HAEM5:Langerhans cell histiocytosis

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Langerhans Cell Histiocytosis.

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

Dr Malaika Perchard BSci(MedSci), MBBS, FRACP, FRCPA, (Paediatric Haematologist) Pathology Queensland

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	Histiocytic/Dendritic cell neoplasms
Family	Langerhans cell and other dendritic cell neoplasms
Type	Langerhans cells neoplasms
Subtype(s)	Langerhans cell histiocytosis

Definition / Description of Disease

Tumours derived from Langerhans cells (LCs) are rare disorders characterized by clonal proliferation of LCs that can be subdivided in to two groups based on severity of cytological atypia and clinical aggressiveness. These two groups are LC histiocytosis (LCH) and LC sarcoma. LCH does not display overt malignant cytological features and is less clinically aggressive.

Synonyms / Terminology

Langerhans cell histiocytosis (LCH)

Obsolete terms:

·        Langerhans cell histiocytosis; unifocal

·        Langerhans cell histiocytosis; multifocal

·        Langerhans cell histiocytosis; disseminated

·        Langerhans cell granulomatosis

·        Solitary lesions: Histiocytosis X, eosinophilic granuloma

·        Multiple lesions/disseminated: Hand-Schuller-Christian disease, Letterer-Siwe disease

Epidemiology / Prevalence

Langerhans cell histiocytosis

·        Rare, annual incidence ~5 per 1 million population

·        More common in paediatric age group

·        Male predilection M:F 3.7:1

·        More common in Caucasian population of Northern European descent than Black population

Clinical Features

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Signs and Symptoms	EXAMPLE: Asymptomatic (incidental finding on complete blood counts) EXAMPLE: B-symptoms (weight loss, fever, night sweats) EXAMPLE: Fatigue EXAMPLE: Lymphadenopathy (uncommon)
Laboratory Findings	EXAMPLE: Cytopenias EXAMPLE: Lymphocytosis (low level)

editv4:Clinical Features

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Patients with unifocal disease often present with lytic bone lesions and are usually older children or adults.

Patients with single system disease are usually young children that present with a combination of destructive bone lesions and associated soft tissue masses. Commonly the destructive bone lesions involve the skull and mandible. If there is cranial involvement patients can present with diabetes insipidus.

Patients with multi-system disease are usually infants who present with fever, cytopenias, hepatosplenomegaly and/or skin and skeletal lesions. Pulmonary involvement is possible but less common and variable in severity.

A trans-differentiation phenomenon is recognized with an association between tumours derived from Langerhans cells and T-lymphoblastic leukaemia. The leukemia-associated TR gene rearrangement is present in the Langerhans Cell Histiocytosis cells .

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Sites of Involvement

Solitary lesions most commonly involve:

·        Skull

·        Femur

·        Vertebra

·        Pelvic bones

·        Ribs

Solitary lesions less commonly involve:

·        Lymph node

·        Skin

·        Lung

Multifocal lesions most commonly involve:

·        Skin

·        Bones (as above)

·        Liver

·        Spleen

·        Bone marrow

Gonadal tissue and kidneys are rarely involved, even in the context of disseminated disease.

Morphologic Features

The key feature to the diagnosis is the presence of the LCH cells. These cells are oval with distinctive nuclear features including a grooved, folded, indented or lobed nucleus with fine chromatin and inconspicuous nucleoli. Nuclear atypia is minimal. These cells have moderately abundant cytoplasm that is slightly eosinophilic. LCH cells are usually devoid of cytoplasmic processes. Ultrastructural assessment of LCH demonstrates the hallmark cytoplasmic Birbeck granules. Birbeck granules have a tennis-racket shape with a zipper-like appearance. Identification of LC’s can be confirmed by langerin (CD207) expression.  

LCH often has characteristic LC’s (including multinucleate and osteoclast like forms) surrounded by a milieu of eosinophils, neutrophils and small lymphocytes. In early lesions the LC predominate, but as the disease progresses LC’s decrease and there is an increase in foamy macrophages and fibrosis .    

Tissue specimens:

·        Spleen – shows nodular red pulp involvement.

·        Liver – strong preference for intrahepatic biliary involvement with progressive sclerosing cholangitis

·        Bone marrow – trephine is preferred to aspirate to demonstrate involvement.    

Immunophenotype

LCH consistently express CD1a, langerin (CD2017) and S100 which can be used to distinguish LCH from other histiocytic disorders and non-neoplastic macrophages.

