Gisela Estela RAPP
Ana Carolina Fragoso MOTTA
Disciplina de Periodontia, Departamento de Diagnóstico e Terapêutica, Faculdade de Odontologia, Universidade Federal da Bahia, Salvador, BA, Brasil
Braz Dent J (2000) 11(1): 59-66 ISSN 0103-6440
Introduction | Case Report | Discussion | Resumo | References
A clinical case of Langerhans' cell histiocytosis, type eosinophilic granuloma, in a young adult patient is presented. Because of the occurrence of oral manifestations in initial stages of the disease, there is a need for a differential diagnosis, especially with the early-onset periodontitis.
Key Words: Langerhans' cell histiocytosis, histiocytosis X, eosinophilic granuloma, periodontal disease.
Langerhans' cell histiocytosis describes a disorder of the reticuloendothelial system which is characterized by an abnormal proliferation of histiocytes and eosinophilic leukocytes (Watanabe, 1990; Stewart, 1991; Moghadam et al., 1991).
The nomenclature - histiocytosis X - was coined by Lichtenstein in 1953 to account for three clinical varieties which showed some histological characteristics in common: eosinophilic granuloma, Letterer-Siwe syndrome and Hand-Schüller-Christian syndrome. The term "histiocytosis" refers to a proliferation of histiocytes and other inflammatory cells whereas the letter "X" was added to denote the unknown etiology of the disease (Hanapiah et al., 1993). The recent adoption of the terminology "Langerhans' cell histiocytosis" is due to the fact that the histiocytes involved in the disease present a phenotype which is similar to that of Langerhans' cells found in normal mucosa and skin (Rapidis et al., 1978; Stewart, 1991).
Histopathologic diagnosis may be established through histochemical analysis or electron microscopy. Histochemical analysis may show positive cells for HLA-DR, S-100 protein, PNA and CD1a. Electron microscopy identifies the presence of cytoplasmic granules, called Birbeck granules, which possess a tennis-racket morphology with transverse striations and are thought to be specific markers of Langerhans' cells (Lombardi et al., 1993).
Although both the etiology and the pathogenesis of this disease are unknown, some immunological abnormalities resulting from a suppressor cell deficiency have been suggested as a cause (Moghadam et al., 1991; Lombardi et al., 1993). Other factors, such as viruses and bacteria as well as genetic components, have been considered as possible etiologic factors (Hanapiah et al., 1993), but a satisfactory explanation for the proliferation of Langerhans' cells in the lesions of histiocytosis X is still missing.
The Letterer-Siwe syndrome is considered to be the acute disseminated form of the disease, characterized by cutaneous lesions, hepatomegalies, splenomegalies and ganglionic hypertrophies, usually occurring in infants and newborns. Bone lesions occur in the skull, long bones and mandible. Lesions in the mandible show a definite radiolucent image which may mimic both juvenile and severe periodontal disease. The prognosis is not favorable and most of the patients die within a short time (Stewart, 1991; Hanapiah et al., 1993).
The Hand-Schüller-Christian syndrome is considered to be the chronic disseminated form of histiocytosis X, characterized by a triad of symptoms which include exophthalmos, diabetes insipidus and osteolytic lesions in the skull. Systemic signs are frequent and include fever, skin rash, otitis, mastoiditis and upper respiratory infection. Lymphadenopathy, hepatomegaly and splenomegaly may also occur. Nearly half of the patients present granulomatous involvement of the posterior pituitary gland or hypothalamus. Oral involvement is characterized by increased gingival volume and bleeding, deep pockets, alveolar bone loss and dental mobility, resembling periodontitis. The earliest signs of this disease usually manifest during childhood. The prognosis for this clinical variety is better than that for the Letterer-Siwe syndrome. Nevertheless, death occurs in some cases within a few years (Stewart, 1991; Hanapiah et al., 1993).
Eosinophilic granuloma is the most frequently reported and mildest form of the disease (Hanapiah et al., 1993). This variety is considered to be a chronic localized form, characterized by single or multiple osseous lesions, usually affecting children and young adults. Any bone in the skeletal system, including the mandible, may be affected. Roentgenographic characteristics are similar to those for Letterer-Siwe syndrome, resembling juvenile and severe periodontites. The prognosis is excellent and the lesions may spontaneously recede within one or two years (Stewart, 1991; Hanapiah et al., 1993).
Alternative classifications have been suggested. In 1969, Lieberman et al. proposed a simpler classification in which eosinophilic granuloma is classified into two entities: unifocal eosinophilic granuloma (eosinophilic granuloma) and multifocal eosinophilic granuloma (Hand-Schüller-Christian syndrome). Krutchkoff and Jones (1984) suggested that the Letterer-Siwe syndrome might be a separate clinical entity and considered it to be the most malignant of the three varieties.
