Tislelizumab-induced bullous epidermal necrolysis: case reports and pathogenetic insights

Introduction

The advent of immune checkpoint inhibitors (ICIs) has revolutionized oncology therapeutics; however, their expanding use has revealed a spectrum of immune-related adverse events (irAEs) that complicate clinical management. These case reports are unique in detailing the clinical course and management of bullous epidermal necrolysis (BEN), a rare and severe irAE, specifically linked to programmed cell death protein 1 (PD-1) inhibitor monotherapy. ICIs such as tislelizumab have revolutionized oncology by blocking inhibitory receptors like PD-1, thereby enhancing antitumor immunity. However, this immune activation can lead to a spectrum of irAEs. Among these, cutaneous irAEs are the most common, but severe blistering disorders, including BEN, are rare and potentially fatal. BEN straddles the spectrum of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), characterized by widespread keratinocyte apoptosis and epidermal detachment. Unlike autoimmune bullous disorders such as bullous pemphigoid or paraneoplastic pemphigus, BEN typically shows full-thickness epidermal necrosis with minimal dermal inflammation on histopathology (1). Tislelizumab has demonstrated efficacy in diverse malignancies. Severe blistering reactions associated with immune checkpoint inhibitors are rare and remain incompletely characterized (2,3). This report advocates for heightened clinician awareness and contributes to evolving frameworks for biomarker-driven toxicity prediction in precision immuno-oncology. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0109/rc) (4).

Case presentation

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Case 1

A 56-year-old male patient with metastatic retroperitoneal lymph node adenocarcinoma developed pruritic erythematous macules with progressive blistering three days after the third cycle of tislelizumab (200 mg IV q3w). He did not receive any concurrent chemotherapy, radiotherapy, or other targeted therapy during tislelizumab administration. He had no history of smoking or alcohol consumption. He denied any prior dermatologic conditions or drug allergies. The rash began as pruritic erythematous macules that rapidly progressed to flaccid bullae with easy rupture, predominantly involving the trunk and proximal extremities. Dermatologic examination revealed Nikolsky-positive flaccid bullae involving 25% of the body surface area (BSA). The bullae were distributed predominantly over the trunk and proximal extremities. The Nikolsky sign was positive at multiple sites. Mucous membranes were spared. Management included high-dose intravenous methylprednisolone (1.5 mg/kg/day; 120 mg daily) tapered over 12 days, adjunctive intravenous immunoglobulin (IVIG; 20 g/day for 5 days), and broad-spectrum antibiotics to prevent secondary bacterial infection of denuded skin areas, given the risk of sepsis in patients with extensive epidermal loss. Topical therapy included calamine lotion for intact skin, ozonated oil for erosions, and dexchlorpheniramine maleate (4 mg bid) for pruritus control. Laboratory tests revealed leukocytosis (WBC 14.5×10⁹/L) and elevated C-reactive protein (85 mg/L). A skin biopsy from the edge of a bulla showed full-thickness epidermal necrosis with subepidermal clefting, sparse lymphocytic infiltration, and no eosinophils, consistent with BEN. Direct immunofluorescence was negative for IgG, IgA, IgM, and C3 deposition, ruling out autoimmune bullous disorders. Epidermal re-epithelialization was achieved by day 14, with transition to oral prednisolone (0.5 mg/kg/day) by day 21. Tislelizumab was permanently discontinued. After complete skin healing, the patient’s oncologist switched to alternative chemotherapy (Figure 1).

Figure 1 Histopathology of metastatic adenocarcinoma in a retroperitoneal lymph node and cutaneous findings in Case 1. (A) Histopathology of metastatic adenocarcinoma in a retroperitoneal lymph node (H&E, ×200). (B-D) Clinical photographs showing confluent erythema and flaccid bullae on the trunk and extremities; the Nikolsky sign was positive.

