HAEM5:Histiocytic sarcoma

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:Histiocytic Sarcoma.

(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)*

Marie-France Gagnon, MD, Mayo Clinic, Xinjie Xu, PhD FACMG, Mayo Clinic

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	Histiocytic/Dendritic cell neoplasms
Family	Histiocyte/macrophage neoplasms
Type	Histiocytic neoplasms
Subtype(s)	Histiocytic sarcoma

WHO Essential and Desirable Genetic Diagnostic Criteria

(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)

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)

The content below was from the old template. Please incorporate above.

Very few reports have described the genetic landscape of histiocytic sarcoma, with current literature being restricted to case reports and case series, thus limiting the ability to derive a comprehensive portrait of genetic alterations in HS.

No universal or recurrent chromosomal rearrangement are identified in histiocytic sarcoma. In cases where HS arises in association with follicular lymphoma, both neoplasms may exhibit the translocation t(14;18)(q32;q21) with identical breakpoints. In fact, such cases may reflect a phenomenon of transdifferentiation from a lymphoid to a histiocytic phenotype. This was suggested by Feldman et al. in a compelling study reporting on 8 cases of clonally related follicular lymphoma and HS (with presence of t(14;18) in both tumors and identical IGH and BCL2 gene rearrangements). The authors posited that transdifferentiation may be mediated by changes in transcription factors (as evidenced by repression of PAX5, a B-cell lineage commitment factor, with upregulation of the myeloid transcription factors C/EBPα and β). Interestingly, the translocation t(14;18) has also rarely been documented in sporadic HS. Similarly, a CCND1-IgH fusion has been described by Hure et al in patients diagnosed with HS and mantle cell lymphoma. In addition, other gene fusions have been reported sporadically in individual cases. For example, Egan et al have identified a novel fusion between exon 12 of TTYH3 and exon 8 of BRAF on chromosome 7 using RNA-Seq. This TTYH3-BRAF fusion, subsequently confirmed with RT-PCR, was associated with increased levels of BRAF transcripts.

Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence
t(14;18) (q32;q21)	IGH/BCL2	der(14)	Unknown

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editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

Please incorporate this section into the relevant tables found in:

• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

Histiocytic sarcoma is a very rare neoplasm and very little is known about the genetic landscape of this malignancy. Reports on the clinical significance of genomic alterations are scarce and limited to case reports and case series, limiting the ability to draw conclusions regarding their prognostic and therapeutic significance.

Diagnosis: The diagnosis of HS is largely based on morphologic and immunophenotypic findings rather than on genetic features.

Prognosis: More data is warranted to decipher the prognostic relevance of genetic alterations found in HS.

Therapeutic: While case reports have documented the use of BRAF inhibitors in the setting of BRAF V600E mutations and of MEK inhibitors for MAP2K1 pathway mutations, these agents should not be used as first-line therapy outside of a clinical trial.

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Individual Region Genomic Gain/Loss/LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)

Chr #	Gain, Loss, Amp, LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7	EXAMPLE: Unknown	EXAMPLE: D, P	EXAMPLE: No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8	EXAMPLE: Unknown	EXAMPLE: D, P		EXAMPLE: Common recurrent secondary finding for t(8;21) (add references).
EXAMPLE: 17	EXAMPLE: Amp	EXAMPLE: 17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]	EXAMPLE: ERBB2	EXAMPLE: D, P, T		EXAMPLE: Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

editv4:Genomic Gain/Loss/LOH

The content below was from the old template. Please incorporate above.

None recurrent.

In a series of 28 cases of HS assessed with targeted next-generation sequencing, CDKN2A was frequently inactivated by focal deletion at 9p21.3. Loss of CDKN2A has also been documented in some patients by FISH analysis. Copy-number loss or Loss-of-heterozygosity (LOH) involving chromosome 17 (including the NF1 gene) and amplification of PTPN11 can also be seen. In a case series describing three pediatric patients with clonally related HS with predating acute leukemia, methylation array profiling revealed the presence of CDKN2A deletions at chromosome 9p in two patients.

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Characteristic Chromosomal or Other Global Mutational Patterns

Put your text here and fill in the table (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. 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.)

Chromosomal Pattern	Molecular Pathogenesis	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: Co-deletion of 1p and 18q	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).	EXAMPLE: Common (Oligodendroglioma)	EXAMPLE: D, P
EXAMPLE: Microsatellite instability - hypermutated		EXAMPLE: Common (Endometrial carcinoma)	EXAMPLE: P, T

editv4:Characteristic Chromosomal Aberrations / Patterns

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No characteristic chromosomal aberrations have been described in HS. Rarely, histiocytic sarcoma may arise in patients with mediastinal germ cell tumor. In this setting, the germ cell tumor and HS may display isochromosome 12p.