According to the literature, Langerhans' cell histiocytosis is a rare disorder, usually occurring in children and young adults, with no bias for race, but with males being affected more frequently than females (Hartman, 1980; Moghadam et al., 1991; Hanapiah et al., 1993; Rodd and Gerrard, 1994; Ünlü et al., 1997).
Numerous reports stress the fact that oral manifestations may be among the earliest signs of the disease (Winther et al., 1972; Hanapiah et al., 1993; Ünlü et al., 1997), which cause patients to seek treatment (Nicopoulou-Karayianni et al., 1989).
In an excellent review of 1,120 cases of documented histiocytosis X, Hartman (1980) reported that 114 (10%) of the cases had oral involvement. Seventy-eight percent of the oral lesions were diagnosed as eosinophilic granuloma. Seventy-nine percent of the 29 cases of multifocal eosinophilic granuloma presented by Moorthy (1986) showed oral involvement. Artzi et al. (1989) observed periodontal manifestations in 28 cases of histiocytosis in young adults.
The mandible is more frequently affected than the maxilla, with most of the lesions occurring in the molar area. Destruction of lamina dura results in the radiographic appearance of "floating teeth" (Hartman, 1980; Bhaskar et al., 1993; Hanapiah et al., 1993; Yul et al., 1995). However, other bones may be affected such as the skull, long bones and ribs (Stewart, 1991).
A wide spectrum of treatment modalities has been adopted to deal with Langerhans' cell histiocytosis, including wide surgical excision together with radiotherapy (Rodd and Gerrard, 1994). Other treatments have been suggested such as chemotherapy, isolated radiotherapy and the use of alkalizing agents (Winther et al., 1972; Nicopoulou-Karayianni et al., 1989).
The purpose of this study is to present a case history of a young adult patient with Langerhans' cell histiocytosis of the variety eosinophilic granuloma who presented oral lesions.
A 27-year-old male patient of dark complexion was seen at the Clinic of the Department of Periodontics, School of Dentistry, Federal University of Bahia, with the main complaint of tooth mobility and dental loss. The past medical history revealed that the patient had a previous diagnosis of Langerhans' cell histiocytosis of the variety eosinophilic granuloma which had been established by a biopsy of a cervical nodular lesion about 15 years earlier. Following the diagnosis, the patient underwent radiotherapy and chemotherapy with no recurrence of the disease. Six years before being seen at the periodontic clinic the patient noticed tooth mobility, halitosis and spontaneous gingival bleeding as well as dental loss during mastication, which caused him to seek dental care.
Physical examination showed the scar resulting from the surgical excision of the cervical nodular lesion. Intraoral examination revealed multiple dental loss, severe tooth mobility, deep periodontal pockets in all sextants, a large amount of dental plaque, spontaneous gingival bleeding, gingival recession, increased gingival volume (Figure 1) and halitosis.
Panoramic and periapical radiographs showed well-defined radiolucent images comprising alveolar bones of both molar and premolar areas in the maxilla and the mandible, providing the radiographic image of "floating teeth" (Figure 2).
In order to investigate a possible genetic influence, the patient was further questioned about the disease occurrence in his family. No familial occurrence was reported. The family pedigree flowchart, however, revealed consanguineous marriage, the patient being a "third cousin" of his own father.
From the available data, the patient was considered to have sequelae from Langerhans' cell histiocytosis as well as periodontal disease, resulting from an altered tissue response in view of his systemic involvement.
The patient underwent scaling and root planing, exodontia in the indicated units and prosthetic rehabilitation with partial, removable maxillary and mandibular prostheses. Supportive periodontal treatment was carried out, starting on a monthly basis for three months and every three months for six months, followed by every six months, thereafter. The periodontal condition has remained stable for 2 years.
Langerhans' cell histiocytosis is a rare disease, the etiology and pathogenesis of which remain unknown. A variety of etiological factors have been proposed including immunologic reactions, viruses, bacteria and genetic influence (Nicopoulou-Karayianni et al., 1989; Moghadam et al., 1991; Lombardi et al., 1993; Hanapiah et al., 1993).
Langerhans' cells are dendritic bone marrow-derived cells situated suprabasally in most stratified squamous epithelia. They are thought to act as antigen-presenting cells during induction of immune responses. Besides having functions which are similar to other dendritic cells and macrophages, Langerhans' cells are specialized and able to migrate, playing an important role in antigen presentation to the T-lymphocytes. It has been suggested that they play a key role in the induction of immune responses and also in immunopathological reactions taking place at cutaneous and/or mucosal levels. Langerhans' cells may represent a "first line" of sensitization of the immune system, leading to clearance of the antigen or to pathological phenomena. It is not known, however, what leads to the proliferation of these cells in the histiocytosis lesions (Lombardi et al., 1993).
