E222 Med Oral Patol Oral Cir Bucal. 2009 May 1;14 (5):E222-8. Langerhans cell histiocytosis Journal section: Oral Medicine and Pathology Publication Types: Review Langerhans cell histiocytosis: Literature review and descriptive analysis of oral manifestations Cristina Madrigal-Martínez-Pereda ¹, Vanesa Guerrero-Rodríguez 2, Blanca Guisado-Moya ³, Cristina Me- niz-García ¹ 1 Profesora Asociada. Departamento de Medicina y Cirugía Bucofacial. Facultad de Odontología. UCM 2 Licenciada en Odontología. Práctica privada 3 Profesora Titular. Departamento de Medicina y Cirugía Bucofacial. Facultad de Odontología. UCM Correspondence: Facultad de Odontología. UCM. Madrid. Spain crismadrigalmp@hotmail.com Received: 12/06/2008 Accepted: 24/01/2009 Madrigal-Martínez-Pereda C, Guerrero-Rodríguez V, Guisado-Moya B, Meniz-García C. Langerhans cell histiocytosis: Literature review and descriptive analysis of oral manifestations. Med Oral Patol Oral Cir Bu- cal. 2009 May 1;14 (5):E222-8. http://www.medicinaoral.com/medoralfree01/v14i5/medoralv14i5p222.pdf Abstract Langerhans cell histiocytosis (LCH) is a rare disease, of unknown pathogenesis, characterized by intense and abnormal proliferation of bone marrow-derived histiocytes (Langerhans cells). It can present both local and sys- temic manifestations involving bone, skin and mucosal tissue, and internal organs. Three basic clinical forms develop: Letterer-Siwe disease (subacute or acute disseminated form), Hand-Schüller-Christian disease (dissemi- nated chronic form) and eosinophilic granuloma (localized chronic form). LCH may manifest orally with single or multiple lesions of the alveolar or basal bone, ulcerated mucosal lesions accompanied by adenopathies and/or periodontal lesions, presenting gingival inflammation, bleeding, recession, necrosis, odontalgia, dental hypermobility and premature loss of teeth. The principal differential diagnoses in- clude advanced periodontal disease or a periapical process of dental or periodontal origin. The odontologist plays a vital role in the diagnosis and multidisciplinary treatment of such patients, by performing routine examinations for periodic follow-up of the disease and its possible oral manifestations, bearing in mind that these may be the first or only signs of LCH. Keywords: Langerhans cell histiocytosis, histiocytosis X, oral manifestations. Article Number: 1111111858 http://www.medicinaoral.com/ © Medicina Oral S. L. C.I.F. B 96689336 - pISSN 1698-4447 - eISSN: 1698-6946 eMail: medicina@medicinaoral.com Indexed in: -SCI EXPANDED -JOURNAL CITATION REPORTS -Index Medicus / MEDLINE / PubMed -EMBASE, Excerpta Medica -SCOPUS -Indice Médico Español E223 Med Oral Patol Oral Cir Bucal. 2009 May 1;14 (5):E222-8. Langerhans cell histiocytosis Concept Langerhans cell histiocytosis (LCH) (formerly his- tiocytosis X) is characterized by intense and abnor- mal proliferation of bone marrow-derived histiocytes (Langerhans cells), together with a variable number of leucocytes, eosinophils, neutrophils, lymphocytes, plasma cells and giant multi-nucleated cells causing tis- sue destruction. This tissue destruction is a result of the cellular infiltration that replaces bone and invades skin, mucosa and internal organs (1-3). Lichtenstein classified LCH into three clinical forms depending on the age of the patient when the lesions first appear and their distribution. Although other clas- sifications have been proposed, this remains the most used in the literature, adding congenital reticulohistio- cytosis described some years later. - Chronic focal LCH (eosinophilic granuloma): is con- sidered the most frequent and benign of the clinical forms. It appears as a uni- or multifocal lesion in a sin- gle, or occasionally various bones, with or without soft- tissue involvement, without systemic involvement and presenting at any age (3). - Chronic diffuse LCH (Hand-Schüller-Christian dis- ease): usually appears in children or young adults, with lesions that arise desynchronously over the years. It manifests with the characteristic triad of exophthalmos, osteolytic lesions of the cranium and diabetes insipidus. Other manifestations, petechiae, purpura, ulcerations, lesions mimicking seborrheic dermatitis, pulmonary dysfunction, tachypnea, dyspnea and cyanosis, may appear. This clinical form may imitate cystic lesions, leukemia, lymphoma, metastasis, meningioma, and congenital processes such as encephalocele (3, 4). - Acute disseminated LCH (Letterer-Siwe disease): the patients are generally children under three years old, who, due to the aggressive behavior of the disease