International Journal of Clinical Dentistry ISSN: 1939-5833

Volume 9, Number 1 © 2016 Nova Science Publishers, Inc.

DIAGNOSIS AND MANAGEMENT OF ORAL

LANGERHANS CELL HISTIOCYTOSIS

Emanoele Paixão da Silva Silva1,, Carina Myung Rodenbeck2,†,

Monira Samáan Kallas3,‡, Cássia Maria Fischer Rubira4,§
and Paulo Sérgio da Silva Santos5,#
1
Department of Stomatology of the Bauru School of Dentistry,
University of São Paulo – Alameda Octávio Pinheiro Brisolla, Bauru-SP, Brazil
2
Municipal Hospital Dr. Cármino Caricchio, Tatuapé, São Paulo, Brazil
3
Premier Residence Hospital, Vila Cordeiro- São Paulo-SP, Brazil
4
Department of Stomatology of the Bauru School of Dentistry,
University of São Paulo – Alameda Octávio Pinheiro Brisolla, Bauru-SP, Brazil
5
Department of Stomatology of the Bauru School of Dentistry,
University of São Paulo – Alameda Octávio Pinheiro Brisolla, Bauru-SP, Brazil

ABSTRACT
The term Langerhans-cell histiocytosis (LCH) comprises a set of closely related
clinic pathological disorders to abnormal proliferation and dissemination of Langerhans
cells. It may involve both local and systemic manifestations involving bone, skin and
mucosal tissue, and internal organs. The head and neck are affected in almost 90% of
cases. The oral manifestations can be one of the first manifestations of the disease which
may come disguised as a periodontal disease until severe bone lesions. The definitive
diagnosis of LCH be rendered with a presence of Birbeck granules and when
immunoreaction with CD1a and CD207 are present. Therapy includes surgery, use of
corticosteroids, radiation and chemotherapy, either individually or in combinations.
Treatment is dependent on the numbers of lesions, the type and extent of organ
involvement. The purpose of this paper is review the history and pathogenesis of LCH,
discuss its differential diagnosis, provide guidance to dentists to diagnosis and manage
patients with LCH.


E-mail: emanoelepaixao@usp.br. Tel.: +55 14 3235-8373(FAX)
†
E-mail: carina_rodenbeck@yahoo.com.br Tel: +55.11 3394-6980.
‡
E-mail: monirask@gmail.com Tel.: +55 11 5090 5000.
§
E-mail: rubira@fob.usp.br. Tel.: +55 14 3235-8373(FAX).
#
E-mail: paulosss.fob.us.br Tel.: +55 14 3235-8373(FAX).
2 E. Paixão da Silva Silva, C. Myung Rodenbeck, M. Samáan Kallas et al.

Clinical Significance

Oral LCH may present gingival inflammation, bleeding, gengival recession or

asymptomatic intraosseous lesions. Differential diagnoses includes severe periodontal to
benign and malignant bone lesion. LCH may involve one system or multisystem.
Corticosteroids, radiation and chemotherapy, either individually or in combinations are usual
therapy. Treatment is dependent on the numbers of lesions, the type and extent of organ
involvement. The aim of this review is to describe the history and pathogenesis of LCH,
discuss its differential diagnosis, provide guidance to dentists to diagnosis and manage
patients with LCH.

Keywords: histiocytosis, langerhans cell, langerhans cells histiocytosis, oral manifestation,

