Risk Organ Involvement Research Articles

Clinical characteristics and outcomes of Langerhans cell histiocytosis at a single institution in Thailand: a 20-year retrospective study.

Langerhans cell histiocytosis (LCH) is a rare disease characterized by the various systems involved and clinical manifestations with a wide range of symptoms. To describe clinical characteristics, imaging, treatment, and outcomes of pediatric LCH at Phramongkutklao Hospital, Bangkok, Thailand. We conducted a 20-year retrospective review of the medical records of patients diagnosed with LCH from birth to 21 years old from January 1, 1997, to December 31, 2016. In all, 14 patients with median age of 2.5 years were studied. Six (43%) patients had single-system (SS) LCH. Five patients (63%) with multisystem (MS) LCH (n = 8. 57%) had risk-organ involvement (RO+). All patients had plain X-ray imaging of their skull with 11 (79%) showing abnormal findings. Tc-99m bone imaging and fluorodeoxyglucose F18 (FDG) positron emission tomography (PET)-computed tomography (CT) demonstrated abnormal findings in 8 (89%) and 4 (29%) patients, respectively. The 5-year event-free survival (EFS) for patients with RO+ MS-LCH was less than that for those without risk-organ involvement (RO-) MS-LCH and SS-LCH (20% vs. 100%, P = 0.005). Hematological dysfunction, hypoalbuminemia, and conjugated hyperbilirubinemia may be worse prognostic factors for RO+ MS-LCH. FDG-PET-CT might have a greater accuracy to detect LCH disease than conventional plain X-ray and Tc-99m bone imaging. RO+ MS-LCH has been encountered with relapse and poor outcomes. Hematopoietic involvement, hypoalbuminemia, and conjugated hyperbilirubinemia may be worse prognostic factors for RO+ MS-LCH.

Additive Prognostic Impact of Gastrointestinal Involvement in Severe Multisystem Langerhans Cell Histiocytosis

To evaluate the prognostic impact of gastrointestinal involvement on the survival of children with Langerhans cell histiocytosis(GI-LCH) registered with the international clinical trials of the Histiocyte Society. This was a retrospective analysis of 2414 pediatric patients registered onto the consecutive trials DAL-HX 83, DAL-HX 90, LCH-I, LCH-II, and LCH-III. Among the 1289 patients with single-system LCH, there was no single case confined to the GI tract; 114 of 1125 (10%) patients with multisystem LCH (MS-LCH) had GI-LCH at initial presentation. GI-LCH was significantly more common in children aged <2years at diagnosis (13% vs 6% in those aged >2years; P<.001) and in those with risk organ involvement (15% vs 6% in those without risk organ involvement; P<.001). The 5-year overall survival (OS) in patients without risk organ involvement was excellent irrespective of GI disease (98% vs 97% in patients with GI-LCH; P=.789). In patients with risk organ involvement, the 5-year OS was 51% in 70 patients with GI-LCH vs 72% in 394 patients without GI-LCH (P<.001). GI-LCH has an additive unfavorable prognostic impact in children with MS-LCH and risk organ involvement. The emerding need for more intensive or alternative treatments mandates prospective evaluation.

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Series and Literature Review.

Langerhans cell histiocytosis (LCH) is characterized pathologically by langerin-positive (CD207+) dendritic cell proliferation and is considered by some as a myeloid neoplastic disorder. Hemophagocytic lymphohistiocytosis (HLH) is associated with immune dysregulation characterized by the accumulation of activated macrophages and hypercytokinemia. However, these 2 histiocytosis rarely coexist. Currently, the etiology, risk factors, optimal therapy, and outcomes of LCH-HLH remain unclear. We reviewed the medical records of 7 LCH-HLH patients from our hospital and analyzed 50 LCH-HLH patients reported in scientific literature. The median age of LCH onset of these 57 LCH-HLH patients was 1 year, and 91% (52/57) of patients diagnosed as LCH were less than 2 years old. Fifty-six LCH-HLH patients belonged to the multisystem LCH category and 84% (47/56) patients had risk-organ involvement. Twenty-three LCH-HLH patients were complicated with infection and 3 patients had a primary pathogenic mutation of HLH. Overall, 90% of LCH patients developed HLH at the diagnosis or during chemotherapy. Of the 57 LCH-HLH patients, 15 died. Multisystem LCH patients with risk-organ involvement under 2 years old were most likely to develop HLH when complicated with infection at diagnosis or during chemotherapy. Identifying LCH-HLH patients during early stages and treating them with prompt chemotherapy, hematopoietic stem cell transplantation, or supportive therapies are important for better survival.

