Pembrolizumab‐Associated Bullous Pemphigoid with Laryngeal Involvement

Abstract

Pembrolizumab is a monoclonal antibody with increasing use in many malignancies. We describe a case of pembrolizumab‐associated bullous pemphigoid (BP) with laryngeal involvement in a 69‐year‐old male patient. Diagnosis was made after 2 months of symptoms via biopsy of concurrent, easily accessible cutaneous lesions. Pembrolizumab was discontinued and the patient was started on steroids and dupilumab with ultimate resolution of his cutaneous and laryngeal lesions while on immunosuppression. This case report describes the third case of pembrolizumab‐associated laryngeal pemphigoid to increase awareness of this rare immune‐related adverse effect. Laryngoscope, 135:243–246, 2025

We describe a case of pembrolizumab‐associated bullous pemphigoid (BP) with laryngeal involvement. Presentation and latency of symptom onset is variable, and multidisciplinary management and close airway surveillance are necessary. Awareness of this exceedingly rare adverse effect is important, particularly as immunotherapy becomes standard of care for an increasing number of malignancies.

INTRODUCTION

Pembrolizumab is a monoclonal antibody against programmed cell death receptors (PD‐1) that not only leads to T cell activation against tumor cells, but also induce autoimmune responses. ¹ We describe a case of pembrolizumab‐associated bullous pemphigoid (BP) with laryngeal involvement. Laryngeal involvement secondary to pembrolizumab is exceedingly rare, with only two other cases reported. ² , ³

CASE REPORT

A 69‐year‐old male with metastatic clear cell renal cell carcinoma on pembrolizumab for 24 months developed hoarseness, odynophagia, and dysphagia, prompting otolaryngology evaluation. He had trialed lansoprazole without improvement. Oral exam demonstrated a desquamating lesion of the soft palate. Flexible stroboscopy noted fibrinous debris and ulceration of the epiglottis and left aryepiglottic fold (Fig. 1). The true vocal folds were bilaterally mobile and without lesions. Oropharyngeal symptoms were preceded by an ongoing pruritic, blistering rash over his lower extremities, back, and chest.

Fig. 1.

Flexible laryngoscopy demonstrating laryngeal findings at presentation: supraglottic edema, fibrinous debris, and ulceration affecting the (A) epiglottis and (B) left aryepiglottic fold and arytenoid mucosa.

The presence of laryngeal manifestations prompted dermatology biopsy of the cutaneous lesions (Fig. 2). After multidisciplinary discussion, pembrolizumab was discontinued, and he was started on 0.75 mg/kg/day prednisone while awaiting dermatopathology. Immunohistopathologic and serologic analysis was consistent with BP. Direct immunofluorescence (DIF) demonstrated strongly positive linear IgG and C3 staining along the dermal‐epidermal junction. Enzyme‐linked immunosorbent assay for BP180 was positive, whereas BP230, desmoglein‐1, and ‐3 were negative. Dupilumab was added approximately 1 week after presentation once the diagnosis of BP was confirmed.

Fig. 2.

Concurrent cutaneous manifestations. Biopsy for DIF obtained adjacent to blistered skin.

On 6‐week ENT follow‐up, his oral and laryngeal mucosal lesions had cleared without scarring and a prednisone taper guided by dermatology was started. At 8 weeks, his cutaneous manifestations fully cleared. Over the next 2 months, steroids were weaned to off; however, both cutaneous and oral lesions recurred. At 6 month dermatology follow‐up, he remains on dupilumab and 10‐mg prednisone daily. He has not had symptoms suggestive of laryngeal recurrence. His metastatic disease is stable.

DISCUSSION

Pembrolizumab‐associated pemphigoid is a rare immune related adverse effect (irAE). A recent literature review of pembrolizumab‐associated BP identified just 47 patients. Most patients exhibited cutaneous symptoms alone, with mucosal involvement in 20%. ¹ Although reports of pembrolizumab‐induced predominantly mucosal disease exist, laryngeal involvement is exceedingly rare, with only two other cases reported in the literature (Table I). ² , ³

TABLE I.

