Difference between revisions of "HAEM5:Histiocytic sarcoma"

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Latest revision as of 12:37, 24 March 2025

Haematolymphoid Tumours (WHO Classification, 5th ed.)

This page is under construction

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). ^[1] Interestingly, the translocation t(14;18) has also rarely been documented in sporadic HS. ^[2]^[3] Similarly, a CCND1-IgH fusion has been described by Hure et al in patients diagnosed with HS and mantle cell lymphoma.^[4] 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.^[5]

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

End of V4 Section

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.

End of V4 Section

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

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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.^[6] Loss of CDKN2A has also been documented in some patients by FISH analysis.^[5] Copy-number loss or Loss-of-heterozygosity (LOH) involving chromosome 17 (including the NF1 gene) and amplification of PTPN11 can also be seen.^[5] 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.^[7]

End of V4 Section

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
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.^[8]

End of V4 Section

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)

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

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.^[6] 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).^[5]

Gene	Mutation	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)	Prevalence (COSMIC/TCGA/Other)
BRAF	p.V600E^[5]^[9]^[10] and non-V600E p.F595^[11], p.G464V^[12], p.G466R^[12] p.N581S^[12], p.G469R^[6], p.G469A, p.D594N, p.G469V^[5])	Oncogene	GOF	12%^[5]
KRAF	p.Q61H^[12], p.G13D^[6], p.A146T, p.G12D^[5], p.G12C^[5], p.Q61H^[5], p.A146V^[5], p.A66fs^[7]	Oncogene	GOF
NRAS	p.G61K^[13], p.Q61R^[5], p.G12C^[6], p.G12D^[14]	Oncogene	GOF
MAP2K1	p.C121S^[6], p.I103N^[5]^[6], p.L177M^[6], p.F53S^[6], p.F53L^[5]^[6]^[15]^[16], p.C121S ^[5]^[17], p.K57E^[5], p.Y125C^[5], p.R181K^[5]	Oncogene	GOF
ARID1A	p.L2011fs^[5], p.G2087R^[5]	Chromatin remodeling	LOF
HRAS	p.G61R(23)^[11]	Oncogene	GOF
PTPN11	p.G503^[12], p.Y63S^[18], p.Q506R^[18], p.E72K^[19], p.G60V^[6], p.E69K^[6], p.F71V^[5], p.E76G^[5], p.A72V^[5]	Oncogene	GOF
NF1	p.W229^[6], p.C1032Lfs7^[6], p.Q1822^[5], p.V1182D^[5], p.Q1086^[5], p.R304^[5], p.Q1775^[5], p.L298*^[5], p.K600fs^[5]	Tumor suppressor	LOF
CBL	p.Y371C(29)^[17], T402_L405del^[6]	Oncogene	GOF
PTEN	p.L125E^[12], p.R130Q^[12], p.Q171^[5]^[6], p.D24H^[5]^[6], c.79+1G>C(19)^[5], p.L140(19)^[5]	Tumor suppressor	LOF
PIK3CA	p.H1047L^[6]^[12]	Oncogene	GOF
MTOR	p.S2215F^[6], p.I2501F	Oncogene	GOF
SGK1	p.R285K^[5], p.I238T^[5], p.H237Y^[5], p.K213R^[5], p.P147S^[5], p.E162G^[5], p.K136R^[5], p.Q125H^[5], c.437+1G>A^[5], c.362-1G>A^[5]	Other (stress response, apoptosis…)
SETD2	c.7432-2A>C^[5], p.V1820E^[5], p.P132fs^[5], c.4715_1G>T^[5], c.7432-1G>A^[5]	Epigenetic regulator/tumor suppressor	LOF
CREBBP	p.Y1433C^[5]	Tumor suppressor	LOF
KMT2D	pE2225fs(19)^[5], p.K1752fs(19)^[5], p.G5428S^[17], p.Q2796^[17], p.R904^[17], p.R5351Q^[17], p.A2119Rfs^[17], p.L3432D^[17]	Epigenetic modification, tumor suppressor	LOH

Other Mutations

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

End of V4 Section

Epigenomic Alterations

KMT2D, a gene involved in epigenetic regulation, has been reported as recurrently mutated in histiocytic sarcoma.^[17] Egan et al also reported mutations in epigenetic modifier genes such as SETD2, ARID1A and KMT2D.^[5]

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.^[6] Egan et al also identified a high frequency of alterations within the RAS/RAF/MAPK pathway.^[5] Histiocytic sarcoma may also be associated with perturbations of chromatin regulation.^[20]

End of V4 Section

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. ^[3]^[21] 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,^[22] 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.^[3]