Overview of Langerhans Cell Histiocytosis among Children

Aim: To analyze clinical manifestations, course and outcome of Langerhans Cell Histiocytosis in children in resource limited settings lacking salvage therapy. Study design: Observational retrospective study Place and duration of study: Department of Haematology/Oncology, The Children’s Hospital, Lahore Pakistan from 1st January 2011 to 31st December 2018. Methodology: Sixty-five patients with age range from&lt;1 to 8 years included analysing their age, gender, clinical classification, course of therapy and outcome. The major treatment was composed of either prednisolone and vinblastine or cytarabine pulses. Results: There were 59% males and 41% females. Forty-seven (72%) patients presented with multi system-LCH with 49% Risk Organ involvement. Most of them 42 (65%) had bone lesions while 15patients (23%) presented with central nervous system involvement. Forty patients (61%) have completed treatment, 11(17%) left against medical advice and 12(18%)patients expired due to progressive disease and worsening infection. Only 2 patients were put on palliation with progressive brain parenchyma disease. 22 patients (34%) had reactivations of disease requiring therapy for more than one-year (p-value=0.06), while 15 (23%) patients received two cycles of initiation therapy before continuation therapy started. The treatment initiated &gt;6 months after the onset of symptoms in 48 (74%) patients. Conclusion: Early diagnosis and timely initiation of therapy are of utmost importance to reduce mortality and morbidity. There is a dire need of social support to reduce treatment abandonment in low-middle-income countries LMIC. Keywords: Paediatric Langerhans cell histiocytosis, Resource-limited settings, Delayed diagnosis, Abandonment

Phenotypes and prognostic factors in adults with Langerhans cell histiocytosis.

7049 Background: Langerhans cell histiocytosis (LCH) can manifest as single system (SS) disease, multisystem (MS) disease, or pulmonary LCH (smoking-related). There is a paucity of data on prognostic factors including risk organ (RO) involvement (liver, spleen, and bone marrow) in adult LCH, which we sought to address in this study. Methods: Single-center retrospective study of patients ≥18y diagnosed with LCH from 1998 to 2020. Univariate and multivariate analyses for progression free survival (PFS) and overall survival (OS) were conducted using age, sex, organ involvement, LCH subtype, year of diagnosis, BRAF V600E status, and treatments. Results: We included 219 patients with LCH; median age 43y (range 19-88), females 51%, SS unifocal (23%), SS multifocal (6%), pulmonary (31%) and MS (40%). Commonly involved organs included lung (53%), bone (42%), skin (24%), pituitary (16%), and CNS (12%). BRAF V600E was positive in 40/88 (46%). Median follow-up duration was 6.1y (95% CI, 5.1- 7.1). On univariate analysis, factors associated with worse PFS were bone LCH, RO involvement, multifocal/MS LCH, and radiation therapy alone; those with worse OS included RO involvement, MS disease, BRAF V600E+, and age ≥45y at diagnosis. In multivariate analysis, BRAF V600E and age ≥45y at diagnosis were associated with worse mortality (Table). Median PFS was not reached (NR-NR) for SS unifocal LCH, 5mo (0-12.7) for SS multifocal LCH, 110mo (84.7-135.3) for pulmonary LCH, and 27mo (17.2-36.8) for MS LCH. 5-year OS was 97.4% for SS unifocal LCH, 100% for SS multifocal LCH, 96.1% for pulmonary LCH, and 79.9% for MS LCH. 41 (18.7%) developed a second primary malignancy (SPM), of which 11 were hematologic neoplasms. There was a trend towards a higher prevalence of SPMs in patients with BRAF V600E (28% vs. 17%; p = 0.22). Conclusions: In our large single-center study, PFS for multifocal and MS LCH was worse than SS unifocal or pulmonary LCH. RO involvement was not associated with outcomes in multivariate analysis. Overall prognosis was excellent for all subtypes except MS LCH. BRAF V600E and older age were associated with worse OS. The prevalence of SPMs was very high and needs to be explored further.[Table: see text]

BRAFV600E frequency and impact on outcomes in adults with langerhans cell histiocytosis.

