Histiocitosis: a propósito de dos casos clínicos / Histiocytosis: report of two clinical cases

INTRODUCCIÓN: La histiocitosis es una patología infrecuente consistente en una proliferación incontrolada y acumulación de células de Langerhans, más frecuente en hueso con una clínica poco específica. El número y tipo de órganos afectados es lo que marca la clasificación y la necesidad de tratamiento quimioterápico en esta patología. Caso clínico 1: Presentamos un caso de histiocitosis ósea que es interpretado inicialmente como hematoma. Caso clínico 2: Presentamos un caso de histiocitosis ósea que debuta como otorrea de 4 semanas de evolución, siendo diagnosticada al inicio de otitis purulenta. CONCLUSIONES: A pesar de su rareza, la histiocitosis es una enfermedad a tener en cuenta al evaluar la persistencia de lesiones, tumoraciones o patología que en un primer momento puede parecer banal. Los avances respecto al conocimiento de la patogénesis de esta enfermedad y el descubrimiento de genes implicados abren el camino a nuevas terapias dirigidas

INTRODUCTION: Histiocytosis is an uncommon pathology, consisting of an uncontrolled proliferation and accumulation of Langerhans cells. It most often affects the bones with an unspecified clinical presentation. The amount and kind of affected organs is what marks the classification and the necessity of chemotherapy treatment in this pathology. Clinical case 1: We present a case of histiocytosis of bone initially interpreted as an hematoma. Clinical case 2: We present a case of histiocytosis of bone which starts as an otorrhea lasting 4 weeks. It was diagnosed at the beginning with purulent otitis. CONCLUSIONS: Despite its infrequency, histiocytosis is a disease that should be considered when assessing the persistence of lesions, tumors or pathology that may initially seem banal. Advances in the knowledge of the pathogenesis of this disease and the discovery of the genes involved open the way to new targeted therapies

[Histiocytosis in the dermatological context of the new classification]. / Histiozytäre Neoplasien im Kontext der aktuellen Klassifikation.

Histiocytoses comprises a heterogeneous group of inflammatory diseases for which dendritic cells and macrophages are the main cellular components. The inflammatory infiltrate can affect the skin and other organs, and clinical outcome varies from mild to lethal depending on the involved cell subset and organ infiltration as well as comorbidities. Until recently, the group of histiocytosis was divided into Langerhans cell histiocytosis, non-Langerhans cell histiocytosis and malignant histiocytosis. With the new classification from JF Emile et al., the subgroups were determined regarding clinical, histiopathological, radiological, phenotype, genetic, and molecular features. In this review, we explain the revised classification with emphasis on dermatological and molecular aspects.

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.

[BRAF-V600E mutation and its clinical significance in children with Langerhans cell histiocytosis].

OBJECTIVE: To investigate the clinical significance of BRAF-V600E mutation in children with Langerhans cell histiocytosis (LCH). METHODS: Real-time fluorescence quantitative PCR was used to detect BRAF-V600E mutation in paraffin-embedded tissue samples from 26 children with LCH. A retrospective analysis was performed for the association of BRAF-V600E mutation with clinical features and prognosis of children with LCH. RESULTS: Of the 26 children, 25 received standard chemotherapy, with a 2-year overall survival (OS) rate of 100% and a 2-year event-free survival (EFS) rate of 88%. Of the 26 pathological samples, 18 (70%) came from bone tissue, and the positive rate of BRAF-V600E mutation reached 50% (13/26). The positive rate of BRAF-V600E gene mutation was not associated with age, sex, affected organ, clinical classification, early treatment response, recurrence, and 2-year OS and EFS rates of the children with LCH (P>0.05), but it was associated with clinical grouping of LCH (P<0.05). CONCLUSIONS: Children with LCH tend to have a high OS rate and a high incidence rate of BRAF-V600E mutation. BRAF-V600E mutation is associated with clinical grouping of LCH.

Nueva clasificación de las histiocitosis / New classification of histiocytosis

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[Neuro-Langerhans cell histiocytosis]. / Neurohistiocytose langerhansienne.

