TagedEnVol. 136 No.
1 July 2023
TagedH1Osteonecrosis of the jaw associated with pembrolizumabTagedEn
TagedPIsabel Pennings, DDS,a Alison Moskowitz, MD,b Gunjan Shah, MD,b Cherry Estilo, DMD,c
Joseph M. Huryn, DDS,c and SaeHee K. Yom, DDS, MPHcTagedEn
TagedPEn
We report a case of osteonecrosis of the jaw (ONJ) with pembrolizumab, a rare yet possibly emerging complication. In this case, a
temporal relationship between the development of ONJ and the patient’s treatment regimen suggested an association between
pembrolizumab/GVD therapy and the development of ONJ. Thrombocytosis and anatomic factors may also have played a role.
The number of patients using pembrolizumab will likely continue to increase. We document this instance in order to better inform
dental treatment around cancer patients undergoing pembrolizumab therapy. (Oral Surg Oral Med Oral Pathol Oral Radiol
2023;136:e11 e14)
TAGEDH1CASE REPORTTAGEDN
TagedPA 44-year-old woman presented to the Dental Service
for evaluation of a painful gum lesion in December
2021. Her medical history included stage IVB classical
Hodgkin lymphoma, nodular sclerosis subtype, diag-
nosed in 2017, and initially treated with doxorubicin,
bleomycin, vinblastine, and dacarbazine. In September
2021, she had a biopsy-proven relapse. She was also
noted to have diffuse osseous hypermetabolic metastatic
foci throughout the skull base, axial, and appendicular
skeleton. She was found to have grade 2 cord compres-
sion at T9 on MRI in October 2021 and was admitted
for observation and treatment. In November 2021, she
initiated weekly treatment with gemcitabine, vinorelbine,
doxorubicin (GVD), and pembrolizumab with plans for
autologous transplant. A positron emission tomography
on 12/10/21 showed abnormal uptake at the lingual plate
of the right mandible with cortical irregularity. Asym-
metric activity was noted in the right submandibular
gland, possibly obstructive per pathosis report.TagedEn
TagedPAs of the patient’s initial presentation to our Service,
she had received 4 doses of GVD/pembrolizumab. Her
blood counts indicated mild anemia and thrombocytosis.TagedEn
TagedPHer chief oral complaint was pain to the mandibular
right lingual gingiva and mobility of maxillary right
third molar #1 and mandibular right first molar #30.
Examination revealed swelling involving the mandibu-
lar right lingual gingiva adjacent to teeth #29 and #30.
This area of firm swelling extended from the floor of
mouth to the lingual occlusal table and was exquisitely
tender to palpation. No purulence or dental caries was
TagedEn Department of Surgery, Memorial Sloan Kettering Cancer Center,
a
1275 York Ave, New York, NY, 10065, USA.
b
Department of Medicine, Memorial Sloan Kettering Cancer Center,
New York, NY, USA.
c
Department of Surgery, Memorial Sloan Kettering Cancer Center,
New York, NY, USA.
TagedEnCorresponding author: SaeHee K. Yom. E-mail address:
Kims2@mskcc.org
Received for publication Oct 18, 2022; returned for revision Dec 20,
2022; accepted for publication Dec 28, 2022.
Ó 2023 Elsevier Inc. All rights reserved.
2212-4403/$-see front matter
https://doi.org/10.1016/j.oooo.2022.12.013
noted, and teeth #29 and #30 were not sensitive to per-
cussion. The buccal gingiva was not affected, and the
dentition was otherwise generally well maintained.
Bilateral mandibular tori were noted.TagedEn
TagedPRadiographic examination of bone near #30 revealed
a moth-eaten radiolucent pattern, and slight extrusion
of tooth #30 with unopposed dentition (Figure 1).TagedEn
TagedPAt initial evaluation, the patient denied trauma to the
area. The gingival swelling did not appear to be of
odontogenic origin. It was suspected that the oral lesion
was related to therapy or systemic disease, and pallia-
tive measures as well as an oral hygiene regimen with
chlorhexidine rinse were recommended.TagedEn
TagedPThe patient returned 1 month later in January 2022.
