A 42-year-old female with a 15 pack-year history of smoking presented for extraction of root tip #20. A well-defined multilocular radiolucency of the anterior mandible of unknown duration was discovered on a panoramic radiograph (Figure 1). The differential diagnosis of multilocular lesions of the gnathic bones is broad (Table 1). In the present case, lesion borders were considered to be overall well-defined. The unique radiographic presentation which suggested uninvolved alveolar bone between teeth #3.3 and 3.4 (21 and 22) broadened the list of diagnostic possibilities to include multifocal multilocular entities. Despite minimal to no effect of the surrounding dentition, the conspicuous osseous expansion and cortical perforation suggested at least a locally aggressive pathology. Malignant lesions were also considered to a variable extent depending on the type of malignancy. In addition to the radiographic features, the patient's age and the asymptomatic clinical presentation in an otherwise healthy patient were important factors considered in the formulation of the differential diagnosis. Given the close proximity of the epicenter of the lesion to the dentition, odontogenic tumors and cysts with a destructive biologic potential were favored. Ameloblastomas, which frequently harbor BRAF V600E mutations, are the most common odontogenic tumor and typically present as a multilocular radiolucency with variably thick septations imparting a ''honey-comb" appearance.1 They are frequently associated with tooth displacement and resorption, cortical destruction and osseous expansion. While reported synchronously with other odontogenic cysts and tumors, multifocal lesions have not been documented in the literature. The newly described entity, adenoid ameloblastoma (AA) also presents with similar clinical and radiographic features. Unlike conventional ameloblastoma, they are not characterized by BRAF mutations.2 While 2/3 of cases of AA will exhibit dentinoid on histologic examination, approximately 82% of cases will be predominantly radiolucent radiographically. While more commonly a mixed lesion (∼ 75%), calcifying epithelial odontogenic tumors (CEOT) can present as large, expansile multilocular lesions capable of bone erosion, expansion and perforation.3 Rare cases have been reported to involve multiple sites, sometimes synchronously involving the mandible and maxilla.4, 5 Even in cases of multifocal lesions, most patients will not report pain associated with the tumor(s). Osseous expansion can occur, but cortical boundaries are usually respected in cases of CEOT. Other developmental odontogenic entities which can present multifocally include squamous odontogenic tumors, dentigerous cysts, odontogenic keratocysts, orthokeratinized odontogenic cysts, lateral periodontal cysts and their multilocular counterparts, botryoid cysts. With the exception of botryoid cysts, all entities are more frequently unilocular. With expansion of these lesions, cortical thinning may occur, but breaching of the cortices and evident osseous destruction are uncommon. In regard to malignant considerations, odontogenic carcinomas and sarcomas can also present as aggressive multilocular radiolucencies. Lesion borders tend to be ill-defined and infiltrative which contrast with the more demarcated boundaries of this case.6 Given the radiographic findings, the incidental discovery, and completely asymptomatic state of the patient, these entities were considered more unlikely. For similar reasons, solitary plasmacytomas and plasma cell lesions in the setting of multiple myeloma as well as metastatic disease originating from an occult primary were judged less probable, despite their capability of causing expansion and osseous destruction.7, 8 Giant cell lesions including aneurysmal bone cysts (ABC), central giant cell granulomas (CGCG) and brown tumors of hyperparathyroidism (BTH) share similar radiographic findings. In 2017, the World Health Organization recognized ABCs as neoplasms with approximately 70% of cases characterized by the USP6::CDH11 gene fusion. ABCs affect the head and neck region in less than 3% of cases with the mandible representing the most common site (37%), particularly the posterior body and ascending ramus. ABCs can reach a sizable dimension and still remain asymptomatic in some cases. 