7050 Background: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm manifesting as unifocal, multifocal, multisystem (MS) or pulmonary LCH (smoking-related). In pediatric LCH, somatic BRAFV600E prevalence is reported at 55-70%, and associated with increased risk of multisystem disease and early treatment failure. Our aim was to describe the prevalence of BRAFV600E mutation and evaluate its association with clinical manifestations and outcomes in adults with LCH. Methods: A retrospective review of adult patients diagnosed with LCH consecutively seen at Mayo Clinic from 2011 to 2020 was performed.Evaluation of association of BRAFV600E mutational status and clinical factors was conducted by the Chi-square test for independence. Progression-free survival (PFS) and overall survival (OS) were analyzed via the Kaplan Meier method and compared with the log-rank test to assess the effect of BRAFV600E. Results: Of the total LCH cohort ( n= 128), 88 patients with available BRAFV600E results were included in the study. Median age at diagnosis was 41y (range 19 - 88); 52.3% were male. 40 (45.5%) patients had a BRAFV600E mutation. Increasing age was associated with BRAFV600E (10-year increase OR 1.42, 95%CI 1.07-1.89; p= 0.017). No correlation was observed between BRAFV600E status and site of disease, risk organ (RO: liver, spleen, marrow) involvement, or MS disease. Patients with BRAFV600E were 4 times more likely to receive targeted therapy ( BRAF inhibitor) than non- BRAFV600E patients ( p= 0.018). After a median follow up of 46 mo (95% CI 30.8-61.2), PFS was similar between BRAFV600E and non- BRAFV600E patients ( p= 0.167). However, patients with BRAFV600E had a worse 3-year OS compared with non- BRAFV600E patients (84% vs. 97.1%, p= 0.027). Patients who died had a significantly higher age at LCH diagnosis (median 62 vs. 38 years; p= 0.0002). Conclusions: In our cohort of adults with LCH, BRAFV600E was less frequent than reported in pediatric literature and was associated with worse OS. The frequency of BRAFV600E was positively correlated with increasing age. Contrary to reports in pediatric LCH, there were no significant associations between BRAFV600E and high-risk or multisystem disease.[Table: see text]

Immune Microenvironment in Langerhans Cell Histiocytosis: Potential Prognostic Indicators.

In this study, the immune microenvironment in Langerhans cell histiocytosis (LCH) was characterized to determine if immune indices are predictive of severity. Serum samples from 54 treatment-naïve patients were analyzed quantitatively for inflammatory cytokines and immunoglobulins before and after the induction of chemotherapy. The initial serum sIL-2R, TNF-α, and IL-10 of untreated LCH patients with risk organ involvement (RO+) were significantly higher than those with single-system (SS) involvement. LCH patients with hematologic involvement exhibited a significantly higher sIL-2R, TNF-α, IL-10, and IL-1β expression, as compared to the group without involvement. sIL-2R, TNF-α, and IL-10 were increased in patients with liver or spleen involvement. Th cells have decreased in the liver+ and spleen+ group, and Ts cells were significantly decreased in non-response group after induction chemotherapy. The serum level of immune indices represents, to some extent, the severity of the disease. Pertinent laboratory inspections can be used to improve risk stratification and guide immunotherapy.

A study of pathological characteristics and BRAF V600E status in Langerhans cell histiocytosis of Vietnamese children.

BackgroundLangerhans cell histiocytosis (LCH) is more common in children than adults and involves many organs. In children, the BRAF V600E mutation is associated with recurrent and high-risk LCH.MethodsWe collected paraffin blocks of 94 pediatric LCH patients to detect BRAF_V600E mutation by sequencing. The relationship between BRAF V600E status and clinicopathological parameters were also critically analyzed.ResultsBRAF V600E mutation exon 15 was detected in 45 cases (47.9%). Multiple systems LCH showed a significantly higher BRAF_V600E mutation rate than a single system (p=.001). No statistical significance was evident for other clinical characteristics such as age, sex, location, risk organs involvement, and CD1a expression.ConclusionsIn Vietnamese LCH children, the proportion of BRAF V600E mutational status was relatively high and related to multiple systems.

