Langerhans Cell Histiocytosis Involvement Research Articles

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.

Langerhans cell histiocytosis in children with refractory diarrhoea and hypoalbuminaemia as the initial presentation: two case reports and a literature review

Langerhans cell histiocytosis (LCH) involving the gastrointestinal tract is a rare condition for which clinical experience is limited. We describe the cases of two patients who initially presented with chronic diarrhoea, hypoproteinaemia, and intermittent fever. These findings suggest that in cases of refractory diarrhoea accompanied by recurrent hypoalbuminaemia, especially with abdominal rash, LCH should be considered. Gastrointestinal endoscopy, biopsy, and imaging studies are essential for obtaining a definitive diagnosis. This approach might be helpful for the early recognition of gastrointestinal tract involvement in LCH.

Hematological Involvement in Childhood Langerhans Cell Histiocytosis: A Cohort Study of 303 Patients

Introduction: Hematological involvement (HI) is a life-threatening involvement of Langerhans cell histiocytosis (LCH). Since 1975, its definition is based on the Lahey criteria: Anemia (Hb &amp;lt;10 g/dL and &amp;lt;9 g/dL in infants) and/or thrombocytopenia (platelet count &amp;lt;100x10 9/l). Methods: Among 2,234 patients &amp;lt; 18 years enrolled in the French histiocytosis registry (cutoff date May 2023), 303 patients presented HI. We differentiated mild HI (MHI) (Hb &amp;gt; 7 g/dl and Platelets &amp;gt; 20x10 9/l) from severe HI (SHI) (Hb ≤ 7 g/dl and Platelets ≤ 20x10 9/l) by using usual cutoffs for transfusion requirements. Results: Median age at diagnosis was one year and sex was male in 49%. The median follow-up in the 258 survivors was 10.9 years, while death occurred after a median of 0.9 years in the 45 patients who died (Figure 1A). Only 3 patients died later than two years of initial diagnosis. The HI was mild in 150 cases and severe in 153 cases. BRAF v600E was found in 88 among the 101 patients for which mutation analysis was documented. Patients with SHI had significantly more lung involvement (35 % vs 19 %), more hepatic involvement (72 % vs 21 %), and more skin involvement (85 % vs 61 %). Morphological bone marrow infiltration by CD1a positive cells could not differentiate between SHI and MHI and bone marrow features were hardly informative. Signs of myelofibrosis were documented in 9 patients mostly later in the disease course. Lastly, 44 macrophage activation syndromes were observed exclusively in SHI. For 11 of those patients panel analyses of hemophagocytic lymphohistiocytosis genes did not show any bi-allelic pathogenic variants. 20 patients did not receive any therapy, including one with SHI and 19 with MHI. An intensive approach with hematologic stem cell transplantation (HSCT) (n=11) and 2-Cda-Cytarabine (2-Cda-AraC) (n=44) was proposed almost only for SHI. MAPK-inhibition was used in 40 patients. Three deaths were observed among the MHI and 42 among the SHI. From 1983 to 1998 mortality was about 50% and 30 of 63 patients died. With the establishment of the second-line treatment by 2-Cda-AraC mortality decreased drastically and from 1998 to 2014 only 13 of 194 patients died. From 2014 on patients received exclusively MAPK-inhibition as second line treatment and 2 of 46 patients died (one without therapy, one at the initiation). The overall survival is depicted in figure 1A. Neurodegenerative (ND) complications were observed in 32 patients (10.5%) with a median delay of 4.8 years after initial LCH diagnosis and incidence of ND was independent of the MHI or SHI group (Figure 1B). Conclusion: In Langerhans cell histiocytosis, the classic definition of hematological involvement by the Lahey criteria should be reconsidered. HI may be limited to severe HI that included almost all medical complications and warrants innovative approaches, while mild HI can be managed by the classic therapeutical approach. Even if progress has been achieved in the treatment of LCH patients with HI with more than 95% achieving short-term control, long term neurodegeneration remains a challenge in this group of patients, which warrants further research. Figure 1: A) Kaplan-Meier curve of cumulative incidence of death for all the 303 patients, regardless of therapy. B) Risk of clinical neurodegenerative symptoms in the same cohort (considering death as a censor).

