Cemento-ossifying fibroma

Cemento-ossifying fibroma (COF) is a benign fibro-osseous neoplasm of the jaws characterized by replacement of normal bone with cellular fibrous stroma containing variable amounts of mineralized material in the form of bone trabeculae and cementum-like deposits.[1][2] The lesion is believed to arise from pluripotent cells of the periodontal ligament capable of producing both osteoid and cementum.[3][4] COF presents as a well-demarcated, often encapsulated intraosseous mass with a predilection for the premolar–molar mandible in women during the third to fourth decades of life.[1][5] The signature radiographic pattern is a well-defined, corticated radiolucency or mixed radiolucent–radiopaque lesion whose internal density increases with maturity.[1][6] Treatment is conservative surgical enucleation or excision, facilitated by the fibrous capsule that allows the tumor to shell out from surrounding bone.[1]

The WHO 4th edition (2017) restored the prefix "cemento-" to this entity, yielding the current preferred term cemento-ossifying fibroma, to reflect its odontogenic origin and restriction to tooth-bearing areas of the jaws.[7] The 5th edition WHO classification (2022) retains this terminology within the category of odontogenic and maxillofacial bone tumors.[8] Acceptable synonyms include ossifying fibroma and cemento-ossifying fibroma (COF); the shortened form "ossifying fibroma" remains widely used in the literature.[1][2] The older term "cementifying fibroma" is obsolete but may be encountered in historical reports.[9] COF is classified separately from the two juvenile subtypes—juvenile trabecular ossifying fibroma (JTOF) and psammomatoid ossifying fibroma (PsOF)—which differ in age of onset, histology, molecular profile, and biologic behavior.[7][10] The term "periodontoma" is an archaic synonym no longer in clinical use.[11]

• Age: Peak incidence in the 3rd–4th decades; mean age at diagnosis approximately 35–36 years.[1][5]
• Sex: Strong female predominance; female-to-male ratio approximately 2.5:1 in large series, reaching 86.6% female in a 112-case multicenter cohort.[1][5]
• Site: The premolar and molar regions of the mandible are the most common location (approximately 65% of cases). Maxillary involvement is less frequent, with the canine fossa and zygomatic arch region most often affected.[1][5]
• Frequency: COF is uncommon among jaw lesions overall but is the most common true neoplasm within the fibro-osseous lesion group of the jaws.[12]
• Synchronous (multifocal) COF is rare; a systematic review identified only 20 reported cases, most involving simultaneous mandibular and maxillary lesions.[13]

Presentation and symptoms

• Approximately 31% of COFs are asymptomatic and discovered incidentally on routine dental radiographs.[1]
• When symptomatic, the most common finding is a slowly enlarging, painless, bony-hard swelling producing buccolingual expansion (reported in up to 84% of clinically apparent cases) and facial asymmetry (66%).[1][6]
• Pain is uncommon, reported in approximately 16% of cases.[1]
• Average size at diagnosis ranges from 1 to 5 cm in greatest dimension. Rarely, COF attains massive proportions with extension into the infratemporal or parapharyngeal spaces.[1][4]

Examination findings

• Firm, non-tender, bony expansion of the buccal and/or lingual cortex.
• Overlying mucosa is typically intact and normal in color.
• Teeth in the region may be displaced or mobile; malocclusion may develop with larger lesions.[1][6]

Tempo and complications

• Growth is characteristically slow and progressive. Rapid enlargement should raise concern for a juvenile subtype or secondary aneurysmal bone cyst.[1]
• With continued growth, COF can displace the inferior alveolar nerve canal, the mandibular inferior border, or the maxillary sinus floor.[1]

Location and distribution

• COF arises centrally within the alveolar process or body of the mandible, most often in the premolar–molar region. Mandibular lesions predominate over maxillary by roughly 2:1.[1][5]
• The lesion typically presents as a solitary, unilocular mass centered above or at the level of the inferior alveolar canal. Synchronous bilateral lesions are rare.[1][6][13]