Long-term outcome, clinical course and treatment approaches of paediatric langerhans cell histiocytosis: A greek reference centre report.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with diverse clinical behaviour. In this article, we studied the clinical course, management and long-term outcomes of a paediatric cohort treated by our reference centre. We retrospectively studied 66 children with LCH, consecutively diagnosed by a Greek reference centre from 1974 to 2020. The patients had a median age of 3.9 (range 0.0-15.9)years, 39 and 6 patients were diagnosed with unifocal or multifocal single system disease and 14 and 7 had multisystem disease with or without risk organ involvement. No late occurrence of clinical neurodegenerative disease or diabetes insipidus were observed at a median follow-up period of 4.1 (range 0.5-27.7) years. The 10-year event-free survival and overall survival were 65.0% and 90.3% and improved significantly over a 45-year period. Survival was superior in single system than multisystem cases. BRAF V600E mutation was found in 8/14 tested patients. Reactivation occurred in 12/66 patients (18.2%); 11 achieved remission and one patient died after a second relapse. LCH survival rates significantly increased in our cohort over time. Reactivation occurred in 18.2% patients, but no late neurodegeneration was found. The prognostic value of single system disease status vs. multisystem LCH was confirmed.

Clinical manifestations of Langerhans cell histiocytosis with multisystem involvement in 53 children

Objective: To analyze the clinical characteristics and long-term outcome of Langerhans cell histiocytosis with multisystem involvement (MS-LCH) in children, and to evaluate the efficacy of modified DAL-HX83/90 protocol. Methods: This retrospective study included 53 patients with MS-LCH admitted to the Department of Pediatric Hematology and Oncology, First Affiliated Hospital of Zhengzhou University from January 2011 to May 2019. Modified DAL-HX83/90 protocol was used in all patients as an initial treatment. The patients were divided into the group with (RO+) or without (RO-) risk organ involvement. The RO+group was further divided into two groups, as RO+Ⅰ group (lung involvement only) and RO+Ⅱ group (extra-pulmonary, with or without lung involvement). The clinical characteristics and the long-term outcome were summarized. Event-free survival (EFS) and overall survival (OS) curves were analyzed with Kaplan-Meier method. Univariate and multivariate analysis of prognostic factors including age, sex, risk organ involvement and response to 6-week induction were analyzed with Log-Rank test and Cox proportional hazards models. Results: Among the 53 children with MS-LCH, 34 were male and 19 were female. The age of onset was 21 months (3 months-13 years). There 22 were in RO+group, with 12 in RO+Ⅰ group and 10 in RO+Ⅱ group, and 31 in RO-group. The follow-up period was 51 (12-144) months. The overall response rate of 6-week induction was 89% (47/53), and the recurrence rate was 30% (16/53). The 5-year EFS and OS were (67±6) % and (83±5) %, respectively. Univariate analysis showed that the 5-year EFS and OS of patients who responded well to 6-week induction chemotherapy were significantly higher than those who had no response ((76±6) % vs. 0, (88±4) % vs. (41±22) %, χ2 = 34.743, 10.608, both P<0.05). The 5-year EFS and OS of RO-group were significantly higher than that of RO+group ((80±7) % vs. (49±10) %, (93±4) % vs. (70±10) %, χ2=6.022, 4.793, both P<0.05). And the 5-year EFS of RO+Ⅰ group was significantly higher than that of RO+Ⅱ group ((83±10) % vs. (10±9) %, χ2=9.501, P=0.002). While age and sex were not significantly associated with 5-year EFS and OS (all P>0.05). Cox proportional hazard regression model showed that response to 6-week induction chemotherapy was the independent risk factor for EFS (HR=13.114, 95%CI 3.759-45.742, P<0.01) and OS (HR=7.748, 95%CI 1.542-38.920, P=0.013). Conclusions: Most of the children without risk organ involvement treated with modified DAL-HX83/90 protocol could achieve long-term survival. However, the children involved liver, spleen, or hematopoietic system had a high risk of disease progression and recurrence.

