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Central giant cell granuloma of the head & neck: A case report and
systematic review
Jordan Richardsona,*, Dani Stanboulyb, Eric Litmana, Kevin C. Leec, Elizabeth Philiponec
a
Michigan State University College of Osteopathic Medicine, East Lansing, MI 48824
b
Columbia University College of Dental Medicine, New York, NY 10032
c
Division of Oral and Maxillofacial Surgery, NewYork-Presbyterian/Columbia University, Irving Medical Center, New York, NY 10032

A R T I C L E I N F O A B S T R A C T

Article History: Purpose: The purpose of this paper is to describe a recent case of central giant cell granuloma (CGCG) that
Received 4 May 2021 rapidly progressed post corticosteroid treatment while also providing a review of the existing literature on
Accepted 11 August 2021 CGCG of the head and neck (HNCGCG), with particular emphasis on extra-mandibular and maxillary cases.
Available online xxx
Materials and Methods: The investigators designed and implemented a 32-year review of literature, using the
online databases: PubMed, Google Scholar, Medline, and Proquest. The total number of cases analyzed was
Keywords:
55 (42 case reports; 3 case series; 8 comparative studies; 1 retrospective cohort).
Central giant cell granuloma
Case Presentation: We present a case of a CGCG in a 10-year old male. The lesion originated in the right ante-
head and neck cancer
Oral pathology
rior mandibular body and progressed after corticosteroid treatment. Diagnosis was made using a combina-
MAXILLOFACIAL SURGERY tion of imaging and histology. A timely debulking procedure of the hemi-mandible was performed and there
was no recurrence of the lesion at follow up.
Results: The average age at the time of diagnosis of CGCG was 27.5 years. HNCGCG was most commonly
detected in the jaw (43.1%), but was also found in the temporal bone (33.3%). The most frequently employed
treatment modality was complete surgical excision (76.9%). 93.2% of patients were alive with no evidence of
disease at follow-up, while 6.8% of patients exhibited recurrence at follow-up. The median follow up was 13
months.
Conclusion: It is important for clinicians to recognize that CGCGs are capable of manifesting outside of the
jaw. CGCG should be considered in the differential diagnosis of non-odontogenic radiolucent lesions, espe-
cially in young patients. CGCGs also need to be distinguished from brown tumor of hyperparathyroidism
(BTH) and giant cell tumors, which are histologically similar.
© 2021 Elsevier Masson SAS. All rights reserved.

1. Case report was obtained. The radiological report revealed a well-circumscribed,

A 10-year old male presented to the division of oral and maxillofa-
cial surgery at Columbia University with swelling of the anterior
mandible. Extraoral examination was significant for mandibular
asymmetry. On intraoral examination, buccal expansion was visual-
ized from the right mandibular first molar towards the midline of the
mouth. The lesion lacked pulsatility. Mandibular teeth, specifically
the right mandibular molar region to the left premolar region were
loose and painful. The patient presented after having undergone an
initial treatment of intralesional corticosteroid injections at another
institution. The details of this treatment were not provided. This
treatment was not successful as the mass continued to grow. Com-
puted Tomography (CT) of the maxillofacial region without contrast
* Corresponding author at: 965 Wilson Rd.
E-mail addresses: richa880@msu.edu (J. Richardson), ds3840@cumc.columbia.edu
(D. Stanbouly), litmaner@msu.edu (E. Litman), kcl2136@cumc.columbia.edu (K.C. Lee),
ep2464@cumc.columbia.edu (E. Philipone).
large expansile lesion involving mainly the anterior right mandibular
body. Additional internal lytic areas were noted as was slight hetero-
geneous mineralization. Expansion of the lesion into the buccal and
lingual cortices were noted; however, no cortical perforation was
present. Multiple tooth roots proved to be involved. Magnetic Reso-
nance Imaging (MRI) of the head with and without intravenous con-
trast indicated an expansile lucent lesion involving the right anterior
body segment to a greater extent than that of the left. Their scans
exhibited an absence of periosteal reaction, which is typically seen in
malignant lesions, such as Ewing’s sarcoma or osteosarcoma. Histo-
logical analysis through incisional biopsy led to a diagnosis of CGCG
(Fig. 1). The patient ultimately underwent debulking of the mandibu-
lar lesion. There was no recurrence of the lesion at follow-up 5
months later. The patient’s postoperative course was uneventful
other than some mild numbness of the right lower lip that subsided
shortly after.

https://doi.org/10.1016/j.jormas.2021.08.004
2468-7855/© 2021 Elsevier Masson SAS. All rights reserved.