Because of the microscopic features which are presented in Langerhans' cell histiocytosis, an inflammatory etiology has been proposed (Nicopoulou-Karayianni et al., 1989). A bacteriologic origin has also been suggested although no specific causative microoganism has been identified in histiocytosis lesions (Hartman, 1980; Nicopoulou-Karayianni et al., 1989). From microbiological analysis, the flora was found to be similar to that seen in periodontitis lesions showing the presence of gram negative anaerobic rods, including bacteroides spp., fusobacterium spp. and capnocytophaga spp., together with large quantities of spirochetes and motile rods (Nicopoulou-Karayianni et al., 1989).
The present case reveals a possible genetic influence because the mother's mother is the father's first cousin which renders the patient a "third cousin" of his own father. In 1993, Hanapiah et al. reported the occurrence of Langerhans' cell histiocytosis in a family in which two of four children had histiocytosis lesions. After further investigation, it was found that the patient's parents were genetically related (the wife was the husband's second niece). Falk and Gellei reported a case in 1957 in which three of five children showed the Letterer-Siwe syndrome, the parents being first cousins. Though the occurrence of histiocytosis in members of the same family is rare, these cases may point to an important genetic role in the transmission of histiocytosis (Hanapiah et al., 1993).
The oral manifestations of Langerhans' cell histiocytosis may be the first and/or the single sign of the disease. These manifestations present distinct characteristics when compared to those found in other locations. This is probably due to the unique anatomy of the tooth-supporting structures, and to the bacterial milieu of the mouth which predisposes to secondary infections. That is why lesions of histiocytosis have been erroneously diagnosed as periodontal disease (Winther et al., 1972). A number of signs can be clinically observed such as severe periodontal loss, erosion and ulceration of the mucosa, bleeding gingiva, purulent exudate, mobility and premature exfoliation of the teeth, precocious eruption of complete dentition and ectopic eruption of permanent molars (Hartman, 1980; Moghadam et al., 1991; Hanapiah et al., 1993). The radiographic features comprise solitary or multiple areas of well-defined radiolucency in the alveolar bone mimicking severe periodontal disease. Destruction of lamina dura provides the radiographic appearance of "floating teeth" (Hartman, 1980; Bhaskar et al., 1993), which has been considered, by some authors, as the most representative radiographic feature of the disease (Yu et al., 1995).
The case reported here presented signs similar to those of severe periodontal disease, namely gingival bleeding, severe tooth mobility, halitosis and alveolar bone loss, both in the maxilla and in the mandible. The histopathologic findings, showing proliferation of histiocytic cells with cell pleomorphism characterized by varied forms and nuclei, are consistent with the microscopic characteristics of Langerhans' cell histiocytosis, which are known to present proliferation of large cells with copious cytoplasm and a number of eosinophilic cells (Krutchkoff and Jones, 1984; Nicopoulou-Karayianni et al., 1989) (Figure 3).
Eosinophilic granuloma is considered to be the mildest form of the disease (Hartman, 1980) and appears to be less aggressive than the other varieties (Nicopoulou-Karayianni et al., 1989). The destruction of the alveolar bone is thought to be one of the characteristic signs of eosinophilic granuloma and, in this location, the disease may simulate severe localized periodontitis or periapical infection (Shaw and Glenwright, 1988). This may be diagnosed as periodontal disease because it shares similar clinical and radiographic characteristics with severe periodontal disease and the microbiologic composition is also similar to the microbiota found in periodontal disease. Osseous lesions are an important feature of eosinophilic granuloma. When these lesions occur in children, they may be mistaken for prepubertal periodontitis, and when they occur in young adults, they may resemble rapidly progressive periodontitis, which is why a differential diagnosis between eosinophilic granuloma and early-onset periodontitis must be established.
It has been reported that the periodontitis-like lesions in eosinophilic granuloma may respond, at least partially, to treatment, when evaluated by periodontal parameters alone (Nicopoulou-Karayianni et al., 1989). Nevertheless, this treatment approach has to be considered as inappropriate and chemotherapy or radiotherapy are the treatments of choice.
The case reported here presents sequelae from Langerhans' cell histiocytosis of the variety eosinophilic granuloma because this patient sought dental care after having concluded surgery, radiotherapy and chemotherapy for histiocytosis.
In addition, the occurrence of periodontal disease associated with the systemic disease is suggested. It is known that, if the patient presents systemic involvement, periodontal tissue may respond in an altered manner to an offending agent, which leads to the classification of periodontal disease associated with systemic diseases. The result is often the occurrence of rapidly progressive periodontitis (Watanabe, 1990).
