Rosai-Dorfman-Destombes disease (RDD) is a rare non–Langerhans cell histiocytosis characterized by accumulation of activated histiocytes within affected tissues. RDD, which now belongs to the R group ...of the 2016 revised histiocytosis classification, is a widely heterogeneous entity with a range of clinical phenotypes occurring in isolation or in association with autoimmune or malignant diseases. Recent studies have found NRAS, KRAS, MAP2K1, and ARAF mutations in lesional tissues, raising the possibility of a clonal origin in some forms of RDD. More than 1000 reports have been published in the English literature; however, there is a lack of consensus regarding approach for the clinical management of RDD. Although in most cases RDD can be observed or treated with local therapies, some patients with refractory or multifocal disease experience morbidity and mortality. Here we provide the first consensus multidisciplinary recommendations for the diagnosis and management of RDD. These recommendations were discussed at the 32nd Histiocyte Society Meeting by an international group of academic clinicians and pathologists with expertise in RDD. We include guidelines for clinical, laboratory, pathologic, and radiographic evaluation of patients with RDD together with treatment recommendations based on clinical experience and review of the literature.
The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 ...different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.
Histiocytoses are rare disorders of unknown origin with highly heterogeneous prognosis. BRAFV600E gain-of-function mutations have been observed in 57% of cases of Langerhans cell histiocytosis (LCH) ...and 54% of cases of Erdheim-Chester disease (ECD), but not in other types of histiocytoses. Targeted therapy with an inhibitor of mutated BRAF (vemurafenib) improves survival of patients with melanoma. Here, we report vemurafenib treatment of 3 patients with multisystemic and refractory ECD carrying the BRAFV600E mutation; 2 also had skin or lymph node LCH involvement. The patients were assessed clinically, biologically (CRP values), histologically (skin biopsy), and morphologically (positron emission tomography PET, computed tomography and magnetic resonance imaging). For all patients, vemurafenib treatment led to substantial and rapid clinical and biologic improvement, and the tumor response was confirmed by PET, computed tomography, and/or magnetic resonance imaging 1 month after treatment initiation. For the first patient treated, the PET response increased between months 1 and 4 of treatment. The treatment remained effective after 4 months of follow-up although persistent disease activity was still observed. Treatment with vemurafenib, a newly approved BRAF inhibitor, should be considered for patients with severe and refractory BRAFV600E histiocytoses, particularly when the disease is life-threatening.
•Treatment with vemurafenib induced a dramatic response in 3 patients with histiocytosis harboring BRAF V600E mutations.•Tumor response was observed in both Erdheim-Chester disease and Langerhans cell histiocytosis.
Off-label use of vemurafenib (VMF) to treat
mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated.
Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They ...were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events version 4.3) and therapeutic responses according to Disease Activity Score.
LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 (
< .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood
allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment;
< .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the
clone.
VMF seemed safe and effective in children with refractory
-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a genetic disease characterized by neutropenia, lymphopenia, susceptibility to infections, and myelokathexis, which ...describes degenerative changes of mature neutrophils and hyperplasia of bone marrow myeloid cells. Some patients present with hypogammaglobulinemia and/or refractory warts of skin and genitalia. Congenital cardiac defects constitute uncommon manifestations of the disease. The disorder, which is inherited as an autosomal dominant trait, is caused by heterozygous mutations of the chemokine receptor CXCR4. These mutations lead to an increased sensitivity of neutrophils and lymphocytes to the unique ligand CXCL12 and to an increased accumulation of mature neutrophils in the bone marrow. Despite greatly improved knowledge of the disease, therapeutic choices are insufficient to prevent some of the disease outcomes, such as development of bronchiectasis, anogenital dysplasia, or invasive cancer. The available therapeutic measures aimed at preventing the risk for infection in WHIM patients are discussed. We critically evaluate the diagnostic criteria of WHIM syndrome, particularly when WHIM syndrome should be suspected in patients with congenital neutropenia and lymphopenia despite the absence of hypogammaglobulinemia and/or warts. Finally, we discuss recent results of trials evaluating plerixafor, a selective antagonist of CXCR4, as a mechanism-oriented strategy for treatment of WHIM patients.