Patient Characteristics of Pembrolizumab‐Associated Laryngeal Pemphigoid.

Reference	Age (Y) /Sex	Cancer diagnosis	Pembrolizumab dosing	Symptom Latency* (mo)	Presenting symptom	Laryngeal symptoms	Laryngeal site	Extralaryngeal sites
Current patient	69/M	Metastatic clear cell renal cell carcinoma	400 mg q6w	24	Cutaneous	Hoarseness, Odynophagia, Dysphagia	Epiglottis Aryepiglottic fold	Oral Cutaneous
Bezinelli et al. 3	47/F	Metastatic ovarian adenocarcinoma	2 mg/kg q3w	1.5	Oral	Hoarseness Discomfort in the larynx Dysphagia	Epiglottis Posterior glottic scar	Conjunctiva Oral (gingiva, tongue) Oropharyngeal (soft palate) Nasal cavity
Lagos‐Villaseca et al. 2	84/M	Metastatic urothelial carcinoma	200 mg q3w	13.5	Laryngeal	Dysphonia, Odynophagia, Dyspnea	Epiglottis Aryepiglottic fold	Oropharyngeal (Soft palate, Posterior pharyngeal wall)

F = female; kg = kilogram; M = male; mg = milligram; Mo = months; q3w = every 3 weeks; q6w = every 6 weeks; Y = years.

^*Time from pembrolizumab initiation to onset of first symptom.

BP is an autoimmune bullous disease (AIBD) induced by autoantibodies targeting BP180 and BP230 hemidesmosomal proteins at the dermal‐epidermal junction. ¹ , ⁴ AIBDs are characterized by subepithelial blistering and differentiated by degree of mucous membrane involvement. BP classically presents with pruritus followed by tense blistering on the trunk and extremities with mucosal involvement in 10%–30% and usually limited to oral mucosa. ¹ , ² , ⁴ Mucous membrane pemphigoid (MMP), in contrast, may affect any mucous membrane, most commonly oral and conjunctival. Skin lesions are present in 20%–35% but are usually less extensive. The disease hallmark is significant cicatrix formation. ⁴

In cases of irAEs, median time to onset of cutaneous BP was 4 months after pembrolizumab initiation but varied significantly (weeks‐28 months). ¹ Onset can occur even after completion of therapy. ¹ , ² All cases with laryngeal involvement developed while the patient was receiving therapy but differed in time to symptom onset (1.5–24 months), presenting symptom, and degree of extralaryngeal involvement (Table I). In the present case, cutaneous then laryngeal symptoms developed after 24 months of pembrolizumab treatment, demonstrating a latency period significantly longer than the median.

Diagnosis is made through a combination of clinical history, serology, and immunohistopathology, with clinical presentation distinguishing BP from MMP. ⁴ Anti‐BP180 and anti‐BP230 are the most common circulating autoantibodies, present in 50%–90% of cases and 10%–30%, respectively. ¹ , ² Immunohistopathology is necessary to differentiate BP and MMP from other mucous membrane‐involving diseases including Stevens‐Johnson syndrome, pemphigus vulgaris, paraneoplastic pemphigus, lichen planus, and epidermolysis bullosa. DIF is the gold standard and demonstrates linear deposits of IgG, IgA, and/or C3 along the subepithelial basement membrane. Consensus guidelines recommend perilesional tissue biopsy and favor skin biopsy for patients with both mucous membrane and skin involvement. ⁴ Given the specialized testing that must be requested, diagnosis requires a high index of suspicion and is often delayed. In the present case, the patient was diagnosed quickly, with immediate discontinuation of pembrolizumab and initiation of immunosuppression within 1 week of presentation to otolaryngology (Table II).

TABLE II.

Diagnosis, Treatment, Response, and Follow‐Up.