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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↑ Feldman, Andrew L.; et al. (2008-06-15). "Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone". Blood. 111 (12): 5433–5439. doi:10.1182/blood-2007-11-124792. ISSN 1528-0020. PMC 2424145. PMID 18272816.
↑ Hayase, Eiko; et al. (2010-11). "Aggressive sporadic histiocytic sarcoma with immunoglobulin heavy chain gene rearrangement and t(14;18)". International Journal of Hematology. 92 (4): 659–663. doi:10.1007/s12185-010-0704-8. ISSN 1865-3774. PMID 20976632. Check date values in: |date= (help)
↑ ^{Jump up to: 3.0} ^3.1 ^3.2 Chen, Wei; et al. (2009-06). "High frequency of clonal immunoglobulin receptor gene rearrangements in sporadic histiocytic/dendritic cell sarcomas". The American Journal of Surgical Pathology. 33 (6): 863–873. doi:10.1097/PAS.0b013e31819287b8. ISSN 1532-0979. PMID 19145200. Check date values in: |date= (help)
↑ Hure, Michelle C.; et al. (2012-02-10). "Histiocytic sarcoma arising from clonally related mantle cell lymphoma". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 30 (5): e49–53. doi:10.1200/JCO.2011.38.8553. ISSN 1527-7755. PMID 22184374.
↑ ^{Jump up to: 5.00} ^5.01 ^5.02 ^5.03 ^5.04 ^5.05 ^5.06 ^5.07 ^5.08 ^5.09 ^5.10 ^5.11 ^5.12 ^5.13 ^5.14 ^5.15 ^5.16 ^5.17 ^5.18 ^5.19 ^5.20 ^5.21 ^5.22 ^5.23 ^5.24 ^5.25 ^5.26 ^5.27 ^5.28 ^5.29 ^5.30 ^5.31 ^5.32 ^5.33 ^5.34 ^5.35 ^5.36 ^5.37 ^5.38 ^5.39 ^5.40 ^5.41 ^5.42 ^5.43 ^5.44 ^5.45 ^5.46 ^5.47 ^5.48 ^5.49 ^5.50 ^5.51 ^5.52 ^5.53 Egan, Caoimhe; et al. (2020-04). "Genomic profiling of primary histiocytic sarcoma reveals two molecular subgroups". Haematologica. 105 (4): 951–960. doi:10.3324/haematol.2019.230375. ISSN 1592-8721. PMC 7109753 Check |pmc= value (help). PMID 31439678. Check date values in: |date= (help)
↑ ^{Jump up to: 6.00} ^6.01 ^6.02 ^6.03 ^6.04 ^6.05 ^6.06 ^6.07 ^6.08 ^6.09 ^6.10 ^6.11 ^6.12 ^6.13 ^6.14 ^6.15 ^6.16 ^6.17 ^6.18 ^6.19 Shanmugam, Vignesh; et al. (2019-06). "Identification of diverse activating mutations of the RAS-MAPK pathway in histiocytic sarcoma". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 32 (6): 830–843. doi:10.1038/s41379-018-0200-x. ISSN 1530-0285. PMID 30626916. Check date values in: |date= (help)
↑ ^{Jump up to: 7.0} ^7.1 Bleeke, Matthias; et al. (2020-02). "Genome-wide analysis of acute leukemia and clonally related histiocytic sarcoma in a series of three pediatric patients". Pediatric Blood & Cancer. 67 (2): e28074. doi:10.1002/pbc.28074. ISSN 1545-5017. PMID 31737984. Check date values in: |date= (help)
↑ Nichols, C. R.; et al. (1990-05-17). "Hematologic neoplasia associated with primary mediastinal germ-cell tumors". The New England Journal of Medicine. 322 (20): 1425–1429. doi:10.1056/NEJM199005173222004. ISSN 0028-4793. PMID 2158625.
↑ Go, Heounjeong; et al. (2014-08). "Frequent detection of BRAF(V600E) mutations in histiocytic and dendritic cell neoplasms". Histopathology. 65 (2): 261–272. doi:10.1111/his.12416. ISSN 1365-2559. PMID 24720374. Check date values in: |date= (help)
↑ Shimono, Joji; et al. (2017-11-17). "Prognostic factors for histiocytic and dendritic cell neoplasms". Oncotarget. 8 (58): 98723–98732. doi:10.18632/oncotarget.21920. ISSN 1949-2553. PMC 5716762. PMID 29228722.
↑ ^{Jump up to: 11.0} ^11.1 Kordes, M.; et al. (2016-04). "Cooperation of BRAF(F595L) and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling". Leukemia. 30 (4): 937–946. doi:10.1038/leu.2015.319. ISSN 1476-5551. PMID 26582644. Check date values in: |date= (help)
↑ ^{Jump up to: 12.0} ^12.1 ^12.2 ^12.3 ^12.4 ^12.5 ^12.6 ^12.7 Liu, Qingqing; et al. (2016-08). "Somatic mutations in histiocytic sarcoma identified by next generation sequencing". Virchows Archiv: An International Journal of Pathology. 469 (2): 233–241. doi:10.1007/s00428-016-1965-2. ISSN 1432-2307. PMID 27259537. Check date values in: |date= (help)
↑ Burger, Jan A.; et al. (2016-05-20). "Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition". Nature Communications. 7: 11589. doi:10.1038/ncomms11589. ISSN 2041-1723. PMC 4876453. PMID 27199251.
↑ Thakral, Beenu; et al. (2016-11-17). "Histiocytic sarcoma: secondary neoplasm or "transdifferentiation" in the setting of B-acute lymphoblastic leukemia". Blood. 128 (20): 2475. doi:10.1182/blood-2016-08-735795. ISSN 1528-0020. PMID 27856472.
↑ Gounder, Mrinal M.; et al. (2018-05-17). "Trametinib in Histiocytic Sarcoma with an Activating MAP2K1 (MEK1) Mutation". The New England Journal of Medicine. 378 (20): 1945–1947. doi:10.1056/NEJMc1511490. ISSN 1533-4406. PMC 6062005. PMID 29768143.
↑ Kumamoto, Tadashi; et al. (2019-02). "A case of recurrent histiocytic sarcoma with MAP2K1 pathogenic variant treated with the MEK inhibitor trametinib". International Journal of Hematology. 109 (2): 228–232. doi:10.1007/s12185-018-2553-9. ISSN 1865-3774. PMID 30361829. Check date values in: |date= (help)
↑ ^{Jump up to: 17.0} ^17.1 ^17.2 ^17.3 ^17.4 ^17.5 ^17.6 ^17.7 ^17.8 Hung, Yin P.; et al. (2017-08). "Histiocytic sarcoma: New insights into FNA cytomorphology and molecular characteristics". Cancer Cytopathology. 125 (8): 604–614. doi:10.1002/cncy.21851. ISSN 1934-6638. PMID 28805986. Check date values in: |date= (help)
↑ ^{Jump up to: 18.0} ^18.1 Batra, Sandeep; et al. (2016). "Histiocytic Sarcoma Associated with Coombs Negative Acute Hemolytic Anemia: A Rare Presentation". Case Reports in Oncological Medicine. 2016: 3179147. doi:10.1155/2016/3179147. ISSN 2090-6706. PMC 4939191. PMID 27429816.
↑ Voruz, Sophie; et al. (2018-01). "Response to MEK inhibition with trametinib and tyrosine kinase inhibition with imatinib in multifocal histiocytic sarcoma". Haematologica. 103 (1): e39–e41. doi:10.3324/haematol.2017.179150. ISSN 1592-8721. PMC 5777214. PMID 29097496. Check date values in: |date= (help)
↑ Hung, Yin P.; et al. (2020-05). "Histiocytic Sarcoma". Archives of Pathology & Laboratory Medicine. 144 (5): 650–654. doi:10.5858/arpa.2018-0349-RS. ISSN 1543-2165. PMID 31070934. Check date values in: |date= (help)
↑ Alonso-Dominguez, J. M.; et al. (2012). "Cytogenetics findings in a histiocytic sarcoma case". Case Reports in Hematology. 2012: 428279. doi:10.1155/2012/428279. ISSN 2090-6579. PMC 3420615. PMID 22937328.
↑ Takahashi, Emiko; et al. (2013). "Histiocytic sarcoma : an updated literature review based on the 2008 WHO classification". Journal of clinical and experimental hematopathology: JCEH. 53 (1): 1–8. doi:10.3960/jslrt.53.1. ISSN 1880-9952. PMID 23801128.

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 Associate Editor or other CCGA representative. When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

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.

[:1-1] Feldman, Andrew L.; et al. (2008-06-15). "Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone". Blood. 111 (12): 5433–5439. doi:10.1182/blood-2007-11-124792. ISSN 1528-0020. PMC 2424145. PMID 18272816.

[2] Hayase, Eiko; et al. (2010-11). "Aggressive sporadic histiocytic sarcoma with immunoglobulin heavy chain gene rearrangement and t(14;18)". International Journal of Hematology. 92 (4): 659–663. doi:10.1007/s12185-010-0704-8. ISSN 1865-3774. PMID 20976632. Check date values in: |date= (help)

[:12-3] {Jump up to: 3.0} ^3.1 ^3.2 Chen, Wei; et al. (2009-06). "High frequency of clonal immunoglobulin receptor gene rearrangements in sporadic histiocytic/dendritic cell sarcomas". The American Journal of Surgical Pathology. 33 (6): 863–873. doi:10.1097/PAS.0b013e31819287b8. ISSN 1532-0979. PMID 19145200. Check date values in: |date= (help)

[:5-4] Hure, Michelle C.; et al. (2012-02-10). "Histiocytic sarcoma arising from clonally related mantle cell lymphoma". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 30 (5): e49–53. doi:10.1200/JCO.2011.38.8553. ISSN 1527-7755. PMID 22184374.

