Langerhans Cell Histiocytosis Research Articles

Differential Gene Analysis of Langerhans Cell Histiocytosis and the Significance of MMP1-Targeted Drug Repositioning.

Langerhans cell histiocytosis (LCH) is a rare condition predominantly affecting young children. Activation of the MAPK pathway has offered key new insights into the pathogenesis of LCH; however, the precise mechanisms underlying its occurrence and development are still far from being completely elucidated. There is still a relapse/reactivation rate in patients with multisystem LCH. Therefore, this study aimed to investigate other potential LCH pathophysiologies and prospective therapeutic targets. The gene expression omnibus (GEO) database was used to retrieve gene expression profiles of LCH (GSE16395). Three distinct types of analyses were performed after identifying the common differentially expressed genes (DEGs) in LCH: hub gene identification, functional annotation, module construction, drug repositioning, and expression analysis via immunohistochemistry (IHC). We identified 417 common DEGs and 50 central hub genes. This functional study highlighted the significance of keratinization, skin development, and inflammation. In addition, we predicted new drug candidates (RS2 drugs targeting matrix metalloprotease1, MMP1) that could be used for LCH treatment. Finally, gene-miRNA and gene-TF networks and immune cell infiltration were analyzed for MMP1-related genes. MMP1 expression levels in LCH tissues were validated by IHC. Our study identified the central communal genes and novel drug candidates. These shared pathways and hub genes offer new perspectives on future mechanisms of action and therapeutic targets.

A rare case of multisystemic Langerhans cell histiocytosis in an adult affecting the thyroid gland, skeletal system, and pituitary gland: A case report.

Langerhans cell histiocytosis (LCH) is a rare disorder affecting usually children and rarely adults. The most common site affected is bone. The involvement of the thyroid gland in LCH is extremely rare and it is usually observed in an adult as a multisystemic disease. Adult males presented with anterior neck swelling, and fine needle aspiration cytology (FNAC) diagnosed it as suspicious for malignancy. On frozen sectioning, differential diagnosis was given as non-Hodgkin lymphoma and poorly differentiated malignancy. On immunohistochemistry (IHC), tumor cells were positive for CD1a and S100p. Thus, the final diagnosis offered was LCH-thyroid. The pathogenesis is unclear and believed to be related to immune dysfunction, cytokine mediators, viral infection, smoking, and genetic factors. Due to its rarity, thyroid LCH is often misinterpreted as other common disorders of the thyroid and results in delayed diagnosis. This case highlights the importance of histomorphology and the use of ancillary techniques such as IHC to arrive at a diagnosis in time and hence the treatment.

Clinical features and treatment outcomes of liver involvement in paediatric Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder in children, and liver involvement in LCH is rare. This retrospective study reported the clinical features and prognosis of patients with hepatic LCH. Liver involvement was defined by histopathological findings, liver dysfunction or abnormalities, or ultrasound imaging. A total of 130 patients (14.5%) with hepatic LCH out of 899 in the LCH population were enrolled. Patients with liver involvement had greater frequencies of skin, lung, hearing system, and haematologic system involvement, and hemophagocytic lymphohistiocytosis (P<0.001, 0.001, 0.002, 0.009, and <0.001, respectively). Overall survival and progression-free survival were lower in LCH patients with liver involvement than in those without liver involvement (P<0.001 and <0.001). In patients with liver involvement, the overall survival (OS) and progression-free survival (PFS) rates were lower in patients with cholangitis than in those without cholangitis (P<0.020 and 0.030). For the treatment response, the response rate of hepatic LCH patients to initial first-line therapy (n=89) was 22.5%. However, there was no significant difference in the response rate or recurrence rate between patients who shifted from first-line treatment to second-line treatment (n=29) or to targeted therapy (n=13) (P=0.453 and 1.000). The response rate of hepatic LCH patients who received initial second-line therapy (n=13) was 38.5%. Two of these patients subsequently experienced bone recurrence. The response rate of hepatic LCH patients who received initial targeted therapy (n=16) was 75.0%. Three patients subsequently experienced recurrence, including 2 in the bone and 1 in the liver and skin. A total of 39.3% of patients who received second-line treatment had severe myelosuppression (grade III-IV), and 50.8% had varying degrees of gastrointestinal events, whereas there was no severe toxicity in patients who received first-line treatment and targeted therapy. Four patients underwent liver transplantation because of liver cirrhosis. The patients’ liver disease improved within a follow-up period of 18-79 months. This study demonstrated that LCH with liver involvement, especially cholangitis, indicates a poor prognosis. Targeted therapy provides a good treatment response and less toxicity. However, it may relapse after withdrawal. Liver transplantation is still a reliable salvage option for patients with end-stage liver disease.

