Langerhan’s cell histiocytosis with oral manifestation in a 3-year-old child: a case report

Langerhans cell histiocytosis (LCH) is a disorder that may affect the bones, skin, liver, lung, and hematopoietic and neuroendocrine systems. This condition may manifest as a single lesion, multiple lesions, or as a disseminated and potentially fatal disease. We aim to report a case of a 3-year-old child with LCH in the mandible, sharing with the readers the challenging process of this diagnosis. A three-year-old male patient with persistent swelling in the right submandibular region was referred to the Department of Pediatrics of the Erasto Gaertner Hospital for an evaluation. Initial physical exam revealed a diffuse flaccid swelling occupying the entire right mandibular ramus, from the angle to the preauricular region and CT scan showed an osteolytic lesion with erosion of the internal and external cortices of the mandible and an extension to soft tissues that displaced the masseter muscle. Immunohistochemical analysis confirmed the diagnosis of Langerhans cell histiocytosis through positive tests for CD1a, CD68, S-100, and Vimentin. The treatment proposed was a combination of Vinblastine 6 mg/m3 for 6 weeks and Prednisone 40mg for 4 weeks.The differential diagnosis included pathologies such as rhabdomyosarcoma, Ewing's sarcoma, and, less likely, osteosarcoma and central giant cell granuloma.

LCH in the oral cavity represent about 30% of cases of the disease, and the jaws are involved in 10% to 20% of cases.
The mandible is one of the most commonly affected bones along with the skull, ribs and vertebrae (Peters et al., 2017). Oral lesions may be the first or only sign of manifestation the condition (Merglová et al., 2014), which increases the importance to early and assertive diagnosis. Detection of the disorder at an early stage results in fewer complications and sequelae to the patient.
The diagnosis of oral LCH lesions is generally challenging, mainly because the condition has a varied clinical presentation, and its characteristics may simulate infectious or periodontal diseases (Peters et al., 2017). Gingival lesions may cause bleeding and gingival retraction, commonly associated with tooth mobility or periodontal attachment loss. When mucosa is involved, LCH lesions have an irregular surface and may involve adjacent bone (Tenório, 2020), usually causing edema, pathological fractures, and severe tooth mobility. Osteolytic lesions with irregular edges and sclerotic margins are the most common signs identified in images (Merglová et al., 2014).
Being so, we aim to report a case of a 3-year-old child with LCH in the mandible, sharing with the readers the challenging process of this diagnosis.

Methodology
This is a retrospective, descriptive, observational case study that demonstrates the challenge of diagnosing Langerhans' cell histiocytosis in a 3-year-old child. The study was approved by the Ethics Committee of Erasto Gaertner Cancer Center (n. 4.379.641) in respection to the Ethics Principle from Declaration of Helsinque. Epidemiological data, medical history, and photographic records were obtained from the medical records, after parental consent, following the precepts for publication without identification of the patient. In order to complement the paper, current literature searches were made using the MeSH Database through the keywords: Histiocytosis; Langerhans-Cell; Jaw Neoplasms; Mandible; Pediatrics.
Based on the results found, a brief discussion on the subject was made.

Case Report
A three-year-old male patient with persistent swelling in the right submandibular region was referred to the Department of Pediatrics of the Erasto Gaertner Cancer Center (Curitiba, Paraná, Brazil) for an evaluation. The swelling had appeared 20 days before the appointment and was initially treated as parotitis, and subsequently as an odontogenic infection; neither treatment yielded results. According to the mother, the patient complained of pain only during palpation and did not have a fever or lost weight. The medical history revealed that the patient had been treated for iron deficiency anemia. No other diseases or medications were recorded. The initial physical exam revealed a diffuse flaccid swelling occupying the entire right mandibular ramus, from the angle to the preauricular region, shown in Figure 1. The skin surrounding the swelling appeared normal. The patient's primary dentition was complete, and all teeth were in good condition, without cavities, fillings, lesions, or fistula ( Figure 2).  A periosteal reaction was also observed on both sides of the bone, suggesting an aggressive lesion. Three enlarged lymph nodes of up to 18mm were observed, on the IB and IIA cervical levels, near the facial vessels on the right.
An incisional biopsy of the lesion was performed under general anesthesia. A whitish hard material was harvested from the mandibular body through intraoral access (Figure 4). The lesion did not seem to bleed, and the pathological cavity was wide but mostly empty. The anatomopathological result was that of a fusocellular neoplasm with discrete nuclear anaplasia, without mitosis or necrosis ( Figure 5).  Table 1. Despite the histopathologic characteristics, questions remained about the real nature of the lesion. Therefore, a new biopsy was performed to obtain a definitive diagnosis. A larger specimen was removed along with the largest cervical lymph node ( Figure 6). Research, Society andDevelopment, v. 10, n. 5, e40310515136, 2021 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v10i5.15136 6  The lymph node analysis showed multifocal involvement by atypical and eosinophilic histiocyte aggregates ( Figure   8).  (Table 2). The patient was then referred to Pediatric Oncology for treatment. The treatment proposed was a combination of Vinblastine 6 mg/m3 for 6 weeks and Prednisone 40mg for 4 weeks. Surgical treatment was discarded once the lymph nodes compromised by the disease were identified. After one month of chemotherapy, a new CT showed a reduction in the dimensions of the lesion and no more evidence of mass involving soft tissues. No more lymph nodes were identified at IB and IIA levels. Currently, the patient remains in follow up, without use of medication. Last CT showed a nearly complete resolution of the mandibular lesion and no altered cervical lymph nodes.