[:6-5] {Jump up to: 5.00} ^5.01 ^5.02 ^5.03 ^5.04 ^5.05 ^5.06 ^5.07 ^5.08 ^5.09 ^5.10 ^5.11 ^5.12 ^5.13 ^5.14 ^5.15 ^5.16 ^5.17 ^5.18 ^5.19 ^5.20 ^5.21 ^5.22 ^5.23 ^5.24 ^5.25 ^5.26 ^5.27 ^5.28 ^5.29 ^5.30 ^5.31 ^5.32 ^5.33 ^5.34 ^5.35 ^5.36 ^5.37 ^5.38 ^5.39 ^5.40 ^5.41 ^5.42 ^5.43 ^5.44 ^5.45 ^5.46 ^5.47 ^5.48 ^5.49 ^5.50 ^5.51 ^5.52 ^5.53 Egan, Caoimhe; et al. (2020-04). "Genomic profiling of primary histiocytic sarcoma reveals two molecular subgroups". Haematologica. 105 (4): 951–960. doi:10.3324/haematol.2019.230375. ISSN 1592-8721. PMC 7109753 Check |pmc= value (help). PMID 31439678. Check date values in: |date= (help)

[:7-6] {Jump up to: 6.00} ^6.01 ^6.02 ^6.03 ^6.04 ^6.05 ^6.06 ^6.07 ^6.08 ^6.09 ^6.10 ^6.11 ^6.12 ^6.13 ^6.14 ^6.15 ^6.16 ^6.17 ^6.18 ^6.19 Shanmugam, Vignesh; et al. (2019-06). "Identification of diverse activating mutations of the RAS-MAPK pathway in histiocytic sarcoma". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 32 (6): 830–843. doi:10.1038/s41379-018-0200-x. ISSN 1530-0285. PMID 30626916. Check date values in: |date= (help)

[:2-7] {Jump up to: 7.0} ^7.1 Bleeke, Matthias; et al. (2020-02). "Genome-wide analysis of acute leukemia and clonally related histiocytic sarcoma in a series of three pediatric patients". Pediatric Blood & Cancer. 67 (2): e28074. doi:10.1002/pbc.28074. ISSN 1545-5017. PMID 31737984. Check date values in: |date= (help)

[:13-8] Nichols, C. R.; et al. (1990-05-17). "Hematologic neoplasia associated with primary mediastinal germ-cell tumors". The New England Journal of Medicine. 322 (20): 1425–1429. doi:10.1056/NEJM199005173222004. ISSN 0028-4793. PMID 2158625.

[9] Go, Heounjeong; et al. (2014-08). "Frequent detection of BRAF(V600E) mutations in histiocytic and dendritic cell neoplasms". Histopathology. 65 (2): 261–272. doi:10.1111/his.12416. ISSN 1365-2559. PMID 24720374. Check date values in: |date= (help)

[10] Shimono, Joji; et al. (2017-11-17). "Prognostic factors for histiocytic and dendritic cell neoplasms". Oncotarget. 8 (58): 98723–98732. doi:10.18632/oncotarget.21920. ISSN 1949-2553. PMC 5716762. PMID 29228722.

[:9-11] {Jump up to: 11.0} ^11.1 Kordes, M.; et al. (2016-04). "Cooperation of BRAF(F595L) and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling". Leukemia. 30 (4): 937–946. doi:10.1038/leu.2015.319. ISSN 1476-5551. PMID 26582644. Check date values in: |date= (help)

[:8-12] {Jump up to: 12.0} ^12.1 ^12.2 ^12.3 ^12.4 ^12.5 ^12.6 ^12.7 Liu, Qingqing; et al. (2016-08). "Somatic mutations in histiocytic sarcoma identified by next generation sequencing". Virchows Archiv: An International Journal of Pathology. 469 (2): 233–241. doi:10.1007/s00428-016-1965-2. ISSN 1432-2307. PMID 27259537. Check date values in: |date= (help)

[13] Burger, Jan A.; et al. (2016-05-20). "Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition". Nature Communications. 7: 11589. doi:10.1038/ncomms11589. ISSN 2041-1723. PMC 4876453. PMID 27199251.

[14] Thakral, Beenu; et al. (2016-11-17). "Histiocytic sarcoma: secondary neoplasm or "transdifferentiation" in the setting of B-acute lymphoblastic leukemia". Blood. 128 (20): 2475. doi:10.1182/blood-2016-08-735795. ISSN 1528-0020. PMID 27856472.

[15] Gounder, Mrinal M.; et al. (2018-05-17). "Trametinib in Histiocytic Sarcoma with an Activating MAP2K1 (MEK1) Mutation". The New England Journal of Medicine. 378 (20): 1945–1947. doi:10.1056/NEJMc1511490. ISSN 1533-4406. PMC 6062005. PMID 29768143.

[16] Kumamoto, Tadashi; et al. (2019-02). "A case of recurrent histiocytic sarcoma with MAP2K1 pathogenic variant treated with the MEK inhibitor trametinib". International Journal of Hematology. 109 (2): 228–232. doi:10.1007/s12185-018-2553-9. ISSN 1865-3774. PMID 30361829. Check date values in: |date= (help)

[:10-17] {Jump up to: 17.0} ^17.1 ^17.2 ^17.3 ^17.4 ^17.5 ^17.6 ^17.7 ^17.8 Hung, Yin P.; et al. (2017-08). "Histiocytic sarcoma: New insights into FNA cytomorphology and molecular characteristics". Cancer Cytopathology. 125 (8): 604–614. doi:10.1002/cncy.21851. ISSN 1934-6638. PMID 28805986. Check date values in: |date= (help)

[:11-18] {Jump up to: 18.0} ^18.1 Batra, Sandeep; et al. (2016). "Histiocytic Sarcoma Associated with Coombs Negative Acute Hemolytic Anemia: A Rare Presentation". Case Reports in Oncological Medicine. 2016: 3179147. doi:10.1155/2016/3179147. ISSN 2090-6706. PMC 4939191. PMID 27429816.

[19] Voruz, Sophie; et al. (2018-01). "Response to MEK inhibition with trametinib and tyrosine kinase inhibition with imatinib in multifocal histiocytic sarcoma". Haematologica. 103 (1): e39–e41. doi:10.3324/haematol.2017.179150. ISSN 1592-8721. PMC 5777214. PMID 29097496. Check date values in: |date= (help)

[20] Hung, Yin P.; et al. (2020-05). "Histiocytic Sarcoma". Archives of Pathology & Laboratory Medicine. 144 (5): 650–654. doi:10.5858/arpa.2018-0349-RS. ISSN 1543-2165. PMID 31070934. Check date values in: |date= (help)

[21] Alonso-Dominguez, J. M.; et al. (2012). "Cytogenetics findings in a histiocytic sarcoma case". Case Reports in Hematology. 2012: 428279. doi:10.1155/2012/428279. ISSN 2090-6579. PMC 3420615. PMID 22937328.

[22] Takahashi, Emiko; et al. (2013). "Histiocytic sarcoma : an updated literature review based on the 2008 WHO classification". Journal of clinical and experimental hematopathology: JCEH. 53 (1): 1–8. doi:10.3960/jslrt.53.1. ISSN 1880-9952. PMID 23801128.

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Difference between revisions of "HAEM5:Histiocytic sarcoma"

Latest revision as of 12:37, 24 March 2025

Contents

Primary Author(s)*

WHO Classification of Disease

WHO Essential and Desirable Genetic Diagnostic Criteria

Related Terminology

Gene Rearrangements

Individual Region Genomic Gain/Loss/LOH

Characteristic Chromosomal or Other Global Mutational Patterns

Gene Mutations (SNV/INDEL)