A Report of Pediatric Langerhans Cell Histiocytosis in a Hospital-Based Study

Background: The reports of Iranian Pediatric Langerhans Cell Histiocytosis (LCH) are rare and there is no specific survival rate for those cases. Objectives: This study was designed as a hospital-based project for evaluating the epidemiological data and survival rates of the mentioned patients. Methods: This was a cross-sectional descriptive study that enrolled patients younger than 15 years old with approved LCH malignancy. Data was gathered based on a unique questionnaire and analyzed by SPSS Software version 25. Results: There were 32 cases (male/female ratio = 0.88) who were categorized as high risk (n = 18), moderate (n = 9) and low risk (n = 5), respectively. The mean age of patients was 5.1 years and the common chief complaint in them was bone pain, with the skeleton site of involvement. The 5-years overall and event-free survival rates were 93.3% and 72.9%, respectively. Conclusions: The suggestion is to provide a national registry for pediatric LCH followed by designing future projects around affective genes on the treatment response of the mentioned patients. In that way, we can improve the survival rate of these patients and decrease mortality.

Solitary primary intraosseous xanthoma of the mandible in a 15-year-old boy: a case report

BackgroundA xanthoma is a rare bone condition consisting of a predominant collection of lipid-rich, foamy histiocytes. The central xanthoma of the jaws is a unique benign tumor.Case reportA 15-year-old Caucasian male has been presented to our department. He had radiological changes in the area of the left mandibular angle, with an area of diffuse osteolysis of 3.0 cm by 2.0 cm. Computed tomography reveals an area of diffuse osteolysis that starts from the distal root of the lower second molar and reaches the ascending process. A bone biopsy was performed, which revealed a benign proliferative process composed of histiocytic cells involving and infiltrating trabecular bone in a background of loose fibrous connective tissue devoid of any other significant inflammatory infiltrate. The size of the formation was 2.9 cm by 2.0 cm. Immunohistochemical staining for CD68 was strongly positive and negative for S-100 and CD1a. From routine blood tests, cholesterol, triglycerides, and blood sugar are within normal values, which excludes systemic metabolic disease. Subsequent to the surgical intervention, the patient underwent postoperative assessments at intervals of 14, 30, 60 days, and a year later, revealing the absence of any discernible complications during the aforementioned observation periods.ConclusionThe diagnosis of primary xanthoma of the mandible is rare and can often be confused with other histiocytic lesions. A differential diagnosis should be made with nonossifying fibroma and Langerhans cell histiocytosis, as in our case. In these cases, immunohistochemistry with CD 68, S-100, and CD1a, as well as blood parameters, are crucial for the diagnosis.

A case of langerhans cell histiocytosis accompanying hypothalamus, mastoid bone and liver involvement

A case of langerhans cell histiocytosis accompanying hypothalamus, mastoid bone and liver involvement

Langerhans cell histiocytosis presenting spinal cord compression after diabetes insipidus diagnosis: a case report

Langerhans cell histiocytosis presenting spinal cord compression after diabetes insipidus diagnosis: a case report

Langerhans cell histiocytosis: NACHO update on progress, chaos, and opportunity on the path to rational cures.

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts.

