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Langerhans Cell Histiocytosis: A Case Report and Brief Review of the Literature

Sumith Gunawardane, Kanchana Kapugama, W.M.B.S. Wijekoon, Primali Jayasooriya, W M Tilakaratne

Abstract: Langerhans cell histiocytosis (LCH) formerly known as histiocytosis X is rare spectrum of disease characterized by a monoclonal proliferation of bone marrow-derived Langerhans cells. LCH involves the head and neck region quite commonly, in particularly the bones of the skull and jaws. This is a case report of 14 years old female, presented with a complaint of intermittent abdominal pain, short stature and delayed puberty, which was subsequently presented with pain and swelling on left side upper premolar region with bleeding gums, which was finally histopathologically diagnosed as Langerhans cell histiocytosis following an incisional biopsy.

Keywords: langerhans cell histiocytosis, histiocytosis X, Head and Neck

Citation: Sumith Gunawardane, Kanchana Kapugama, W.M.B.S. Wijekoon, Primali Jayasooriya, W M Tilakaratne, Langerhans Cell Histiocytosis: A Case Report and Brief Review of the Literature. American Journal of Medical Case Reports, 4 (9). 328-331. January 2016. doi:10.12691/ajmcr-4-9-10

1. Introduction

Langerhans cell histiocytosis (LCH), which was previously termed Histiocytosis ‘X’, is a rare clonal disorder characterized by the proliferation of clonal CD1 a- positive immature dendritic cells (LCH cells). [1,2] The unifying term Histiocytosis’X’ to embrace several previous eponyms including, Eosinophilic granuloma (solitary disease), Hand-Schuller-Crystian disease (triad of skull defects, exophthalmos and diabetes incipidus), and Letterer-Siwe disease (systemic disease with fever, otitis media, hepatosplenomegaly, lymphadenopathy, bone and cutaneous lesions). Histiocytosis ’X‘term coined by Lichtenstein in 1953 to encompass above group of lesions, originally described by Schuller and Christian in 1915 and 1920. [3] Many cases do not fit in to this rigid category, and more useful categorization incorporates mainly unifocal disease, multifocal single system disease and multifocal multi system disease. [1] First case was described in 1865 in a 4 years old child with impetigo and large punched out osteolytic lesions in calvarium, but it was not recognized as a histiocytic disease. More than half the patients younger than 2 years with disseminated Langerhans cell histiocytosis and organ dysfunction, die of the disease, whereas unifocal LCH and most cases of congenital self -healing histiocytosis are self- limited. Multifocal chronic LCH is self- limited in most cases but increased mortality has been observed among infants with pulmonary involvement [4].

Although the etiology is unknown and various theories suggest a role for environmental, infectious, immunological, genetic causes and even some believe that LCH is a neoplastic process [5]. LCH affects a number of different organ systems therefore its clinical presentation can be extremely variable. It has a tendency to favor the skull bones but can present in any bone, mucosal and cutaneous involvement on the head and neck region [1]. The most common oral manifestations are local pain, swelling, mucosal ulceration, gingival necrosis, mobile teeth and exfoliation of teeth [6].

Langerhans cells are derived from CD34-positive haemopoitic myeloid stem cells in the bone marrow. Langerhans cells become mature as dendritic cells and obtain important immunological functions. Langerhans cells are capable of presenting alloantigens and soluble foreign antigens to naïve helper T cell lymphocytes (CD4+) [7]. Langerhans cell histiocytes are immature dendritic cells that are responsible for this rare unique disease LCH. These cells are lack of dendritic processes, have proven to be clonal and lack of the ability of antigen presenting function. To diagnose LCH it is essential to perform a pathological examination. Immunohistochemical features like S-100 positivity and CD1a positivity, ultra structural features like presence of Birbeck granules are also play an important role in diagnosis [2]. Current treatment strategies depend on the presentation of the disease. Surgical curettage, radiotherapy and chemo therapy can be used alone or in combination [6].

2. Case Report

A 14 years old female patient complaining of intermittent abdominal pain, short stature and delayed puberty was presented in December 2014. The patient was referred to the Oral and maxillofacial unit for pain and swelling on left side upper premolar region with bleeding gums after 4 days. On her past medical history gastritis, thyroiditis, anemia, comorbid depressive disorder were significant. No significant past dental history was found. On examination, generally patient was having low Body mass index (height -132cm/weight - 24Kg). Bilateral cervical lymphadenopathy and bilateral onycholysis, were presented. Patient was pale and icteric. Intra orally inflamed gingiva on left side upper premolar region, grade three mobility in 14, 15, 16, 24, 25, 26, 34, 35, 36, 44, 45, 46 and gingival bleeding were noted.

