Superficial EWSR1-negative undifferentiated small round cell sarcoma with CIC/DUX4 gene fusion: a new variant of Ewing-like tumors with locoregional lymph node metastasis

Abstract

The present study describes a new case of EWSR1-negative undifferentiated sarcoma with CIC/DUX4 gene fusion. This case is similar to tumors described as primitive undifferentiated round cell sarcomas that occur mainly in the trunk and display an aggressive behavior. To our knowledge, this is the first report of such a tumor presenting locoregional lymph node metastasis. In view of previous studies that prove the existence of a particular variant of undifferentiated sarcoma with Ewing-like morphology and CIC/DUX-4 gene fusion, a search for this gene fusion in all undifferentiated round cell sarcomas should be considered if a conclusive diagnosis cannot be reached following other conventional studies. Although additional cases with more extensive follow-up studies are needed, we believe that EWSR1-negative undifferentiated small round cell sarcoma with CIC/DUX4 gene fusion should be added to the list of new sarcoma variants with the possibility of lymph node metastasis.

CIC-DUX sarcomas demonstrate frequent MYC amplification and ETS-family transcription factor expression

“…Although most cases of CIC-DUX sarcoma demonstrated some CD99 immunoreactivity, in our experience, the CD99 pattern in CIC-DUX sarcomas is different from that seen in Ewing sarcoma cases. We, 11 and others 2,5-8 have observed mostly focal to patchy staining, though our single CIC-DUX4L case with diffuse CD99 (although not membranous) is cautionary and correlates a with a few other reported CIC-DUX cases that showed diffuse CD99 2,3,6 immunoreactivity.…”

“…These sarcomas, originally characterized in the pediatric population, [2][3][4][5] have been found to occur over a wide age range, though they arise predominantly in young adults. [6][7][8][9][10] We recently reported four undifferentiated round cell sarcomas harboring CIC-DUX4 fusions, 11 which, together with reported CIC-DUX4L 6 cases, we term 'CIC-DUX sarcomas'.…”

The “Grep” Command But Not FusionMap, FusionFinder or ChimeraScan Captures the CIC-DUX4 Fusion Gene from Whole Transcriptome Sequencing Data on a Small Round Cell Tumor with t(4;19)(q35;q13)

“…This fusion has not been reported before [5], [12]–[14]. CIC fusions have been reported at nt 4552, 4579, 4740, 4750 [12]–[14], [16] and for DUX4 at nt 1071, 1078, and 1145 of the reference sequence with accession number NM_033178.4 [5], [12]–[14].…”

“…So far, there are roughly 20 reported cases of sarcoma with the t(4;19)(q35;q13) and/or CIC-DUX4 fusion [1]–[5], [10]–[15]. In seven other cases with CIC-DUX4 , the DUX4 gene involved in the fusion apparently stems from the locus on 10q26 [13], [16]. The current data suggest that the CIC-DUX4 fusion defines a subgroup of primitive round cell sarcomas, different from Ewing sarcoma, with distinctive histopathology and rapid disease progression [1]–[5], [10]–[15].…”

Soft Tissue Sarcomas

“…Recent publications suggest that CIC-DUX4 fusion sarcomas have characteristic morphological features such as extensive necrosis, mild nuclear pleomorphism, coarse chromatin, prominent nucleoli, and foci of clear cells and myxoid matrix [ 305 ]. Lymph node metastasis, an unusual feature with Ewing sarcoma, also appears to be a distinctive feature of CIC-DUX4 sarcomas [ 306 ].…”