Langerhans Cell Histiocytosis in the Sphenoid Wing

Langerhans Cell Histiocytosis (LCH) is a rare and broad-spectrum of disease caused by uncontrolled proliferation of pathologic Langerhans cell resulting in localize and systemic organ infiltration. The clinical presentation can be unspecific and varies between individuals depending on the anatomical location and organ involvement. In view of bony infiltration is the most common in LCH, clinicians have to deal with the challenge of diagnosis dilemmas such as Giant Cell Tumour, Ewing’s sarcoma, osteogenic sarcoma, plasmacytoma, osteomyelitis or bony metastasis, particularly from neuroblastoma. Hence, it requires an excellent multidisciplinary team to establish the diagnosis and start targeted treatment early to prevent fatal complications. The treatment modalities include surgery, immunosuppressive therapy, chemotherapy or in combination. Recently, a seven months old boy presented to our centre with one-week duration of left cheek swelling and left eye proptosis. After detailed clinical evaluation together with imaging and biopsy, the lesion over the bilateral sphenoid and left zygoma were concluded to be Langerhans Cell Histiocytosis (LCH).

Juvenile xanthogranuloma manifesting with LCH-associated neurodegenerative disease-like radiological findings.

Here, we describe two patients with juvenile xanthogranuloma (JXG) manifesting with Langerhans cell histiocytosis (LCH)-associated neurodegenerative disease (ND)-like radiological findings. One patient showed typical radiological abnormalities at onset, which worsened with progressing central nervous system symptoms 7years after LCH-oriented chemotherapy. Another showed spontaneous regression of clinical symptoms, with a transient radiological change 1year after salvage chemotherapy for recurrence of JXG. These data regarding JXG-associated ND will facilitate future investigation of the disease, as well as development of therapeutic interventions.

Exploration of treatment in childhood Langerhans cell histiocytosis based on inflammatory and malignant symptoms: a pilot study

BackgroundMultisystem childhood Langerhans cell histiocytosis (LCH) patients, especially those with risk organ (RO) involved, had not been satisfactorily treated under the international traditional schemes as high incidences of reactivation with late sequelae were largely reported. Over years, we have observed that LCH patients with varied clinical symptoms responded differently to different drugs, suggesting the current grouping strategies based only on the number of organs involved might be inadequate. LCH has been defined as an inflammatory myeloid tumor, thus this study has innovatively divided LCH pediatric patients into inflammatory or malignant symptoms group, and given different intensity treatment regimens to different groups.AimThis clinical study aimed to explore a more appropriate patient grouping system according to the LCH symptom presentations and examine the clinical outcomes of treatment strategies in different groups.MethodsAccording to the clinical manifestations, 37 cases of children were divided into Group A (only inflammatory symptoms) and Group B (malignant symptoms with or without inflammatory symptoms). Patients in Group A and B were initially treated with vindesine (VDS) and methylprednisolone (PSL), and VDS, PSL, pirarubicin (THP) and cyclophosphamide (CTX), respectively. Treatment responses were evaluated six weeks after the induction therapy in all patients, and the criteria were disease status and clinical scores of symptoms.ResultsPre- and post-treatment scores were 1.22 ± 0.547 and 0.00 ± 0.00 in Group A, and 14.79 ± 1.686 and 1.00 ± 1.563 in Group B, respectively. All patients had subsequentlly received maintenance therapy without progressive disease. The 4-year overall survival (OS) rate was 100% in both groups and the 4-year event-free survival (EFS) was 94.4% in Group A and 89.5% in Group B, respectively. There were no obvious adverse events (AE) in Group A, whereas the main AE in Group B were alopecia and non-lethal hematological toxicity.ConclusionStratification according to patients’ clinical symptoms, with low-intensity treatment for inflammatory symptoms (mild manifestations) and intensive treatment with multiple drugs for malignant symptoms (severe manifestations), is a positive exploration that simplifies stratification method, achieves good long-term remission of the disease, and obtains a higher survival rate and quality of life, which seemed to be more appropriate for LCH patients.

Isolated Langerhans cell histiocytosis in the stomach of adults: four-case series and literature review.