Please cite this article as: J. Richardson, D. Stanbouly, E. Litman et al., Central giant cell granuloma of the head & neck: A case report and
systematic review, Journal of Stomatology oral and Maxillofacial Surgery (2021), https://doi.org/10.1016/j.jormas.2021.08.004
JID: JORMAS
ARTICLE IN PRESS
J. Richardson, D. Stanbouly, E. Litman et al.
Fig. 1. Histology of central giant cell granuloma (CGCG).
Legend: High-power microscopic image (magnification 100x) demonstrates a
benign fibro-endothelial cell population (Red arrow) with scattered multinucleated
giant cells (Yellow arrow) and extravasated red blood cells.
2. Introduction
Henry L. Jaffe first articulated Giant Cell Granuloma (GCG) as a
non-neoplastic, local reparative reaction of bone that is separate
from giant cell tumor of bone (GCT) [1]. When GCG was first
described the lesions were hemorrhagic, leading many to believe
their etiology was related to trauma; hence, the name giant cell
“reparative” granuloma (GCRG) was coined [1,2]. However, the etiol-
ogy of GCGs is not fully understood as there have been several cases
reported lacking a history of trauma [4,11,12,23,24]. Giant cell granu-
lomas are further classified as: central or peripheral and aggressive
or non-aggressive. Central giant cell granulomas (CGCG) correspond
to intraosseous lesions (e.g., mandible and maxilla), while peripheral
giant cell granulomas (PGCG) pertain to soft tissue regions (e.g., oral
cavity). While some have proposed that GCG and GCT are two var-
iants of the same disease [4], GCT is generally understood to exist as
a separate entity [5].
Giant cell granulomas occur at an incidence rate of 1.1 per million
per year [6]. Central giant cell granulomas are almost universally
located in the jaw [9,47]. Brown tumor of hyperparathyroidism, GCT,
cherubism, aneurysmal bone cyst, and osteosarcoma are formidable
imitators of GCG, warranting stuach consideration in the differential
diagnosis [15,16]. The mainstay of treatment for GCG is surgical exci-
sion, however, for lesions unfavorable for surgery, alternative treat-
ments include: intralesional corticosteroid injections, calcitonin
injections, and interferon treatment. The main concern with GCG is
recurrence, which can be as high as 49% in some cases that are
treated surgically [18]. The literature concerning HNGCG occurring in
locations outside of the jaw is scarce. While this study does include
mandibular and maxillary GCGs, it also includes many cases of GCG
manifesting in other locations in the head and neck. The goal of this
study is to shed light on the clinical presentation, diagnostic
approaches, and treatment of all HNGCGs.
3. Materials and methods
3.1. Medical subject heading terms
Medical subject heading (MeSH) terms used for the search were
“Giant Cell Granuloma of x,” where “x” represented specific locations
in the head and neck including the mandible, maxilla, nasal cavity,
temporal bone, and sinuses (Table 1). Four search engines were que-
ried with MeSH terminology to obtain articles pertinent to Giant cell
granuloma: PubMed, Google Scholar, Medline, and Proquest. All
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Table 1
Medline search criteria.
(Central Giant Cell Granuloma of the Maxilla)) AND (Central Giant Cell Granu-
loma of the Mandible)) AND (Central Giant Cell Granuloma of the Mandible))
AND (Central Giant Cell Granuloma of Temporal Bone)) AND (Central Giant
Cell Granuloma of the Sinus)) AND (Central Giant Cell Granuloma of the
Nasal Cavity)) AND (Central Giant Cell Granuloma of the Palate)) AND (Cen-
tral Giant Cell Granuloma of the Glands)
Filters: Full text, from 1988-2021
Legend: The exact terminology used to search for articles related to head and neck
central giant cell granuloma across all four databases.
articles included in the final review process were published in the
past 32 years to optimize relevant management and access to full-
manuscripts. The Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) diagram illustrates the steps of screen-
ing and analyzing the various articles during the selection process for
this review.
3.2. Eligibility criteria
Abstracts of all articles were screened by two independent exam-
iners (J.R and E.R) to ensure sufficient information was present. Liter-
ature that was not in the English language, not published in a peer-
reviewed journal, irrelevant to Central Giant Cell Granuloma of the
head and neck, or from an animal, cadaveric, or histologic study were
excluded. Studies with unobtainable full-text, insufficient demo-
graphic data, inadequate treatment data, aggregate data, or anatomic
locations outside of the head and neck were further excluded. Articles
describing a previously published case were excluded to avoid double
counting. For inclusion criteria to be met, each case report, case
series, comparative study, and retrospective study necessitated: (1)
at least 1 case of Centrally-Located Giant Cell Granuloma of the Head
and Neck, (2) incidence of case(s) between the years of 1988-2020
(Fig. 2).
3.3. Data collection process
The following data was collected from each study: author name,
publication year, study design, patient age and gender, histological
subtypes, associated presenting symptoms, GCG size and location
(including extension), history of trauma, imaging modality utilized to
locate the tumor, treatment modality and prognosis.
3.4. Statistical analysis
Statistical calculations were performed using SPSS version 26 for
Mac (IBM Corp., Armonk, N.Y., USA). Descriptive statistics were pre-
sented as mean and range for continuous variables.
4. Results
4.1. Study selection
The published literature on cases of HNGCG was searched through
December 27th, 2020. 177 results were identified, which were
screened with the designated eligibility criteria. On the basis of the
selection criteria, 52 articles related to HNGCG remained after the
screening process. Of these, there were no articles written in non-
English language and 125 articles were excluded from the review
due to lack of required details. None of the articles were excluded on
the basis of duplicate patient information. Furthermore, it was possi-
ble to retrieve the full-text for the aforementioned 52 articles. Ulti-
mately, 52 articles were included for final review and analysis and
were published over the past 32 years (1988−2020) (Fig. 2). This
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J. Richardson, D. Stanbouly, E. Litman et al.
Fig. 2. PRISMA search criteria.
Legend: Visual representation of search criteria after analyzing articles from four different databases (PubMed, Google Scholar, Medline, Proquest).
study qualified as non-human subject research as per the protocol of
the institutional review board (IRB) of Columbia University in the city
of New York, and consequently did not require IRB approval.
4.2. Description of studies
Data on a total of 55 cases of HNGCG were extracted from 52
articles included in the final review and analysis. Information regard-
ing the age at the time of diagnosis was available for 49 cases. The
mean age was 27.5 years (range: 5 days - 74 years). There was no
gender predilection, as the cases were evenly divided between males
(50%) and females (50%). Of the 52 articles included, insight into
study type was available for 40 studies: the majority of cases were
derived from case reports (78.2%), with the remaining from compara-
tive studies (14.5%), case series (5.5%), and retrospective cohort stud-
ies (1.8%) (Table 2).
4.3. Tumor characteristics, symptomatology, trauma-history and
location
Information pertaining to tumor size was available for 17 cases.
The mean maximal tumor dimension at the time of diagnosis was
4.3 cm (range: 1.5-7.6 cm). The histologic subtype of CGCG was
reported in 47 cases: the majority of which displayed non-aggressive
features (80.9%), with only nine cases displaying aggressive features
(19.1%). The presenting symptomatology exhibited marked variance,
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depending on the anatomical site occupied by the tumor. For
instance, a case of CGCG located in the nasal cavity presented with
epistaxis and nasal obstruction. Additionally, extension of the tumor
into the orbit accounted for presenting proptosis and epiphora [33].
On the other hand, a patient with a tumor in the temporal bone
extending into the middle-ear cavity presented with hearing loss:
the external auditory canal was completely blocked by the tumoral
extensions. Further ear symptoms included: otalgia and auricular
fullness [10]. Concerning the location of the GCG, the jaw (maxilla
and mandible) proved to be the most frequently occupied site in our
sample (43.1%), followed by the temporal bone (33.3%) and sinuses
(11.8%). There was one case of GCG in the literature that presented in
the hard palate, a rather erratic site since the tumors typically present
in the anterior jaws [29]. We included the presence of previous
trauma or lack thereof in CGCG cases analyzed, given its potential
role in CGCG etiology. Insight was available for 24 cases, with only 3
of them illustrating a history of trauma (Table 2).
4.4. Diagnostic imaging
Insight into the diagnostic modality employed in the identifica-
tion of GCG was available for 48 cases. CT was the most frequently
employed diagnostic modality, utilized in 91.7% of cases. Addition-
ally, the next most common diagnostic modality was MRI (45.8%), fol-
lowed by radiography (20.8%) (Table 2).
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J. Richardson, D. Stanbouly, E. Litman et al. Journal of Stomatology oral and Maxillofacial Surgery 00 (2021) 1−8

