Postherpes zoster programmed death-1 inhibitor−associated zosteriform granulomatous reactions

Abstract

Immune checkpoint inhibitors (ICPIs) that inhibit programmed death-1 (PD-1) or its target receptor have side effect profiles consisting of “immune-related adverse events,” which include varied cutaneous reactions. Although eczematous and lichenoid reactions are most common, granulomatous reactions have also been reported.1Cornejo C.M. Haun P. English 3rd, J. Rosenbach M. Immune checkpoint inhibitors and the development of granulomatous reactions.J Am Acad Dermatol. 2019; 81: 1165-1175Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar We report 2 cases of patients who developed granulomatous reactions in the distribution of a previous herpes zoster eruption while receiving treatment with pembrolizumab, which is a unique manifestation of Wolf postherpetic isotopic response in the immunotherapy setting. A woman in her 50s, previously treated with chemotherapy for metastatic triple-negative inflammatory breast cancer, presented with a pruritic papular eruption along the C7-C8 dermatome of her upper right arm (Fig 1). Six months earlier, the patient developed herpes zoster involving the same dermatome and received valacyclovir with resolution of the cutaneous reaction; however, she experienced persistent postherpetic neuralgia. Four weeks before the onset of eruption, carboplatin chemotherapy was replaced with pembrolizumab monotherapy. After cycle 1, the patient developed pembrolizumab-induced thyroiditis, and after cycle 2, she developed mauve, grouped, polygonal, and flat-topped papules extending from the upper right side of her back to the ulnar aspect of her hand without vesicles, scaling, or nail involvement. A punch biopsy was performed, which revealed necrotizing granulomatous dermatitis (GD) and a mixed perivascular inflammatory infiltrate with mucin, consistent with the findings of granuloma annulare (GA) (Fig 2, A). The distribution of her rash suggested Wolf postherpetic isotopic response in the setting of a pembrolizumab-induced granulomatous reaction. She was treated with triamcinolone cream. Her pembrolizumab immunotherapy was not interrupted, and she was maintained on acyclovir for prophylaxis.Fig 2A, Case 1 histopathology. The sections demonstrate an infiltrate comprising mononucleated cells and multinucleated histiocytes palisading around the areas of degenerated collagen and mucin. B, Case 2 histopathology. The sections demonstrate a loose nonpalisaded granulomatous infiltrate without degenerated collagen or increased mucin. (A and B, Hematoxylin-eosin stain; original magnifications: A, ×100; B, ×100.)View Large Image Figure ViewerDownload Hi-res image Download (PPT) A woman in her 80s having metastatic lung adenocarcinoma with elevated PD-1 ligand-1 expression and hyperthyroidism presented with clustered reddish brown 2-3-mm macules and thin papules involving the left side of her postauricular and preauricular skin, jawline, and posterior aspect of the neck with associated burning, which were persistent for 1 month. The patient developed herpes zoster involving the V3 and C3 dermatomes 1 month after the initiation of pembrolizumab. Then, about 6 months later, the patient presented to our clinic with a new cutaneous eruption, which started after cycle 10 of therapy. A punch biopsy revealed interstitial and focal nodular collections of histiocytes forming loose granulomas in the dermis, consistent with the findings of GD (Fig 2, B). Her history of herpes zoster in the same distribution suggested Wolf postherpetic isotopic response in the setting of pembrolizumab-induced GD. Her treatment included the application of topical corticosteroids to the affected region for 2-3 months, which resulted in improvement and flattening of lesions and initial resolution of pruritus. She was continued on pembrolizumab and experienced a recurrence of burning and pruritus along the neck and jawline, which was managed with intermittent application of triamcinolone cream and oral antipruritics. Reported granulomatous reactions to ICPIs are rare but include GA, GD, granulomatous panniculitis, and, most commonly, sarcoidosis-like reactions (Table 1) .1Cornejo C.M. Haun P. English 3rd, J. Rosenbach M. Immune checkpoint inhibitors and the development of granulomatous reactions.J Am Acad Dermatol. 