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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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BRAF mutations (V600E and non-V600E) have been identified in a subset of patients with histiocytic sarcoma. Additionally, a study in which targeted next-generation sequencing was performed on 28 cases, reported recurrent mutations in the MAP kinase pathway (including KRAS, NRAS, MAP2K1, BRAF, PTPN11, NF1, CBL), and the PI3K signaling pathway (including PTEN, MTOR, PIK2R1, PIK3CA). Also, some cases, mostly those with a prior diagnosis of B-cell lymphoma, harbored a mutational signature of “aberrant somatic hypermutation” with mutations in genes such as BCL6, BCL2, CIITA, MYC, SOCS1, PAX5. In this study, CDNK2A was the most commonly altered gene (13/28, 46%). The authors identified a mean coding mutational burden of 3.56/Mb in their cohort, a number that is relatively low as compared with other malignancies. In another series reporting on 21 cases of primary HS investigated with whole-exome sequencing and RNA sequencing, Egan et al identified a high frequency of alterations within the RAS/RAF/MAPK pathway (such as NF1, PTPN11, MAP2K1, NRAS, KRAS).

Gene	Mutation	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)	Prevalence (COSMIC/TCGA/Other)
BRAF	p.V600E and non-V600E p.F595, p.G464V, p.G466R p.N581S, p.G469R, p.G469A, p.D594N, p.G469V)	Oncogene	GOF	12%
KRAF	p.Q61H, p.G13D, p.A146T, p.G12D, p.G12C, p.Q61H, p.A146V, p.A66fs	Oncogene	GOF
NRAS	p.G61K, p.Q61R, p.G12C, p.G12D	Oncogene	GOF
MAP2K1	p.C121S, p.I103N, p.L177M, p.F53S, p.F53L, p.C121S , p.K57E,  p.Y125C, p.R181K	Oncogene	GOF
ARID1A	p.L2011fs, p.G2087R	Chromatin remodeling	LOF
HRAS	p.G61R(23)	Oncogene	GOF
PTPN11	p.G503, p.Y63S, p.Q506R, p.E72K, p.G60V, p.E69K, p.F71V, p.E76G, p.A72V	Oncogene	GOF
NF1	p.W229*, p.C1032Lfs*7, p.Q1822*, p.V1182D, p.Q1086*, p.R304*, p.Q1775*, p.L298*, p.K600fs	Tumor suppressor	LOF
CBL	p.Y371C(29), T402_L405del	Oncogene	GOF
PTEN	p.L125E, p.R130Q, p.Q171*, p.D24H, c.79+1G>C(19), p.L140*(19)	Tumor suppressor	LOF
PIK3CA	p.H1047L	Oncogene	GOF
MTOR	p.S2215F, p.I2501F	Oncogene	GOF
SGK1	p.R285K, p.I238T, p.H237Y, p.K213R, p.P147S, p.E162G, p.K136R, p.Q125H, c.437+1G>A, c.362-1G>A	Other (stress response, apoptosis…)
SETD2	c.7432-2A>C, p.V1820E, p.P132fs, c.4715_1G>T, c.7432-1G>A	Epigenetic regulator/tumor suppressor	LOF
CREBBP	p.Y1433C	Tumor suppressor	LOF
KMT2D	pE2225fs(19), p.K1752fs(19), p.G5428S, p.Q2796*, p.R904*, p.R5351Q, p.A2119Rfs, p.L3432D	Epigenetic modification, tumor suppressor	LOH

Other Mutations

Please refer to the above “Gene Mutations (SNV/INDEL)” section.

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Epigenomic Alterations

KMT2D, a gene involved in epigenetic regulation, has been reported as recurrently mutated in histiocytic sarcoma. Egan et al also reported mutations in epigenetic modifier genes such as SETD2, ARID1A and KMT2D.

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete the table.)

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations	EXAMPLE: Histone modification, chromatin remodeling	EXAMPLE: Abnormal gene expression program

editv4:Genes and Main Pathways Involved

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A recent molecular profiling study by Shanmugam et al highlighted that alterations in the MAP kinase, PI3K- and cyclin-CDK4/6-INK4 signaling pathways appear involved in the pathogenesis of histiocytic sarcoma. Egan et al also identified a high frequency of alterations within the RAS/RAF/MAPK pathway. Histiocytic sarcoma may also be associated with perturbations of chromatin regulation.

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Genetic Diagnostic Testing Methods

Histiocytic sarcoma diagnosis relies on histopathologic evaluation. In addition to histologic appearance, immunohistochemistry is central in diagnosing this malignancy and in excluding other morphologic mimics. Excisional or incisional biopsy is generally preferable to fine needle aspirate or core needle biopsy.

Of note, in the 2001 World Health Organization (WHO) classification, HS was originally defined based on the absence of clonal immunoglobulin heavy chain (IGH) or T-cell receptor (TCR) gene rearrangements. However, in 2008, the WHO revised the classification to include IGH and TCR rearrangements in light of a growing literature describing such rearrangements in HS cases. While, clonal immunoglobulin receptor gene rearrangements may be seen in the setting of secondary HS from a phenomenon of cross-lineage transdifferentiation of neoplastic B cells into malignant histiocytes, they have also been described in primary HS. In this respect, in a study reporting on 23 patients with sporadic HS, Chen et al identified that IGH (+/- IGK) rearrangements were present in 39% of cases.

Staging at diagnosis is further completed by imaging studies such as PET scan or computed tomography scans.

Familial Forms

Not applicable

Additional Information

None

Links

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References

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Notes

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Prior Author(s):

*Citation of this Page: “Histiocytic sarcoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 03/24/2025, https://ccga.io/index.php/HAEM5:Histiocytic_sarcoma.