Page 109 - Haematologica April 2020

Hystiocyte DIsordes
Genomic profiling of primary histiocytic sarcoma reveals two molecular subgroups
Caoimhe Egan,1 Alina Nicolae,1 Justin Lack,2 Hye-Jung Chung,1
Shannon Skarshaug,1 Thu Anh Pham,1 Winnifred Navarro,1 Zied Abdullaev,1 Nadine S. Aguilera,3 Liqiang Xi,1 Svetlana Pack,1 Stefania Pittaluga,1
Elaine S. Jaffe1 and Mark Raffeld1
1Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD; 2NIAID Collaborative Bioinformatics Resource (NCBR), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD and 3University of Virginia Health System, Charlottesville, VA, USA
ABSTRACT
Histiocytic sarcoma is a rare malignant neoplasm that may occur de novo or in the context of a previous hematologic malignancy or mediastinal germ cell tumor. Here, we performed whole exome sequencing and RNA-sequencing (RNA-Seq) on 21 archival cases of pri- mary histiocytic sarcoma. We identified a high number of genetic alter- ations within the RAS/RAF/MAPK pathway in 21 of 21 cases, with alter- ations in NF1 (6 of 21), MAP2K1 (5 of 21), PTPN11 (4 of 21), BRAF (4 of 21), KRAS (4 of 21), NRAS (1 of 21), and LZTR1 (1 of 21), including single cases with homozygous deletion of NF1, high-level amplification of PTPN11, and a novel TTYH3-BRAF fusion. Concurrent NF1 and PTPN11 mutations were present in 3 of 21 cases, and 5 of 7 cases with alterations in NF1 and/or PTPN11 had disease involving the gastrointestinal tract. Following unsuper- vised clustering of gene expression data, cases with NF1 and/or PTPN11 abnormalities formed a distinct tumor subgroup. A subset of NF1/PTPN11 wild-type cases had frequent mutations in B-cell lymphoma associated genes and/or clonal IG gene rearrangements. Our findings expand the cur- rent understanding of the molecular pathogenesis of this rare tumor and suggest the existence of a distinct subtype of primary histiocytic sarcoma characterized by NF1/PTPN11 alterations with predilection for the gas- trointestinal tract.
Introduction
Histiocytic sarcoma (HS) is a rare and aggressive malignant neoplasm that has morphological and immunophenotypic features of mature tissue histiocytes.1 It predominantly occurs in adulthood, although any age may be affected. Sites of involvement may be nodal or extranodal, and include the gastrointestinal (GI) tract, skin, and liver.2 Histologically, the tumor cells are usually pleomorphic with cyto- logic atypia and can be multinucleated or have a spindled or xanthomatous mor- phology. The diagnosis of HS requires the demonstration of histiocytic markers (CD68, CD163, CD4 or lysozyme) and the exclusion of tumors of other lineages by negativity of immunohistochemical stains for Langerhans cells (CD1a, langerin), follicular dendritic cells (CD21, CD23, clusterin), B and T cells, cells of myeloid or epithelial lineage (MPO, CK), and melanocytic markers.3,4
Histiocytic sarcoma may arise as a primary neoplasm (pHS), but is also well described in the context of an existing or concurrently diagnosed hematologic malignancy, most frequently a follicular lymphoma, but also chronic lymphocytic leukemia (CLL) and B- or T-lymphoblastic leukemia (B-ALL/T-ALL).5-9 Rare cases have also been associated with mediastinal germ cell tumor.3 Cases arising in the context of a lymphoid neoplasm are often referred to as “secondary” HS (sHS), and frequently possess identical clonal antigen receptor gene rearrangements or occa- sionally identical structural events (e.g. identical IGH/BCL2 rearrangements) as in the associated lymphoma. However, on histological and immunophenotypic
Ferrata Storti Foundation
Haematologica 2020 Volume 105(4):951-960
Correspondence:
MARK RAFFELD
mraff@mail.nih.gov
Received: June 25, 2019. Accepted: August 21, 2019. Pre-published: August 22, 2019.
doi:10.3324/haematol.2019.230375
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/4/951
©2020 Ferrata Storti Foundation
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