Diffuse plate-like sheets of desquamation

Abstract

A 69-year-old woman with a history of relapsed acute lymphocytic leukemia presented for evaluation of a diffuse, asymptomatic scaly rash appearing 15 days after initiating inotuzumab ozogamicin 0.5 mg/m2 infusions and ponatinib 45 mg daily, which were started 2 months previously. Review of systems, including pruritus and flu-like symptoms, was negative. The patient received prednisone 20 mg daily and triamcinolone 1% topical treatment without improvement of the rash. The rash only improved upon cessation of ponatinib, while inotuzumab ozogamicin was continued. Examination revealed thick plate-like sheets of desquamation to the scalp, upper portion of the chest, dorsal aspect of the forearms, and distal parts of both legs (Fig 1). Punch biopsies of the upper portion of the chest and lateral aspect of the shin were performed (Figs 2 and 3).Fig 2View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 3View Large Image Figure ViewerDownload Hi-res image Download (PPT) Question 1: Based on the clinical presentation and histopathologic findings, what is the most likely diagnosis?A.Acquired ichthyosisB.Pityriasis rotundaC.Eczema craquelé (asteatotic eczema)D.Progressive symmetric erythrokeratoderma (PSEK)E.Atopic dermatitis Answers:A.Acquired ichthyosis – Correct. This is a drug-induced acquired ichthyosis secondary to ponatinib therapy. Acquired ichthyosis is a rare condition with onset in adulthood and can be associated with underlying malignancies, infections, inflammatory disorders, or medications. Ichthyotic scaling commonly presents on the trunks, limbs, and scalp. Scales can be white, brown, or gray and vary in size from 1 mm to 1 cm.1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Saunders/Elsevier, 2017Google Scholar, 2Alloo A. Sheu J. Butrynski J.E. et al.Ponatinib-induced pityriasiform, folliculocentric and ichthyosiform cutaneous toxicities.Br J Dermatol. 2015; 173: 574-577https://doi.org/10.1111/bjd.13692Google Scholar, 3Vastarella M. Fabbrocini G. Sibaud V. Hyperkeratotic skin adverse events induced by anticancer treatments: a comprehensive review.Drug Saf. 2020; 43: 395-408https://doi.org/10.1007/s40264-020-00907-6Google Scholar It has been reported that third-generation tyrosine kinase inhibitors, such as ponatinib, are associated with ichthyosiform eruptions.2Alloo A. Sheu J. Butrynski J.E. et al.Ponatinib-induced pityriasiform, folliculocentric and ichthyosiform cutaneous toxicities.Br J Dermatol. 2015; 173: 574-577https://doi.org/10.1111/bjd.13692Google Scholar, 3Vastarella M. Fabbrocini G. Sibaud V. Hyperkeratotic skin adverse events induced by anticancer treatments: a comprehensive review.Drug Saf. 2020; 43: 395-408https://doi.org/10.1007/s40264-020-00907-6Google Scholar, 4Eber A.E. Rosen A. Oberlin K.E. Giubellino A. Romanelli P. Ichthyosiform pityriasis rubra pilaris-like eruption secondary to ponatinib therapy: case report and literature review.Drug Saf Case Rep. 2017; 4: 19https://doi.org/10.1007/s40800-017-0055-yGoogle Scholar Histopathology, which is nonspecific, may show compact ortho- and/or parakeratotic hyperkeratosis and inflammatory infiltrate in the papillary dermis. The granular layer may be absent (similar to ichthyosis vulgaris), normal, or thickened.1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Saunders/Elsevier, 2017Google Scholar, 2Alloo A. Sheu J. Butrynski J.E. et al.Ponatinib-induced pityriasiform, folliculocentric and ichthyosiform cutaneous toxicities.Br J Dermatol. 