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. Author manuscript; available in PMC: 2018 Oct 1.
Published in final edited form as: Am J Surg Pathol. 2017 Oct;41(10):1381–1389. doi: 10.1097/PAS.0000000000000900

Table 2.

Clinicopathologic studies of non-lichenoid eruptions following treatment with anti-PD-1

Study Cutaneous eruption Tumor typea Oncologic agenta Clinical morphologya Histologic patterna
Carlos et al.1 Bullous pemphigoid Melanoma anti-PD-1 Erythematous papules and plaques, few intact and ruptured vesicles and bullae Subepidermal blisters with eosinophilic infiltration, +DIFb
Naidoo et al.2 Bullous pemphigoid

  1. Melanoma

  2. Melanoma

  3. SCLC

  1. anti-PD-1

  2. anti-PD-L1

  3. anti-PD-1

  1. Tense bullae

  2. Two fluid-filled pruritic tense blisters

  3. Small vesicles and bullae

  1. Ulcerated and inflamed subepidermal vesicular dermatitis with eosinophils, +DIFb

  2. Subepidermal cleft, +DIFb

  3. Subepidermal bullous dermatitis with eosinophils, +DIFb
Jour et al.3 Bullous pemphigoid (patients 1–4)
Bullous erythema multiforme (patient 5)

  1. HNSCC

  2. Melanoma

  3. Urothelial

  4. Adeno-carcinoma

  5. Melanoma

  1. anti-PD-1

  2. anti-PD-1 + anti-CTLA-4

  3. anti-PD-1

  4. anti-PD-1

  5. anti-PD-1

  1. Mucosal blisters, erythematous plaques with overlying tense vesicles

  2. Tense bullae

  3. Pink, pruritic annular patches, multiple vesicles and tense bullae

  4. Tense bullae and crusted papules and plaques

  5. Erythematous tender confluent plaques and flaccid bullae

  1. Subepidermal blister with mixed inflammatory infiltrate; +DIFb

  2. Consistent with BP

  3. Consistent with BP

  4. Subepidermal blister cavity with dermal lymphocytic inflammation with eosinophils; -DIF

  5. Blister cavity with interface dermatitis, associated dyskeratotic keratinocytes and lymphocytic inflammation; DIF not available
Ohtsuka et al.4 Psoriasis Melanoma anti-PD-1 Well-demarcated, scaly, erythematous plaques Parakeratotic hyperkeratosis, irregular elongation of the rete ridges, dermal mononuclear cell infiltration
Totonchy et al.5 Inverse psoriasiform eruption Melanoma anti-PD-1 Vaginal and intergluteal pink-red plaque with erosions and yellow crusting Psoriasiform epidermal hyperplasia, spongiosis, and predominantly lymphocytic inflammatory infiltrate with scattered eosinophils and dermal edema
Matsumura et al.6 Psoriasis exacerbation Melanoma anti-PD-1 Psoriatic plaques Mild parakeratotic hyperkeratosis, regular acanthosis, mild telangiectasia in the papillary dermis, mild lymphocytic infiltrate
Kato et al.7 Psoriasis exacerbation Melanoma anti-PD-1 Sharply bordered, scaly, erythematous plaques Perivascular lymphocytic infiltration, slight elongation of rete ridges, dilated vessels in papillary dermis, thinning of granular layer, neutrophils in cornified layer
Chia et al.8 Psoriasis exacerbation NSCLC anti-PD-1 Erythematous, scaly plaque-like lesions Minor hyperkeratosis (after 2 months of topical steroids and daily phototherapy)
Murata et al.9 Psoriasis Melanoma anti-PD-1 Erythematous, pruritic and sharp-bordered plaques with silvery scale Uniform elongation of the rete ridges, thinning of the suprapapillary plate with intermittent parakeratosis, hyperkeratosis, loss of the granular layer, neutrophil aggregation in the stratum corneum
Law-Ping-Man et al.10 Psoriasis NSCLC anti-PD-1 Erythematous and scaly lesions Epidermal hyperplasia with parakeratotic hyperkeratosis, acanthosis, dilated superficial dermal capillaries, moderate lymphocytic infiltrate in upper dermis
Danlos et al.11 Sarcoid-like granulomatous reaction Melanoma anti-PD-1 Subcutaneous nodule Dermal granulomatous infiltrate consistent with sarcoidosis
Suozzi et al.12 Cutaneous sarcoidosis Lung anti-PD-1 +
anti-CTLA-4		 >50 skin-colored to pink firm papules coalescing into annular plaques, some umbilicated Epithelioid granulomatous infiltrate
Nayar et al.13 Toxic epidermal necrolysis Melanoma anti-PD-1 Widespread maculopapular skin rash with bullae and areas of skin detachment Interface dermatitis with lymphocytic infiltrate in the dermal-epidermal junction and apoptotic keratinocytes; complete necrosis of the epidermis with minimal infiltrate
Mutgi et al.14 Pityriasis lichenoides chronica-like drug eruption Melanoma anti-PD-1 Pruritic 3–4 mm red-brown thin papules with centrally adherent micaceous scale Parakeratotic, spongiotic, and focally acanthotic epidermis with exocytosis of cytologically bland-appearing lymphocytes and rare neutrophils; focal basal layer vacuolar degeneration with interface and perivascular lymphocytic inflammation and extravasated red blood cells
Shi et al.15 N/A Lung anti-PD-1 + erlotinib, then anti-PD-1 alone Papular Vacuolar interface dermatitis
Belum et al.16 N/A

  1. Astro-cytoma

  2. NSCLC

  3. SCLC

  4. Melanoma

  5. Melanoma

  6. B-cell lymphoma

 anti-PD-1 (all patients)