Periphery and shape

• The hallmark is a well-defined, corticated border that distinguishes COF from fibrous dysplasia. A thin radiolucent rim—representing the fibrous capsule—often separates the lesion from adjacent normal bone, particularly in mature, heavily mineralized examples.[1][2][6]
• Shape is typically round to ovoid, expanding centrifugally from a discernible epicenter.[1]
• Cortical expansion is common (approximately 53% of cases in a multicenter series), usually involving the buccal plate and, to a lesser extent, the lingual cortex. The expanded cortex is generally thinned but intact; cortical disruption is uncommon in conventional COF and, on cross-sectional imaging, was maintained in 7 of 8 COFs in one series.[5][14]

Internal architecture

The internal density of COF varies with lesion maturity and the proportion of mineralized tissue produced by the stroma:[1][6]

• Early (immature) lesions: Entirely radiolucent, mimicking an odontogenic cyst or other lytic jaw lesion.
• Intermediate lesions: Mixed radiolucent–radiopaque, the most frequently observed pattern (approximately 50% of cases in a 112-case cohort). Radiopaque foci appear as irregular flecks, wisps, or granular densities scattered within the radiolucency.[5]
• Mature (long-standing) lesions: Predominantly radiopaque, occasionally approaching the density of surrounding bone, with a persistent thin peripheral radiolucent line representing the fibrous capsule.[1]
• A target-like appearance—a dense central core surrounded by a lower-density peripheral zone—has been described on CT as a characteristic, though not pathognomonic, pattern of ossifying fibromas.[14]
• Homogeneous ground-glass density, more typical of fibrous dysplasia, was observed in a subset of COFs on CT (5 of 8 cases in one series), underscoring that imaging overlap exists.[14]
• Purely radiopaque presentation is exceptional.[6]

Effects on teeth and adjacent structures

• Tooth displacement: COF grows centrifugally and displaces adjacent teeth, often tilting roots away from the lesion center.[1][6]
• Root resorption: External root resorption of involved teeth is visible in approximately 20% of cases.[1]
• Inferior alveolar canal: Larger mandibular lesions displace the canal inferiorly.[1]
• Maxillary sinus: Maxillary COF may elevate or remodel the sinus floor.[1]
• Teeth remain vital unless coincidentally affected by caries or periodontal disease.

Growth pattern and extent

• Growth is concentric and expansile from a central epicenter, a feature that helps distinguish COF from the diffuse, ill-defined expansion of fibrous dysplasia.[1]
• Multilocular presentation is exceptionally uncommon and, when present, is most often attributable to a secondary aneurysmal bone cyst developing within the COF.[1]

Medical CT

On medical CT, COF typically appears as a well-circumscribed, expansile mass with density ranging from soft-tissue attenuation (in early lesions) to ground-glass or mixed hyper-/hypodense patterns depending on the degree of mineralization.[14][15] Well-defined margins and preserved continuity of the overlying cortex are characteristic of COF, in contrast to the cortical disruption more often seen in juvenile subtypes.[14] A target-like density pattern (dense center, lower-density periphery) has been described as suggestive of ossifying fibroma.[14]

MRI

MRI signal characteristics are variable. COF may show homogeneous or heterogeneous signal; on T1-weighted images, the soft-tissue component is typically isointense to gray matter, while on T2-weighted images it tends toward iso- to hypointensity, reflecting the fibrous and mineralized composition.[14][15] Moderate to marked enhancement is observed after gadolinium administration.[15] MRI is most useful for delineating soft-tissue extent in large lesions approaching the orbit, skull base, or parapharyngeal space, and for identifying a secondary aneurysmal bone cyst component (fluid–fluid levels on T2-weighted sequences).[15]

The radiographic differential depends on the maturity of the lesion: early radiolucent COF overlaps with cystic and lytic jaw lesions, while mixed and mature COF overlaps with other fibro-osseous and mixed-density entities. Biopsy with clinico-radiologic correlation is required for definitive diagnosis because histologic overlap among fibro-osseous lesions is substantial.[16][17]

The highest-risk diagnostic pitfall is misclassifying a low-grade osteosarcoma as COF, because ossifying fibroma may be more cellular and contain more mitoses than the osteosarcoma it mimics.[20] When imaging features are equivocal—particularly ill-defined margins, cortical destruction, or periosteal reaction—incisional biopsy with adequate sampling and, when available, MDM2 amplification testing should be pursued before definitive surgery.[10]

