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. Author manuscript; available in PMC: 2026 Apr 1.
Published in final edited form as: J Cutan Pathol. 2025 Feb 8;52(4):324–331. doi: 10.1111/cup.14792

Ancillary Tools for the Diagnosis of CIC-Rearranged Sarcoma: A Comprehensive Review

Jeffrey M Cloutier 1,2, Rami N Al-Rohil 3,4, Rajiv M Patel 5, Jennifer S Ko 6, Konstantinos Linos 7
PMCID: PMC12435752  NIHMSID: NIHMS2107423  PMID: 39921488

Abstract

CIC-rearranged sarcoma is a rare and aggressive undifferentiated round cell sarcoma that presents significant diagnostic challenges due to its histologic overlap with other round cell sarcomas. This review, conducted on behalf of the American Society of Dermatopathology Appropriate Use Criteria Committee (soft tissue subgroup), provides an overview of current immunohistochemical, cytogenetic, and molecular tests used to support the diagnosis of CIC-rearranged sarcoma. This comprehensive analysis included 36 studies, encompassing 436 CIC-rearranged sarcomas. The immunohistochemical markers, CD99 (typically non-diffuse), nuclear WT1, ETV4, and DUX4, were found to be relatively highly sensitive for CIC-rearranged sarcoma (CD99: 87%, WT1: 83%, ETV4: 85%, DUX4: 97%). However, the specificity of these markers is variable, with CD99 being highly non-specific, while WT1 (81-90%), ETV4 (95%), and DUX4 (100%) offering greater specificity. CIC break-apart FISH can be a helpful and cost-effective assay for detection of CIC-rearrangements, but has a false-negative rate that ranges from 26-43%. Next-generation sequence RNA fusion analysis also carries a risk of false negatives, which may be partly mitigated through manual data review. Ultimately, an accurate diagnosis of CIC-rearranged sarcoma requires careful morphologic assessment in combination with immunohistochemical studies and cytogenetics/molecular assays.

Keywords: CIC, sarcoma, WT1, ETV4, CD99, DUX4

1. Introduction

CIC-rearranged sarcoma is a rare, highly aggressive tumor characterized by recurrent fusions involving the CIC gene. They typically present as deep soft masses in young adults (median age 25-35 years), with a slight male predominance.1-3 Most tumors arise in the extremities or trunk, with less frequent involvement of the head and neck and retroperitoneum. Rarely, they may present more superficially in the dermis or subcutaneous adipose tissue.4-6 The prognosis is poor, even for patients with superficial tumors, with high rates of metastasis and recurrence contributing to overall low survival rates.2,3,5

CIC-rearranged sarcoma is an undifferentiated round cell sarcoma characterized histopathologically by lobules and sheets of primitive-appearing round cells with coarse chromatin, conspicuous nucleoli, and a variable amount of clear to pale eosinophilic cytoplasm (Fig. 1 and Fig.2). The tumor cells, while relatively uniform, often exhibit a degree of nuclear pleomorphism, and may occasionally be spindled. Mitotic figures are typically abundant and geographic necrosis is common. Tumor lobules are often separated by fibrous bands, and occasionally, the tumor may have myxoid features. Immunohistochemically, these sarcomas show variable, often focal or patchy, membranous CD99 expression (Fig. 1), in comparison to the strong and diffuse membranous CD99 typical of Ewing sarcoma.3 CIC-rearranged sarcomas also commonly express WT1, DUX4, and ETV4, as discussed in detail below (Fig. 2).7-9

Figure 1.

Figure 1.

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Histopathologic and immunohistochemical features of a superficial CIC-rearranged sarcoma. (A) Well-circumscribed nodular tumor involving dermis and subcutis (H&E, 40× magnification). (B) Sheets of tumor cells separated by thick fibrous bands (H&E, 200× magnification). (C) Relatively monomorphic round cells with conspicuous nucleoli and pale eosinophilic cytoplasm (H&E, 400× magnification). (D) Patchy (non-diffuse) membranous and cytoplasmic immunoreactivity for CD99 (400× magnification).

Figure 2.

Figure 2.

