Whole-body magnetic resonance imaging for staging Langerhans cell histiocytosis in children and young adults.

INTRODUCTION: Radiographic skeletal survey (R-SS) is the standard imaging technique for the initial staging of Langerhans cell histiocytosis (LCH). Whole-body magnetic resonance imaging (WB-MRI) has been proposed as an effective, radiation-free alternative. METHODS: We prospectively assessed patients with LCH followed at three tertiary centers in Italy and Austria. Two national study protocols were independently designed, and data were then pooled to increase the power of their findings. R-SS and WB-MRI were performed at diagnosis and repeated at the follow-up to confirm the nature of the identified lesions and to study their evolution. RESULTS: Data from 67 patients were analyzed (52 from Italy and 15 from Austria). Compared to R-SS, WB-MRI identified 29 additional skeletal lesions in 14 patients (including two false-positive lesions). Two skeletal lesions were detected at R-SS and missed at WB-MRI (false negative). Per-lesion sensitivity rates were 78.6% (95% CI: 71.0-85.9) for R-SS and 98.4% (95% CI: 94.4-99.8) for WB-MRI, respectively. Based on WB-MRI findings, six patients would have been upstaged to a higher risk class than staging with R-SS. CONCLUSIONS: WB-MRI had a significantly higher detection rate for skeletal lesions compared to R-SS. Clinical and radiology expertise is required to avoid upstaging and overtreatment.

[Therapeutic Strategies In Children And Adolescents With Langerhans Cell Histiocytosis]. / Therapiestrategien bei Kindern und Jugendlichen mit Langerhanszell Histiozytosen.

The current standard therapy for children and adolescents with newly diagnosed Langerhans cell histiocytosis (LCH) is based on the two drugs prednisone and vinblastine. In patients with insufficient treatment response or disease relapse, the choice of second-line treatment depends on risk organ involvement (liver, spleen, and hematopoietic system). This article will give an overview of current data concerning therapeutic options in the different settings of children and adolescents with LCH. Due to limited evidence, these strategies have not been described in detail in the updated guidelines on pediatric LCH. In addition, the use of targeted therapy such as MAP-kinase inhibitors will be discussed. The reference center for LCH should be contacted if therapeutic options beyond the standard regimen are considered for treatment. All children and adolescents with LCH should be enrolled in registries or prospective studies.

[Updated AWMF Guideline on the Diagnosis and Treatment of Langerhans cell Histiocytosis in Children and Adolescents]. / Aktualisierte AWMF Leitlinie zur Diagnostik und Therapie der Langerhanszell Histiozytose (LCH) im Kindes- und Jugendalter.

Langerhans cell Histiocytosis is a rare neoplastic disease, which occurs mainly in children and adolescents. The disease may affect any organ, and therefore, the clinical symptoms vary widely. Some patients have a spontaneous remission of the disease, whereas others experience a rapid and potentially lethal clinical course. The therapeutic approach depends on the extent of the disease, and reaches from a watch-and-wait strategy to chemotherapy with the standard drugs vinblastine and prednisone. The identification of mutations in the MAPK-pathway resulted in growing interest in targeted therapy using compounds such as the BRAF inhibitors. Chronic relapses and permanent sequelae are important problems of LCH and are the focus of current research.

[Little frog in the mouth: a visual diagnosis?] / Fröschlein im Mund: eine Blickdiagnose?

Ranula, from the Latin "little frog", is a retention cyst filled with saliva in the oral cavity. Simple ranulas most commonly affect the sublingual gland and typically present as a hemispherical bluish cyst on the floor of the mouth, making it a visual diagnosis. A 7-year-old girl presented with a swelling on the underside of the tongue, an uncommon location for a ranula that made diagnostic assignment difficult. The optimal treatment of a ranula is still controversial in the literature. Many authors favor surgery as the treatment of choice. Our case shows that a watch and wait approach with simple mechanical pressure on the cyst can be sufficient.

Langerhans Cell Histiocytosis of the Orbit: Spectrum of Clinical and Imaging Findings.