Table 2 obtained. Giant cell granuloma is a rare lesion that most commonly
Central giant cell granuloma of the head and neck: demographic, pathogenic manifests in the jaw (i.e. mandible and maxilla) [1]. According to
characteristics, treatment regimens and outcomes.
Pubmed, there is only one other systematic review concerning
Age mean in years (range) 27.5 (5 days-74 years) HNGCG, however, this study specifically focuses on GCGs located in
Gender the jaw [16]. In our literature review of CGCG, we were surprised to
Male 24 (50%) find numerous case reports and case series discussing occurrences of
Female 24 (50%)
Study Type
CGCG in the head and neck regions, outside of the jaw. Unfortunately,
Case Report 43 (78.2%) there is a paucity of literature commenting on extragnathic CGCGs as
Case Series 3 (5.5%) far as symptomatology, diagnostics, treatment, and prognosis goes.
Retrospective Cohort 1 (1.8%) To the best of our knowledge, this is the first systematic review of
Comparative Study 8 (14.5%)
CGCG that includes extra-mandibular and maxillary cases.
Maximal dimension of tumor, mean (range) 4.3 cm (1.5-7.6cm)
Histologic Subtype Giant cell granulomas occur most frequently in younger popula-
Non-aggressive 38 (80.9%) tions. One study reported that nearly 75% of patients diagnosed with
Aggressive 9 (19.1%) GCGs are younger than thirty [20]. Devi et al. also determined that
Location GCGs are most likely to occur in the second or third decades of life
Maxilla 13 (25.5%)
Mandible 9 (17.6%)
[8]. In the systematic review by Chranovic et al., out of 2,216 cases of
Teeth 1 (2.0%) GCG, the average age at diagnosis was 25.8 § 15.3 [16]. These results
Nasal Cavity 3 (5.9%) are consistent with the findings in our study with a calculated
Hard Palate 1 (2.0%) median age of diagnosis of 27.5 years old. Females are generally
Temporal Bone 17 (33.3%)
understood to have a higher propensity to acquire GCG, with some
Sinuses 6 (11.8%)
Gland 1 (2.0%) studies stating that they are three times more likely to be afflicted
History of Trauma than males. However, our study found an even split between genders
Yes 3 (12.5%) (1:1 males to females) [7,8]. This may be misleading due to our
No 21 (87.5%) smaller sample size (n=55), compared to Chrcanovic et al., who ana-
Diagnostic Imaging
Computed Tomography
lyzed 2,233 cases, 60.8% of which were female [16].
Yes 44 (91.7%) It is well-documented that the vast majority of CGCGs occur in the
No 4 (8.3%) jaw [5,9,21]. More specifically, one study proposes that CGCG are two
Magnetic Resonance Imaging to three times more common in the mandible compared to the max-
Yes 22 (45.8%)
illa (8]. These findings are consistent with the results of our study as
No 26 (54.2%)
Radiography the jaw was the most common location for CGCG (43.1%). Contrary to
Yes 10 (20.8%) Devi et al., our study determined that the maxilla (25.5%) was slightly
No 38 (79.2%) more affected than the mandible (17.6%). In the current study, CGCGs
Treatment were also found in a multitude of locations outside of the jaw. In
Complete Surgical Resection 40 (76.9%)
Calcitonin 5 (9.6%)
2020, Alzaidi et al., described a case of a patient who presented to
Corticosteroids 3 (5.8%) their department with a slowly enlarging swelling over the left
Denosumab 1 (1.9%) parotid gland, which was later diagnosed as a CGCG that infiltrated
Complete Surgical Excision + Corticosteroids 1 (1.9%) the zygomatic bone [19]. A year earlier, in 2019, Song et al. described
Corticosteroids + Bisphosphonates 1 (1.9%)
a case of a patient who complained of four years of hearing loss in the
Complete Surgical Excision + Bisphosphonates 1 (1.9%)
Outcome left ear as well as two months of preauricular swelling. Radiologic
Alive with no evidence of disease 41 (93.2%) imaging of the temporal bone identified a mass in the left lateral skull
Recurrence of disease 3 (6.8%) base that was further removed and pathologically determined to be a
Follow up period in months (range) 26 (1-144 months) CGCG [20]. This is one of several documented cases of CGCG occurring
Legend: Table detailing the results of the literature review for each variable in the temporal bone [20-27,33]. Moreover, Ishinaga et al. described a
studied in this research project. case of a patient with a two-month history of right-sided nasal
obstruction, epistaxis, proptosis, and diplopia [28]. A mass located in
the nasal cavity was diagnosed as a CGCG. There have also been cases
4.5. Treatment, outcome, and follow-up of CGCG manifesting in the hard palate. In 1998, Hernandez et al.,
described a case of a patient presenting with a right-sided hard palate
Surgery alone, particularly complete surgical excision, was the mass that ended up being a GCG [29]. While it is important to under-
most frequent treatment modality for GCG, executed in 40 cases stand that a majority of CGCGs manifest in the jaw region, it is pivotal
(76.9%). Less frequently, several different pharmaceuticals were to recognize that these lesions can manifest elsewhere in the head
employed either as standalone therapy or in conjunction with sur- and neck region. In the current study, the temporal bone was the
gery. Calcitonin was administered in five cases (9.6%) and corticoste- most common extra-gnathic location for GCG, comprising 35.3% of
roids in three cases (5.8%). Denosumab was administered in one case the cases.
(Table 2). Since CGCGs have a propensity to occur in the gnathic region, the
Insight into treatment outcomes was available in 44 cases. The most prevalent symptom is a painless swelling of the jaw [9,17]. The
majority of cases (93.2%) had a favorable prognosis, resulting in present study, instead, suggests that symptomatology related to
patients alive with no evidence of disease at follow-up. The rest of CGCG is dependent on location of the lesion and even then, symp-
the cases (6.8%) illustrated recurrence at follow-up. The median fol- tomatology is highly variant. While painless swelling of the jaw was
low-up period was 13.0 months (Table 2). observed in cases of CGCG manifesting in the mandible and maxilla
[33,36], lesions occurring in other regions of the head and neck
5. Discussion including the temporal bone, nasal cavity, and sinuses were not con-
gruent with this presentation. Seo et al. highlights this premise as
The present study aimed to analyze the existing literature con- they describe a case of nasal cavity CGCG in a pediatric patient who
cerning HNGCG. Information regarding demographics, symptomatol- presented with a one-month history of epistaxis, nasal obstruction,
ogy, diagnostic imaging, treatment, recurrence and prognosis was proptosis, and epiphora [34]. Additionally, Gupta et al. explicates a
4
 Table 3
Reported cases of giant cell granuloma, 1988-2020.