In the area where swelling was previously noted, the
patient now showed a 12 £ 5 mm area of exposed bone
(Figure 2). The surrounding gingiva was inflamed, and
purulence was expressed upon palpation of the area.
Adjacent teeth #29 and #30 still had no sensitivity to
percussion, and class 1 mobility noted with tooth #30
was unchanged.TagedEn
TagedPThe patient reported that she had stopped brushing
her teeth with a toothbrush due to bleeding since her
previous visit, and the patient presented with heavy
plaque deposits throughout the mouth. In addition, gin-
gival overgrowth was noted on the lingual papillae
between teeth #11 to #15 and teeth #22 to #27. A sharp
area was noted on the exposed bone that corresponded
with an ulcer on the lateral border of the right tongue.TagedEn
TagedPThe sharp area of exposed bone was smoothed to the
patient’s comfort, and the exposed bone was irrigated
with chlorhexidine. She was advised on proper oral
Statement of Clinical Relevance
We report a case of osteonecrosis of the jaw with
pembrolizumab, a rare yet possibly emerging com-
plication. The number of patients using pembrolizu-
mab will likely continue to increase. We document
this instance to better inform dental treatment
around patients with cancer undergoing pembrolizu-
mab therapy.
e11
ORAL MEDICINE
TagedEne12 Pennings et al.
TagedFiur
Fig. 1. Periapical radiograph of tooth #30 revealing moth-eaten radiolucent pattern.TagedEn
hygiene measures and was instructed to irrigate the
gums with chlorhexidine rinse for 2 weeks. She
returned in 1 week for a dental debridement as her
blood counts allowed.TagedEn
TagedPThree weeks later, she returned for follow-up. Her
oral health was much improved with a reduction in gin-
gival inflammation. The previously noted area of
exposed bone on the right mandible was noted to have
increased in size to 17 £ 10 mm. The surrounding gin-
giva was slightly inflamed but without purulence. Upon
manipulation with cotton pliers, the entire bony segment
approximately 17 £ 10 mm was removed to reveal soft
tissue underneath (Figure 3). Tooth #30 remained grade
1 mobile; no other dental symptoms were noted.TagedEn
TagedPThe patient was advised to continue fastidious oral
home care after removal of the necrotic bone segment.
TagedFiur
Fig. 2. (A) Intraoral photograph showing exposed bone on mandibular torus. (B) Close-up photo of exposed bone and purulent
gingiva.TagedEn
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July 2023
She underwent autologous stem cell transplant 4 days
later and experienced no further oral symptoms. On
follow-up examination in June 2022, she remained
symptom free without further areas of exposed bone or
acute gingival inflammation.TagedEn
TAGEDH1DISCUSSIONTAGEDN
TagedPThe oral lesion was first noted on positron emission
tomography/computed tomography approximately 1
month after initiation of pembrolizumab/GVD, and
exposed bone was noted clinically shortly thereafter.
