Case Report/Clinical Techniques Langerhans Cell Histiocytosis Mimicking Periapical Pathology in a 39-Year-Old Man Scott M. Peters, DDS,* Julie Pastagia, DMD,† Angela J. Yoon, DDS, MAMSc, MPH,* and Elizabeth M. Philipone, DMD* Abstract Langerhans cell histiocytosis (LCH) is a clonal neoplastic proliferation of Langerhans-type dendritic cells, with more than 50% of cases of LCH seen in children younger than 15 years of age. The most common clinical presentation of LCH is solitary or multiple bony lesions. The jaws are affected in approximately 10%–20% of cases, with a strong predilection for the mandible. The maxilla is involved in only 1% of head and neck cases. When the jaws are involved, lesions of LCH may mimic periapical pathology as seen in patients requiring endodontic therapy or bone loss as seen in periodontal disease. We report the case of a 39-year-old man with LCH involving the posterior maxilla. This is a rare presentation of LCH with respect to both location and patient age. Clinicians should consider LCH when developing a differential diagnosis of an apical radiolucency of vital teeth or teeth that fail to respond to endodontic therapy and be aware of its clinical and radiographic mimics. (J Endod 2017;:1–6) Key Words Langerhans cell histiocytosis, periapical pathology, posterior maxilla From the *Division of Oral and Maxillofacial Pathology, Columbia University College of Dental Medicine, New York; and †Periodontist, Private practice, Manhattan, New York Address requests for reprints to Dr Elizabeth M. Philipone, Columbia University Medical Center, 630 West 168th Street, PH15W-1562, New York, NY 10032. E-mail address: [email protected] 0099-2399/$ - see front matter Copyright ª 2017 American Association of Endodontists. http://dx.doi.org/10.1016/j.joen.2017.05.020 JOE — Volume -, Number -, - 2017 L angerhans cells are Significance dendritic cells of the This is a rare presentation of Langerhans cell histioskin and mucosa from cytosis with regard to both its location (posterior which 2 main subgroups maxilla) and age of onset. Awareness of such preof tumors can arise. The sentation and consideration of Langerhans cell hisfirst, Langerhans cell histiocytosis in the differential diagnosis are critical in tiocytosis (LCH), refers to patient management. a clonal neoplastic proliferation of Langerhanstype cells, whereas the second, Langerhans cell sarcoma, is a high-grade neoplasm with overtly malignant cytologic features (1). LCH was classically referred to as histiocytosis X; this condition was further subdivided into 3 categories depending on the clinical presentation (2). Eosinophilic granuloma was the term used for a solitary or multiple bony lesions without visceral involvement. If multiple lesions involving the bone, skin, and viscera were present, the condition was referred to as Hand-Sch€uller-Christian disease. Prominent cutaneous, bone marrow, and visceral involvement occurring mainly in infants was termed Letterer-Siwe disease. These classical designations were often unclear because of overlapping clinical features, and the generic term of Langerhans cell histiocytosis was later introduced (3, 4). In the current classification system, LCH is categorized on the basis of degree of organ involvement. According to this system, lesions are first designated as having single organ involvement or multiorgan involvement. Those affecting only a single organ, typically the bone or skin, are further classified as unifocal or multifocal. On the other hand, multiorgan involvement is further categorized by the presence or absence of organ dysfunction. If organ dysfunction is present, the condition is considered to be high or low risk on the basis of which organs are involved (high risk includes lung, liver, spleen, and/or bone marrow, and low risk includes skin, bone, lymph nodes, and/ or pituitary gland) (5–8). LCH is a rare disease with an incidence of 5 cases per 1 million per year (9). More than 50% of cases are seen in children younger than 15 years of age. LCH has a definite male predilection, with a male to female ratio of 3.7:1 (10). The clinical presentation of LCH varies, but in more than half of cases (55%) the disease is limited to one organ (10). The bone is affected most frequently, followed by skin, lymph nodes, liver, spleen, oral mucosa, lung, and central nervous system (6). Most commonly, bony lesions occur in the skull, ribs, vertebrae, and mandible (11). In addition, there appears to be a correlation between age of onset of LCH and the bones that are affected by the disease. Children younger than 10 tend to have skull and femoral lesions (9), whereas those older than 20 are more likely to have rib, shoulder girdle, and mandibular lesions (12). Other clinical presentations depend on the organs involved by the disease process and can include lymphadenopathy, diabetes insipidus, hepatosplenomegaly, and cytopenia (13). Bone