Reported cases Demographics Key characteristics Location of incidence Screening Clinical presentation Treatment Follow-up

Author/Year Study Design Age/ Central/ Size Cystic Areas History of Primary Location Direct Extension Diagnostic Symptom Profile Differential Diagnosis Aggressive/ Primary/Ancillary Therapy Prognosis
JID: JORMAS

Gender Peripheral Trauma Modality (First impression) Non-aggressive

Eisenbud et al., 198835 Case Report and *Could not

Literature Review access full
article
Govett et al., 199136 Case Report *Could not
access
article
Harris et al., 199337 Case Report Unspecified Central Unspecified Unspecified Unspecified Jaws Unspecified Unspecified Unspecified Unspecified Unspecified Human Calcitonin Alive with no evidence of disease
Stolovitzky et al., 19944 Case Report 22/F Central 2 cm Unspecified No Maxilla nasal area Radiography enlarging mass Unspecified Non-aggressive Complete surgical excision Recurrence 2 and 4 years after initial dx. Pro-
gressed to giant cell tumor. Since last surgery,
has been disease free for 11 years.
J. Richardson, D. Stanbouly, E. Litman et al.

Stolovitzky et al., 19944 Case Report 42/F Central Unspecified Unspecified Unspecified Maxillary canine Radiography, CT numbness in mouth, loos- Unspecified Non-aggressive Complete surgical excision Alive with no evidence of disease 5 years after
and ening of teeth diagnosis
premolar teeth
Stolovitzky et al., 19944 Case Report 60/M Unspecified Unspecified Unspecified Unspecified Nasal cavity No CT epistaxis, nasal congestion Unspecified Non-aggressive Complete surgical excision Alive with no evidence of disease 3 years after dx
Spraggs et al., 199711 Case Report 67/M Central Unspecified Unspecified No Maxilla floor of the orbit CT facial swelling, epiphora Unspecified unspecified Complete surgical excision Alive with no evidence of disease at 4 year follow
and nasal obstruction up
Spraggs et al., 199711 Case Report 74/M Central Unspecified Unspecified No Maxilla No CT facial swelling, nasal Unspecified Non-aggressive Complete surgical excision Alive with no evidence of disease after 4 years
obstruction and
increasing snoring.
Hernandez et al., 199829 Case Report 65/M Central 3 cm Unspecified Yes Hard palate Nasal and oral cavities CT hard palate mass Unspecified Non-aggressive Complete surgical excision Alive with no evidence of disease at 8 month fol-
low up
de Lange et al., 199938 Case Report 4/M Central Unspecified Unspecified Unspecified Mandible Unspecified Radiography, CT, orthopantomography Painless swelling Unspecified Non-aggressive Intranasal calcitonin (200 IU) for 14 mo
Alive without evidence
of disease 10 mo
after treatment
ended
de Lange et al., 199938 Case Report 11/M Central Unspecified Yes Unspecified Mandible Unspecified orthopantogram Progressive swelling Hyperparathyroidism Non-aggressive SubQ calcitonin (50 IU) for 12 Alive without evidence of disease 18 mo after
and CT mo treatment
de Lange et al., 199938 Case Report 18/F Central Unspecified Unspecified Unspecified Mandible Unspecified orthopantogram, Mandibular swelling Unspecified Non-aggressive SubQ calcitonin (87.5 IU) for Alive without evidence of disease 3 years after tx
radiography 13 mo
de Lange et al., 199938 Case Report 16/M Central Unspecified Unspecified Unspecified Mandible Unspecified orthopantogram Mandibular swelling Hyperparathyroidism Non-aggressive SubQ calcitonin (100 IU) for Alive without evidence of disease 7 mo after tx
15 mo
Kaban et al., 199912 Case Report 5/F Central 5 cm Yes No Mandible No CT painful, rapidly growing ABC Non-aggressive 1. Complete Surgical resec- Recurrence @ 9 and 20 weeks after surgery.
mass tion 2. Complete surgical Lesioned progressed to giant cell tumor that
resection 3. Calcitonin was successfully treated with interferon alfa-