Laboratory investigations were done and full blood count showed elevated white blood cell count (12.34×10³ µL), with slightly elevated neutrophil count. Her hemoglobin level was markedly low (7.6 g/dl) with low MCV, and MCH levels. Liver function tests were revealed elevated AST, ALP and low Ca⁺² levels in serum electrolytes. ESR was increased prominently in this patient (138 mm). Ultra Sound Scan and Computer Tomographs of abdomen (CE-CT) were performed for hepatosplenomegaly and reveled that multiple cystic and solid lesions in liver with para-aortic lymphadenopathy. CT scan for head and neck followed by USS of thyroid gland revealed diffuse enlargement of thyroid gland with disease of thyroiditis confirming her past medical history.

Dental Panaromic Tomograph was obtained as a part of radiological investigations and it revealed bone loss in relation to 14,15,16,24,25,26,34,35,36,44,45,46. ‘Floating teeth’ appearance was significant on radiograph. An incisional biopsy was performed and confirmed the histopathological diagnosis of Langerhans cell histiocytosis on the basis of histopathological features including the corium composed of sheets of large cells with grooved nuclei, granulation tissue containing a mixed population of lymphocytes, eosinophils and scattered plasma cells with immunohistochemicaly the strong positivity for S-100 protein.

Figure 1. Langerhans cell histiocytes arranged in sheets with infiltration of eosinophils, lymphocytes and plasma cells. (×200)

Figure 2. ‘coffee-bean’ appearance of Langerhans cells (×400)

Figure 3. Strong positivity for s-100 protein, ( ×100)

A liver biopsy was also performed. Microscopically the portal tracts showed marked expansion with a heavy mixed infiltrate of histiocytes, eosinophils, lymphocytes, plasma cells and occasional neutrophils. Ballooning degeneration of the lobules and CD₆₈ positive in histiocytes, CD1a positive in 20% of histiocytes were found. Liver biopsy conclusion was moderate chronic, hepatitis with probable cirrhosis and evidence of bile duct injury. In view of the presence of CD1a positive histiocytes of liver biopsy, and previous oral biopsy findings of similar histological appearance, LCH was indicated as a main possibility.

3. Discussion

Langerhans cell histiocytosis is a very rare pathology with an incidence of 1 in 5600006. Hicks J et al [8], found that, it is predominantly a childhood disease with more than 50% of affected individuals being younger than 15 years. Unifocal single system, multifocal single system, multifocal multisystem disease tend to be nearly equally represented. The gender ratio is equal in all LCH categories, with the exception of pulmonary only disease. According to Morimoto A et al [2], LCH appears to be more common in males than females (1.2:2.1). It occurs more frequently in young adults than in older adults, mostly in the 2nd and 3rd decade of life. The present case is also a 14 years old female, who is younger than 15 years.

The development of the disease is usually sporadic. However, genetic predisposition may play a role in the development of LCH and patients with LCH are more likely to develop malignant disorders than normal population [2]. It has been debated for many years whether LCH is a neoplasm or reactive. LCH lesions sometimes regress spontaneously [9]. However, the fact that LCH cells are monoclonal sometimes show chromosomal deletion or gain suggests the opposite conclusions [10,11].

Langerhans cell proliferation may be induced by a viral infection, a defect in intercellular communication (T cell–macrophage interaction), and/or a cytokine-driven process mediated by tumor necrosis factor, IL-11, and leukemia inhibitory factor. Specifically, human herpes virus 6 (HHV6) has been proposed to contribute to the initiation and/or modulation of persistent LCH4. In the present case, etiology is unclear. According to the Histiocyte society categorization for current treatment protocols, there are several types (Table 1). Unifocal disease, multifocal single system disease, multifocal multisystem disease, congenital self-healing LCH, pulmonary Langerhans cell histiocytosis, secondary LCH associated with neoplasm.

Table 1. Histiocyte society classification of LCH

When considering international literature of clinical features, the most common presenting symptom is localized bone pain, which is about 41%. Various symptoms based on organ system involvement have been noted among affected individuals. Of interest for the head and neck region are painful scalp mass (6%), scalp rash (3%), cervical lymphadenopathy (2%), mucous membrane ulcer (2%), otitis media (2%), orbital proptosis, loose teeth, bony involvement is quite common. The skull and mandible are frequently affected as well [8,12,13,14,15,16].

Hernandez Juyol et al [17] reported a case of fourteen years old boy that developed osteolytic lesions in the jaw which led to loosening of molars. Minguez et al. [5] described 10 children with oral manifestations of LCH. Oral manifestations were the first sign of more generalized disease in 50% of cases, presenting as tooth mobility and loss, gingival bleeding and ulcerations, In some patients nonspecific pain, candidosis, and orofacial swelling. Patient of present case was also presented with an agreement to the international literature.

When there is hypothalamic/pituitary gland involvement, the affected individual may experience diabetes incipidus and growth hormone deficiency [8]. Central nervous system/endocrine involvement express as precocious puberty or delayed puberty, thyroid deficiency, and amenorrhea are some of the presentations of multi-systemic LCH [15]. When comparing with international literature present case presented delayed puberty and thyroid deficiency suggesting multi-systemic LCH. Neurological symptoms including ataxia, tremor, dysarthria, dysphagia and hyperreflexia, within several years, followed by further deterioration [2]. In current case patient was not developed any neurological symptoms to compare with international literature.

