Stereotactic Radiosurgery for Localized Cranial Langerhans Cell Histiocytosis: A Single Institution Experience and Review of Literature.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare idiopathic disease characterized by the clonal proliferation of Langerhans histiocytes in various parts of the body and capable of leading to organ damage and tumor formation. Reports of cranial LCH in the adult population are extremely rare. Although surgery remains the preferred option for localized LCH lesions, the role of stereotactic radiosurgery (SRS) is emerging. OBJECTIVE: To retrospectively review a rare case series to determine the safety and effectiveness of SRS for patients with localized cranial LCH. METHODS: We retrospectively reviewed histopathologically confirmed cases of localized cranial LCH treated with SRS at our institute in the adult population between January 2005 and September 2022. Five patients were identified with a median age of 34 years (19-54 years). The tumor location was in the pituitary stalk in 3 patients, the orbit in one patient, and the parietal skull in one patient. The median target volume was 2.8 cc (range: 0.37-6.11). Treatment was delivered in a single fraction in 4 patients (median margin dose of 8 Gy, range: 7-10 Gy) and in 3 fractions (22.5 Gy) in 1 patient. The median follow-up was 12 years (range: 4-17). None of the patients required craniotomy for tumor debulking before or after SRS. RESULTS: The local tumor control rate for the lesions was 100%. All 3 patients with LCH in the pituitary stalk had diabetes insipidus at the initial presentation and developed panhypopituitarism after SRS. Diabetes insipidus was not improved after SRS. The other 2 patients presented no adverse radiation effects. Based on the literature review, our case series was the largest retrospective series on SRS for localized cranial LCH, with the longest median follow-up. CONCLUSIONS: SRS for patients with localized cranial LCH was a safe and effective treatment modality in this case series. Larger studies are encouraged to validate the role of SRS in the treatment of localized cranial LCH.

Aggressive unifocal bone Langerhans cell histiocytosis with soft tissue extension both responsive to radiotherapy: a case report.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare haematological neoplasm characterized by the accumulation of CD1a+, CD207/Langerin+ histiocytes within inflammatory lesions. LCH can involve any organ, but osteolytic bone lesions are most often encountered. Unifocal bone lesions may regress spontaneously after a thick needle biopsy has been taken. CASE PRESENTATION: In this case report, we describe the initial presentation of a single BRAFV600E mutated osteolytic LCH lesion in the left proximal humerus of a 46-year-old previously healthy woman. Despite multiple surgical interventions, she unexpectedly experienced progressive disease manifestation with significant soft tissue extension to the surrounding musculature, subcutis and epidermis. Because the disease manifestation remained loco-regional, radiotherapy (RT) (total dose of 20 Gy in 10 fractions) was initiated. CONCLUSION: The patient achieved a complete remission without any side effects. This case highlights that RT is a rational and relative mild local treatment option for patients with aggressive LCH affecting the bone and surrounding soft tissue.

Role of Stereotactic Radiosurgery in Intracranial Histiocytosis: a Systematic Review of Literature of an Emerging Modality for Localized Disease.

BACKGROUND: A histiocytosis is a group of immunoproliferative disorders of clonal cells. The management protocols are still evolving, with chemotherapy as the mainstay of treatment. OBJECTIVE: This study aims to evaluate the feasibility, safety, efficacy, and complication profile of stereotactic radiosurgery for intracranial histiocytosis. METHODOLOGY: The authors reviewed PubMed, Scopus, Web of Science, and Embase for "radiosurgery" and "histiocytosis" in the English/Japanese language following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The patient profile, radiosurgical parameters (dose and isodose), target volume, and mode of radiosurgery (Gamma knife, LINAC radiosurgery, etc.) were collected. Its use as primary or adjuvant therapy, clinical and radiological outcome was also evaluated. RESULTS: We identified 7 studies (9 patients); mean age: 41.9 years (24-57 years). Six patients received Gamma-knife radiosurgery, whereas 3 received CyberKnife radiosurgery. The Langerhans cell histiocytosis variants were eosinophilic granuloma in 3, whereas 4 were not defined. Two cases had Rosai-Dorfman disease, and 2 different yet pathogenetically related histiocytic disorders. Four patients harbored lesions in the pituitary stalk and posterior pituitary, 2 patients in the petrous region, 1 patient had a pontine lesion, and 2 patients had multiple lesions. The dose delivered ranged from 8 to 28 Gy. A total of 18 lesions (9 patients) were followed for 81.67 patient-years: 7 (39%) disappeared, 8 (44.4%) showed radiological reduction, and 2 (11%) remained stable. One lesion (5%) showed an increase in size needed surgical excision. There were no adverse effects. CONCLUSION: The role of stereotactic radiosurgery needs to be further evaluated as the current cohort with only 9 cases (2 are Rosai-Dorfman disease) is insufficient to make conclusions. It may be a viable alternative in localized disease, along with chemotherapy and targeted surgery.