Clinical and prognostic characteristics of 95 cases of Langerhans cell histiocytosis in children: a single-institute experience from 2013 to 2020

Background This study aimed to understand the clinical characteristics and outcomes of children with Langerhans cell histiocytosis (LCH) in China. Methods We conducted a retrospective study of 95 paediatric patients with LCH in West China Second University Hospital of Sichuan University between July 2013 and August 2020. Results The onset age of multisystem LCH (MS-LCH) patients with risk organ (RO) involvement was younger than that of MS-LCH without RO involvement (p = .002) and single system LCH (p < .001) patients; bone was the most frequently involved organ, followed by the skin. Of all, the BRAF-V600E mutation was detected in 48 out of 84 patients who underwent gene analysis. Additionally, in our study, BRAF p.N486_T491 > K, BRAF p.L485_P490delinsF, BRAF p.R506_K507insLLR, ARAF p.Q349_F351delinsL and MAP2K1 p.Q58_E62del were known mutations in the mitogen-activated protein kinase (MAPK) pathway. The BRAF-V600E genotype in the tissue and plasma prior to therapy were detected in 16 patients, and the concordance was only 37.5% (6/16). According to the modified LCH-III-based-protocol, JLSG-02 protocol chemotherapy, and vemurafenib, the estimated five-year overall survival, event-free survival (EFS) and cumulative reactivation rates of 95 patients were 98.8%, 74.6% and 24.5%, respectively. The EFS rate in good responders was better than that in poor responders at 12-week (HR = 0.022, 95%CI 0.002–0.231, p = .002), and EFS was not affected by age, RO involvement or BRAF-V600E mutation. Regarding sequelae, nine patients had central diabetes insipidus and two had growth retardation. Conclusions In this study, LCH was a highly heterogeneous disease characterized molecularly by MAPK-pathway activating mutations. Vincristine, prednisone and cytarabine-based chemotherapy combined with vemurafenib improved the prognosis of childhood LCH. In future, prospective clinical trials and novel therapeutic strategies should be developed to improve outcomes in paediatric patients with LCH. KEY MESSAGE Children with Langerhans cell histiocytosis in China present highly heterogeneous clinical characteristics, with up to 60% of cases harbouring mutations in MAPK pathway. Treatment response at 12-week is associated with EFS in our study. Vincristine, prednisone and cytarabine-based chemotherapy combined with vemurafenib improved the prognosis of Chinese childhood LCH, but the reactivation rate is still high.

The Clinical and Laboratory Characteristics of Adult Langerhans Cell Histiocytosis Patients and the Influencing Factors of Prognosis

To observe the clinical and laboratory characteristics of adult Langerhans cell histiocytosis(LCH) patients and to analyze the influencing factors of its prognosis. The clinical and laboratory charac-teristics of 38 adult LCH patients treated in our hospital from January 2010 to August 2019 were retrospective analyzed, and the clinical prognosis of the patients was analyzed. The median age of 38 patients was 41 (21-65) years old, and the ratio of male and female was about 2∶1. Among 38 patients, 44.7% (17/38) were involved in multiple systems, and 31.6% (12/38) were involved in high-risk organs (including liver, lung, hematopoietic system or spleen). The bone involvement was the most common (21/38, 55.3%), and the most common clinical symptom was pain (19/38, 50.0%). The result of laboratory showed that anemia (4/38，10.5%), thrombocytopenia (1/38，2.6%), neutropenia (2/38，5.3%), lymphopenia (6/38，15.8%), monocytosis (11/38，28.9%), C-reactive protein increasing (6/21，28.6%), erythrocyte sedimentation rate increasing (10/18, 55.3%), and ferritin protein increasing (9/17, 55.3%). The median follow-up time was 53 months, and a total of 5 patients were died. The 10-year overall survival rate of patients with single-system involvement was 100%, which was significantly higher than that of patients with multiple-system involvement (70.1%) (P=0.0078). The prognosis of patients without risk-organ involvement was better than that of patients with risk-organ involvement (10-year overall survival rate: 100% vs 60.6%) (P=0.0007). Further analysis showed that in addition to multiple-system involvement and risk-organ involvement, the increase of peripheral blood monocyte cells and the increase of ferritin protein were also associated with poorer prognosis of the patients. The multiple system involve-ment and risk-organ involvement, the increasing of monocyte cells and the increasing of ferritin protein were the independent risk factors of adult LCH patients.

