Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a group of rare disorders histologically characterized by the proliferation of Langerhans cells. Multiple organs and systems may be involved by the disease. Typically, there is bone involvement and, less frequently, lesions may be found in the lungs, liver, lymph nodes, skin, and mucosa. Oral soft tissue lesions without bone involvement are rare. We present a case of oral lesions associated with LCH in a young woman.

INTRODUCTION

Histiocytic disorders constitute heterogeneous group of diseases characterized by accumulation of reactive or neoplastic histiocytes in various tissues. The histiocytic disorders cover a wide range of primary and secondary, solitary and multiple, benign and malignant disorders.[1] Langerhans cell histiocytosis (LCH) is a reactive disorder in which cells having the phenotypic markers of epidermal Langerhans cells are found in skin and other organs where they cause damage by excessive production of cytokines and prostaglandins.[12]

Although this condition has been described using numerous different terms (histiocytosis X, Letterer-Siwe diseases, Hand-Schuller-Christian disease, eosinophilic granuloma), the Writing Group of the Histiocyte Society 3 divided histiocytosis into the following three classes: Class I: LCH; Class II: non-LCH; and Class III: malignant histiocytic diseases.[2]

LCH belongs in class I and encompasses a number of diseases. The clinical spectrum includes on one end, an acute fulminant, disseminated disease called Letterer-Siwe disease and, on the other end, solitary or few, indolent and chronic, lesions of bone or other organs called eosinophilic granulomas. The intermediate clinical form called Hand-Schόller-Christian disease is characterized by multifocal, chronic involvement and classically presents as the triad of diabetes insipidus, proptosis, and lytic bone lesions.[2]

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.[2-5]

The Hand-Schθller-Christian syndrome is considered to be the chronic disseminated form characterized by a triad of symptoms which include exophthalmos, diabetes insipidus, and osteolytic lesions in the skull. Oral involvement is characterized by increased gingival volume and bleeding, deep pockets, alveolar bone loss, and tooth 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.

Eosinophilic granuloma is the most frequently reported and mildest form of the disease. 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. The prognosis is excellent and the lesions may spontaneously recede within one or two years.

LCH affects patients from neonates to adults. The age at onset varies according to the variety of LCH. Letterer-Siwe disease occurs predominantly in children younger than 2 years. The chronic multifocal form, including Hand-Schüller-Christian syndrome, has a peak of onset in children aged 2 to 10 years. Localized eosinophilic granuloma occurs mostly frequently in those aged 5 to 15 years, with a male-to-female ratio of 2: 1. The estimated annual incidence ranges from 0.5 to 5.4 cases per million persons per year.[2-5]

The diagnosis of LCH had been based on the histopathological pattern identified in biopsy specimen showing multinucleated Langerhans cells, histiocytes, and eosinophils. Antigenic markers that react with CD1a glycoprotein, cytoplasmatic protein S100 detected by immunoperoxidase staining and/or presence of Birbeck granules on electron microscopic examination, are required for a definitive diagnosis of multiple oral lesions.[45]

CASE REPORT

A 26-year-old female patient was reported to the Department of Periodontics, V.S. Dental College and Hospital, Bangalore, with a chief complaint of pain, burning sensation, swelling, and bleeding of the gums.

Dental and family history were nonsignificant. Medical history revealed the previous diagnosis of LCH of the posterior wall of the vaginal wall and patient was treated with total excision of the clitoral growth and cynomycin for 45 days.

Patient was moderately built and nourished. No signs of pallor, icterus, clubbing, cyanosis, and edema were observed. No facial asymmetry or temporo mandibular joint (TMJ) abnormalities were detected.

On clinical examination, the right and left submandibular lymph nodes were palpable and were nontender. Gingiva was erythematous and fragile, i. r. t 4, 47 and 15, 16, 17 and 31, 32, 41, 42. with missing interdental papilla i.r.t 42 Grade II mobility i. r. t 45, 46, 47, 31, 41 [Figures 1 and 2].

Figure 1

Erythematous gingiva - frontal view

Figure 2

Erythematous gingiva - buccal view

Root surface denudation with grade II furcation involvement i. r. t 16, 46, 47. On palpation of external surface of gingiva, a yellowish cheesy material was expressed. Patient had poor oral hygiene, particularly in the lower anteriors and molar region where the lesions were more inflamed and painful.

Radiographic examination revealed generalized angular bone loss and furcation involvement [Figures 3 and 4].

Figure 3

Generalized angular bone loss

Figure 4

Furcation involvement

Laboratory parameters were normocytic normochromic blood picture with eosinophilia.

Chest X-ray and skull-PA were normal and ultrasound test of the abdomen showed normal-sized spleen and liver. These investigations ruled out multisystem involvement. Based on the history, clinical and radiographic findings, a provisional diagnosis of chronic generalized periodontitis associated with systemic disease was given.