Hematopoietic involvement is seen in disseminated LCH. In severe cases, serious anemia and thrombocytopenia may develop and are often associated with a secondary hemophagocytic syndrome followed by a fatal course. Anemia with thrombocytopenia, with or without leukopenia and hypoalbuminemia, are associated with a worse prognosis in children with multi-systemic LCH [2]. In this case her heamatological investigations revealed anemia, hypoalbuminemia and leukocytosis and compatible with international literature.

According to organ involvement in LCH increases the risk for motility. High risk organs include the lung, liver, bone marrow, and spleen. Death occurs in 30% to 50% of those with high risk organ involvement, compared with only 10% without lesions in organs. Low risk sites are defined as skin, bone, lymph nodes, and pituitary glands. Special sites that demand more aggressive therapy are mastoid bone, orbit, temporal bone, and central nervous system [8].

The Histiocyte Society has established guidelines to assist in the diagnosis and evaluation of LCH. All patients with suspected LCH must undergo a thorough physical examination, inclusive of height and weight measurements. Laboratory evaluation should include a complete hematological panel and coagulation studies, liver function tests, and urine osmolality. In addition to the laboratory investigations radiographic investigations are very important [16]. Such as skeletal radiographic survey, dental panoramic radiographs and chest radiographs. Liver biopsy, oral biopsy, skin biopsy computerized tomography, ultra sound scans, and magnetic resonance imaging (MRI) play a major role. Patient of present case has undergone all the above investigations except skeletal radiographic survey, skin biopsy and MRI. Her liver function tests revealed that her AST, ALP, SGOT, AND SGPT were elevated with high serum Ca⁺² levels. Serological tests were showed markedly elevated ESR. USS and CT showed multiple cystic solid lesions in liver.

On microscopy, LCH is characterized by the proliferation of Langerhans cells, arranged in sheets or clusters [1]. The nuclei appear twisted with a longitudinal groove and the small nucleolus has a “coffee bean” appearance [2]. An inflammatory infiltrate composed mainly of eosinophils, lymphocytes and polymorphonuclear leukocytes is also present. Multinuclear giant cells may occasionally be seen. The Birbeck granule is a Langerhans cell-specific tennis racquet-shaped organelle that can be detected by electron microscopy. Immunohistochemically, cytoplasm staining of Langerhans cells with S-100 protein and cell membrane staining with CD1a1, [2]. The liver is particularly susceptible to biliary cirrhosis due to bile duct damage and sclerosis caused by infiltration of Langerhans cell histiocytes [8]. This patient’s incisional biopsy of attached gingiva was consisted of all the cardinal histopathological features of LCH according to the international literature and histopathological features of liver biopsy suggesting systemic involvement. The performed biopsies showed strong positivity for S-100 protein and CD1a [1,2,3].

Radiologically, LCH presents as localized, punched-out radiolucencies with no calcification and no sign of sclerosis or reactions at the borders. Severe alveolar bone resorption producing the appearance of teeth “floating in space” 6 which was a marked radiological finding of present case. Apart from that, bone loss in relation to premolar regions of maxillary and mandibular alveolar bones was significant. Although the clinical differential diagnosis for patient’s oral condition was aggressive periodontitis and multifocal eosinophilic granuloma. They were excluded after the incisional oral biopsy and liver biopsy. When considering systemic involvement differential diagnoses are inflammatory bowel disease (Chron’s disease), Turner syndrome, Langerhans cell histiocytosis- multifocal multisystem type, auto immune polyendocrinopathy type 2.

Treatment modalities for LCH are variable according to location, extension and number of lesions, surgical curettage, and radiotherapy and chemo therapy can be used alone or in combination6. In patients with LCH, the aim of treatment is to relieve clinical symptoms and signs and prevent complication4. In patients with localized, unifocal bone disease, LCH may resolve spontaneously. Curettage is generally sufficient for either diagnosis or therapy. Intra lesional steroids or low dose radiation may be employed. For multi-systemic disease as first line therapy high dose prednisolone is advocating. whereas others suggest use of single agent chemotherapy [16]. Now patient is on high dose prednisolone therapy as patient presented with systemic involvement and thyroxin, vitamin A+D, folic acid and ferrous sulphate under supportive treatment.

4. Conclusion

Awareness of this rare condition, Langerhans cell histiocytosis is very important for early diagnosis. From a clinical point of view according to the clinical type prognosis is vary as high risk categories need early therapy for reduce mortality and morbidity. Another Emphasis of the review is oral manifestations may be the 1st clue to guide the diagnosis of LCH.

Conflict of Interest

The authors declare no conflict of interest whatsoever arising out of the publication of this manuscript.

References

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