The frequent occurrence of oral manifestations emphasizes the need for an interdisciplinary approach to treatment in patients with Langerhans' cell histiocytosis so that an accurate diagnosis can be established and adequate treatment can be provided.
Rapp GE, Motta ACF: Doença periodontal associada à histiocitose de células de Langerhans. Relato de um caso clínico. Braz Dent J 11(1): 59-66, 2000.
Apresenta-se um caso clínico de histiocitose de células de Langerhans tipo granuloma eosinofílico em um jovem paciente adulto. Tendo em vista a ocorrência de manifestações orais no estágio inicial da doença faz-se necessário o seu diagnóstico diferencial, especialmente com a periodontite de início precoce.
Unitermos: histiocitose de células de Langerhans, histiocitose X, granuloma eosinofílico, doença periodontal.
Artzi Z, Gorsky M, Raviv M: Periodontal manifestations of adult onset
of histiocytosis X. J Periodontol 60: 57-66, 1989
Bhaskar PB, White CS, Baughman RA: Eosinophilic granuloma of the mandibular condyle. Oral Surg Oral Med Oral Pathol 76: 557-560, 1993
Falk W, Gellei B: The familial occurrence of Letterer-Siwe disease. Acta Paediat Scand 46: 471-480, 1957
Hanapiah F, Yaacob H, Ghani KS, Hussin AS: Histiocytosis X: evidence for a genetic etiology. J Nihon Univ Sch Dent 35: 171-174, 1993
Hartman KS: Histiocytosis X: a review of 114 cases with oral involvement. Oral Surg Oral Med Oral Pathol 49: 38-54, 1980
Krutchkoff DJ, Jones CR: Multifocal eosinophilic granuloma: a clinical pathological conference. J Oral Pathol 13: 472-488, 1984
Liebermann PH, Jones CR, Dargeon HWK, Begg CF: A reappraisal of eosinophilic granuloma of bone. Hand-Schüller-Christian syndrome and Letterer-Siwe syndrome. Medicine 48: 375-400, 1969
Lichtenstein L: Histiocytosis X: integration of eosinophilic granuloma of bone: "Letterer-Siwe Disease" and "Schüller-Christian Disease" as related manifestation of a single nosologic entity. Arch Pathol 56: 84-102, 1953
Lombardi T, Hauser C, Budtz-Jörgensen E: Langerhans' cells: structure, function and role in oral pathological conditions. J Oral Pathol Med 22: 193-202, 1993
Moghadam BKH, Saedi S, Gier RE: Adult-onset multifocal histiocytosis X presenting as a periodontal problem. J Oral Maxillofac Surg 49: 417-419, 1991
Moorthy AP: Eosinophilic granuloma manifesting as a periodontal problem. Br Dent J 161: 66, 1986
Nicopoulou-Karayianni K, Mombelli A, Lang NP: Diagnostic problems of periodontitis-like lesions caused by eosinophilic granuloma. J Clin Periodontol 16: 505-509, 1989
Rapidis AD, Langdon JD, Harvey PW, Patel MF: Histiocytosis X: an analysis of 50 cases. Int J Oral Surg 7: 76-84, 1978
Rodd HD, Gerrard MP: Multifocal Langerhans' cell histiocytosis in a 4-year-old child: a case report. Int J Paediatr Dent 4: 35-40, 1994
Shaw L, Glenwright HD: Histiocytosis X: an oral diagnostic problem. J Clin Periodontol 15: 312-315, 1988
Stewart JCB: Tumores benignos não odontogênicos. In: Regezi JA, Sciubba JJ. Patologia Bucal: Correlações Clinico-Patológicas. Guanabara Koogan, Rio de Janeiro, 1991
Watanabe K: Prepubertal periodontitis: a review of diagnostic criteria, pathogenesis, and differential diagnosis. J Periodont Res 25: 31-48, 1990
Winther JE, Fejerskov O, Philipsen H: Oral manifestations of histiocytosis X. Acta Dermatovener (Stockholm) 52: 75-79, 1972
Ünlü F, Gürses N, Seçkin T, Ünal T: Multifocal eosinophilic granuloma with sequential periodontitis-like lesions. J Clin Periodontol 24: 384-387, 1997
Yu Q, Wang P-Z, Shi H-M, Wang L, Sun D-X: Radiographic findings in Langerhans' cell disease affecting the mandible. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 79: 251-254, 1995
Correspondence: Profa. Gisela Estela Rapp, Disciplina de Periodontia, Departamento de Diagnóstico e Terapêutica, Faculdade de Odontologia, Universidade Federal da Bahia (UFBA), Av. Araújo Pinho, 62, Canela, Salvador, BA, Brasil. Fax: +55-71-240-7301. E-mail: email@example.com
Accepted June 29, 1999
Eletronic publication July, 2000