The central granular cell odontogenic tumor (CGCOT) is a rare, benign, slowly growing, odontogenic neoplasm. CGCOT was not considered as a distinct entity in the WHO classification reported on 2017. This study reports a rare case of CGCOT involving the right side of maxillary anterior region of a 39-year-old white woman. In addition, to better delineate the clinical, radiographic, histopathologic and immunohistochemical characteristics of CGCOT, a literature review of all published cases (in PubMed/ Google Scholar/ MEDLINE/Scopus) of CGCOT is provided. CGCOT is a very uncommon tumor, with only 51 reported cases in the literature. The present case is interesting regarding to its rarity for being in the maxillary anterior region, which has not been previously reported in Asia. The immunohistochemical findings of the current case and other cases in the literature review, verified the mesenchymal origin of granular cells and odontogenic nature of the epithelium islands, which can be a possible promise for placing this lesion in the future WHO odontogenic tumor classification.
The rare granular cell odontogenic tumor (GCOT) was primarily reported by Werthemann in 1950 [ 1 ], named as sponginocytic adamantinoma. There are immense controversies concerning the notion and the definition of this lesion. This lesion has been differently named as granular cell ameloblastic fibroma [ 2 ], ameloblastic fibroma with stroma of granular cells [ 3 ], central granular cell tumor of the jaw [ 4 ], central granular cell odontogenic fibroma [ 5 ], central odontogenic fibroma (granular cell variant) [ 6 ], central odontogenic granular cell tumor (COGCT) [ 7 ], central granular cell odontogenic tumor (CGCOT) [ 8 ], and finally GCOT [ 9 ].
Even though WHO proposed the term CGCOT for this lesion [ 10 ], there is still a great debate on this nomenclature since it was not considered as a distinct entity in the recent WHO classification [ 11 ] of odontogenic tumors. However, recent published studies suggest the term CGCOT for tumors characterized by varying amount of large eosinophilic granular cells with eccentrically placed nuclei associated with apparently inactive odontogenic epithelium [ 8 , 12 - 24 ]. CGCOT is defined as a rare, benign, slow-growing, noninvasive, though non-encapsulated odontogenic neoplasm [ 25 ]. This lesion is usually detected in the posterior mandible of women, predominantly in the fifth decade of life [ 20 ]. An extraosseous variant [ 26 , 27 ] and a malignant case of central granular cell odontogenic fibroma has also been reported [ 28 ].
Herein, we report the new rare case of CGCOT in the anterior area of maxilla in a 39-year-old female. Subsequently, we provide a literature review of all published cases (51 cases) of CGCOT.
A 39-year-old white woman with a chief complaint of two- week history of painless swelling in the anterior region on right side of the maxilla was examined. A noticeable intra oral hard, asymptomatic swelling in the palatal and buccal area of maxilla extending from maxillary right central incisor to the first premolar was detected (Figure 1). The overlying mucosa of the region was smooth with normal color. The patient reported negative history of trauma, infection, prior tumors or any instance of radiation. All teeth in the quadrant showed a positive response to vitality test. The cone beam computed tomography (CBCT) sans showed a well-defined corticated unilocular radiolucent lesion measuring 21.3×20.4mm from maxillary right central incisor to the first premolar, causing expansion, thinning of palatal and labial cortex, and divergence between central and lateral incisor roots (Figure 2).
The aspiration examination of the lesion was negative. Regarding the clinical, radiological, and aspiration examinations, odontogenic tumors including ameloblastoma and odontogenic myxoma were considered in our differential diagnosis list. Afterwards, an incisional biopsy was performed for histopathological examination. Grossly, the specimen was multiple pieces of irregular, gray-brown soft tissue, measuring 1.6×1.3×0.4cm. Incut surface, the lesion was creamy-gray, homogeneous and solid. Microscopic examination of Hematoxylin and Eosin (H&E) stained soft tissue sections discovered a benign mesenchymal odontogenic neoplasm with lobulated pattern containing large polygonal cells abundant pale eosinophilic, granular cytoplasm, and eccentric vesicular nuclei. Narrow cords and nests of odontogenic epithelium that were scattered among the granular cells were observed (Figure 3a-b). On immunohistochemical (IHC) staining, the granular cells showed positive expression for CD68 antigen (Figure 4a) and vimentin (Figure 4b) and negative expression for S-100 protein (Figure 4c). Regarding the histopathological and immunohistochemical findings, an accurate diagnosis of CGCOT was made. Informed consent was obtained from the patient for the information required to report the case. Unfortunately, because of financial limitations, the patient did not return for further treatment and therapeutic surgery.