Other Mutations

Epigenomic Alterations

Genes and Main Pathways Involved

Genetic Diagnostic Testing Methods

Familial Forms

Additional Information

Links

References

Notes

Navigation menu

Search

@@ Line 4: / Line 4: @@
 {{Under Construction}}
-<blockquote class='blockedit'>{{Box-round|title=Content 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]].
+<blockquote class="blockedit">{{Box-round|title=Content 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]].
 }}</blockquote>
-<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ 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 to a table, click within the table and select the > symbol that appears to be given options. 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 </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>
+<span style="color:#0070C0">(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 [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], 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 </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)</span>
 ==Primary Author(s)*==
 Marie-France Gagnon, MD, Mayo Clinic, Xinjie Xu, PhD FACMG, Mayo Clinic
-__TOC__
 ==WHO Classification of Disease==
@@ Line 37: / Line 34: @@
 |}
-==Definition / Description of Disease==
+==WHO Essential and Desirable Genetic Diagnostic Criteria==
+<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
-Histiocytic sarcoma (HS) is a very rare and aggressive non-Langerhans histiocyte neoplasm. It is included among histiocytic and dendritic cell neoplasms in the World Health Organization classification<ref name=":0">Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France.</ref> and among malignant histiocytoses (M group) in the revised classification of the Histiocyte Society.<ref>{{Cite journal|last=Emile|first=Jean-François|last2=Abla|first2=Oussama|last3=Fraitag|first3=Sylvie|last4=Horne|first4=Annacarin|last5=Haroche|first5=Julien|last6=Donadieu|first6=Jean|last7=Requena-Caballero|first7=Luis|last8=Jordan|first8=Michael B.|last9=Abdel-Wahab|first9=Omar|date=2016-06-02|title=Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages|url=https://pubmed.ncbi.nlm.nih.gov/26966089|journal=Blood|volume=127|issue=22|pages=2672–2681|doi=10.1182/blood-2016-01-690636|issn=1528-0020|pmc=5161007|pmid=26966089}}</ref> While, the etiology of HS remains unknown, it appears that it is generally derived from the myeloid (monocyte-macrophage) lineage. Some cases may nevertheless arise from evolutionary mechanisms such as transdifferentiation of another primary hemopathy, often of B-cell lineage, as evidenced by shared identical molecular alterations between the two malignancies.<ref name=":1">{{Cite journal|last=Feldman|first=Andrew L.|last2=Arber|first2=Daniel A.|last3=Pittaluga|first3=Stefania|last4=Martinez|first4=Antonio|last5=Burke|first5=Jerome S.|last6=Raffeld|first6=Mark|last7=Camos|first7=Mireia|last8=Warnke|first8=Roger|last9=Jaffe|first9=Elaine S.|date=2008-06-15|title=Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone|url=https://pubmed.ncbi.nlm.nih.gov/18272816|journal=Blood|volume=111|issue=12|pages=5433–5439|doi=10.1182/blood-2007-11-124792|issn=1528-0020|pmc=2424145|pmid=18272816}}</ref> Additionally, in other cases, separate development of two malignancies from a common progenitor may lead to HS occurring in the setting of another clonally-related hemopathy.<ref name=":2">{{Cite journal|last=Bleeke|first=Matthias|last2=Johann|first2=Pascal|last3=Gröbner|first3=Susanne|last4=Alten|first4=Julia|last5=Cario|first5=Gunnar|last6=Schäfer|first6=Hansjörg|last7=Klapper|first7=Wolfram|last8=Khoury|first8=Joseph|last9=Pfister|first9=Stefan|date=2020-02|title=Genome-wide analysis of acute leukemia and clonally related histiocytic sarcoma in a series of three pediatric patients|url=https://pubmed.ncbi.nlm.nih.gov/31737984|journal=Pediatric Blood & Cancer|volume=67|issue=2|pages=e28074|doi=10.1002/pbc.28074|issn=1545-5017|pmid=31737984}}</ref><ref name=":3">{{Cite journal|last=Brunner|first=P.|last2=Rufle|first2=A.|last3=Dirnhofer|first3=S.|last4=Lohri|first4=A.|last5=Willi|first5=N.|last6=Cathomas|first6=G.|last7=Tzankov|first7=A.|last8=Juskevicius|first8=D.|date=2014-09|title=Follicular lymphoma transformation into histiocytic sarcoma: indications for a common neoplastic progenitor|url=https://pubmed.ncbi.nlm.nih.gov/24850291|journal=Leukemia|volume=28|issue=9|pages=1937–1940|doi=10.1038/leu.2014.167|issn=1476-5551|pmid=24850291}}</ref>
+{| class="wikitable"
+|+
-==Synonyms / Terminology==
+|WHO Essential Criteria (Genetics)*
+|
-True histiocytic lymphoma (obsolete)
+|-
+|WHO Desirable Criteria (Genetics)*
-==Epidemiology / Prevalence==
+|
+|-
-Owing to the rarity of histiocytic sarcoma, only a limited number of cases of this malignancy have been described in the literature. While HS may affect patients of all ages, it occurs mainly in adulthood. A study based on the Surveillance, Epidemiology, and End Results (SEER) database reporting on 159 cases, documented an overall incidence of 0.17 per 100,000 individuals. Median age at diagnosis was 63 years.<ref name=":4">{{Cite journal|last=Kommalapati|first=Anuhya|last2=Tella|first2=Sri Harsha|last3=Durkin|first3=Martin|last4=Go|first4=Ronald S.|last5=Goyal|first5=Gaurav|date=2018-01-11|title=Histiocytic sarcoma: a population-based analysis of incidence, demographic disparities, and long-term outcomes|url=https://pubmed.ncbi.nlm.nih.gov/29183888|journal=Blood|volume=131|issue=2|pages=265–268|doi=10.1182/blood-2017-10-812495|issn=1528-0020|pmc=5757688|pmid=29183888}}</ref> Also, a higher incidence of HS has been reported, although inconsistently, in males.
+|Other Classification
+|
-HS may occur in isolation as well as synchronously or metachronously to another hematologic malignancy such as follicular lymphoma. Cases occurring in the setting of an existing hematologic malignancy are often referred to as secondary HS (as opposed to primary HS).
+|}
+<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
-==Clinical Features==
+==Related Terminology==
+<span style="color:#0070C0">(''Instructions: The table will have the related terminology from the WHO <u>autocompleted</u>.)''</span>
-Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>
 {| class="wikitable"
-|'''Signs and Symptoms'''
+|+
-|<span class="blue-text">EXAMPLE:</span> Asymptomatic (incidental finding on complete blood counts)
+|Acceptable
+|
-<span class="blue-text">EXAMPLE:</span> B-symptoms (weight loss, fever, night sweats)
-<span class="blue-text">EXAMPLE:</span> Fatigue
-<span class="blue-text">EXAMPLE:</span> Lymphadenopathy (uncommon)
 |-
-|'''Laboratory Findings'''
+|Not Recommended
-|<span class="blue-text">EXAMPLE:</span> Cytopenias
+|
-<span class="blue-text">EXAMPLE:</span> Lymphocytosis (low level)
 |}
+==Gene Rearrangements==
-<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}