Clinical diagnosis and dental treatment

Excisional biopsy was performed following administration of local anesthesia. Gingival biopsy was sent for histopathological examination [Figures 5 and 6]

Figure 5

Mixed infiltration of eosinophils and histiocytes - low magnification

Figure 6

Langerhans cells after histopathological staining - high magnification

The histopathological examination revealed an intense and mixed infiltrate of eosinophils and histiocytes. Immunohistochemical analysis was performed with both anti-S100 and anti-CD1a primary antibodies. These cells, mainly organized in sheets, groups, or single elements, showed brown immunohistochemical positivity for both S100 and CD1a proteins [Figures 7 and 8].

Figure 7

Brown immunohistochemical positivity of Langerhans cells for both S100 and CD1a proteins - low magnification

Figure 8

Brown immunohistochemical positivity of Langerhans cells for both S100 and CD1a proteins - high magnification

On the basis of the clinical, general morphology, and the immunohistochemical results, a diagnosis of LCH was made.

Periodontal treatment

It has been reported that periodontitis-like lesion in LCH may respond at least partially to treatment when evaluated by periodontal parameters alone.[6] It was reported that there was recurrence of periodontal lesion refractory to conventional therapy, which included scaling, root planning, modified Widman flap, and local application of antiseptic agents.[4]

The present case is an LCH of single system involvement. A conservative palliative treatment was performed which included Scaling and Root planning, curettage i. r. t., 45, 46, 47 and 14,15,16,17. Oral hygiene was reinforced with proper brushing habits and mouth rinse. Patient was reevaluated after one month and the pain and the burning sensation had reduced, gingival inflammation was reduced with gingival recession at the treated areas [Figure 9].

Figure 9

Gingival recession seen postoperatively

DISCUSSION

LCH is a group of disorders histologically characterized by the proliferation of Langerhans cells.

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.[7]

The etiology and pathogenesis of LCH is still unclear, but the following two different hypotheses have been proposed: a disorder of immune regulation or a neoplastic process. The presence of aggregates of other immunologically active cells in lesions, the presence of thymic abnormalities, and a deficiency in the number of suppressor T lymphocytes and increased cytokines suggest an exuberant reaction of Langerhans cells to an unknown antigen or neoantigen. However, the monoclonal proliferation of Langerhans cells infers the neoplastic origin of the disease. Different organs and systems may be affected by LCH, particularly bone, most commonly the skull and maxillary bones. Soft tissue involvement may occur, whereby lymph nodes, the lungs, and mucous membranes are commonly affected.[45]

Periodontal manifestations were observed 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.[8] The case reported here presents sequelae from LCH of the posterior vaginal wall, and patient sought dental care after having concluded surgery for histiocytosis.

When the periodontal tissues are involved, symptoms and clinical features can resemble advanced periodontitis, especially when osseous lesions are associated with an apical shifting of marginal tissues which is also seen in the present case.[9]

In addition, denudation of root surface with Grade II furcation involvement was seen.

Clinically, it is difficult to distinguish oral LCH lesions from bone metastases, lymphoma, ulceration by HIV infection, vasculitis (in particular, Wegener granulomatosis), and simple chronic periodontal inflammation.[45] Furthermore, LCH is a very rare disease, with an incidence of one case in 560 000.7,15. For this patient, the definitive diagnosis was based on the histological and immunohistochemical analysis of the lesional biopsy specimens. The strong positivity for both of the most significant markers used to detect the disease, S-100 and CD1a, made the ultrastructural examination unnecessary. A presumptive diagnosis of LCH may be made based upon light microscopic findings and a compatible clinical picture, but a definitive diagnosis requires that lesional cells exhibit positive staining with S-100 and CD1a, and the subsequent identification of Birbeck granules upon electron microscopy. Although the “gold standard” for identification of LC has been detection of Birbeck granules by transmission electron microscopy, this technique is rarely performed today.[10]

A wide spectrum of treatment modalities has been adopted to deal with LCH, including wide surgical excision together with radiotherapy. Other treatments have been suggested such as chemotherapy, isolated radiotherapy, and the use of alkalizing agents.[6] In the present case, nonsurgical periodontal therapy was instituted and oral hygiene instructions were given. The patient is still under nonsurgical therapy.

CONCLUSION

The clinicians’ view should not be limited to the periodontal tissue conditions, but include the patient as a whole. The presence of previously mentioned systemic symptoms associated with periodontal lesions may be a guide for correct LCH diagnosis. The suspicion of the LCH should be considered in case of recurrence of periodontal lesions and rapid severe and localized loss of periodontal bone.