lesions, either solitary or multiple, are the most common clinical presentation of LCH (14). Radiographically, the lesions appear as punched out radiolucencies without cortication. The jaws are affected in 10%–20% of all cases (15). The most frequently affected intraoral site is the posterior mandible, and here lesions may appear scooped out or scalloped as a result of the destruction of superficial alveolar bone (16). With advanced bone destruction, clinical symptoms may mimic those of severe chronic Langerhans Cell Histiocytosis of Maxilla 1 Case Report/Clinical Techniques disease process spreads from the bone to adjacent oral soft tissues (18, 19). Soft tissue lesions are also associated with pain, bleeding, gingival inflammation, impaired healing, and halitosis (20). LCH has a strong predilection for the mandible; maxillary involvement by LCH is uncommon and occurs in only 1% of head and neck cases (5). Here we report the case of a 39-year-old man with LCH involving the posterior maxillary bone. The lesion presented as a periapical radiolucency associated with tooth #3, leading to initial improper management with root canal therapy (RCT). Case Presentation Figure 1. Pretreatment radiograph of tooth #3. Possible area of decreased bone density, which may have been interpreted as periapical pathology, is present around the distal root. Tooth tested vital with both electric pulp testing and Endo Ice; however, RCT was performed. Triangular-shaped radiolucency extending from center of crown to coronal portion of root is a radiographic artifact. periodontitis, and the teeth are described as ‘‘floating in air’’ after the loss of alveolar bone (16, 17). Patients may complain of dull pain or tenderness as a result of intraosseous oral lesions. Patients may also develop proliferative or ulcerative mucosal or gingival lesions if the A 39-year-old man presented to his periodontist with a chief complaint of pain and swelling associated with tooth #3 (maxillary right first molar). The patient reported that he had previously experienced similar symptoms at that site 2 years ago. At that time he was seen by an endodontist who prescribed antibiotics that were ineffective at alleviating the pain or swelling. A periapical radiograph was taken that showed a possible area of decreased bone density around the distal root of tooth #3, which may have been interpreted as periapical pathology (Fig. 1). The tooth tested vital with both Endo Ice (Coltene/Whaledent Inc, Cuyahoga Falls, OH) and electric pulp testing; however, it was subsequently treated endodontically via RCT. The patient’s medical history is significant for an isolated lesion of LCH diagnosed within the skull approximately 1 year ago. With regard to the patient’s history of LCH, he first presented to his neurologist with complaints of headaches refractory to nonsteroidal anti-inflammatory drugs. A magnetic resonance imaging scan was performed that showed a radiolucent lesion within the skull (Fig. 2). On the basis of the patient’s symptoms and radiographic presentation, a presumptive clinical diagnosis of a meningioma was made. The lesion was then excised and sent for pathologic analysis, at which time a final diagnosis of LCH was rendered. No other lesions of LCH were observed on imaging at this time. On presentation to his periodontist, the patient was not in acute distress. Clinical examination revealed a gingival swelling in the area of tooth #3. A radiograph was taken that showed a radiolucency at the apex of the RCT-treated tooth (Fig. 3). Different treatment Figure 2. Sagittal (A) and coronal (B) magnetic resonance imaging scans showing lytic lesion at right skull base. Lesion is indicated with an asterisk (*). 2 Peters et al. JOE — Volume -, Number -, - 2017 Case Report/Clinical Techniques Figure 3. Periapical radiograph of tooth #3 showing punched out radiolucency at root apex. Tooth had been endodontically treated approximately 2 years before this radiograph was taken. options, including endodontic re-treatment and extraction, were discussed with the patient. The patient elected to have the tooth extracted. The periodontist subsequently extracted tooth #3 and curetted out the apical lesion and surrounding bone, which were sent for pathologic analysis. The excised specimen consisted of 3 pieces of tissue ranging from 0.1 to 0.5 cm in greatest dimension. Microscopic examination showed pieces of edematous fibrous connective tissue infiltrated by both acute and chronic inflammatory cells (Fig. 4A). Abundant eosinophils were present, as well as atypical histiocytes with indented (kidney bean shaped) nuclei (Fig. 4B). Also identified within the specimen were small and thin-walled blood vessels and pieces of non-vital bone exhibiting loss of osteocytes from lacunae (sequestrum formation) and peripheral resorption (Fig. 4C). Immunohistochemical analysis of the lesional tissue was performed. The