Craniofacial involvement in Langerhans cell histiocytosis: A review of 44 cases at a single medical center

BackgroundCraniofacial bones are the most commonly involved site of Langerhans cell histiocytosis (LCH). The main purpose of this study was to clarify the relation between subsites of craniofacial bone and clinical presentation, treatment modalities, outcomes, and permanent consequences (PCs) in patients with LCH. MethodsForty-four patients diagnosed with LCH involving the craniofacial region presenting at a single medical center during 2001–2019 were collected and divided into four groups: single system with unifocal bone lesion (SS-LCH, UFB); single system with multifocal bone lesions (SS-LCH, MFB); multisystem without risk organ involvement (MS-LCH, RO-); and multisystem with risk organ involvement (MS-LCH, RO+). Data including demographics, clinical presentation, treatments, outcomes, and the development of PC were retrospectively reviewed. ResultsTemporal bone (66.7% versus 7.7%, p = 0.001), occipital bone (44.4% versus 7.7%, p = 0.022), and sphenoid bone (33.3% versus 3.8%, p = 0.041) involvement were more common in SS-LCH, MFB than they were in SS-LCH, UFB. No difference of reactivation rate was noted among the four groups. The most common PC is diabetes insipidus (DI), reported in 9 of the 16 (56.25%) patients with PC. The single system group was reported with the lowest incidence of DI (7.7%, p = 0.035). The reactivation rate was also higher in patients with PC (33.3% versus 4.0%, p = 0.021) or DI (62.5% versus 3.1%, p < 0.001). ConclusionAn increased risk of multifocal or multisystem lesions was associated with temporal bone, occipital bone, sphenoid bone, maxillary bone, eye, ear, and oral involvement, which may indicate poor outcomes. Longer follow-up may be indicated if there is the presence of PC or DI due to the high risk of reactivation. Therefore, multidisciplinary evaluation and treatment according to risk stratification are vital for patients diagnosed with LCH involving the craniofacial region.

Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study.

Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder caused by somatic genetic alterations in hematopoietic precursor cells differentiating into CD1a+/CD207+ histiocytes. LCH clinical manifestation is highly heterogeneous. BRAF and MAP2K1 mutations account for ∼80% of genetic driver alterations in neoplastic LCH cells. However, their clinical associations remain incompletely understood. Here, we present an international clinicogenomic study of childhood LCH, investigating 377 patients genotyped for at least BRAFV600E. MAPK pathway gene alterations were detected in 300 (79.6%) patients, including 191 (50.7%) with BRAFV600E, 54 with MAP2K1 mutations, 39 with BRAF exon 12 mutations, 13 with rare BRAF alterations, and 3 with ARAF or KRAS mutations. Our results confirm that BRAFV600E associates with lower age at diagnosis and higher prevalence of multisystem LCH, high-risk disease, and skin involvement. Furthermore, BRAFV600E appeared to correlate with a higher prevalence of central nervous system (CNS)-risk bone lesions. In contrast, MAP2K1 mutations associated with a higher prevalence of single-system (SS)-bone LCH, and BRAF exon 12 deletions seemed to correlate with more lung involvement. Although BRAFV600E correlated with reduced event-free survival in the overall cohort, neither BRAF nor MAP2K1 mutations associated with event-free survival when patients were stratified by disease extent. Thus, the correlation of BRAFV600E with inferior clinical outcome is (primarily) driven by its association with disease extents known for high rates of progression or relapse, including multisystem LCH. These findings advance our understanding of factors underlying the remarkable clinical heterogeneity of LCH but also question the independent prognostic value of lesional BRAFV600E status.

Isolated Hepatobiliary Involvement in an Infant with Langerhans Cell Histiocytosis: A Case Report with Review of Literature

Background: Langerhans cell histiocytosis (LCH) is a rare condition in which there is the proliferation of cells of the monocyte-dendritic cell lineage, including Langerhan's cells, with variable clinical manifestations and outcomes. Hepatic involvement is often seen as a part of multi-system LCH and is associated with a fulminant course. Isolated hepatobiliary involvement in LCH is rare. Clinical Description: We report an 11-month-old female infant presenting with prolonged fever associated with progressive jaundice, clay-colored stools, and a massive hepatomegaly. Liver biopsy showed CD1a and Langerin positivity. There was no other system involvement, and hence, the infant was diagnosed with a case of single-system LCH with isolated hepato-biliary LCH. Management and Outcome: A customized chemotherapeutic regimen was started with cytarabine and prednisolone. The patient has responded and there has been gradual improvement in the general clinical condition as well as the laboratory parameters. Conclusions: This case report creates the awareness of possible presentation of pediatric LCH with isolated liver involvement. A high index of suspicion, carefully customized chemotherapeutic regimen may help in the timely diagnosis and successful management.

