[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.

The Non-Langerhans Cell Histiocytoses (Rare Histiocytoses) - Clinical Aspects and Therapeutic Approaches.

Rare histiocytoses, also called non-Langerhans cell histiocytoses, include all proliferative disorders of histiocytes, macrophages and dendritic cells that are not classified as Langerhans cell histiocytosis (LCH) and do not belong to the hemophagocytic lymphohistiocytosis (HLH) group of diseases. Thus, the term includes numerous benign or malignant, localized or systemic, adult or pediatric diseases. The classification of the histiocytic disorders has been revised several times. Here, we follow the classification recently published by Jean Francois Emile and an international expert panel, defining subgroups of histiocytoses described as L-Group, C-Group, M-Group, R-Group, and H-Group, which stands for LCH-like, cutaneous or mucocutaneous, malignant, Rosai-Dorfman-Disease like and HLH like. Some of the diseases have an excellent prognosis after resection or even disappear spontanously, others progress rapidly, requiring intensive systemic therapies. The malignant non-Langerhans cell histiocytoses in general have a poor prognosis, here, complex chemotherapy protocols are usually applied, with inconsistant results. An interesting perspective in non-malignant rare histiocytoses might be small molecular inhibitors, in particular BRAF inhibitors, since BRAF mutations have been found in some subtypes of non-Langerhans cell histiocytoses. By prospective and retrospective collection of experiences in a new registry (the "International Rare Histiocytic Disorders Registry", IRHDR), knowledge about these rare diseases might hopefully be improved.

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.

Multicentric reticulohistiocytosis and fibroblastic rheumatism.

Multicentric reticulohistiocytosis (MRH) and fibroblastic rheumatism (FR) are uncommon disorders with similar joint and skin manifestations. They are usually included among the non-Langerhans histiocytoses, but recent insights drive some criticism. The diagnosis is often challenging and must be confirmed by the histological typical features. If the skin manifestations are missing, the arthritic complaints may be confused with those of other rheumatic disorders. In these cases, only a careful clinical and radiological evaluation leads to the correct diagnosis. The natural course of the diseases may rapidly develop into disabling manifestations, making an aggressive treatment strongly recommendable. There is emerging evidence that anti-tumour necrosis factor-α agents and bisphosphonates are promising drugs for MRH, while a course of methotrexate and steroids seems to be the best option for FR. Finally, the clinician should be aware that in many cases MRH, but not FR, is associated with a large number of systemic manifestations and with malignancy. This eventuality must be accurately ruled out.

High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses.

Histiocytoses are rare disorders of unknown origin with highly heterogeneous prognosis. BRAF mutations have been observed in Langerhans cell histiocytosis (LCH). We investigated the frequency of BRAF mutations in several types of histiocytoses. Histology from 127 patients with histiocytoses were reviewed. Detection of BRAF(V600) mutations was performed by pyrosequencing of DNA extracted from paraffin embedded samples. Diagnoses of Erdheim-Chester disease (ECD), LCH, Rosai-Dorfman disease, juvenile xanthogranuloma, histiocytic sarcoma, xanthoma disseminatum, interdigitating dendritic cell sarcoma, and necrobiotic xanthogranuloma were performed in 46, 39, 23, 12, 3, 2, 1, and 1 patients, respectively. BRAF status was obtained in 93 cases. BRAF(V600E) mutations were detected in 13 of 24 (54%) ECD, 11 of 29 (38%) LCH, and none of the other histiocytoses. Four patients with ECD died of disease. The high frequency of BRAF(V600E) in LCH and ECD suggests a common origin of these diseases. Treatment with vemurafenib should be investigated in patients with malignant BRAF(V600E) histiocytosis.

Progressive nodular histiocytosis: a case report with literature review, and discussion of differential diagnosis and classification.

