Clinical, Laboratory, and Genetic Features of Erdheim-Chester Disease Patients from Two Reference Centers in a Developing Country

INTRODUCTION: Erdheim-Chester Disease (ECD) is a rare histiocytic neoplasm with a heterogenous clinical course with asymptomatic localized course or systemic compromise involving multiples organs causing significant morbidity and mortality. There are few cohorts published however mainly from North America and Europe. Given the scarcity of data on ECD in Latin America, we have established a local registry in the city of São Paulo to collect clinical and biological material of ECD patients. METHODS: We retrospectively collected clinical data on biopsy-proven ECD patients diagnosed and treated at two reference centers for histiocytic disorders (Hospital das Clínicas da Universidade de São Paulo e Hospital Sírio-Libanês, Brazil) from January 2006 to February 2020. RESULTS: Sixteen patients with confirmed diagnosis of ECD were included with median age of 53 years. 75% were males and a median follow-up time of 50 months (7-163). Median time from onset of symptoms to diagnosis was 13 months (0.1-142). Immunohistochemistry (IHC) findings showed positivity for CD68 in 15/16 (94%) and for S100 in 3/16 (19%) patients, no case had CD1a positivity. The most frequent organs involved were: bone (75%), skin (44%), central nervous system (CNS) (44%), lymph nodes (31%), lung (13%), liver (6%), spleen (6%), and gastrointestinal tract (6%) of cases. CNS lesions involvement occurred mostly in the pituitary gland (86%). Twelve of 16 (75%) patients presented disease in more than one organ. Xanthelasma and xanthoma were the most common skin lesions (44%). The most frequent histiocytosis-related clinical manifestations were bone pain (44%) and diabetes insipidus (38%). The most frequent radiologic findings were osteosclerosis in 12/16 (75%) patients, retroperitoneal fibrosis around the kidneys in 6/16 (38%), the coated aorta sign and orbital infiltration were found in 4/16 (25%) of cases. 18FDG/PET-CT was performed in all patients, of whom 13 (81%) had hypermetabolic lesions. BRAF status at diagnosis was available in 13/16 patients using the technique of Sanger in 5/13, pyrosequencing in 3/13, IHC in 3/13 and polymerase chain reaction (PCR) in 2/13. Mutations were detected in only 3/16 (19%) cases. All patients received treatment due to symptomatic disease with a median of two lines of therapy (1-7). Median time between diagnosis and the first treatment was one month. First-line treatments were interferon in 12/16 patients, steroids in 5/16, and each one of thalidomide, vemurafenib and tumoral resection in one patient. Beyond first-line therapy, the most conventional chemotherapy regimens used were cladribine (4/16 patients) and LCH-like etoposide-containing vinblastine, methotrexate and mercaptopurine (2/16 patients). Other treatments included radiotherapy (4/16 patients) and a single patient used cobimetinib, imatinib and infliximab. Median progression free survival (PFS) after the first line treatment was 7.5 months (95% CI 5-10), and median overall survival (OS) was not reached to this date. Time to next treatment was 9 months in patients who did not achieved at least partial response after first line, and 15 months in those who attained it. PFS at 2 years was 45% (95% CI 0.17-0.71), and OS at 2 years was 100%. One patient died due to infection complication after the first cycle of cladribine after 50 months of follow-up. CONCLUSION: To our knowledge, despite the low number of patients, this is the largest Latin American cohort of patients with ECD reported to date. Our findings resemble demographic characteristics, sites of involvement and treatment choices reported by other groups. However, it is noteworthy that the proportion of ECD patients bearing a BRAF mutation (18.8%) was pretty lower than previously reported (approximately 50%). This needs to be taken cautiously due to the small number of subjects and due to technical issues, since all samples analyzed by PCR or Sanger were negative for BRAF mutation. A national registry of histiocytosis is needed to confirm these preliminary data. Disclosures No relevant conflicts of interest to declare.

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FDG-PET in the Erdheim–Chester disease: its diagnostic and follow-up role

Rheumatology International ◽

10.1007/s00296-010-1676-y ◽

2010 ◽

Vol 32 (3) ◽

pp. 675-678 ◽

Cited By ~ 21

Author(s):

Emőke Šteňová ◽

Boris Šteňo ◽

Pavol Povinec ◽

František Ondriaš ◽

Jana Rampalová

Keyword(s):

Fdg Pet ◽

Erdheim Chester Disease ◽

Erdheim Chester ◽

Chester Disease

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18F-FDG PET/CT in Erdheim–Chester Disease: Imaging Findings and Potential BRAF Mutation Biomarker

Journal of Nuclear Medicine ◽

10.2967/jnumed.117.200741 ◽

2017 ◽

Vol 59 (5) ◽

pp. 774-779 ◽

Cited By ~ 16

Author(s):