Clinicoradiological Discrepancy in Multisystem Langerhans Cell Histiocytosis with Central Nervous System Involvement.

Langerhans cell histiocytosis (LCH) is a rare neoplasm that is caused by an uncontrolled proliferation of Langerhans cells. The clinical presentation of LCH is heterogeneous and can manifest as single or multiple osteolytic lesions, skin ulcerations, and involvement of single or multiple systems. Central nervous system (CNS) involvement is reported in 3.4-57% of patients with multisystem disease. In this article, we present the case of a young man with single system involvement (bone) of LCH who presented with seizures, headache, papilledema, and tinnitus. His magnetic resonance imaging (MRI) of the brain findings were reported as a normal study. The subtle signs of CNS involvement were missed by the radiologist. However, the high index of suspicion resulted in early diagnosis and treatment. The presence of empty sella turcica in neuroimaging could be the first sign of intracranial disease with chronic intracranial hypertension associated with LCH. This is especially correct if previous computed tomography (CT) scan of the brain was normal with normal appearance of the pituitary gland and the sella. Neuroimaging films should be reviewed by an expert neuroradiologist. In patients with new neurological symptoms who were diagnosed previously with LCH, intracranial disease has to be excluded. The workup in such case should include an MRI of the brain, CT of the brain and temporal bones, bone scan, cerebrospinal fluid analysis, ophthalmological assessment, and measurement of intracranial pressure. In patients with LCH who present with symptoms and signs of raised intracranial pressure, the term idiopathic intracranial hypertension should not be applied until an intracranial disease has been excluded totally. Keywords: Langerhans Cell Histiocytosis; Central Nervous System Involvement; Neuroimaging; Intracranial Hypertension.

Radiotherapy for Langerhans cell histiocytosis with paraplegia: A rare oncologic emergency case report in infancy and literature review.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a clonal disease with focal or disseminated lesions that may compress the surrounding tissues, including the spinal cord. Because few reports have described the spinal symptoms as the first manifestation of pediatric LCH, the long-term neurological outcomes remain unclear. CASE REPORT AND LITERATURE REVIEW: We report a 21-month-old boy who presented with sudden-onset paraplegia. Imaging analyses revealed that osteolytic lesions and epidural tumors compressing the spinal cord at the T7-9 vertebrae. Twelve days after he developed leg weakness, emergency radiotherapy was started after a tumor biopsy. During the course of radiotherapy, paralysis steadily ameliorated. After we excluded infections and determined the pathological diagnosis of LCH, multi-drug chemotherapy was started. Apparent improvement in his complete paraplegia was observed after a total 15 Gy of radiotherapy and subsequent chemotherapy, leaving no neurological sequelae at 4 years of age. Through a literature search of studies published from 1980 to 2017, we found that children with LCH showed a generally favorable recovery from neurological dysfunction after the acute phase of spinal symptoms. CONCLUSION: This report underscores the utility of emergency radiotherapy for the neurological recovery of spinal LCH in infants. Our long-term observation further denotes the value of this treatment in terms of the intact survival with preserved motor functions and physical growth.

Outcome After Radiation Therapy for Langerhans Cell Histiocytosis Is Dependent on Site of Involvement.

