Oral manifestation of Langerhans cell histiocytosis: a case report

Langerhans cell histiocytosis (LCH), formerly known under a variety of different names such as histiocytosis X, eosinophilic granuloma, Hand-Schüller-Christian disease or Letterer-Siwe disease, is a rare disease of the family of histiocytosis characterized by the accumulation of histiocytic cells in various tissues. The discovery of Birbeck granules in the histiocytes of this disease and the expression of similar antigens has led to the name Langerhans cell histiocytosis. However newer findings show that LCH origins from dendritic myeloid progenitor cells rather than Langerhans cells of the skin [1]. LCH has a relatively higher incidence in children under the age of 15 years (5:1′000’000) but can also occur more rarely in adults (around 1:1′000’000). The etiology of the disease is still unknown, and there has been considerable debate whether LCH represents an inflammatory or a neoplastic disease. The discovery of recurrent mutations in the mitogen activated protein kinase (MAPK) pathway (i.e. BRAF and MAP2K1 mutations) indicates that it is a neoplastic disease [2, 3]. Recently the Histiocyte Society has published a revised classification of histiocytoses in which LCH is sub classified according to site of manifestation and organ involvement: single system LCH, lung LCH and multi system LCH with or without risk organ involvement (risk organs: liver, spleen, bone marrow) [4]. Single system LCH affecting the skin or bone are the most frequent clinical manifestations, other less frequent sites of involvement include: pituitary gland, liver, spleen, bone marrow, lungs, lymph nodes and the central nervous system, although every organ can be affected. Lung LCH is considered separately in the classification, as it is very frequently associated with cigarette smoking, occurs predominantly in adults and is considered a form of interstitial lung disease [5]. A small, but not neglectable number of patients with multisystem, cranial or facial bone osteolytic lesions may develop diabetes insipidus, caused by lesions of the neurohypophysis or the supraoptic and paraventricular nuclei, sometimes representing the initial manifestation of the disease [6]. The clinical symptoms of LCH are usually seen as a secondary consequence of organ dysfunction. Skin lesions may present as papules or eczematous lesions, isolated or generealised [5]. Patients with bone LCH most often present localized pain and swelling of the affected area, sometimes with concurrent fever and the most commonly affected bones are the skull and the jawbone. In the oral region reported symptoms are gingivitis, periodontitis, tooth rotation or loss and malocclusion [7].

Possible differential diagnoses of LCH are other cutaneous histiocytoses such as xanthogranulomas, normolipemic granulomas, histiocytomas or haemophagocytic lymphohistiocytosis and should be considered [8]. In the present case the clinical presentation is difficult to be distinguished from medication related osteonecrosis of the jaw (MRONJ) or possible neoplastic lesions. Definite diagnosis will be achieved by the histopathological examination [9].

This case report informs the readership on methods of clinical and radiographic examination as well as treatment of this rare disease on the basis of this case. The importance of a thorough dental examination has also been underlined in a case of oral Multisystem LCH [10]. Although LCH is rare, it should be considered as a potential diagnosis.

A 46-year-old male patient was examined in May 2015 due to tympanic effusion and right-sided hearing loss. The patient had a history of diabetes insipidus centralis of unknown aetiology, diagnosed in 2008. A ¹⁸F-fluoro-D-deoxyglucose (FDG) positron emission tomography /computed tomography (PET/CT) showed multiple FDG-avid lesions in the skull base, the temporal bone, the mandible and maxilla, but no lesions outside the head and neck area. Magnetic resonance imaging (MRI) of the same region showed a mass in the right-sided infratemporal fossa, erosions of the skull base and the alveolar ridge.

Due to the osteolysis of both the upper and lower jaw, the patient was transferred to our clinic. Here we conducted a cone beam computed tomography (CBCT) to determine the extent of the osteolysis. Clinically, an exposed alveolar ridge and ulcerative granulation tissue was present in region 45–47 and in the left upper jaw (Fig. 1a, b). Past medical history revealed that multiple teeth had been extracted by different dentists, and that the extraction sites showed prolonged or incomplete healing.

LCH is a rare disease and by virtue of this, at great risk of being under- or misdiagnosed. It is therefore of utmost importance that LCH is kept in mind when dealing with unclear osteolytic bone lesions, especially in the absence of exposure to drugs associated with osteonecrosis (e.g. bisphosphonates). In our case report two biopsies were necessary to diagnose the patient’s condition, highlighting the challenge of sampling error. Bone scan may be falsely negative in osseous LCH. FDG-PET/CT was shown to be a reliable tool in the assessment of patients with various histiocytic diseases, including LCH. FDG-PET/CT can identify active lesions, guide biopsy, and assess the response to treatment [12, 13]. Literature on manifestations in the oral region is limited and mostly consists of case reports or retrospective series [14‐16]. Surgical treatment has been shown to be very effective in the treatment of localised oral manifestations of LCH and is usually regarded as being sufficient as a sole treatment, sometimes combined with steroid injections [16, 17]. If surgical removal of the affected area is not possible or if LCH reoccurs in the same location, radiation therapy may serve as an alternative or second line treatment [18]. In severe cases with organ dysfunction or systemic LCH manifestations, chemotherapy significantly improves the outcome, however due to the rareness of the disease, it is still unclear which regimens are best suited for different clinical situations [11]. With the recent discovery of the molecular pathology of the disease, targeted therapy might represent a future treatment option [19]. As other rare diseases, international collaborations are needed to conduct clinical trials, The Histiocyte Society (Histiocyte Society Home. Available at: http://​www.​histiocytesociet​y.​org. Accessed 25.05.2017) regularly undertakes clinical trials to improve treatment protocols (e.g. LCH-III study) [20]. LCH may be self-limiting or locally recurrent, but high risk and systemic cases can have fatal outcomes, highlighting the importance of optimal management, in accordance to international guidelines.¹⁵

LCH is a rare disease and optimal management requires interdisciplinary collaboration between specialists (oral surgeon, dentist, ENT, radiologist, pathologist and oncologist). In case of unclear osteolytic changes of the jawbone or unexplained diabetes insipidus centralis, LCH should be considered as a possible cause and biopsy should be sought to establish a definitive diagnosis. Possible differential diagnoses are other cutaneous histiocytosis, bone metastases or malignant tumours and should be considered. Surgical treatment of LCH is effective in localised disease, but radical excision is discouraged. In systemic cases, relapses or high-risk disease systemic chemotherapy is the treatment of choice.