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Severe Oral Mucositis: A Rare Adverse Event of Pembrolizumab

Treatment of malignancy with anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors can cause mucocutaneous side effects resulting from T cell activation. Due to their recent development, the full side effect profile remains to be fully elucidated, however dermatologic adverse events are most common. The main oral toxicities of these immune checkpoint inhibitors include: xerostomia, dysgeusia, and lichenoid reactions. Oral mucositis occurs more rarely in the setting of PD-1 inhibition, and few other reports of a Grade 3 or higher, severe, stomatitis have been reported in the literature. JDD authors present a case of a 78-year-old woman with Grade 3 ulcerative oral mucositis that occurred 13 months after initiation of PD-1 inhibitor, pembrolizumab, for the treatment for lung adenocarcinoma. She was successfully treated with prednisone, and pembrolizumab was temporarily held by her oncologist. Physicians should be aware of the possibility of severe mucositis in the setting of PD-1 inhibitors, as well as the management.

Case Report

A 78-year-old Chinese woman with a history of metastatic lung adenocarcinoma presented to the hospital for evaluation of an acute, painful erosive eruption involving the intraoral mucosa and lips of two weeks duration. She was unable to tolerate oral intake of food or liquid due to the severity of her pain. She denied fever, cough, lesions elsewhere on the body, or other systemic complaints. Thirteen months prior to presentation, she was started on pembrolizumab every three weeks for metastatic lung adenocarcinoma, and several days prior to the onset of her symptoms she received her last dose. There were no other new medications.


Physical examination revealed diffuse erosions with hemorrhagic crusting, within the vermillion border on the lower lip (Figure 1A). Scattered on the tongue and buccal mucosa were numerous erosions (Figure 1B). The ocular and genital mucosae were clear. The remainder of the skin exam was unremarkable.
Laboratory workup was notable for seropositivity for herpes simplex virus (HSV) IgG and IgM and Mycoplasma pneumoniae (MP) IgG and IgM. Viral culture and HSV polymerase chain reaction (PCR) studies of the lip were negative. Paraneoplastic pemphigus IgG antibodies on indirect immunofluorescence (IIF) were negative.


Two punch biopsies were obtained from the lower lip, one lesional for hematoxylin and eosin (H&E) and one perilesional for direct immunofluorescence (DIF). Histopathology demonstrated an ulcer bed with underlying pale edematous stroma with increased number of capillaries and a mixed inflammatory cell infiltrate comprised predominately of lymphocytes, histiocytes, and neutrophils. Epithelium was not present in multiple examined sections (Figure 2). DIF detected no specific immunoreactants for C3, IgA, IgG, IgM, or fibrinogen.


While inpatient, she was treated with empiric intravenous acyclovir, dexamethasone solution swish and spit, and topical mupirocin ointment mixed with triamcinolone 0.1% ointment. Oral prednisone 80 mg daily was initiated during hospitalization, and a taper was continued after discharge. She resumed pembrolizumab with her oncologist one day after discharge. The patient was seen two weeks after hospital discharge, and examination revealed persistence of mucositis, although with mild improvement (Figure 1C) and no other mucocutaneous involvement. She continued on the prednisone taper in addition to fluocinonide 0.05% gel. She was prescribed oral azithromycin and a second course of acyclovir in the setting of seropositive HSV IgM and MP IgM antibodies. Pembrolizumab was held in light of severe Grade 3 mucositis. Her symptoms had nearly resolved at her six-week follow-up visit (Figure 1D).
Oral Mucositis
FIGURE 1. Initial hospital presentation was notable for diffuse erosions with hemorrhagic crusting, strictly obeying the vermillion border on the lower lip (A), and numerous erosions scattered on the tongue and buccal mucosa, also with moist white plaque consistent with oral thrush on the dorsal tongue (B). Two weeks after discharge vermilion of the lip and oral erosions were persistent (C), however, at six weeks after discharge, she had near resolution (D).


Oral Mucositis
FIGURE 2. Biopsy of the lower lip revealed an ulcer bed with underlying pale edematous stroma visible at 40X (A) and mixed inflammatory cell infiltrate comprised predominately of lymphocytes, histiocytes, and neutrophils at 100X (B).