5
therapy 4. interferon alfa- 2a for 1 year and no signs of disease recur-
2a rence 3 years after stopping interferon alfa-
2a.
Khafif et al., 200032 Case Report 36/F Central 4 cm Unspecified Unspecified Maxilla No CT Painful swelling + sinus Unspecified Aggressive Corticosteroid Injections Alive, mass is completely calcified on CT 2 years
infection after diagnosis with no evidence of recurrent
growth
Williams et al., 200022 Case Report 38/M Unspecified 5.4 cm Unspecified No Temporal bone floor of middle fossa, Radiography (nega- ear fullness, hearing loss, Unspecified Non-aggressive Complete surgical excision Alive without disease 1 mo after diagnosis
semicircular tive), CT, MRI and cacosmia
canals, mastoid air
cells
Ust€
unda
g et al., 200239 Case Report 4/F Central 3 cm Unspecified No mandible No CT swelling Brown tumor, cherubism, Non-aggressive Complete surgical excision Alive with no evidence of recurrence at 20 mo
aneurysmal bone cyst follow up
and fibrous dysplasia
Arda et al., 200314 Case Report 7/M Central Unspecified Unspecified Unspecified Ethmoid sinus orbit, frontal sinus, lamina CT, MRI swelling of his right eye, Unspecified Unspecified Complete surgical excision Recurrence of GCG at 6 and 10 weeks after intial
ARTICLE IN PRESS

papyracea nasal obstruction, diagnosis

epistaxis
Boedeker et al., 200324 Case Report 17/F Unspecified 4 cm Unspecified No Temporal bone sphenoid bone, infratem- CT, MRI hearing loss, vertigo, tin- Brown tumor of hyper- Aggressive Complete surgical excision Alive without disease 2 years after diagnosis
poral fossa, pterygoid nitus, facial weakness, parathyroidism, ABC,
fossa, temporoman- and paresthesia Cherubism, Fibrous
dibular joint, and mid- dysplasia, Giant cell
dle cranial fossa with tumor, osteosarcoma
extension into the
right temporal lobe
Sezer et al., 200540 Case Report 1/M Central Unspecified Unspecified Unspecified Unspecified Unspecified Unspecified Unspecified Unspecified Non-aggressive corticosteroid injections Alive with no evidence of disease
Ruiz et al., 200741 Case Report 6/M Unspecified 4 cm Unspecified Yes Maxilla Unspecified CT painless swelling Unspecified Non-aggressive Complete surgical excision Unspecified
Rudic et al., 200823 Case Report 40/F Central 3.7 cm Unspecified No Temporal bone middle cranial fossa CT hearing loss and weight Unspecified Non-aggressive Complete surgical excision Alive with no evidence of recurrence at 7 months
loss
Menge et al., 200925 Case Report 20/F Unspecified 4 cm Unspecified Unspecified temporal bone Mastoid, middle cranial CT, MRI hearing loss and tinnitus osteosarcoma, cherubism, Non-aggressive Complete surgical excision Alive with no evidence of disease at 3 mo follow
fossa, TMJ, External aneurismal bone cyst up
auditory canal and brown tumor of
hyperparathyroidism
Al Yamani et al., 201142 Retrospective Unspecified Unspecified Unspecified Unspecified *Insuffient Unspecified Unspecified Unspecified Unspecified Unspecified Non-aggressive Unspecified Unspecified
Cohort information
Wiles et al., 201113 Case Report 5 day old/F Central 4 cm No No Temporal bone Unspecified CT, MRI External auditory canal giant cell tumor, osteo- Unspecified Steroid injections, followed Steroids shrunk the lesion and pt is alive without
mass blastoma, aneurysmal by complete surgical evidence of disease at 30 mo. The patient
bone cyst, Langerhans resection began walking at 14 months and demon-
cell histiocytosis, and strated no sign of vestibular dysfunction at
rhabdomyosarcoma the last follow-up visit, at which time she was
31/2 years old.
Maerki et al., 201226 Case Report 27/M Unspecified Unspecified Unspecified Yes temporal bone middle cranial fossa CT headaches, fatigue, light- Unspecified Aggressive Complete surgical excision Unspecified
headedness, and diffi-
culty concentrating
Ma et al., 201221 Comparative study 36/F Unspecified Unspecified Unspecified No Tempral bone TMJ Unspecified Aggressive Complete surgical excision Alive without disease 13 mo after diagnosis
Journal of Stomatology oral and Maxillofacial Surgery 00 (2021) 1−8
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(continued on next page)