58-75% are multilocular and up to 15% in some series are multifocal.9, 10 Nonetheless, ABCs remain more common in younger patients with less than 10% of cases occurring over the age of 40.10 CGCG and BTH are histologically identical. A late manifestation of hyperparathyroidism, BTH affects the head and neck region in approximately 4% of cases and both jaws are involved in 23-30% of cases.11 An increase in parathyroid hormone can lead to bone resorption through its effect on the osteoprotegerin–receptor activator of nuclear factor-κB ligand-receptor activator of nuclear factor-κB system. BTH can be multilocular or unilocular with occasionally ill-defined borders. While some cases are asymptomatic, patients may experience signs and symptoms common to locally aggressive lesions such as pain, limited mouth opening, facial swelling and malocclusion. CGCG can present as single or multiple unilocular to multilocular generally well-defined radiolucencies. They are components of many syndromes including cherubism, Noonan syndrome, Jaffe-Campanacci syndrome and neurofibromatosis type I. KRAS, TRPV4 , or FGFR1 mutations are identified in 70% of sporadic CGCG.12 CGCG have a variable symptomatology profile depending on size and location of the lesion. However, they do remain overwhelmingly more common in younger patients with more than 75% of cases diagnosed in individuals younger than 30 years of age. Cemento-ossifying fibromas (OF), now characterized as cemento-ossifying dysplasia in the 2022 WHO classification, are radiolucent to mixed lesions that can reach a sizable dimension causing bucco-lingual expansion as well as downward bowing and thinning of the inferior mandibular cortex.2 They frequently affect the premolar to molar region; however, they are usually unilocular and rarely multifocal (5% of sporadic cases). Pain is uncommon (10% of cases), but swelling is frequent (90% of cases).13 5% of sporadic cases harbor mutations of the tumor suppressor gene CDC73 associated with hyperparathyroidism-jaw tumor syndrome. Cone beam CT was performed. A lesion measuring approximately 7.1 cm x 3.4 cm x 1.7 cm (Figure 2A, B) demonstrating severe bone resorption and cortical perforation (Figure 2C) was removed and submitted to pathology. Microscopic examination revealed a mass of fibrovascular connective tissue containing vital bone, a robust lymphocytic infiltrate, and numerous cells with large oval nuclei, indistinct cell borders and a pale "foamy" cytoplasm (Figure 3A). Upon examination at higher power, foci of eosinophils were noted, and the pale cells exhibited folded or "kidney bean" shaped nuclei (Figure 3B). CD1a (Figure 4A) and S-100 staining (Figure 4B) confirmed that these were Langerhans cells. Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder, characterized by aberrant function and differentiation or proliferation of cells of the mononuclear phagocyte system. The disease is more common in children and adolescents, with an annual incidence of 4.6 cases per 1 million children under 15 years of age and a male-to-female ratio of 1.2:1. A higher incidence has been reported for Hispanics, and a lower incidence in African Americans. It can also be seen in adults, with an incidence of 1-2 cases per million, usually presenting in the 4th decade.14 There is currently a debate regarding the nature of LCH. The benign histologic appearance of the Langerhans cells, the associated inflammatory infiltrate, and a characteristic cytokine storm support a lesion of inflammatory origin, while the clonality, somatic activating gene mutations in the mitogen-activated protein kinase (MAPK) pathway (the BRAF V600E mutation), and shared mutations with hematopoietic precursor cells favor its classification as a myeloid neoplastic disorder.14 Indeed, the extent and severity of the different forms of LCH depend on the state of differentiation of the precursor cell in which the somatic MAPK activating mutations arise.14 Monostotic or polyostotic eosinophilic granuloma of bone (the chronic focal form) has an excellent prognosis and arises from mutations late in dendritic cell differentiation, whereas chronic disseminated histiocytosis (chronic multifocal, also known as Hand-Schüller-Christian Disease) involves bone, skin and viscera and acute disseminated histiocytosis (Letterer-Siwe Disease) shows prominent visceral, cutaneous and bone marrow involvement and a poor prognosis as a result of mutations arising earlier in blood dendritic cell precursors or hematopoietic stem cells, respectively.15 Also favoring a neoplastic process is the association of LCH with other malignancies, with frequencies varying from 2.6% in children to 32% in adults. The most common hematologic malignancy reported is acute myeloid leukemia (AML), often occurring years after LCH, but others include lung and thyroid carcinomas and acute lymphoblastic leukemia (ALL). Coincident LCH and ALL share the same oncogenic mutations or have identical T-cell receptor or immunoglobulin rearrangements, suggesting a clonal relationship between the two.16 Pulmonary LCH (PLCH), which is the most common manifestation in adults, is considered a specific type of LCH. Although PLCH cells have similar histopathologic characteristics as LCH, most proliferations are polyclonal. Pulmonary LCH is also strongly related to smoking as more than 90% of patients are smokers and cessation has led to remission without treatment in some cases.17 [ABSTRACT FROM AUTHOR]