Langerhans cell histiocytosis (LCH) of the stomach is rare. Moreover, it is usually found in pediatric patients with systemic diseases and may be associated with a poor prognosis. Solitary gastric LCH in adults is extremely rare and is often misdiagnosed or missed. The aim of our study was to review cases of gastric LCH and explore the characteristics of the disease further. A retrospective study of all patients admitted with solitary gastric LCH was conducted between 2013 and 2023. Clinical manifestations, endoscopic and pathological features, immunophenotypes, and molecular changes were collected from medical records. We examined four cases (one female, three males) of gastric LCH. The affected patients were between 33 and 70 years of age. Endoscopically, three patients presented with a solitary polyp or elevated lesions, whereas one patient showed no abnormalities. Under a microscope, all cases showed abnormal proliferation of histiocytoid cells infiltrating in a nested or sheet-like fashion. The tumor cells were medium-sized, with a slightly eosinophilic cytoplasm, irregular or renal-shaped nuclei, folded nuclear membranes, visible nuclear grooves, and the infiltration of inflammatory cells in the background. Immunohistochemically, all lesions expressed CD1a, S-100, langerin, and cyclinD1. One case showed diffuse BRAF V600E positivity. Follow-up data were available for all patients from 4 to 36 months, and all patients were alive without recurrence or progress at the time of manuscript preparation. Combined with previously reported data, solitary adult gastric LCH is more common in male patients, most of whom are asymptomatic or exhibit only mild gastrointestinal symptoms, with a good prognosis. Endoscopy often reveals solitary polyps or protruding lesions; rare cases may progress to multifocal/multisystem lesions, necessitating long-term close follow-up.

Langerhans Cell Histiocytosis With Unusual Hexagonal Crystals in Addition to Usual Charcot-Leyden Crystals. Report of a Patient With Possible Process of Crystal Formation and Clinical Significance of a "Necrotic" Change.

Langerhans cell histiocytosis is a rare neoplastic disorder characterized by the proliferation of Langerhans cells and often accompanied by eosinophil infiltration. Charcot-Leyden crystals, composed of galectin 10, are occasionally observed in Langerhans cell histiocytosis; however, histological images are rarely reported. We herein present a patient with Langerhans cell histiocytosis with Charcot-Leyden crystals and hexagonal crystals by describing the histologic and immunohistochemical features of a lymph node. A unique distribution of Charcot-Leyden crystals and hexagonal crystals was observed in this patient, shedding light on their possible formation process of the latter. We discuss the biological significance of eosinophilic abscesses in Langerhans cell histiocytosis and propose that these crystals may be linked to extracellular trap-cell death (ETosis). This example challenges the conventional characterization of "necrosis" in Langerhans cell histiocytosis and underscores the importance of recognizing ETosis as a potential mechanism involved in the pathogenesis of Langerhans cell histiocytosis. Further studies are underway to validate significance of these findings in a larger cohort of Langerhans cell histiocytosis patients.

Congenital localized cutaneous Langerhans cell histiocytosis in a Holstein calf.

Distinct solitary dermal nodules, either covered by an alopecic, or sometimes ulcerated, epidermis, were noticed on the head of a stillborn Holstein calf. The head was submitted for autopsy, and the nodules were found to consist of homogeneous, diffuse pale-yellow, soft-tissue masses with distinct margins that elevated the epidermis above the adjacent skin. Histologically, the dermal nodules were well-delineated on the deep margin approaching the cutaneous muscle and consisted of perivascular neoplastic infiltrates of round cells that in some places coalesced into sheets that extended into the dermis and subcutis. Neoplastic cells separated adnexa and collagen. Immunohistochemistry revealed intense tumor cell expression of vimentin, Iba1, E-cadherin, and CD204; expression of CD18 was faint. The masses were diagnosed as Langerhans cell histiocytosis. Congenital cutaneous Langerhans cell histiocytosis has not been reported previously in cattle, to our knowledge, and should be included in the differential diagnosis of congenital nodular skin lesions.

From mutation to management: Advancing Langerhans cell histiocytosis treatment through combination therapies.