Langerhans cell histiocytosis (LCH) is a rare multisystemic disease. LCH is characterized by proliferation of myeloid progenitors with altered differentiation program and similar phenotypic features to epidermal dendritic cells termed Langerhans cell. LCH cells express CD1a+ and langerin and exhibit BRAF V600E mutation in ∼50% of cases. Neurological involvement or neuro-LCH is observed in 5 to 10% of cases. Three subtypes of neuro-LCH are individualized. The tumor type, accounting for 45% of neuro-LCH, affect mainly young adults. Tumor neuro-LCH is characterized by space occupying lesion(s) with contrast enhancement on MRI. Clinical symptoms are due to tumor brain location(s). Pathological examination of tumor neuro-LCH lesions reveals typical features of LCH. Treatment relies on surgical resection with/without chemotherapy. Degenerative neuro-LCH, accounting for 45% of cases, is usually revealed, mostly in children, by: (i) a cerebellar syndrome, (ii) a pyramidal syndrome, (iii) a pseubulbar palsy, and/or (iv) cognitive disorders. On MRI, several signs may coexist: (i) cortex atrophy, (ii) white matter T2 hyperintensities, and (iii) deep gray matter T1 hyperintensities. Pathological analysis of degenerative neuro-LCH lesions have been rarely performed and have never detected CD1a+ histiocytes but unspecific lesions (i.e. gliosis, neuronal loss and/or demyelination). Treatment of degenerative neuro-LCH patients is poorly standardized and poorly efficient. Functional rehabilitation and socio-educational care of these young patients are crucial. The mixed subtype of neuro-LCH combines clinico-radio-pathological characteristics of the first two first forms in the same patient, and represents 10% of neuro-HL. Neuro-HL, therefore, includes three very distinct entities with epidemiological, clinical, radiological and histological specific features requiring specific medical management.

Langerhans Cell Histiocytosis and Langerhans Cell Sarcoma: Current Understanding and Differential Diagnosis.

Langerhans cell (LC) histiocytosis (LCH) and LC sarcoma (LCS) are proliferative processes consisting of cells having morphologic and phenotypic features of Langerhans cells (LCs), although the latter may have lost some of these features. Because neoplastic nature of LCH as well as LCS is more likely by recent studies, a category of LC hyperplasia can be better characterized. LCH and LCS are rarely seen in daily pathology practice, but it is important to accurately characterize these lesions. For this purpose, an outline covering proliferations of LC and related cells was constructed. The scheme of this outline is based especially on evaluating borderline lesions, neoplastic trans-differentiation, and degree of similarity with the normal counter-parts. In addition, the organization and update of the current classification scheme for histiocytic and dendritic-cell proliferations is presented.

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.

Histologic patterns of thymic involvement in Langerhans cell proliferations: a clinicopathologic study and review of the literature.

Thymic involvement by Langerhans cell histiocytosis (LCH) has been described mainly in isolated case reports. A description of the histopathologic patterns of LCH proliferations in the thymus, together with therapeutic implications, has not, to our knowledge, been previously addressed. The pathology consultation files at Children's Hospital of Pittsburgh of the University of Pennsylvania Medical Center were reviewed for cases of thymic involvement by LCH. Relevant cases in the literature were also reviewed, and the histopathology and clinical course of those cases were collected. Nine consultation cases of thymic involvement were reviewed, together with 23 cases in the literature, which provided adequate pathologic description and ancillary confirmation (n  =  32), revealing 4 distinct pathologic groups. Group 1 showed microscopic collection of hyperplastic LCH-like cells in incidental thymectomies of patients without LCH disease, requiring no further treatment (n  =  7; 22%). Group 2 showed solitary and/or cystic LCH of the thymus with gland disruption, and at least 3 cases resolved without systemic therapy (n  =  10; 31%). Group 3 showed more variable thymic involvement in multisystemic LCH disease, with either a medullary restricted pattern or more diffuse gland involvement, requiring adjuvant therapy and having a higher mortality rate (n  =  13; 41%). Group 4 showed a mixed histiocytic lesion with a concurrent LCH and juvenile xanthogranuloma-like proliferation (n  =  2; 6%). Thymic involvement in LCH is quite rare. Based on our cases and those in the literature, we propose 4 distinct pathologic groups of thymic involvement in Langerhans cell proliferations with relevance for diagnosis and treatment.

Progress in understanding the pathogenesis of Langerhans cell histiocytosis: back to Histiocytosis X?

Langerhans cell histiocytosis (LCH), the most common histiocytic disorder, is characterized by the accumulation of CD1A(+) /CD207(+) mononuclear phagocytes within granulomatous lesions that can affect nearly all organ systems. Historically, LCH has been presumed to arise from transformed or pathologically activated epidermal dendritic cells called Langerhans cells. However, new evidence supports a model in which LCH occurs as a consequence of a misguided differentiation programme of myeloid dendritic cell precursors. Genetic, molecular and functional data implicate activation of the ERK signalling pathway at critical stages in myeloid differentiation as an essential and universal driver of LCH pathology. Based on these findings, we propose that LCH should be re-defined as an inflammatory myeloid neoplasia. Increased understanding of LCH pathogenesis will provide opportunities to optimize and personalize therapy through improved risk-stratification, targeted therapy and assessment of therapy response based on specific molecular features and origin of the pathological myeloid cells.

Langerhans cell histiocytosis: 23 years' paediatric experience highlights severe long-term sequelae.