Case 2

An 81-year-old male patient with stage IV squamous cell carcinoma of the right lung (EGFR wild-type) presented with generalized confluent erythema, hemorrhagic vesicles, and sheet-like desquamation covering 40% of the BSA 2 days after the seventh infusion of tislelizumab. He denied any personal or family history of autoimmune or dermatologic diseases. He was not receiving any antibiotics or other potentially causative drugs. Histopathological analysis revealed full-thickness keratinocyte necrosis and subepidermal clefting, with notably prominent periadnexal keratinocyte necrosis, confirming BEN diagnosis. Blood tests showed lymphopenia (0.6×10⁹/L), elevated eosinophils (0.8×10⁹/L), and normal liver/kidney function. Treatment included intravenous methylprednisolone 80 mg/day in two divided doses for 8 days, combined with IVIG (20 g/day for 5 days). Upon discharge, he was prescribed oral prednisolone, starting at 60 mg/day and decreasing by 20 mg each week, along with topical fusidic acid cream for infection prevention. Mucosal involvement was mild, presenting as Grade 2 oral erythema according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Tislelizumab was permanently withdrawn. After skin healing, the patient received palliative chemotherapy (Figure 2).

Figure 2 Histopathology of primary squamous cell carcinoma of the right lung and cutaneous manifestations in Case 2. (A,B) Histopathology of primary squamous cell carcinoma of the right lung (H&E, ×200). (C) Clinical photograph of the extremities showing confluent erythema, hemorrhagic vesicles, and sheet-like desquamation.

Case 3

A 70-year-old male patient with locally advanced esophageal squamous cell carcinoma developed sudden-onset painful erythema with bullae formation affecting 30% of the BSA 48 hours after his fifth tislelizumab dose. He had a history of occasional alcohol consumption and reported no prior dermatologic conditions. His family history was unremarkable for autoimmune diseases. Treatment mirrored that of Case 2, incorporating combination immunosuppression with methylprednisolone (2 mg/kg/day) and IVIG. Significant clinical improvement was observed by day 7, leaving residual post-inflammatory hyperpigmentation. Tislelizumab was permanently discontinued, and no rechallenge occurred. The patient’s esophageal cancer was subsequently managed with radiotherapy (Figure 3).

Figure 3 Clinical photograph of the cutaneous manifestations in Case 3.

Discussion

Tislelizumab, a PD-1 inhibitor, enhances antitumor immunity by blocking the PD-1/PD-L1 axis. However, immune dysregulation can lead to severe cutaneous adverse reactions (CARs), such as BEN, characterized by widespread keratinocyte apoptosis. The pathogenesis involves multifaceted mechanisms. PD-1 inhibition potentiates cytotoxic CD8+ T-cell responses, triggering excessive cytokine release (e.g., TNF-α and IFN-γ) and Fas-FasL-mediated keratinocyte death. Specific human leukocyte antigen (HLA) alleles (e.g., HLA-B*15:02, HLA-A*31:01) may predispose individuals to CARs through altered antigen presentation. Comorbidities, polypharmacy, and prior dermatologic conditions may also exacerbate toxicity (5,6). Histopathologic hallmarks include full-thickness epidermal necrosis with minimal dermal inflammation; clinical severity should be graded separately using CTCAE v5.0.

The diagnosis of BEN was established based on the acute onset of widespread bullous lesions with Nikolsky sign, histopathological confirmation in Cases 1 and 2 of full-thickness epidermal necrosis, and the temporal relationship with tislelizumab administration. The primary differential diagnoses considered included SJS/TEN spectrum, autoimmune bullous disorders such as bullous pemphigoid and paraneoplastic pemphigus, and severe drug eruption from concomitant medications. The absence of mucosal involvement in Case 1, combined with the rapid onset following PD-1 inhibitor infusion and histopathological findings, favored the diagnosis of ICI-induced BEN over other etiologies. No diagnostic challenges related to access, finances, or culture were encountered.

Compared to classic drug-induced SJS/TEN, which typically occurs 4–28 days after drug exposure, our patients developed BEN after a median of 2 days (range, 2–3 days) following tislelizumab infusion. This shorter latency may reflect a recall immune response due to prior immune checkpoint exposure. In addition, none of our patients received concomitant antibiotics or other high-risk drugs known to trigger SJS/TEN in the 4 weeks prior to symptom onset, suggesting that tislelizumab alone served as the trigger. However, we cannot exclude subclinical viral reactivation or other host factors as contributing cofactors, as described in the “two-hit” hypothesis. Histopathologically, in Case 2, we observed more prominent keratinocyte necrosis around hair follicles and sweat glands. This periadnexal accentuation has been reported in ICI-induced epidermal necrolysis and may help differentiate it from classic SJS/TEN.

