PD-L1 expression in keratinocyte and infiltration of CD4 + T lymphocyte can predict a severe type of erythema multiforme major induced by the anti-PD-1 antibody, pembrolizumab

Abstract

Skin toxicity is the most common adverse event of treatment with immune check point inhibitors. Among them, erythema multiforme is a rare occurrence with a frequency of 4%, with most of the cases developing grade 1/2 disease. We experienced high grade erythema multiforme major developing with pembrolizumab treatment for anal canal cancer with extensive skin metastases. Steroid ointment was ineffective, and the skin lesions with blisters expanded to > 45% of the body surface area. The patient was at risk for symptom aggravation, and a pulse therapy with methylprednisolone and increasing the dose of oral prednisolone (1 mg/kg) were started. The skin lesions improved in 1.8 months. Unless urgent and appropriate treatments such as high dose steroid administration were conducted, the skin toxicities could not be controlled. The presence of CD4⁺ T cells and PD-L1⁺ keratinocytes in the skin biopsy might be a predictive marker of erythema multiforme major resistant to standard steroid treatment.

Supplementary information: The online version contains supplementary material available at 10.1007/s13691-024-00676-4.

Keywords: Anti-PD-1 antibody; CD8+ T cell; Erythema multiforme major; PD-L1 expression; Severe cutaneous adverse reaction.

Fig. 1

Presentation of anal canal cancer. A A biopsy specimen of anal canal cancer (mucinous adenocarcinoma). The black bar indicates 100 μm. B Computed tomography (CT) imaging of lymph node metastasis around the external and internal iliac arteries. C Positron emission tomography (PET) imaging of (B). D CT imaging of the anal canal cancer and inguinal lymph node metastasis. E PET imaging of CD. F Biopsy specimen of abdominal wall metastasis. The black bar indicates 250 μm

Fig. 2

Presentation of skin lesions. A Skin lesions on the day of admission (April 2023). B Skin lesions on day 17. Lesions were consistent with “Bullous Dermatoses” in ASCO guideline. C The edematous erythemata, which are called “Bullous Dermatoses” lesions in ASCO guideline was sampled as biopsy specimen. D–E The biopsy specimen shows that the subepidermal blister is seen in the center of the lesion (D) and that the interface and perivascular dermatitis with sparse eosinophils in dermis and prominent dyskeratotic keratinocytes in epidermis is seen in the margin of the lesion (E). F Skin lesions on day 45. G Skin lesions on day 54. The black bars in (D) and (E) indicate 250 μm and 100 μm, respectively

Fig. 3

Schematic summary of the treatment protocol. PSL prednisolone, mPSL methylprednisolone. Antibiotics such as ceftriaxone, minocycline, and sulfamethoxazole, were used promptly. Dimethyl isopropylazulene was used for the inflammation. White petrolatum was used to moisture her skin. Fexofenadine hydrochloride, an antihistamine, bilastine, or ebastine, nonsedating second generation antihistamines were used to relieve allergy symptoms

Fig. 4

Immunohistochemical staining of the skin lesions. Two “Bullous Dermatoses” lesions are indicated in (A–M). Skin metastasis lesions are indicated in (N–R). Cancer infiltration lesions in to skin are indicated in (T–Y). Hematoxylin and eosin (HE) staining are (A, H, N, T). Immunohistochemistry (IHC) with anti-CD3 antibody is (B, I, O, U). IHC with anti-CD4 antibody is (C, J, P, V). IHC with anti-CD8 antibody is (D, K, Q, W). IHC with anti- PD-1 antibody is (F, L, R, X). IHC with anti- PD-L1 antibody is (G, M, S, Y). The black bar indicates 100 μm