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March 25, 2020

Treatment of PD-1/PD-L1 Inhibitor–Induced Dermatitis Resolves Concomitant Eruptive Keratoacanthomas

Author Affiliations
  • 1Department of Dermatology, University of California, San Francisco
  • 2Department of Pathology and Laboratory Medicine, University of Colorado School of Medicine, Aurora
  • 3Helen Diller Cancer Center, Department of Pathology and Dermatology, University of California, San Francisco
JAMA Dermatol. Published online March 25, 2020. doi:10.1001/jamadermatol.2020.0176

Patients who develop eruptive keratoacanthomas (KAs) in the setting of PD-1/PD-L1 inhibitor–induced dermatitis are challenging to treat and discontinue immunotherapy at a much higher rate than those without KAs.1-4 We successfully used 3 different nonsurgical anti-inflammatory therapies to treat both immunotherapy-induced dermatitis and concomitant eruptive KAs.

Report of Cases

Patient 1 (Figure 1), a man with metastatic melanoma, and patient 2, a woman with metastatic mesothelioma, both in their 70s, developed severely pruritic violaceous plaques on the trunk and extremities shortly after the initiation of pembrolizumab immunotherapy. In addition to this lichenoid dermatitis, they concomitantly developed numerous scaly papules, plaques, and crateriform nodules on the extremities. We considered a diagnosis of hypertrophic lichen planus; however, the biopsy specimens in these cases showed either a crateriform configuration or contiguous cup-shaped invaginations in the epidermal surface consistent with KAs and not seen in hypertrophic lichen planus. Both patients stopped immunotherapy because of cutaneous adverse reactions. Within 2 months of starting treatment with hydroxychloroquine, patient 1 had drastic improvement in the dermatitis, pruritus, and KAs. The hydroxychloroquine treatment was discontinued after 2 years, and the patient remains melanoma-free without further cancer treatment. Patient 2 improved considerably after 7 treatments at a day-care outpatient center with the Goeckerman regimen.5 The few remaining KAs resolved with the at-home application of clobetasol ointment and in-office administration of intralesional triamcinolone (20 mg/mL) to the 6 largest lesions on the legs. At last follow-up she was being treated with traditional chemotherapy, bevacizumab, and radiotherapy for progressive metastatic mesothelioma.

Figure 1.  Patient 1: Clinical and Histopathologic Features
Patient 1: Clinical and Histopathologic Features

A, Dermatitic plaque studded with eruptive keratoacanthomas (KAs). A large plaque of lichenoid dermatitis (black star) studded with KAs (white arrows) on the left lower extremity. B, Improvement with hydroxychloroquine. Same plaque as in part A, 2 months after the initiation of hydroxychloroquine (at a dosage of 3.75-5.0 mg/kg/d), demonstrating resolution of KAs (white arrows) and improvement in dermatitis (black star). C, Shave biopsy specimen from a papulonodule of a KA showing a proliferation of keratinocytes with abundant pale, glassy-appearing cytoplasm and monomorphous nuclei arranged in lobules that radiate from a keratin-filled crater. There is a subjacent infiltrate of lymphocytes, neutrophils, and eosinophils (hematoxylin-eosin; original magnification ×20). D, Lichenoid and interface dermatitis. Punch biopsy specimen from the dermatitic area on the chest showing a bandlike lymphocytic infiltrate in the papillary dermis with vacuolar change, single necrotic keratinocytes along the dermal-epidermal junction, and collections of them in the mid and upper spinous layers (hematoxylin-eosin; original magnification ×200).

Patient 3 (Figure 2), a man in his 60s who was receiving nivolumab for metastatic lung adenocarcinoma, presented with pruritic, ill-defined scaly plaques on the trunk and extremities that were shown histopathologically to be spongiotic dermatitis, and numerous verrucous papules on the legs that were biopsy-proven KAs. He was treated in the wound care clinic because he was unable to apply topical therapy. Most KAs resolved after initial weekly changes of antibacterial wound dressing (Hydrofera Blue, Hydrofera, LLC), conforming stretch bandages (Conform, Kendall), and thromboembolism deterrent (TED) hose (Medtronic), followed by a transition to weekly occlusion and compression therapy with zinc oxide (Unna boots). The pruritus and KAs recurred when the Unna boots were temporarily discontinued for the right leg. After 1 year of Unna boot therapy, the patient continued to receive nivolumab treatment, and his metastatic disease was stable.

