Histiocytic and dendritic cell tumors
2025-07-30 Paola Dal Cin, PhD , Judith Ann Ferry, MD Affiliation1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)
2.Massachusetts General Hospital/ Harvard Medical School
Keywords
Histiocytic-dendritic cell neoplasm,xanthogranuloma, Erdheim−Chester disease,Rosai−Dorfman disease, Langerhans cell histiocytosis, follicular dendritic cell sarcomaClassification
Definition
Histiocytic-dendritic cell neoplasms are rare. Those encountered in head and neck region include juvenile xanthogranuloma (JXG}; Erdheim−Chester disease (ECD); Rosai−Dorfman disease RDD); Langerhans cell histiocytosis (LCH) and follicular dendritic cell sarcoma. Most published reports of histiocytic-dendritic cell neoplasms involving the head and neck consist of case reports and small series.
Molecular genetic studies have linked LCH, ECD and RDD with the identification of somatic mutations of genes in the MAPK-ERK signaling pathway including BRAF, ARAF, MAP2K1, NRAS and KRAS, 1 albeit with highly variable frequencies among the different types of histiocytic diseases. 2
LCH, ECD and RDD are distinct pathologic entities. Some questions remain about JXG as an entity, at least in a subset of cases, since BRAF V600E somatic mutations have been detected in cases reported as JXG of the CNS; such cases may be better interpreted as ECD. In addition, clinicopathologic features of cases of ALK+ histiocytosis show some overlap with systemic JXG, 3 performing a stain for ALK in such cases will avoid misdiagnosis.
| Histiocytic and dendritic cell tumors | Genetic events |
|---|---|
| Juvenile xanthogranuloma (JXG) | Juvenile xanthogranuloma (JXG) is a non-Langerhans cell histiocytosis, mainly affecting infants and young children. Adults are infrequently affected. Lesions are confined to skin in most cases but extracutaneous involvement, including multiple different head and neck sites, is reported. 4-6 Activating mutations of NRAS, KRAS, ARAF, MAP2K1, and others, and NTRK1 and BRAF gene fusions, have been reported. 7-9 JXG-like histopathology with a rare KIF5B::ALK fusion in a subglottic lesion. 10 JXG-like lesions involving the CNS and harboring BRAF V600E mutation may be better classified as Erdheim-Chester disease.11 JXG-like cases with systemic involvement and ALK translocations are better considered to represent ALK+ histiocytosis. 12,13 Several cases of JXG have been reported in children with germline mutations in NF1 , NF2, SLC12A3, PTPN11. The incidence of juvenile myelomonocytic leukemia (JMML) is increased in patients with neurofibromatosis type 1 but the additional finding of JXG in these patients likely does not further increase the risk of JMML.3,14 |
| Erdheim-Chester disease (ECD) | Erdheim-Chester disease (ECD) consists of a proliferation of mature neoplastic histiocytes that can involve many different anatomic sites. BRAF V600E is found in the majority of cases. In the absence of mutated BRAF, other mutually exclusive mutations of MAPK and non-MAPK pathway genes MAP2K1, KRAS, NRAS or PIK3CA mutations can be identified. 15,16 |
| Rosai-Dorfman disease (RDD) | The hallmark of Rosai-Dorfman disease (RDD) is a proliferation of large, S100+ histiocytes with emperipolesis of leukocytes, mostly lymphocytes. Lymph nodes and many different extranodal sites can be involved. Disease can be localized or widespread. Mutations of MAPK/ERK pathway genes are identified in about 50% of the cases; they include KRAS, NRAS, MAP2K1, ARAF, CSF1R and rarely BRAF V600E mutation. 16-18 |
| Langerhans cell histiocytosis (LCH) | Langerhans cell histiocytosis (LCH) is a neoplasm of dendritic cells with the immunophenotype of Langerhans cells.(S100+, CD1a+, CD207+) Patients may have single-system or multisystem disease. Common sites of involvement include skin and bone; lymph nodes and multiple other extranodal sites can be involved.19,20 MAPK pathway mutations are usually detected, with BRAF V600E being the most common , followed by MAP2K1 and more rarely, ARAF ,ERBB3, NRAS, and KRAS mutations. MAP2K1 and BRAF mutations are mutually exclusive. 16,21 |
