Abstract
Other rare neoplasms may arise from myeloid progenitors, including Histiocytic/ Dendritic Neoplasms and mast cell neoplasms. The Classification of both categories in the 5th edition of WHO has some modifications with newly introduced entities. Histiocytic neoplasms exhibit diverse somatic oncogenic alterations. Their clinical presentation ranges from incidental findings to critical illness with severe organ dysfunction. Each subtype has distinct morphologic and immunophenotypic features. However, some overlap exists between the different subtypes. Mastocytosis involves abnormal mast cells accumulating in various organs. It develops as a clonal expansion of mast cells derived by constitutive activation of the KIT receptor. The clinical course varies from asymptomatic to diffuse systemic involvement with comorbidities mainly related to mediators' release.
TopIntroduction
Histiocytic and mast cell neoplasms are two rare categories of myeloid origin. Each encompasses a spectrum of subtypes with heterogeneous clinical courses, pathological features, and prognoses. Histiocyte/dendritic neoplasms have an accumulation of macrophages, monocytes, dendritic cells, interdigitating reticulum cells, or Langerhans cells in affected tissues. (Durham, 2019).
The molecular landscape of histiocytosis often involves the MAPK/ERK pathway (RAS-RAF-MEK-ERK) and correlates with phenotypes of various entities. (Tzankov et al., 2018)
Mastocytosis results from abnormal mast cells accumulating in various organs. It develops as a clonal expansion of mast cells derived by constitutive activation of the KIT receptor. The clinical course varies from asymptomatic to diffuse systemic involvement with comorbidities mainly related to mediators' release.
The diagnostic approach to both categories integrates pertinent clinical features, morphology, immunohistochemistry of tissue lesions, molecular analysis, and risk assessment. The broad differential diagnosis of each category includes several reactive and neoplastic disorders.
TopHistiocytic/Dendritic Neoplasms
Systemic histiocytic neoplasms originate from hematopoietic stem/progenitor cells (HSPCs) and may be associated with hematological malignancies bearing the same genetic alteration(s).
Pathogenesis and Molecular Landscape of Dendritic Cell and Histiocytic Neoplasms
Driver mutations in particular genes (e.g., N/KRAS) may predispose to an additional clonally related hematological malignancy or secondary histiocytic neoplasm. A multipotent HSPC origin emphasizes the importance of adequate bone marrow staging, molecular analysis, and long-term follow-up of all histiocytosis patients. (Kemps et al., 2021)
Histiocytic neoplasms exhibit diverse somatic oncogenic alterations (Figure 1), often involving the MAPK/ERK pathway (RAS-RAF-MEK-ERK) and potentially other pathogenic mechanisms in certain subtypes which provide essential diagnostic and therapeutic channels. (Durham, 2019).
Figure 1. The molecular landscape and subtypes of histiocytic neoplasms
MAPK pathway mutations include:
- a)
BRAF proto-oncogene is the most frequent mutation and includes BRAF V600D and BRAF V600insDLAT in LCH, BRAF F595L in histiocytic sarcoma
- b)
ARAF Proto-oncogene mutations in non-LCH and about 21% of ECD
- c)
NRAS mutations in 3–7% of ECD and less frequently in LCH. Driver mutations in particular genes such as N/KRAS may predispose to developing additional clonally related hematological malignancy or secondary histiocytic neoplasm. (Kemps et al., 2021)
- d)
MAP2K1 in 10–40% of LCH and non-LCH and 14% of ECD
- e)
PI3K mutation, including activating PIK3CA in 17% of BRAF V600E-wild type ECD.