2019; 81: 1165-1175Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar ICPI-induced GA manifests with the onset of lesions between 6 weeks and 8 months after initiating anti-PD-1 therapy. The eruptions appear with erythematous, annular plaques and pink papules, commonly localized to the dorsal arms and upper side of the back before spreading bilaterally to the legs.2Haselden V.N.V.R. Koon H. Gerstenblith M.R. Granuloma annulare in the setting of ipilimumab therapy.J Clin Exp Dermatol Res. 2015; 6: 1-2Google Scholar,3Wu J. Kwong B.Y. Martires K.J. et al.Granuloma annulare associated with immune checkpoint inhibitors.J Eur Acad Dermatol Venereol. 2018; 32: e124-e126Crossref PubMed Scopus (14) Google Scholar Histopathology revealed necrobiotic collagen and mucin surrounded by palisaded histiocytes and lymphocytes. Treatment with topical and oral steroids was found to be effective in all reported cases, with a definitive resolution of GA at the completion of PD-1 therapy.2Haselden V.N.V.R. Koon H. Gerstenblith M.R. Granuloma annulare in the setting of ipilimumab therapy.J Clin Exp Dermatol Res. 2015; 6: 1-2Google Scholar, 3Wu J. Kwong B.Y. Martires K.J. et al.Granuloma annulare associated with immune checkpoint inhibitors.J Eur Acad Dermatol Venereol. 2018; 32: e124-e126Crossref PubMed Scopus (14) Google Scholar, 4Fontecilla N.M. Kittler N.W. Lopez A. et al.Programmed cell death protein-1 inhibitor-induced granuloma annulare and hypertrophic lichen planus masquerading as squamous cell carcinoma.JAAD Case Rep. 2018; 4: 636-639Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar The eruptions appear with erythematous or violaceous coalescing papules and plaques involving the torso and extremities. Although the reported cases of ICPI-induced GD are mainly mild (grade 1, low body surface area involvement, and little to no impact on quality of life), a severe reaction (grade 3, >50% body surface area involvement, and impact on quality of life) has been reported.5Diaz-Perez J.A. Beveridge M.G. Victor T.A. Cibull T.L. Granulomatous and lichenoid dermatitis after IgG4 anti-PD-1 monoclonal antibody therapy for advanced cancer.J Cutan Pathol. 2018; 45: 434-438Crossref PubMed Scopus (12) Google Scholar Histopathology revealed dermal histiocytic infiltrate with sparing of the epidermis. Similar to that for GA, the mainstays of treatment are topical and oral steroids; however, several cases of GD did not resolve fully until an average period of 21 weeks after the cessation of immunotherapy.6Kubicki S.L. Welborn M.E. Garg N. et al.Granulomatous dermatitis associated with ipilimumab therapy.J Cutan Pathol. 2018; 45: 636-638Crossref PubMed Scopus (15) Google ScholarTable ISpectrum of granulomatous reactions associated with immune checkpoint inhibitor therapy1Cornejo C.M. Haun P. English 3rd, J. Rosenbach M. Immune checkpoint inhibitors and the development of granulomatous reactions.J Am Acad Dermatol. 2019; 81: 1165-1175Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar,4Fontecilla N.M. Kittler N.W. Lopez A. et al.Programmed cell death protein-1 inhibitor-induced granuloma annulare and hypertrophic lichen planus masquerading as squamous cell carcinoma.JAAD Case Rep. 2018; 4: 636-639Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar,7Martín-Carrasco P. Pérez-Ruiz C. de Zulueta-Dorado T. Conejo-Mir J. Postherpetic granulomatous dermatitis in a man treated with nivolumab.Actas Dermosifiliogr. 