| Follicular dendritic cell sarcoma (FDCS) | Follicular dendritic cell sarcoma (FDCS) is a low-grade malignant neoplasm composed of stroma-derived cells recapitulating the FDC normally residing in germinal centers. It most often affects lymph nodes but extranodal sites can be involved.22 The mutational spectrum is somewhat heterogeneous. MAPK pathway mutations are rare, while NF-κB pathway mutations are common, with NFKBIA inactivation as the most common genetic alteration followed by BIRC3 , NFKBIA, TRAF3, SOCS3 and TNFAIP3. Other alterations affect CDKN2A and TP53. Fusions are uncommon. 23-26 |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 32601132 | 2021 | MAP-Kinase-Driven Hematopoietic Neoplasms: A Decade of Progress in the Molecular Age. | Chakraborty R et al |
| 2 | 35312979 | 2022 | Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Hematolymphoid Proliferations and Neoplasia. | Ferry JA et al |
| 3 | 35378409 | 2022 | Juvenile and adult xanthogranuloma: A 30-year single-center experience and review of the disorder and its relationship to other histiocytoses. | Salari B et al |
| 4 | 26189188 | 2015 | Juvenile Xanthogranuloma Involving the Eye and Ocular Adnexa: Tumor Control, Visual Outcomes, and Globe Salvage in 30 Patients. | Samara WA et al |
| 5 | 26744443 | 2016 | Imaging Features of Juvenile Xanthogranuloma of the Pediatric Head and Neck. | Ginat DT et al |
| 6 | 38832444 | 2024 | Juvenile Xanthogranuloma of the Head and Neck: Imaging Findings in 11 Cases. | Chalard F et al |
| 7 | 28752840 | 2017 | Genetic evaluation of juvenile xanthogranuloma: genomic abnormalities are uncommon in solitary lesions, advanced cases may show more complexity. | Paxton CN et al |
| 8 | 31768065 | 2019 | Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms. | Durham BH et al |
| 9 | 37115038 | 2023 | Molecular and clinicopathologic characterization of pediatric histiocytoses. | Hélias-Rodzewicz Z et al |
| 10 | 31351348 | 2019 | Atypical juvenile histiocytosis with novel KIF5B-ALK gene fusion mimicking subglottic hemangioma. | Wolter NE et al |
| 11 | 31685033 | 2019 | BRAF V600E mutation in Juvenile Xanthogranuloma family neoplasms of the central nervous system (CNS-JXG): a revised diagnostic algorithm to include pediatric Erdheim-Chester disease. | Picarsic J et al |
| 12 | 32822792 | 2023 | Systemic juvenile xanthogranuloma has a higher frequency of ALK translocations than BRAFV600E mutations. | Xu J et al |
| 13 | 34727172 | 2022 | ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition. | Kemps PG et al |
| 14 | 28189268 | 2017 | The relationship between neurofibromatosis type 1, juvenile xanthogranuloma, and malignancy: A retrospective case-control study. | Liy-Wong C et al |
| 15 | 32187362 | 2020 | Erdheim-Chester disease: consensus recommendations for evaluation, diagnosis, and treatment in the molecular era. | Goyal G et al |
| 16 | 39998733 | 2025 | Langerhans Cell Histiocytosis and Other Histiocytic Lesions. | McKinney RA et al |
| 17 | 26966089 | 2016 | Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. | Emile JF et al |
| 18 | 32591351 | 2020 | Rosai-Dorfman disease: an overview. | Bruce-Brand C et al |
| 19 | 11496348 | 2001 | Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study. | Titgemeyer C et al |
| 20 | 23589673 | 2013 | Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. | Gadner H et al |
| 21 | 30157397 | 2018 | Langerhans-Cell Histiocytosis. | Allen CE et al |
| 22 | 25917851 | 2016 | Follicular dendritic cell sarcoma of the head and neck: Case report, literature review, and pooled analysis of 97 cases. | Pang J et al |
| 23 | 26564005 | 2016 | Targeted genomic sequencing of follicular dendritic cell sarcoma reveals recurrent alterations in NF-κB regulatory genes. | Griffin GK et al |
| 24 | 32816379 | 2021 | Fine needle aspiration of an intranodal follicular dendritic cell sarcoma: A case report with molecular analysis and review of the literature. | Andersen MJ Jr et al |
| 25 | 33904632 | 2021 | Histiocytic and Dendritic Cell Sarcomas of Hematopoietic Origin Share Targetable Genomic Alterations Distinct from Follicular Dendritic Cell Sarcoma. | Massoth LR et al |
| 26 | 40289262 | 2025 | Morphological, immunohistochemical and molecular analysis of follicular dendritic cell sarcomas: L1CAM as a new diagnostic marker. | Schelbert S et al |
Citation
Paola Dal Cin, PhD ; Judith Ann Ferry, MD
Histiocytic and dendritic cell tumors
Atlas Genet Cytogenet Oncol Haematol. 2025-07-30
Online version: http://atlasgeneticsoncology.org/solid-tumor/209330/histiocytic-and-dendritic-cell-tumors