Histiocytoses are a heterogeneous group of disorders which are difficult to categorize because of overlapping clinical and microscopic features, and incompletely understood mechanisms of cellular origin and triggers of proliferation. Progressive nodular histiocytosis (PNH) is a rare non-Langerhans cell histiocytic (NLH) disorder. We present the case of a 34-year-old woman with PNH, who has involvement of the back, head and neck, face, and uniquely, extensive involvement of the posterior pharynx and larynx, which has shown progressive worsening and deformity over a 7-year course. Clinically it is best classified as PNH, although it microscopically closely resembles juvenile and adult xanthogranulomatosis. This study reinforces the concept that the NLH is a closely related group of disorders, possibly representing a spectrum of a single underlying process.

Unusual variants of non-Langerhans cell histiocytoses.

Histiocytic syndromes represent a large, heterogeneous group of diseases resulting from proliferation of histiocytes. In addition to the classic variants, the subset of non-Langerhans cell histiocytoses comprises rare entities that have more recently been described. These last include both forms that affect only the skin or the skin and mucous membranes, and usually show a benign clinical behavior, and forms involving also internal organs, which may follow an aggressive course. The goal of this review is to outline the clinical, histologic, and ultrastructural features and the course, prognosis, and management of these unusual histiocytic syndromes.

Primary adult-onset macrophage activation syndrome with multisystemic tissue phagocytosis.

The histiocyte disorders are divided into the following 3 categories according to the specific lineage of the histiocytes involved and their biological behavior: the dendritic cell-related disorders, which include Langerhans cell histiocytosis and dermal dendrocyte disorders; the macrophage cell disorders, hemophagocytic lymphohistiocytosis being the main entity; and the malignant histiocyte disorders. We present a case of a 36-year-old woman who was referred to our hospital because of fever of unknown origin, lethargy, anemia, and impaired hepatic function. Following a thorough investigation, we diagnosed extensive histiocyte-mediated phagocytosis in many areas (skin, liver, bone marrow), without any identifiable cause. The disease was controlled by immunosuppressive therapy, and the patient remains in complete remission. This case supports the concept of idiopathic generalized histiocyte activation as a distinct entity; this putative disease entity produces massive phagocytosis, regardless of the type of histiocyte differentiation. Similar cases necessitate further study for classification and management.

[Progressive nodular histiocytosis--rare variant of cutaneous non-Langerhans cell histiocytosis]. / Progressive noduläre Histiozytose--seltene Variante einer kutanen Non-Langerhanszell-Histiozytose.

Progressive nodular histiocytosis is an extremely rare skin disease is clinically characterized by the coincidence of two distinct lesions, namely, superficial xanthomatous papules up to 5 mm and deep nodules and tumors 1-3 cm. Histologically the nodules represent spindle cell xanthogranulomas. We report a 24-year-old women with these findings. The distinction from other non-Langerhans cell histiocytoses, in particular multiple juvenile xanthogranulomas, which may be more likely to show spontaneous remission, is somewhat unclear; patients with progressive nodular histiocytosis usually follow a serious and disfiguring clinical course.

[Diffuse cutaneous reticulohistiocytosis]. / Reticulohistiocitosis cutánea difusa.

The reticulohistiocytoses make up a heterogeneous group of diseases whose origin lies in an accumulation of cells of histiocytic lineage in different tissues and primarily in the skin. Three main clinical forms have been described (multicentric, solitary, diffuse cutaneous), which present with identical histological, ultrastructural and immunohistochemical characteristics. We present a case of diffuse cutaneous reticulohistiocytosis, which is the least common clinical pattern in the spectrum of this disease.

Uncommon histiocytic disorders: the non-Langerhans cell histiocytoses.

BACKGROUND: Histiocytic disorders are currently identified by their component cells. The non-Langerhans Cell Histiocytoses (non-LCH) are a group of disorders defined by the accumulation of histiocytes that do not meet the phenotypic criteria for the diagnosis of Langerhans cells (LCs). The non-LCH consist of a long list of diverse disorders which have been difficult to categorize. A conceptual way to think of these disorders that make them less confusing and easier to remember is proposed based on immunophenotyping and clinical presentation. RESULTS: Clinically the non-LCH can be divided into 3 groups, those that predominantly affect skin, those that affect skin but have a major systemic component, and those that primarily involve extracutaneous sites, although skin may be involved. Immunohistochernically many of the non-LCH appear to arise from the same precursor cell namely the dermal dendrocyte. Juvenile Xanthogranuloma (JXG) is the model of the dermal dendrocyte-derived non-LCH. Other non-LCH with differing clinical presentation and occurring at different ages but with an identical immunophenotype appear to form a spectrum of the same disorder, deriving from the same precursor cell at different stages of maturation. They should be considered as members of a JXG family. Non-JXG family members include Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). CONCLUSION: The non-LCH can be classified as JXG family and non-JXG family and subdivided according to fairly clear-cut clinical criteria. Utilization of this type of approach will allow better categorization, easier review of the literature and more accurate therapy decision-making.

