Multifocal Oral Langerhans Cell Histiocytosis

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J Oral Maxillofac Surg69:2585-2591, 2011

Multifocal Oral LangerhansCell Histiocytosis

Matthew Murray, DDS, MD,* Jeffrey Dean, DDS, MD, FACS,†

and Lee Slater, DDS, MS‡

Langerhans cell histiocytosis (LCH), previouslyknown as histiocytosis X, is a rare disorder in whichbone marrow– derived pathologic cells infiltrateand destroy tissue. It has traditionally been recog-nized to present as Letterer-Siwe disease (acutedisseminated multisystem disease occurring in in-fants), Hand-Schüller-Christian disease (chronic dis-seminated disease arising in children), and eosinophilicgranuloma (disease limited to bones, occurring inadolescents and young adults).1 This schema remainsuseful, but it is an oversimplification because infantscan have single-system self-healing skin disease andadults can have multisystem life-threatening dis-ease.2,3 We report the case of a 22-month-old boywith disease simultaneously presenting in the maxillaand mandible.

Report of Case

A 22-month-old boy presented to the Loma Linda Uni-versity Emergency Department with mandibular andmaxillary alveolar ridge and palatal swellings. He had a7-month history of swelling on his upper gums (Fig 1)and lower gums (Fig 2A). Intraorally, we observed ery-thematous fusiform mucosal swellings measuring approx-imately 2.0 � 0.5 cm from the buccal to molar teeth in all4 jaw quadrants and palatal lesions that were erythema-tous and like cobblestone in appearance, with ulcer-ations in multiple locations. His mother had taken him tosee the same general dentist 6 times over the 7-monthperiod. The dentist had observed the lesions over thecourse of several appointments but did not obtain anybiopsy specimens. He eventually prescribed amoxicillin,

*Resident, Department of Oral and Maxillofacial Surgery, Loma

Linda University School of Dentistry, Loma Linda, CA.

†Program Director, Department of Oral and Maxillofacial Sur-

gery, Loma Linda University Medical Center, Loma Linda, CA.

‡Oral Pathologist, Scripps Oral Pathology Service, San Diego, CA;

and Lecturer, Department of Oral and Maxillofacial Surgery, Loma

Linda University School of Dentistry, Loma Linda, CA.

Address correspondence and reprint requests to Dr Dean: De-

partment of Oral and Maxillofacial Surgery, Loma Linda University

School of Dentistry, Loma Linda, CA; e-mail: matthewdeanmurray@

gmail.com

© 2011 American Association of Oral and Maxillofacial Surgeons

278-2391/11/6910-0021$36.00/0

oi:10.1016/j.joms.2011.01.008

2585

which did not aid in the resolution of the disease. Thechild saw the dentist the final time with a new finding ofpalatal swelling of 2 weeks duration (Fig 2B). The dentistbecame alarmed and sent the patient to the emergencydepartment for further evaluation.

The patient was an otherwise healthy child with nomedical comorbidities. There was no family history ofsimilar disease. As the lesions enlarged and became pain-ful, he refused solid food and his diet consisted largely ofchocolate milk; his mother justifiably became alarmed.

The patient had been spiking fevers reportedly up to102.0°F at home. In the emergency department, his tem-perature was 100.7°F. Multiple teeth were noted to beloose. The white blood cell count (WBC) was 15.6 �103/�L; hemoglobin level, 10.4 g/dL; and hematocrit con-centration, 34%. The WBC differential was as follows:neutrophils, 48.3%; lymphocytes, 42.7%; monocytes,8.2%; and segmented leukocytes, 68%. The coagulationprofile was normal, with a prothrombin time of 10.5seconds, partial thromboplastin time of 25.3 seconds,and international normalized ratio of 1.0. The urinaryanalysis findings were negative. The child was admittedby the pediatric team for additional workup. An oralswab grew out moderate gram-positive cocci in pairs,gram-negative rods, and gram-negative diplococci. Thisoral culture was consistent with normal oral flora. Bloodcultures were taken and were negative. Iron studies weredone as part of the anemia workup and showed a ferritinlevel of 6.0 ng/mL, total iron-binding capacity of 281�g/dL, and iron level of 16 �g/dL (normal, 65-175 �g/dL), which is consistent with iron deficiency anemia.Rheumatoid factor was 7 IU/mL (normal), and C3 level,184 g/dL (elevated).