 Table 3 (Continued)

Reported cases Demographics Key characteristics Location of incidence Screening Clinical presentation Treatment Follow-up

Author/Year Study Design Age/ Central/ Size Cystic Areas History of Primary Location Direct Extension Diagnostic Symptom Profile Differential Diagnosis Aggressive/ Primary/Ancillary Therapy Prognosis
Gender Peripheral Trauma Modality (First impression) Non-aggressive
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CT, MRI, Hearing loss, tinnitus,

angiography otalgia
Ma et al., 201221 Comparative study 42/M Unspecified Unspecified Unspecified No Tempral bone TMJ CT, MRI tinnitus, otalgia Unspecified Non-aggressive Complete surgical excision Alive without disease 16 mo after diagnosis
Ma et al., 201221 Comparative study 38/F Unspecified Unspecified Unspecified No Tempral bone TMJ, sphenoid CT, MRI hearing loss Unspecified Non-aggressive Complete surgical excision Alive without disease 13 mo after diagnosis
Ma et al., 201221 Comparative study 35/F Unspecified Unspecified Unspecified No Tempral bone TMJ CT, MRI tinnitus, otalgia Unspecified Non-aggressive Complete surgical excision Lost to follow up
Ma et al., 201221 Comparative study 33/M Unspecified Unspecified Unspecified No Tempral bone TMJ, sphenoid CT, MRI mass Unspecified Non-aggressive Complete surgical excision Alive without disease 58 mo after diagnosis
Ma et al., 201221 Comparative study 21/M Unspecified Unspecified Unspecified No Tempral bone sphenoid CT, MRI hearing loss, mass Unspecified Non-aggressive Complete surgical excision Alive without disease 42 mo after diagnosis
Ma et al., 201221 Comparative study 50/F Unspecified Unspecified Unspecified No Tempral bone sphenoid CT, MRI hearing loss, dizziness Unspecified Non-aggressive Complete surgical excision Alive without disease 14 mo after diagnosis
Ma et al., 201221 Comparative study 40/M Unspecified Unspecified Unspecified No Tempral bone sphenoid CT, MRI hearing loss, tinnitus, Unspecified Non-aggressive Complete surgical excision Alive without disease 12 mo after diagnosis
dizziness
Devi et al., 20128 Case Report 40/F Central 6 cm No Unspecified Maxilla Unspecified Radiography, CT Facial swelling Giant cell tumor, ABC, Unspecified Complete surgical excision Recurrence 6 mo after surgery
Brown tumor
J. Richardson, D. Stanbouly, E. Litman et al.

Fasolis et al., 201344 Case Report 46/M Central Unspecified Unspecified Unspecified Mandible No Radiography, CT Enlarging mass Unspecified Non-aggressive Complete surgical excision Alive with no evidence of disease at 30 mo follow
up
Ishinaga et al., 201328 Case Report 49/F central Unspecified Unspecified Nasal cavity orbit, ethmoid sinus, max- CT nasal obstruction, epi- Unspecified Aggressive Complete surgical excision Alive without disease 1 year after diagnosis
illary sinus, and intra- staxis, proptosis, and
cranial region diplopia
Gupta et al., 201331 Case Report 16/F Central Unspecified Unspecified Unspecified Ethmoid sinus Unspecified Unspecified recurrent nasal bleeding, a Unspecified Aggressive Complete surgical excision Alive without disease 1 year after diagnosis
mass in the nose, diffi-
culty in nasal breath-
ing, a change in voice,
and bilateral proptosis.
Takata et al., 201310 Case Report 37/M Unspecified Unspecified Unspecified No Temporal bone Middle ear cavity CT, MRI Hearing loss, otalgia, Unspecified Non-aggressive Complete surgical excision Alive without disease 1 year after diagnosis
auricular fullness
Shah et al., 201445 Case Series 6/F Unspecified Unspecified Unspecified Unspecified Maxillary sinus Unspecified CT, MRI Swelling, nasal Unspecified Non-aggressive Complete surgical excision Alive without disease 15 months after diagnosis
obstruction
Shah et al., 201445 Case Series 10/M Unspecified Unspecified Unspecified Unspecified Ethmoid sinus Unspecified CT, MRI epistaxis, blurred vision, Unspecified Non-aggressive Complete surgical excision Alive without disease 12 months after diagnosis
proptosis
Shah et al., 201445 Case Series 30/M Unspecified Unspecified Unspecified Unspecified Sphenoid sinus Unspecified CT, MRI HA, nasal obstruction, epi- Unspecified Non-aggressive Complete surgical excision Recurrence of mass that resolved after tx with
staxis, loss of vision, external beam radiotherapy
pain on mouth
opening
Schreuder et al., 201446 Case Report 25/? Central Unspecified Unspecified Unspecified Maxilla Unspecified Unspecified Unspecified Unspecified Non-aggressive Denosumab Unspecified
Van Buren et al., 201427 Case Report 6/M Unspecified Unspecified yes No temporal bome mastoid air cells, bony CT, MRI bone mass + hearing loss rhabdomyosarcoma, aggressive Complete surgical excision Unspecified
external canal, and fibrous dysplasia, giant
otic capsule, semicir- cell tumor, osteosar-
cular canals and the coma, and aneurysmal