jaw

INTRODUCTION
Langerhans cell histiocytosis (LCH) is characterized by intense and abnormal
proliferation of Langerhans-type histiocytic cells, and others inflammatory cells causing
tissue destruction [1-5]. The tissue destruction is a result of the cellular infiltration that
replaces bone and invades skin, mucosa and internal organs [6]. A definitive diagnosis of
LCH should be based on histological features and supported by clinical and radiographic
examination [4-7].The classical histopathology of LCH is confirmed by presence of positivity
of CD1a and/or Langerin or Birbeck granules on electronic microscopy [1, 8, 9]. LCH
pathogenesis is unknown, although many hypotheses exist as immune dysregulation or
neoplastic process [4, 10].
In 1953, Lichtenstein observed cytoplasmic bodies, known as X bodies, within
histiocytes from tissues of patients suffering from that were previously considered distinct
clinical disorders: eosinophilic granuloma, Hand-Schüller-Christian disease and Abt-Letterer-
Siwe disease. As a result of their common underlying histopathology, Lichtenstein grouped
these diseases together under the name of histiocytosis X [1, 3, 4, 6].
In 1973, Nezelof discovered that those histiocytes were in fact Langerhans cells so the
disorder was renamed Langerhans cell histiocytosis. LCH has also been referred to as
Langerhans cell granulomatosis, histiocytosis X, Hashimoto-Pritzker’s syndrome, non lipidic
reticuloendotheliosis, type [13, 6].
Currently, LCH classification is according to site and extension of the disease, into two
major categories [8, 9]:

1. ‘Single-system’ (SS) LCH: one organ/system involved and subdivided further into
single site (unifocal bone, skin, lymph node, hypothalamic-pituitary or lung) and
multiple site (multifocal bone or multiple lymph nodes) [8, 9].
2. ‘Multisystem’ (MS) LCH: defined as involvement of two or more organs at diagnosis
with or without organ dysfunction; MS-LCH is subdivided into a ‘low-risk’ and a
‘risk’ group. Low-risk patients account for 20% of all MS-LCH, characterized by the
absence of involvement of ‘risk’ organs such as liver, lungs, spleen, Central Nervous
System (CNS) or haematopoetic system and have a good prognosis [8, 9]. ‘Risk’
 Diagnosis and Management of Oral Langerhans Cell Histiocytosis 3

patients (80% of MS patients) have at least one or more risk organs involved and a
high mortality rate. [8, 9, 11].

EPIDEMIOLOGY
In Children, the incidence is 8-10 cases per million/year, ranging in presentation from 1
to 15 years of age, with peak frequency from 1-3 years. The occurrence in males is more
frequent than females. The incidence in adult is 1 to 2 cases per million inhabitants, ranging
between 15 to 91 years (mean age 35 years) [3, 10, 11].

ETIOPATHOGENESIS
Etiology and pathogenesis of LCH is still unclear, but two different hypotheses have been
proposed: a disorder of immune regulation or a neoplastic process [2, 4, 5, 9]. Other
immunologically active cells in lesions, thymic abnormalities, deficiency in the number of
suppressor T lymphocytes and increased cytokines are presented and suggest an exuberant
reaction of Langerhans cells to an unknown antigen or neoantigen [1, 2, 6]. However, the
monoclonal proliferation of Langerhans cells and cancer association mutation (BRAFV600E)
was found in more than half of investigated specimes inferring the neoplastic origin of the
disease [9].

Clinical Features

The LCH clinical features are very heterogeneous. The spectrum of features may range a
single bone until wide spreading (skin, hematopoietic system, spleen, liver, lung, mucosa,
eye, ear, pituitary, CNS and others) [8-12]. Children and adults show different patterns of
involvement by LCH. The children’s involvement is common in bones, skin and presence of
diabetes insipidus. However in adults are frequently involved bones, skin, teeth, lungs, genital
and diabetes insipidus presence [12, 13].

Craniofacial Features

Maxillofacial manifestations are common in LCH and a papular rash may appear on skin
and a seborrhea-like dermatitis in the scalp [3, 11, 12]. The cutaneous lesions are associated
with mucosal lesions. Oral mucosa involvement appears as gingival hypertrophy or ulcers in
buccal mucosa, hard/soft palate mucosa and tongue [1, 2, 6,11-14]. 30% of patients with oral
lesions present cervical lymphadenopathies [6, 7, 12]. The mucosal lesions are usually
accompanied by enlargement of the lymph nodes which also reflects the degree of histiocytic
infiltration [1, 7, 11].Osseous involvement is observed in 78% of patients where 49% in
cranium and 30% in mandible, particularly posterior area (15). Radiographic features of LCH
in the skull reveals a punched-out pattern [5, 8] without evidence of periosteal reaction or
marginal sclerosis, known as “geographic skull (11).Pain and swelling of the mandible, with
mobility and loss of teeth, may be the presenting symptoms of the disease [3, 5-7, 12].
4 E. Paixão da Silva Silva, C. Myung Rodenbeck, M. Samáan Kallas et al.

