Langerhans Cell Histiocytosis in Paediatric Zygoma Swelling

Abstract

Langerhans cell histiocytosis (LCH) is a rare neoplasm characterized by accumulation of histiocytes in various tissues. It has a wide clinical spectrum and its presentation may mimic clinical features of common diseases. High level of suspicion is required for early diagnosis. Here is a rare case of a rapidly aggressive LCH which first presented with right zygomatic swelling.

Introduction

“Langerhans cell histiocytosis (LCH)”, unlike the Langerhans cells in skin, is a neoplasm consisted of clonal proliferation of CD1a+/CD207+ myeloid dendritic cells with variable clinical presentations ranging from skin manifestations to disseminated systemic involvement [1, 2]. LCH with its incidence of five to six cases per one million people and more than half diagnosed in paediatric patients, is a rare disease [3]. The presentation of LCH is variable and can be classified based on the tissues involved, whether local or multifocal, mono-systemic or multisystemic and risk organs involvement [1]. It is most commonly localized in the head and neck, consisting of almost two-third of the cases and among the otorhinolaryngology sites, the prevalence in descending order is skull vault and orbit, cervical lymph nodes, temporal bone and lastly upper and lower jaw. The other possible sites are pituitary gland, lung, lymph nodes and skin while hematopoietic systems including liver and spleen involvement are one of the poor prognostic factors. The disease progression and treatment response of LCH is complex, ranging from spontaneous resolution in localised low risk patients to guarded prognosis in high risk patients complicated with treatment failure and reactivation [4, 5].

Case Report

A 6 months old male baby presented with painless rapidly progressive right zygomatic swelling of 1 month duration with bilateral ear discharge and crusting scalp lesions. There were no neurological symptoms or polyuria. Examination revealed generalised flaky lesions of the scalp. The right zygomatic swelling was firm, not tender, with normal overlying skin, measuring approximately 40 by 30 mm. Bilateral extraocular movements were not restricted. Otoscopy revealed bilateral ear canal edema with minimal whitish discharge. Tympanic membranes were visualised and intact. There were no palpable cervical, axillary or inguinal lymph nodes and other systemic examination was unremarkable.

Contrast enhanced computed tomography (CECT) scan of the brain and neck showed a round smooth well lineated homogeneously enhancing mass involving right lateral wall of orbit, right temporal bone and right ramus of mandible, extending into right orbit displacing the lateral rectus muscle and infiltrating the right temporal bone with displacement of right temporal lobe (Fig. 1). A small nodule was also noted in the right upper lobe of the lung. There was no hepatosplenomegaly.

Fig. 1.

Axial view of CECT Neck soft tissue window showed a round smooth well lineated homogeneously enhancing mass involving right lateral wall of orbit, right temporal bone and right ramus of mandible, extending into right orbit displacing the lateral rectus muscle and infiltrating the right temporal bone with displacement of right temporal lobe

The patient underwent incisional biopsy of the right zygomatic swelling and the histopathological examination revealed sheets of Langerhans cells which was confirmed by positive immunohistochemical studies (S-100 protein and CD1a) (Fig. 2). Skeletal survey, CT of chest, abdomen and pelvis and bone marrow biopsy were negative for signs of involvement.

Fig. 2.

Sections from fibromuscular tissue show sheets of Langerhans cells confirmed by S-100 (a) and CD1a (b) stains positive. The cells have moderate amounts of pale eosinophilic cytoplasm and round to oval to irregular nuclei with nuclear grooving/folds, fine chromatin pattern and inconspicuous to tiny nucleoli. Mitoses are frequently seen. The background shows intermingled eosinophils, histiocytes, neutrophils and small lymphocytes

He was stratified as a low risk multisystem LCH (skin and temporal bone) and was referred to the Oncology centre and received chemotherapy according to LCH IV Stratum I protocol which included vinblastine and prednisolone for 12 cycles.

However the child’s condition worsened despite the chemotherapy. His zygomatic swelling expanded and abdomen became distended. Examination revealed hepatosplenomegaly, which was confirmed by ultrasound of abdomen suggestive of disease infiltration. Peripheral blood film showed pancytopenia. Repeat CT scan post chemotherapy revealed skull changes typical of LCH had progressed (Fig. 3). He was re-stratified to multisystem LCH with risk organ involvement and started on Stratum III treatment based on LCH IV protocol which consisted of Cytarabine and Cladribine.

Fig. 3.

a axial view of soft tissue window, b coronal view of soft tissue window, c axial view of bone window, d coronal view of bone window was the CECT brain and neck post first chemotherapy, revealing that the lesion had progressed. The soft tissue window showed the extensive mass effect and proptosis of the right eye. The bone window showed further erosion of right orbital wall, temporal bone and anterior half of cranial floor extending to meninges of right temporal lobe. A new smaller size lesion noted at left supraorbital region eroding left superolateral orbital wall