RAF-Independent MEK Mutations Drive Histiocytic Neoplasms In Vivo and Are Sensitive to Single-Agent ERK Inhibition in Patients

Histiocytic neoplasms are clonal disorders of the monocyte/macrophage lineage that include Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD). Histiocytoses are defined by recurrent, mutually exclusive mutations activating MAP kinase signaling, including BRAFV600E mutations in ~50% of LCH and ECD patients, which confer robust lasting clinical responses to BRAF inhibition. Mutations in MEK1/2, ARAF, and a diverse array of other kinases are present in BRAF wild-type histiocytoses patients and are broadly responsive to the allosteric MEK1/2 inhibitor cobimetinib. Following genomic analysis of ~300 pediatric and adult patients with diverse histiocytoses, the single most common genomic alteration following BRAFV600E mutations are MEK1 E102_I103 in-frame deletions. In contrast to BRAFV600E, the biological impact of activating mutations in MEK1/2 kinases are unknown, and no cancer associated MEK1/2 mutation has ever been modeled in vivo. MEK1/2 mutations are recurrent across a wide variety of human cancers and RASopathies and are now often found at resistance to emerging KRAS-mutant selective inhibitors. These findings motivated us to generate Map2k1E102_I103del conditional knock-in mice within the endogenous locus of Map2k1 (encoding MEK1 kinase), which represent the first genetically engineered mouse model of MEK1/2 mutations. We first crossed Map2k1E102_I103del mice to inducible Mx1-cre driver mice. Interestingly, Mx1-cre Map2k1E102_I103del knock-in mice developed a 100% penetrant lethal myelomonocytic disorder by 5-6 weeks of age while their cre-negative Map2k1E102_I103del littermates did not develop disease (Figure A). Notably, recombination of the Map2k1E102_I103del alleleoccurred spontaneously without pIpC administration and resulted in strong activation of phosphorylated ERK1/2 in bone marrow and spleen mononuclear cells. Mx1-cre Map2k1E102_I103del mice developed a myelomonocytic neoplasm with suppression of B-lymphopoiesis and expansion of classical and non-classical monocyte subsets, macrophages, and Cd11b+ conventional dendritic cells. Monocyte, macrophage, and dendritic cells infiltrated hematopoietic organs (bone marrow, spleen, and peripheral blood), as well as liver and skin, each of which are common sites of LCH and ECD disease involvement. The Mx1-cre Map2k1E102_I103del disease was hematopoietic cell autonomous and could be propagated by serial hematopoietic reconstitution in irradiated recipient mice, as well as using Vav1-cre Map2k1E102_I103del knock-in mice (where Cre is expressed only in hematopoietic cells from earliest hematopoietic development). Finally, restricting MEK1 mutant expression to monocyte and dendritic cell precursors using CD11c-cre resulted in similar lethal expansions of monocyte, macrophage, and dendritic cells as seen in the Mx1-cre and Vav1-cre models. Prior in vitro work has demonstrated that MEK1 p.E102_I103del activates MEK and ERK without requiring activated GTP-bound RAS and is associated with resistance to allosteric MEK inhibitors. Consistent with this, we identified nine histiocytosis patients with this specific MEK1 mutation, three of which had de novo resistance to cobimetinib. These three patients and one treatment-naïve patient were treated with an oral ERK1/2 inhibitor ulixertinib under the FDA single-patient compassionate use program. Three of 4 patients had a clinical or radiological partial or complete response to ulixertinib (Figure B). Overall, these data identify the impact of oncogenic MEK kinase mutations in vivo as found in children and adults with histiocytoses and RASopathies. Expression of a RAF-independent MEK1 mutation in vivo gave rise to disease reminiscent of human systemic histiocytic neoplasms. Importantly, this molecular entity is resistant to MEK inhibition in some patients, a phenomenon previously undocumented, but responsive to ERK inhibition, which may be a promising therapeutic approach to histiocytic neoplasms unresponsive to allosteric MEK inhibition. The clinical observation of efficacy of ERK inhibition in MEK inhibitor resistant histiocytoses patients has resulted in a soon-to-be initiated focused phase 2 clinical trial of ulixertinib in adults with histiocytoses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

