What is Histiocytic Disorder?

introduction
Classification
Pathophysiology
Reference
Further reading

Histiocytic disorders are a group of disorders that arise from the overproduction of histiocytic white blood cells called histiocytes. ‘Histiocytosis’, meaning ’tissue cell’, is a general concept for a disease exemplified by myeloid cells, i.e. mononuclear phagocytes, which share histological features with macrophages or dendritic cells.

Classification

Histiocytic disorders were initially classified by the histologic features of the pathological cells as compared to their putative physiological counterparts. There are competing systems for classifying histiocytosis. According to the World Health Organization (WHO), they can be divided into three categories as proposed in the 1999 classification:

- Langerhans cell histiocytosis: may be localized and asymptomatic, as in isolated bone lesions, or may involve multiple organs and systems. LCH mainly affects children < 10 years. Adults are also affected (usually in the third to fifth decades of life). The clinical manifestations and extent of the disease are defined, therefore, depending on the location of the lesion, the organs and systems involved, and their function.
  - Limited LCH: Limited LCH involves skin lesions without involvement of other sites. Among these, patients may present with a solitary (monostotic) lesion with or without diabetes insipidus, involvement of adjacent lymph nodes, or a rash.
  - Extensive LCH: In polyostotic lesions, patients may present with multiple sites of involvement i.e., multiple bones involved or more than two lesions observed in one bone, with or without diabetes insipidus, involvement of adjacent lymph nodes, or rash. Extensive LHC involves involvement of visceral organs with or without bony lesions, diabetes insipidus, involvement of adjacent lymph nodes, and/or rash. In addition, patients may or may not show signs of liver, hematopoietic system, or lung dysfunction. Lesions to the spleen, liver and bone marrow are considered high risk because of the increased potential for death compared to other low risk sites.

LCH-associated neurodegeneration (LCH-ND) is a severe complication that can arise with systemic symptoms or several years following an initial LCH diagnosis. LCH-NF shows clinical signs of cerebella dysfunction and abnormal MRI findings in the cerebellum, pons, and brain stem. Positive clinical responses have been demonstrated with chemotherapy and MAPK inhibitors.

Class II
- Non-Langerhans cell histiocytosis
  - Hemophagocytic Lymphohistiocytosis (HLH): this is a syndrome of extreme immune activation. HLH has been divided into primary and secondary forms. The main form is genetic. Primary HLH is caused by a predisposition to inherited defects resulting from pathogenic variants in genes that form part of inflammatory function, cellular cytotoxicity, and other cellular functions. Secondary HLH appears in the absence of an underlying defect in cytotoxicity. Secondary forms of HLH often occur in association with a strong immunological stimulus – usually infection, malignancy, autoimmune or autoinflammatory conditions. in the absence of rapid immune suppression, children, as well as adults, are at high risk of death in cases where they present with clinical and laboratory findings that reflect pathological information. For long-term survival in patients with persistent immune defects associated with HLH, allogeneic hematopoietic stem cell transplantation is required.
Class III
- Malignant Histiocytic Disorder

Classification of histiocytic disorders is necessary to ensure optimal treatment. While there are dozens of types of histiocytosis, the most common include Class I LCH, and the Class II Erdheim–Chester disease (ECD), juvenile xanthogranuloma (JXG), Rosai–Dorfman disease (RDD; sometimes known as Rosai–Dorfman–Destombes disease) and HLH. The first four diseases demonstrate characteristics of malignant cells, although the implications of oncogenic drivers on classification as ‘cancer’ is a contentious topic.

Related: Haemophilia Causes

Pathophysiology

LCH, ECD, JXG, RDD, and HLH are characterized by the accumulation of cells in various tissues. All of these histiocytic disorders co-present with intense inflammatory infiltrate that has a fundamental role in producing organ specific lesions on clinical symptoms. However, the pathological cell may have a different origin and or phenotype in each condition. Although there is overlapping physiology between LCH, JXG, RDD, and ECD, associated with the accumulation of mononuclear phagocytes, the origin of HLH differs significantly, primarily involving activated CD8+ T cells that subsequent drive macrophage activation and extreme systemic inflammation.

Numerous types of histiocytosis have been reviewed in the literature. Overarchingly, they represent a collection of disorders that share a terminal phenotype with features that are congruent with mononuclear phagocytotic cells. LCH, ECD, JXG, and some cases of RDD represent clonal disorders associated with oncogene drivers, which cause aberrant differentiation of myeloid precursors.

Treatment strategies for the variety of these disorders depend on the type of disease and elucidation of optimal therapeutic strategies are often uncertain for most patients. Cytotoxic therapies are often used to cure patients with systemic LCH, ECD, JXG, and RDD – the goal of this is to clear the pathogenic clone.

More recently, MAPK pathway inhibitors are being evaluated for the treatment of subtypes that are driven by MAPK pathways. While many trials have shown high response rates, it has been shown that cessation of MAPK inhibition may result in recurrence. In addition to these two treatment modalities, modulation of the immune system may be used to control inflammation and manage symptoms. Prompt initiation of immune suppression is essential in HLH and hematopoietic stem cell transplantation is necessary when patients present with intractable immune dysfunction.

Histiocytic disorders

Search This Blog

Vly News - Professional news Platform