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Year : 2018  |  Volume : 11  |  Issue : 2  |  Page : 134-139  

Langerhans cell histiocytosis of the orbit: A study of eight cases

Ocular Oncology Service, The Operation Eyesight Universal Institute for Eye Cancer, L V Prasad Eye Institute, Hyderabad, Telangana, India

Date of Web Publication28-May-2018

Correspondence Address:
Swathi Kaliki
The Operation Eyesight Universal Institute for Eye Cancer, L V Prasad Eye Institute, Hyderabad - 500 034, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ojo.OJO_226_2016

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BACKGROUND: Langerhans cell histiocytosis (LCH) of the orbit is a rare clinical entity with a diagnostic and therapeutic dilemma.
MATERIALS AND METHODS: This was a retrospective study of eight patients with orbital LCH.
RESULTS: All eight patients in our series were male, and the mean age at presentation was 8 years (median 6 years; range, 7 months–23 years). All of them had unilateral disease, and the most common presenting complaint was upper eyelid swelling (n = 6). The mean duration of symptoms was 6 weeks (median, 3 weeks; range, 2–20 weeks). Visual acuity was unaffected in seven cases. Clinical diagnosis included rhabdomyosarcoma (n = 4), malignant lacrimal gland tumor (n = 2), orbital cysticercosis (n = 1), and orbital tuberculosis (n = 1). The diagnosis of orbital LCH was confirmed by incisional biopsy (n = 7) or fine-needle aspiration cytology (n = 1). Four cases underwent careful limited curettage and received intralesional steroid, and four cases were treated with intralesional steroid alone after incisional biopsy. Complete tumor resolution was achieved in seven cases after receiving a mean of one intralesional steroid injection (median, 1; range, 1–2), while one patient was advised systemic chemotherapy for residual tumor. No tumor recurrence was noted in any case at a mean follow-up duration of 30 months (median, 23 months; range, 7–96 months). None of the cases developed diabetes insipidus or multisystem disease during the follow-up period.
CONCLUSION: Minimal local intervention with intralesional steroids with/without careful curettage achieves complete tumor resolution in unifocal orbital LCH.

Keywords: Eosinophilic granuloma, eye, intralesional steroids, Langerhans cell histiocytosis, orbit

How to cite this article:
Singh S, Kaliki S, Reddy Palkonda VA, Palkonda R, Naik MN. Langerhans cell histiocytosis of the orbit: A study of eight cases. Oman J Ophthalmol 2018;11:134-9

How to cite this URL:
Singh S, Kaliki S, Reddy Palkonda VA, Palkonda R, Naik MN. Langerhans cell histiocytosis of the orbit: A study of eight cases. Oman J Ophthalmol [serial online] 2018 [cited 2021 Nov 27];11:134-9. Available from: https://www.ojoonline.org/text.asp?2018/11/2/134/233313

   Introduction Top

Langerhans cell histiocytosis (LCH) represents a clonal proliferation of Langerhans cells and can be unifocal or multifocal.[1],[2] The disease spectrum of LCH ranges from acute disseminated form (Letterer–Siwe syndrome) with lethal outcomes to chronic intermediate benign forms (Hand–Schüller–Christian disease and eosinophilic granuloma) with favorable outcomes.[3] Historically, all these three diseases were grouped as histiocytosis X.[4] Currently, the recommended terminology for orbital eosinophilic granuloma is LCH of the orbit. Orbital LCH presents as a unifocal lesion with erosion into the surrounding bone mimicking malignant conditions.[5] The pathogenesis of the disease is that it arises as either a response to an external inflammatory stimulus or a genetic event.[6] The recent discovery of oncogenic BRAF mutations along with rare KRAF and TP53 mutations suggests that the disease is a myeloid neoplasm with prominent inflammatory component.[6]

Orbital LCH is a rare clinical entity and presents a diagnostic dilemma because of its radiological features. A detailed systemic workup is required to rule out multifocal/disseminated disease. Treatment options for localized orbital disease include observation, surgical removal with bone curettage, intralesional corticosteroids, and systemic chemotherapy in unresponsive cases.[5],[7],[8],[9],[10],[11] Herein, we analyzed our experience and describe clinical features, radiological features, treatment modalities, and outcomes of LCH of the orbit.

