Eli L. Diamond

Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease

Erdheim-Chester disease (ECD) is a rare, non-Langerhans histiocytosis. Recent findings suggest that ECD is a clonal disorder, marked by recurrent BRAFV600E mutations in >50% of patients, in which chronic uncontrolled inflammation is an important mediator of disease pathogenesis. Although ∼500 to 550 cases have been described in the literature to date, increased physician awareness has driven a dramatic increase in ECD diagnoses over the last decade. ECD frequently involves multiple organ systems and has historically lacked effective therapies. Given the protean clinical manifestations and the lack of a consensus-derived approach for the management of ECD, we provide here the first multidisciplinary consensus guidelines for the clinical management of ECD. These recommendations were outlined at the First International Medical Symposium for ECD, comprised of a comprehensive group of international academicians with expertise in the pathophysiology and therapy of ECD. Detailed recommendations on the initial clinical, laboratory, and radiographic assessment of ECD patients are presented in addition to treatment recommendations based on critical appraisal of the literature and clinical experience. These formalized consensus descriptions will hopefully facilitate ongoing and future research efforts in this disorder.

Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages

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.

Recurrent RAS and PIK3CA mutations in Erdheim-Chester disease

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.

Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms

UNLABELLED 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. SIGNIFICANCE 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.

Prospective Blinded Study of BRAFV600E Mutation Detection in Cell-Free DNA of Patients with Systemic Histiocytic Disorders

UNLABELLED Patients with Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) have a high frequency of BRAF(V600E) mutations and respond to RAF inhibitors. However, detection of mutations in tissue biopsies is particularly challenging in histiocytoses due to low tumor content and stromal contamination. We applied a droplet-digital PCR assay for quantitative detection of the BRAF(V600E) mutation in plasma and urine cell-free (cf) DNA and performed a prospective, blinded study in 30 patients with ECD/LCH. There was 100% concordance between tissue and urinary cfDNA genotype in treatment-naïve samples. cfDNA analysis facilitated identification of previously undescribed KRAS(G12S)-mutant ECD and dynamically tracked disease burden in patients treated with a variety of therapies. These results indicate that cfDNA BRAF(V600E) mutational analysis in plasma and urine provides a convenient and reliable method of detecting mutational status and can serve as a noninvasive biomarker to monitor response to therapy in LCH and ECD. SIGNIFICANCE Patients with BRAF(V600E)-mutant histiocytic disorders have remarkable responses to RAF inhibition, but mutation detection in tissue in these disorders is challenging. Here, we identify that analysis of plasma and urinary cfDNA provides a reliable method to detect the BRAF(V600E) mutation and monitor response to therapy in these disorders.

Detection of an NRAS mutation in Erdheim-Chester disease

To the editor: In a recent paper in Blood , Haroche et al reported dramatic efficacy of vemurafenib in 3 cases of multisystem and refractory Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis harboring the BRAF V600E mutation.[1][1] The findings of an ∼50% prevalence of BRAF

Mixed glioma with molecular features of composite oligodendroglioma and astrocytoma: a true “oligoastrocytoma”?