-Patients with histiocytic sarcoma often present with systemic symptoms such as fatigue, weight loss and fever. Additional clinical manifestations are often related to site(s) of disease involvement. Some patients may come to clinical attention with a palpable mass or from organ compression by the malignant mass. Skin lesions may range from a minor rash to multiple tumors on the trunk and extremities. Gastrointestinal involvement may present with intestinal obstruction. Lytic lesions may arise from bone involvement. Hepatosplenomegaly is also described. Cytopenias are found in about a third of patients, with hemophagocytosis seen on bone marrow evaluation in a small fraction of patients. Additionally, histiocytic sarcoma may present in the setting of another hematologic neoplasm such as follicular lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, mantle cell lymphoma, hairy cell leukemia, chronic lymphocytic leukemia or MALT lymphoma. <ref name=":1" /><ref name=":3" /><ref>{{Cite journal|last=Zhang|first=Da|last2=McGuirk|first2=Joseph|last3=Ganguly|first3=Siddhartha|last4=Persons|first4=Diane L.|date=2009-05|title=Histiocytic/dendritic cell sarcoma arising from follicular lymphoma involving the bone: a case report and review of literature|url=https://pubmed.ncbi.nlm.nih.gov/19343479|journal=International Journal of Hematology|volume=89|issue=4|pages=529–532|doi=10.1007/s12185-009-0300-y|issn=1865-3774|pmid=19343479}}</ref><ref name=":5">{{Cite journal|last=Hure|first=Michelle C.|last2=Elco|first2=Christopher P.|last3=Ward|first3=David|last4=Hutchinson|first4=Lloyd|last5=Meng|first5=Xiuling|last6=Dorfman|first6=David M.|last7=Yu|first7=Hongbo|date=2012-02-10|title=Histiocytic sarcoma arising from clonally related mantle cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/22184374|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=30|issue=5|pages=e49–53|doi=10.1200/JCO.2011.38.8553|issn=1527-7755|pmid=22184374}}</ref><ref>{{Cite journal|last=Alvaro|first=T.|last2=Bosch|first2=R.|last3=Salvadó|first3=M. T.|last4=Piris|first4=M. A.|date=1996-11|title=True histiocytic lymphoma of the stomach associated with low-grade B-cell mucosa-associated lymphoid tissue (MALT)-type lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/8898846|journal=The American Journal of Surgical Pathology|volume=20|issue=11|pages=1406–1411|doi=10.1097/00000478-199611000-00013|issn=0147-5185|pmid=8898846}}</ref><ref>{{Cite journal|last=Bouabdallah|first=R.|last2=Abéna|first2=P.|last3=Chetaille|first3=B.|last4=Aurran-Schleinitz|first4=T.|last5=Sainty|first5=D.|last6=Dubus|first6=P.|last7=Arnoulet|first7=C.|last8=Coso|first8=D.|last9=Xerri|first9=L.|date=2001-06|title=True histiocytic lymphoma following B-acute lymphoblastic leukaemia: case report with evidence for a common clonal origin in both neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/11442501|journal=British Journal of Haematology|volume=113|issue=4|pages=1047–1050|doi=10.1046/j.1365-2141.2001.02841.x|issn=0007-1048|pmid=11442501}}</ref><ref>{{Cite journal|last=Castro|first=Eumenia C. C.|last2=Blazquez|first2=Cristina|last3=Boyd|first3=Jaime|last4=Correa|first4=Hernán|last5=de Chadarevian|first5=J.-P.|last6=Felgar|first6=Raymond E.|last7=Graf|first7=Nicole|last8=Levy|first8=Norman|last9=Lowe|first9=Eric J.|date=2010-05|title=Clinicopathologic features of histiocytic lesions following ALL, with a review of the literature|url=https://pubmed.ncbi.nlm.nih.gov/19642834|journal=Pediatric and Developmental Pathology: The Official Journal of the Society for Pediatric Pathology and the Paediatric Pathology Society|volume=13|issue=3|pages=225–237|doi=10.2350/09-03-0622-OA.1|issn=1093-5266|pmid=19642834}}</ref><ref>{{Cite journal|last=Kumar|first=Riten|last2=Khan|first2=Shakila P.|last3=Joshi|first3=Divya-Devi|last4=Shaw|first4=Gene R.|last5=Ketterling|first5=Rhett P.|last6=Feldman|first6=Andrew L.|date=2011-02|title=Pediatric histiocytic sarcoma clonally related to precursor B-cell acute lymphoblastic leukemia with homozygous deletion of CDKN2A encoding p16INK4A|url=https://pubmed.ncbi.nlm.nih.gov/20973102|journal=Pediatric Blood & Cancer|volume=56|issue=2|pages=307–310|doi=10.1002/pbc.22810|issn=1545-5017|pmid=20973102}}</ref><ref>{{Cite journal|last=McClure|first=Rebecca|last2=Khoury|first2=Joseph|last3=Feldman|first3=Andrew|last4=Ketterling|first4=Rhett|date=2010-02|title=Clonal relationship between precursor B-cell acute lymphoblastic leukemia and histiocytic sarcoma: a case report and discussion in the context of similar cases|url=https://pubmed.ncbi.nlm.nih.gov/19744706|journal=Leukemia Research|volume=34|issue=2|pages=e71–73|doi=10.1016/j.leukres.2009.08.020|issn=1873-5835|pmid=19744706}}</ref><ref>{{Cite journal|last=Michonneau|first=David|last2=Kaltenbach|first2=Sophie|last3=Derrieux|first3=Coralie|last4=Trinquand|first4=Amelie|last5=Brouzes|first5=Chantal|last6=Gibault|first6=Laure|last7=North|first7=Marie-Odile|last8=Delarue|first8=Richard|last9=Varet|first9=Bruno|date=2014-12-10|title=BRAF(V600E) mutation in a histiocytic sarcoma arising from hairy cell leukemia|url=https://pubmed.ncbi.nlm.nih.gov/24567436|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=32|issue=35|pages=e117–121|doi=10.1200/JCO.2013.49.0078|issn=1527-7755|pmid=24567436}}</ref><ref>{{Cite journal|last=Shao|first=Haipeng|last2=Xi|first2=Liqiang|last3=Raffeld|first3=Mark|last4=Feldman|first4=Andrew L.|last5=Ketterling|first5=Rhett P.|last6=Knudson|first6=Ryan|last7=Rodriguez-Canales|first7=Jaime|last8=Hanson|first8=Jeffrey|last9=Pittaluga|first9=Stefania|date=2011-11|title=Clonally related histiocytic/dendritic cell sarcoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: a study of seven cases|url=https://pubmed.ncbi.nlm.nih.gov/21666687|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=24|issue=11|pages=1421–1432|doi=10.1038/modpathol.2011.102|issn=1530-0285|pmc=3175277|pmid=21666687}}</ref> Association of HS with a germ cell tumor or autoimmune lymphoproliferative syndrome has also been described.<ref name=":13">{{Cite journal|last=Nichols|first=C. R.|last2=Roth|first2=B. J.|last3=Heerema|first3=N.|last4=Griep|first4=J.|last5=Tricot|first5=G.|date=1990-05-17|title=Hematologic neoplasia associated with primary mediastinal germ-cell tumors|url=https://pubmed.ncbi.nlm.nih.gov/2158625|journal=The New England Journal of Medicine|volume=322|issue=20|pages=1425–1429|doi=10.1056/NEJM199005173222004|issn=0028-4793|pmid=2158625}}</ref>
-</blockquote>
-==Sites of Involvement==
-Histiocytic sarcoma may present as unifocal or multifocal disease. While, isolated lymph node involvement is seen in a subset of patients, extranodal involvement is more common. Among extranodal sites, the skin, soft tissues, gastrointestinal tract and nervous system are most frequently involved.<ref name=":4" />
-==Morphologic Features==
-According to the WHO, microscopic evaluation of histiocytic sarcoma reveals a diffuse discohesive proliferation of malignant cells with features suggestive of mature tissue histiocytes. A sinusoidal distribution may also be seen. HS is characterized by large, atypical pleomorphic neoplastic cells. These display abundant, eosinophilic cytoplasm in which fine vacuoles may be found. While focal spindling may be noted, malignant cells are usually round to ovoid. Nuclei, often large in size, may appear round or oval or display more irregular folded forms. Multinucleated cells are often described. Chromatin pattern may appear vesicular with a variable degree of atypia. Neoplastic cells may be admixed with reactive cells. Sometimes, these may form a prominent inflammatory infiltrate shrouding the malignant cells. Importantly, tumors with features consistent with histiocytic sarcoma arising in association with acute monocytic leukemia should not be classified as HS.<ref name=":0" />
-==Immunophenotype==
-Histiocytic sarcoma is characterized by the expression of at least one histiocytic marker such as CD68, CD163 (KP1 and PGM1) and lysozyme. Langerhans cell (CD1a, langerin), follicular dendritic cell (CD21, CD35) and myeloid cell (CD13, MPO) markers are typically negative. B-cell and T-cell markers are also usually absent. There is no expression of HMB45, EMA and keratin. Conversely, CD45, HLA-DR and α1-antitrypsin are commonly positive. Weak staining with CD15 may seldom be found. CD4 is often expressed at the cytoplasmic level. S100 is usually negative, yet a focal and weak pattern of expression may be seen.
+Put your text here and fill in the table <span style="color:#0070C0">(''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.'')</span>
 {| class="wikitable sortable"
 |-
-!Finding!!Marker
+!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
 |-
-|Positive (universal)||One of CD68, CD163, lysozyme
+|<span class="blue-text">EXAMPLE:</span> ''ABL1''||<span class="blue-text">EXAMPLE:</span> ''BCR::ABL1''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)
+|<span class="blue-text">EXAMPLE:</span> Common (CML)
+|<span class="blue-text">EXAMPLE:</span> D, P, T
+|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
+|<span class="blue-text">EXAMPLE:</span>
+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).
 |-
-|Positive (subset)||CD45, HLA-DR, α1-antitrypsin, CD4
+|<span class="blue-text">EXAMPLE:</span> ''CIC''
-|-
+|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
-|Negative (universal)||HMB45, EMA, keratin
+|<span class="blue-text">EXAMPLE:</span> 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''.
+|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
+|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)
+|<span class="blue-text">EXAMPLE:</span> D
+|
+|<span class="blue-text">EXAMPLE:</span>
+''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).
 |-
-|Negative (subset)||CD1a, langerin, CD21, CD35, CD13, MPO, CD15, S100
+|<span class="blue-text">EXAMPLE:</span> ''ALK''
-|}
+|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''
-==Chromosomal Rearrangements (Gene Fusions)==
-Put your text here and fill in the table
+Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
+|<span class="blue-text">EXAMPLE:</span> 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.
+|<span class="blue-text">EXAMPLE:</span> N/A
+|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
+|<span class="blue-text">EXAMPLE:</span> T
+|
+|<span class="blue-text">EXAMPLE:</span>
-{| class="wikitable sortable"
+Both balanced and unbalanced forms are observed by FISH (add references).
 |-
-!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
+|<span class="blue-text">EXAMPLE:</span> ''ABL1''
-!Diagnostic Significance (Yes, No or Unknown)
+|<span class="blue-text">EXAMPLE:</span> N/A
-!Prognostic Significance (Yes, No or Unknown)
+|<span class="blue-text">EXAMPLE:</span> 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.
-!Therapeutic Significance (Yes, No or Unknown)
+|<span class="blue-text">EXAMPLE:</span> N/A
-!Notes
+|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
+|<span class="blue-text">EXAMPLE:</span> D, P, T
+|
+|
 |-
-|<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)||<span class="blue-text">EXAMPLE:</span> 3'ABL1 / 5'BCR||<span class="blue-text">EXAMPLE:</span> der(22)||<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
+|
-<span class="blue-text">EXAMPLE:</span> 30% (add reference)
+|
-|Yes
+|
-|No
+|
-|Yes
+|
-|<span class="blue-text">EXAMPLE:</span>
+|
+|
+|
+|}
-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).
+<blockquote class="blockedit">{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}</blockquote>
-|}
-<blockquote class='blockedit'>{{Box-round|title=v4: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). <ref name=":1" /> Interestingly, the translocation t(14;18) has also rarely been documented in sporadic HS. <ref>{{Cite journal|last=Hayase|first=Eiko|last2=Kurosawa|first2=Mitsutoshi|last3=Yonezumi|first3=Masakatsu|last4=Suzuki|first4=Sachiko|last5=Suzuki|first5=Hiroaki|date=2010-11|title=Aggressive sporadic histiocytic sarcoma with immunoglobulin heavy chain gene rearrangement and t(14;18)|url=https://pubmed.ncbi.nlm.nih.gov/20976632|journal=International Journal of Hematology|volume=92|issue=4|pages=659–663|doi=10.1007/s12185-010-0704-8|issn=1865-3774|pmid=20976632}}</ref><ref name=":12">{{Cite journal|last=Chen|first=Wei|last2=Lau|first2=Sean K.|last3=Fong|first3=Dean|last4=Wang|first4=Jun|last5=Wang|first5=Endi|last6=Arber|first6=Daniel A.|last7=Weiss|first7=Lawrence M.|last8=Huang|first8=Qin|date=2009-06|title=High frequency of clonal immunoglobulin receptor gene rearrangements in sporadic histiocytic/dendritic cell sarcomas|url=https://pubmed.ncbi.nlm.nih.gov/19145200|journal=The American Journal of Surgical Pathology|volume=33|issue=6|pages=863–873|doi=10.1097/PAS.0b013e31819287b8|issn=1532-0979|pmid=19145200}}</ref> Similarly, a ''CCND1-IgH'' fusion has been described by Hure et al in patients diagnosed with HS and mantle cell lymphoma.<ref name=":5" /> 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.<ref name=":6">{{Cite journal|last=Egan|first=Caoimhe|last2=Nicolae|first2=Alina|last3=Lack|first3=Justin|last4=Chung|first4=Hye-Jung|last5=Skarshaug|first5=Shannon|last6=Pham|first6=Thu Anh|last7=Navarro|first7=Winnifred|last8=Abdullaev|first8=Zied|last9=Aguilera|first9=Nadine S.|date=2020-04|title=Genomic profiling of primary histiocytic sarcoma reveals two molecular subgroups|url=https://pubmed.ncbi.nlm.nih.gov/31439678|journal=Haematologica|volume=105|issue=4|pages=951–960|doi=10.3324/haematol.2019.230375|issn=1592-8721|pmc=7109753|pmid=31439678}}</ref>
+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). <ref name=":1">{{Cite journal|last=Feldman|first=Andrew L.|last2=Arber|first2=Daniel A.|last3=Pittaluga|first3=Stefania|last4=Martinez|first4=Antonio|last5=Burke|first5=Jerome S.|last6=Raffeld|first6=Mark|last7=Camos|first7=Mireia|last8=Warnke|first8=Roger|last9=Jaffe|first9=Elaine S.|date=2008-06-15|title=Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone|url=https://pubmed.ncbi.nlm.nih.gov/18272816|journal=Blood|volume=111|issue=12|pages=5433–5439|doi=10.1182/blood-2007-11-124792|issn=1528-0020|pmc=2424145|pmid=18272816}}</ref> Interestingly, the translocation t(14;18) has also rarely been documented in sporadic HS. <ref>{{Cite journal|last=Hayase|first=Eiko|last2=Kurosawa|first2=Mitsutoshi|last3=Yonezumi|first3=Masakatsu|last4=Suzuki|first4=Sachiko|last5=Suzuki|first5=Hiroaki|date=2010-11|title=Aggressive sporadic histiocytic sarcoma with immunoglobulin heavy chain gene rearrangement and t(14;18)|url=https://pubmed.ncbi.nlm.nih.gov/20976632|journal=International Journal of Hematology|volume=92|issue=4|pages=659–663|doi=10.1007/s12185-010-0704-8|issn=1865-3774|pmid=20976632}}</ref><ref name=":12">{{Cite journal|last=Chen|first=Wei|last2=Lau|first2=Sean K.|last3=Fong|first3=Dean|last4=Wang|first4=Jun|last5=Wang|first5=Endi|last6=Arber|first6=Daniel A.|last7=Weiss|first7=Lawrence M.|last8=Huang|first8=Qin|date=2009-06|title=High frequency of clonal immunoglobulin receptor gene rearrangements in sporadic histiocytic/dendritic cell sarcomas|url=https://pubmed.ncbi.nlm.nih.gov/19145200|journal=The American Journal of Surgical Pathology|volume=33|issue=6|pages=863–873|doi=10.1097/PAS.0b013e31819287b8|issn=1532-0979|pmid=19145200}}</ref> Similarly, a ''CCND1-IgH'' fusion has been described by Hure et al in patients diagnosed with HS and mantle cell lymphoma.<ref name=":5">{{Cite journal|last=Hure|first=Michelle C.|last2=Elco|first2=Christopher P.|last3=Ward|first3=David|last4=Hutchinson|first4=Lloyd|last5=Meng|first5=Xiuling|last6=Dorfman|first6=David M.|last7=Yu|first7=Hongbo|date=2012-02-10|title=Histiocytic sarcoma arising from clonally related mantle cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/22184374|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=30|issue=5|pages=e49–53|doi=10.1200/JCO.2011.38.8553|issn=1527-7755|pmid=22184374}}</ref> 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.<ref name=":6">{{Cite journal|last=Egan|first=Caoimhe|last2=Nicolae|first2=Alina|last3=Lack|first3=Justin|last4=Chung|first4=Hye-Jung|last5=Skarshaug|first5=Shannon|last6=Pham|first6=Thu Anh|last7=Navarro|first7=Winnifred|last8=Abdullaev|first8=Zied|last9=Aguilera|first9=Nadine S.|date=2020-04|title=Genomic profiling of primary histiocytic sarcoma reveals two molecular subgroups|url=https://pubmed.ncbi.nlm.nih.gov/31439678|journal=Haematologica|volume=105|issue=4|pages=951–960|doi=10.3324/haematol.2019.230375|issn=1592-8721|pmc=7109753|pmid=31439678}}</ref>
 {| class="wikitable sortable"
@@ Line 138: / Line 136: @@
 |}
+<blockquote class="blockedit">
+<center><span style="color:Maroon">'''End of V4 Section'''</span>
+----
 </blockquote>
-<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
+<blockquote class="blockedit">{{Box-round|title=v4: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)}}
+* Gene Mutations (SNV/INDEL)}}</blockquote>
 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.
@@ Line 155: / Line 156: @@
 <u>Therapeutic:</u> 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.
+<blockquote class="blockedit">
+<center><span style="color:Maroon">'''End of V4 Section'''</span>
+----
 </blockquote>
-==Individual Region Genomic Gain / Loss / LOH==
+==Individual Region Genomic Gain/Loss/LOH==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable. Do not delete table.'') </span>
+Put your text here and fill in the table <span style="color:#0070C0">(''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.'') </span>
 {| class="wikitable sortable"
 |-
-!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
+!Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)'''
-!Diagnostic Significance (Yes, No or Unknown)
+!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
-!Prognostic Significance (Yes, No or Unknown)
+!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
-!Therapeutic Significance (Yes, No or Unknown)
+!'''Clinical Relevance Details/Other Notes'''
-!Notes
 |-
 |<span class="blue-text">EXAMPLE:</span>
 |<span class="blue-text">EXAMPLE:</span> Loss
 |<span class="blue-text">EXAMPLE:</span>
+chr7
-chr7:1- 159,335,973 [hg38]
 |<span class="blue-text">EXAMPLE:</span>
+Unknown
-chr7
+|<span class="blue-text">EXAMPLE:</span> D, P
-|Yes
+|<span class="blue-text">EXAMPLE:</span> No
-|Yes
-|No
 |<span class="blue-text">EXAMPLE:</span>
+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).
-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 reference).
 |-
 |<span class="blue-text">EXAMPLE:</span>
 |<span class="blue-text">EXAMPLE:</span> Gain
 |<span class="blue-text">EXAMPLE:</span>
+chr8
-chr8:1-145,138,636 [hg38]
+|<span class="blue-text">EXAMPLE:</span>
+Unknown
+|<span class="blue-text">EXAMPLE:</span> D, P
+|
+|<span class="blue-text">EXAMPLE:</span>
+Common recurrent secondary finding for t(8;21) (add references).
+|-
+|<span class="blue-text">EXAMPLE:</span>
+|<span class="blue-text">EXAMPLE:</span> Amp
+|<span class="blue-text">EXAMPLE:</span>
+q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
 |<span class="blue-text">EXAMPLE:</span>
+''ERBB2''
-chr8
+|<span class="blue-text">EXAMPLE:</span> D, P, T
-|No
+|
-|No
-|No
 |<span class="blue-text">EXAMPLE:</span>
+Amplification of ''ERBB2'' is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
-Common recurrent secondary finding for t(8;21) (add reference).
+|-
+|
+|
+|
+|
+|
+|
+|
 |}
-<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}
+<blockquote class="blockedit">{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote>
 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.<ref name=":7">{{Cite journal|last=Shanmugam|first=Vignesh|last2=Griffin|first2=Gabriel K.|last3=Jacobsen|first3=Eric D.|last4=Fletcher|first4=Christopher D. M.|last5=Sholl|first5=Lynette M.|last6=Hornick|first6=Jason L.|date=2019-06|title=Identification of diverse activating mutations of the RAS-MAPK pathway in histiocytic sarcoma|url=https://pubmed.ncbi.nlm.nih.gov/30626916|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=32|issue=6|pages=830–843|doi=10.1038/s41379-018-0200-x|issn=1530-0285|pmid=30626916}}</ref> Loss of ''CDKN2A'' has also been documented in some patients by FISH analysis.<ref name=":6" /> Copy-number loss or Loss-of-heterozygosity (LOH) involving chromosome 17 (including the ''NF1'' gene) and amplification of ''PTPN11'' can also be seen.<ref name=":6" /> 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.<ref name=":2" />
+In a series of 28 cases of HS assessed with targeted next-generation sequencing, ''CDKN2A'' was frequently inactivated by focal deletion at 9p21.3.<ref name=":7">{{Cite journal|last=Shanmugam|first=Vignesh|last2=Griffin|first2=Gabriel K.|last3=Jacobsen|first3=Eric D.|last4=Fletcher|first4=Christopher D. M.|last5=Sholl|first5=Lynette M.|last6=Hornick|first6=Jason L.|date=2019-06|title=Identification of diverse activating mutations of the RAS-MAPK pathway in histiocytic sarcoma|url=https://pubmed.ncbi.nlm.nih.gov/30626916|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=32|issue=6|pages=830–843|doi=10.1038/s41379-018-0200-x|issn=1530-0285|pmid=30626916}}</ref> Loss of ''CDKN2A'' has also been documented in some patients by FISH analysis.<ref name=":6" /> Copy-number loss or Loss-of-heterozygosity (LOH) involving chromosome 17 (including the ''NF1'' gene) and amplification of ''PTPN11'' can also be seen.<ref name=":6" /> 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.<ref name=":2">{{Cite journal|last=Bleeke|first=Matthias|last2=Johann|first2=Pascal|last3=Gröbner|first3=Susanne|last4=Alten|first4=Julia|last5=Cario|first5=Gunnar|last6=Schäfer|first6=Hansjörg|last7=Klapper|first7=Wolfram|last8=Khoury|first8=Joseph|last9=Pfister|first9=Stefan|date=2020-02|title=Genome-wide analysis of acute leukemia and clonally related histiocytic sarcoma in a series of three pediatric patients|url=https://pubmed.ncbi.nlm.nih.gov/31737984|journal=Pediatric Blood & Cancer|volume=67|issue=2|pages=e28074|doi=10.1002/pbc.28074|issn=1545-5017|pmid=31737984}}</ref>
+<blockquote class="blockedit">
+<center><span style="color:Maroon">'''End of V4 Section'''</span>
+----
 </blockquote>
-==Characteristic Chromosomal Patterns==
+==Characteristic Chromosomal or Other Global Mutational Patterns==
-Put your text here <span style="color:#0070C0">(''EXAMPLE PATTERNS: 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. Do not delete table.'')</span>
+Put your text here and fill in the table <span style="color:#0070C0">(I''nstructions: 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.'')</span>
 {| class="wikitable sortable"
 |-
 !Chromosomal Pattern
-!Diagnostic Significance (Yes, No or Unknown)
+!Molecular Pathogenesis
-!Prognostic Significance (Yes, No or Unknown)
+!'''Prevalence -'''
-!Therapeutic Significance (Yes, No or Unknown)
+'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
-!Notes
+!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
+!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
+!'''Clinical Relevance Details/Other Notes'''
 |-
 |<span class="blue-text">EXAMPLE:</span>
 Co-deletion of 1p and 18q
-|Yes
+|<span class="blue-text">EXAMPLE:</span> See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
-|No
+|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
-|No
+|<span class="blue-text">EXAMPLE:</span> D, P
+|
+|
+|-
 |<span class="blue-text">EXAMPLE:</span>
+Microsatellite instability - hypermutated
-See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
+|
+|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
+|<span class="blue-text">EXAMPLE:</span> P, T
+|
+|
+|-
+|
+|
+|
+|
+|
+|
 |}
-<blockquote class='blockedit'>{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}
+<blockquote class="blockedit">{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}</blockquote>
-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.<ref name=":13" />
+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.<ref name=":13">{{Cite journal|last=Nichols|first=C. R.|last2=Roth|first2=B. J.|last3=Heerema|first3=N.|last4=Griep|first4=J.|last5=Tricot|first5=G.|date=1990-05-17|title=Hematologic neoplasia associated with primary mediastinal germ-cell tumors|url=https://pubmed.ncbi.nlm.nih.gov/2158625|journal=The New England Journal of Medicine|volume=322|issue=20|pages=1425–1429|doi=10.1056/NEJM199005173222004|issn=0028-4793|pmid=2158625}}</ref>
+<blockquote class="blockedit">
+<center><span style="color:Maroon">'''End of V4 Section'''</span>
+----
 </blockquote>
-==Gene Mutations (SNV / INDEL)==
+==Gene Mutations (SNV/INDEL)==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well as either disease defining and/or clinically significant. Can include references 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. Do not delete table.'') </span>
+Put your text here and fill in the table <span style="color:#0070C0">(''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.'') </span>
 {| class="wikitable sortable"
 |-
-!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
+!Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene, Oncogene, Other'''!!'''Prevalence -'''
-!'''Diagnostic Significance (Yes, No or Unknown)'''
+'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
-!Prognostic Significance (Yes, No or Unknown)
+!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  '''
-!Therapeutic Significance (Yes, No or Unknown)
+!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
-!Notes
+!'''Clinical Relevance Details/Other Notes'''
 |-
-|<span class="blue-text">EXAMPLE:</span> TP53; Variable LOF mutations
+|<span class="blue-text">EXAMPLE:</span>''EGFR''
-<span class="blue-text">EXAMPLE:</span>
+<br />
+|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
-EGFR; Exon 20 mutations
+|<span class="blue-text">EXAMPLE:</span> Oncogene
+|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
-<span class="blue-text">EXAMPLE:</span> BRAF; Activating mutations
+|<span class="blue-text">EXAMPLE:</span> T
-|<span class="blue-text">EXAMPLE:</span> TSG
+|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
-|<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
+|<span class="blue-text">EXAMPLE:</span> 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).
+|-
-<span class="blue-text">EXAMPLE:</span> 30% (add Reference)
+|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
-|<span class="blue-text">EXAMPLE:</span> IDH1 R123H
+<br />
-|<span class="blue-text">EXAMPLE:</span> EGFR amplification
+|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
+|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
+|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
+|<span class="blue-text">EXAMPLE:</span> P
+|
+|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
+|-
+|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
+|<span class="blue-text">EXAMPLE:</span> Activating mutations
+|<span class="blue-text">EXAMPLE:</span> Oncogene
+|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
+|<span class="blue-text">EXAMPLE:</span> T
+|
+|
+|-
+|
+|
+|
+|
 |
 |
 |
-|<span class="blue-text">EXAMPLE:</span>  Excludes hairy cell leukemia (HCL) (add reference).
+|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
-<br />
-|}
-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.
-<blockquote class='blockedit'>{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}
+<blockquote class="blockedit">{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote>
 ''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.<ref name=":7" /> 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'').<ref name=":6" />
@@ Line 377: / Line 425: @@
 Please refer to the above “Gene Mutations (SNV/INDEL)” section.
+<blockquote class="blockedit">
+<center><span style="color:Maroon">'''End of V4 Section'''</span>
+----
 </blockquote>
 ==Epigenomic Alterations==
@@ Line 384: / Line 435: @@
 ==Genes and Main Pathways Involved==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table. Do not delete table.'')</span>
+Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
 {| class="wikitable sortable"
 |-
 !Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 |-
-|<span class="blue-text">EXAMPLE:</span> BRAF and MAP2K1; Activating mutations
+|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations
 |<span class="blue-text">EXAMPLE:</span> MAPK signaling
 |<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
 |-
-|<span class="blue-text">EXAMPLE:</span> CDKN2A; Inactivating mutations
+|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
 |<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
 |<span class="blue-text">EXAMPLE:</span> Unregulated cell division
 |-
-|<span class="blue-text">EXAMPLE:</span>  KMT2C and ARID1A; Inactivating mutations
+|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
-|<span class="blue-text">EXAMPLE:</span>  Histone modification, chromatin remodeling
+|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
-|<span class="blue-text">EXAMPLE:</span>  Abnormal gene expression program
+|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
+|-
+|
+|
+|
 |}
-<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}
+<blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>
 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.<ref name=":7" /> Egan et al also identified a high frequency of alterations within the RAS/RAF/MAPK pathway.<ref name=":6" /> Histiocytic sarcoma may also be associated with perturbations of chromatin regulation.<ref>{{Cite journal|last=Hung|first=Yin P.|last2=Qian|first2=Xiaohua|date=2020-05|title=Histiocytic Sarcoma|url=https://pubmed.ncbi.nlm.nih.gov/31070934|journal=Archives of Pathology & Laboratory Medicine|volume=144|issue=5|pages=650–654|doi=10.5858/arpa.2018-0349-RS|issn=1543-2165|pmid=31070934}}</ref>
+<blockquote class="blockedit">
+<center><span style="color:Maroon">'''End of V4 Section'''</span>
+----
 </blockquote>
 ==Genetic Diagnostic Testing Methods==
@@ Line 425: / Line 484: @@
 ==Links==
-Put your text placeholder here (or anywhere appropriate on the page) and use the "Link" icon at the top of the page <span style="color:#0070C0">(''Instructions: Highlight text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "<nowiki>http://www</nowiki>." portion.'')</span>
+Put a link here or anywhere appropriate in this page <span style="color:#0070C0">(''Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the wiki page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "<nowiki>http://www</nowiki>." portion.'')</span>
 ==References==
-(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />
+(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span> <references />
-'''
+<br />
 ==Notes==
-<nowiki>*</nowiki>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.
+<nowiki>*</nowiki>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 [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
+Prior Author(s):
 <nowiki>*</nowiki>''Citation of this Page'': “Histiocytic sarcoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Histiocytic_sarcoma</nowiki>.
-[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases H]]
+[[Category:HAEM5]]
+[[Category:DISEASE]]
+[[Category:Diseases H]]