OBJECTIVE: To evaluate the clinical and imaging characteristics of orbital lesions of pediatric Langerhans cell histiocytosis (LCH). STUDY DESIGN: A retrospective analysis of clinical data and central review of magnetic resonance imaging scans in patients with LCH, enrolled into one of the consecutive international trials LCH I-III, or submitted for a second opinion between 1994 and 2015. RESULTS: Data from 31 children (34 involved orbits) were analyzed. Orbital LCH was the only disease manifestation in 15, part of a multifocal skeletal in 5, or a multisystem LCH in 11 patients. Orbital LCH was part of the initial disease presentation in 23 or developed at relapse in 8 cases. Orbital involvement was unilateral in 28 and bilateral in 3 patients (34 affected orbits). Proptosis was present in 9 patients. Frontal and zygomatic bone were most commonly affected. All orbital lesions were extraconal. Associated extraorbital imaging findings were dural tail sign in 19, neurodegeneration in 8, and hypothalamic-pituitary mass in 3 patients. Sixteen patients (52%) had at least 1 documented disease relapse. Permanent consequences were prominent proptosis in 1, diabetes insipidus in 8, growth hormone deficiency in 2, radiologic neurodegeneration in 8, and clinical neurodegeneration in 3 patients. CONCLUSIONS: Predominantly unilateral orbital LCH can be the only disease manifestation or part of a disseminated disease. Orbital lesions in LCH are exclusively extraconal, typically located at the roof and the lateral wall of the orbit. The optimal treatment approach of unifocal LCH of the orbit remains controversial and warrants a prospective evaluation.

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

OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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 <2 years at diagnosis (13% vs 6% in those aged >2 years; 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). CONCLUSIONS: 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.

Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. In the HLH-94 study, with an estimated 5-year probability of survival (pSu) of 54% (95% confidence interval, 48%-60%), systemic therapy included etoposide, dexamethasone, and, from week 9, cyclosporine A (CSA). Hematopoietic stem cell transplantation (HSCT) was indicated in patients with familial/genetic, relapsing, or severe/persistent disease. In HLH-2004, CSA was instead administered upfront, aiming to reduce pre-HSCT mortality and morbidity. From 2004 to 2011, 369 children aged <18 years fulfilled HLH-2004 inclusion criteria (5 of 8 diagnostic criteria, affected siblings, and/or molecular diagnosis in FHL-causative genes). At median follow-up of 5.2 years, 230 of 369 patients (62%) were alive (5-year pSu, 61%; 56%-67%). Five-year pSu in children with (n = 168) and without (n = 201) family history/genetically verified FHL was 59% (52%-67%) and 64% (57%-71%), respectively (familial occurrence [n = 47], 58% [45%-75%]). Comparing with historical data (HLH-94), using HLH-94 inclusion criteria, pre-HSCT mortality was nonsignificantly reduced from 27% to 19% (P = .064 adjusted for age and sex). Time from start of therapy to HSCT was shorter compared with HLH-94 (P =020 adjusted for age and sex) and reported neurological alterations at HSCT were 22% in HLH-94 and 17% in HLH-2004 (using HLH-94 inclusion criteria). Five-year pSu post-HSCT overall was 66% (verified FHL, 70% [63%-78%]). Additional analyses provided specific suggestions on potential pre-HSCT treatment improvements. HLH-2004 confirms that a majority of patients may be rescued by the etoposide/dexamethasone combination but intensification with CSA upfront, adding corticosteroids to intrathecal therapy, and reduced time to HSCT did not improve outcome significantly.