been raised as to whether the diagnosis of oligoastrocytoma itself should be jettisoned from future WHO classification schemes [5]. Here, we report the case of a 53-year-old female who was initially diagnosed with a non-enhancing right frontal brain anomaly approximately 4 years prior to subtotal resection at our institution, by which time small punctate areas of enhancement had emerged on post-contrast magnetic resonance imaging. Histopathological examination of the substantial (~4 cm in greatest dimension) resection specimen revealed that the majority of the tumor exhibited the morphological features of low-grade oligodendroglioma, including round, monomorphic nuclei, perinuclear halos, and delicate chicken wire microvasculature (Fig. 1a). Focally, however, the tumor demonstrated higher-grade astrocytic features, including nuclear pleomorphism, in both diffusely infiltrating and densely cellular, mitotically active patterns (Fig. 1f, k). Immunohistochemical staining revealed that both oligodendroglial and astrocytic components expressed IDH1 R132H (Fig. 1b, g). However, nuclear ATRX expression was completely retained in oligodendroglial cells and lost in astrocytic cells (Fig. 1c, h, m). Similarly, p53 staining was weak to absent in oligodendroglial cells and strongly positive in astrocytic cells (Fig. 1d, i, n). Finally, fluorescence in situ hybridization (FISH) revealed widespread 1p/19q codeletion in the oligodendroglial component, but multiple copies of 1p and 19q in the astrocytic component (Fig. 1e, j). Whole-arm 1p/19q codeletion in the oligodendroglial component was confirmed by molecular inversion probe (MIP) array (Fig. 1o). Thus, the astrocytic and oligodendroglial areas of the neoplasm were associated with distinct and non-overlapping molecular alterations characteristic of each tumor lineage in pure form. The patient was subsequently treated with ionizing radiation and temozolomide before experiencing The current World Health Organization (WHO) classification system designates oligoastrocytoma as a diffusely infiltrating glial neoplasm exhibiting morphological features of both astrocytoma and oligodendroglioma [4]. Perhaps not surprisingly, a broad spectrum of diffuse gliomas having varying proportions of oligodendroglial and astrocytic character falls into this diagnostic category, with the classification of each tumor as astrocytoma, oligodendroglioma, or oligoastrocytoma suffering from significant interobserver variability [9]. Recent large-scale molecular profiling efforts [1–3, 10] have emphatically confirmed earlier work [6] indicating that the vast majority of oligoastrocytomas, in addition to harboring mutations in IDH1/2, exhibit the signature genomic abnormalities of either pure oligodendroglioma (1p/19q codeletion, CIC and FUBP1 mutations) or astrocytoma (ATRX mutation, TP53 mutation) with almost complete mutual exclusivity. Moreover, studies to date, including a recent correlative investigation of 43 oligoastrocytomas [8], have failed to demonstrate distinct molecular abnormalities characterizing the astrocytic and oligodendroglial components of individual tumors. From a molecular standpoint then, oligoastrocytomas, as a group, seem to largely consist of tumors having either astrocytoma or oligodendroglioma signatures, and questions have

Rates and risks for late referral to hospice in patients with primary malignant brain tumors

BACKGROUND Primary malignant brain tumors (PMBTs) are devastating malignancies with poor prognosis. Optimizing psychosocial and supportive care is critical, especially in the later stages of disease. METHODS This retrospective cohort study compared early versus late hospice enrollment of PMBT patients admitted to the home hospice program of a large urban, not-for-profit home health care agency between 2009 and 2013. RESULTS Of 160 patients with PMBT followed to death in hospice care, 32 (22.5%) were enrolled within 7 days of death. When compared with patients referred to hospice more than 7 days before death, a greater proportion of those with late referral were bedbound at admission (97.2% vs 61.3%; OR=21.85; 95% CI, 3.42-919.20; P < .001), aphasic (61.1% vs 20.2%; OR = 6.13; 95% CI, 2.59-15.02; P < .001), unresponsive (38.9% vs 4%; OR = 14.76,;95% CI, 4.47-57.98; P < .001), or dyspneic (27.8% vs 9.7%; OR = 21.85; 95% CI, 3.42-10.12; P = .011). In multivariable analysis, male patients who were receiving Medicaid or charitable care and were without a health care proxy were more likely to enroll in hospice within 1 week of death. CONCLUSIONS Late hospice referral in PMBT is common. PMBT patients enrolled late in hospice are severely neurologically debilitated at the time hospice is initiated and therefore may not derive optimal benefit from multidisciplinary hospice care. Men, patients with lower socioeconomic status, and those without a health care proxy may be at risk for late hospice care and may benefit from proactive discussion about end-of-life care in PMBT, but prospective studies are needed.