Finding	Marker
Positive (universal)	Langerin, CD1a, CD4, S100, HLA-DR
Positive (subset)	CD68, Lysozyme (low), CD45 (low) Ki-67 highly variable.
Negative (universal)	B and T cell markers (except CD4), Factor XIIIa, CD21, CD35, CD123, CD162, Fascin, TCL1, Fc receptors
Negative (subset)	N/A

WHO Essential and Desirable Genetic Diagnostic Criteria

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WHO Essential Criteria (Genetics)*
WHO Desirable Criteria (Genetics)*
Other Classification

*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.

Related Terminology

(Instructions: The table will have the related terminology from the WHO autocompleted.)

Acceptable
Not Recommended

Gene Rearrangements

Put your text here and fill in the table (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: ABL1	EXAMPLE: BCR::ABL1	EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.	EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: Common (CML)	EXAMPLE: D, P, T	EXAMPLE: Yes (WHO, NCCN)	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).
EXAMPLE: CIC	EXAMPLE: CIC::DUX4	EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5.	EXAMPLE: t(4;19)(q25;q13)	EXAMPLE: Common (CIC-rearranged sarcoma)	EXAMPLE: D		EXAMPLE: DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
EXAMPLE: ALK	EXAMPLE: ELM4::ALK Other fusion partners include KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1	EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18.	EXAMPLE: N/A	EXAMPLE: Rare (Lung adenocarcinoma)	EXAMPLE: T		EXAMPLE: Both balanced and unbalanced forms are observed by FISH (add references).
EXAMPLE: ABL1	EXAMPLE: N/A	EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.	EXAMPLE: N/A	EXAMPLE: Recurrent (IDH-wildtype Glioblastoma)	EXAMPLE: D, P, T

editv4:Chromosomal Rearrangements (Gene Fusions)

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LCH has been shown to be clonal, using an X-linked androgen receptor gene assay in many cases (not seen in some adult pulmonary lesions).

About 30% of cases have a detectable clonal IGH, IGK or TR rearrangement .

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Individual Region Genomic Gain/Loss/LOH

Recurrent regional losses, gains, or regions with loss of heterozygosity have not been identified in the context of Langerhans cell histiocytosis.

Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes

Characteristic Chromosomal or Other Global Mutational Patterns

Recurrent chromosomal abnormalities have not been described in the context of Langerhans cell histiocytosis.

Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes

Gene Mutations (SNV/INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Gene	Genetic Alteration	Tumor Suppressor Gene, Oncogene, Other	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE:EGFR	EXAMPLE: Exon 18-21 activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (lung cancer)	EXAMPLE: T	EXAMPLE: Yes (NCCN)	EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
EXAMPLE: TP53; Variable LOF mutations	EXAMPLE: Variable LOF mutations	EXAMPLE: Tumor Supressor Gene	EXAMPLE: Common (breast cancer)	EXAMPLE: P		EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations	EXAMPLE: Activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (melanoma)	EXAMPLE: T

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

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More than half of LCH cases display a BRAF V600E variant. Approximately 25% of LCH cases have an associated somatic MAP2K1 mutation in parallel with a germline BRAF variant .

Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)
BRAFV600E	Oncogene	~50%	Unknown	No	Yes

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

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Epigenomic Alterations

Epignomic alterations in the context of Langerhans cell histiocytosis are not described.

Genes and Main Pathways Involved

B-RAF encodes B-Raf, a cytoplasmic serine/threonine kinase that has a role in regulating the mitogen-activated protein kinase signal transduction pathway. V600E is an activating missense mutation in codon 600 of exon 15 that causes substitution of valine to glutamate. This causes independent activation of the RAS-RAF-MEK-ERK signalling pathway, leading to unregulated cell growth and proliferation .

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
BRAF and MAP2K1; Activating mutations	MAPK signaling	Increased cell growth and proliferation

Genetic Diagnostic Testing Methods

PCR or sequencing for BRAF variants, X-linked androgen receptor gene assay.

Familial Forms

Familial forms of Langerhans cell histiocytosis have not been described

Links

HAEM5:Langerhans cell sarcoma

References

1)     Arber DA, et al., (2017). Histocytic and dendriic cell neoplasms, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Pileris SA, Jaffe R, Facchettic F, Jones DM and Jaffe ES, Editors. IARC Press: Lyon, France, p466-472

2)     Richtig G, Hoeller C, Kashofer K, Aigelsreiter A, Heinemann A, Kwong LN, et al.. Beyond the BRAF V 600E hotspot: biology and clinical implications of rare BRAF gene mutations in . British Journal of Dermatology. British Journal of Dermatology; 2017;177(4):936–44.

Notes

*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

*Citation of this Page: “Langerhans cell histiocytosis”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/10/2025, https://ccga.io/index.php/HAEM5:Langerhans_cell_histiocytosis.