Discussion

LCH is a rare disease capable of great mimicry, presenting with a wide range of symptoms involving different organs and is frequently misdiagnosed [6]. Due to the wide spectrum of presentations, LCH was historically divided into 3 clinical types based on disease severity, which included eosinophilic granuloma (chronic and indolent form), Hand Schuller-Christian disease and Letterer-Siwe disease (acute and fulminant form) [7]. Multiple revisions had been done for the classification system however the most widely used in deciding management is the clinical subtypes devised by Histiocyte society 9. The organ or system involved is identified based on the criteria provided by guidelines for management of histiocytic disease [1, 8, 9]. When there is single organ involvement while the lungs and risk organs are spared, the patient is classified as LCH-SS (single system), LCH-MS when there are multiple systems (MS) involved. LCH-MS-RO + when risk organs are affected (RO +) while LCH-MS-RO- when risk organs are spared (RO−). The risk organs are involved when either of these systems are affected, including hematopoietic system, liver and spleen. When lungs are involved, the patient is classified as LCH-lung [10]. The prognosis of the patients are greatly dependent on the age of onset, number of affected organs and degree of functional lesions [11]. Younger age, multiple systems with risk organs involvement carries worse prognosis while single affected organ, especially skin or bone, has better prognosis. Our patient was initially diagnosed to have LCH-MS (skin and bone involvement) with central nervous system risk but unfortunately had later progressed to a multisystem and fulminant variant affecting risk organs, liver and hematopoietic system.

The symptoms of LCH may be as minor as cradle cap, swelling, lymphadenopathy or otorrhea, progressing to involve other organs and lastly the fulminant form affecting the CNS and hematopoietic system. Patients who presented with common symptoms but resistant to standard therapy should undergo further workout including radiological imaging and biopsy for histopathological examination. Simple radiological imaging eg skeletal x-ray may provide clues for diagnosis by showing destructive lytic bone lesions [12, 13]. Differential diagnoses included dermoid cysts or bone tumors. The gold standard radiology imaging to identify and monitor bony LCH is CT scan as it demonstrates a well defined soft tissue density and delineates bony erosion better than magnetic resonance imaging (MRI). However MRI is more superior in viewing the soft tissues and its extension [2]. The choice of radioimaging should be dependent on clinical assessment on the location and extent of the disease. The diagnosis of LCH, despite clinical and radiological evidence, must include tissue biopsy revealing characteristic Langerhans cells with positive CD1a and/or CD207 (Langerin) staining. Demonstration of Birbeck granules under electron microscopy is no longer compulsory as the Langerins correspond with its presence [9].

The management of LCH is dependent on the number, site and size of the lesions. The treatment includes surgery, chemotherapy or radiotherapy, which can be given in combination. The mainstream treatment of LCH is a chemotherapy regimen based on Langerhans Cell Histiocytosis-IV (LCH-IV) study by Histiocyte Society (ClinicalTrials.gov number, NCT02205762). LCH-IV is a randomised open label prospective trial started in 2014 to determine efficacy and duration of different chemotherapy regimens for variable subtypes of LCH and treatment of LCH-related neurodegeneration. The patients are divided into LCH-SS, LCH-MS, LCH-MS-RO- and LCH-MS-RO + and treated based on 7 strata of LCH-IV [1]. Surgery is usually for histopathology diagnosis and may be useful in isolated LCH lesion. Radiotherapy and chemotherapy may be added in refractory cases [3].

The patients may develop permanent consequences due to LCH as early as at the time of presentation or delayed to years and decades later. Hence it is important to monitor these patients until they enter adulthood when growth is completed [9]. The long term complications may involve any body system. However the most common ones are endocrine, hearing and orthopaedic. These complications are more commonly seen in younger children with multisystem involvement as the growth and development may be affected, thus worse prognosis. The patients with unifocal SS-LCH have comparatively better prognosis as they may recover with symptomatic treatment only. The children at risk may develop diabetes insipidus, stunted growth and delayed puberty. Anterior pituitary profile should be taken if hormonal dysfunction is suspected and followed by MRI Brain. Xray and bone mineral density (DEXA) scan can be done to assess bone age and bone density.

The paediatric LCH patients should be followed up for at least 5 years after therapy ended or after last disease reactivation and ideally until completion of final growth and pubertal development. During each visit, routine assessment including growth and development, pubertal status, history of thirst and polyuria and routine blood investigation should be carried out. Additional endocrine test is warranted if patients complained of endocrine symptoms. Patients with skeletal involvement should have X-ray repeated at 6 weeks, 3 and 6 months or more frequently if indicated. If vertebrae was involved, the patients are at risk of developing scoliosis during pubertal spurt. Head MRI can be repeated after 1 year and then at 2,4,7 and 10 years, if previous MRI showed evidence of neurodegenerative findings and pituitary involvement. Chest X-ray will be helpful in patients with respiratory symptoms. Baseline ultrasound of liver and hearing assessment at the end treatment can be considered.

The outcomes of the patients greatly varied along the spectrum. Children without risk organ involvement have excellent prognosis with 100% survival probability however the rate of disease reactivation is high. The mortality risk among patients with risk organ involvement although had reduced significantly from 54.5% in 1990’s [15] and 20 to 25% in 2000’s, it still remained high despite the advancement in the treatment of LCH. The prognosis of the patients is closely linked to the risk organ involvement and their therapeutic response to initial therapy (assessed after 6–12 weeks of treatment). Hence high risk patients are advisable for greater intensity initial therapy to achieve higher rapid response and survival rates [14].

Conclusion

LCH is a master of mimicry. Due to its variable presentation, high index of suspicion is required for early diagnosis. It is an aggressive disease which may involve multiple systems resulting in various sequelae. Therefore prompt management is required and regular follow up may lead to better outcomes.

Funding

The authors have no relevant financial or non-financial interests to disclose.

Declaration

Conflicts of interest

The authors have no conflicts of interest to declare that are relevant to the content of this article.