The rarity of BEN as a complication of PD-1 inhibitor monotherapy deserves comment. Existing literature primarily implicates CTLA-4 inhibitors or combination ICI therapies in severe blistering reactions, making PD-1 inhibitor-associated BEN less frequently documented. Our three cases add to the limited body of evidence and highlight the need for heightened clinician awareness.

Timely intervention with corticosteroids and IVIG remains the cornerstone of treatment. In our cases, high-dose methylprednisolone (1.5–2 mg/kg/day) combined with IVIG (20 g/day for 5 days) achieved re-epithelialization within 14–21 days. Supportive care, including broad-spectrum antibiotics to prevent secondary infection in denuded skin, was also essential.

Multidisciplinary collaboration

The management of ICI-induced BEN exemplifies the importance of multidisciplinary collaboration in oncology practice. The involvement of oncologists, dermatologists, intensivists, and infectious disease specialists is essential for optimal patient care. Dermatologists provide expertise in diagnosis, biopsy interpretation, and topical management. Intensivists are needed for patients with extensive skin involvement requiring intensive care monitoring. Infectious disease specialists guide antimicrobial therapy and prophylaxis.

Furthermore, communication with patients and their families is critical. Patients should be informed about the nature of the reaction, the rationale for drug discontinuation, and the importance of adherence to treatment. Psychological support may be needed, as severe cutaneous reactions can be traumatic and disfiguring.

Future directions

Several unanswered questions warrant further investigation. First, the incidence and risk factors for ICI-induced BEN need to be better defined through prospective registries and pooled analyses. Second, genetic markers that predict susceptibility to severe cutaneous irAEs should be explored. Third, the role of histopathological features in distinguishing ICI-induced BEN from classic SJS/TEN requires validation in larger series. Fourth, comparative effectiveness studies are needed to determine the optimal immunosuppressive regimen for ICI-induced BEN. Finally, the possibility of reintroducing immunotherapy after recovery from BEN should be evaluated, although this approach should only be undertaken with extreme caution.

Study limitations

Several limitations of this study should be acknowledged. First, as a case series of three patients, the findings may not be generalizable to the broader population of patients receiving tislelizumab. Second, the retrospective nature of the data collection may have introduced bias. Third, genetic testing for HLA alleles was not performed, limiting our ability to comment on genetic susceptibility. Fourth, long-term follow-up data on skin sequelae and cancer outcomes were not systematically collected. Fifth, we were unable to obtain patient perspectives due to loss of contact during follow-up, which may have enriched our understanding of the patient experience. Despite these limitations, we believe that our cases contribute valuable information to the literature on this rare but serious complication of PD-1 inhibitor therapy.

Conclusions

In clinical practice, tislelizumab should be discontinued immediately upon signs of a drug eruption. Appropriate symptomatic and supportive treatment should be administered based on symptom severity (5,6). Mild erythema or pruritus may be managed with topical corticosteroids, while extensive skin involvement or bullous epidermal detachment necessitates systemic corticosteroids and immunosuppressive therapy. Multidisciplinary collaboration between oncologists and dermatologists is essential for monitoring cutaneous and systemic recovery, optimizing rehabilitation, maintaining skin hydration, and minimizing exposure to potential irritants. This multidisciplinary approach aims to minimize discomfort during cancer treatment.

Acknowledgments

We would like to thank all reviewers and editors for their comments on this study. We thank The Affiliated Hospital of Yangzhou University and Northern Jiangsu People’s Hospital for supporting this research.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0109/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0109/prf

Funding: This work was supported by the National Natural Science Foundation of China (Grant No. 61972335) and cross-collaboration between Northern Jiangsu People’s Hospital and Yangzhou University (Grant No. SBJC21002).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0109/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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