The oral surgery department was consulted regardingthe oral lesions. Initially, the oral and maxillofacial sur-gery team recommended oral health care including Peri-dex (Xttrium Laboratories Inc, Chicago, IL) and brushing,antibiotics including clindamycin and Flagyl (Metronida-zole; Pfizer, New York, NY) because of the WBC of 15 �103/�L and fevers, and a computed tomography (CT)scan. The differential diagnosis included periodontitis,acute necrotizing periodontitis, infectious disease (tuber-culosis, fungal infection), autoimmune disease, an inflam-matory condition (sarcoidosis), reactive lesion, allergicreaction, oral manifestation of a systemic disease, LCH,leukemia/lymphoma, and soft tissue sarcoma. The CTscan showed erosion of the maxillary and mandibularbone, with the lesion extending into the right maxillarysinus (Fig 3). On the basis of the maxillofacial CT radio-logic findings, bilateral subcentimeter level 1 and level 2alymph nodes were present. There was a soft tissue opaci-fication of the right maxillary sinus with absence of theposterior wall of the maxillary sinus, as well as no signif-icant adjacent soft tissue swelling. There was also mild
mucosal thickening in the left maxillary sinus and eth-
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M

2586 MULTIFOCAL ORAL LANGERHANS CELL HISTIOCYTOSIS

FIGURE 1. A 22-month-old boy with swellings of maxillary buccal alveolar mucosa bilaterally. A, Right gingiva. B, Left gingiva.

urray, Dean, and Slater. Multifocal Oral Langerhans Cell Histiocytosis. J Oral Maxillofac Surg 2011.

MURRAY, DEAN, AND SLATER 2587

FIGURE 2. Langerhans cell histiocytosis. A, Gingival mass lingual to left mandibular incisors. B, Bosselated swellings of mucosa palatal tomaxillary incisors bilaterally.

Murray, Dean, and Slater. Multifocal Oral Langerhans Cell Histiocytosis. J Oral Maxillofac Surg 2011.


moid air cells. Findings were suspicious for neoplasmsuch as rhabdomyosarcoma or, less likely, an inflamma-tory process such as histiocytosis. The teeth had loss ofsupporting bone and appeared to stand in space.

The patient was taken to the operating room, and 6 siteswere biopsied (maxillary and mandibular gingiva, palatalmucosa). The bone was noted to be thin or absent when weinjected a local anesthetic, and all of the primary molarsexhibited at least Class I mobility. Grossly mobile primarytooth K was an aspiration risk; it was extracted. The patientrecovered well after the operation. His oral intake wasadequate, he was afebrile, and his white count began todecline.

Tissue biopsied from all 6 sites showed similar histo-logic features. Sheets of histiocytic cells showed inter-spersed eosinophils (Fig 4). The histiocytic cells exhib-ited oval, reniform, and infrequent irregularly shapednuclei; moderately abundant pale-grayish amphophiliccytoplasm; and indistinct cytoplasmic borders. Histio-cytic cells showed little evidence of nuclear pleomor-phism and a low mitotic index. Lesional histiocytic cellswere immunoreactive for CD1a (Fig 5) and S-100 butlacked immunoreactivity for desmin. The histologic andimmunohistochemical findings were diagnostic of LCH.