fol- low a fatal course in a short time. It manifests in multiple organs and systems, such as liver, lung, lymph nodes, skin, SNC, bone marrow and bone, finding variable manifestations such as eczema, hepatosplenomegaly, otitis media, anemia, hemorrhages, lymphadenopathies and osteolytic lesions (3, 5). - Congenital reticulohistiocytosis (Hashimoto-Pritzker syndrome): believed to be a purely cutaneous form, characterized by the appearance of dark nodules on the trunk, face and scalp. The mucosae are always involved, without implication of other organs (6). Epidemiology LCH is an infrequent disease. The relative incidence of LCH is not well known, due principally to the het- erogeneous clinical expression, but is estimated at ap- proximately 2-5 cases per million inhabitants per year, being more frequent between the first and third decades of life, although it may affect any age group. Eighty per- cent of cases occur in Caucasians, with a predominance in males (1-3, 7). Etiopathogenesis The pathogenesis of LCH is unknown, and various hy- potheses have been proposed about its possible etiol- ogy. It may be caused by a dysfunction of the immune system, representing a hypersensitive reaction to an unknown antigen, with stimulation of the histiocytes- macrophage system (8,9). Deficiency of suppressor lym- phocytes (T8), altered immunoglobins, autoantibodies, anomalous lymphocytic response to various mitogens and structural changes in the thymus in all the advanced forms have been found in LCH patients (7). An inflammatory origin is also suspected due to the microscopic characteristics and clinical evolution; or a bacteriological origin, although no specific causal mi- croorganisms have been identified (8,9). The systemic alterations presenting in these patients re- sult from the accumulation of Langerhans cell infiltrate that produces different clinical manifestations depend- ing on the location (10). Oral manifestations of LCH Oral manifestations may be the first sign of LCH, and on some occasions the oral cavity may be the only area affected (11). The incidence of oral lesions in LCH is 77% (7), therefore the initial diagnosis in many cases is made by the odontologist. For a more detailed descrip- tion, we have classified these lesions into bone, mucosal and periodontal. - Bone lesions. Alongside the cranium, the maxilla and mandible are the most affected bones, usually infiltrat- ing together. Mandibular lesions are clearly more fre- quent in all three forms of LCH (1). Dagenais et al. (2) in a review of 29 cases of LCH found the majority of bone lesions presented in the posterior section of the mandible (distal and canine region) and in the ramus of mandible. When osteolysis is found in the anterior area of the mandible it is as an extension of the posterior. They also observed that when two or more lesions are present, these are always located in the alveolar ridge, finding different forms of bone loss even within the same patient. The different types of lesions produced by LCH in the maxilla and mandible are de- scribed according to their radiographic characteristics (1,2). - Solitary intra-bony lesions: localized outside the al- veolar process, these are the most frequent in the initial phases. The images are circular or elliptical, solitary or unifocal, found principally in the body and ramus of mandible. They may be obvious and painful, causing facial swelling, or they may be asymptomatic being an incidental radiographic finding. - Multiple alveolar lesions: normally present with well- E224 Med Oral Patol Oral Cir Bucal. 2009 May 1;14 (5):E222-8. Langerhans cell histiocytosis defined though not corticalized margins. However, 37.7% of alveolar lesions may have poorly-defined or invasive margins. - ‘Scooped-out’ alveolar lesions: formed by bone de- struction beginning below the alveolar crest, either at furcal level or at half the tooth root height and normally a part of the coronal portion of the bone crest remains intact on the mesial and/or distal margin of the damaged bone. This form of intra-bony destruction is not seen in periodontal disease, and may therefore be useful in a differential diagnosis. - Alveolar lesions with bone sclerosis: common in in- flammatory lesions of the jaws, the fact that sclerosis appears in alveolar lesions in LCH may be explained by the communication of these with the oral cavity with added infection. Thus, intra-bony lesions do not present sclerosis as they do not communicate with the oral ca- vity. - Alveolar lesions with bone neoformation: formation of new bone in lesions classified as intra-bony