Cutaneous-group histiocytoses associated with myeloid malignancies: A systematic review of 102 cases.

Histiocytoses are haematological disorders of bone marrow origin that share many biological and clinical features with haematological neoplasms. The association between histiocytoses of the cutaneous-group and myeloid malignancies is a poorly investigated topic of high biological and clinical impact. We performed a systematic review of the scientific literature, compliant with PRISMA guidelines, to unravel the clinical and pathological features of this intriguing association. We gathered and analysed 102 patients. Most were children with generalised cutaneous eruptions and displayed risk organ involvement (i.e. bone marrow, spleen, liver). Interestingly, all these features are uncommonly encountered in C-group histiocytosis not associated with haematological neoplasms. Our review shows that generalised eruptions and risk organ involvement in cutaneous-group histiocytosis should raise a suspicion for a concomitant myeloid neoplasm both in children and in adults and warrant further investigations. A rapid recognition of this association is required to start a prompt and effective therapeutic management given the aggressive behaviour of the associated myeloid neoplasm in most instances.

Combination of Neoadjuvant Therapy and Liver Transplantation in Pediatric Multisystem Langerhans Cell Histiocytosis With Liver Involvement.

Background: Langerhans cell histiocytosis (LCH) is characterized by misguided myeloid differentiation, whose prognosis was poor with involvement of risk organs. Remaining issues include how to improve the outcomes of patients with risk-organ involvement.Methods: A retrospective study was conducted in Renji Hospital exploring the effects of neoadjuvant therapy in combination with pediatric liver transplantation (LT) for LCH patients based on data collected between October 2006 and October 2019.Results: We presented here five cases of multisystem LCH patients underwent systemic chemotherapy to control active lesions, followed by LT to treat end-stage liver diseases. Manifestations before LT included elevated transaminase levels (n = 5, 100%), jaundice (n = 4, 80%), ascites (n = 3, 60%), and variceal hemorrhage (n = 1, 20%). Three patients underwent orthotopic liver transplantation (OLT) and two underwent living donor liver transplantation (LDLT). Until December 2019, median follow-up time was 32 months (range, 2–67 months). Liver functions significantly improved compared with pre-operative conditions. One patient had perioperative hepatic artery complications and one patient had a recurrence in the lung. EBV infection occurred in four (80%) patients and CMV infection occurred in one (20%). There was one case of drug-induced liver injury diagnosed on biopsy 13 months after LT. None underwent re-transplantation and there were no rejection or portal vein and biliary complications.Conclusion: Combination of neoadjuvant therapy and LT is an effective paradigm in treatment of multisystem LCH with severe liver dysfunction. With advances in chemotherapy regimen for multisystem LCH and LT surgery, perspectives on prognosis for LCH children are promising.

Adult Langerhans cell histiocytosis presenting with multisystem involvement and sarcomatoid features: a case report

BackgroundLangerhans cell tumors are rare clonal disorders characterized by neoplastic proliferation of dendritic cells that can be further classified into the subtypes Langerhans cell histiocytosis and Langerhans cell sarcoma, which are rare neoplasms exhibiting aggressive features and a poor prognosis. In addition to illustrating the refractoriness and poor outcomes of multisystem Langerhans cell histiocytosis in adults, specific events in this case highlight important characteristics of disease biology that warrant detailed discussion and exposition to a wider audience.Case presentationWe describe the case of a 42-year-old Caucasian man with Langerhans cell histiocytosis diagnosed from a lesion on the left arm that presented with constitutional symptoms, early satiety, and weight loss. Esophagogastroduodenoscopy showed extensive esophageal and duodenal involvement by Langerhans cell histiocytosis with features of Langerhans cell sarcoma. He was initially treated for Langerhans cell histiocytosis with low doses of cytarabine until he eventually presented clear transformation to acute monoblastic leukemia with complex karyotype that could not be properly controlled, leading eventually to death.ConclusionsLangerhans cell histiocytosis remains an exceedingly rare entity in adults, frequently presenting as multisystem disease with risk organ involvement. Langerhans cell sarcoma represents an aggressive subtype with extremely poor prognosis for which intensive acute myeloid leukemia induction should be strongly considered.