  1. Multiple (>100), discrete, slightly raised, pink to erythematous papules (coalescing at places)

  2. Few, light pink, monomorphic macules, follicular at places; some coalescing into patches

  3. Few, non-scaly, erythematous papules and plaques

  4. Multiple (>100), erythematous papules with ill-defined borders (few, coalescing at places)

  5. Erythematous, discrete, eczematous patches (some with impetiginized crust); yellow-crusted plaque with underlying erythema

  6. Flat-topped, slightly scaly shiny (lichenoid) papules

  1. Mild vacuolar interface dermatitis with superficial perivascular lympho-eosinophilic infiltrate

  2. Perivascular lymphocytic dermatitis with few eosinophils

  3. Spongiotic, vesicular and superficial perivascular dermatitis with eosinophils

  4. Interface, perivascular and periadnexal lymphocytic dermatitis, with few plasma cells and minor vascular damage

  5. Psoriasiform, spongiotic and superficial dermal lympho-eosinophilic dermatitis; sparse perivascular lymphocytic dermatitis

  6. Superficial and deep perivascular, periadnexal and interface dermatitis with vasculopathic changes and keratinocyte dysmaturation
Goldinger et al.17 N/A Melanoma anti-PD-1 Psoriasiform lesions Two biopsies over time from the same patient: (1) Focal acanthosis and spongiosis and some apoptotic keratinocytes with lichenoid aspect; (2) lymphocytic infiltration of the adnexa

Abbreviations:

CTLA-4, cytotoxic T lymphocyte associated antigen 4; DIF, direct immunofluorescence; HNSCC, head and neck squamous cell carcinoma; NSCLC, non-small cell lung carcinoma; PD-1, programmed cell death protein 1; PD-L1, PD1 ligand; SCLC, small cell lung carcinoma.

Legend:

a

Per patient

b

Immunofluorescence findings diagnostic for BP (linear deposition of IgG and C3 at the dermal-epidermal junction)

References

1

Carlos G, Anforth R, Chou S, Clements A, Fernandez-Penas P. A case of bullous pemphigoid in a patient with metastatic melanoma treated with pembrolizumab. Melanoma Res. 2015;25(3):265–268.

2

Naidoo J, Schindler K, Querfeld C, et al. Autoimmune Bullous Skin Disorders with Immune Checkpoint Inhibitors Targeting PD-1 and PD-L1. Cancer Immunol Res. 2016;4(5):383–389.

3

Jour G, Glitza IC, Ellis RM, et al. Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1 antibody therapy: a report on bullous skin eruptions. J Cutan Pathol. 2016;43(8):688–696.

4

Ohtsuka M, Miura T, Mori T, Ishikawa M, Yamamoto T. Occurrence of Psoriasiform Eruption During Nivolumab Therapy for Primary Oral Mucosal Melanoma. JAMA Dermatol. 2015;151(7):797–799.

5

Totonchy MB, Ezaldein HH, Ko CJ, Choi JN. Inverse Psoriasiform Eruption During Pembrolizumab Therapy for Metastatic Melanoma. JAMA Dermatol. 2016;152(5):590–592.

6

Matsumura N, Ohtsuka M, Kikuchi N, Yamamoto T. Exacerbation of Psoriasis During Nivolumab Therapy for Metastatic Melanoma. Acta Derm Venereol. 2016;96(2):259–260.

7

Kato Y, Otsuka A, Miyachi Y, Kabashima K. Exacerbation of psoriasis vulgaris during nivolumab for oral mucosal melanoma. J Eur Acad Dermatol Venereol. 2015.

8

Chia PL, John T. Severe Psoriasis Flare After Anti-Programmed Death Ligand 1 (PD-L1) Therapy for Metastatic Non-Small Cell Lung Cancer (NSCLC). J Immunother. 2016;39(5):202–204.

9

Murata S, Kaneko S, Harada Y, Aoi N, Morita E. Case of de novo psoriasis possibly triggered by nivolumab. J Dermatol. 2016.

10

Law-Ping-Man S, Martin A, Briens E, Tisseau L, Safa G. Psoriasis and psoriatic arthritis induced by nivolumab in a patient with advanced lung cancer. Rheumatology (Oxford). 2016.

11

Danlos FX, Pages C, Baroudjian B, et al. Nivolumab-Induced Sarcoid-Like Granulomatous Reaction in a Patient With Advanced Melanoma. Chest. 2016;149(5):e133–136.

12

Suozzi KC, Stahl M, Ko CJ, et al. Immune-related sarcoidosis observed in combination ipilimumab and nivolumab therapy. JAAD Case Rep. 2016;2(3):264–268.

13

Nayar N, Briscoe K, Fernandez Penas P. Toxic Epidermal Necrolysis-like Reaction With Severe Satellite Cell Necrosis Associated With Nivolumab in a Patient With Ipilimumab Refractory Metastatic Melanoma. J Immunother. 2016;39(3):149–152.

14

Mutgi KA, Milhem M, Swick BL, Liu V. Pityriasis lichenoides chronica-like drug eruption developing during pembrolizumab treatment for metastatic melanoma. JAAD Case Rep. 2016;2(4):343–345.

15

Shi VJ, Rodic N, Gettinger S, et al. Clinical and Histologic Features of Lichenoid Mucocutaneous Eruptions Due to Anti-Programmed Cell Death 1 and Anti-Programmed Cell Death Ligand 1 Immunotherapy. JAMA Dermatol. 2016.

16

Belum VR, Benhuri B, Postow MA, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60:12–25.

17

Goldinger SM, Stieger P, Meier B, et al. Cytotoxic Cutaneous Adverse Drug Reactions during Anti-PD-1 Therapy. Clin Cancer Res. 2016;22(16):4023–4029.