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Histopathologic and immunohistochemical features of CIC-rearranged sarcoma. (A) Multinodular subcutaneous tumor with prominent fibrous septa (H&E, 40× magnification). (B) Sheets of relatively uniform round tumor cells with vesicular chromatin and prominent nucleoli (H&E, 200× magnification). (C) Diffuse nuclear positivity for WT1 (400× magnification). (D) Diffuse nuclear positivity for DUX4 (400× magnification). (E) Diffuse nuclear positivity for ETV4 (200× magnification; image courtesy of David Papke, MD, PhD, Mass General Brigham).

Molecularly, these tumors are characterized by a recurrent gene fusion involving CIC, located on chromosome 19q13, most commonly with DUX4 (~95% of cases), located on chromosome 4q35, or its paralog, DUX4L, located on chromosome 10q26.3.10,11 CIC encodes a transcriptional repressor that inhibits ETS transcription factors (ETV1/4/5) and regulates receptor tyrosine kinase signaling pathways.12,13 DUX4 is a highly regulated transcript expressed during early embryonic development and is epigenetically silenced in somatic tissue.14 The CIC::DUX4 fusion produces an oncogenic chimeric transcription factor that aberrantly regulates gene expression, leading to upregulation of ETV1/4/5 and WT1.7 Recently, several non-canonical CIC fusion partners, including FOXO4 and NUTM1, have been identified.3,15-17

Accurate diagnosis of CIC-rearranged sarcoma can be challenging due to its undifferentiated round cell appearance, which can closely mimic other round cell sarcomas, including Ewing sarcoma. As such, ancillary diagnostic tools, including immunohistochemical (IHC) stains, cytogenetic methods, and molecular assays, play a critical role in the classification of this tumor. However, the effectiveness and reliability of these ancillary tools are variable, further complicating the diagnostic process.

This review provides a comprehensive overview of the current ancillary tests for diagnosing CIC-rearranged sarcoma, with a focus on their respective strengths and limitations. By synthesizing the current literature, this review aims to equip pathologists, including dermatopathologists, with practical insights to aid in the accurate diagnosis of this rare and aggressive sarcoma.

2. Methods

2.1. Literature Search

A literature search was conducted using the PubMed database for articles published in the English literature between 2006 and 2024. The search terms "CIC" and "sarcoma" were used to identify relevant studies. Articles lacking sufficient details on the diagnostic methodology for CIC-rearranged sarcoma were excluded. Due to the rarity of this tumor, select case reports with well-documented methods were included. Only cases confirmed by molecular and/or cytogenetic assays were considered. Studies focusing on CIC-rearranged sarcoma exclusively in the central nervous system were excluded.

2.2. Literature Review and Data Extraction

A total of 36 articles were reviewed, representing 436 CIC-rearranged sarcomas. For each case, the immunohistochemical, cytogenetic, and molecular findings were reviewed and tabulated. Based on the compiled data, the percentage of cases showing CD99, WT1, ETV4, and DUX4 expression were calculated. Data for CIC break-apart fluorescence in situ hybridization (FISH) and RNA next-generation sequencing (NGS) assays were also extracted and summarized.

3. Results

3.1. Immunohistochemical Tools

3.1.1. CD99 Immunohistochemistry

CD99, a cell surface glycoprotein involved in cell adhesion, migration, and apoptosis,18 is a well-established marker of Ewing sarcoma. CD99 is also commonly expressed in CIC-rearranged sarcoma. Among the 32 studies reviewed, 263 out of 304 cases (87%) showed some degree of CD99 expression, while 13% of cases were negative for this marker.1-3,5-11,15-17,19-34 In contrast to Ewing sarcoma, which shows strong and diffuse membranous CD99, CIC-rearranged sarcomas typically exhibit non-diffuse CD99. Of the cases where the staining pattern was detailed, the majority (76%, n=188) exhibited focal or patchy staining, in contrast to the diffuse pattern, which was observed in only 25% (n=61) The subcellular localization of CD99 in CIC-rearranged sarcoma is typically described as membranous or both membranous and cytoplasmic.

Importantly, CD99 is highly non-specific, being expressed in a variety of other tumors, including synovial sarcoma35, round cell sarcomas with EWSR1 non-ETS fusions36, and acute lymphoblastic leukemia37. Therefore, while non-diffuse CD99 can help support a diagnosis of CIC-rearranged sarcoma, the poor specificity of CD99 highlights the need for additional ancillary studies.