lesion was strongly positive for CD1a (Fig. 4D). Staining results with S100, CD45, and langerin were also positive. CD138 stain was negative. The Ki-67 proliferation index was moderately elevated. Staining for BRAF was equivocal. On the basis of the histologic findings, a diagnosis of LCH was made. Because this was the second lesion of LCH in this patient, it was recommended that he receive further testing to identify any additional lesions that may be present. The patient subsequently underwent positron emission tomography/computed tomography imaging at Memorial Sloan Kettering Hospital, which showed no further evidence of LCH but did reveal residual lesion in the area of tooth #3 that had not been fully removed. The patient is currently under observation Figure 4. (A) Low-power image showing pieces of edematous fibrous connective tissue infiltrated by acute and chronic inflammatory cells (hematoxylin-eosin; original magnification, 20). (B) On higher magnification, abundant eosinophils and atypical histiocytes with indented (kidney bean shaped) nuclei can be appreciated (hematoxylin-eosin; original magnification, 400). (C) Also identified within the specimen are small and thin-walled blood vessels and pieces of non-vital bone exhibiting loss of osteocytes from lacunae (sequestrum formation) and peripheral resorption. Abundant eosinophils are present ( hematoxylin-eosin; original magnification, 200). (D) LCH, diffusely positive for CD1a (hematoxylin-eosin; original magnification, 20). JOE — Volume -, Number -, - 2017 Langerhans Cell Histiocytosis of Maxilla 3 Peters et al. Author/year (reference) Schepman et al/1998 (31) Shao et al/2004 (32) Shekhar and Ponnudurai/2009 (29) Jindal et al/2009 (28) Abdul-Jalil and Hin-Lau/ 2009 (30) Azreen et al/2012 (33) Terada/2013 (27) Vargas et al/2016 (20) JOE — Volume -, Number -, - 2017 Peters et al/2017 (current case) Case no. Patient age (y)/gender Location of maxillary involvement Additional lesions Treatment Years of follow-up/ outcome 1 3/m Posterior, multifocal Mandible Surgery None provided 2 19/m Posterior, multifocal Mandible Chemotherapy 3 23/m Anterior and posterior Mandible and extraoral Surgery, radiotherapy, and chemotherapy 4 46/m Posterior, multifocal Mandible and extraoral 5 6 7 8 — — — 4/m — — — Right posterior None Mandible Mandible Mandible Surgery and chemotherapy Surgery Surgery Surgery Bone curettage 1.5/extension of oral lesions 5/new oral lesions and progression of extraoral lesions 5/new oral lesions 9 6/m Mandible and skull Not discussed None provided 10 2/m Multifocal, anterior and posterior Right posterior Mandible Not discussed None provided 11 12 1/f 2/m Not discussed Not discussed None provided None provided 13 14 15 16 2/f 2/m 46/m 16/m None provided 1/no new lesions 2/no new lesions* 5/no new lesions 17 39/m Not discussed Chemotherapy Bone curettage Lesion healed spontaneously after incisional biopsy Extraction of tooth #3 and bone curettage Left maxilla Right alveolus and palatal swelling Multifocal Right maxillary sinus Not specified Radiolucency apical to tooth #14 Radiolucency apical to tooth #3 f, female; m, male. *Patient has total follow-up time of 7 years. Maxillary lesion in this case occurred 5 years after initial diagnosis of mandibular lesion. None Skin rashes, scalp lesions, orbital lesions Mandible Orbit, skull, liver Mandible None Skull None provided None provided None provided 5.7/no new lesions 6 mo/no new lesions at the time of writing Case Report/Clinical Techniques 4 TABLE 1. Reported Cases of Maxillary LCH Case Report/Clinical Techniques only at this time, with a plan to follow up every 3 months for reassessment. At the time of writing, the patient has been followed for 6 months without any new lesions. Discussion This case is an unusual presentation of LCH occurring as a periapical radiolucency of the maxilla in an adult male. The jaws are affected in 10%–20% of cases, with a strong predilection for the mandible (15). Clinical and radiographic differential diagnosis often includes generalized chronic periodontitis, periapical granuloma, or periapical cyst. Although these conditions will successfully respond to conventional periodontal or endodontic therapy, oral manifestations of LCH will be refractory to treatment, as was seen in our case. Histopathologic analysis is necessary to confirm a diagnosis of LCH. On hematoxylin-eosin stain, Langerhans cells appear as large cells with grooved, folded, or indented nuclei and an abundant eosinophilic cytoplasm. Nucleoli are not well-appreciated in these cells (1, 11). Langerhans cells are often seen in a mixed inflammatory background consisting of variable amounts of neutrophils, eosinophils, histiocytes, and lymphocytes. Areas of necrosis and hemorrhage may also be present (1, 10). Classically, lesional Langerhans cells were identified by the presence of Birbeck granules on electron microscopy (21). With the