6
facial nerve canal bone cyst
Bayar et al., 20157 Case Report 42/M central 1.5 cm Unspecified No Maxilla Unspecified CT Swelling Brown tumor Non-aggressive Corticosteroid Injections Alive without disease 1 year after diagnosis
Janas et al., 201549 Case Report 8/M Central Unspecified Unspecified Unspecified Maxilla Unspecified Radiography Unspecified Brown tumor Non-aggressive Complete surgical excision Alive without disease 34 mo after diagnosis
Seo et al., 201530 Case Report 10/F Unspecified Unspecified Yes Unspecified Nasal cavity orbit, ethmoid CT, MRI epistaxis, nasal obstruc- Mucocele, pyogenic Non-aggressive Complete surgical excision Recurrent GCG 6 weeks post-op, but since second
sinusand anterior cra- tion, proptosis, and granuloma surgery has been alive without disease for 2
nial fossa epiphora. years
Eivaz et al., 201548 Case Report Unspecified/F Central 7 cm Yes Unspecified Maxillary sinus orbital floor, medial and CT sinus pressure and facial Unspecified Aggressive Complete surgical excision Alive with no evidence of recurrence at 5 months
posterior maxillary swelling and external
walls, and anterior deviation of nasal
ethmoid air cells septum
Arai et al., 20166 Case Report 44/F Central 7.6 cm Unspecified Unspecified Maxilla No CT, PET-CT, MRI painless swelling Unspecified Non-aggressive Complete surgical excision Alive without disease 12 mo after dx
Garg et al., 201730 Case Report 48/F Central Unspecified No Unspecified Maxilla No Orthopantomo- Jaw swelling Radicular cyst, Adenoma- Non-aggressive Complete surgical excision Alive without disease 6 mo after diagnosis
gram, CT toid odontogenic
ARTICLE IN PRESS

tumour (AOT), calcify-

ing epithelial odonto-
genic cyst (CEOC),
desmoplastic amelo-
blastoma, fibrous
dysplasia
Wang et al., 201949 Case Report 6/F Central 5.8 cm Yes Unspecified Mandible Condyle Radiography, CT, Facial swelling Brown tumors, cherubism Unspecified Complete surgical excision
MRI
de Mendonça Case Report 12/F Central Unspecified Unspecified Unspecified Maxilla Teeth 12,13 Radiography (nega- facial asymmetry and pal- Brown tumor, giant cell Aggressive Corticosteroid Injections + Bisphosphonates
et al., 201950 tive), CT atine and vestibular tumor
swelling
Clinical and imaging
follow-up over
12 years demon-
strates improve-
ment in the patient’s
condition.
Song et al., 201920 Case Report Unspecified Unspecified Unspecified Unspecified *Could not access Tempral bone Unspecified CT, MRI Hearing loss, preauricular Unspecified Non-aggressive Complete surgical excision Unspecified
full article swelling
Alzaidi et al., 202019 Case Report 28/F Unspecified 3.5 cm Unspecified No Parotid temporal and zygomatic CT, MRI Swelling Unspecified Non-aggressive Complete surgical excision Alive without disease 1 year after diagnosis
bones
Lin et al., 202051 Case Report 10/M Central Unspecified yes Unspecified Mandible No Panorex, CT, MRI enlarging mass Unspecified Non-aggressive Denosumab + Complete sur- Unspecified
gical excision