is observed in a high number of cases. This is a relevant charac- teristic when differentiating LCH lesions from those of periodontal disease. - Mucosal lesions. These are ulcerated, ovoid or round lesions, with erythematous, inflamed borders, painful on palpation (Fig. 1). They are localized principally in the buccal mucosa and at the back of the vestibule. They are associated with cutaneous lesions such as the typical eczematoid rash, that may be confused with a sebaceous dermatitis. Occasionally subcutaneous nodules present, therefore the initial evaluation of the patient should also include a meticulous skin examination (12). Some unusual cases of oral soft tissue lesions in the ab- sence of bone lesions have been described (1). The mu- cosal lesions are usually accompanied by enlargement of the lymph nodes which also reflects the degree of his- tiocytic infiltration. Thirty percent of patients with oral lesions present cervical lymphadenopathies (7). - Periodontal lesions. Alveolar bone lesions form the basis for all the associated periodontal involvement in these patients. As new osteolytic areas develop, accom- panying gingival ulceration and inflammation are ob- served, such that all the quadrants of the oral cavity are affected to a greater or lesser degree, even though the process began initially in only one quadrant. Dagenais et al. (2) observed slight radicular resorption associated with these lesions in 53% of cases studied, seen in the retro alveolar radiographies as images typical of a peri- odontal lesion (1). As a consequence of the alveolar bone loss, these pa- tients manifest gingival inflammation, ulceration, de- struction of the keratinized gingiva, gingival recession, periodontal pockets and bleeding of the oral soft tis- sues, associated with pain and even swelling (Fig. 2). As a result of this loss of bone support the teeth begin to progressively move giving rise to the characteristic ‘floating teeth’, completely surrounded by a radiolucent defect accompanied by dental displacement, odontalgia and on occasions cervical adenopathies. This excessive mobility gives rise to the inevitable premature loss of these teeth (3, 7, 10). The general and oral manifestations and the treatments established in cases of LCH published by the different au- thors reviewed (4-6, 13-19) are summarized in Table 1. Diagnostic and complementary examination The diagnosis is confirmed by histological study sup- ported by clinical and radiographic examination. Biop- sy by conventional microscopy shows areas of conjunc- tive fibrous tissue related with a mixed inflammatory infiltrate. Non-malignant histiocytic proliferation is seen together with the Langerhans cells (with Birbeck granules). These large mononuclear histiocytic cells are round or oval in shape, with a vesicular nucleus, a moderate quantity of eosinophilic cytoplasm, and lami- Fig. 1. Ulcerated lesions in the buccal mucosa. Fig. 2. Periodontal lesions with inflammation, recession and tooth mobility. E225 Med Oral Patol Oral Cir Bucal. 2009 May 1;14 (5):E222-8. Langerhans cell histiocytosis D A T E / A U T H O R A G E /S E X G E N E R A L M A N IF E ST A T IO N S O R A L A N D B O N E M A N IF E ST A T IO N S T R E A T M E N T 19 88 Sh aw L a nd G le nw rig ht H D (5 ) 6 M al e Su bm an di bu la r l ym ph ad en op at hy . In te rs tit ia l c ha ng es w ith h is tio cy tic in fil tr at e in b re as t. Bl ee di ng , p oc ke ts a nd b on e lo ss in th e lo w er in ci - so rs . Su pr ag in gi va l c al cu lu s i n 31 ,3 2 an d 41 . B on e lo ss in 3 1 an d 41 . Te tr ac yc lin e 25 0 m g, 2 v /d 2 m . Su rg ic al c ur et ta ge a nd c he m ot he ra py . 19 89 A rt zi Z e t a l. (1 3) 32 M al e A lte ra tio n in th yr oi d gl an ds a nd e xt er - na l o tit is . M ul tif oc al n on b on y no du le in he ad a nd n ec k. Su bm ax ill ar y gl an du la r i nv ol ve m en t. U lc er at io n an d Er os io n. 5 m m -d ia m et er le si on . Ex ci si on o f s ub m ax ill ar y gl an ds . H em ith yr oi de ct om y. C he m ot he ra py . 