advent of immunohistochemistry, diagnosis of LCH is now made after positive staining of lesional cells for CD1a and langerin. Lesional Langerhans cells will also stain positive for S100, CD68, vimentin, HLA-DR, CD45, CD4, and lysozyme. Other T-cell and B-cell markers, as well as follicular dendritic cell markers, should not stain Langerhans cells (1, 10, 21). The prognosis of LCH depends on the clinical stage at presentation. Usually the prognosis is favorable when the disease is limited to a single organ, with a survival rate of greater than 99%, but is less favorable with multiorgan involvement, with a survival rate of approximately 33% (10). Certain affected sites, such as the lung, liver, and bone marrow, are associated with a worse prognosis (1). When LCH presents with bony lesions, the treatment varies on the basis of the affected site. Easily accessible locations, such as the mandible or maxilla, are treated with curettage or intralesional injection of corticosteroid agents (22). Less surgically accessible bony lesions are treated with radiation therapy. Both single and multi-agent chemotherapy have also been used to treat disseminated LCH, with low-dose cytosine arabinoside showing the best response in adult patients (23, 24). In 40%–60% of LCH cases, mutations in BRAF have been identified; however, the clinical and prognostic implications of this mutation are unclear (25, 26). Because of the rarity of LCH, it has been difficult to establish a gold standard of treatment. Although lesions of the skull and mandible are more frequently seen in cases of LCH presenting in the head and neck, maxillary manifestations of LCH are quite rare. Hicks and Flaitz (5) report that the maxilla is involved in only 1% of head and neck cases. Within the published literature, there are only a few documented cases of LCH occurring within the maxillary bone. Vargas et al (20) describe a case of a 16-year-old male patient with an asymptomatic osteolytic lesion in the periapical region of tooth #14 (left maxillary first molar). The lesion was diagnosed as ‘‘monostotic eosinophilic granuloma of the maxillary bone’’ on incisional biopsy. Surgical excision was planned as definitive treatment; however, it was not performed because the lesion healed spontaneously after the initial biopsy. Terada (27) reports a case of recurrent multifocal LCH in a 46-year-old man. In this patient, osteolytic lesions were found in both the mandible (3.0 1.0 1.0 cm) and the maxilla (0.5 0.5 0.4 cm). Similarly, Jindal et al (28) and Shekhar and Ponnudurai (29) document cases of oral LCH involving both the mandible and maxilla. In a retrospective study by Abdul-Jalil and JOE — Volume -, Number -, - 2017 Hin-Lau (30), the clinicopathologic presentation of oral LCH in Malaysian children was examined during a 40-year time period. Of the 17 cases of LCH documented, only 2 occurred solely in the maxilla, and an additional 2 involved both the maxilla and mandible. Schepman et al (31) provided a retrospective report of 11 cases of LCH affecting the jaw bones. They reported maxillary involvement in 4 of these cases, each with concurrent mandibular lesions. Shao et al (32) analyzed 21 cases of LCH with jaw involvement and found that only 1 of these cases solely affected the maxilla, and an additional 2 involved both the maxilla and the mandible. Azreen et al (33) reported a case of a 2-year-old boy with multiorgan LCH involving the maxillary sinus. In this case, however, no osteolytic lesion of the bone proper was observed. A complete listing of the reported cases of maxillary LCH can be found in Table 1. Our case adds an additional report of oral LCH, but in the uncommon location of the posterior maxilla. Although maxillary involvement by LCH has been described in the literature, the frequency of such involvement is quite low, and most cases report osteolytic lesions in both the maxilla and mandible. However, in our case, the mandible was completely spared, although the patient did have a separate osteolytic lesion of his skull. In addition, most documented cases of oral LCH are seen in younger children; however, our patient is a 39-year-old man. In conclusion, one should consider the possibility of LCH when developing a differential diagnosis for a radiolucent lesion of the maxilla or mandible and be cognizant of its potential clinical and radiographic similarities to more common periapical pathoses. Furthermore, when weighing the likelihood of different diagnoses, one should not rule out LCH simply on the basis of patient age, but rather a full work-up of oral symptoms and evaluation of the patient’s medical history are indicated to arrive at a diagnosis. Acknowledgments The authors deny any conflicts of interest related to this study. References 1. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoeitic and Lymphoid Tissues, 4th ed. 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