2017; 108: 783-784Crossref PubMed Scopus (6) Google Scholar,8Assi T. Danu A. Mateus C. et al.Post-shingles granulomatous dermatosis related to anti-programmed cell death 1.Immunotherapy. 2019; 11: 591-598Crossref PubMed Scopus (7) Google ScholarTime to symptoms∗Time ranges reported from first dose of immunotherapy.Morphological characteristicsClinical distributionsHistologic featuresTreatment strategiesAssociated immune-related adverse eventsCutaneous granulomatous reactions Sarcoidosis-like reactions (n = 59)†The summary of reactions is based on the data from previous case reports. The number of case reports included in each summary is indicated by “n” values.From 1 to 27 monthsAverage: 6.3 monthsSubcutaneous nodules or skin-colored papules and plaques, occasionally within tattoos or scarsFace, neck, and upper extremitiesNoncaseating granulomatous dermatitisSystemic steroidsPulmonary and ophthalmologic involvement, thyroiditis Granulomatous panniculitis (n = 4)From 5 weeks to 10 monthsAverage: 5.3 monthsTender subcutaneous nodulesLower extremitiesMixed septal and lobular granulomatous panniculitisTopical or systemic steroids or hydroxychloroquinePneumonitis, sarcoidosis-like reaction Granuloma annulare (n = 7)From 6 weeks to 8 monthsAverage: 4.3 monthsPink papules, annular plaquesExtremitiesNecrotizing and palisading granulomatous infiltrateTopical or systemic steroidsHypertrophic lichen planus, vitiligo Granulomatous dermatitis (n = 7)From 2 days to 5 yearsAverage: 3 weeksCoalescing papules and plaquesExtremities and trunkSuperficial, perivascular and interstitial granulomatous infiltrateTopical or systemic steroids or topical calcineurin inhibitorsAcneiform and morbilliform eruptions, generalized pruritus, hepatitis, and pancreatitisLess common cutaneous granulomatous reactions Granulomatous foreign body reactions (n = 1)4 weeksCoalescing pink papulesExtremities and trunkGranulomatous inflammatory response with lichenoid and perivascular distributionSystemic steroidsAdapted from Tables I and II reported by Cornejo et al.1Cornejo C.M. Haun P. English 3rd, J. Rosenbach M. Immune checkpoint inhibitors and the development of granulomatous reactions.J Am Acad Dermatol. 2019; 81: 1165-1175Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar∗ Time ranges reported from first dose of immunotherapy.† The summary of reactions is based on the data from previous case reports. The number of case reports included in each summary is indicated by “n” values. Open table in a new tab Adapted from Tables I and II reported by Cornejo et al.1Cornejo C.M. Haun P. English 3rd, J. Rosenbach M. Immune checkpoint inhibitors and the development of granulomatous reactions.J Am Acad Dermatol. 2019; 81: 1165-1175Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar ICPIs function by disrupting the immunologic response and can thus cause adverse reactions that are autoimmune or inflammatory in nature, such as granulomatous reactions. It is hypothesized that the blockade of PD-1 by pembrolizumab induces Th1 and Th17 immune-cell hyperactivity, causing granuloma formation.1Cornejo C.M. Haun P. English 3rd, J. Rosenbach M. Immune checkpoint inhibitors and the development of granulomatous reactions.J Am Acad Dermatol. 2019; 81: 1165-1175Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Previous studies have demonstrated that immunotherapy-induced GA and GD were less likely to be associated with systemic granulomatous disease; in contrast, systemic manifestations, including thyroiditis, are more likely to be associated with sarcoid-like reactions.1Cornejo C.M. Haun P. English 3rd, J. Rosenbach M. Immune checkpoint inhibitors and the development of granulomatous reactions.J Am Acad Dermatol. 2019; 81: 1165-1175Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Wolf postherpetic isotopic response manifests as the occurrence of an unrelated eruption at the exact site of a previous, resolved herpes zoster infection, and granulomatous infiltrate is commonly noted in this phenomenon.7Martín-Carrasco P. Pérez-Ruiz C. de Zulueta-Dorado T. Conejo-Mir J. Postherpetic granulomatous dermatitis in a man treated with nivolumab.Actas Dermosifiliogr. 