HAEM4Backup:Langerhans Cell Histiocytosis

Primary Author(s)*

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

Cancer Category/Type

Histiocytic and dendritic cell neoplasms

Cancer Sub-Classification / Subtype

Tumours derived from Langerhans cells

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

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 .

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

Chromosomal Rearrangements (Gene Fusions)

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 .

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 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)

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.

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

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

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