   Materials and Methods Top

We retrospectively reviewed the clinical and histopathology records of “eosinophilic granuloma” or “LCH” managed at the Ocular Oncology Service, L.V. Prasad Eye Institute, Hyderabad, from January 2000 to January 2015. Inclusion criteria were histopathologically confirmed cases of LCH with detailed systemic workup (skeletal survey or bone marrow biopsy with bone scan, renal function tests, complete blood count, abdominal ultrasound, and chest radiograph) as per the guidelines of the Histiocyte Society.[12] The institutional ethics committee approval was obtained and informed consent was available for all cases.

Medical records were analyzed for age at presentation, gender, laterality, symptoms, duration of symptoms, clinical features, differential diagnosis, radiological features, modality of treatment, histopathological features, and treatment outcome. Computed tomography (CT) images of the orbit were reviewed from the photography archives. A medical oncologist examined all cases at initial presentation, and systemic workup (bone marrow biopsy with bone scan, renal function tests, complete blood count, abdominal ultrasound, and chest radiograph) was done.

Management protocol was to perform incision biopsy to confirm the diagnosis of LCH. After the histopathology confirmation of the diagnosis, the tumor was debulked and intralesional steroid triamcinolone acetonide (40 mg/ml) was injected under general/local anesthesia. Intralesional steroid injection was repeated after 4 weeks if there was any evidence of residual tumor. If the lesion showed no response to a minimum of three steroid injections, low-dose irradiation or systemic chemotherapy was administered as per the medical oncologist opinion. Follow-up was done 3 monthly for 1-year postresolution and yearly thereafter. Detailed systemic evaluation was done at each follow-up visit by the medical oncologist.

   Results Top

A total of eight cases met the inclusion criteria [Table 1]. All patients were males, and the mean age at presentation was 8 years (median 6 years; range, 7 months–23 years). All of them had unilateral disease with left eye being involved in five and right in three patients. The presenting complaints included swelling in the upper eyelid (n = 6) and proptosis (n = 2). The mean duration of symptoms was 6 weeks (median, 3 weeks; range, 2–20 weeks). No incidental history of trauma or systemic illness could be elicited in any of the cases. There were no neurological symptoms.
Table 1: Summary of clinical details and treatment outcome of 8 patients with orbital Langerhans cell histiocytosis

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All patients had proptosis (mean 4 mm) with limited elevation. Globe displacement was seen in three patients. Superior sulcus fullness was seen in all cases, with palpable mass lesion documented in two cases. Visual acuity was unaffected in seven cases. One case had vision <20/60 attributed to macular striae. There was no regional lymphadenopathy. Clinical diagnosis included rhabdomyosarcoma (n = 4), malignant lacrimal gland tumor (n = 2), orbital cysticercosis (n = 1), and orbital tuberculosis (n = 1). One patient with suspected orbital cysticercosis received a prior 2-week course of oral albendazole, with no apparent clinical or radiological change. Contrast-enhanced CT orbit revealed superiorly located well-defined heterogeneous mass with bony erosion involving frontal bone in eight, sphenoid in one, and zygomatic in one patient. Mass effect with globe indentation was present in one case. Intracranial extension into anterior cranial fossa was seen in five cases and one case had temporal fossa involvement [Figure 1].
Figure 1: Clinical presentation of Langerhans cell histiocytosis. (a) A 7-month-old child with superotemporal mass in the right orbit, (b) computed tomography orbit revealed a soft-tissue lesion in the superotemporal orbit with erosion of frontal bone, (c) complete tumor resolution was achieved with careful limited tumor debulking along with intralesional triamcinolone acetonide, (d) A 23-year-old patient with the left hypoglobus, (e) computed tomography orbit revealed a superior orbital mass extending intracranially, (f) complete tumor resolution was achieved with intralesional triamcinolone acetonide

