Page 12 - Haematologica April 2020

Editorials
strategies than studies based on large numbers of healthy donors which may be flawed by the great level of noise in the signals generated with this strategy.
Funding
Supported by grants from the National Cancer (P01- CA108671), Heart, Lung and Blood (1R01-HL134684) Institute, Associazione Italiana Ricerca Cancro (AIRC IG23525)
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Genomic profiling of histiocytic sarcoma: new insights into pathogenesis and subclassification
Jonathan Said
Department of Pathology and Laboratory Medicine, UCLA Medical Center and David Geffen School of Medicine, Los Angeles, CA, USA
E-mail: JONATHAN SAID - jsaid@mednet.ucla.edu doi:10.3324/haematol.2019.246314
Arevised classification of histiocytoses and their neoplasms was long overdue when members of the Histiocyte Society suggested dividing them into five groups, designated L (Langerhans cell), C (Cutaneous), M (Malignant), R (Rosai-Dorfman), and H (Hemophagocytic) (Figure 1).1 As an example, the L group, which includes Langerhans cell histiocytosis and Erdheim Chester disease, is characterized by mutations in the MAPK pathway and BRAF V600E. In contrast his- tiocytic sarcomas in the M group remain an elusive cate- gory. These rare and highly malignant neoplasms occur at all ages, and frequently involve extranodal sites including skin, soft tissues, and the gastrointestinal tract. There are few objective criteria for diagnosis other than expression of histiocyte markers (CD68, CD163, CD4, lysozyme, CD21, CD35, S100) and exclusion of other tumors by a panel of antibodies including, but not limited to, S100, keratins, EMA, Melan-A, HMB45, and B- and T-lymphoid markers.2 Further complications arise in the apparent plasticity between histiocytic sarcomas and other malig- nancies, such as follicular lymphomas, demonstrated by translocations, immunoglobulin gene rearrangements, or mutational analysis.3 Because of these pitfalls, histiocytic sarcoma has been vastly over diagnosed, with mimics including T-cell and other lymphomas with histiocyte-
rich backgrounds, and, in particular, CD30 positive anaplastic large cell lymphomas. Clearly, any progress in diagnosing and treating these aggressive neoplasms will depend on identifying specific molecular and other mark- ers for their accurate diagnosis.
Until recently, molecular analysis of histiocytic sarco- mas has given confusing results, and there have been no consistent cytogenetic abnormalities. Mutations involving the RAS-MAPK signaling pathway, BRAF V600E muta- tions, as activation of PI3K and the tumor suppressor gene CDKN2A4 have been most frequently reported, and there have been no reports of ALK translocations. Some cases, particularly in patients with associated B-cell lymphomas, have demonstrated immunoglobulin heavy or light chain gene rearrangements.
In this issue of Haematologica, Egan et al. performed genomic profiling of 21 primary histiocytic sarcomas, and in addition to confirming frequent alterations in the RAS/MAPK pathway, identified a novel intra-chromoso- mal transcript between exon 12 of TTYH3 and exon 8 of BRAF on chromosome 7. Moreover, differential expres- sion analysis identified two distinct molecular subgroups with distinct molecular profiles and associated clinical characteristics based on the presence or absence of NF1/PTP11 mutations.5 Cases that had NF1/PTPN11
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