Jason R. Young ◽

Geoffrey B. Johnson ◽

Robert C. Murphy ◽

Ronald S. Go ◽

Stephen M. Broski

Keyword(s):

Braf Mutation ◽

Fdg Pet ◽

Imaging Findings ◽

Erdheim Chester Disease ◽

Pet Ct ◽

18F Fdg ◽

Fdg Pet Ct ◽

Erdheim Chester ◽

Chester Disease

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Scintigraphic findings and follow up in Erdheim-Chester disease

European Journal of Nuclear Medicine ◽

10.1007/bf01566013 ◽

1990 ◽

Vol 16 (1) ◽

pp. 55-60 ◽

Cited By ~ 32

Author(s):

Dirk Sandrock ◽

Maria J. Merino ◽

Beate H. B. Scheffknecht ◽

Ronald D. Neumann

Keyword(s):

Erdheim Chester Disease ◽

Erdheim Chester ◽

Chester Disease

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Clinical Presentation, Diagnosis, Treatment, and Outcome of Patients with Erdheim-Chester Disease: The Mayo Clinic Experience

Blood ◽

10.1182/blood.v124.21.1405.1405 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1405-1405 ◽

Cited By ~ 4

Author(s):

Mithun Vinod Shah ◽

Timothy G Call ◽

Carl C. Hook ◽

Patrick B. Johnston ◽

Louis Letendre ◽

...

Keyword(s):

Survival Time ◽

Mayo Clinic ◽

Clinical Presentation ◽

Interleukin 1 ◽

Braf Inhibitors ◽

Receptor Antagonists ◽

Erdheim Chester Disease ◽

Erdheim Chester ◽

Chester Disease

Abstract INTRODUCTION: Erdheim-Chester Disease (ECD) is a rare hematologic disease manifesting as granulomatous or fibrotic infiltration of long bones and non-skeletal tissues by non-Langerhans foamy histiocytic (CD68+, CD1a-, S100-) cells. The clinical presentation can be diverse and any organ can be affected. It is estimated that less than 500 cases have been reported in the literature. METHODS: We retrospectively reviewed the medical records of patients evaluated at Mayo Clinic from January 2001 to May 2014. A tissue biopsy review by pathologists at Mayo Clinic was necessary for inclusion in the study. In all cases, the diagnosis of ECD was confirmed using clinical criteria in conjunction with histopathologic findings. Clinical data such as patient characteristics, disease presentation, management strategies, treatment responses, and survival time were collected. RESULTS: Forty-five patients with confirmed ECD were included in our study. The median age at diagnosis was 53 years (range, 32-78), while the median age of onset of symptoms prior to diagnosis was 24 months (range, 1-180). There was a male predilection with a male to female ratio of 2.4. The duration of follow-up ranged from 1-168 months (median, 20). At the time of last follow-up, 38 patients were alive and 5 were dead, while the vital statuses of 2 patients were unknown. The median and mean survival times from the time of diagnosis were 150 and 130 months respectively. The median survival time from the time of symptom onset was not reached and mean time was 154 months (Figures 1A and 1B). Bone pain was the most common presenting symptom (27%). Other common presentations included diabetes insipidus (24%), abdominal pain (22%), B symptoms (13%), visual changes (13%), renal failure/obstruction (11%), pleural effusion (9%), other neurologic symptoms (9%), ataxia (7%), pericardial effusion (7%), edema (7%), dyspnea (7%), and hypertension (7%). The organs/sites involved were bone (80%), central nervous system (59%), kidneys (56%), lungs (38%), retroperitoneum (33%), heart (22%), sinuses (22%), bone marrow (14%), adrenal glands (13%), liver (11%), spleen (11%), and skin (16%). Only 18 (40%) patients had the diagnosis established by the first biopsy. The rest required multiple biopsies before the diagnosis was confirmed (median, 2; range, 1-5). Testing for BRAF V600Ewas performed in 12 patients and 8 (67%) tested positive for the mutation. Eight patients have not required ECD-specific treatment so far. Of the 37 patients who required treatment, the median number of treatments received was 2 (range, 1-7). The systemic treatments received and their response rates are summarized in Table 1. Four patients received radiotherapy but none responded. At the time of the last follow up, 5 patients with BRAFV600E were receiving treatment with vemurafenib or dabrafenib. However, follow-up is insufficient for proper assessment of response. CONCLUSIONS: ECD is an extremely rare diagnosis as exemplified in our retrospective analysis. The diagnosis is often challenging due to protean and diverse clinical presentation as well as frequent inconclusive initial biopsies. There is usually a long-latency period of smoldering symptoms leading to definitive diagnosis. A high level of suspicion is essential in order to make the diagnosis and BRAFmutation analysis should be considered an integral part of work up even if biopsy is non-diagnostic. Traditional oncologic systemic therapies and even novel rheumatologic anti-inflammatory agents generally have limited objective activity. BRAF inhibitors offer a novel treatment option and results of prospective studies are eagerly awaited. Abstract 1405. Table 1: Summary of Response to Various Treatment Modalities in Patients with ECD Therapeutic Agent Number of Patients Treated Response (%) Complete Response Partial Response Stable Disease No response Corticosteroids 11 0 0 9 91 Methotrexate 9 0 0 11 89 Cyclophosphamide 4 0 0 25 75 2-CDA 12 8 17 25 50 Interferon-α 8 0 29 14 57 Vinorelbine 4 0 50 0 50 Tumor necrosis-α factor Inhibitors 7 0 0 14 86 Interleukin-1 Receptor Antagonists 6 17 17 0 67 Tamoxifen 2 0 50 0 50 Radiotherapy 4 0 0 0 100 Figure 1 Figure 1. Disclosures Off Label Use: We report among all treatments utilized at our institution for ECD including the use of steroids, immunosupressants, TNF blockers, interleukin-1 receptor antagonists, and BRAF inhibitors in patients with Erdheim Chester Disease. These treatments, though supported by other reports in the literature, have not been explicitly approved by the FDA for ECD..