Intraorbital involvement can produce proptosis [8]. Middle ear involvement leads to deafness
[7]. Other soft tissues have been reported such as eyelids, parotid and submandibular glands,
external auditory canal, middle ear, thyroid and gastrointestinal tract [11, 12].

ORAL MANIFESTATIONS
Oral manifestations may be early sign of LCH (10%) and in some cases is the only area
affected [1, 16], therefore, the dentist may be the first professional to diagnose LCH [1, 17].
Oral manifestation of LCH may involve both bone tissues as soft tissue [1, 7]. Bone lesions
are involved twice as frequently as the oral mucosa lesions [5]. The mandible is three times
more frequently affected than the maxilla [1, 5]. We describe these lesions into bone and soft
tissue.

Bone Lesions

Unifocal lesions intraosseous of the jaws are most frequent in initial phase of LCH [6]
and may be accompanied by lesions in others long bones, pelvis and vertebra [6, 7].
Intraosseous lesions may produce facial swelling and painful [6], but these lesion may be
asymptomatic being an incidental radiographic finding [6, 15-17].

Soft Tissue Lesions

Alveolar bone lesions are associated with periodontal involvement in these patients [5,
12, 15]. The common clinical presentation include gingival inflammation, ulceration,
destruction of the keratinized gingiva, gingival recession, periodontal pockets and bleeding of
the oral soft tissues [1, 15], associated with pain and even swelling, typically involving a
small group of teeth and often exposing the roots of teeth(6). Some unusual cases of oral soft
tissue lesions in the absence of bone lesions have been described [2, 4].
Oral mucosa lesions are ovoid erosions or ulcerations with erythematous, inflamed
borders, painful on palpation [6, 4], localized principally in the buccal mucosa and at the back
of the vestibule [6]. When LCH cells infiltrating the gums cause granulomatous gingivitis
[1, 4].

IMAGING FEATURES
The radiological spectrum of LCH in jaws is quite varied. On the conventional
radiography, solitary lesions intraosseus are circular or elliptical, solitary or unifocal and
aggressive [7]. It is normally localized in body and ramus of mandible [6, 7]. Alveolar lesions
are commonly multiples. Multiple alveolar lesions are frequently well-defined and not
corticalized margins [6]. Alveolar lesions with bone sclerosis are associated to
communication of these with the oral cavity with added infection [7, 15] Scooped-out
alveolar lesions present intraosseous bone destruction, located below alveolar crest, involving
at furca level or at half the tooth root height [6, 12]. Alveolar bone lesions present the bone
 Diagnosis and Management of Oral Langerhans Cell Histiocytosis 5

resorption of periodontitis-like lesions [6, 7, 11, 15]. Slight radicular resorption may be seen
in radiographics of the posterior alveolar region associated to periodontal lesions of LCH
[12]. The typical radiological image of “floating teeth” [1, 6-8, 11] is associated to destruction
of lamina dura [1, 5, 15] and extensive bone resorption [5, 15].

DIFFERENTIAL DIAGNOSIS
Clinical and radiography findings of this disease are not specific for diagnosis. The
differential diagnosis includes a variety of benign and malignant bone lesions and diseases of
the oral mucosa and periodontal tissue [6, 7].

Bone Lesions

Multifocal LCH

 Osteomyelitis.
 Ewing’s sarcoma.
 Brown tumor hyperparathyroidism.
 Multiple odontogenic keratocyst.
 Multilocular cyst.
 Leukemia.
 Lymphoma.

