Clinical Presentation A 63-year-old female presented to her oral surgeon for evaluation of a right mandibular lesion. She reported recent onset swelling and pain without associated neurosensory deficits or changes in occlusion. Her past medical history was significant for hypercholesterolemia, hypertension, and osteoporosis, which were under pharmacologic control. Her social history was neither remarkable for tobacco use nor alcohol consumption. Extraoral examination revealed mild right-sided facial swelling associated with a palpable mass of the inferior border of the mandible. Intraoral examination of the corresponding area showed an expansile mass surfaced by normal-appearing mucosa. The lesion was slightly tender to palpation, and no overt evidence of infection or purulence was observed. The patient was partially edentulous and missing all teeth posterior to the right second premolar. On further inquiry, it was disclosed that the patient had undergone a right mandibular biopsy 7 years prior, which was diagnosed as a traumatic (simple) bone cyst. Graphical AbstractLow-power view of first biopsy showing spicules of viable bone surrounded by fibrin, neutrophils, and erythrocytes (H&E, 10x). View Large Image Figure Viewer Download Hi-res image Differential Diagnosis The clinical and radiographic differential diagnosis for an expansive, multilocular radiolucency of the mandible in an older adult is extensive.1,2 A comprehensive list would include: ameloblastoma, odontogenic keratocyst, odontogenic myxoma, glandular odontogenic cyst, intraosseous mucoepidermoid carcinoma, odontogenic fibroma, calcifying epithelial odontogenic tumor, central giant cell granuloma, and intraosseous vascular malformation or hemangioma. Ameloblastoma is an aggressive but benign odontogenic tumor with a strong predilection for the posterior mandible. The majority of cases represent conventional or multicystic ameloblastoma, which may present as a unilocular radiolucency, but is often multilocular.3 Cortical expansion is a common finding as well as root resorption of adjacent teeth.2 Pain may be a presenting symptom in a minority of cases.3,4 While the multilocular appearance, cortical expansion, and presence of pain in this case would be consistent with ameloblastoma, the notable absence of root resorption of the teeth in the area of the lesion, as well as the sclerotic septations and foci of sclerotic bone, would be unusual for ameloblastoma. Odontogenic keratocyst (OKC) is a relatively common developmental cyst with the potential for aggressive clinical behavior. It is commonly found in the posterior mandible and occurs across a wide age range.2 Small OKCs are typically asymptomatic and unilocular while larger lesions may appear multilocular radiographically.5 In most cases, OKCs demonstrate minimal cortical expansion as they tend to spread along the intramedullary space.5 Resorption of adjacent tooth roots is less commonly observed in OKCs than other radiographically similar lesions such as ameloblastoma, dentigerous cyst, and radicular cyst.2 While the absence of root resorption in this case would be supportive of a radiographic diagnosis of OKC, the clinical and radiographic cortical expansion as well as sclerotic septations and foci of sclerotic bone would not. Odontogenic myxoma is a rare benign neoplasm more commonly found in the mandible than the maxilla.6 It typically occurs in young adults, with an average age of 25 to 30 years.2 A multilocular radiographic appearance is common, characterized by straight, thin or wispy septations that form rectangular or triangular spaces.6 The patient in this case is older than average for odontogenic myxoma, and the radiographic septations are markedly curvilinear, thick, and sclerotic, rather than straight and wispy. Glandular odontogenic cyst (GOC) is an uncommon benign cystic lesion of the jaws that often occurs in the anterior mandible of middle-aged adults.2 Approximately half of reported lesions present radiographically as unilocular and half as multilocular.7 Cortical expansion is a common finding in GOC.7 While lesions are typically asymptomatic, larger lesions may occasionally be associated with pain or paresthesia.2,8 The clinical and radiographic features of GOC show overlap with our case, although the posterior localization is less in favor of this diagnosis.9 Intraosseous mucoepidermoid carcinoma (IMEC) is a rare presentation of a centrally arising salivary gland malignancy occurring across a wide age range but most commonly in middle-aged adults.2 It is found more often in the mandible than the maxilla, most frequently localized to the molar-ramus area.2 Clinically, IMEC typically presents as an asymptomatic swelling; however, pain, paresthesia, and trismus are occasionally noted.10 Although the radiographic appearance of IMEC can be variable, it is most often described as a well-defined unilocular or multilocular radiolucency with or without association of an impacted tooth.11 Cortical perforation