Search strategy for literature review
As searching strategy, several databases (PubMed/ Google Scholar/ MEDLINE/Scopus) were searched for case reports and case series reported since September 2021, with using combinations of the keywords including central granular cell odontogenic tumor, granular cell ameloblastic fibroma, odontogenic tumor and central granular cell odontogenic fibroma. We screened the title and abstract for manuscript selection. Reference lists from the citations were also reviewed for the relevant publications. We found 36 reports [ 1 - 9 , 12 - 24 , 29 , 42 ] including 51 cases with certified histopathological diagnosis of CGCOT or suggestive histopathological features of CGCOT which has been reported with other terminologies for the present review. These studies are collected in Tables 1-2.
|Author(s)||Year||Age yrs.||Gender||Location||Radiographic features||Treatment||Follow-up (m/yrs.)|
|1||Werthemann [ 1 ]||1950||39||M||Left mandibular premolar/molar||NS||NS||NS|
|2||Couch et al. [ 2 ]A||1962||55||F||Left mandibular/ second molar||Radiolucent lesion with loculated borders||Conservative removal of the lesion with tooth extraction||NR 8 m|
|3||Couch et al. [ 2 ]B||1962||59||F||Left mandibular/ canine||Loculated radiolucency with focal densities||Removal of tumor||NR 27 m|
|4||Waldron et al. [ 29 ] A||1963||60||F||Left mandibular/ canine||2.0 cm radiolucent lesion||Removal of tumor||NR 29 m|
|5||Waldron et al. [ 29 ]B||1963||53||F||Left mandibular/ molar||2.0–3.0 cm cystic radiolucency displacing teeth||Removal of the mass with tooth extraction||NR 3 m|
|6||Gorlin and Goldman [ 30 ]||1970||50||F||Mandibular molar region||NS||Curettage||NS|
|7||Dalforno and Donna [ 3 ]||1970||57||NS||Left mandibular/ molar||NS||Curettage||NR 6 m|
|8||White et al. [ 4 ] A||1978||50||F||Mandibular canine area||Radiolucency||Curettage||NR 6 m|
|9||White et al.[ 4 ] B||1978||50||F||Mandibular posterior area||Radiolucency||Curettage||NR 7 yrs.|
|10||White et al.[ 4 ] C||1978||55||F||Maxillary premolar||Radiolucency||Surgical excision||NR 3 yrs.|
|11||White et al.[ 4 ] D||1978||65||F||Mandibular premolar/molar||Radiolucency||Surgical excision||NR 2 yrs.|
|12||Regezi et al. [ 31 ]A||1978||29||F||Maxilla||NS||NS||NS|
|13||Regezi et al. [ 31 ]B||1978||16||M||Mandible||NS||NS||NS|
|14||Vincent et al. [ 4 ]A||1987||51||F||Right mandibular premolar/ molar||4–2 cm radiolucency with sclerotic border||Conservative removal of the mass||NS|
|15||Vincent et al.[ 5 ] B||1987||27||M||Right mandibular second premolar/first molar||1.5 cm unicystic radiolucency with sclerotic borders||Surgical excision||NR 24 m|
|16||Shiro et al. [ 6 ]||1989||45||F||Left mandibular premolars||0.7–0.4 cm unicystic radiolucency||Surgical excision||NR 4 yrs.|
|17||Mirchandani et al. [ 7 ]||1989||33||F||Mandible||radiolucency||NS||NS|
|18||Ruhl and Akuamoa-Boateng [ 32 ]||1989||22||M||Left maxillary first and second molars||4.5 cm with slight displacement of teeth||En bloc resection||NS|
|19||Chen [ 33 ]A||1991||50||F||Right mandibular canine||1.0–0.8 cm radiolucency||NS||NS|
|20||Chen [ 33 ]B||1991||45||F||Left mandibular premolar/molar||5.0–3.0 cm radiolucency||NS||NS|
|21||Chen [ 33 ]C||1991||64||F||Left mandibular canine/premolar||3.0–2.0 cm radiolucency||NS||NS|
|22||Chen [ 33 ]D||1991||77||F||Left mandibular/ premolars||0.5–0.5 cm radiolucency||NS||NS|