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All but one patient underwent orbitotomy via subbrow approach, by extraperiosteal route. After reflecting periosteum, incisional biopsy was performed from the mass lesion. In one case, fine-needle aspiration cytology was done because of suspicion of adenoid cystic carcinoma of lacrimal gland. Intraoperative frozen section biopsy was performed in four cases, and histopathological features were suggestive of LCH. The diagnosis was confirmed on paraffin sections. These four cases were given intralesional steroid in the same sitting after debulking the tumor with limited curettage of the bone. The remaining four cases were given intralesional steroid after receiving histopathological confirmation of the diagnosis on paraffin sections. No postoperative complications were noted. Complete resolution of proptosis was seen in all cases except one after receiving a mean of one intralesional steroid injection (median, 1; range, 1–3). Case 3 (3-year-old male child) received three injections of triamcinolone 1cc (40 mg/ml), with 60% reduction in tumor size. For residual disease, the patient was advised systemic chemotherapy. At the time of this manuscript preparation, the patient is still undergoing treatment with systemic chemotherapy with vincristine and cisplatin. Systemic workup was negative in all cases. There was no evidence for multifocal LCH in any case. None of the patients received radiation treatment. No tumor recurrence was seen in any case at a mean follow-up duration of 30 months (median, 23 months; range, 7–96 months). None of the cases developed diabetes insipidus or multisystem disease during the follow-up period.

Intraoperative gross examination showed yellowish-white mass with necrotic appearance in all cases. All cases showed similar histopathological features [Figure 2]. Light microscopic examination revealed highly cellular areas with small areas of necrosis and hemorrhage. A polymorphous population of cells was seen along with prominent histiocytes with abundant cytoplasm and a very prominent convoluted nucleus. In the background, multinucleated giant cells and inflammatory cells, predominantly eosinophils along with neutrophils and lymphocytes, were seen. Tumor cells showed diffuse expression of S-100 with positivity for CD1a. Histiocytes showed high expression of CD68.
Figure 2: Histopathology of Langerhans cell histiocytosis. (a) Photomicrograph shows prominent histiocytes with abundant cytoplasm against the background of mixed population of eosinophils and multinucleated giant cells (H and E, ×10 magnification), (b) eosinophils in the background (H and E, ×40 magnification), (c) histiocytes, lymphocytes, and eosinophils in the background (H and E, ×40 magnification), (d) tumor cells displaying immunopositivity for CD1a (×40 magnification)

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   Discussion Top

Earlier studies postulated that LCH was not a true neoplasm but an atypical proliferation of one cell population.[13] However, with recent genetic studies, there is an increasing evidence that LCH represents myeloid neoplasia with prominent inflammatory component.[14],[15] Badalian-Very et al. studied 61 LCH specimens and revealed the presence of monoclonal Langerhans cells with oncogenic BRAF V600E mutation in 35 (57%) specimens, suggesting that LCH represents a myeloid neoplasia.[15] It is presumed that the lesions in LCH expand by local proliferation of neoplastic Langerhans cells.[6] These new insights have changed the view on LCH and help in partly understanding its pathogenesis, but it does not change anything on its mostly benign behavior.[16] These proliferating Langerhans cells produce interleukin 1 (IL-1) and prostaglandin E2 (PGE2) which have osteolytic activity.[17] Hence, bone destruction with soft-tissue expansion is seen in almost all cases (100% in our series).

Orbital LCH is rare and mostly affects pediatric population in the first decade of life as seen in our series.[2],[3] It has a predilection for superior orbital rim. Frontal bone marrow remains active until the second decade of life and may thus influence the tumor location.[7] Orbital LCH in adults is uncommon and most commonly affects the greater wing of sphenoid bone, where there is still active bone marrow in young adults.[18],[19] In our series, there was only one adult patient (23 years of age), and the lesion was located in the frontal bone. The lesion is more common in boys than girls.[20] In our series, all patients were males.

Orbital LCH is usually unifocal with a benign course. Orbital involvement along with systemic LCH was reported by Moore et al. in 18 of 76 (24%) children.[1] In our series, all the lesions were unifocal without any evidence of systemic LCH. Visual outcome is generally good as mass is located in anterior/mid-orbit. All cases in our series had normal visual acuity at the last follow-up. Clinical differential diagnosis of orbital unifocal orbital LCH includes rhabdomyosarcoma, Ewing's sarcoma, neuroblastoma, and inflammatory lesions involving bone like giant reparative granuloma of frontal bone, and tuberculosis.[2] Orbital mass with bony erosion and a progressive disease course presenting in the first decade of life may raise a suspicion of malignant cause. Hence, biopsy is indicated in all cases, as no characteristic clinical or radiological features are pathognomonic of LCH.