19 96 C le ve la nd D B e t a l. (1 4) 63 M al e D ia be te s. H yp er te ns io n. B on y le si on s i n oc ci pi ta l r eg io n an d pe lv is . U lc er at ed a re as in b uc ca l m ax ill ar y gi ng iv a. 1 6 an d 37 in p oo r p er io do nt al c on di tio n. C irc um sc rib ed un ilo cu la r r ad io lu ce nt le si on in m an di bu la r c an in e/ pr em ol ar a re a. In su lin a nd h yp ot en so r. Ex tr ac tio n of 1 6 an d 37 . Ex ci si on o f l es io na l t is su e. 34 Fe m al e D ia be te s i ns ip id us . U lc er s i n m uc os a of h ar d pa la te . N ot tr ea te d. 60 M al e H yp er te ns io n. R ed a nd w hi te le si on s i n m uc os a an te rio r m an di bu - la r v es tib ul e. E de nt ul ou s m an di bl e. U pp er te et h in po or p er io do nt al c on di tio n. H yp ot en so r. 20 01 M ili án M e t a l. (6 ) 50 M al e U ro lit hi as is , h ia tu s h er ni a an d di ab et es m el lit us . N o ex op ht ha lm os n or d ia be te s i ns ip id us . U lc er 1 c m in h ar d pa la te w ith n on in du ra te m ar - gi ns a nd c le an b as e. T ee th a nd p er io do nt iu m w ith - ou t p at ho lo gy . O ra l H yp og ly ce m ia nt s. Tr ia m ci no lo ne a ce to ni de (2 5 m g; o ne in je ct io n ev er y 3 w ee ks . 8 se ss io ns ). 52 Fe m al e N o m an ife st at io ns . Pa in fu l u lc er at io n in li ng ua l a re a of 3 6. R ad io th er ap y. 20 01 Lo du cc a S V L et a l. (1 5) 10 B on y le sio ns in c ra ni um R ad ic ul ar e xp os ur e an d m ob ili ty o f 3 6. In fla m ed g in gi va l t is su e an d gr an ul om at os is . C he m ot he ra py . Ex tr ac tio n of 3 6. 20 02 M uz zi L e t a l. (1 6) 24 Fe m al e Pu lm on ar y an om al ie s. Pe rio do nt al le si on s i n lo w er m ol ar re gi on s. Pa in , b ur ni ng se ns at io n an d bl ee di ng . V as op re ss in . 20 02 B ec el li R e t a l. (4 ) 61 Fe m al e Sp le no m eg al ia . C ut an eo us E ru pt io ns . R ig ht o to rr he a. M ul tip le o st eo ly tic le sio ns in ri gh t m as to id a po ph ys is , sc ap ul a, il ia c cr es t, tib ia , o cc ip ita l a nd sp he no id s. Pa in in b ot h ja w s. Sw el lin g of m ax ill ar y re gi on . O st eo ly tic le si on s i n m an di bl e. Su rg ic al c ur et ta ge o f l es io ns . 20 05 M ito m i T e t a l. (1 7) 3 Fe m al e Ec ze m a pa rie ta l r eg io n. L ym ph ad en - op at hi es . O st eo ly tic le si on s i n sc ap ul a an d cr a- ni um . Bl ee di ng g in gi va in m ol ar re gi on . D em in er al iz ed lo w er te et h an d bo ne re so rp tio n. O st eo ly tic le si on s i n m an di bl e ex te nd in g to w ar d co nd yl es . C he m ot he ra py . 20 05 M an fr ed i M e t a l. (1 8) 23 M al e O tit is . C ut an eo us le si on s b eh in d an d w ith in th e au ric ul ar c av ity . C ou gh w ith dy sp ne a. D ia be te s i ns ip id us . Pa in fu l u lc er at io ns in m ol ar re gi on . P ai n, b ur ni ng se ns at io n an d sp on ta ne ou s b le ed in g. A m ox ic ill in . C he m ot he ra py a nd c or tic os te ro id s. 20 05 N ak am ur a S et a l. (1 9) 31 M al e D ia be te s i ns ip id us . Lo w le ve ls o f s om e ho rm on es su ch a s G H . R ed a nd w hi te st ai ni ng o f l ow er le ft m ol ar s. Pa in an d bl ee di ng a t l ow er 2 nd P M a nd 1 st M . A nt ib io tic th er ap y. R ad io th er ap y. Ta bl e 1. C as es O f L ch W ith O ra l M an ife st at io ns . E226 Med Oral Patol Oral Cir Bucal. 2009 May 1;14 (5):E222-8. Langerhans cell histiocytosis nated or dispersed distribution. Abundant eosinophils and other inflammatory cells such as lymphocytes and mononuclear phagocytes may be found accompanying these cells. Electron microscopy reveals Birbeck granules in the lesional cells, described as organelles with rod-shaped or tennis-racket morphology that could represent struc- tural changes of the membrane following contact with an antigen. The percentage of histiocytes with Birbeck granules is not related with prognosis. Using immuno- histochemical techniques, the mononuclear histiocytic cells show positive to markers S-100 and/or CD1A, and demonstrate ATPase activity of the cellular membrane (6, 20-22). The biopsy is similar in all LCH except in the acute dis- seminated form, as this may demonstrate microscopic findings of other diseases, such as acute forms of lym- phoma. There are no specific laboratory tests for LCH, however, blood and urine tests exist that reveal the extent and se- riousness of the disease. Routine laboratory analyses, liver function tests and coagulation tests are made. Imaging studies include X-ray of thorax, computed tomography (CT) and magnetic resonance imaging (MRN) of the affected areas, with the aim of delimiting the bone and soft tissue lesions. CT is useful to evalu- ate the cranium and facial bones, which are difficult to visualize in conventional radiographies (23). Bone scin- tigraphy is indicated to evaluate multiple involvement and to discard polyostotic disease. This test will show hyperuptake in affected bone (6). In the presence of oral manifestations, orthopantomo- graph, intraoral radiography and even maxillofacial CT are necessary to localize and delimit lytic lesions in any of the previously-described forms. Given the periodon- tal