Unifocal LCH

Children
 Metastatic neuroblastoma.
 Intra bony hemangioma.
 Fibrous dysplasia.
 Hemophilic pseudotumor.
 Epidermoid cyst.
 Giant cell granuloma

Adult
 Osteolytic metastasis.
 Multiple myeloma.
 Myxoma.
 Ameloblastoma.
 Osteogenic sarcoma.
 Fibrosarcoma.
6 E. Paixão da Silva Silva, C. Myung Rodenbeck, M. Samáan Kallas et al.

Soft tissue lesions is difficult to distinguish of advanced periodontal disease, Periapical

abscess. Parodontitis, Submucous abscess, Subperiostal abscess, Trauma, Necrotizing
sialometaplasia, Tuberculosis, Deep, mycotic infection, Melanoma, Cyclic neutropenia.

Histopathologic Features

Classical histopathologic feature of LCH is presence of lesional histiocytes of LC

phenotype, with varying proportions of macrophages, T-lymphocytes, eosinophils and
multinucleated giant cells [1, 5, 6, 11, 10]. Langerhans cells are oval or rounded in shape,
pale, and eosinophilic cytoplasm and oval or lobulated nucleus, with a typical central sulcus,
giving a “coffee bean” appearance [6, 8]. In 1987, the Histiocyte Society Writing group
defined the criteria for the diagnosis of LCH as: classical LCH histopathology confirmed by
the presence of Birbeck granules (BG) on electron microscopy or by demonstration of CD1a
on immunohistochemistry [5-8]. The presence of BG in LCs can be currently more easily
proven by immunohistochemical staining of Langerin (CD207), a novel C type lectin, specific
to the cell surface and cytoplasm of LCs, which induces the formation of BG [5, 6, 8].
Positivity of CD1a and/or Langerin (or BG) in the lesion is the current gold standard for the
diagnosis of LCH, but only in the correct clinical setting [1, 3, 9].

Pre-Treatment Clinical Evaluation

The Euro Histio Net Work Group for LCH recommended the following patient
evaluation for patients with definitive diagnosis of LCH [3, 8, 9]: Complete History;
Complete Physical Examination; Laboratory and Radiographic Evaluation: Thyroid
Stimulating Hormone (TSH), Free T4 (in particular for adult), Full blood count, Bood
Chemistry, Coagulation Studies, Urine analysis, Chest Radiograph, Skeletal Radiograph
Survey, Erythrocyte Sedimentation Rate, Abdominal ultrasound.

Prognosis/Management

Prognosis depends of lesions extensions and diagnosis age [1, 4].

Various treatment modalities for LCH have been described such as follow-up only,
surgical curettage, local injection of corticosteroids, low-dose radiotherapy, high-dose
systemic corticosteroids, chemotherapy and, for more resistant cases, bone marrow
transplantation and antibody therapy [1, 2, 7, 11]. Generally therapeutic depends of severity
of disease and number of systems involved [1, 4].
Localized lesions with bone involvement of “non-CNS-Risk facial bones” local therapy
and rigorous follow-up is recommended [8, 11].
Biopsy or curettage is suitable for histopathologic diagnosis and initiating a healing
process [6, 8-11]. Complete excision of bone lesions is not indicated. It may increase the size
of the bony defect and the time to healing or result in permanent skeletal defects [8-11].
Intralesional injection of steroid may increase healing [4, 6, 8, 11] (40 to 160 mg of
methylprednisolone) [5, 7]. Limited radiation therapy is indicated if there is an impending
 Diagnosis and Management of Oral Langerhans Cell Histiocytosis 7

neurological deficit and a high surgical risk, e.g., lesion in the odontoid peg or cranial
base [6-8, 11].
In cases with severe involvement of oral mucosa, topical nitrogen mustard may be used
[3, 4, 7, 9].
Chemotherapy is used in LCH disseminated [2, 4, 8, 9, 11]. Low to moderate doses of
methotrexate, prednisone and vinblastine have been used successfully [1, 2, 11]. The patients
should continue to be monitored once a year for assessment of clinical recurrence [4, 8].
Oral manifestation of LCH may be the first sign of systemic disease, therefore dentist
should be able to recognize oral lesions, make biopsy and conduct appropriate treatment
together to multidisciplinary team.

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