3.1.2. WT1 Immunohistochemistry

WT1, a nuclear protein involved in transcriptional regulation,38 is commonly overexpressed in CIC-rearranged sarcoma, due to transcriptional activation by the CIC fusion protein.7 A review of 24 studies found that 83% of cases (n=201/241) were positive for WT1 expression, defined as nuclear immunoreactivity, with or without cytoplasmic staining (considered non-specific).1-3,5,7-9,15-17,25-34,39-42 Tumors typically had moderate-to-strong and diffuse (>50% of tumor cells) WT1 expression.8

Two commonly used WT1 antibody clones are available that target different regions of the WT1 protein: one targets the N-terminus, the other the C-terminus. The N-terminal antibody has been more commonly used in studies of CIC-rearranged sarcoma. Several studies have compared WT1 expression in CIC-rearranged sarcoma to histologic mimics.2,7-9,26 In the largest comparative study to date, nuclear WT1 expression, detected using the N-terminal antibody, was observed in 95% of cases of CIC-rearranged sarcoma.8 Among 182 histologic mimics tested, the antibody demonstrated an overall specificity of 81%.8 While the C-terminal antibody showed a slightly higher specificity (90%) in another study, it had overall lower sensitivity (75%).9 WT1 can be a useful marker to support a diagnosis of CIC-rearranged sarcoma, yet its imperfect specificity means it should be used in conjunction with other markers.

3.1.3. ETV4 Immunohistochemistry

ETV4, a transcription factor involved in various developmental processes and oncogenesis,43 is significantly upregulated in CIC-rearranged.7 Of the 119 cases reviewed across 14 articles, 85% showed nuclear ETV4 expression, typically with strong and diffuse positivity (>50% of cells).8,9,16,17,19,28,29,31-33,39-41 Several studies have also examined ETV4 expression in histologic mimics.8,9,16,39,44 Among the 384 cases evaluated, only 19 of the histologic mimics were positive for ETV4, typically in a focal (<50% of cells) manner.7-9,39,44 These results suggest that ETV4 is relatively highly sensitive (85%) and specific (95%) for CIC-rearranged sarcoma, although the number of tested cases remains relatively low.

3.1.4. DUX4 Immunohistochemistry

DUX4, a transcription factor expressed during early embryogenesis,45 has recently emerged as a valuable diagnostic marker of CIC-rearranged sarcoma. This utility is rooted in the biology of fusion oncoproteins, which are often abundantly expressed and localized to the nucleus, making them ideal targets for detection by immunohistochemistry. Across five studies encompassing a total of 62 cases, 60 (97%) demonstrated strong, diffuse nuclear DUX4 expression, highlighting the high sensitivity of this marker for CIC-rearranged sarcoma.5,27,28,31,46 Furthermore, in studies analyzing 180 other round cell sarcomas and potential histologic mimics, all cases were negative for DUX4 expression, underscoring its high specificity.27,46

A notable limitation of DUX4 IHC for the diagnosis of CIC-rearranged sarcoma lies in its inherent specificity for tumors driven by the DUX4 rearrangement. While this approach is effective in the vast majority of cases—given that CIC::DUX4 is the most common fusion, occurring in ~95% of cases—it will miss a rare subset of tumors harboring alternative non-DUX4 fusions. Notably, the two documented cases of CIC-rearranged sarcoma that were negative for DUX4 IHC harbored alternative fusions, namely CIC::NUTM128 and CIC::FOXO446. This limitation underscores the need for an immunohistochemical panel that includes multiple markers, such as CD99, ETV4, and WT1, for improved diagnostic accuracy.

In cases where DUX4 IHC is negative but CIC-rearranged sarcoma remains in the differential based on morphologic or other immunohistochemical findings, NUT immunohistochemistry may be considered as a second-line marker, specifically for identifying rare cases with CIC::NUTM1 fusions. Although only a limited number of cases have been studied, CIC:NUTM1 sarcomas have shown strong, diffuse nuclear expression of NUT.16,28,29 While NUT is not specific for CIC::NUTM1 sarcomas and is frequently expressed in NUT carcinomas, the staining patterns differ: NUT carcinomas typically exhibit a distinct speckled nuclear pattern, whereas CIC::NUTM1 sarcomas demonstrate a homogenous nuclear staining pattern.16 This difference, when used alongside other markers, may aid in differentiating these entities.