and soft tissue extension is possible. The periphery tends to be sclerotic and when present, loculations are multiple and small.11 The presence of internal sclerotic bony masses appears to be a characteristic feature of IMEC not typically present in other jaw lesions, which aligns well with the imaging in this case.11,12 Both central odontogenic fibroma (COF) and calcifying epithelial odontogenic tumor (CEOT) are rare benign tumors that may occur across a broad age range, but predominantly affect middle-aged adults.2,13 They present radiographically as unilocular or multilocular, with or without internal calcification. Cortical expansion, tooth displacement, root resorption, and association with an impacted tooth are variable features.13,14 While the multilocular nature and cortical expansion with tooth displacement are consistent with this case, pain would be an unusual symptom of both entities.2 Central giant cell granuloma (CGCG) is an uncommon pathology of the jaws that most often occurs in the mandible. CGCG may occur across a broad age range although most cases are found in patients less than 30 years of age.2,15 Lesions can present as a painless, slow-growing swellings.15 CGCG is radiographically diverse and can vary from a unilocular to multilocular radiolucency with generally well-defined but non-corticated borders.2 Displacement of anatomic structures including teeth is relatively common.16 When present, septations in CGCG are described as low-density and granular,11 which is in contrast to this case. Lastly, intraosseous vascular malformation or hemangioma is a very rare lesion in the jaws that typically affects younger patients and may present clinically with painless expansion .17 The mandible is more often affected than the maxilla.17 Intraosseous vascular lesions can appear radiographically as unilocular to multilocular, with either small or large loculations.18 The borders may be well-defined or ill-defined, but are usually not sclerotic,18 as seen in this case. Diagnosis and Management Graphical AbstractMedium power view of second biopsy depicting cystic islands of squamous, mucous, and clear cells surrounded by bone (H&E, 20x). View Large Image Figure Viewer Download Hi-res image Graphical AbstractPhotomicrographs of third biopsy. A. Low-power view showing multiple cystic islands of varying sizes infiltrating bone (H&E, 10x); B. Medium-power view of cystic island composed of squamous and intermediate cells admixed with numerous mucous cells (H&E, 20x). View Large Image Figure Viewer Download Hi-res image Discussion Intraosseous mucoepidermoid carcinoma (IMEC) was initially described in 1939 by Lepp and reintroduced by way of literature review in 1970.19,20 The histogenesis remains at topic of debate and proposed origins include the epithelial lining of dentigerous cysts, epithelium associated with entrapped or ectopic salivary glands, and sinonasal epithelium with subsequent intraosseous extension.21–23 Overall, IMECs comprise 2-3% of all mucoepidermoid carcinomas19,20,24,25 and represent the most common salivary gland malignancy to arise centrally in the jaws.20,21,23 Lesions occur over a wide age range with a peak in the fourth and fifth decades of life. A slight female predilection has been reported, and the mandible is affected three times more frequently than the maxilla.20 The most common presenting symptoms include swelling and pain. Trismus, paresthesia, and mobility of the associated teeth have also been described. IMECs can show a varied radiographic presentation. Most cases appear as a well-defined, unilocular or multilocular radiolucency characterized internally by foci of amorphous, sclerotic bone or coarse septations.11 Lesions may cause expansion or perforation of the cortices.11 Approximately 28-54% of cases are associated with an impacted tooth or cyst.10,19,26,27 Table 1Clinical staging of intraosseous mucoepidermoid carcinomas Stage Clinical features Stage I Intact cortical plates, no expansion Stage II Intact cortical plates, some expansion Stage III Cortical perforation, breakdown of overlying periosteum, and/or nodal spread (Adapted from Brookstone and Huvos)10 Open table in a new tab The diagnosis of IMEC requires correlation between clinical, radiographic, and histologic characteristics. The following diagnostic criteria have been proposed to aid in distinguishing IMECs from mucosal mucoepidermoid carcinomas: 1. Presence of intact cortical plates, 2. Radiographic evidence of bone destruction, 3. Exclusion of another primary tumor, 4. Histopathological confirmation, and 5. Detectable intracellular mucin.20,28,29 Several studies have evaluated MAML2 gene rearrangements in IMECs.9,10,30–34 Reddy and colleagues performed a review of the literature and found MAML2 rearrangements reported in 19 of the 28 published cases.9 The fusion partner in most cases was CRTC1; however, the CRTC3-MAML2 fusion transcript has been documented in at least one case.31 IMECs are treated by complete surgical