1

Case report

60 years old medically fit female presented to our clinic complaining of a mass in the labial aspect of the anterior maxilla. The lesion has been excised twice and the last excision was 3 years ago. The previous interventions were done in another facility and the nature of procedure as well as the histopathology were lacking. On examination, an exophytic, pedunculated and nontender swelling with the size about 2 by 2 cm was located at the labial aspect of left maxillary central and lateral incisors. The overlying mucosa was reddish and with areas of pseudomembrane. Adjacent teeth (NO 9 and 10) were mobile ( Fig. 1 A). CT scan showed localized erosion of the buccal cortex in relation to the lesion ( Fig. 1 , B). CBC, renal and liver function tests were within normal limits. Incisional biopsy was performed under local anesthesia. The histopathological examination showed stroma with abundant mucoid tissue containing few collagen fibrils and loosely arranged spindle and stellate shaped cells. Scant blood vessels and scattered mast cells were also identified. No odontogenic epithelium was found and there was no evidence of atypia ( Fig. 2 ).

A: Clinical Presentation showing exophytic pedunculated mass in the maxillary incisor area. B: CT sagittal section through the tumor showing bone involvement. C: excision with safety margin. D: denuded bone after excision. E: removal of involved buccal bone.

A: H & E stain: Stratified squamous epithelial mucosa with underlying un-encapsulated myxoid lesion. Magnification 4×. B: H & E stain: spindled and stellate cells with few interspersed collagen fibers and small sized blood vessels. Magnification 10×. C: The myxoma cells focally reaching the surrounding bone trabeculae. Magnification 40×.

Due to previous recurrences, the finding of tooth mobility and radiographic evidence of bone erosion, the treatment plan included the following: excision along with safety margin (5mm uninvolved tissue, periosteum, and buccal plate), extraction of associated teeth as well as peripheral ostectomy of remaining bone ( Fig 1 C, D, E). As the lesion was located in the anterior maxilla, bilateral advancement flap was planned to cover the defect. The procedure was completed under local anesthesia and the excised specimen sent for histopathological examination. The final diagnosis was the same with a note that the removed buccal bone was infiltrated with tumor cells. Postoperative course was uneventful and the patient has been followed up for 12 months with no evidence of recurrence. The patient is scheduled for bone grafting and implant restoration.

2

Discussion

Odontogenic myxoma (OM) is a benign tumor of ectomesenchymal origin and characterized by excessive mucoid ground substance. However, due to the nature of mucoid matrix, it has infiltrative and aggressive nature. The primary cell causing this rare lesion is the myofibroblast, a subtype of fibroblasts. These cells produce significant amount of ground substance. OMs contribute to 1–17% of all odontogenic tumors. Peripheral odontogenic myxoma (POM) is considered rare type of OM with less aggressive behavior than the central type. POM is found more in females and run in the range of 30–60 years of age. More cases have been reported in Africa [ ].

Clinically, POM is seen as exophytic slowly growing sessile or pedunculated mass. Overlying mucosa is normal in color but can be ulcerated and covered with pseudomembrane. It shows signs of unlimited growth and some cases reached up to 12 cm in length [ ]. Adjacent teeth may drift or become loose and the underlying bone may have features of pressure erosion or bony infiltration. CT imaging helps to rule out central lesions [ ]. Clinically POM may be confused with many lesions like: pyogenic granuloma (PG), peripheral giant cell granuloma (PGCG), peripheral odontogenic fibroma (POF) and oral focal mucinosis (OFM).

Grossly, POM appears tan-yellow in color with gelatinous, soft or rubbery consistency. Microscopically, it is characterized by absence of encapsulation, excessive mucoid ground substance and hypocellularity [ , ].

Cellular component is composed mainly of fibroblast-like spindle cells characterized by long thin cytoplasmic processes. The ultrastructure of these cells shows α smooth muscle actin (SMA) and fibronexi which suggests myofibroblastic differentiation [ , ]. Active secretory function is also suggested by the presence of perinuclear rough endoplasmic reticulum and Golgi apparatus [ , , ]. In a proteomic study of odontogenic myxoma by Muñoz et al. [ ], Orosomucoid 1 protein was consistently overexpressed in the cytoplasm of the tumor cells. It is believed that this protein has role in the production of mucoid ground substance which facilitates the migration of cells and immune modulation in favor of tumor growth. The presence of odontogenic epithelium was reported by several authors [ , , , ]. In a study by Lombardi et al. [ ], the detection of epithelial islands was improved from 8% to 24.2% when immunohistochemical stains were used. Mast cells may also contribute to the cellular component and but been only occasionally observed. Lombardi found that with toluidine blue stain, mast cells were present in 37.1% of their cases, while with the use of IHC stains this finding increased to 72.6%. Mast cells are known to play role in tumor growth and are generally present in 96% of odontogenic tumors [ ].