The patient’s case was presented to the hospital’s tumorboard, and additional workup was ordered including skele-tal radiographs and a chest radiograph. A bone scan identi-fied a 4-cm right parietal bone lesion as well as the previ-ously identified maxillary and mandibular bony defects. A28-day course of prednisone was begun with follow-up withthe departments of pediatric oncology and oral surgery. Thepatient returned 6 weeks later for a follow-up CT scan,which showed overall improvement. The radiologic assess-ment showed there was decreased size of erosive lesions,with residual soft tissue densities in the right maxillarysinus, resolution of posterior lateral margin of the rightmaxillary sinus, increase in soft tissue densities of the leftmaxillary sinuses, and healing lytic lesion of the right hard

FIGURE 3. Paramedian sagittal CT scan showing marked destruc-tion of maxillary and mandibular alveolar bone such that primarymolars appear to “stand in space.” Mandibular expansion withbuccal cortical bone erosion and buccal extraosseous extension ofsoft tissue mass.

Murray, Dean, and Slater. Multifocal Oral Langerhans Cell His-tiocytosis. J Oral Maxillofac Surg 2011.

palate.

Discussion

Normal Langerhans cells are dendritic antigen-presenting cells, but LCH cells are ovoid, lack den-dritic processes, and are clonal; such monoclonalitycan be indicative of a dysfunctional immune re-sponse or a neoplastic proliferation (benign or ma-lignant).4 When histologically evaluating biopsiedperiradicular inflamed granulation tissue, the oralpathologist always considers Langerhans cell histi-ocytosis and seeks to identify a pale “clonal” focusof histiocytic cells. The nodule is pale becauseclosely packed lesional histiocytic cells demon-strate pale oval nuclei with finely divided evenlydispersed chromatin and abundant pale cytoplasm.Within this pale nodule, the pathologist searchesfor evidence of LCH cells, which exhibit character-istic irregularly shaped nuclei; the nuclei can alsoappear reniform, notched, “coffee bean” shaped,grooved, or lobulated. Eosinophils in the granula-tion tissue alert the pathologist to carefully searchfor LCH cells, but eosinophils are not always pres-ent and are not necessary for a diagnosis of eosin-ophilic granuloma. Early enlarging lesions with in-distinct radiographic margins often show a readilyidentifiable component of LCH cells, but matureradiographically circumscribed lesions may exhibitonly small, difficult-to-identify pale clonal aggrega-tions of LCH cells.5

A diagnosis of LCH is confirmed if lesional cellsshow membranous immunoreactivity for CD1a, amajor histocompatibility complex class 1–like mol-ecule, which facilitates receptor-mediated endocy-tosis of glycolipid antigens and subsequent surfaceantigen presentation.4 Pathologists who have ex-tensive experience with childhood histiocytosis be-

FIGURE 4. Photomicrograph showing sheets of closely packedhistiocytic cells with interspersed eosinophils (hematoxylin-eosinstain, original magnification �200).

Murray, Dean, and Slater. Multifocal Oral Langerhans Cell His-
tiocytosis. J Oral Maxillofac Surg 2011.

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lieve that a definitive diagnosis of LCH is warrantedonly if lesional CD1a-positive cells also show ultra-structural or immunohistochemical evidence of Bir-beck granules.5 Birbeck granules are unique toangerhans cells; they are derived from apposedndocytotic membranes and ultrastructurally ap-ear as tennis racquet–shaped pentalaminar struc-ures exhibiting zipper-like striations.1 Evidence ofirbeck granules can be reliably immunohisto-hemically detected by a monoclonal antibody toangerin (CD207, clone 12D6).6 Langerin is a man-ose-specific type II transmembrane lectin that in-uces Birbeck granule formation.7

If a mandibular lesion shows typical radiographicfindings (marked periradicular osteolysis with a“tooth-standing-in-space” appearance or an under-mined “scooped-out” cortical bone defect) andcharacteristic pathologic findings (CD1a-positivehistiocytic cells displaying irregular nuclear con-tours), treatment as for LCH would be justified,whether or not evidence of Birbeck granules ispresent. A proliferation of CD1a-positive butCD207-negative histiocytic cells would be diag-nosed as “indeterminate cell histiocytosis”; this is ascientifically accurate, clinically irrelevant designa-tion, because patients with indeterminate cell his-tiocytosis are recognized as having an LCH-like con-dition and are accordingly treated as though they

FIGURE 5. Langerhans cell histiocytosis cells exhibiting diffuse inteoriginal magnification, �40).