excision with or without neck dissection. Post-operative radiation therapy and adjuvant chemotherapy have been used in select cases. A recurrence rate of 40% for conservative treatment and 4% for radical treatment have been reported.35 The overall prognosis is good, although occurrence in males, maxillary involvement, and high histological grade portend a poorer prognosis according to Merna et al.27 Notch inhibitors, EGFR inhibits, and RNA interference strategies are currently being explored and show promise as potential therapeutic avenues.30,36 A 63-year-old female presented to her oral surgeon for evaluation of a right mandibular lesion. She reported recent onset swelling and pain without associated neurosensory deficits or changes in occlusion. Her past medical history was significant for hypercholesterolemia, hypertension, and osteoporosis, which were under pharmacologic control. Her social history was neither remarkable for tobacco use nor alcohol consumption. Extraoral examination revealed mild right-sided facial swelling associated with a palpable mass of the inferior border of the mandible. Intraoral examination of the corresponding area showed an expansile mass surfaced by normal-appearing mucosa. The lesion was slightly tender to palpation, and no overt evidence of infection or purulence was observed. The patient was partially edentulous and missing all teeth posterior to the right second premolar. On further inquiry, it was disclosed that the patient had undergone a right mandibular biopsy 7 years prior, which was diagnosed as a traumatic (simple) bone cyst. The clinical and radiographic differential diagnosis for an expansive, multilocular radiolucency of the mandible in an older adult is extensive.1,2 A comprehensive list would include: ameloblastoma, odontogenic keratocyst, odontogenic myxoma, glandular odontogenic cyst, intraosseous mucoepidermoid carcinoma, odontogenic fibroma, calcifying epithelial odontogenic tumor, central giant cell granuloma, and intraosseous vascular malformation or hemangioma. Ameloblastoma is an aggressive but benign odontogenic tumor with a strong predilection for the posterior mandible. The majority of cases represent conventional or multicystic ameloblastoma, which may present as a unilocular radiolucency, but is often multilocular.3 Cortical expansion is a common finding as well as root resorption of adjacent teeth.2 Pain may be a presenting symptom in a minority of cases.3,4 While the multilocular appearance, cortical expansion, and presence of pain in this case would be consistent with ameloblastoma, the notable absence of root resorption of the teeth in the area of the lesion, as well as the sclerotic septations and foci of sclerotic bone, would be unusual for ameloblastoma. Odontogenic keratocyst (OKC) is a relatively common developmental cyst with the potential for aggressive clinical behavior. It is commonly found in the posterior mandible and occurs across a wide age range.2 Small OKCs are typically asymptomatic and unilocular while larger lesions may appear multilocular radiographically.5 In most cases, OKCs demonstrate minimal cortical expansion as they tend to spread along the intramedullary space.5 Resorption of adjacent tooth roots is less commonly observed in OKCs than other radiographically similar lesions such as ameloblastoma, dentigerous cyst, and radicular cyst.2 While the absence of root resorption in this case would be supportive of a radiographic diagnosis of OKC, the clinical and radiographic cortical expansion as well as sclerotic septations and foci of sclerotic bone would not. Odontogenic myxoma is a rare benign neoplasm more commonly found in the mandible than the maxilla.6 It typically occurs in young adults, with an average age of 25 to 30 years.2 A multilocular radiographic appearance is common, characterized by straight, thin or wispy septations that form rectangular or triangular spaces.6 The patient in this case is older than average for odontogenic myxoma, and the radiographic septations are markedly curvilinear, thick, and sclerotic, rather than straight and wispy. Glandular odontogenic cyst (GOC) is an uncommon benign cystic lesion of the jaws that often occurs in the anterior mandible of middle-aged adults.2 Approximately half of reported lesions present radiographically as unilocular and half as multilocular.7 Cortical expansion is a common finding in GOC.7 While lesions are typically asymptomatic, larger lesions may occasionally be associated with pain or paresthesia.2,8 The clinical and radiographic features of GOC show overlap with our case, although the posterior localization is less in favor of this diagnosis.9 Intraosseous mucoepidermoid carcinoma (IMEC) is a rare presentation of a centrally arising salivary gland malignancy occurring across a wide age range but most commonly in middle-aged adults.2 It is found more often in the mandible than the maxilla, most frequently localized to the molar-ramus area.2 Clinically, IMEC typically presents