She had no history of dental procedure, trauma, and
denied prior history of medications conventionally
associated with medication related osteonecrosis of
the jaw (MRONJ). In addition, there was no recent
history of general anesthesia or intubation before
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TagedEnVolume 136, Number 1
TagedFiur
Fig. 3. (A) Bone segment after removal from oral cavity. (B) Mandibular gingiva with epithelialization immediately after
removal of necrotic bone.TagedEn
onset of bone exposure which could have caused
oral trauma.TagedEn
TagedPThe clinical presentation appeared consistent with
MRONJ. Medication related osteonecrosis of the jaw
is most commonly associated with anti-resorptive
medications such as IV bisphosphonates, denosumab
(humanized monoclonal antibody), and anti-angio-
genic medications such as bevacizumab (humanized
monoclonal antibody) and sunitinib (tyrosine kinase
inhibitor).1 An increased risk of MRONJ is also asso-
ciated with local factors such as dental surgery, local
trauma, and anatomic factors. Medication related
osteonecrosis of the jaw has been more commonly
reported in the mandible (73%) than maxilla
(22.5%), although it can be seen in both jaws
(4.5%).2 In addition, mandibular and palatal tori are
usually considered anatomic risk factors for the
development of the condition.3 Genetic factors, cor-
ticosteroid use, and tobacco also play a role. For
patients with cancer in particular, anemia (hemoglo-
bin <10 g/dL), diabetes, and cancer type have been
variably associated with increased risk of MRONJ.2TagedEn
TagedPThe current understanding of MRONJ identifies sys-
temic abnormalities in coagulation and fibrinolysis as
key elements of the pathophysiologic cascade, where
intravascular coagulation and thrombotic occlusion of
bone microcirculation lead to ischemic bone destruc-
tion.4 In this patient, abnormally high platelet counts
coincided with the period of bone exposure, with plate-
let counts measured at peak numbers of 510K, 497K,
and 593K in December, January, and February, respec-
tively. Thrombocytosis may have played a role in
ischemic bone destruction in our patient.TagedEn
TagedPImmune checkpoint inhibitors such as pembrolizu-
mab are generally better tolerated in most patients with
fewer oral toxicities compared with conventional che-
motherapy. However, oral immune-related adverse
events have been reported, including mucosal changes
(presenting commonly as inflammatory/immune condi-
tions, such as lichenoid reactions, gingival sloughing,
or erythema), dry mouth, and taste changes.
CASE REPORT
Pennings et al. e13
Osteonecrosis of the jaw (ONJ) is less frequently
reported with immune checkpoint inhibitors, but it has
been reported with ipilimumab.5TagedEn
TagedPIpilimumab, a humanized antibody against the inhib-
itory co-receptor CTLA-4, was the first checkpoint-
block monoclonal antibody to be approved. Ipilimu-
mab increases the presence of systemic activated T
cells by preventing binding of inhibitory receptors to
their natural ligands.6TagedEn
TagedPInterestingly, CTLA-deficient T cells have been
shown to be associated with osteonecrosis. Activated T
cells may elicit osteoclastogenesis via osteoprotegerin
ligand resulting in bone loss. In a case report of ONJ
with ipilimumab, Owosho et al. posited that incidences
of oral trauma in this setting could result in localized
bone necrosis.1TagedEn
TagedPPembrolizumab is a more recently approved immune
checkpoint inhibitor which targets programmed cell
death 1 (PD-1), a ligand which negatively regulates T-
cell activation to prevent autoimmune disease but can
also prevent T-cells from killing cancer cells. Inhibi-
tion of the PD-1 checkpoint allows for T-cell reactiva-
tion, restoring the immune system, and helping to
prevent tumor escape.6TagedEn
TagedPThere currently exists 1 report of ONJ associated with
pembrolizumab/epacadostat therapy. Authors of this case
study posit that inhibition of PD-1 and an increase in
anti-osteoclastogenic interferon-gamma could lead to the
development of ONJ.7 Furthermore, as suggested by
Owosho et al., incidences of trauma in a setting of
decreased osteoclastogenesis could heighten risk of local-
ized bone necrosis.1 In this patient’s case, it is plausible
that the patient could have traumatized the thin area of
the gingiva overlying the large mandibular torus, an ana-
tomic morphology already a risk factor for ONJ.3 It may
be that trauma to the mandibular torus in the setting of
decreased osteoclastogenesis as a result of pembrolizu-
mab therapy manifested in our patient’s condition.TagedEn
TagedPIn this patient, the temporal relationship between
the development of ONJ and her treatment regimen
suggests an association between pembrolizumab/
ORAL MEDICINE
TagedEne14 Pennings et al.