PURPOSE: To review the presentation and outcome of patients with Langerhans cell histiocytosis attending The Royal Hospital for Sick Children, Glasgow over a 23-year period. METHOD: Thirty-one children were diagnosed with Langerhans cell histiocytosis between January 1990 and December 2012. Retrospective information from medical records was gathered on age at diagnosis, presenting symptoms, classification of disease, treatment and long-term outcome. RESULTS: There were 17 boys and 14 girls; median age at diagnosis 2 years 9 months (interquartile range: 1 year 6 months to 4 years 4 months). Eleven were below 2 years and two were below 6 months of age at diagnosis. Eighteen (58%) children had single system disease of which four were multifocal; 13 (42%) had multisystem disease. Seventeen children improved with conservative treatment. Fourteen required steroids and dual agent chemotherapy; three required further chemotherapy. One child died. Two children had successfully treated relapses. Ten developed diabetes insipidus, seven were growth hormone deficient, two suffered from hypothyroidism and one panhypopituitarism. Median follow-up of the cohort was 8 years 10 months (interquartile range: 5 years 5 months to 12 years 7 months). CONCLUSION: Langerhans cell histiocytosis is a rare disease in infants and young children, with a variable course ranging from self-limiting to life threatening. In very young children (under 2 years of age), multisystem disease is more common, requiring intensive chemotherapy and lifelong follow-up. Lasting sequelae were identified in over a third of patients, including endocrine dysfunction, hearing difficulties, neurological and psychological problems.

IL-17A receptor expression differs between subclasses of Langerhans cell histiocytosis, which might settle the IL-17A controversy.

Langerhans cell histiocytosis (LCH) is a lymphoproliferative disorder consisting of abnormal Langerhans cell-like cells and other lymphoid cells. LCH presents as either a multisystem LCH (LCH-MS) or a single-system LCH (LCH-SS). Currently, neither the pathogeneses nor the factors that define these disease subclasses have been elucidated. The interleukin (IL)-17A autocrine LCH model and IL-17A-targeted therapies have been proposed and have engendered much controversy. Those authors showed high serum IL-17A levels in LCH and argued that serum IL-17A-dependent fusion activities in vitro, rather than serum IL-17A levels, correlated with LCH severity (i.e. the IL-17A paradox). In contrast, others could not confirm the IL-17A autocrine model. So began the controversy on IL-17A, which still continues. We approached the IL-17A controversy and the IL-17A paradox from a new perspective in considering the expression levels of IL-17A receptor (IL-17RA). We detected higher levels of IL-17RA protein expression in LCH-MS (n = 10) as compared to LCH-SS (n = 9) (P = 0.041) by immunofluorescence. We reconfirmed these data by re-analyzing GSE16395 mRNA data. We found that serum levels of IL-17A were higher in LCH (n = 38) as compared to controls (n = 20) (P = 0.005) with no significant difference between LCH subclasses. We propose an IL-17A endocrine model and stress that changes in IL-17RA expression levels are important for defining LCH subclasses. We hypothesize that these IL-17RA data could clarify the IL-17A controversy and the IL-17A paradox. As a potential treatment of LCH-MS, we indicate the possibility of an IL-17RA-targeted therapy.

Langerhans cell histiocytosis: two clinical presentations in the same patient.

Langerhans cell histiocytosis (LCH) is a heterogeneous group of diseases characterized by a pathological proliferation of cells phenotypically similar to Langerhans cells. The disease course is variable, alternating between resolving and potentially fatal forms. The diagnosis is based on clinical appearance and confirmed by CD1a positivity and / or immunohistochemistry. We report the case of a male child of 3 months with two different presentations of Langerhans cell-histiocytosis (LCH) at different times. The first presentation was classified as a self-healing LCH (formerly known as Hashimoto-Pritzker). The last presentation, although clinically suggestive of Letterer-Siwe (former designation), was not associated with systemic disease. This emphasizes that LCH cannot be compartmentalized into four groups, but considered a single disease with a wide spectrum of clinical presentations. This case underscores the importance of frequent and long-term follow-up of these patients.

[Reactive and neoplastic histiocytic diseases in the dog]. / Reaktive und neoplastische histiozytäre erkrankungen beim hund.