2015; 173: 574-577https://doi.org/10.1111/bjd.13692Google Scholar, 3Vastarella M. Fabbrocini G. Sibaud V. Hyperkeratotic skin adverse events induced by anticancer treatments: a comprehensive review.Drug Saf. 2020; 43: 395-408https://doi.org/10.1007/s40264-020-00907-6Google ScholarB.Pityriasis rotunda – Incorrect. Pityriasis rotunda is characterized by hypopigmented or hyperpigmened, well-demarcated, scaly, round patches or thick plaques, often 10 cm in size. Microscopic features resemble ichthyosis vulgaris with a diminished granular cell layer along with hyperkeratosis and no parakeratosis.1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Saunders/Elsevier, 2017Google ScholarC.Eczema craquelé (asteatotic eczema) – Incorrect. Xerosis is the predisposing factor for eczema craquelé and has an indolent course over years. Eczema craquelé is characterized by pruritic skin with fine scale and interconnected fissures.1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Saunders/Elsevier, 2017Google ScholarD.PSEK – Incorrect. Also known as Darier-Gottron syndrome, PSEK presents during infancy, extending into puberty but rarely into adulthood. PSEK is characterized by symmetric, well-demarcated, fixed, erythematous, hyperkeratotic plaques involving the cheeks, the extensor surfaces of the upper and lower extremities, and the buttocks. Histopathology demonstrates acanthosis, basket-weave and patchy parakeratotic hyperkeratosis, and a prominent granular layer.1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Saunders/Elsevier, 2017Google ScholarE.Atopic dermatitis – Incorrect. Atopic dermatitis is a relapsing, pruritic condition commonly affecting infants and children. It is characterized by scaly, erythematous papules and plaques involving flexural areas with lichenification in chronic cases.1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Saunders/Elsevier, 2017Google Scholar Question 2: Which of the following eruptions is not a cutaneous adverse reaction associated with ponatinib therapy?A.Pityriasis rubra pilaris-likeB.SeborrheicC.Lichen planopilaris-likeD.FolliculocentricE.Psoriasiform Answers:A.Pityriasis rubra pilaris-like – Incorrect. Reported pityriasis rubra pilaris-like cases describe asymptomatic, red-orange papules coalescing to plaques with islands of sparing progressively developing over 2 to 12 weeks after ponatinib initiation.2Alloo A. Sheu J. Butrynski J.E. et al.Ponatinib-induced pityriasiform, folliculocentric and ichthyosiform cutaneous toxicities.Br J Dermatol. 2015; 173: 574-577https://doi.org/10.1111/bjd.13692Google Scholar, 3Vastarella M. Fabbrocini G. Sibaud V. Hyperkeratotic skin adverse events induced by anticancer treatments: a comprehensive review.Drug Saf. 2020; 43: 395-408https://doi.org/10.1007/s40264-020-00907-6Google Scholar, 4Eber A.E. Rosen A. Oberlin K.E. Giubellino A. Romanelli P. Ichthyosiform pityriasis rubra pilaris-like eruption secondary to ponatinib therapy: case report and literature review.Drug Saf Case Rep. 2017; 4: 19https://doi.org/10.1007/s40800-017-0055-yGoogle ScholarB.Seborrheic – Incorrect. A case of ponatinib-induced seborrheic eruption has been reported presenting with follicular prominence with hyperkeratotic spicules over the beard area and eyebrows with lateral eyebrow alopecia 10 days after drug initiation.2Alloo A. Sheu J. Butrynski J.E. et al.Ponatinib-induced pityriasiform, folliculocentric and ichthyosiform cutaneous toxicities.Br J Dermatol. 2015; 173: 574-577https://doi.org/10.1111/bjd.13692Google ScholarC.Lichen planopilaris-like – Incorrect. Few cases of lichen planopilaris-like eruptions associated with ponatinib have been reported. These have been characterized by follicular erythematous papules with perifollicular scale and loss of hair follicles along the scalp. Additionally, erythematous papules of the eyebrows with nonscarring alopecia were present.5Patel A.B. Solomon A.R. Mauro M.J. Ehst B.D. Unique cutaneous reaction to second- and third-generation tyrosine kinase inhibitors for chronic myeloid leukemia.Dermatology. 2016; 232: 122-125https://doi.org/10.1159/000437383Google ScholarD.Folliculocentric – Incorrect. There are reported cases of ponatinib causing a folliculocentric eruption presenting as asymptomatic perifollicular erythema with prominent follicular hyperkeratotic spicules and dyskeratosis over the chest and abdomen.2Alloo A. Sheu J. Butrynski J.E. et al.Ponatinib-induced pityriasiform, folliculocentric and ichthyosiform cutaneous toxicities.Br J Dermatol. 