[Langerhans and non-Langerhans histiocytosis]. / Histiocytoses langerhansiennes et non langerhansiennes.

Although Langerhans cell histiocytosis (LCH) was described a century ago, its cause and pathogenesis are still unknown. A wide spectrum of disease and variable clinical behavior are characteristic. The clinical varieties of this enigmatic disease range from a lethal leukemia-like disorder that primarily affects infants to a curable solitary lytic lesion of bone. LCH is a clonal proliferative disorder of histiocytes that resembles in morphology and phenotype the dendritic antigen-presenting Langerhans' cells of the skin and other organs. Despite gaps in understanding, significant improvements in the therapies for this disease have been made. Careful risk stratification is critical for the appropriate administration of therapy. Patients with good prognostic factors may need only observation as their disease spontaneously regresses, or minimal intervention. The active search for more effective treatments for patients with poor prognostic features is a major future challenge for the Histiocyte Society.

Recent developments in the management of haemophagocytic lymphohistiocytosis.

Over the past two decades, the underlying pathophysiology of haemophagocytic lymphohistiocytosis (HLH) (synonyms: haemophagocytic syndrome, macrophage activation syndrome) has been well recognised. Cytokine storm plays a major role, which derives from an inappropriate immune reaction caused by proliferating and activated T-cell or natural killer (NK) cells associated with macrophage activation and inadequate apoptosis of immunogenic cells. Many biological parameters reflecting activity of disease or response to treatment have been identified, in particular, serum ferritin has been confirmed to be one of the markers for HLH. The common types of HLH consist of non-hereditary (acquired) infection-associated disease such as Epstein-Barr virus (EBV)-haemophagocytic lymphohistiocytosis (HLH) and hereditary (familial) disease such as FHL, in which, at the molecular level, dysfunctional perforin was clarified. Regarding the therapeutic strategies, prompt differential diagnosis of underlying disease is essential and choice of treatment should be based on the risk (low or high) of prognosis, where either cyclosporin A, steroids or iv. immunoglobulin (IVIG) may be indicated as initial treatment for low-risk patients, with etoposide-containing regimens for high-risk patients. Significant improvement of prognosis has been obtained by incorporating intensive supportive care at the disease onset and prompt introduction of immunosuppressants to control cytokine storm. Subsequent immunochemotherapy and haemopoietic stem cell transplantation have contributed significantly to further improve survival of hereditary and refractory HLH patients.

Síndrome hemofagocítico en pediatría / Hemophagocytic syndrome in pediatrics

El síndrome hemofagocítico, también conocido como síndrome de activación del macrófago o histiocitosis reactiva, es una entidad nosológica heterogénea que fue descrita por vez primera hace más de 60 años. Su etiología es aún desconocida, pero se ha relacionado con un descontrol y respuesta exagerada del sistema inmunológico. Tiene una incidencia de 1-2 por cada millón de niños sin predominio de edad o sexo. Las manifestaciones clínicas incluyen la presencia de síndrome febril, hepatoesplenomegalia, alteraciones de la coagulación, disfunción hepática, trastornos neurológicos y falla orgánica múltiple. En los estudios paraclínicos se demuestra pancitopenia y especialmente en el mielograma una franca hemofagocitosis. El tratamiento es variado, dependiendo de la causa desencadenante. El pronóstico también depende directamente del tipo de síndrome hemofagocítico de que se trate. La mortalidad promedio puede ser de 60 por ciento.