no new lesions occurred during close follow-up. Pembrolizumab treatment was continued without disruption in all 3 cases, and all patients had complete responses of their primary cancers. Conclusions and Relevance: Pembrolizumab is used in advanced melanoma, advanced non-small-cell lung cancer, and in head and neck cancer. A variety of dermatologic immune-related adverse events including maculopapular eruption, lichenoid reactions, pruritus, and vitiligo have been described. This case series demonstrates that pembrolizumab therapy may also be associated with eruptive KAs with characteristic dermal inflammation, which improved with corticosteroid treatment (topical and intralesional) alone or in combination with cryosurgery, allowing patients to continue therapy with pembrolizumab.