1. Sven Seiwerth UZSM and KBC Zagreb Zagreb, Croatia
Case 41 CIC-DUX sarcoma
Sven Seiwerth
UZSM and KBC Zagreb
Zagreb, Croatia

2. Case history
In 2015 A 15-year old girl was admitted to hospital with progressive suprapubic painful swelling. Inflammatory laboratory parameters were slightly elevated. Under introduced antibiotic therapy the lesion progressed becoming hemorrhagic.

3. Biopsy was performed resulting in largelly necrotic and hemorrhagic tumorous tissue consisting mainly of poorly differentiated small cells with hyperchromatic nuclei.
Histological diagnosis, with rouled out hematological malignancy and other SBRCT, supported by positive CD99 staining was Ewing's sarcoma. Molecular testing could not demonstrate neither EWS/FLI fusions (using PCR) nor EWS rearrangement (FISH). Diagnosis of a Ewing sarcoma – like tumor was given.
Euro Ewing protocol therapy introduced.
The local status ameliorated steppwise but never completelly.

4. Two years later (2017) a solitary lung metastasis was detected on follow-up and removed surgically.
The repeated immunohistochemical workup, now with addition of WT-1 and calretinin together with the negative EWS molecular panel resulted with the working diagnosis of a Ewing sarcoma – like tumor, possibly CIC rearranged.

6. CD 99
WT-1
EWS - BA

7. A paraffin block was sent to Raf Sciot (Loeven BE), where a CIC-DUX4 change in 87% of cells and no BCOR rearrangement was demonstrated.
Diagnosis: CIC-DUX4 sarcoma.
Follow-up: the patient died a few months later due to multiple lung metastases.

8. Ewing sarcoma family/-like
Fusions between a gene of the RNA-binding TET family (EWSR1 or FUS) with a gene of the ETS-transcription family (FLI1, ERG, ETV1, ETV4 or FEV).
Less frequent cases designated as Ewing-like sarcomas show different rearrangements between EWSR1 and non-ETS genes (NFATC2, POU5F1, SMARCA5, PATZ, ZSG, SP3).

9. SBRCT – Differential diagnosis
Traditional
Ewing’s sarcoma family
Rhabdomyosarcoma
Neuro-blastoma (Retino-; Nephro-; Hepato-; Pulmonary-)
Lymphoma/Leukemia
Synovial sarcoma
Small cell osteosarcoma
Mesenchymal condrosarcoma
Melanoma
Poorly differentiated & neuroendocrine carcinoma

10. New(er) entities Desmoplastic small round cell tumor (1989)
NUT midline carcinoma (1991)
CIC – rearranged sarcomas (2006/2012)
BCOR-CCNB3 round cell sarcomas (2012)

11. CIC- rearranged sarcomas
CIC-rearranged sarcomas show nuclear WT1, ERG, and FLI1 expression, along with variable CD99 immunoreactivity – non specific
ETV4 (ETS variant 4; also known as PEA3 or E1AF) stains only 5% DDx
Showing negativity for NKX2.2., in contrast to EWS family

12. Clinics and genetics
Different age (young adults) and location – mostly soft tissue
In general rapidly progressive course with fatal outcome
Poor or no reaction to chemotherapy including EWS protocols
Arround 60% have a CIC-DUX fusion
Most studies reported so far include small series with limited follow-up information
Sarcomas With CIC-rearrangements Are a Distinct Pathologic Entity With AggressiveOutcome: A Clinicopathologic and Molecular Study of 115 Cases.
Am J Surg Pathol. 2017

13. CIC-NUTM1 Fusion: A Case Which Expands the Spectrum of NUT-Rearranged Epithelioid Malignancies. (Genes Chromosomes Cancer ahead of print )
Review with novel markers facilitates precise categorization of 41 cases of diagnostically challenging, “undifferentiated small round cell tumors”. A clinicopathologic, immunophenotypic and molecular analysis. (Annals of Diagnostic Pathology. 2018)
CIC break-apart fluorescence in-situ hybridization misses a subset of CIC-DUX4 sarcomas: a clinicopathological and molecular study. (Histopathology. 2017)
NUTM2A-CIC fusion small round cell sarcoma: a genetically distinct variant of CIC-rearranged sarcoma. (Hum. Pathol. 2017)
A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma. (Am J Surg Pathol. 2014)
ETW 4 +; NKX2.2 -

14. CONCLUSION
In addition to the chalenges of „traditional” DDx there is significant pathological and IHC overlap among Ewing-like tumors, some with prognostic and therapeutic impacts.
When FISH or RT-PCR fail to detect EWSR1-rearrangements additional IHC (NKX2.2, ETV4 and BCOR) and molecular studies (FUS, CIC or BCOR analysis) may support the final diagnosis
Molecular findings should always be interpreted in relation to the specific clinical and pathological context.