S2081 Rare Colonic Polyps: A Case of Langerhans Histiocytosis

Introduction: Langerhans Cell Histiocytosis (LCH) is a rare inflammatory myeloid disorder mostly seen in children before the age of 5. The clinical presentation is heterogeneous with potential for wide-ranging organ involvement, primarily in the bone, skin, and lungs. Gastrointestinal tract involvement is very rare in LCH, and in symptomatic patients, etiology could be confused with infectious, allergic, and autoimmune bowel diseases. In children, LCH GI tract involvement has been associated with decreased survival due to multisystem involvement and digestive complications including diarrhea, vomiting, malabsorption, and failure to thrive. Review of literature shows less than twenty adults with incidences of GI tract involvement of LCH and only 4 cases of adults with LCH colon polyps. Case Description/Methods: A 66-year-old man presented for screening colonoscopy. He reported generally good health without any GI or systemic symptoms or medical history. Family history was significant for leukemia in his brother. He currently smokes cigarettes and has a 2.5 pack-year history. On colonoscopy, 6 benign-appearing polyps were removed using cold snare polypectomy: 3 from the ascending colon (largest 0.5 cm in size), one from the splenic flexure of the transverse colon (0.4 cm in size), and 2 from the rectum (largest 0.4 cm in size). Quality of bowel preparation was excellent and the procedure was without complication. Rectal polyps were hyperplastic. Submucosal sections of the ascending and transverse colon polyps stained positive for CD1a, CD68, and S-100, consistent with Langerhans-type cells. The LCH diagnosis was further supported by irregular nuclei within focal nuclear grooves and an eosinophilic cytoplasm. Genomic testing of the colon sample revealed BRAFV600E mutation, the most recognized targetable mutation in LCH. He underwent further testing with PET scan and bone marrow biopsy, both of which were negative for LCH. Surveillance colonoscopy was recommended in 7 years (Figure 1). Discussion: With his lack of systemic disease and asymptomatic presentation, watchful waiting and Oncology follow-up was recommended. Given the unusual diagnosis of LCH via a colon polyp, it is possible for lesions to be clinically unsuspected and histologically overlooked. With increasing rates of screening colonoscopy, more polyps demonstrating LCH on histopathology may be identified. Reports of LCH in the GI tract and colon polyps are infrequent and characterization of outcomes will rely on further cases in this population.Figure 1.: Positive immunostaining for CD1a, classically expressed by Langerhans cells.

Diffuse Bone Marrow Involvement of Langerhans Cell Histiocytosis Detected with F-18 FDG PET/CT

Diffuse Bone Marrow Involvement of Langerhans Cell Histiocytosis Detected with F-18 FDG PET/CT

Current perspectives on the role of liver transplantation for Langerhans cell histiocytosis: A narrative review.

Langerhans cell histiocytosis (LCH) is a malignant disease of the histiocytes involving various organ systems. The spectrum of liver involvement in LCH ranges from mild transaminitis to end-stage liver disease. The hallmark of hepatic LCH is secondary sclerosing cholangitis, which manifests due to a progressive destruction of the biliary tree by malignant histiocytes. Chemotherapy remains the mainstay of treatment for active LCH. Early recognition, diagnosis and a systematic approach to the management of LCH can ameliorate the disease process. Nonetheless, the liver involvement in these patients may progress despite the LCH being in remission. Liver transplantation (LT) remains central in the management of such patients. Various facets of the management of LCH, especially those with liver involvement remain unclear. Furthermore, aspects of LT in LCH with regards to the indication, timing and post-LT management, including immunosuppression and adjuvant therapy, remain undefined. This review summarises the current evidence and discusses the practical aspects of the role of LT in the management of LCH.