Figure 2.  Patient 3: Clinical and Histopathologic Features
Patient 3: Clinical and Histopathologic Features

A, Keratoacanthomas (KAs) on a background of eczematous and stasis dermatitis. Verrucous nodules (white arrows) represent multiple KAs after discontinuation of Unna boot therapy for the right leg. B, Improvement with Unna boot therapy. One residual KA (white arrow) on the left leg with ongoing Unna boot therapy. C, Involuting KA. Shave biopsy specimen of a verrucous papule from the left medial leg showing contiguous cup-shaped invaginations of the epidermal surface. These contain lamellar hyperkeratosis and are lined by a thin layer of mature-appearing squamous keratinocytes with subjacent fibrosis, consistent with an involuting KA (hematoxylin-eosin; original magnification ×20). D, Spongiotic dermatitis. Punch biopsy specimen from a scaly plaque on the trunk demonstrating spongiotic dermatitis (hematoxylin-eosin; original magnification ×100).

Discussion

We describe the successful use of anti-inflammatory therapies, including hydroxychloroquine (an immunomodulatory medication), the Goeckerman regimen (combination of steroids-under-occlusion “cool-down,” UV-B phototherapy, and crude coal tar),5 and Unna boots (zinc oxide occlusion and compression bandages), to treat both dermatitis and KAs in patients receiving anti–PD-1/PD-L1 immunotherapy. Other clinicians have reported successful treatment of both with doxycycline and niacinamide2 as well as topical, intralesional, and oral corticosteroids.2,3 This suggests that inflammation unleashed by PD-1/PD-L1 inhibition is the driver of both the dermatitis and the KAs. Treating the underlying inflammation resolves the eruptive KAs, perhaps by removing the stimulus for their growth and allowing them to involute.

Although most cases of eruptive KAs in patients receiving immunotherapy have been reported in the setting of lichenoid dermatitis, eruptive KAs have also been reported with bullous and psoriasiform eruptions2,4 and, in 1 of the present patients, with spongiotic dermatitis. We hypothesize that the initial trigger for eruptive KAs is the damage to the dermal-epidermal junction as a consequence of lichenoid or bullous eruptions. In cases of pruritic eruptions that do not involve the dermal-epidermal junction, such as spongiotic or psoriasiform dermatitis, the inciting event could be trauma from scratching. This explains why eruptive KAs develop in patients with chronic pruritus in the absence of dermatitis,6 as well as the efficacy of Unna boots in their resolution.7

We propose that eruptive KAs represent reactive reversible hyperplasia, rather than neoplasia, on the basis of 3 observations: (1) They present on a spectrum ranging from scaly lichenified papules to well-formed crateriform nodules; (2) they exhibit minimal cytologic atypia compared with that observed in most solitary, actinically driven KAs; and (3) they resolve with treatment of the underlying dermatitis. These findings encourage the use of nonsurgical anti-inflammatory therapies for eruptive KAs.

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Article Information

Corresponding Author: Rita Khodosh, MD, PhD, Department of Dermatology, University of California, San Francisco, 1701 Divisadero St, PO Box 0316, San Francisco, CA 94143 (rita.khodosh@ucsf.edu).

Published Online: March 25, 2020. doi:10.1001/jamadermatol.2020.0176

Conflict of Interest Disclosures: Dr Crow is an investigator for clinical trials sponsored by Castle Biosciences, Leo Pharma, Sun Pharma, Pfizer, PellePharm, and Eli Lilly and Company. Dr Fassett reports receiving personal and consulting fees from Regeneron and personal fees from Sanofi. Dr Berger is an investigator for clinical trials sponsored by Kiniksa and Trevi. No other conflict of interest disclosures were reported.

Additional Contributions: We thank the patients for granting permission to publish this information.

References
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Gupta  R, Debbaneh  M, Butler  D,  et al.  The Goeckerman regimen for the treatment of moderate to severe psoriasis.  J Vis Exp. 2013;July 11(77):e50509. doi:10.3791/50509PubMedGoogle Scholar
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Wu  TP, Miller  K, Cohen  DE, Stein  JA.  Keratoacanthomas arising in association with prurigo nodules in pruritic, actinically damaged skin.  J Am Acad Dermatol. 2013;69(3):426-430. doi:10.1016/j.jaad.2013.03.035PubMedGoogle ScholarCrossref
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