2015; 173: 574-577https://doi.org/10.1111/bjd.13692Google ScholarE.Psoriasiform – Correct. BCR-ABL inhibitors, including imatinib and nilotinib, angiogenesis inhibitors, immune checkpoint inhibitors, and anti-CD20 monoclonal antibodies are anticancer therapies associated with psoriasis hyperkeratotic reactions. There are no reports thus far of ponatinib causing psoriasiform eruptions.3Vastarella M. Fabbrocini G. Sibaud V. Hyperkeratotic skin adverse events induced by anticancer treatments: a comprehensive review.Drug Saf. 2020; 43: 395-408https://doi.org/10.1007/s40264-020-00907-6Google Scholar Question 3: What is the reported appropriate next step in management for these refractory lesions?A.Topical retinoidB.Systemic retinoidC.Ammonium lactateD.Mycophenolate mofetilE.Urea Answers:A.Topical retinoid – Incorrect. Traditionally, topical retinoid therapy has been used as first-line agents along with topical steroids and anti-seborrheic agents in mild cases.2Alloo A. Sheu J. Butrynski J.E. et al.Ponatinib-induced pityriasiform, folliculocentric and ichthyosiform cutaneous toxicities.Br J Dermatol. 2015; 173: 574-577https://doi.org/10.1111/bjd.13692Google Scholar, 3Vastarella M. Fabbrocini G. Sibaud V. Hyperkeratotic skin adverse events induced by anticancer treatments: a comprehensive review.Drug Saf. 2020; 43: 395-408https://doi.org/10.1007/s40264-020-00907-6Google Scholar, 4Eber A.E. Rosen A. Oberlin K.E. Giubellino A. Romanelli P. Ichthyosiform pityriasis rubra pilaris-like eruption secondary to ponatinib therapy: case report and literature review.Drug Saf Case Rep. 2017; 4: 19https://doi.org/10.1007/s40800-017-0055-yGoogle ScholarB.Systemic retinoid – Correct. Refractory cases have been treated successfully with oral acitretin 10 mg daily. Systemic retinoids should be considered with caution, as liver enzyme abnormalities can occur. The mechanism behind retinoids as effective therapy is unknown. One proposed theory involves retinoids causing upregulation of heparin-binding epidermal growth factor-like growth factor leading to local chemotherapeutic resistance in keratinocytes. Another theory describes the role of retinoids in aiding to terminally differentiate epidermal cells leading to reduced uptake of chemotherapy within keratinocytes.2Alloo A. Sheu J. Butrynski J.E. et al.Ponatinib-induced pityriasiform, folliculocentric and ichthyosiform cutaneous toxicities.Br J Dermatol. 2015; 173: 574-577https://doi.org/10.1111/bjd.13692Google Scholar, 3Vastarella M. Fabbrocini G. Sibaud V. Hyperkeratotic skin adverse events induced by anticancer treatments: a comprehensive review.Drug Saf. 2020; 43: 395-408https://doi.org/10.1007/s40264-020-00907-6Google Scholar, 4Eber A.E. Rosen A. Oberlin K.E. Giubellino A. Romanelli P. Ichthyosiform pityriasis rubra pilaris-like eruption secondary to ponatinib therapy: case report and literature review.Drug Saf Case Rep. 2017; 4: 19https://doi.org/10.1007/s40800-017-0055-yGoogle ScholarC.Ammonium lactate – Incorrect. Ammonium lactate is not used for severe, refractory cases. It has previously been used for mild-to-moderate hyperkeratotic lesions secondary to ponatinib.2Alloo A. Sheu J. Butrynski J.E. et al.Ponatinib-induced pityriasiform, folliculocentric and ichthyosiform cutaneous toxicities.Br J Dermatol. 2015; 173: 574-577https://doi.org/10.1111/bjd.13692Google ScholarD.Mycophenolate mofetil – Incorrect. Mycophenolate mofetil can be considered as a steroid-sparing agent for psoriasiform and erythrodermic eruptions secondary to tyrosine kinase inhibitors; however, it is contraindicated in the setting of this patient’s leukemia.1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Saunders/Elsevier, 2017Google ScholarE.Urea – Incorrect. Keratolytics, such as urea, have been used as initial therapy for mild-to-moderate ponatinib-induced rashes alongside high-potency topical steroids. Urea has not been used as a first-line agent in severe, refractory cases.3Vastarella M. Fabbrocini G. Sibaud V. Hyperkeratotic skin adverse events induced by anticancer treatments: a comprehensive review.Drug Saf. 2020; 43: 395-408https://doi.org/10.1007/s40264-020-00907-6Google Scholar None disclosed. The authors thank Dr Alun Wang and Dr Garrett Vick for providing the histology images for this manuscript.