Immune checkpoint inhibition is a novel treatment strategy intended to activate the immune system against malignancy.¹ Pembrolizumab is an IgG4 antagonist monoclonal antibody to programmed-cell-death-1 (PD-1) receptor approved by the FDA in 2014.1,2 When PD-1 binds to programmed-cell-death-ligand-1 (PD-L1), T-cell proliferation is suppressed; thus tumor cells that express PD-L1 are protected from cytotoxic T-cell-mediated tumor destruction.1 By preventing this suppression of host T-cells targeting tumor cells, PD-1 and PD-L1 inhibitors are being used in the treatment of multiple malignancies.1 However, PD-1 inhibitors also remove self-protective PD-1-mediated T-cell inhibition and thus have the potential to trigger autoimmune-related adverse events.2,3 While such autoimmune-related side-effects have been described, given the recent development of these immunotherapies, the extent of adverse events is still not well delineated.2 The most common adverse events reported with anti-PD-1 antibodies are cutaneous reactions, largely non-specific maculopapular skin eruptions, and pruritus; however, lichenoid dermatitis and mucosal involvement have been reported.3-5 Oral mucosal involvement has been described,2-4,6 although only one previous report of severe oral mucositis (Grade 3 or higher) has been reported.7

Here we present a case of ulcerative mucositis representing a severe Grade 3 reaction associated with PD-1 inhibitor pembrolizumab in a patient undergoing this therapy for treatment of lung adenocarcinoma. The differential diagnosis included paraneoplastic pemphigus and infectious etiologies such as HSV-associated mucositis and mycoplasma-pneumoniae-induced rash and mucositis (MIRM). Biopsy for DIF and IIF serologies were negative for paraneoplastic pemphigus. There was initial concern for MIRM versus HSV-associated mucositis due to the confounding positive IgM titers for both MP and HSV, although HSV PCR and viral culture were negative. Furthermore, her eruption persisted despite appropriate empiric treatment with acyclovir. MIRM was thought to be unlikely as it classically presents in children and adolescents, rarely involves fewer than two mucosal sites, and often has a prodrome of cough, fever, or malaise. Additionally, diagnosis should not rely on MP IgM titer, which may be elevated in patients without an acute infection8. Azithromycin was added to this patient’s course empirically, without effect, although MIRM typically resolves within weeks regardless of treatment.8

Our patient presented with delayed oral mucosal symptoms which began after 13 months of pembrolizumab therapy. The onset of cutaneous adverse events with PD-1 inhibitors has been described as late as 15 months after initial treatment, and incidence appears to rise with increasing length of treatment time.9,10 A recent case series demonstrated that although the clinical presentation of anti-PD-1 mucocutaneous adverse effects were varied, 94% of patients’ biopsies were demonstrative of a lichenoid interface dermatitis.2 In this case, lack of epidermis on histopathology prevented assessment for lichenoid features. Oral lichenoid eruptions in the setting of PD-1/PD-L1 inhibitors often presents as confluent white papules or reticular streaks, consistent with Wickham’s striae, which may involve the dorsal or lateral sides of the lips, tongue, gingiva, hard palate or buccal mucosae.2,4,6 The affected areas may be painful or asymptomatic.3,4,6 Infrequent cases of oral mucositis have been reported.

The majority of PD-1-inhibitor-induced mucocutaneous reactions are self-limiting.2-4 In the presence of painful oral lesions, treatment with topical steroids and dexamethasone swish and spit solution have been reportedly effective.2-4,6 One other reported case of severe mucositis occurred in a patient who had undergone 14 cycles of pembrolizumab for the treatment of laryngeal squamous cell carcinoma; pembrolizumab was discontinued and the patient was treated with IV methylprednisolone 2 mg/kg/day followed by a slow taper of oral prednisone over the course of 5 months due to recurrence.7 However, discontinuation of therapy is rarely necessary, as most reactions are not severe enough to warrant such management.2-4 Our patient was initially recalcitrant to oral corticosteroids, most likely because of the continued treatment with a PD-1 inhibitor. However, continued treatment with oral corticosteroids after pembrolizumab was held led to near resolution of mucositis at six-week follow-up. In the case of severe mucosal reactions, temporary cessation of the PD-1 inhibitor may be considered; however, given treatment of the underlying malignancy is of utmost priority, if it is not feasible to withhold PD-1 inhibitor, initiation of elevated dosage of corticosteroids, such as that described by Acero et al, may be beneficial.7 As the use of immunotherapy is increasing, providers should be aware of the potentially severe oral mucosal adverse reactions as well as their management.


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    9. Hwang SJ, Carlos G, Wakade D, et al. Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: A single-institution cohort. J Am Acad Dermatol. 2016;74(3):455-461 e451.
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Margo H. Lederhandler MD, Anthony Ho BA, Nooshin Brinster MD, Roger S. Ho MD, Tracey N. Liebman MD, Kristen Lo Sicco MD, (2018). Severe Oral Mucositis: A Rare Adverse Event of Pembrolizumab. Journal of Drugs in Dermatology, 17(7), 807-809.

Content and images used with permission from the Journal of Drugs in Dermatology.

Adapted from original article for length and style.

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