Longitudinal assessment of peripheral blood BRAFV600E levels in patients with Langerhans cell histiocytosis.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a histiocytic disorder driven by a constitutive activation of the MAPK signaling pathway in myeloid cells. In 50-60% of cases, it is caused by the BRAFV600E mutation. There is evidence that levels of BRAFV600E in the peripheral blood of patients with LCH correlate with disease burden and could be used as marker for disease extent and response to therapy. However, there is currently no consensus on how testing for minimal disseminated disease should be performed. METHODS: Different approaches to determine the mutation load in patients with LCH were assessed and longitudinal evaluation of patient DNA during treatment with chemotherapy and/or the RAF inhibitor vemurafenib was performed. DNA was isolated from whole blood, different leukocyte subsets, and circulating cell-free DNA (ccf-DNA). RESULTS: We show that determining BRAF levels from whole blood is superior to using ccfDNA. Furthermore, it is important to identify the clinically relevant BRAF-mutated cellular subpopulations such as CD14+ monocytes or CD1c+ DCs, since other blood cells can also harbor the mutation and therefore confound whole blood or ccfDNA measurements. CONCLUSION: Our data support the view that single-agent treatment with an RAF inhibitor reduces disease activity but does not cure LCH.

Langerhans cell histiocytosis in children: History, classification, pathobiology, clinical manifestations, and prognosis.

Langerhans cell histiocytosis (LCH) is an inflammatory neoplasia of myeloid precursor cells driven by mutations in the mitogen-activated protein kinase pathway. When disease involves the skin, LCH most commonly presents as a seborrheic dermatitis or eczematous eruption on the scalp and trunk. Evaluation for involvement of other organ systems is essential, because 9 of 10 patients presenting with cutaneous disease also have multisystem involvement. Clinical manifestations range from isolated disease with spontaneous resolution to life-threatening multisystem disease. Prognosis depends on involvement of risk organs (liver, spleen, and bone marrow) at diagnosis, particularly on presence of organ dysfunction, and response to initial therapy. Systemic treatment incorporating steroids and cytostatic drugs for at least one year has improved prognosis of multisystem LCH and represents the current standard of care.

Langerhans cell histiocytosis in children: Diagnosis, differential diagnosis, treatment, sequelae, and standardized follow-up.

A definitive diagnosis of Langerhans cell histiocytosis (LCH) requires a combination of clinical presentation, histology, and immunohistochemistry. The inflammatory infiltrate contains various proportions of LCH cells, the disease hallmark, which are round and have characteristic "coffee-bean" cleaved nuclei and eosinophilic cytoplasm. Positive immunohistochemistry staining for CD1a and CD207 (langerin) are required for a definitive diagnosis. Isolated cutaneous disease should only be treated when symptomatic, because spontaneous resolution is common. Topical steroids are first-line treatment for localized disease of skin and bone. For multifocal single-system or multisystem disease, systemic treatment with steroids and vinblastine for 12 months is the standard first-line regimen. Current research is seeking more effective regimens because recurrence rates, which increase the risk of sequelae, are still high (30-50%) in patients with multisystem disease. An active area of research is the use of targeted therapy directed at the mitogen-activated protein kinase pathway. Adequate follow-up to monitor for disease progression, relapse, and sequelae is recommended in all patients.

A consensus review on malignancy-associated hemophagocytic lymphohistiocytosis in adults.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune activation and dysregulation resulting in extreme and often life-threatening inflammation. HLH has been well recognized in pediatric populations, and most current diagnostic and therapeutic guidelines are based on pediatric HLH. Recently there has been recognition of HLH in adults, especially secondary to immune deregulation by an underlying rheumatologic, infectious, or malignant condition. This review is focused on malignancy-associated HLH (M-HLH), in which possible mechanisms of pathogenesis include severe inflammation, persistent antigen stimulation by the tumor cells, and loss of immune homeostasis because of chemotherapy, hematopoietic stem cell transplantation, or infection. Previously considered rare, M-HLH may occur in up to 1% of patients with hematologic malignancies. M-HLH is often missed or diagnosed late in most published studies, and it has been associated with a poor median survival of less than 2 months. Identification of the clinical and laboratory features specific to M-HLH in adults may allow early detection, consultation with HLH experts, and intervention. Improved management of adult M-HLH with optimal combinations of T-lympholytic and immunosuppressive agents and the incorporation of novel agents based on the pediatric experience hopefully will improve outcomes in adults with M-HLH. Cancer 2017;123:3229-40. © 2017 American Cancer Society.