There are different histiocytic diseases in dogs that are characterized by the proliferation of histiocytic cells (macrophages and myeloid dendritic cells). Histiocytic diseases can be devided into neoplastic (cutaneous histiocytoma complex, histiocytic sarcoma, dendritic cell leukaemia) and reactive forms (reactive histiocytosis, haemophagocytic syndrome). All subtypes of the cutaneous histiocytoma complex (cutaneous histiocytoma, metastatic histiocytoma and Langerhans' cell histiocytosis) are of Langerhans' cell origin. Histiocytoma, which is a solitary tumour of the skin in young dogs, shows spontaneous regression in most cases. Occasionally, metastasis to lymph nodes can be seen (metastatic histiocytoma). Only one dog with Langerhans' cell histiocytosis has been described and was euthanized. Histiocytic sarcoma, which arises from myeloid dendritic cells, can be classified as localised histiocytic sarcoma or disseminated histiocytic sarcoma. Another form of histiocytic sarcoma - haemophagocytic histiocytic sarcoma - is derived from macrophages. Histiocytic sarcoma displays a very aggressive clinical course and has a poor prognosis. Breed predispositions have been reported for the disseminated and haemophagocytic form of histiocytic sarcoma in Bernese mountain dogs, Rottweilers and varoiusretrievers. In contrast, reactive histiocytosis (cutaneous and systemic forms) develops by reactive proliferation of interstitial dendritic cells. In systemic histiocytosis, breed predilections are similar to histiocytic sarcoma. Haemophagocytic syndrome develops as a consequence of proliferation of activated macrophages in different tissues. Prognosis in general is moderate to poor and depends on the origin of the underlying disease process.

[Langerhans cell histiocytosis]. / Histiocytose langerhansienne.

Langerhans cell histiocytosis (ex histiocytosis X) is usually present in children. It is a clonal proliferation of non-functional Langerhans's cells. Histological aspects are variable. The diagnosis is made in immunolabeling by anti-CD1a. Clinical presentations are variable, depending on their extension. Three syndromes are actually the same pathogenic process: eosinophilic granuloma (single or multiple osseous localizations), Hand-Schüller-Christian disease (chronic form with bone and visceral dissemination) and Abt-Letterer-Siwe disease (disseminated and acute malignant presentation).

Langerhans cell histiocytosis: oral/periodontal involvement in adult patients.

OBJECTIVE: Langerhans cell histiocytosis (LCH) is a clonal proliferative multisystem disease. Although bone and mucosae have been classified as non-risk organs, their involvement may increase the risk of disease progression. Oral and periodontal lesions are burdened with a significant impairment of quality of life for associated signs, symptoms and loss of function. Most of information regards paediatric disease; the disease in adults has received limited attention. SUBJECTS AND METHODS: A total of 31 adult patients affected by immuno-histopathology confirmed LCH have been prospectively examined; attention was paid to the occurrence and characterization of oral lesions. RESULTS: Twelve patients developed oral lesions. Posterior regions of jawbones were always affected; the involvement of anterior regions was not constant. Unifocal oral involvement was significantly associated with multisystemic disease while multifocal lesions were associated with unisystemic disease. Oral disease presented with soft tissue ulcers (50% of cases), gingival bleeding (66.7%), pain (83.4%), periodontal damage (50%), tooth mobility (16.7%), non-healing extraction socket (8.3%); 41.6% of patients complained of negative outcomes on quality of life. Oral lesions were easily handled with local measures. CONCLUSIONS: Posterior regions require attention; single oral lesions may be part of multisystemic disease; oral and periodontal lesions may be early signs of disease reactivation.

Langerhans cell histiocytosis with multifocal bone lesions: comparative clinical features between single and multi-systems.

Langerhans cell histiocytosis (LCH) can be a single system or multi-system disease. Both disease types can be associated with multi-focal bone lesions, but their bone involvement patterns have not been compared systematically. Of the new pediatric LCH cases enrolled into the JLSG-02 study during 2002-2007, 67 cases of single system multifocal bone (SMFB) LCH and 97 cases of multi-system bone (MSB) LCH were analyzed to determine if the bone involvement patterns differ in these two types, and whether these differences correlate with outcome. Statistical analysis was performed with Mann-Whitney U test, Fisher's exact test, and other measures. Onset ages were higher for SMFB (P < 0.001), but the two types did not differ in the number of bone lesions per patient. The skull was most frequently affected in both types, followed by the spine. Lesions in the temporal bone (P = 0.002), ear-petrous bone (P < 0.001), orbita (P = 0.003), and zygomatic bone (P = 0.016) were significantly more common in MSB. The two types did not differ in response to treatment, but MSB was associated with a significantly higher incidence of diabetes insipidus (DI) (P < 0.001). Novel measures are required in preventing the development of DI in MSB-type LCH patients with "risk" bone lesions.

Langerhans cell histiocytosis: an update.

The histiocytoses represent a heterogeneous group of disorders that are characterized by the proliferation and accumulation of reactive or neoplastic histiocytes within various tissues. Langerhans cell histiocytosis (LCH) is the commonest of these disorders and it is associated with high morbidity and mortality, especially in children. LCH is a poorly understood disease with features suggestive of a neoplastic, reactive, or immune dysregulation process. The clinical spectrum of LCH is considered to be broad and includes from self-resolving involvement of a single organ to a potentially fatal multisystem disease. The purpose of this review is to undertake an update of LCH with emphasis on the current recommendations regarding the classification, evaluation and treatment of this enigmatic disease.