A "Wait-and-See" Approach to Quiescent Single-System Langerhans Cell Histiocytosis to Spare Children From Chemotherapy.

Background: Langerhans Cell Histiocytosis (LCH) is a childhood disorder of histiocytes that is generally treated with systemic chemotherapy. Spontaneous resolution has been previously reported in Single System LCH (SS-LCH), which is less aggressive than multisystem disease. However, there are no clear guidelines on which patients can be safely spared from systemic chemotherapy. Here, we propose a risk stratification framework based on disease quiescence as determined by clinical and biochemical features of inflammation, to identify low risk patients who may be potentially spared from chemotherapy through a conservative “wait-and-see” approach.Methods: Retrospective analysis in a single institution was conducted in children with SS-LCH, comparing features of inflammation and outcomes of those who received chemotherapy vs. those with quiescent disease, who were managed conservatively.Results: Of 44 children with SS-LCH, only patients without risk-organ involvement were considered for conservative management. A “wait-and-see” approach was adopted for patients with quiescent disease as defined by clinical and biochemical evidence of disease activity. Following 2 weeks of watchful observation, decisions were made to either start treatment or continue conservative management. Based on data collected at diagnosis, patients with quiescent disease had a lower mean platelet count 339 × 109/L (95%C.I: 285–393) vs. 482 × 109/L (95% C.I: 420–544) p < 0.01, a lower mean white cell count 9.3 × 109/L (95%C.I: 7.5–11.1) vs. 13.1 × 109/L (95%C.I: 11–15.2) p < 0.01 and lower Erythrocyte-Sedimentation-Rate (ESR) 8.2 mm/h (95%C.I: 5.4–11) vs. 53.7 mm/h (95%C.I: 11–96.3) p = 0.04, suggesting that these are potential biochemical markers of disease activity. Other features of disease quiescence noted were rapid progression, functional disability, presence of a skull depression rather a lump and the lack of fever.Conclusions: Further studies are required to validate our proposed framework to determine disease activity in SS-LCH. Within the limits of this current analysis, it appears that low-risk patients with clinically and biochemically quiescent SS-LCH, may potentially be spared from chemotherapy with good long-term outcomes.

Chest computed tomography findings for a cohort of children with pulmonary Langerhans cell histiocytosis.

This study was undertaken to describe the spectrum of lung computed-tomography (CT) findings in children with pulmonary Langerhans cell histiocytosis (PLCH) and to evaluate for this population the CT-scan nodule and cyst scores proposed by adult pulmonologists at diagnosis and during follow-up. Among 175 children with PLCH identified in the French national population-based Langerhans cell histiocytosis cohort, 60 were retrospectively selected by the availability of CT for a central review by three pediatric radiologists. These 60 patients are representative of childhood PLCH for almost all clinical aspects, except a lower percentage of risk organ involvement (38% vs 54%; P = 0.05). The 60 children's chest CT scans (n = 218) were reviewed. At diagnosis, 63% of them had nodules, 53% had cysts, and 29% had both. The percentages of patients with nodules or cysts increased from diagnosis to peak disease activity, respectively, from 63% to 73% and from 53% to 66%. The costophrenic angle was involved in 71%. Patients with pneumothorax (25%) had a higher median cyst score. Alveolar consolidation was observed in 34%. Patients with low CT-scan nodule and cyst scores had no long-term pulmonary sequelae. Well-known characteristics of adult PLCH (nodules and cysts) were observed in children. The chest CT scores proposed by adult pulmonologists could easily be applied to childhood PLCH. Lesions in children, unlike those in adults, are frequently located near the costophrenic angles. Alveolar consolidation might be considered an atypical feature of childhood PLCH.

