Pediatric histiocytic disorders: morphology, immunophenotype and genetics

Histiocytic disorders in children are marked by the abnormal proliferation of cells from the mononuclear phagocyte system, which includes dendritic cells, monocytes, and macrophages. These cells, derived from common myeloid progenitors, exhibit diverse terminal immunophenotypes. The classification of these disorders has evolved significantly, with the early Working Group of Histiocytoses distinguishing them into Langerhans cell histiocytosis (LCH), non-Langerhans histiocytosis, and malignant histiocytosis based on antigen expression and clinical features. Over the past decades, the understanding of these disorders has deepened, leading to more precise diagnostic criteria and better therapeutic strategies.

LCH

LCH is a clonal proliferative disorder of Langerhans cells, which are specialized dendritic cells involved in antigen presentation. It presents with a spectrum of clinical symptoms ranging from single-system involvement, such as isolated bone lesions, to multisystem disease affecting organs like the liver, spleen, and hematopoietic system. The diagnostic hallmark of LCH is the presence of Birbeck granules on electron microscopy and positive staining for CD1a and langerin (CD207). Recent genetic studies have identified BRAF V600E mutations in a significant subset of LCH cases, providing potential targets for therapy. The discovery of this mutation has revolutionized the treatment approach, leading to the use of targeted therapies like BRAF inhibitors for refractory cases.

Juvenile Xanthogranuloma (JXG)

JXG is a benign disorder primarily affecting infants and young children. It manifests as cutaneous nodules that may involve extracutaneous sites such as the eye and internal organs. Histologically, JXG is characterized by the presence of Touton giant cells and lipid-laden histiocytes. Immunohistochemically, these cells are typically CD68 and factor XIIIa positive but CD1a and S100 negative, distinguishing JXG from LCH. Although JXG is generally self-limiting and does not require treatment, involvement of critical organs like the eye may necessitate intervention to prevent complications such as visual impairment.

Rosai-Dorfman-Destombes Disease (RDD)

RDD, also known as sinus histiocytosis with massive lymphadenopathy, is characterized by the overproduction of histiocytes within lymph nodes and other tissues. Clinically, it presents with painless lymphadenopathy, fever, and weight loss. Histopathological examination reveals large S100 positive histiocytes exhibiting emperipolesis, a phenomenon where intact lymphocytes are engulfed by histiocytes. The etiology of RDD remains largely unknown, but it is believed to involve an aberrant immune response possibly triggered by infections or other environmental factors. Treatment is often conservative, focusing on symptomatic relief, although more severe cases may require corticosteroids or chemotherapy.

ALK-positive Histiocytosis

ALK-positive histiocytosis, a recently recognized entity, involves aberrations in the ALK gene. This disorder presents in two forms: multisystemic disease with infantile onset and isolated lesions predominantly in older children and adults. The diagnosis is confirmed by ALK immunoreactivity and the presence of ALK gene rearrangements. ALK inhibitors have shown efficacy in treating this condition, highlighting the importance of genetic analysis in guiding therapy. The identification of ALK rearrangements has provided a molecular basis for diagnosis and treatment, allowing for personalized medicine approaches that improve patient outcomes.

Histiocytic Sarcoma (HS)

HS is a rare malignant proliferation of histiocytes. It can arise de novo or from pre-existing hematologic malignancies. HS is characterized by the presence of large, atypical histiocytes that are CD68 and CD163 positive. This aggressive neoplasm often involves multiple organ systems and requires a combination of chemotherapy and radiotherapy for treatment. Due to its rarity and aggressive nature, histiocytic sarcoma poses significant therapeutic challenges, and ongoing research is focused on identifying novel treatment strategies and improving early diagnostic methods to enhance prognosis.

Hemophagocytic Lymphohistiocytosis (HLH)

HLH is a severe systemic condition characterized by excessive immune activation and inflammation. It includes both familial and acquired forms, with the familial type often involving mutations in genes related to immune regulation. HLH's diagnosis and treatment are challenging, necessitating comprehensive clinical and genetic evaluation.

Conclusions

The evolving understanding of pediatric histiocytic disorders underscores the importance of integrating morphological, immunophenotypic, and genetic data for accurate diagnosis and management. Advances in genetic and molecular profiling have not only refined the classification of these disorders but also opened new avenues for targeted therapies. As research progresses, it is anticipated that novel biomarkers and therapeutic strategies will emerge, improving outcomes for affected children.

In summary, this comprehensive review of pediatric histiocytic disorders highlights the diverse clinical presentations and pathological features of these rare diseases. The integration of advanced diagnostic techniques is crucial for the precise identification and effective treatment of these complex conditions. This detailed understanding facilitates the development of targeted therapies, promising better management and improved quality of life for patients suffering from these rare pediatric disorders.

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https://www.xiahepublishing.com/2771-165X/JCTP-2023-00027

The study was recently published in the Journal of Clinical and Translational Pathology.

Journal of Clinical and Translational Pathology (JCTP) is the official scientific journal of the Chinese American Pathologists Association (CAPA). It publishes high quality peer-reviewed original research, reviews, perspectives, commentaries, and letters that are pertinent to clinical and translational pathology, including but not limited to anatomic pathology and clinical pathology. Basic scientific research on pathogenesis of diseases as well as application of pathology-related diagnostic techniques or methodologies also fit the scope of the JCTP.

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