18F-fluorodeoxyglucose-positron emission tomography/computed tomography delineates involved sites in the cervical spine in Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH), a granulomatous tumorous lesion consisting of CD1a-positive clonal immature dendritic cells in association with various inflammatory cells, develops in tissues including bone, skin, lungs, and lymph nodes. When bone LCH exhibits osteolytic lesions, the spine is often involved, and each part of the vertebral body, vertebral arch, and vertebral spinous process can be affected. Such vertebral LCH can occur at the onset of disease and in relapse. To confirm pathological sites, a computed tomography (CT) scan is generally used to characterize lytic lesions of vertebrae, while MRI is suitable for delineating marrow and soft tissue. Additionally, to identify specific locations, 18F-fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) is useful. We describe three LCH cases showing characteristic cervical spinal involvement. Case 1: A 39-year-old woman complained of right temporal pain and was found to have osteolytic lesions of right temporal/sphenoid/petrous bones. She also had central diabetes insipidus (CDI). After the diagnosis of LCH from biopsied tissue, she was treated with chemotherapy and attained remission. Four years later, she complained of neck/shoulder pain associated with herpes zoster in the right arm. PET/CT revealed a cervical spine (C3)-vertical body lesion (Figure 1A). With a revised chemotherapy regimen, she attained a second remission. Case 2: A 70-year-old man, a heavy smoker for more than 40 years, complained of shortness of breath, and a chest X-ray revealed characteristic honeycomb lungs. PET/CT showed hot lesions in the lungs, cervical spine (C3) right vertebral arch (Figure1B), and ribs. Lung lesion biopsy confirmed the diagnosis of LCH. He had no CDI and was treated with irradiation to the cervical spine and with chemotherapy. Case 3: A 40-year-old man who had severe atopic dermatitis since the age of 20 complained of nuchal pain after a traffic accident. He was also noted to have lymphadenopathy in the bilateral axillary and inguinal areas. PET/CT revealed hot signals at the spinous process of the cervical spine (C6) (Figure 1C) and lymph node lesions. Biopsy of the C6 lesion confirmed LCH. He attained a remission treated with chemotherapy and zoledronic acid. Three years later, relapse at the lymph nodes was noted, but not in the C6 lesion. He was treated with chemotherapy for refractory LCH and attained a second remission. An analysis of 76 cases of vertebral LCH by Huang et al. [1] consisted of 40 children and 36 adults, with a male to female ratio of 55:21. Lesions were predominantly in the cervical spine, followed by the thoracic and lumbosacral spines. In an analysis of 30 LCH patients with cervical spine involvement by Jiang et al. [2], 14 had atlantoaxial lesions (C1 and C2), and 16 had sub-axial (C3–C7) lesions. Chemotherapy is recommended for the management of cervical spine lesions in cases of multifocal LCH. In our three cases, two patients had spinal involvement at onset while the other developed it at relapse. All received chemotherapy because of multifocal LCH lesions. In summary, as an imaging study of cervical spine involvement in LCH, PET/CT seems to be useful for pinpointing the involved sites of vertebrae. None The authors declare no conflict of interest.

Clinical outcomes and screening for organ involvement in pediatric Langerhans cell histiocytosis in Thailand: multicenter study on behalf of the Thai Pediatric Oncology Group.

Langerhans cell histiocytosis (LCH) is a rare disease across all age groups and is characterized by various degrees of severity and organ system involvement. A multi-institutional retrospective study of pediatric patients with LCH treated between 1999 and 2018 at five pediatric oncology centers was conducted to describe the clinical characteristics, prognostic factors, and outcomes of LCH and to validate screening tools for organ system involvement in pediatric LCH in Thailand. A total of 127 patients with a median age of 2.7years were studied. The single-to-multisystem (MS) LCH ratio was 1:1. Forty-seven patients (71%) with MS-LCH had risk-organ involvement (RO +), whereas 19 (29%) patients had no risk-organ involvement (RO -). The 5-year overall and event-free survival rates were 91.3% and 73.6%, respectively, which were comparable to those in developed countries. Prognostic factors included age < 2years, RO + MS-LCH, and number of RO + . Abnormal complete blood count was a highly sensitive indicator of bone marrow involvement. Plain radiography is an appropriate screening tool to detect bone involvement.

Hepatobiliary and Gastrointestinal Involvement in Langerhans Cell Histiocytosis-Spectrum of Three Cases.

Langerhans cell histiocytosis (LCH) is a rare group of disorder, due to clonal neoplastic proliferation of dendritic cells in the bone marrow expressing a Langerhans cell phenotype. 1 This disease particularly affects the pediatric age group and young adults and often presents with skin rashes, lung infiltrates, and bone lesions. It can also manifest with endocrine dysfunction and hematopoietic disorders. Involvement of gastrointestinal tract is very rare. Herein, we present a spectrum of three cases with gastrointestinal involvement.