The treatment of LCH depends on the tumor location, size, surgical accessibility, presence of adjacent soft-tissue changes, presence of functional impairment, and the risk of permanent sequelae. The treatment options for unifocal lesions include observation for small asymptomatic unifocal osseous or cutaneous lesions, surgical procedures including biopsy, careful curettage, or resection and intralesional steroids for symptomatic unifocal bone lesions, and systemic chemotherapy or low-dose radiotherapy (6–10 Gy) for large, symptomatic, or recurrent lesions which are not easily accessible and bear high chances of permanent sequelae.[16],[21],[22],[23] Rare case scenarios of spontaneous resolution of unifocal orbital disease have also been reported.[24],[25] The treatment options for disseminated disease include systemic chemotherapy, bone marrow transplantation, and immunoglobulin therapy.[16],[21],[22],[23] With new insights into the pathogenesis of LCH, there is an increasing interest toward management of LCH with targeted treatment strategies with targeted inhibition of MAPK pathway, especially in patients with severe life-threatening LCH.[16] In view of excellent prognosis in localized skeletal lesions including orbital LCH, the lesions are best managed conservatively.[16] Corticosteroids act in LCH by inhibiting the release of PGE2 and IL-1.[13] Harris and Woo reported a series of six cases with unifocal orbital LCH, in which 100% tumor resolution was achieved in four cases with subtotal curettage and intralesional steroid injection.[10],[11] Nonorbital LCH involving bone also respond well to intralesional steroids. Yasko et al. reported a series of 35 cases of nonorbital LCH and showed that complete response was achieved in 89% of cases with one intralesional injection and in 100% cases with two or more injections.[22] In our series, careful curettage and targeted therapy in the form of intralesional steroid injection achieved complete tumor resolution in 88% (7) cases without systemic side effects. One case displayed incomplete response to multiple injections of intralesional steroids and thus was advised systemic chemotherapy.

Orbital involvement by LCH has been postulated as a risk factor for developing diabetes insipidus.[23] As per the guidelines of Histiocyte Society, prophylactic systemic chemotherapy is recommended in cases with multisystem involvement of high-risk organs such as liver, spleen, lungs, and skull/orbital bones.[23] In the LCH III study, all cases who developed diabetes insipidus had orbital involvement with multisystem disease.[23] In their protocol, the lesions in the orbital bones with intracranial soft-tissue extension were regarded as “central nervous system (CNS)-risk” lesions, which may lead to CNS complications such as diabetes insipidus, and thus mandated systemic chemotherapy.[23] However, reports suggest that unifocal osteolytic lesions that arise in the anterolateral frontal bone and erupt into the orbital and intracranial cavities, undergo complete resolution after relatively minor local intervention, without the need for systemic chemotherapy.[2],[10],[11],[26] In our study, none of the patients with intracranial extension (n = 5) received systemic chemotherapy as primary treatment, and complete tumor regression was achieved with careful curettage and intralesional steroid injection in four of five patients. Systemic chemotherapy was started in one patient due to incomplete response with steroids. None of the patients developed CNS complications or diabetes insipidus during the mean follow-up period of 18 months.

   Conclusion Top

Our preferred approach for orbital LCH is tumor debulking with intralesional steroids. This modality of treatment achieved complete resolution in 88% cases. No association with diabetes insipidus was observed in our series.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

This study was supported by the Operation Eyesight Universal Institute for Eye Cancer (SK) and Hyderabad Eye Research Foundation (SK), Hyderabad, India. The funders had no role in the preparation, review, or approval of the manuscript.

Financial support and sponsorship

This study was supported by the Operation Eyesight Universal Institute for Eye Cancer (SK) and Hyderabad Eye Research Foundation (SK), Hyderabad, India. The funders had no role in the preparation, review, or approval of the manuscript.

Conflicts of interest

There are no conflicts of interest.

   References Top

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  [Table 1]


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