High and low-risk LCH correspond to different origins from hematopoietic progenitor and tissue-restricted precursor dendritic cells. (Emile et al., 2021)
Common mutations in histiocytosis involve CSF1R, ALK, RET, NTRK, RAS, RAF, MAP2K, and other kinase genes, which link myeloid growth factor receptor-binding to ERK activation. Some subtypes may co-occur, such as LCH lesions with ECD. Mutually exclusive with BRAFV600E are additional genetic aberrations in the same pathway, including MAP2K1 and ARAF in LCH, KRAS, NRAS, and PIK3CA ARAF in ECD. The molecular profile of CSF1 receptor signaling-related macrophage and dendritic cell neoplasm overlaps with somatic activation of genes in the thrombopoietin signaling pathway genes in myeloproliferative disorders. On the other hand, no specific mutations are unique in LCH. The MAP kinase pathway is strongly activated (attested by ERK phosphorylation and nuclear translocation) in LCH without identified mutations.
Key Terms in this Chapter
Faisalabad (or H) Syndrome (OMIM #602782): An Autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the SLC29A3 gene on chromosome 10q22, which encodes the human equilibrative nucleoside transporter (hENT3) protein. It is characterized by cutaneous hyperpigmentation, hypertrichosis, Hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, and low height. It comprises features of four histiocytic disorders that were previously thought to be distinct: Faisalabad histiocytosis (FHC), Sinus histiocytosis with massive lymphadenopathy (SHML), H syndrome, and Pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome (PHID).
Myeloid Skewing Of Hematopoietic Cells: Myeloid skewing refers to an imbalance in the production of blood cells, specifically myeloid cells, which include granulocytes (such as neutrophils, eosinophils, and basophils) and monocytes at the level of hematopoietic stem and primitive progenitor cells (HSPPCs). This is often observed in c hronic inflammation and autoimmune diseases. The main drivers for this phenomenon involve the inflammatory environment, the up-regulation of myeloid-specific transcripts, such as S100a8, and disease persistence.
Neutrino-Prism (nuPRISM): A novel cellular nucleus sorting platform utilizing advances in microfluidics technologies and phenotypic CRISPR screening. It allows the high-throughput detection of regulators of nuclear protein accumulation, undetected by conventional platforms. The technique is particularly effective in intranuclear protein targets drug discovery, opening new avenues for targeted therapeutics development.
Fas Protein Deficiency: An Autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the FAS gene on chromosome 10q24.1. Defects in Fas protein lead to impaired apoptosis regulation, affecting immune homeostasis and tissue integrity. It is Clinically characterized by lymphadenopathy, hyperimmunoglobulinemia, autoimmune manifestations, and maybe autoimmune lymphoproliferative syndrome (ALPS).
Ultraviolet Mutational Signature: A specific pattern of mutations observed in genomic DNA due to exposure to ultraviolet radiation. The most prominent mutation is the C?T transition ( cytosine to thymine) at di-pyrimidine sites Additionally, UV exposure can lead to CC?TT substitutions a t di-pyrimidine sites. UV radiation directly damages DNA, causing pyrimidine dimers and oxidative processes. UV signature mutations serve as a diagnostic tool for assessing sun-exposed tumors. They also help guide cancer treatment strategies.
Familial Rosai-Dorfman Disease (RDD)- Not Otherwise Specified: A rare variant of RDD characterized by a familial pattern of occurrence, has an autosomal recessive inheritance, and is associated with mutations in the SLC29A3 gene on chromosome 10q22. It is part of the ‘ R group ’ of histiocytoses, which includes familial RDD, sporadic RDD, and other miscellaneous non-cutaneous, non-Langerhans cell histiocytoses. The disorder may be associated with IgG4-related disease.
X-Chromosome Inactivation Pattern Of The Human Androgen Receptor Gene (HUMARA) Assay: The HUMARA (short for human androgen receptor) assay is a widely used method for determining the clonal origin of a tumor. It leverages the X chromosome inactivation process and exploits the differential methylation status of the HUMARA gene located on the X chromosome. The HUMARA gene has varying numbers of CAG repeats in its alleles. The assay PCR amplification of DNA. The resulting gel bands will determine clonality a single band suggests monoclonality, while a double band indicates polyclonality.