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Neuroradiologic manifestations of Erdheim-Chester disease

Neurology Clinical Practice ◽

10.1212/cpj.0000000000000422 ◽

2018 ◽

Vol 8 (1) ◽

pp. 15-20 ◽

Cited By ~ 13

Author(s):

Natalie E. Parks ◽

Gaurav Goyal ◽

Ronald S. Go ◽

Jay Mandrekar ◽

W. Oliver Tobin

Keyword(s):

Spinal Cord ◽

Diabetes Insipidus ◽

Brain Mri ◽

Urine Osmolality ◽

Erdheim Chester Disease ◽

Hypothalamic Pituitary Axis ◽

Spine Mri ◽

Erdheim Chester ◽

Chester Disease

BackgroundWe describe the neuroradiologic features of a cohort of patients with Erdheim-Chester disease.MethodsWe assessed patients at Mayo Clinic Rochester between January 1, 1990, and July 31, 2016, with pathologically confirmed Erdheim-Chester disease (n = 53).ResultsNeuroimaging, including head CT (n = 17), brain MRI (n = 39), orbital MRI (n = 15), and spine MRI (n = 16), was available for 42 participants. Median age at diagnosis was 55 years (interquartile range 46–66) with higher male prevalence (33:20). Neurologic symptoms were identified in 47% (25/53); BRAFV600E mutation in 58% (15/26). Median follow-up was 2 years (range 0–20) with 18 patients deceased. Radiologic disease evidence was seen in dura (6/41), brainstem (9/39), cerebellum (8/39), spinal cord (2/16), spinal epidura (2/16), hypothalamic-pituitary axis (17/39), and orbits (13/42). T2 white matter abnormalities (Fazekas score ≥1) were present in 21/34 patients. Diabetes insipidus was present in 30% (16/53); 8 had abnormal hypothalamic–pituitary axis imaging. Radiographic evidence of CNS involvement (i.e., dural, brain, including Fazekas score >1, or spinal cord) occurred in 55% (22/40) and was unassociated with significantly increased mortality.ConclusionsErdheim-Chester disease commonly and variably involves the neuraxis. Patients with suspected Erdheim-Chester disease should undergo MRI brain and spine and screening investigations (serum sodium, serum and urine osmolality) for diabetes insipidus to clarify extent of neurologic disease.

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PLATINO, a nine-year follow-up study of COPD in the city of São Paulo, Brazil: the problem of underdiagnosis

Jornal Brasileiro de Pneumologia ◽

10.1590/s1806-37132014000100005 ◽

2014 ◽

Vol 40 (1) ◽

pp. 30-37 ◽

Cited By ~ 14

Author(s):

Graciane Laender Moreira ◽

Beatriz Martins Manzano ◽

Mariana Rodrigues Gazzotti ◽

Oliver Augusto Nascimento ◽

Rogelio Perez-Padilla ◽

...