Murray, Dean, and Slater. Multifocal Oral Langerhans Cell Histi

had LCH.8

After the diagnosis of gnathic LCH is confirmed,the extent of disease (staging) should be assessed.The initial assessment is rather straightforward; itincludes a thorough physical examination, hemato-logic panel, coagulation studies, liver functiontests, urine osmolality, arginine vasopressin (to de-tect diabetes insipidus), radiographic skeletal sur-vey, and chest radiograph.9 If disease is limited tohe jaws, the prognosis is excellent, but if there isysfunction of a high-risk organ such as the liver or

ungs, then an unfavorable outcome would be pre-icted and chemotherapy would be indicated (Ta-

Table 1. CLINICAL STRATIFICATION OF LCH

Single–organ system diseaseUnifocalMultifocal

Multiorgan diseaseNo organ dysfunctionOrgan dysfunction

Low-risk sites*High-risk sites†

NOTE. Modified from Table 2 of Satter and High.9

*Low-risk sites include skin, bone, lymph node, and pitu-itary.

†High-risk sites include lung, liver, spleen, and bone mar-row (hematopoietic).

Murray, Dean, and Slater. Multifocal Oral Langerhans Cell His-

mbranous immunoreactivity for CD1a (immunohistochemical stain,

s. J Oral Maxillofac Surg 2011.

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bles 1 and 2). Extraoral head and neck presenta-tions include classic “punched-out” lesions of thecalvaria, mucopurulent otorrhea and postauricularswelling with petrous temporal bone involvement,and orbital swelling with proptosis and erythema.In addition, diabetes insipidus develops in approx-imately 40% of patients if the orbit/skull base isinvolved.10 The patient’s prominent febrile presen-ation likely resulted from a “cytokine storm” inhich activated lesional cells secreted interleukin 1

nd tumor necrosis factor, which induced synthesisf proinflammatory prostaglandins (prostaglandin E2),hich in turn acted on the hypothalamus to reset the

emperature set point at a higher level.11

Our patient had multifocal single-system diseasewith painful lesions in the mandible, maxilla, andparietal bones. Such patients with disease limited tobones generally have a favorable prognosis; althoughapproximately 75% of patients have a relapse, onlyabout 3% die of disease (Table 2).9 Conservative treat-

ent is indicated for such patients. The bone lesionsften spontaneously resolve after minimal interven-ion such as curettage for a diagnostic biopsy.12,13 Aingle dose of injected intralesional steroids can beurative.14-17 Nonsteroidal anti-inflammatory drugs

(oral indomethacin) can result in complete remis-sion.18 Riskier therapy, such as low-dose radiationherapy (6-10 Gy) or chemotherapy (vinblastine andrednisone in children, azathioprine and oral etopo-ide in adults), is probably warranted only for man-gement of skull base lesions or multifocal bone dis-ase, which—if untreated or reactivated after initialemission—could eventuate in late diabetes insipidus,ypopituitarism, and central nervous system dysfunc-

Table 2. INCIDENCE, RELAPSE, AND MORTALITY RATE B

UnifocalBone Cutaneous Only I

Approximateincidence†

28%-83% Overall, 10%; neonates,33%-37%

O

Disease-freesurvival

95% 83%-88%

Relapse 10% 5% 3ortality 0.9% 2%

NOTE. Used with permission of Pediatric Dermatology pu*Patients aged under 2 years with organ dysfunction.†The incidence rate of organ involvement depends on th

of isolated and multifocal bone lesions, whereas adults mo‡Survival rates vary depending on patient age, extent of

chemotherapy, with the best predictor of prognosis being atherapy.

Murray, Dean, and Slater. Multifocal Oral Langerhans Cell Histi

ion.10,19

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d PulmonaryMultifocal

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27% (96% ofare adults)

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85% 91% 76%-83% 75%

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Multifocal Oral Langerhans Cell Histiocytosis