BRAF-V600E in Peripheral Mononuclear Cells and Microglia-like Brain Cells Suggest Hematopoietic Origin of Langerhans Cell Histiocytosis-Associated Neurodegeneration

Introduction: Langerhans cell histiocytosis (LCH) is a myeloid neoplasia characterized by inflammatory lesions with pathologic CD207+ myeloid dendritic cells (DC). Activation of ERK occurs in all patients with the most common somatic driver mutation being BRAF-V600E being found in up to 60% of patients.Mononuclear cells harboring the BRAF-V600E mutation have been found in peripheral blood of patients with involvement of the liver, spleen, or bone marrow, known as high risk organs. LCH involvement of the brain may include mass lesions in 25% of patients, most commonly the pituitary gland, or a progressive neurodegenerative syndrome (LCH-ND) that arises in approximately 5% of patients. LCH-ND may arise years after the initial LCH episode was presumed to have been cured and may lead to permanent neurologic deficits. The pathogenesis of LCH-ND is poorly understood, but is believed to be due to an autoimmune or paraneoplastic process. No standard approaches to surveillance or therapy exist. In order to define the etiology of LCH-ND, develop clinical tools for identifying patients at risk for LCH-ND, and to identify potential targets for novel therapies, we evaluated cerebral spinal fluid (CSF) proteins, extracellular BRAF- V600E DNA in CSF, and BRAF-V600E + cells in peripheral blood and brain biopsies.Methods: CSF biomarkers, including 121 unique proteins associated with inflammation and/or neurodegeneration and extracellular BRAF- V600E, were evaluated in 40 patients with LCH brain lesions and/or LCH-ND. CSF samples from 29 patients with acute lymphoblastic leukemia in remission and 25 patients with pediatric brain tumors represented control samples. Peripheral mononuclear cells were evaluated for BRAF-V600E by qPCR in blood samples collected pre-therapy (14 LCH-ND, 140 non-ND LCH), post-therapy at the time of relapse (14 LCH-ND, 28 non-ND LCH) and post-therapy with no evidence of active disease (35 LCH-ND, 25 non-ND LCH). Brain biopsy specimens were tested for the presence of cells harboring BRAF-V600E and relative expression of osteopontin.Results: Osteopontin was significantly elevated and S100B was decreased in CSF from patients with LCH compared to patients with brain tumors and other neurodegenerative conditions. While extracellular BRAF-V600E was detected in CSF of only 2/23 patients with LCH CNS lesions or LCH-ND, peripheral blood mononuclear cells with the BRAF- V600E mutation were more frequently found in patients with LCH-ND. In pre-therapy samples, mononuclear cells harboring the BRAF-V600E mutation were identified in 10/17 LCH-ND patients (3/9 with LCH limited to the CNS and 7/8 with active LCH beyond the CNS) vs 21/140 non-ND LCH patient samples. Comparing pre-therapy samples from patients with active LCH outside of the CNS, circulating BRAF-V600E was associated with LCH-ND with a sensitivity of 0.875 and specificity of 0.85 (P=<0.0001). In post-therapy blood collected at a time of relapsed non-CNS LCH, BRAF-V600E was detected in 6/14 LCH-ND samples and 2/28 non-ND LCH samples (sensitivity 0.4286, specificity 0.9286, P=0.0105). In post-therapy blood collected in patients with no active non-CNS LCH, circulating BRAF-V600E was detected in 8/29 LCH-ND samples vs 0/43 non-ND LCH samples (sensitivity 0.2162, specificity 1, P=0.0013). Brain biopsies of patients with LCH-ND demonstrate diffuse infiltration by BRAF-V600E + cells with a transformed microglial phenotype and elevated osteopontin expression, surrounded by CD3+ T cells. Three of four patients with LCH-ND treated with BRAF inhibitors experienced significant clinical and radiologic improvement.Conclusions: Prior theories of LCH-ND pathogenesis include autoimmune or inflammatory mechanisms. Our results support a model of LCH lesions and LCH-ND arising from a common hematopoietic precursor: whereas ERK-activated myeloid precursors differentiate into CD207+ DCs in non CNS LCH lesions, they may migrate to the brain and differentiate into hyper activated inflammatory microglia-like cells in LCH-ND. This revised model of pathogenesis supports evaluation for LCH mutations in serial blood samples prospectively along with long-term clinical surveillance to identify patients at risk for LCH-ND who may benefit from early initiation of therapy directed against the clonal reservoir of myeloid precursors with activated ERK. DisclosuresBaiocchi:Prelude therapeutics: Research Funding; viracta: Membership on an entity's Board of Directors or advisory committees, Research Funding; essanex: Research Funding; Theravectys: Consultancy.