Summary Histiocytoses are disorders characterised by inflammation and the accumulation of cells derived from the monocyte and macrophage lineages, which results in tissue damage. Although they are ...often considered rare disorders with protean clinical manifestations, considerable advances in the understanding of their genetics have led to increased clinical recognition of these conditions, and fuelled further insights into their pathogenesis. In this Review, we describe insights into the cells of origin, molecular pathology, clinical features, and treatment strategies for some of the most common histiocytic disorders, including Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease. With the discovery of recurrent mutations affecting the mitogen-activated protein kinase and mTOR–AKT pathways in some of these histiocytoses, our understanding of these diseases has now evolved from the concept of a primary inflammatory condition to that of a clonal neoplastic disease. This understanding has led to the development of effective mechanism-based therapeutic strategies for patients with histiocytic diseases.
Erdheim-Chester disease (ECD) is a rare histiocytic disorder that is challenging to diagnose and treat. We performed molecular analysis of BRAF in the largest cohort of ECD patients studied to date ...followed by N/KRAS, PIK3CA, and AKT1 mutational analysis in BRAF wild-type patients. Forty-six of 80 (57.5%) of patients were BRAFV600E-mutant. NRAS mutations were detected in 3 of 17 ECD BRAFV600E wild-type patients. PIK3CA mutations (p.E542K, p.E545K, p.A1046T, and p.H1047R) were detected in 7 of 55 patients, 4 of whom also had BRAF mutations. Mutant NRAS was present in peripheral blood CD14+ cells, but not lymphoid cells, from an NRASQ61R mutant patient. Our results underscore the central role of RAS-RAF-MEK-ERK activation in ECD and identify an important role of activation of RAS-PI3K-AKT signaling in ECD. These results provide a rationale for targeting mutant RAS or PI3K/AKT/mTOR signaling in the subset of ECD patients with NRAS or PIK3CA mutations.
•PIK3CA and NRAS mutations are recurrent in BRAFV600E wild-type ECD patients.•57.5% (46/80) of ECD patients have a BRAFV600E mutation, and an additional 10.9% and 3.7% have PIK3CA and NRAS mutations, respectively.
Langerhans cell histiocytosis (LCH)-III tested risk-adjusted, intensified, longer treatment of multisystem LCH (MS-LCH), for which optimal therapy has been elusive. Stratified by risk organ ...involvement (high RO+ or low RO– risk groups), >400 patients were randomized. RO+ patients received 1 to 2 six-week courses of vinblastine+prednisone (Arm A) or vinblastine+prednisone+methotrexate (Arm B). Response triggered milder continuation therapy with the same combinations, plus 6-mercaptopurine, for 12 months total treatment. 6/12-week response rates (mean, 71%) and 5-year survival (84%) and reactivation rates (27%) were similar in both arms. Notably, historical comparisons revealed survival superior to that of identically stratified RO+ patients treated for 6 months in predecessor trials LCH-I (62%) or LCH-II (69%, P < .001), and lower 5-year reactivation rates than in LCH-I (55%) or LCH-II (44%, P < .001). RO– patients received vinblastine+prednisone throughout. Response by 6 weeks triggered randomization to 6 or 12 months total treatment. Significantly lower 5-year reactivation rates characterized the 12-month Arm D (37%) compared with 6-month Arm C (54%, P = .03) or to 6-month schedules in LCH-I (52%) and LCH-II (48%, P < .001). Thus, prolonging treatment decreased RO– patient reactivations in LCH-III, and although methotrexate added no benefit, RO+ patient survival and reactivation rates have substantially improved in the 3 sequential trials. (Trial No. NCT00276757 www.ClinicalTrials.gov).
• Reactivations of multisystem Langerhans cell histiocytosis (MS-LCH) are reduced by prolonging initial chemotherapy.• The previously high mortality of high-risk (risk-organ–positive) MS-LCH in children has been markedly reduced.
Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and ...non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAF(V600E) mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAF(V600E)-wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAF(V600E)-wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders.
We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders.
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