PURPOSE: To characterize the efficacy and safety of radiation therapy in a contemporary Langerhans cell histiocytosis (LCH) cohort and to explore whether there are sites at higher risk for local recurrence. PATIENTS AND METHODS: Between 1995 and 2015 we identified 39 consecutive LCH patients who were treated primarily with radiation therapy. Patients were staged by single/multisystem involvement and established risk organ criteria. In 46 irradiated lesions, clinical and radiologic responses were evaluated at multiple time points after radiation therapy. Patient demographics, treatment, and local failure were compared by site of lesion. RESULTS: Median age at radiation therapy was 35 years (range, 1.5-67 years). Twelve patients had multisystem involvement, and of those, 5 patients had disease in organs considered to be high risk. The following sites were irradiated: bone (31), brain (6), skin (3), lymph node (3), thyroid (2), and nasopharynx (1). Median dose was 11.4 Gy (range, 7.5-50.4 Gy). At a median follow-up of 45 months (range, 6-199 months), local recurrence or progression was noted in 5 of 46 lesions (11%). There were no local failures of the 31 bone lesions evaluated, whereas the 3-year freedom from local failure in the 15 non-bone lesions was 63% (95% confidence interval 32-83%; P=.0008). Local failures occurred in 2 of 3 skin lesions, in 2 of 6 brain lesions, and 1 of 3 lymph node lesions. Deaths were recorded in 5 of 39 patients (13%), all of whom were adults with multisystem disease. CONCLUSION: Radiation therapy is a safe and effective measure for providing local control of LCH involving the bone. Whereas bone lesions are well controlled with low doses of radiation, disease in other tissues, such as the skin and brain, may require higher doses of radiation or additional treatment modalities.

Multifocal soft tissue Langerhans' cell histiocytosis treated with PET-CT based conformal radiotherapy.

INTRODUCTION: Langerhans' cell histiocytosis (LCH) is a proliferative disorder of Langerhans cells, which is seen extremely rarely in adults. Conventional imaging modalities, such as skeletal surveys and bone scans, were accepted to be standard methods for diagnosis; however, 18-fluorodeoxyglucose positron emission tomography (PET-CT) has been increasingly used. METHODS: We report on a 33-year-old female patient with disseminated LCH treated with radiotherapy and systemic chemotherapy where PET-CT has been used for defining the extent of the disease, RT planning and assessment of treatment response during follow-up. RESULTS: The patient was treated with 24 Gy 3-dimensional conformal radiotherapy (RT), given as 2 Gy a day, 5 days a week. The patient was also treated with systemic prednisolone 20 mg/m(2), concurrently. The chemotherapeutic regimen switched to cytosine-arabinoside with a dose of 100 mg/m(2) subcutaneously daily for 4 days, vincristine 1.5 mg/m(2) given on the 1st day and prednisolone 20 mg/m(2) for 4 cycles. After local RT with adjuvant chemotherapy, the patient was alive for 54 months and remained disease-free at last visit. CONCLUSION: RT is a treatment choice in multi-system LCH as well as solitary lesions. Low-dose RT is adequate to control large masses of LCH including soft tissue and lymph nodes.

The pituitary gland in patients with Langerhans cell histiocytosis: a clinical and radiological evaluation.

Langerhans cell histiocytosis (LCH) is a rare disease in which the most common endocrine manifestation is diabetes insipidus (DI). Data on anterior pituitary function in patients with LCH are limited. Thus, the present study investigated anterior pituitary function in LCH patients with DI via the evaluation of clinical and radiological findings at disease onset and during follow-up. The present study retrospectively evaluated nine patients with LCH (five males and four females). All diagnoses of LCH were made following histological and/or immunophenotypic analyses of tissue biopsies, bronchoalveolar lavage, or cerebrospinal fluid (CSF). Basal and, if necessary, dynamic pituitary function tests were used to assess anterior pituitary function, and magnetic resonance imaging (MRI) scans were used to image the pituitary. The LCH treatment modality was based on organ involvement. The mean age at onset of DI was 27.6 years (range 15-60 years). One patient (11%) exhibited single organ involvement, while eight patients (89%) displayed multisystem organ involvement. On admittance, one patient had hypogonadotropic hypogonadism, one patient exhibited panhypopituitarism [hypogonadotropic hypogonadism, central hypothyroidism, hypocortisolism, and growth hormone (GH) deficiency], and four patients (44%) displayed hyperprolactinemia. The MRI data revealed infundibular enlargement in seven patients (78%), a thalamic mass in one patient (11%), and the absence of the bright spot in all patients. A single patient (11%) showed a mass in the pons that had a partially empty sella. The patients were treated with radiation therapy (RT), chemotherapy (CT), or a combination of both (RT+CT) and were followed up for a median of 91.8 months (range 2-318 months). Seven patients were assessed during the follow-up period, of whom four patients (57.1%) developed anterior pituitary hormone deficiency, three (43%) were diagnosed with GH deficiency, and one (14%) exhibited gonadotropin deficiency. The gonadotropin deficiency in the patient, which was diagnosed on admittance, was resolved during the follow-up period. DI persisted in all patients, and the conditions of the seven patients who have remained on follow-up are stable. In the present study, patients with LCH exhibited altered function in the anterior pituitary as well as the posterior pituitary, which may be due to the natural course of the disease or the effects of treatment. The present findings indicate that anterior pituitary function should be assessed in LCH patients on admittance and during follow-up, especially in LCH patients with multisystem organ involvement.

