Histiocytic Sarcoma

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Primary Author(s)*

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

Cancer Category/Type

Histiocytic and dendritic cell neoplasms

Cancer Sub-Classification / Subtype

Not applicable

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[1] and among malignant histiocytoses (M group) in the revised classification of the Histiocyte Society.[2] 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.[3] 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.[4][5]

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.[6] 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).

Clinical Features

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. [3][5][7][8][9][10][11][12][13][14][15] Association of HS with a germ cell tumor or autoimmune lymphoproliferative syndrome has also been described.[16]

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.[6]

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.[1]

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.

Finding Marker
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). [3] Interestingly, the translocation t(14;18) has also rarely been documented in sporadic HS. [17][18] Similarly, a CCND1-IgH fusion has been described by Hure et al in patients diagnosed with HS and mantle cell lymphoma.[8] 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.[19]

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

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.[16]

Genomic Gain/Loss/LOH

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.[20] Loss of CDKN2A has also been documented in some patients by FISH analysis.[19] Copy-number loss or Loss-of-heterozygosity (LOH) involving chromosome 17 (including the NF1 gene) and amplification of PTPN11 can also be seen.[19] 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.[4]

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.[20] 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).[19]

Gene Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other)
BRAF p.V600E[19][21][22] and non-V600E p.F595[23], p.G464V[24], p.G466R[24] p.N581S[24], p.G469R[20], p.G469A, p.D594N, p.G469V[19]) Oncogene GOF 12%[19]
KRAF p.Q61H[24], p.G13D[20], p.A146T, p.G12D[19], p.G12C[19], p.Q61H[19], p.A146V[19],

p.A66fs[4]

Oncogene GOF
NRAS p.G61K[25], p.Q61R[19], p.G12C[20], p.G12D[26] Oncogene GOF
MAP2K1 p.C121S[20], p.I103N[19][20], p.L177M[20], p.F53S[20], p.F53L[19][20][27][28], p.C121S [19][29], p.K57E[19],  p.Y125C[19], p.R181K[19] Oncogene GOF
ARID1A p.L2011fs[19], p.G2087R[19] Chromatin remodeling LOF
HRAS p.G61R(23)[23] Oncogene GOF
PTPN11 p.G503[24], p.Y63S[30], p.Q506R[30], p.E72K[31], p.G60V[20], p.E69K[20], p.F71V[19], p.E76G[19], p.A72V[19] Oncogene GOF
NF1 p.W229*[20], p.C1032Lfs*7[20], p.Q1822*[19], p.V1182D[19], p.Q1086*[19], p.R304*[19], p.Q1775*[19], p.L298*[19], p.K600fs[19] Tumor suppressor LOF
CBL p.Y371C(29)[29], T402_L405del[20] Oncogene GOF
PTEN p.L125E[24], p.R130Q[24], p.Q171*[19][20], p.D24H[19][20], c.79+1G>C(19)[19], p.L140*(19)[19] Tumor suppressor LOF
PIK3CA p.H1047L[20][24] Oncogene GOF
MTOR p.S2215F[20], p.I2501F Oncogene GOF
SGK1 p.R285K[19], p.I238T[19], p.H237Y[19], p.K213R[19], p.P147S[19], p.E162G[19], p.K136R[19], p.Q125H[19], c.437+1G>A[19], c.362-1G>A[19] Other (stress response, apoptosis…)
SETD2 c.7432-2A>C[19], p.V1820E[19], p.P132fs[19], c.4715_1G>T[19], c.7432-1G>A[19] Epigenetic regulator/tumor suppressor LOF
CREBBP p.Y1433C[19] Tumor suppressor LOF
KMT2D pE2225fs(19)[19], p.K1752fs(19)[19], p.G5428S[29], p.Q2796*[29], p.R904*[29], p.R5351Q[29], p.A2119Rfs[29], p.L3432D[29] Epigenetic modification, tumor suppressor LOH

Other Mutations

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

Epigenomics (Methylation)

KMT2D, a gene involved in epigenetic regulation, has been reported as recurrently mutated in histiocytic sarcoma.[29] Egan et al also reported mutations in epigenetic modifier genes such as SETD2, ARID1A and KMT2D.[19]

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.[20] Egan et al also identified a high frequency of alterations within the RAS/RAF/MAPK pathway.[19] Histiocytic sarcoma may also be associated with perturbations of chromatin regulation.[32]

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. [18][33] 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,[34] 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.[18]

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.

Familial Forms

Not applicable

Other Information

None

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References

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Notes

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