Legend: Comprehensive table detailing all of the information collected from each individual article in the literature review.
Journal of Stomatology oral and Maxillofacial Surgery 00 (2021) 1−8
[m5G;August 25, 2021;17:33]
JID: JORMAS
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J. Richardson, D. Stanbouly, E. Litman et al.
case of CGCG of the ethmoids that presented with a six-month his-
tory of recurrent epistaxis, a mass in the nose, difficulty with nasal
breathing, a change in voice, and bilateral proptosis [31]. As men-
tioned earlier, CGCGs occurring in the temporal bone may present
with hearing loss, tinnitus and vertigo. Boedeker et al. reports a case
of temporal bone CGCG that originally presented with hearing loss,
vertigo, tinnitus, facial weakness, and paresthesia [24]. Furthermore,
there have been documented cases of GCG presenting as painful
lesions of the jaw. In 1999, Kaban et al., described a case of mandibu-
lar CGCG that presented as a painful, rapidly growing mass [12]. Simi-
larly, Khafif et al. reported a case of maxillary CGCG that presented as
a painful swelling and sinus infection [32]. These discrepancies in
presentation of CGCG increase the difficulty with diagnosis as there
is, per se, no classic presentation of CGCG. Thus, one of the overarch-
ing aims of this systematic review is to educate clinicians on the vari-
ous presentations and locations that CGCGs may manifest in.
As was mentioned earlier, the etiology of CGCG is not clear. One
hypothesized etiology is trauma, which leads to hemorrhage and ulti-
mately an inflammatory response that culminates with a CGCG. On
the other hand, CGCGs may come about spontaneously without any
history of trauma [19]. In our study, the majority of cases did not
illustrate a history of trauma, supporting the neoplastic nature of
CGCG. It is worth mentioning accounts of CGCG flaring or recurring
during pregnancy, suggesting a possible hormonal dependence of the
lesion [52].
Diagnosing CGCG is challenging. A biopsy is required for definitive
diagnosis: however, imaging studies are usually the initial step in
evaluation of a patient presenting with HNGCG. Radiography, CT and
MRI are frequently utilized imaging modalities to visualize CGCGs.
Imaging plays an important role in the evaluation of CGCGs as it can
determine the extent of disease and subsequently the course of surgi-
cal management. On CT, CGCGs demonstrate osteolytic and expan-
sive changes to the surrounding bone [31]. Seo et al. adds there may
be cystic areas, calcifications, and bony remodeling on CT and that
radiologists need to be aware that these lesions may appear similar
to an infected mucocele or multiseptated cyst [34]. On the other
hand, Devi et al. believes that MRI is the best diagnostic imaging
modality for evaluating the extent of GCGs [8]. On MRI, CGCGs dem-
onstrate a low-to-intermediate signal on both T1-weighted and T2-
weighted images [8,31,35]. In the current study, CT scan was the
most common diagnostic modality employed to locate CGCG
(Table 3).
Giant cell granulomas present similarly to other conditions, most
notably, BTH and giant cell tumor. It is nearly impossible to distin-
guish between BTH and CGCG histologically and radiographically [7].
Thus, laboratory markers are utilized to make a distinction. Patients
who are suspected to have a CGCG should have serum calcium, phos-
phorus, and alkaline phosphatase levels evaluated [7,8]. In CGCG,
these values are expected to remain normal, however, this is not the
case for BTH [7]. It is crucial that CGCG is distinguished from GCT, as
the latter lesion is malignant in nature and is treated differently [24,
33]. Takata et al. determined that one can distinguish between CGCG
and GCT histologically. They have described GCT as classically dem-
onstrating larger multinucleated giant cells than those seen in CGCG,
as well as the presence of mitotic figures [10]. The authors add that
CGCG contains fewer multinucleated giant cells and shows no evi-
dence of mitotic activity.
As mentioned earlier, CGCGs are definitively diagnosed using his-
tology and immunohistochemistry. Under the microscope, GCGs
demonstrate frequent giant cells with a plethora of mononuclear cells
[3,33]. Areas of reactive bone formation, fibrosis and hemorrhage are
frequently isolated [33]. In addition, immunohistochemistry is an
integral tool in the diagnosis of CGCG; the lesions stain positive for
CD68 and CD163, confirming histiocytic origin [33].
Features consistent with non-aggressive CGCG include: painless
swelling, slow-growth pattern and low-risk for recurrence [18].
7
[m5G;August 25, 2021;17:33]
Journal of Stomatology oral and Maxillofacial Surgery 00 (2021) 1−8
Aggressive CGCG characteristics include: pain, paresthesias, rapid-
growth rate, involvement of cortical bone, root resorption, and high-
risk for recurrence [18]. While the aggressive and non-aggressive
subtypes present differently, they are indistinguishable under the
microscope [18]. The aggressive variant occurs more frequently in
younger people [18]. The non-aggressive variant is the more common
form of CGCG and this was demonstrated in the current literature
review as over 80% of the cases included were classified as non-
aggressive.
A multitude of distinctive modalities are postulated in the treat-
ment of CGCG: namely surgery, radiation, interferon, intralesional
corticosteroids, and tyrosine kinase inhibitors (Imatinib). Surgery is
the mainstay treatment of CGCG, particularly for the aggressive vari-
ant of CGCG. The different surgical procedures include: enucleation,
curettage, and segmental resection. Enucleation is advantageous over
segmental resection in its ability to preserve anatomical structures
that segmental resection would not. Nevertheless, the tradeoff of this
conservative approach characteristic of enucleation is its higher
recurrence rate relative to segmental resection [49].
The chief concern with CGCG is recurrence, which is reported as
high as 49% [18]. Giant cell granulomas that are deemed aggressive,
in nature, have a higher risk of recurrence compared to the non-
aggressive subtype [7, 41]. Recurrence rates are highly-dependent on
surgical technique [18] with en bloc resection having the best prog-
nosis. In order to prevent recurrence, Bayar et al. proposed that sur-
geons take five millimeter margins with extension into healthy
tissues [7,43]. If a patient exhibits recurrence of GCG, radiation ther-
apy and anti-angiogenic therapy can be used as salvage treatment
[40]. However, it is duly noted that some cases of CGCG are radiore-
sistant and a sarcomatous transformation may occur long-term [42].
For this reason, Arda et al. believes that anti-angiogenic therapy with
interferon alpha-2a is the gold standard for recurrences [14]. While
there is no definitive time period established, patients are highly
encouraged to regularly follow-up with their clinician due to the pos-
sibility of recurrence.
The findings in this study are not without limitations. Primarily,
52 articles were included in this review, each received screening for
several variables pertinent to CGCG: demographic information,
tumor characteristics, treatment modalities, and prognosis. The most
sizable limitation to this study proved to be that the authors did not
provide data on each of the aforementioned variables in every case.
For instance, some studies did not specify a follow-up period or
demarcate the histologic subtype of CGCG.
Additionally, it is well known that CGCG manifests in the head and
neck regions, particularly within the jaw. This literature review pri-
marily focused on extra-gnathic presentations of CGCG. The previous
literature review by Chranovic et al., was able to document many
more cases than since their study was limited to CGCG presentations
within the jaw only, which is a more frequent site of CGCG occur-
rence. Finally, with regards to the case presentation, the intraoral pic-
tography, CT/MRI were not provided to the reviewers (JR, EL).
6. Conclusion
Overall, CGCGs possess a propensity to occur in the jaw, however,
this is not always the case. The temporal bone, nasal cavity, paranasal
sinuses among other head and neck regions have proven to be loca-
tions of disease manifestation. Diagnosing CGCG is a clinical chal-
lenge as the location of the lesion dictates corresponding
symptomatology. Accurately diagnosing CGCG requires a collective
collaboration of clinical symptomatology, radiographic imaging as
well as histological and biochemical analysis. It is of extreme impor-
tance that an accurate diagnosis be promptly executed and similarly
presenting lesions, such as: BTH and GCT are ruled out. The treatment
for HNGCG is extremely promising with our study presenting some of
the lowest recurrence rates proclaimed by current literature.
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ARTICLE IN PRESS
J. Richardson, D. Stanbouly, E. Litman et al.
Acknowledgements
This study does not endorse competing interests or source(s) of
funding. The case report portion of the manuscript included the ret-
rospective study of one patient chart. Written consent was obtained
by the patient and subsequently IRB approval was not required. All
authors have viewed and agreed to this submission.
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