Reference	Discontinuation of PB (mo after presentation)	Time from presentation to DIF	Immuno‐pathology	Antibodies	Treatments	Airway intervention	Time to disease control (mo)	Follow‐up (mo)	Clinical outcome (treatment) at time of follow‐up
Current patient	Yes (Immediate)	DIF: 1w	DIF: IgG/C3	Anti‐BP180: + Anti‐BP230: − Anti‐DG1: − Anti‐DG3: −	Dexamethasone mouthwash (1) Prednisone (0.75 mg/kg/d) + Dupilumab	None	Larynx: 1.5 Oral: 1.5, relapse Cutaneous: 2, relapse	6	Larynx: complete remission on therapy Oral/cutaneous:partial remission on therapy No scarring (10‐mg prednisone, dupilumab)
Bezinelli et al. 3	Yes (3.75)	Prior biopsy x1 DIF: 7 mo	DIF: IgG	Anti BP180, BP230, DG1 DG3: not performed. Anti‐laminin 332: −	Ophthalmic steroids (1) Prednisone (0.75 mg/kg/d) (2) Infliximab, followed by mycophenolate mofetil (3) Pulse dose methylprednisolone followed by prednisone (4) Intravenous immunoglobulin+ Rituximab+ prednisone	Tracheostomy 9 mo after symptom onset	‐	16	No remission on therapy Severe scarring with supraglottic stenosis Patient expired
Lagos‐Villaseca et al. 2	Yes (4.5)	Prior biopsy x1 DIF: not performed	DIF: Not performed	Anti‐BP180:+ Anti‐BP230:− Anti‐DG1: + Anti‐DG3:−	(1) Prednisone (2) Methotrexate	None	Larynx: 3	12	Larynx: Complete remission on therapy No scarring (10 mg methotrexate)

− = negative; + = positive; d = day; DG1 = desmoglein‐1; DG3 = desmoglein‐3; DIF = direct immunofluorescence; kg = kilogram; mg = milligrams; Mo = months; PB = pembrolizumab; w = weeks.

Laryngeal involvement in pemphigoid is rare, with studies reporting 5%–19% of cases. ² , ⁵ Thus, there is no standard of care treatment paradigm for laryngeal AIBD. Pemphigoid cases with mucosal involvement are classified by risk, where high‐risk includes any extraoral/cutaneous involvement. ⁴ Reported treatments include systemic, topical, and/or intralesional steroids and immune suppression including nonbiologics (dapsone, methotrexate, mycophenolate mofetil, tetracyclines, and cyclophosphamide) and biologics (rituximab and dupilumab). ⁴ , ⁵ Dupilumab is currently an off‐label treatment and was utilized to minimize global immunosuppression with systemic steroids in the setting of metastatic renal cancer.

In the case of pembrolizumab irAEs, treatment may follow guidelines set forth by the American Society of Clinical Oncology. Temporary or permanent discontinuation of pembrolizumab should be discussed with oncology, taking into account severity of BP and patient's tumor control. Notably, most patients must discontinue therapy to gain control of their BP; in one case series, only 10% of patients were able to continue pembrolizumab treatment while receiving systemic treatment. ¹ Additionally, the time to achieve laryngeal disease control is typically longer than for cutaneous manifestations, with a mean of 10 months versus 3 months in a cohort of patients with laryngeal BP of any etiology. ⁵ Both cases with complete remission, including the present, achieved laryngeal control quickly (1.5–3 months) without scarring and remain on therapy. The rationale for prolonged immunosuppression despite stopping pembrolizumab is that the underlying pathophysiology is loss of immunologic tolerance and development of autoantibodies. The third case did not achieve remission and developed supraglottic stenosis. ³ (Table II).

CONCLUSION

Laryngeal manifestations of AIBDs are rare and diagnosis requires a high index of suspicion. The gold standard involves serologic testing and DIF. Awareness of the association with pembrolizumab is important as immunotherapy becomes standard of care for several cancers and given the variable presentation and latency in symptom onset. Multidisciplinary workup and management including otolaryngology, dermatology, and hematology‐oncology is necessary for treatment decisions. Close airway surveillance is strongly encouraged given the risk of airway compromise acutely and scarring long term.