The treatment landscape for relapsed Langerhans cell histiocytosis (LCH) is fraught with uncertainty due to a scarcity of data. Karri etal.'s study provides promising evidence that combining MAPK pathway inhibitors with chemotherapy could improve outcomes, even for patients with multiple relapses. Although larger studies are needed, this approach suggests a shift towards more aggressive, potentially curative strategies in the management of LCH. Commentary on: Karri etal. Clinical, radiological and molecular responses to combination chemotherapy with MAPK pathway inhibition in relapsed and refractory Langerhans cell histiocytosis. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19380.

Mixed histiocytic neoplasms: A multicentre series revealing diverse somatic mutations and responses to targeted therapy.

Histiocytic neoplasms are diverse clonal haematopoietic disorders, and clinical disease is mediated by tumorous infiltration as well as uncontrolled systemic inflammation. Individual subtypes include Langerhans cell histiocytosis (LCH), Rosai-Dorfman-Destombes disease (RDD) and Erdheim-Chester disease (ECD), and these have been characterized with respect to clinical phenotypes, driver mutations and treatment paradigms. Less is known about patients with mixed histiocytic neoplasms (MXH), that is two or more coexisting disorders. This international collaboration examined patients with biopsy-proven MXH with respect to component disease subtypes, oncogenic driver mutations and responses to conventional (chemotherapeutic or immunosuppressive) versus targeted (BRAF or MEK inhibitor) therapies. Twenty-seven patients were studied with ECD/LCH (19/27), ECD/RDD (6/27), RDD/LCH (1/27) and ECD/RDD/LCH (1/27). Mutations previously undescribed in MXH were identified, including KRAS, MAP2K2, MAPK3, non-V600-BRAF, RAF1 and a BICD2-BRAF fusion. A repeated-measure generalized estimating equation demonstrated that targeted treatment was statistically significantly (1) more likely to result in a complete response (CR), partial response (PR) or stable disease (SD) (odds ratio [OR]: 17.34, 95% CI: 2.19-137.00, p = 0.007), and (2) less likely to result in progression (OR: 0.08, 95% CI: 0.03-0.23, p < 0.0001). Histiocytic neoplasms represent an entity with underappreciated clinical and molecular diversity, poor responsiveness to conventional therapy and exquisite sensitivity to targeted therapy.

Increased AXLhigh myeloid cells as pathognomonic marker in Langerhans cell histiocytosis and Langerin expression dependence of mTOR inhibition

Langerhans cell histiocytosis (LCH) is characterized by an expansion and accumulation of pathological histiocytes expressing langerin (CD207) and CD1a in different organs under an inflammatory milieu. The origin of pathognomonic precursors of LCH is widely debated, but monocytes and pre dendritic cells (pre-DC) play significant role. Remarkable we found an expansion of AXLhigh cells in the CD11c+ subset of patients with active LCH, which also express the pathognomonic CD207 and CD1a. Moreover, we obtained a monocyte-derived LC-like (mo-LC-like) expressing high levels of AXL when treated with inflammatory cytokine, or plasma of patients with active disease. Intriguingly, inhibiting mTOR pathway at the initial stages of monocyte differentiation to LC-like, fosters the pathognomonic LCH program highly increasing CD207 levels, together with NOTCH1 induction. We define here that AXLhigh could also be taken as a strong pathognomonic marker for LCH, and the release of Langerin and NOTCH1 expression depends on the inhibition of the mTOR pathway.

A rare diagnosis of Langerhans cell histiocytosis made on thyroid histology with coexisting papillary thyroid cancer and AVP deficiency.