and bone characteristics of LCH, noninfectious bone loss associated with ‘floating teeth’ should be included in the differential diagnosis. Furthermore, alveolar and periodontal lesions could produce an erroneous diagno- sis of advanced periodontal disease, or have similar ap- pearance to a periapical process of dental or periodontal origin (1, 3, 24, 25). When the process is located also in the oral mucosa the differential diagnosis should be made with sarcoidosis and diseases that present giant cells in the histology. The differential diagnosis of oral manifestations and lesions of LCH includes the pathologies described in Table 2 (1, 6, 14). Prognosis and treatment The prognosis of LCH is difficult to assess since this is a rare disease with high clinical variability. In the major- ity of patients LCH is a self-limiting process, although often with alternating phases of relapse and remission. The course of the disease is unpredictable and can evolve with multiple reactivations (7). The most impor- tant factors that may worsen the prognosis are firstly, visceral involvement (liver, lung, bone marrow), as this has a negative effect on survival. Secondly, where age at first presentation is less than two years since mortality rises to 50%. Thirdly, when the disease spreads to vari- ous bones or soft tissues. In general, it is considered that the younger the patient, the worse the prognosis (1, 3). A multidisciplinary evaluation is vital for correct diag- nosis and treatment for these patients. Diverse therapeu- tic options are available, and there is no consensus on ORAL LESIONS Advanced periodontal disease. Periapical abscess. BONE LESIONS MULTIFOCAL LCH Osteomyelitis. Ewing’s sarcoma. Brown tumor hyperparathyroidism. Multiple odontogenic keratocyst. Multilocular cyst. Leukemia. Lymphoma. UNIFOCAL LCH CHILDREN Metastatic neuroblas- toma. Intrabony hemangioma. Fibrous dysplasia. Hemophilic pseudotumor. Epidermoid cyst. Giant cell granuloma ADULTS Osteolytic metastasis. Multiple myeloma. Myxoma. Ameloblastoma. Osteogenic sarcoma. Fibrosarcoma. Table 2. Differential diagnosis of LCH. E227 Med Oral Patol Oral Cir Bucal. 2009 May 1;14 (5):E222-8. Langerhans cell histiocytosis the best treatment combination, although the measures taken will depend on the location and extent of the le- sions (10). Antibiotic therapy, chemotherapy, radiothera- py, surgery, Adrenocorticotropic hormone (ACTH) and corticoids (both systemic and intralesional) are used. Treatment of LCH is constrained both by the natural history of the disease as well as the location and extent of the lesions and the degree of organ dysfunction. Oc- casionally different therapeutic approaches are required in response to changes in behavior of the disease. Unifocal bone lesions do not usually require any ther- apy since they can resolve spontaneously, while multi- focal lesions or disseminated disease may require the combination of various types of therapy, including sur- gical curettage. Some authors suggest treatment with low-dose radiotherapy in large or multifocal lesions that recur or progress after surgery, in lesions carrying risk of fracture, lesions inaccessible to surgery, painful or disseminated lesions, or in those occurring in the os- sification centres of the mandible during infancy. Doses of 600 to 1000 cGy in 3 to 5 sessions seem to achieve local control in the majority of these patients. Its use has decreased as it damages the permanent dental follicles and there is a risk of developing malignant lesions, es- pecially in children, reserving therapy for large recur- rent lesions (1, 15). Systemic chemotherapy should be used in more diffuse lesions, untreatable by surgery, and when local treat- ment is unsuccessful in localized disease or in multi- systemic disease. Recently, the epipodophyllotoxin etoposide (VP16) has emerged as one of the most active and least toxic chemotherapies (6, 26). According to Zhang et al. (12) these patients should be treated surgically and only complemented with a low- dose radiotherapy and/or chemotherapy in serious ca- ses, especially in disseminated forms. Localized and isolated mandibular lesions may be ef- ficiently treated by surgical curettage. When surgery leaves large bony defects, autologous bone grafts can be made in an attempt to reduce the risk of pathological fracture and to facilitate bone regeneration (26). Intralesional corticosteroids may be administered for the monostotic acute form. Triamcinolone acetonide or methylprednisolone sodium succinate are used (27, 28). 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