Vemurafenib for BRAF V600-mutant erdheim-chester disease and langerhans cell histiocytosis analysis of data from the histology-independent, phase 2, open-label VE-BASKET study

Importance The histiocytic neoplasms Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) are highly enriched for BRAF V600 mutations and have been previously shown to be responsive to treatment with vemurafenib, an inhibitor of the BRAF V600 kinase. However, the long-term efficacy and safety of prolonged vemurafenib use in these patients are not defined. Here we analyze the final efficacy and safety data for vemurafenib in patients with ECD and LCH enrolled in the VE-BASKET study. Objective To determine the efficacy and safety of vemurafenib in adults with ECD or LCH enrolled in the VE-BASKET study. Design, Setting, and Participants The VE-BASKET study was an open-label, nonrandomized, multicohort study for patients with nonmelanoma cancers harboring the BRAF V600 mutation. Patients with BRAF V600–mutant ECD or LCH were enrolled in an “other solid tumor” cohort of the VE-BASKET study, and they were enrolled in the present study. Interventions Patients received vemurafenib, 960 mg, twice daily continuously until disease progression, study withdrawal, or occurrence of intolerable adverse effects. Main Outcomes and Measures The primary end point was confirmed objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Secondary end points included progression-free survival (PFS), overall survival (OS), metabolic response by modified positron-emission tomography (PET) Response Criteria in Solid Tumors (PERCIST) using 18F-fluorodeoxyglucose (FDG)-PET/computed tomography (CT), and safety. Results A total of 26 patients from the VE-BASKET trial (22 with ECD, 4 with LCH) were included in the present study (14 women and 12 men; median age, 61 years; age range, 51-74 years). The confirmed ORR was 61.5% (95% CI, 40.6%-79.8%) in the overall cohort and 54.5% (95% CI, 32.2%-75.6%) in patients with ECD. All evaluable patients achieved stable disease or better. The median PFS and OS had not been reached in the overall cohort at study closure despite a median follow-up of 28.8 months; 2-year PFS was 86% (95% CI, 72%-100%), and 2-year OS was 96% (95% CI, 87%-100%). All 15 patients evaluated by FDG-PET/CT achieved a metabolic response, including 12 patients (80%) with a complete metabolic response. The most common adverse events (AEs) in the overall cohort included arthralgia, maculopapular rash, fatigue, alopecia, prolonged QT interval, skin papilloma, and hyperkeratosis. Hypertension and dermatologic AEs occurred at higher rates than those reported in metastatic melanoma. Conclusions and Relevance In this study, vemurafenib had prolonged efficacy in patients with BRAF V600–mutant ECD and LCH and warrants consideration as a new standard of care for these patients.

Histiocytic neoplasms in the era of personalized genomic medicine.

Purpose of reviewSince the discovery of B-Raf proto-oncogene (BRAF) V600E mutations in histiocytic neoplasms, diverse kinase alterations have been uncovered in BRAF V600E-wildtype histiocytoses. The purpose of this review is to outline recent molecular advances in histiocytic neoplasms and discuss their impact on the pathogenesis and treatment of these disorders. Recent findingsActivating kinase alterations discovered in BRAF V600E-wildtype Langerhans (LCH) and non-Langerhans cell histiocytoses (non-LCH) result in constitutive activation of the mitogen-activated protein kinase and/or phosphoinositide 3-kinases-Akt murine thymoma pathways. These kinase alterations include activating mutations in A-Raf proto-oncogene, mitogen-activated protein kinase kinase 1, neuroblastoma rat sarcoma viral oncogene homolog, Kirsten rat sarcoma viral oncogene homolog, and phosphatidylinositol-4,5-bisphosphate 3 kinase, catalytic subunit &agr; kinases in LCH and non-LCH; BRAF, anaplastic lymphoma receptor tyrosine kinase, and neurotrophic tyrosine kinase, receptor type 1 fusions, as well as the Ets variant 3-nuclear receptor coactivator 2 fusion in non-LCH; and mutations in the mitogen-activated protein kinase kinase kinase 1 and Harvey rat sarcoma viral oncogene homolog kinases in LCH and histiocytic sarcoma, respectively. These discoveries have refined the understanding of the histiocytoses as clonal, myeloid neoplasms driven by constitutive mitogen-activated protein kinase signaling and identified molecular therapeutic targets with promising clinical responses to rapidly accelerated fibrosarcoma and mitogen-activated protein kinase kinase inhibition. SummaryGenomic analyses over the last 6 years have identified targetable kinase alterations in BRAF V600E-wildtype histiocytic neoplasms. However, despite this progress, the molecular pathogenesis and therapeutic responsiveness of non-BRAF V600E kinase alterations are still poorly defined in these disorders.