Two Novel Missense Mutations and a 5bp Deletion in the Erythroid-Specific Promoter of the PKLR Gene in Two Unrelated Patients With Pyruvate Kinase Deficient Transfusion-Dependent Chronic Nonspherocytic Hemolytic Anemia.

We report two children with severe chronic hemolytic anemia, the cause of which was difficult to establish because of transfusion dependency. Reduced erythrocyte pyruvate kinase activity in their asymptomatic parents provided the diagnostic clues for mutation screening of the PKLR gene and revealed that one child was a compound heterozygote of a novel paternally derived 5-bp deletion in the promoter region (c.-88_-84delTCTCT) and a maternally derived missense mutation in exon nine (c.1174G>A; p.Ala392Thr). The second child was a compound heterozygote of two novel missense mutations, namely a paternally derived exon ten c.1381G>A (p.Glu461Lys) and a maternally derived exon seven c.907-908delCC (p.Pro303GlyfsX12) variant.

Lack of bone lesions at diagnosis is associated with inferior outcome in multisystem langerhans cell histiocytosis of childhood.

Skeletal involvement is generally, but not universally, characteristic of Langerhans cell histiocytosis (LCH). We investigated whether the presence of bone lesions at diagnosis is a prognostic factor for survival in LCH. Nine hundred and thirty-eight children with multisystem (MS) LCH, both high (386 RO+) and low (RO-) risk, were evaluated for bone lesions at diagnosis. Risk organ (RO+) involvement was defined as: haematopoietic system (haemoglobin <100 g/l, and/or white blood cell count <4·0 × 10(9) /l and/or platelet count <100 × 10(9) /l), spleen (>2 cm below the costal margin), liver (>3 cm and/or hypoproteinaemia, hypoalbuminaemia, hyperbilirubinaemia, and/or increased aspartate transaminase/alanine transaminase). Given the general view that prognosis in LCH worsens with increasing extent of disease, the surprising finding was that in MS+RO+ LCH the probability of survival with bone involvement 74 ± 3% (n = 230, 56 events) was reduced to 62 ± 4% (n = 156, 55 events) if this was absent (P = 0·007). An even greater difference was seen in the subgroup of patients with both liver and either haematopoiesis or spleen involvement: 61 ± 5% survival (n = 105; 52 events) if patients had bony lesions, versus 47 ± 5% (n = 111; 39 events) if they did not (P = 0·014). This difference was retained in multivariate analysis (P = 0·048). Although as yet unexplained, we conclude that bone involvement at diagnosis is a previously unrecognized favourable prognostic factor in MS+RO+ LCH.

Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents.

Haemophagocytic lymphohistiocytosis (HLH) in the context of malignancy is mainly considered a challenge of adult haematology. While this association is also observed in children, little is known regarding inciting factors, appropriate treatment and prognosis. We retrospectively analysed 29 paediatric and adolescent patients for presenting features, type of neoplasm or preceding chemotherapy, treatment and outcome. Haemophagocytic lymphohistiocytosis was considered triggered by the malignancy (M-HLH) in 21 patients, most of whom had T- (n = 12) or B-cell neoplasms (n = 7), with Epstein-Barr virus as a co-trigger in five patients. In eight patients, HLH occurred during chemotherapy (Ch-HLH) for malignancy, mainly acute leukaemias (n = 7); an infectious trigger was found in seven. In M- and Ch-HLH, median overall survival was 1·2 and 0·9 years, and the 6 month survival rates were 67% and 63%, respectively. Seven of 11 deceased M-HLH patients exhibited active malignancy and HLH at the time of death, while only two out of five deceased Ch-HLH patients had evidence of active HLH. To overcome HLH, malignancy- and HLH-directed treatments were administered in the M-HLH cohort; however, it was not possible to determine superiority of one approach over the other. For Ch-HLH, treatment ranged from postponement of chemotherapy to the use of etoposide-containing regimens.

Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis.

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).