as an asymptomatic swelling; however, pain, paresthesia, and trismus are occasionally noted.10 Although the radiographic appearance of IMEC can be variable, it is most often described as a well-defined unilocular or multilocular radiolucency with or without association of an impacted tooth.11 Cortical perforation and soft tissue extension is possible. The periphery tends to be sclerotic and when present, loculations are multiple and small.11 The presence of internal sclerotic bony masses appears to be a characteristic feature of IMEC not typically present in other jaw lesions, which aligns well with the imaging in this case.11,12 Both central odontogenic fibroma (COF) and calcifying epithelial odontogenic tumor (CEOT) are rare benign tumors that may occur across a broad age range, but predominantly affect middle-aged adults.2,13 They present radiographically as unilocular or multilocular, with or without internal calcification. Cortical expansion, tooth displacement, root resorption, and association with an impacted tooth are variable features.13,14 While the multilocular nature and cortical expansion with tooth displacement are consistent with this case, pain would be an unusual symptom of both entities.2 Central giant cell granuloma (CGCG) is an uncommon pathology of the jaws that most often occurs in the mandible. CGCG may occur across a broad age range although most cases are found in patients less than 30 years of age.2,15 Lesions can present as a painless, slow-growing swellings.15 CGCG is radiographically diverse and can vary from a unilocular to multilocular radiolucency with generally well-defined but non-corticated borders.2 Displacement of anatomic structures including teeth is relatively common.16 When present, septations in CGCG are described as low-density and granular,11 which is in contrast to this case. Lastly, intraosseous vascular malformation or hemangioma is a very rare lesion in the jaws that typically affects younger patients and may present clinically with painless expansion .17 The mandible is more often affected than the maxilla.17 Intraosseous vascular lesions can appear radiographically as unilocular to multilocular, with either small or large loculations.18 The borders may be well-defined or ill-defined, but are usually not sclerotic,18 as seen in this case. Intraosseous mucoepidermoid carcinoma (IMEC) was initially described in 1939 by Lepp and reintroduced by way of literature review in 1970.19,20 The histogenesis remains at topic of debate and proposed origins include the epithelial lining of dentigerous cysts, epithelium associated with entrapped or ectopic salivary glands, and sinonasal epithelium with subsequent intraosseous extension.21–23 Overall, IMECs comprise 2-3% of all mucoepidermoid carcinomas19,20,24,25 and represent the most common salivary gland malignancy to arise centrally in the jaws.20,21,23 Lesions occur over a wide age range with a peak in the fourth and fifth decades of life. A slight female predilection has been reported, and the mandible is affected three times more frequently than the maxilla.20 The most common presenting symptoms include swelling and pain. Trismus, paresthesia, and mobility of the associated teeth have also been described. IMECs can show a varied radiographic presentation. Most cases appear as a well-defined, unilocular or multilocular radiolucency characterized internally by foci of amorphous, sclerotic bone or coarse septations.11 Lesions may cause expansion or perforation of the cortices.11 Approximately 28-54% of cases are associated with an impacted tooth or cyst.10,19,26,27 (Adapted from Brookstone and Huvos)10 The diagnosis of IMEC requires correlation between clinical, radiographic, and histologic characteristics. The following diagnostic criteria have been proposed to aid in distinguishing IMECs from mucosal mucoepidermoid carcinomas: 1. Presence of intact cortical plates, 2. Radiographic evidence of bone destruction, 3. Exclusion of another primary tumor, 4. Histopathological confirmation, and 5. Detectable intracellular mucin.20,28,29 Several studies have evaluated MAML2 gene rearrangements in IMECs.9,10,30–34 Reddy and colleagues performed a review of the literature and found MAML2 rearrangements reported in 19 of the 28 published cases.9 The fusion partner in most cases was CRTC1; however, the CRTC3-MAML2 fusion transcript has been documented in at least one case.31 IMECs are treated by complete surgical excision with or without neck dissection. Post-operative radiation therapy and adjuvant chemotherapy have been used in select cases. A recurrence rate of 40% for conservative treatment and 4% for radical treatment have been reported.35 The overall prognosis is good, although occurrence in males, maxillary involvement, and high histological grade portend a poorer prognosis according to Merna et al.27 Notch inhibitors, EGFR inhibits, and RNA interference strategies are currently being explored and show promise as potential therapeutic avenues.30,36