CIC-rearranged Sarcoma

CIC-rearranged sarcoma is presumably staged under Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) TNM principles.

A CIC-DUX4 fusion is present in 95% of cases, resulting from either a t(4;19)(q35;q13) or a t(10;19)(q26;q13) translocation; however, rare examples are associated with non-DUX4 partner genes, including FOXO4, LEUTX, NUTM1, and NUTM2A. CIC encodes a high-mobility group (HMG) box transcriptional repressor. Most CIC breakpoints are located within CIC exon 20. The DUX4 gene, encoding for a double homeobox transcription factor, is located within the D4Z4 macrosatellite repeat region of the chromosomes 4 and 10 subtelomeric regions (4q35 or 10q26.3). DUX4 is normally expressed in germ cells, but it is epigenetically silenced in somatic differentiated tissues. The predicted CIC-DUX4 chimeric protein retains the HMG box, with a large part of the N-terminal DUX4 being lost. In a subset of cases, the CIC-DUX4 fusion leads to a stop codon right after the breakpoint; thus, the resulting chimeric protein lacks any DUX4 sequence, suggesting that a truncated CIC protein may be sufficient to trigger oncogenesis. Trisomy 8 and MYC amplification are some of the other common genetic changes. Concurrent CIC mutations have been described in the context of tumors with CIC-LEUTX fusion. The gene expression profile of CIC sarcoma is distinct from that of Ewing sarcoma. The CIC-DUX4 fusion markedly enhances the CIC transcriptional activity, upregulating its targets, including CCND2, MUC5AC, and PEA3 family genes (e.g., ETV1, ETV4, and ETV5).

The tumors are generally large, well-circumscribed, white or tan, soft masses, with frequent hemorrhage and necrosis.

Tumors are composed of diffuse sheets of undifferentiated round cells, displaying at least in part a lobulated growth pattern, delineated by fibrotic stroma. A minor component of spindle or epithelioid cells may be seen in many cases. The tumor cells have relatively uniform cytomorphology but often reveal a mild degree of nuclear pleomorphism, with vesicular chromatin and prominent nucleoli. The cytoplasm is lightly eosinophilic, with occasional clearing. Necrosis is common and mitotic activity is brisk. In one third of the cases, focal myxoid stromal changes are present, in which tumor cells exhibit reticular or pseudoacinar arrangements. Tumors with CIC–non-DUX4 fusion variants are associated with histological features similar to those of tumors with the canonical CIC-DUX4. By immunohistochemistry, CIC sarcomas often express CD99, mostly in a patchy pattern and less commonly being diffuse and membranous (20%). WT1 (90–95%) and ETV4 (95–100%) are frequently positive and represent useful ancillary markers. NKX2-2 is typically negative. Sarcomas with CIC-NUTM1 fusions express NUT protein. Keratin, S100, and myogenic markers are rarely expressed. Calretinin and ERG can be positive.

Not clinically relevant

Most tumors follow a highly aggressive course with frequent metastases, most commonly to the lung. The estimated 5-year overall survival rate is 17–43%, significantly worse than that of Ewing sarcoma. The chemotherapy response to Ewing sarcoma regimens has been dismal.

CIC gene rearrangements can be detected by a variety of techniques. However, none of these methods are highly sensitive.

Essential: predominant round cell phenotype; mild nuclear pleomorphism; epithelioid and/or spindle cell components; variably myxoid stroma; immunoprofile shows variable CD99 staining, with frequent WT1 and ETV4 positivity.

Desirable: CIC gene rearrangement (in selected cases).