Egyptian experience in Langerhans cells histiocytosis: frequent multisystem affection and reactivation rates

Background: Histiocytoses are unique disorders; their clinical presentations vary from self-healing lesions to life-threatening disseminated disease. Objectives: We aimed to evaluate the different clinical presentations, frequency of reactivations, and treatment outcome of Langerhans cell histiocytosis among Egyptian children. Methods: we restrospectively analyzed the data of 37 Langerhans cell histiocytosis patients (LCH) registered at Ain Shams University Children’s Hospital for clinicopathological features, treatment modalities and their outcomes. Results: Twenty seven (73%) of the studied patients with LCH had multisystem disease (MS), 24 (88.9%) of them had risk organ involvement (MS RO+) and only 3 without risk organ (MS RO-). Most of the patients received LCH III protocols. Eleven patients (29.7%) had reactivations with median time till reactivation of 17 months (IQR 5-23).Reactivation rates were 40% and 50% in patients with no evidence of active disease (NAD) and those with active disease better (AD better) at week 6 evaluation respectively (p = 0.71).We report 9 deaths (all had MS RO+, two died after reactivation and 7 had progressive disease. The 5 years EFS and OS were 49.4% and 81.2% respectively. Risk stratification did not significantly affect the EFS or OS (p = 0.64 and p = 0.5 respectively). Conclusion: A high reactivation rate was encountered in children with LCH and MS-RO + irrespective of 6 weeks response to induction therapy. A high mortality in patients with progressive disease necessitates a possible earlier aggressive salvage in such group.

Analysis of the BRAF and MAP2K1 mutations in patients with Langerhans cell histiocytosis in Japan.

In Langerhans cell histiocytosis (LCH), somatic gene mutations in the mitogen-activated protein kinase pathway have been identified in more than 80% of cases in Western countries, in which mutually exclusive BRAF and MAP2K1 mutations are involved. Among them, BRAF V600E mutation is the major contributor (50-60%). In 59 patients (50 children and nine adults) with LCH (not including pulmonary LCH) in Japan, we first screened for BRAF V600E in all patients followed by target sequencing for other gene mutations in 17 of BRAF V600E-negative patients. As a result, BRAF V600E mutation was detected in 27/59 (46%) patients. We also identified BRAF mutations other than V600E in five and MAP2K1 mutations in nine patients. Thus, gene mutations in BRAF or MAP2K1 were identified in 41/44 (93%) of the fully tested patients. Regarding the correlation of clinical features and genotype in pediatric patients, we found that BRAF V600E mutation status was not correlated with sex, age at diagnosis, disease extent, response to first-line therapy, relapse, or CNS-related sequelae. Interestingly, MAP2K1 exon 2 in-frame deletion was related to the risk organ involvement; however, further studies are required to clarify the impact of these gene mutations on the clinical features of patients with LCH.

The combination of methotrexate and cytosine arabinoside in newly diagnosed adult Langerhans cell histiocytosis: a prospective phase II interventional clinical trial

BackgroundLangerhans Cell Histiocytosis (LCH) is a rare disease puzzling both children and adults, however outcome of adult patients is unfavorable. This prospective interventional trial aims to test the efficacy and safety of the combination of methotrexate and cytosine arabinoside in adult LCH patients.MethodA total of 36 patients enrolled diagnosed with LCH and treated in our center from 1st Jan, 2014 to 30th Jun, 2016.ResultNineteen patients underwent the detection of BRAF mutation, with a positive rate of 21.1%. The overall response rate was 100%, only 16.7% achieved complete response. The overall regression rate of osseous lesions was 100%. Regression of central nervous system involvement was also favorable. After a median follow-up of 44 months, the estimated event-free survival was 48.9 months, the overall survival rate was 97.2%. The risk organ involvement showed strong prognostic value, EFS was 34.1 or 54.6 months (p = 0.001) in groups with/without risk organ involvement respectively. Neutropenia and thrombocytopenia were the most common adverse effects.ConclusionThe regimen of methotrexate and cytosine arabinoside (MA) is effective and safe in treating adult LCH patients, and timely preventions may be considered for the high incidence of hematological adverse effects.Trial registrationTrial No. NCT02389400 on Clinicaltrials.gov, registered on 10th Mar. 2015.