Narrowband ultraviolet B light in Langerhans cell histiocytosis: a case report.

Langerhans cell histiocytosis (LCH) (previously called eosinophilic granuloma, Hand-Schüller-Christian syndrome, Letterer-Siwe disease, and Hashimoto-Pritzker disease) is a rare, heterogeneous disorder with highly variable presentation. LCH commonly affects the skin, as well as internal organs. Because the skin lesions appear benign, and LCH is unfamiliar to most physicians, diagnosis is often delayed. Treatment is controversial, with further clinical study needed. For persons with extensive, skin-limited disease, the existing topical therapies are impractical. We present a child with cutaneous LCH lesions that responded to ultraviolet light phototherapy with minimal adverse effects or patient discomfort.

Clinical outcomes of radiation therapy in the management of Langerhans cell histiocytosis.

OBJECTIVES: Langerhans cell histiocytosis (LCH) is a rare disease with variable clinical presentation. In the present study, we report on the effectiveness and clinical complications of radiation therapy in children with LCH. MATERIALS AND METHODS: We retrospectively reviewed all patients with LCH treated with radiation therapy over a 6-decade period at a single institution. Radiotherapy data, clinical features, radiographic data, and vital status were analyzed. RESULTS: The mean age at diagnosis for 69 patients was 5.3 years (3 mo to 37 y) and the median duration of follow-up was 6 years (7 d to 32 y). Radiation therapy was performed for 169 sites, primarily bone lesions. The median radiotherapy dose was 10 Gy (2.5 to 45 Gy). Radiographic follow-up data were available for 139 of the sites treated and clinical follow-up was available for 156 of sites treated. The radiographic local control was 91.4%, and 13% of lesions showed complete sclerosis or reconstitution of bone. A total of 90.4% of patients reported stabilization or improvement in lesion-related symptoms, most often pain. Twelve patients had diabetes insipidus at diagnosis or during follow-up. Eight of these patients received radiation treatment to the pituitary and none experienced a reduction in desmopressin dosage posttreatment. Radiation complications were few, including femoral neck fracture in 1 patient and facial asymmetry in 3 patients. No secondary malignancies were observed. CONCLUSIONS: Radiotherapy for LCH has high rates of local control and symptomatic improvement. Importantly, however, there is evidence of short-term and long-term morbidity when children are treated with low-dose irradiation.

Radiotherapy in langerhans cell histiocytosis - a rare indication in a rare disease.

INTRODUCTION: Langerhans Cell Histiocytosis (LCH) represents a rare benign disorder, previously designated as "Histiocytosis X", "Type II Histiocytosis" or "Langerhans Cell Granulomatosis". Clinical presentation includes osteolysis, ulcerations of skin and soft tissues but also involvement of the CNS is described.Because treatment concepts are not well defined the German Cooperative Group on Radiotherapy for Benign Diseases performed a retrospective analysis. METHODS AND MATERIAL: Eight closely cooperating centres collected patients' data of the past 45 years. As study endpoints disease free survival, recurrent disease, death and therapy related side effects were defined. RESULTS: A total of 80 patients with histologically proven LCH were irradiated within the past 45 years. According to the LCH classification of Greenberger et al. 37 patients had stage Ia, 21 patients stage Ib, 13 patients stage II and 9 patients stage IIIb and the median age was 29 years. The median Follow up was 54 months (range 9-134 months). A total of 39 patients had a surgical intervention and 23 patients a chemotherapy regimen.Radiation treatment was carried out with a median total dose of 15 Gy (range 3-50.4 Gy). The median single fraction was 2 Gy (range 1.8-3 Gy).Overall, 77% patients achieved a complete remission and 12.5% achieved a partial remission. The long-term control rate reached 80%. Within an actuarial overall 5-year survival of 90% no radiogenic side and late effects ≥EORTC/RTOG II° were observed. CONCLUSION: In the present study a large collective of irradiated patients was analysed. Radiotherapy (RT) is a very effective and safe treatment option and even low RT doses show sufficient local control.