A 48-year-old Asian male, presented to the hospital for an elective total thyroidectomy in the context of 6.3 cm thyroid nodule. The fine needle aspiration cytology of the nodule confirmed papillary thyroid cancer (PTC) with some atypical histiocytes. He has a history of idiopathic arginine vasopressin deficiency (AVP-D) and has been taking oral DDAVP 100 µg daily, self-adjusting the dose based on thirst and polyuria. Additionally, he also has a history of recurrent spontaneous pneumothorax. His total thyroidectomy was aborted due to significant intraoperative bleeding, and his admission was further complicated by post-operative hyponatraemic seizure. Thyroid histology revealed the diagnosis of Langerhans cell histiocytosis (LCH), and further investigation with contrast CT demonstrated multi-organ involvement of the thyroid, lungs, and bones. Langerhans cell histiocytosis (LCH) is a condition that can affect one or more organ systems, including the pituitary, where it can present as AVP deficiency. Strict monitoring of fluid balance, as well as serial monitoring of serum sodium, is essential in all patients with AVP-D in the perioperative setting. Iatrogenic hyponatraemic seizure is an uncommon but serious complication of DDAVP treatment in hospitalised patients with AVP-D. DDAVP dosing must be carefully monitored. LCH with multisystem involvement is an important mimic for metastatic conditions, and histological diagnosis is essential to guide treatment and prognosis. Although LCH without bone marrow involvement is unlikely to increase the risk of bleeding, its effect on tissue integrity may make surgery more challenging. BRAF-V600E mutation is an important driver mutation and a potential therapeutic target in the treatment of LCH.

The plasma-soluble CSF1R level is a promising prognostic indicator for pediatric Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare hematologic neoplasm characterized by the clonal proliferation of Langerhans-like cells. Colony-stimulating factor 1 receptor (CSF1R) is a membrane-bound receptor that is highly expressed in LCH cells and tumor-associated macrophages. In this study, a soluble form of CSF1R protein (sCSF1R) was identified by plasma proteome profiling, and its role in evaluating LCH prognosis was explored. We prospectively measured plasma sCSF1R levels in 104 LCH patients and 10 healthy children using ELISA. Plasma sCSF1R levels were greater in LCH patients than in healthy controls (p<.001) and significantly differed among the three disease extents, with the highest level in MS RO+ LCH patients (p<.001). Accordingly, immunofluorescence showed the highest level of membrane-bound CSF1R in MS RO+ patients. Furthermore, the plasma sCSF1R concentration at diagnosis could efficiently predict the prognosis of LCH patients treated with standard first-line treatment (AUC=0.782, p<.001). Notably, dynamic monitoring of sCSF1R levels could predict relapse early in patients receiving BRAF inhibitor treatment. In vitro drug sensitivity data showed that sCSF1R increased resistance to Ara-C in THP-1 cells expressing ectopic BRAF-V600E. Overall, the plasma sCSF1R level at diagnosis and during follow-up is of great clinical importance in pediatric LCH patients.

Langerhans Cell Histiocytosis Following Hodgkin Lymphoma in Adult: A Case Report

Introduction: Langerhans cell histiocytosis (LCH) is a very rare disorder, and usually considered a disease of childhood. It is rarely observed in adults. Its etiopathogenesis remains to be elucidated. One possible etiological cause is a reactive proliferation of Langerhans cells following chemotherapy or radiotherapy for Hodgkin's disease (HD). Eosinophilic granuloma is the benign accumulation of histiocytes located primarily in the bones, but which also affects other organs, including the skin, lungs and lymph nodes. The time interval between LCH occurrence and previous lymphoma is variable. The occurrence of eosinophilic granuloma in a patient with Hodgkin disease has rarely been reported. Objective: This case report aimed to describe the clinic-pathological, histopathological, immunohistochemical and other features of LCH and to analyze LCH clinical features for improving diagnosis and decreasing misdiagnosis rate. Case report: In this report, a 38-year-old female presented with LCH twenty-two months after diagnosis and treatment of nodular sclerosing HD. The patient presented with generalized lymphadenopathy and general weakness. The Langerhans cells diffusely infiltrated in the inguinal lymph node and the tumor cells were positive for CD1a and S-100 expression. The patient received chemotherapy and show complete remission. Conclusion: LCH has a very rare occurrence following HD in adult. The definitive diagnosis depends on pathological biopsy and immunohistochemistry. Although specific therapeutic approach hasn't been well established, combined chemotherapy for multisystem lesions and surgical operation or radiotherapy for unifocal lesions may improve the therapy.