GVD therapy and the development of ONJ. Thrombo-
cytosis and anatomic factors may also have played a
role. An informed consent for clinical research was
obtained from the patient.TagedEn
TagedPThe body of knowledge regarding oral effects of
immunotherapy continues to grow. Noting oral symp-
toms as they occur in conjunction with specific immu-
notherapies may help us to better understand the nature
of these conditions. In particular, the unexpected devel-
opment of ONJ with highly specific therapies may help
to further elucidate the pathophysiologic mechanism
by which this condition occurs.TagedEn
TAGEDH1CONCLUSIONTAGEDN
TagedPOsteonecrosis of the jaw is not generally associated
with immunotherapy. We describe a case of ONJ with
pembrolizumab, a rare yet possibly emerging compli-
cation. Pembrolizumab has an increasing number of
applications, with its use now approved for >20 can-
cers including melanoma, nonsmall cell lung cancer,
head and neck squamous cell cancer, classical Hodgkin
lymphoma, primary mediastinal B-cell lymphoma, uro-
thelial carcinoma, microsatellite instability-high or a
mismatch repair deficient solid tumors, colon or rectal
cancer, gastric or gastroesophageal junction adenocar-
cinoma, PD-1 positive cervical cancer, hepatocellular
carcinoma, Merkel cell carcinoma, renal cell carci-
noma, endometrial carcinoma, cutaneous squamous
cell carcinoma, and triple-negative breast cancer.8TagedEn
TagedPThe number of patients using pembrolizumab will
likely continue to increase. Any further instances of
ONJ should be documented in order to better inform
dental management around patients with cancer under-
going pembrolizumab therapy. In patients who exhibit
oral and systemic symptoms related to their immuno-
therapy, care should be taken to reduce potential
trauma to the oral cavity.TagedEn
TAGEDH1FUNDINGTAGEDN
TagedPThis research was supported in part by the National
Institutes of Health/National Cancer Institute Cancer
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July 2023
Center Support grant P30 CA008748. The content is
solely the responsibility of the authors and does not
necessarily represent the official views of the National
Institutes of Health.TagedEn
TAGEDH1DISCLOSURESTAGEDN
TagedPDr Shah receives research funding to the institution
from Janssen, Amgen, and Beyond Spring.TagedEn
TAGEDH1ETHICAL APPROVALTAGEDN
TagedPThis report was approved by the Institutional Review
Board of Memorial Sloan Kettering Cancer Center. An
informed consent for clinical research was obtained
from the patient.TagedEn
TAGEDH1REFERENCESTAGEDN
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new complication related to ipilimumab. Oral Oncol. 2015;51:
e100-e101.TagedEn
TagedP2. Ruggiero SL, Dodson TB, Fantasia J, et al. American Association
of Oral and Maxillofacial Surgeons. American Association of
Oral and Maxillofacial Surgeons position paper on medication-
related osteonecrosis of the jaw 2014 update. J Oral Maxillofac
Surg. 2014;72:1938-1956.TagedEn
TagedP3. Schiødt M. Mandibular and palatal tori exposed by trauma are risk
factors for medication-related osteonecrosis of the jaws: a report
from the Copenhagen ONJ cohort. Oral Surg Oral Med Oral
Pathol Oral Radiol. 2020;129:e193.TagedEn
TagedP4. Badescu MC, Rezus E, Ciocoiu M, et al. Osteonecrosis of the
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from pathophysiology to therapeutic implications. Int J Mol Sci.
2022;23:640.TagedEn
TagedP5. Rapoport BL, van Eeden R, Sibaud V, et al. Supportive care for
patients undergoing immunotherapy. Support Care Cancer.
2017;25:3017-3030.TagedEn
TagedP6. Brunner-Weinzierl Monika C, Rudd Christopher E. CTLA-4
and PD-1 control of T-cell motility and migration: implica-
tions for tumor immunotherapy. Front Immunol. 2018;9:
2737.TagedEn
TagedP7. Decaux J, Magremanne M. Medication-related osteonecrosis of
the jaw related to epacadostat and pembrolizumab. J Stomatol
Oral Maxillofac Surg. 2020;121:740-742.TagedEn
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keytruda.com. Accessed June 28, 2022.TagedEn