Keyword(s):

Latin American ◽

Initial Phase ◽

Severe Disease ◽

Sao Paulo ◽

São Paulo ◽

Chi Square ◽

Chi Square Test ◽

Study Population ◽

The City

OBJECTIVE: To determine the underdiagnosis rate in new COPD cases at the end of a nine-year follow-up period-in the study designated "Projeto Latino-Americano de Investigação em Obstrução Pulmonar" (PLATINO, Latin-American Pulmonary Obstruction Investigation Project)-and compare that with the underdiagnosis rate during the initial phase of the study, as well as to identify the clinical features exhibited by the subjects who were not diagnosed until the end of the follow-up phase. METHODS: The study population comprised the 1,000 residents of the city of São Paulo, Brazil, who took part in the PLATINO study. Of those, 613 participated in the follow-up phase, during which the subjects were assessed with the same instruments and equipment employed in the initial phase of the study. We used the chi-square test or the independent sample t-test to analyze the underdiagnosis rate and to identify the characteristics of the subjects who were not diagnosed until the end of the follow-up phase. RESULTS: The underdiagnosis rate for new COPD cases at the end of the nine-year follow-up period was 70.0%. The underdiagnosis rate during the follow-up phase was 17.5% lower than that reported for the initial phase of the study. The subjects who were not diagnosed until the end of the follow-up phase presented with fewer respiratory symptoms, better pulmonary function, and less severe disease than did those previously diagnosed with COPD. CONCLUSIONS: The underdiagnosis rate for new COPD cases was lower in the follow-up phase of the study than in the initial phase. The subjects who were not diagnosed until the end of the follow-up phase of the PLATINO study presented with the same clinical profile as did those who were not diagnosed in the initial phase. These findings underscore the need for spirometry in order to confirm the diagnosis of COPD and provide early intervention.

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Vemurafenib as first-line therapy in BRAF-V600E-mutant Erdheim-Chester disease with CNS involvement

BMJ Case Reports ◽

10.1136/bcr-2018-228280 ◽

2019 ◽

Vol 12 (11) ◽

pp. e228280 ◽

Cited By ~ 1

Author(s):

Gorka Fernández-Eulate ◽

Amaia Muñoz-Lopetegi ◽

Irune Ruiz ◽

Miguel Urtasun

Keyword(s):

Braf V600e ◽

Cns Involvement ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Erdheim Chester Disease ◽

The Central Nervous System ◽

Prompt Diagnosis ◽

Erdheim Chester ◽

Chester Disease

Erdheim-Chester disease (ECD) is a rare histiocytosis that may affect the central nervous system (CNS). Infiltration by the disease occurs throughout the neuroaxis, usually involving the dentate nucleus and the pons, manifested as a pyramido-cerebellar syndrome. CNS involvement is an adverse prognostic factor which warrants prompt evaluation and treatment. BRAF mutation occurs in more than half of the cases and has become central in the therapeutic approach. There is rapidly growing evidence that BRAF inhibitors such as vemurafenib or dabrafenib are effective in treating CNS-spread disease. We present a patient with BRAF-V600E-mutant ECD with a classical pyramido-ataxic onset of disease who improved after prompt diagnosis with vemurafenib treatment as first-line therapy.

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Serial assessments of anterior pituitary hormones in a case of mixed histiocytosis representing Langerhans cell histiocytosis overlapping with Erdheim–Chester disease

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-21-0030 ◽

2021 ◽

Vol 2021 ◽

Author(s):

Kei Ito ◽

Jun Ito ◽

Yuki Yamamoto ◽

Rikako Nakajima ◽

Masanao Fujii ◽

...

Keyword(s):

Anterior Pituitary ◽

Langerhans Cell Histiocytosis ◽

Pituitary Hormones ◽

Langerhans Cell ◽

Erdheim Chester Disease ◽

Erdheim Chester ◽

Serial Assessments ◽

Chester Disease ◽

Posterior Pituitary Lobe

Summary A 61-year-old man developed central diabetes insipidus caused by mixed histiocytosis (MH) representing Langerhans cell histiocytosis overlapping with Erdheim–Chester disease. Bone, skin, vascular, and retroperitoneal involvements were also observed. Dynamic hormonal testing showed normal responses for anterior pituitary hormones, except for impaired secretion of growth hormone (GH). MRI of the brain showed thickening of the pituitary stalk with slightly reduced signal hyperintensity in the posterior pituitary lobe on T1-weighted imaging. During 2 years of follow-up without radical treatment for MH, imaging studies suggested extension of vascular and retroperitoneal involvements. In contrast, brain MRI did not show any particular interval changes, except for the disappearance of hyperintense signalling in the posterior pituitary lobe. Moreover, no other anterior pituitary dysfunctions beyond GH deficiency emerged during the 2 years of follow-up. The natural history of MH in this case is described, focusing on serial assessments of pituitary functions using dynamic tests. Learning points Erdheim–Chester disease and Langerhans cell histiocytosis overlapping as MH was described, focusing on pituitary functions. MH caused both GH deficiency and central diabetes insipidus. Despite a lack of radical therapy for MH, no other anterior pituitary dysfunctions emerged for 2 years. Radiological images showed no particular interval changes in pituitary stalk lesions, while vascular and retroperitoneal involvements extended.

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