Discussion
After the clinical and radiological evaluation of the patient-and considering the most prevalent tumors for patients at this age-, the differential diagnosis included agressive pathologies with osteolytic potential such as rhabdomyosarcoma (Davidson, Soldani & North, 2006), Ewing's sarcoma (Heare, Hensley & Dell' Orfano, 2009), Langerhans cell histiocytosis and, less likely, osteosarcoma (Kontio et al., 2019) and central giant cell granuloma (Wang et al., 2019;Silva et al., 2018).
LCH should be considered as a diagnostic hypothesis for pediatric patients due to the higher incidence of the disease in this population. Early diagnosis is essential for better prognosis. The diagnosis of LCH is clinicopathologic, based on typical findings and histologic/immunohistochemical examination of a biopsy of lesional tissue (Leung, Lam & Leong, 2019;Weitzman & Egeler, 2008;Donadieu, Chalard & Jeziorski, 2012) If the histopathological report does not correspond to the clinical behavior of the disease, a new biopsy is essential to confirm the diagnosis and institute the most appropriate treatment.
A new investigation procedure was decisive for the correct diagnosis and improvement of the patient's condition after treatment commenced.
Depending on the site of accumulation and proliferation of these cells, LCH may be classified into three different categories: unifocal, multifocal-which affect only a single organ, typically bone or skin-and multisystemic-which may cause organ dysfunction to high-risk organs such as lung, liver, or bone marrow. The bone is affected most frequently, and bony lesions occur most commonly in the skull, ribs, vertebrae and mandible. Jaws are involved in 10% to 20% of patients.
The most frequently intraoral site is the posterior mandible (Peters et al., 2017), and according to the literature, lesions in the oral cavity are the first or only visible sign of LCH (Annibali et al., 2009;Merglová et al., 2014). These lesions may vary in characteristics, from ulcerative lesions of the oral mucosa and lesions that mimic periodontal disease (Annibali et al., 2009;Peters et al., 2017) to a considerable swelling, which is a differential diagnosis from malignant tumors such as Ewing's sarcoma (Oliveira et al., 2019).
Our patient presented a multifocal form, with the involvement of cervical lymph nodes, in addition to the mandibular bone lesion. The fast evolution of the lesion led to the diagnostic hypothesis of a malignant or aggressive benign lesion. The erosion of the mandible cortices and the extension to cervical lymph nodes revealed a multifocal disease.
The microscopic examination of the diseased tissue shows cells such as eosinophils, neutrophils, lymphocytes and histiocytes, in addition to Langerhans cells. This set of cells is traditionally described as Eosinophilic Granuloma. Abscess and tissue necrosis may also be present. During the analysis, it is evident the intense proliferation of histiocytes and positivity of CD1a, CD207 and S100 cells. In addition, Langerhans cells have an important pathognomonic sign, the so-called "Birbeck Granules". In both of our cases, CD1a cells were positive during immunohistochemical analysis (Claire et al., 2019).
The prognosis depends on the involvement of other organs, such as liver and bone marrow, and on the patient's response to initial therapy. The systemic treatment includes, as proposed in our case, the use of corticosteroids and cytostatic drugs (Krooks, Minkov & Weatherall, 2018).

Final Considerations
The mandible is one of the most commonly affected bones in LHC along with the skull, ribs and vertebrae. Oral lesions may be the first/only sign of the condition, which increases the importance to early and assertive diagnosis.