|23||Yih et al. [ 38 ]||1995||66||F||Left mandibular/ second premolar||0.5–0.5 cm unilocular radiolucency||Curettage||NR 6 m|
|24||Gesek et al. [ 8 ]||1995||62||F||Left mandibular/ second premolar||Multilocular, well circumscribed radiolucency||Curettage||NR 12 m|
|25||Machado de Sousa et al. [ 39 ]A||1998||19||F||Right maxillary premolar/molar||Well-delineated multilocular radiolucency||Surgical excision||NR 24 m|
|26||Machado de Sousa et al. [ 39 ]B||1998||25||M||Right maxillary premolar/molar||8.0 cm radiopaque lesion||Surgical excision||NR 120 m|
|27||Ardekian et al. [ 12 ]||1998||63||M||Right maxillary premolar/molar||Well-defined radiolucency with sclerotic border||Curettage Teeth extraction||NR 48 m|
|28||Matsumoto et al. [ 34 ]||2000||24||M||Left mandibular/ premolars||Well demarcated radiolucent lesion||Enucleation with teeth extraction||NR 1.5 yrs.|
|29||Brannon et al.[ 13 ]A||2002||36||F||Mandibular canine/ premolar||NS||NS||NS|
|30||Brannon et al.[ 13 ]B||2002||50||F||Jaw, NS||NS||NS||NS|
|31||Brannon et al.[ 13 ]C||2002||32||F||Mandibular canine/premolar||Multilocular radolucency with sclerotic border||Teeth extracted with surgical excision||NR 180 m|
|32||Brannon et al.[ 13 ]D||2002||19||F||Left maxillary first premolar /first molar||Unicystic radiolucency enveloping roots of second premolar||Curettage||R 156 m|
|33||Brannon et al.[ 13 ]E||2002||48||M||Right side of maxilla||NS||NS||NS|
|34||Calvo et al. [ 40 ]||2002||61||M||Anterior region of maxilla||Radiolucency with resorption of anterior teeth||NS||NS|
|35||Meer et al. [ 14 ]||2004||65||F||Left mandibular first premolar/ second molar||Irregular radiolucency from first premolar to second molar||Surgical excision||NR 12 m|
|36||Reichart et al. [ 41 ]||2006||46||F||Right mandibular premolar/molar||Multilocular radiolucent lesion||Surgical excision with reconstruction||NR 2 yrs.|
|37||Gomes et al. [ 9 ]||2006||20||F||Left mandibular premolars/ molars||An intra-osseous mixed lesion,5 cm||Enucleation||NR 7 m|
|38||Kim et al. [ 15 ]||2006||33||M||Right maxillary premolar /first molar||Well-defined unilocular radiolucency||Enucleation with tooth extraction||NR 23 m|
|39||Mesquita et al. [ 16 ]||2009||20||F||Left mandibular second premolar/second molar||Well-defined radiolucency with foci of calcifications||Complete resection of the tumor||NR 4 yrs.|
|40||Lotay et al. [ 42 ]||2010||28||F||Right maxillary/ premolar||1.5–2.5 cm well-defined mixed lesion||Enucleation and curettage||NS|
|41||Silva et al. [ 17 ]||2012||41||F||Left side of maxilla||Well-defined mixed lesion||Surgical excision||NR 2 yrs.|
|42||Sarode et al. [ 18 ]||2013||25||F||Right side of mandible crossing the midline||Well-demarcated multilocular radiolucent lesion||Enucleation and curettage||NR 2 yrs.|
|43||Cheng et al. [ 19 ]||2013||52||F||Right mandibular/ premolars||Well-defined mixed lesion||Enucleation||NR 3 m|
|44||Chiang et al. [ 20 ]||2014||69||M||Left side of the mandible, ramus||well-demarcated radiolucent lesion||Surgical excision||NR 2 m|
|45||Anbiaee et al. [ 21 ]||2014||16||F||Left mandibular angle||Multilocular mixed lesion,3×5cm||Surgical resection with mandibular reconstruction||NR 2 yrs.|
|46||Lee et al. [ 22 ]||2014||19||M||Left mandibular third molar||Enlarged dental follicle||Enucleation with the tooth extraction||NS|
|47||Fletcher et al. [ 35 ]||2015||19||F||Right mandibular second premolar/ molars||Unilocular radiolucent lesion||Curettage||NR 24 m|