The matrix of POM is composed of delicate immature collagen fibers reflecting the dysfunctional state of tumor cells. Amorphous ground substance as indicated by Alcian stain is mucoid in nature and this is believed to play a role in tumor spread and invasion of adjacent structures. Hyaluronic acid makes up the majority of ground substance (about 80%) while the remaining is mainly composed of chondroitin sulphate [ ]. Additional findings include neural components which stain positive with S 100, delicate vasculature [ , ] and evidence of bone infiltration as in our case.

Lesions with histopathology and immunohistochemistry similar to that of POM just described include oral focal mucinosis, nerve sheath myxoma, inflamed odontogenic fibroma, myxoid neurofibroma, and myxoid sarcomatous lesions. Oral focal mucinosis usually has no reticulin fibers and no myofibroblasts so smooth muscle actin (SMA) negative. Nerve sheath myxoma strongly stains with S 100 supporting Schwann cell origin. It also stains positive to neuron specific enolase (NSE) [ ]. POM stains negative for both. Inflamed odontogenic fibroma may have edematous connective tissue which can be mistaken in gross examination with POM. The presence of inflammatory cells, mature collagen and absence of hyaluronic acid in their matrix excludes POM [ ]. Myxoid neurofibroma have characteristic weaved nuclei with wire-like collagen fibers and stains positive to S 100. Myxoid sarcomas show hypercellularity with atypia and increased mitotic activity.

Although the exact histogenesis of POM is not fully understood, the main cell is considered to be actively secreting myofibroblasts. These cells are able to remodel extracellular matrix and produce mucoid ground substance [ ]. The source of myofibroblasts is suggested to be from remnants of ectomesenchyme from dental follicle, dental papilla or periodontal ligaments. This is supported by the fact that OM is seen in tooth bearing area or in area of unerupted teeth and that the principal tumor cell is similar to those seen in dental follicle or dental pulp. However, mesenchymal cells are not exclusively odontogenic and are present in the umbilical cord. In addition, odontogenic myxoma and extra gnathic myxoma have similar cells. It was also found that the myxomatous matrix is different from that found in dental pulp or periodontal ligaments. Therefore, it is possible that these cells may originate from pluripotential mesenchymal cells which are able to differentiate to myofibroblasts [ ]. The role odontogenic epithelium in tumorigeneses is possible by way of induction effects similar to the process of odontogenesis. This was suggested by Harrison et al. [ ] as they noted pericellular clear rim of extracellular matrix surrounding epithelial rests which can be the inductive interface between epithelial and mesenchymal cells. Mata et al. found that altered epithelial cells express transforming growth factor β1 (TGF-β1) which has a role in the differentiation of fibroblasts to myofibroblasts. However, epithelial rests were not detected in all OMs [ ]. The frequent presence of mast cells and their known effect on tumor growth suggest that they may have a role in OMs [ , ]. These cells promote tumor growth by their proangiogenic, remodeling and immunomodulating effects. MCs produce vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), heparin and histamine. Early in tumorigeneses, MCs act by controlling angiogenesis while tumor cells control growth. These roles are “switched” at later stage where MCs act by extracellular matrix remodeling. Mehendiratta [ ] suggested that fibroma, fibromyxoma and myxoma are all related lesions. Myxomatous degeneration of odontogenic fibroma produces fibromyxoma as an intermediate stage and myxoma as the final picture. He stated that fibrosis is possibly involved in the conversion of myxoma to fibromyxoma to fibroma.

3

Treatment and recurrence

Due to the benign nature of the tumor and low recurrence rate in comparison the central type, POMs are treated with conservative excision. However, recurrence also seems to depend on the anatomic location, the behavior of the lesion and adequacy of excision. There may be aggressive variant of POM and this may be suggested by rapid growth and bone erosion. The presence of MCs in histopathological examination may be a sign of aggressiveness. Unfortunately, in our case it is unknown whether the reason for recurrence is incomplete excision or aggressive nature of the lesion as surgical or histopathologic reports of previous treatment were lacking. We suggest that in the presence of signs of bone erosion or recurrence, the lesion should be excised with uninvolved healthy barrier.

4

Conclusion

Peripheral odontogenic myxoma is a rare benign tumor and confusion appears in the literature between odontogenic and non-odontogenic types. This case supports the possibility of origin from periodontal ligament as the tumor appears to be related to the PDL of an adjacent tooth. Although rare, new cases are being reported more frequently possibly due to the advancement in histopathologic techniques which allows better differentiation from other tumors. The treatment of choice is conservative surgical excision. We suggest that in the presence of signs of bone erosion or recurrence, the lesion should be excised with uninvolved healthy barrier.