[Efficacy of radiotherapy for adult patients with Langerhans cell histiocytosis].

OBJECTIVE: To analyze efficacy of radiotherapy for adult patients with Langerhans cell histiocytosis (LCH). METHODS: Clinical features and efficacy of radiotherapy for biopsy-proven adult patient with LCH from January 2000 to October 2012 in our hospital were retrospectively analyzed. RESULTS: Seventeen (11 male and 6 female) adult LCH patients with a mean age of 31 (18-56) years old were treated by irradiation, all patients presented as single-system disease. The mean duration from diagnosis to irradiation was 8.3 (0-108) months. Although 12 of 17 patients (70.6%) had short-term response to radiotherapy, all patients but one (94.1%) progressed during long-term follow-up, the mean progression-free survival (PFS) was 14 (0-131) months. Of the progressed patients, one relapsed in situ, the remaining 15 patients progressed outside the irradiated region. Thirteen patients (76.5%) eventually progressed to multisystem disease. CONCLUSION: Though radiotherapy for LCH in adults produced a high short-term response up to 70.6%, most of patients eventually progressed in situ or outside the irradiation region during long-term follow-up.

Cladribine (2-chlorodeoxyadenosine) in frontline chemotherapy for adult Langerhans cell histiocytosis: A single-center study of seven cases.

BACKGROUND: Adult Langerhans cell histiocytosis is a rare disorder with diverse clinical manifestations and inconsistent treatment outcomes to conventional therapeutic regimens. Cladribine (2-chlorodeoxyadenosine) repeatedly proved effective in cases of relapsed multifocal and multisystem disease forms. In this retrospective study we present an analysis of cladribine in frontline systemic therapy. MATERIAL AND METHODS: A cohort of seven male patients with biopsy proved multisystem (six cases) and multifocal (one case) Langerhans cell histiocytosis received cladribine at a dose of 5 mg/m(2) subcutaneously (five cases) or by two-hour intravenous infusion (two cases) over five consecutive days, every four weeks for a median of four courses (range 4-6). The treatment was enhanced with cyclophosphamide (300 mg intravenously on days 1-5 in cycles 4-6) and corticoids (dexamethasone 24 mg orally or methylprednisolone 250 mg intravenously on days 1-5 in cycles 4-6) in two patients, with radiotherapy (20 Gy on skin or bone lesions) in three patients and with photochemotherapy (psoralen plus ultraviolet A light, PUVA) on skin lesions in one patient. RESULTS: All patients achieved clinically relevant treatment response confirmed by positron emission tomography (PET). Durable complete remissions were maintained in six patients (86%), including two patients with hypophysis involvement, with the median follow-up of 37 months (range 15-94; 49.8 ± 35.2 [ 6 ]). One patient had an aggressive, early relapsing disease requiring further treatment lines. The treatment-related toxicities consisted of transient bone marrow suppression affecting the leukocytes predominantly. Grade 3 lymphopenia occurred in five patients (71%) and grade 3 neutropenia in one patient (14%). CONCLUSION: Cladribine, both as a single agent as well as in combination with an alkylating cytostatic and corticoids, represents an effective treatment option with favorable toxicity profile for adult patients with multisystem or aggressive multifocal form of Langerhans cell histiocytosis.

Langerhans cell histiocytosis treated with narrow-band ultraviolet B.

A 58-year-old man had widespread multiple erythemas that had been untreated for 20 years. The cutaneous lesions increased in size for a year. Histopathological examination revealed increased number of large, dysplastic, histiocytic cells in the dermis; most of these cells tested positive for Langelin, CD1a and S-100 staining. The patient was diagnosed with Langerhans cell histiocytosis (LCH) and treated with narrow-band ultraviolet B (NB-UVB) radiation. The erythema improved after treatment, but the tumor remained. Therefore, the tumor was surgically excised. NB-UVB therapy might be effective for the treatment of superficial lesions, but not tumoral lesions of LCH.