|48||Vennamaneni et al. [ 36 ]||2016||38||M||Right mandibular premolars/first molar||Well defined unilocular radiolucent lesion||Enucleation||NR NS|
|49||Madan et al. [ 23 ]||2016||73||M||Anterior area of mandible||Multilocular radiolucent lesion||Segmental resection||NR 9m|
|50||Atarbashi et al. [ 37 ]||2019||57||F||Left mandibular premolars/ first molar||well- defined radiolucent lesion||Enucleation||NR 12m|
|51||Koth et al. [ 24 ]||2021||42||F||Left maxillary anterior||Unilocular radiolucency||Surgically removal||NR 16m|
|KEY: GCAF: granular cell ameloblastic fibroma; CGCOF: central granular cell odontogenic fibroma, CGCT: central granular cell tumor; COGCT: central odontogenic granular cell tumor; CGCOT: central granular cell odontogenic tumor; GCOT: granular cell odontogenic tumor; F: female; M: male; NS: not stated; NR: no recurrence; R: recurrence; M: months; yrs.: Years.|
|Total case Number||51|
|Year of publication||1950-2021|
|Age (years)||Mean, 43.53 y (range 16-77y)|
|Gender||Female, 36; Male, 14; Not stated, 1|
|Race||White, 16; Black, 10; Yellow, 1;Indian, 1; Oriental, 1; Afro-Caribbean, 1; Caucasian, 1; Not stated, 20|
|Site of lesion||Mandible, 37(premolar/molar area: 28, canine/ anterior region: 6, NS: 3); Maxilla, 13(premolar/molar area: 8, canine/ anterior region: 2, NS: 3); Not stated, 1|
|Signs and symptoms||Painless swelling, 24; Asymptomatic, 8; Painful and no swelling, 3; Not stated, 16|
|Radiographic features||Radiolucency, 34(unilocular: 28, multilocular: 6); Mixed lesion, 8; Opaque, 1; Not stated, 8|
|IHC markers||Positive GC; Mostly: Vimentin, CD 68 (Lesser: Lysozyme, AACT, AAT, B-cl2, CEA, NSE)|
|Negative GC; S-100|
|Positive OE; Mostly: CK 14 (Lesser: CK 13, Pan CK, B-cl2, CK 5, CK 7, CK 8)|
|Treatment||Enucleation and/or Curettage, 24; Surgical resection, 15; Not stated, 12|
|Follow-up||Mean, 33 m (range 2-180 m) ; Not stated 17|
|KEY: m: months; y: years; IHC markers: Immunohistochemical markers; GC: granular cell; OE: odontogenic epithelium; AACT: α1-antichymotrypsin; AAT: α1-antitrypsin; NSE, CEA: carcinoembryonic antigen; NSE: neuron specific enolase; CK: cytokeratin|
CGCOT is considered as an imperative, yet rare, odontogenic tumor. In 1950, Werthemann [ 1 ] first described this lesion in the left side of the mandible and defined it as spongiocytic adamantinoma. Histopathologically, he described this lesion as comparatively large, bright, rounded, and rather polyhedral cells with small nuclei, which were mostly located on the periphery of the cell body, intermixed with epithelial cones and cords. In 1962, Couch et al. [ 2 ] described two cases of central jaw lesions, which were composed of granular cells allied with nests of odontogenic epithelium on microscope. They and some other investigators named this lesion as granular cell ameloblastic fibroma [ 2 , 29 - 32 ].
Dalforno and Donna [ 3 ] defined this lesion as ameloblastic fibroma with stroma of granular cells. Later, other investigators named this tumor as central granular cell tumor of the jaws [ 4 , 33 ], central granular cell odontogenic fibroma [ 5 , 7 ], central odontogenic fibroma, granular cell variant [ 6 , 40 - 41 ] and COGCT [ 34 , 38 - 39 ]. At present, most researchers rather to name this lesion as CGCOT [ 8 , 12 - 24 ]; we also prefer this term. Moreover, four authors describe this lesion as GCOT [ 9 , 35 - 37 ].
The review of literature showed that the mean age of the 51 reported cases was 43.53 years with a range of 16 to 77 years. The mean age was reported in previous researches as 47.3 in Gesek et al. [ 8 ], 46. 2 in Gomes et al. [ 9 ], 45.8 in Chiang et al. [ 20 ], and 45.21 in Sarode et al. [ 10 ]; which were higher than the age of our case. Our review showed that more than half (61%) of patients were older than 40 years of age, which is similarly reported by Sarode et al. [ 10 ] and Neville et al. [ 43 ]. There is a marked female predilection (72%) in this lesion. The most common location was the mandibular premolar/ molar area (64%), followed by maxillary premolar / molar area (18%). Only two cases affecting the anterior region of maxilla (4.5%) was reported [ 24 , 40 ]. In mandible, there was a tendency for tumor growth on the left side (20 cases, 69%), in contrast to the right side (9 cases, 31%).In maxilla, this tendency occurred in the right side of the jaw . However, Chiang et al. [ 20 ] described equal distribution of this tumor on the left side and right side of the maxilla. Our review showed that 52% of cases affected whites, which was similarly reported by Kim et al. [ 15 ] and Chiang et al. [ 20 ].
Clinically, most lesions (24 cases, 68.5%) presented as a asymptomatic mass with localized expansion, and some lesions were completely asymptomatic (8 cases, 23%).Only three cases (8.5%) presented as a painful lesion without swelling [ 17 , 37 , 39 ].
The current case is the first reported case of CGCOT in Asia that occurred in the maxillary anterior region, a very rare location, while other features of our case were approximately similar to most previous studies.
The literature review revealed that the most common radiological finding was a unilocular radiolucent lesion (28 cases, 65%), similar to our case. Some lesions presented as a mixed radiolucent-radiopaque lesion (8 cases, 18.5%), or multilocular radiolucency (6 cases, 14%). Only one case (2.5%) presented as a radiopaque lesion in appearance [ 41 ]. Extraosseous variant of GCOT is rarer than its central type. To our knowledge, only four cases of GCOT have been described in the gingival soft tissues [ 26 - 27 , 44 - 45 ].
Histopathologically, this odontogenic tumor is characterized by varying amount of large eosinophilic granular cells with eccentrically placed nuclei associated with apparently inactive odontogenic epithelium [ 1 - 9 , 12 - 24 , 29 - 42 ], which was also found in our case. Epithelial cells containing a clear cytoplasm were a common feature in the reported studies [ 6 , 13 , 16 - 20 , 41 - 42 ]. Cementum-like material [ 2 , 4 , 8 , 13 , 29 , 31 , 39 ], dystrophic calcifications [ 33 ] and palisading or polarization of the peripheral epithelial cells were also reported [ 8 ].
On IHC examinations, granular cells showed positive immunoreactivity for vimentin (29%) and CD 68 (29%) and negativity for cytokeratin (CK) in all the collected cases. These findings suggest mesenchymal origin of GCs. On the other hand, immunoreactivity for S-100 protein in granular cells was reported negative in all cases, which suggests a non-neural, mesenchymal origin for this tumor. Odontogenic epithelium shows variable expression of CK. Our review showed that CK 14(19%) had the most positive immunoreactivity, followed by CK 13, Pan CK, b-cl2 and AE1. The histopathological differential diagnosis can be considered as GCT of soft tissue, granular cell variant of ameloblastoma and congenital epulis [ 7 ]. GCT does not show odontogenic islands, cementum-like material, or dystrophic calcification and is strongly positive for S-100 protein [ 32 ]. Granular cells in granular cell ameloblastoma are immuno-positive for CK, but negative for S-100 protein. The histological and immunohistochemical aspects of congenital epulis of newborns are comparable to CGCOT, but dissimilar ages of patients who were involved with congenital epulis as well as the location of this lesion (alveolar ridge) are expedient for final diagnosis [ 32 ].
Our review revealed that 24 cases (61.5%) received excision and/or curettage for their treatment, while surgical removal with reconstruction of jaw was performed in 15 cases (38.5 %). The prognosis of this tumor is good; 33 cases (97%) reported no evidence of recurrence, with the range of follow up time from 2 to 180 months). Only one case recurred 13 years after initial treatment [ 13 ]. Piattelli et al. [ 28 ] in 2003 reported the first and the only case of malignancy in this tumor. However, no case of metastasis has been reported until now.
CGCOT is a rare tumor with only 51 reported cases in the literature. The presented case is rare concerning its location on maxillary anterior region, which has not been yet reported in Asia. IHC findings of the current case and other cases in the present review, confirmed the mesenchymal origin of GCs and odontogenic nature of the epithelium islands, a prominence that necessitates its assignment in the future WHO odontogenic tumor classification.
Conflict of Interest
The authors declare that they have no conflict of interest.
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