Cutaneous Langerhans cell histiocytosis in adults: A retrospective cohort study of adult patients presenting to a single academic cancer center between 2003 and 2017

To the Editor: Due to the rarity of adult-onset Langerhans cell histiocytosis (LCH), guidelines on surveillance, staging, and management of cutaneous LCH are lacking.1 We determined the incidence and time to development of systemic LCH for patients first presenting to dermatology with cutaneous involvement of LCH and skin-limited symptoms and evaluated clinical features, disease course, and management.

Multifocal Multisystem Langerhans Cell Histiocytosis in an Adult Female Atypically Presenting With Multiple Abdominopelvic Abscesses

Introduction: Langerhans Cell Histiocytosis (LCH) is a condition of malignant clonal proliferation of myeloid bone marrow cells that more commonly affects children than adults. Furthermore, its presentation remains variable ranging from single organ to multisystem involvement including bone, skin, lymph, liver, spleen, lung, and central nervous system. We report an unusual case of multisystem LCH in an adult female presenting with multiple soft tissue abscesses. Case: We report a case of a 38-year-old female with a past medical history of polysubstance abuse, type 2 diabetes, polycystic ovarian syndrome, and isolated central diabetes insipidus who had multiple hospitalizations for recurrent soft tissue abscesses treated with incision and drainage and antibiotics. Imaging studies revealed multiple osteolytic lesions involving the bilateral iliac crests, acetabulum and femur, as well as an iliopsoas abscess. Given her prior history of isolated central diabetes insipidus, the possibility of LCH as the cause was entertained. Histological evaluation performed on an inguinal soft tissue sample stained positive for CD1a and S100, and a formal diagnosis of Langerhans Cell Histiocytosis (LCH) was made. The patient was treated with chemotherapy with good results. Conclusion: This report presents a rare and unusual case of adult onset multisystem LCH involving bone, skin, lymph, and central nervous system presenting with recurrent large abdominopelvic abscesses. These abscesses may represent a rare and unrecognized form of soft tissue involvement of LCH.

Case Report: Two Infant Cases of Langerhans Cell Histiocytosis Involving the Digestive Tract

Langerhans cell histiocytosis (LCH) is a rare disease with uncertain etiology. Langerhans cell histiocytosis with involvement of the gastrointestinal tract is rare and is typically identified in pediatric patients with systemic disease. The present study reports two infantile cases of LCH who initially presented with diarrhea, hematochezia, and rash and were histologically missed on the original examination of the colonic biopsy sections. The diagnosis of LCH was later verified through immunohistochemistry. By combining our experience and previous reports, the multiple hemorrhagic spots of the colorectal mucosa and narrowness and erosion of the distal duodenum might be suggestive manifestations of gastrointestinal involvement in LCH on endoscopic examination. This might be helpful for the early recognition of the disease.

Chapter 9 - Neuroendocrine manifestations of Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasia that can affect any organ or system in the human body. It is usually diagnosed during childhood but can also affect adults. Recent studies have demonstrated involvement of the hypothalamo-pituitary axis (HPA) in a significant proportion of patients with deficiencies in both anterior and posterior pituitary function that in the majority of cases are permanent and require specific hormone replacement regimes. Central diabetes insipidus is considered the most frequent abnormality of HPA involvement in LCH and can be encountered either as isolated deficiency or along with other pituitary deficiencies. Complete hormonal evaluation of pituitary hormones and long-term follow-up of LCH patients are strongly recommended, especially when pituitary involvement is established.

The Role of Staging Evaluation at Initial Diagnosis of Adult Patients with Clinically Isolated Pulmonary Langerhans Cell Histiocytosis