2017; 108: 783-784Crossref PubMed Scopus (6) Google Scholar Two previous cases of ICPI-induced postherpetic granulomatous reactions have been reported, both in the context of nivolumab therapy.7Martín-Carrasco P. Pérez-Ruiz C. de Zulueta-Dorado T. Conejo-Mir J. Postherpetic granulomatous dermatitis in a man treated with nivolumab.Actas Dermosifiliogr. 2017; 108: 783-784Crossref PubMed Scopus (6) Google Scholar,8Assi T. Danu A. Mateus C. et al.Post-shingles granulomatous dermatosis related to anti-programmed cell death 1.Immunotherapy. 2019; 11: 591-598Crossref PubMed Scopus (7) Google Scholar The additional cases of GA and GD in our study in the context of pembrolizumab therapy suggest that this phenomenon is a class effect of the PD-1 inhibitors. In the 4 reported cases, the granulomatous reaction occurred between 6 months and 2 years after initial herpes zoster eruption and the histology was inconsistent with an active herpes virus infection.7Martín-Carrasco P. Pérez-Ruiz C. de Zulueta-Dorado T. Conejo-Mir J. Postherpetic granulomatous dermatitis in a man treated with nivolumab.Actas Dermosifiliogr. 2017; 108: 783-784Crossref PubMed Scopus (6) Google Scholar,8Assi T. Danu A. Mateus C. et al.Post-shingles granulomatous dermatosis related to anti-programmed cell death 1.Immunotherapy. 2019; 11: 591-598Crossref PubMed Scopus (7) Google Scholar Although the patients in this report had full resolution with topical therapy, in the case reported by Martín-Carrasco et al,7Martín-Carrasco P. Pérez-Ruiz C. de Zulueta-Dorado T. Conejo-Mir J. Postherpetic granulomatous dermatitis in a man treated with nivolumab.Actas Dermosifiliogr. 2017; 108: 783-784Crossref PubMed Scopus (6) Google Scholar nivolumab-induced GD did not resolve with topical corticosteroids or topical calcineurin inhibitors. Assi et al8Assi T. Danu A. Mateus C. et al.Post-shingles granulomatous dermatosis related to anti-programmed cell death 1.Immunotherapy. 2019; 11: 591-598Crossref PubMed Scopus (7) Google Scholar reported the treatment of postherpetic GA exclusively with emollients and the resolution of the eruption only after the interruption of pembrolizumab therapy, emphasizing a correlation between PD-1 therapy and these rare immune-related adverse events, distinct from the isolated postherpetic granulomatous reactions. Although the pathogenesis of Wolf postherpetic isotopic response remains unknown, previous hypotheses have implicated delayed-type hypersensitivity and altered local immune modulation that predisposes the impacted dermatomes to future immune conditions, such as iatrogenic immune dysregulation.8Assi T. Danu A. Mateus C. et al.Post-shingles granulomatous dermatosis related to anti-programmed cell death 1.Immunotherapy. 2019; 11: 591-598Crossref PubMed Scopus (7) Google Scholar Recent guidelines have underscored the importance of ruling out infection and systemic disease when treating the skin reactions in patients on immunotherapy; therefore, the recognition of this postherpetic phenomenon can preclude additional testing.9Brahmer J.R. Lacchetti C. Schneider B.J. et al.Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline.J Clin Oncol. 2018; 36: 1714-1768Crossref PubMed Scopus (1712) Google Scholar Thus, these cases present an interesting phenomenon of immune dysregulation confounded by 2 different etiologies and highlight the importance of considering Wolf postherpetic isotopic response when treating zosteriform lesions.10Ali A.A. Alkhodair R. Thuraisingam T. et al.Multiple granuloma annulare lesions presenting simultaneously with herpes zoster infection: Wolf's isotopic response.JAAD Case Rep. 2018; 4: 631-632Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar