Marie-France Gagnon, MD, Mayo Clinic, Xinjie Xu, PhD FACMG, Mayo Clinic
Histiocytic and dendritic cell neoplasms
Cancer Sub-Classification / Subtype
Definition / Description of Disease
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 and among malignant histiocytoses (M group) in the revised classification of the Histiocyte Society. 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. 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.
Synonyms / Terminology
True histiocytic lymphoma (obsolete)
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. Also, a higher incidence of HS has been reported, although inconsistently, in males.
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).
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.  Association of HS with a germ cell tumor or autoimmune lymphoproliferative syndrome has also been described.
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.
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.
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.
|Positive (universal)||One of CD68, CD163, lysozyme|
|Positive (subset)||CD45, HLA-DR, α1-antitrypsin, CD4|
|Negative (universal)||HMB45, EMA, keratin|
|Negative (subset)||CD1a, langerin, CD21, CD35, CD13, MPO, CD15, S100|
Chromosomal Rearrangements (Gene Fusions)
Very few reports have described the genetic landscape of histiocytic sarcoma, with current literature being restricted to case reports and case series, thus limiting the ability to derive a comprehensive portrait of genetic alterations in HS.
No universal or recurrent chromosomal rearrangement are identified in histiocytic sarcoma. In cases where HS arises in association with follicular lymphoma, both neoplasms may exhibit the translocation t(14;18)(q32;q21) with identical breakpoints. In fact, such cases may reflect a phenomenon of transdifferentiation from a lymphoid to a histiocytic phenotype. This was suggested by Feldman et al. in a compelling study reporting on 8 cases of clonally related follicular lymphoma and HS (with presence of t(14;18) in both tumors and identical IGH and BCL2 gene rearrangements). The authors posited that transdifferentiation may be mediated by changes in transcription factors (as evidenced by repression of PAX5, a B-cell lineage commitment factor, with upregulation of the myeloid transcription factors C/EBPα and β).  Interestingly, the translocation t(14;18) has also rarely been documented in sporadic HS.  Similarly, a CCND1-IgH fusion has been described by Hure et al in patients diagnosed with HS and mantle cell lymphoma. In addition, other gene fusions have been reported sporadically in individual cases. For example, Egan et al have identified a novel fusion between exon 12 of TTYH3 and exon 8 of BRAF on chromosome 7 using RNA-Seq. This TTYH3-BRAF fusion, subsequently confirmed with RT-PCR, was associated with increased levels of BRAF transcripts.
|Chromosomal Rearrangement||Genes in Fusion (5’ or 3’ Segments)||Pathogenic Derivative||Prevalence|
Characteristic Chromosomal Aberrations / Patterns
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.
In a series of 28 cases of HS assessed with targeted next-generation sequencing, CDKN2A was frequently inactivated by focal deletion at 9p21.3. Loss of CDKN2A has also been documented in some patients by FISH analysis. Copy-number loss or Loss-of-heterozygosity (LOH) involving chromosome 17 (including the NF1 gene) and amplification of PTPN11 can also be seen. In a case series describing three pediatric patients with clonally related HS with predating acute leukemia, methylation array profiling revealed the presence of CDKN2A deletions at chromosome 9p in two patients.
Gene Mutations (SNV/INDEL)
BRAF mutations (V600E and non-V600E) have been identified in a subset of patients with histiocytic sarcoma. Additionally, a study in which targeted next-generation sequencing was performed on 28 cases, reported recurrent mutations in the MAP kinase pathway (including KRAS, NRAS, MAP2K1, BRAF, PTPN11, NF1, CBL), and the PI3K signaling pathway (including PTEN, MTOR, PIK2R1, PIK3CA). Also, some cases, mostly those with a prior diagnosis of B-cell lymphoma, harbored a mutational signature of “aberrant somatic hypermutation” with mutations in genes such as BCL6, BCL2, CIITA, MYC, SOCS1, PAX5. In this study, CDNK2A was the most commonly altered gene (13/28, 46%). The authors identified a mean coding mutational burden of 3.56/Mb in their cohort, a number that is relatively low as compared with other malignancies. In another series reporting on 21 cases of primary HS investigated with whole-exome sequencing and RNA sequencing, Egan et al identified a high frequency of alterations within the RAS/RAF/MAPK pathway (such as NF1, PTPN11, MAP2K1, NRAS, KRAS).
|Gene||Mutation||Oncogene/Tumor Suppressor/Other||Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)||Prevalence (COSMIC/TCGA/Other)|
|BRAF||p.V600E and non-V600E p.F595, p.G464V, p.G466R p.N581S, p.G469R, p.G469A, p.D594N, p.G469V)||Oncogene||GOF||12%|
|KRAF||p.Q61H, p.G13D, p.A146T, p.G12D, p.G12C, p.Q61H, p.A146V,
|NRAS||p.G61K, p.Q61R, p.G12C, p.G12D||Oncogene||GOF|
|MAP2K1||p.C121S, p.I103N, p.L177M, p.F53S, p.F53L, p.C121S , p.K57E, p.Y125C, p.R181K||Oncogene||GOF|
|ARID1A||p.L2011fs, p.G2087R||Chromatin remodeling||LOF|
|PTPN11||p.G503, p.Y63S, p.Q506R, p.E72K, p.G60V, p.E69K, p.F71V, p.E76G, p.A72V||Oncogene||GOF|
|NF1||p.W229*, p.C1032Lfs*7, p.Q1822*, p.V1182D, p.Q1086*, p.R304*, p.Q1775*, p.L298*, p.K600fs||Tumor suppressor||LOF|
|PTEN||p.L125E, p.R130Q, p.Q171*, p.D24H, c.79+1G>C(19), p.L140*(19)||Tumor suppressor||LOF|
|SGK1||p.R285K, p.I238T, p.H237Y, p.K213R, p.P147S, p.E162G, p.K136R, p.Q125H, c.437+1G>A, c.362-1G>A||Other (stress response, apoptosis…)|
|SETD2||c.7432-2A>C, p.V1820E, p.P132fs, c.4715_1G>T, c.7432-1G>A||Epigenetic regulator/tumor suppressor||LOF|
|KMT2D||pE2225fs(19), p.K1752fs(19), p.G5428S, p.Q2796*, p.R904*, p.R5351Q, p.A2119Rfs, p.L3432D||Epigenetic modification, tumor suppressor||LOH|
Please refer to the above “Gene Mutations (SNV/INDEL)” section.
KMT2D, a gene involved in epigenetic regulation, has been reported as recurrently mutated in histiocytic sarcoma. Egan et al also reported mutations in epigenetic modifier genes such as SETD2, ARID1A and KMT2D.
Genes and Main Pathways Involved
A recent molecular profiling study by Shanmugam et al highlighted that alterations in the MAP kinase, PI3K- and cyclin-CDK4/6-INK4 signaling pathways appear involved in the pathogenesis of histiocytic sarcoma. Egan et al also identified a high frequency of alterations within the RAS/RAF/MAPK pathway. Histiocytic sarcoma may also be associated with perturbations of chromatin regulation.
Diagnostic Testing Methods
Histiocytic sarcoma diagnosis relies on histopathologic evaluation. In addition to histologic appearance, immunohistochemistry is central in diagnosing this malignancy and in excluding other morphologic mimics. Excisional or incisional biopsy is generally preferable to fine needle aspirate or core needle biopsy.
Of note, in the 2001 World Health Organization (WHO) classification, HS was originally defined based on the absence of clonal immunoglobulin heavy chain (IGH) or T-cell receptor (TCR) gene rearrangements. However, in 2008, the WHO revised the classification to include IGH and TCR rearrangements in light of a growing literature describing such rearrangements in HS cases.  While, clonal immunoglobulin receptor gene rearrangements may be seen in the setting of secondary HS from a phenomenon of cross-lineage transdifferentiation of neoplastic B cells into malignant histiocytes, they have also been described in primary HS. In this respect, in a study reporting on 23 patients with sporadic HS, Chen et al identified that IGH (+/- IGK) rearrangements were present in 39% of cases.
Staging at diagnosis is further completed by imaging studies such as PET scan or computed tomography scans.
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
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.
Put your links here (use "Link" icon at top of page)
(use "Cite" icon at top of page)
- 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.
- Emile, Jean-François; et al. (2016-06-02). "Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages". Blood. 127 (22): 2672–2681. doi:10.1182/blood-2016-01-690636. ISSN 1528-0020. PMC 5161007. PMID 26966089.
- 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.
- 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:
- Brunner, P.; et al. (2014-09). "Follicular lymphoma transformation into histiocytic sarcoma: indications for a common neoplastic progenitor". Leukemia. 28 (9): 1937–1940. doi:10.1038/leu.2014.167. ISSN 1476-5551. PMID 24850291. Check date values in:
- Kommalapati, Anuhya; et al. (2018-01-11). "Histiocytic sarcoma: a population-based analysis of incidence, demographic disparities, and long-term outcomes". Blood. 131 (2): 265–268. doi:10.1182/blood-2017-10-812495. ISSN 1528-0020. PMC 5757688. PMID 29183888.
- Zhang, Da; et al. (2009-05). "Histiocytic/dendritic cell sarcoma arising from follicular lymphoma involving the bone: a case report and review of literature". International Journal of Hematology. 89 (4): 529–532. doi:10.1007/s12185-009-0300-y. ISSN 1865-3774. PMID 19343479. Check date values in:
- 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.
- Alvaro, T.; et al. (1996-11). "True histiocytic lymphoma of the stomach associated with low-grade B-cell mucosa-associated lymphoid tissue (MALT)-type lymphoma". The American Journal of Surgical Pathology. 20 (11): 1406–1411. doi:10.1097/00000478-199611000-00013. ISSN 0147-5185. PMID 8898846. Check date values in:
- Bouabdallah, R.; et al. (2001-06). "True histiocytic lymphoma following B-acute lymphoblastic leukaemia: case report with evidence for a common clonal origin in both neoplasms". British Journal of Haematology. 113 (4): 1047–1050. doi:10.1046/j.1365-2141.2001.02841.x. ISSN 0007-1048. PMID 11442501. Check date values in:
- Castro, Eumenia C. C.; et al. (2010-05). "Clinicopathologic features of histiocytic lesions following ALL, with a review of the literature". Pediatric and Developmental Pathology: The Official Journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. 13 (3): 225–237. doi:10.2350/09-03-0622-OA.1. ISSN 1093-5266. PMID 19642834. Check date values in:
- Kumar, Riten; et al. (2011-02). "Pediatric histiocytic sarcoma clonally related to precursor B-cell acute lymphoblastic leukemia with homozygous deletion of CDKN2A encoding p16INK4A". Pediatric Blood & Cancer. 56 (2): 307–310. doi:10.1002/pbc.22810. ISSN 1545-5017. PMID 20973102. Check date values in:
- McClure, Rebecca; et al. (2010-02). "Clonal relationship between precursor B-cell acute lymphoblastic leukemia and histiocytic sarcoma: a case report and discussion in the context of similar cases". Leukemia Research. 34 (2): e71–73. doi:10.1016/j.leukres.2009.08.020. ISSN 1873-5835. PMID 19744706. Check date values in:
- Michonneau, David; et al. (2014-12-10). "BRAF(V600E) mutation in a histiocytic sarcoma arising from hairy cell leukemia". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 32 (35): e117–121. doi:10.1200/JCO.2013.49.0078. ISSN 1527-7755. PMID 24567436.
- Shao, Haipeng; et al. (2011-11). "Clonally related histiocytic/dendritic cell sarcoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: a study of seven cases". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 24 (11): 1421–1432. doi:10.1038/modpathol.2011.102. ISSN 1530-0285. PMC 3175277. PMID 21666687. Check date values in:
- 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.
- 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:
- 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:
- 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:
- 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:
- 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:
- 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.
- 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:
- 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:
- 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:
- 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:
- 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:
- 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:
- 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.
*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.