Background: Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder that is now recognized as a neoplasm by the World Health Organization. It is generally classified based on the site and extent of disease involvement (single system or multisystem). Pulmonary LCH (pLCH), an uncommon interstitial lung disease associated with smoking, often presents as isolated pulmonary disease. It is unclear whether patients with clinically isolated pLCH have extra-pulmonary lesions at diagnosis or during the course of their disease. The role of [18F] fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET-CT) in the staging of pLCH remains unclear. Our study aims to better characterize the utility of radiographic staging studies at time of diagnosis and prevalence of extrapulmonary disease at follow up in pLCH. Methods: We conducted a retrospective study of patients presenting with clinical findings consistent with isolated pLCH seen at the Mayo Clinic from January 2000 to January 2020. All patients had a diagnosis of pLCH determined by chest imaging studies [computed tomography (CT) or high-resolution CT (HRCT)] or by histopathologic findings from surgical or transbronchial lung biopsy. Histopathologic findings for the diagnosis of pLCH required the presence of Langerhans cells (S100+/CD1a+/Langerin+). Patients were excluded if they had clinically apparent extra-pulmonary organ involvement at the time of diagnosis. BRAF V600E mutation was determined by immunohistochemistry (IHC) or cell-free DNA (cfDNA). Staging was defined as FDG-PET-CT or whole body CT imaging obtained within 3 months of diagnosis of pLCH. Extra-pulmonary LCH involvement was determined by imaging characteristics or by histopathologic findings. Descriptive statistics and overall survival (OS) were analyzed with JMP software, version 14 (SAS Institute Inc., Cary, NC). Results: A total of 112 patients with clinically isolated pLCH were identified. The median age at diagnosis was 45 years (range 21-73), and 48 (43%) were male. The majority (n=110, 99%) were former or current smokers with a median pack year of 25 (range 1-57). Three (3%) patients were noted to have occupational industrial exposure. Nine patients had a history of another cancer prior to their diagnosis and staging of pLCH [lung (n=4), breast (n=2), neuroendocrine (n=2), thyroid (n=1)]. Presenting symptoms included dyspnea on exertion 49 (44%), cough 18 (16%), chest pain 14 (13%), and 29 (28%) were incidentally discovered on imaging studies. On HRCT, the following characteristics were observed: 42 (38%) cystic, 32 (29%) cystic and nodular, 37 (33%) nodular, 1 (&amp;lt;1%) ground glass opacities. Seventy (63%) patients had lung biopsy confirmation, of which 11 (16%) patients underwent BRAF V600Emutation testing (7 by IHC, 4 by cfDNA). Six (55%) of these 11 patients were positive for BRAF V600E mutation. 34 (30%) patients underwent radiographic staging studies within 3 months of diagnosis of pLCH (25 FDG-PET-CT and 9 whole-body CT), and none of these imaging studies showed evidence of extra-pulmonary disease. Of the patients who had at least one year of follow-up (n=52), one (2%) developed extra-pulmonary disease. This patient did not undergo initial staging studies, developed headaches and was found to have a large calvarial lytic lesion within 2 months of pLCH diagnosis (BRAF V600E+). Among those who did not undergo staging at diagnosis (n=78), long term (&amp;gt;5 years) follow up data were available for 23 (29%), and none developed extra-pulmonary disease as determined by clinical notes or imaging studies. No patient had evidence of new extra-pulmonary involvement or second malignancy at the time of last known follow-up. After a median follow-up duration of 2.4 years (95% CI: 1.5-3.6, range: 0.1-17) ten (9%) patients died, of which 5 died of pLCH related complications. The median OS for entire cohort was 15 years (95% CI 9.1-not reached, Figure 1). Conclusion: Our study shows that adult patients with clinically isolated pLCH rarely present with extra-pulmonary manifestations at diagnosis or at follow up. These findings suggest a limited role of routine radiographic staging studies in pLCH unless clinically indicated. Studies on longer follow up of this cohort would provide further insights into the natural history of pLCH and are underway. Disclosures Bennani: Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board; Kite/Gilead: Research Funding; Affimed: Research Funding. Shah:Dren Bio: Consultancy.

Epstein-Barr Virus-Associated Langerhans Cell Histiocytosis of the Thyroid Gland

Thyroid gland involvement of Langerhans cell histiocytosis (LCH) is extremely rare in both systemic and isolated disease. The role of viral infection in LCH development is not yet fully understood. Although several viruses are proposed as etiologic factors, such as Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6), they seem to play a bystander role in LCH. A 29-year old female patient with a prior history of multisystemic LCH (pituitary gland and skull bone), presented with a thyroid nodule. The patient underwent a total thyroidectomy and the histological examination revealed nodular lesions composed of sheets and clusters of histiocytes in the inflammatory background. The histiocytes stained positive for S-100 and CD1a and were negative for HHV-8, cytomegalovirus, and VE1 (anti-BRAFV600E) on immunohistochemistry. The EBER in situ hybridization for EBV showed frequent positive-stained cells. The conventional PCR analysis for EBV was positive and qPCR analysis confirmed a significant DNA copy number difference (p = 0.02) between the tumor and adjacent non-neoplastic thyroid tissue. PCR analysis for HHV-6, HPV, HSV was negative in both tumor and benign samples. In conclusion, the presented case showed a rare thyroid involvement by LCH associated with EBV infection, which has not been reported before. Further studies are required to investigate a possible etiologic link between EBV infection and LCH.