Microscopic features

COF consists of a proliferation of cellular fibrous tissue containing a variable quantity of mineralized material.[1][2] Key diagnostic features include:

• Fibrous stroma: Well-vascularized, variably cellular connective tissue ranging from hypercellular areas with mitotic figures to hypocellular, collagenized zones within the same lesion.[1][2]
• Mineralized component: A mixture of bony trabeculae (woven and/or lamellar bone) and ovoid, basophilic, acellular cementum-like deposits (cementicles or "cementum droplets"). The relative proportion of bone to cementum varies widely.[1][3]
• Osteoblastic rimming: Bony trabeculae are typically rimmed by osteoblasts or show a peripheral "brushed border" of osteoid—a feature absent in fibrous dysplasia.[1]
• Capsule: A thin fibrous capsule separates the lesion from surrounding normal bone, a critical distinguishing feature from both fibrous dysplasia (which merges with host bone) and cemento-osseous dysplasia (which lacks encapsulation).[1][20]

Radiologic–pathologic correlation

The radiographic density of COF directly reflects the quantity and maturity of mineralized tissue within the stroma: early lesions with predominantly fibrous tissue are radiolucent, while increasing deposition of bone and cementum produces progressive radiopacity.[1][6] The peripheral radiolucent rim seen on imaging corresponds to the fibrous capsule.[1]

Molecular findings

No single recurrent cytogenetic or molecular alteration has been consistently identified in conventional COF.[9] Importantly, COF lacks the activating GNAS mutations characteristic of fibrous dysplasia, a distinction that can be exploited diagnostically.[19] DNA methylation profiling has shown that COF clusters with cemento-osseous dysplasia and juvenile ossifying fibroma subtypes rather than with fibrous dysplasia, suggesting a shared odontogenic lineage.[10] HRPT2/CDC73 mutations may be found in COF arising in the context of hyperparathyroidism–jaw tumor syndrome.[1][23]

Treatment

• Standard approach: Conservative surgical enucleation or curettage. The fibrous capsule allows the tumor to shell out from its bony crypt, often in one piece.[1][5]
• Large or destructive lesions: Segmental resection with reconstruction (bone graft or reconstruction plate) may be necessary when the lesion has caused extensive bone loss or involves critical structures.[1][4]
• Complete surgical removal without prior incisional biopsy was the most common management approach in a 112-case multicenter series (61.6%), reflecting the clinical confidence afforded by characteristic imaging.[5]

Recurrence

• Recurrence rates are variable across studies: some report rates below 5%, while others document 8–28%. A multicenter cohort of 112 cases reported recurrence in 8.3% of patients with available follow-up.[1][5][24]
• No histologic feature reliably predicts recurrence risk.[1]
• Long-term radiographic surveillance is therefore recommended for all patients after treatment.[1]

Prognostic considerations

• Prognosis is excellent; COF does not undergo malignant transformation.
• Rapid growth, recurrence, or presentation in a child should prompt reconsideration of the diagnosis in favor of a juvenile ossifying fibroma subtype, which carries a higher recurrence rate and may require more aggressive surgery.[1][9]

Hyperparathyroidism–jaw tumor syndrome

Ossifying fibromas of the jaws occur in 30–40% of individuals with hyperparathyroidism–jaw tumor (HPT-JT) syndrome, an autosomal dominant disorder caused by germline mutations in the CDC73 (HRPT2) tumor suppressor gene.[23][25] Although these jaw tumors are histologically identical to sporadic COF, they may be locally aggressive and continue to enlarge if untreated.[23] HPT-JT syndrome should be suspected when COF is accompanied by primary hyperparathyroidism (especially at a young age or with parathyroid carcinoma), renal cysts or tumors, or a family history of these features.[1][23] Identification prompts CDC73 germline testing, screening for hyperparathyroidism and renal lesions, and cascade genetic testing of at-risk relatives.[23][26]

Synchronous and familial COF

Synchronous (multifocal) COF is rare. In a systematic review of 20 cases, 65% involved simultaneous mandibular and maxillary lesions, and 10% had a first-degree relative previously diagnosed with COF.[13] Familial clustering, even without confirmed HPT-JT syndrome, warrants consideration of genetic evaluation.[13]