3.2. Cytogenetic and Molecular Diagnostics Tools

3.2.1. Fluorescence In Situ Hybridization (FISH):

Fluorescence in situ hybridization (FISH) is one commonly utilized technique for detecting CIC rearrangements. This typically involves a two-color break-apart FISH assay with probes flanking the CIC locus (19q13), whereby separation of these probes indicates a CIC rearrangement. Fusion FISH assays have also been developed, where one probe targets CIC and another targets the DUX4 locus on 4q35; the overlap of these probes indicates a fusion event.11 Fusion FISH has also been used to identify less common 3’ fusion partners, including DUX4L on 10q26.3 and FOXO4 on Xq13.11,15 Break-apart FISH can identify any rearrangement at the CIC locus, regardless of the 3’ fusion partner, while fusion FISH can confirm specific fusion events (i.e. CIC::DUX4) but miss fusions not targeted by the probes.

Estimating FISH sensitivity for detecting CIC rearrangements is difficult due to the lack of a gold-standard diagnostic test and limited large-scale, comparative studies. Some studies have reported concordance between break-apart FISH and reverse transcriptase polymerase chain reaction (RT-PCR) for detecting CIC::DUX4 fusions, although these studies included a total of only 10 cases.1,23 However, subsequent studies have reported a relatively high false-negative rate (26-43%) for CIC break-apart FISH.19,39,47 The reasons for this imperfect sensitivity are not fully understood but may involve cryptic rearrangements that fall below FISH resolution or technical variability.

3.2.2. Next-Generation Sequencing (NGS):

Next-generation sequencing (NGS), particularly RNA-based NGS (RNA-seq), is increasingly seen as the preferred molecular test for detecting oncogenic gene fusions in morphologically undifferentiated tumors. Unlike traditional methods, NGS can identify both known and novel fusion events across the entire transcriptome. In practice, it is often used as a targeted fusion panel, focusing on known fusion-associated genes. RNA-seq, unlike its DNA counterpart, directly interrogates transcribed fusion products, increasing the likelihood of detecting functionally relevant fusions.

Despite the many advantages of NGS, studies have documented its limitations in detecting CIC fusions. While some studies have documented that RNA-seq was able to detect CIC fusion transcripts in more cases (13/13) compared to CIC break-apart FISH (9/13),39 others have showed that RNA-seq often fails to detect the fusion transcript, and that in a subset of cases manual inspection of the data is necessary to identify these fusions.19 However, even after manual data analysis, five of the 14 cases in that study remained negative by RNA-seq despite being FISH-positive. Conversely, 6 cases showed CIC fusions by RNA-seq but were FISH-negative. These findings suggest that both RNA-seq and FISH have limitations.

False-negative results in RNA-seq may be due sequence similarities of the DUX4 and DUX4L loci, which map to regions of 4q35.2 and 10q26.3, respectively, leading to their exclusion by automatic filtering algorithms.19 Low expression levels of the fusion transcript may also contribute.19

4. Discussion:

Diagnosing CIC-rearranged sarcoma remains a significant challenge due to its histologic overlap with other round cell sarcomas and the inherent limitations of current diagnostic tools. Immunohistochemical markers such as CD99, WT1, ETV4, and DUX4 are valuable diagnostic aids, but like many other markers, their utility is constrained by imperfect specificity and sensitivity. Our analysis of multiple studies demonstrates that these markers exhibit relatively high sensitivity for CIC-rearranged sarcoma (CD99: 87%, WT1: 83%, ETV4: 85%, DUX4: 97%). However, their specificities are more variable: CD99 is highly non-specific, whereas WT1 (81-90%), ETV4 (95%), and DUX4 (100%) offer greater specificity. Among these, ETV4 and DUX4 show the most promise due to their combined specificity and sensitivity, though supporting evidence remains somewhat limited compared to the other markers, and many laboratories still do not have access to these newer antibodies. A comprehensive immunohistochemical panel incorporating multiple markers remains the most effective approach for diagnosing CIC-rearranged sarcoma.

Cytogenetic and molecular assays, including FISH and NGS, are critical tools for detecting CIC fusions, each with its own advantages and limitations. CIC break-apart FISH is a commercially available test that can be performed on a relatively limited tissue, such as small biopsy specimens, and is typically less costly and time-consuming than NGS. However, CIC break-apart FISH has a significant false-negative rate (26-43%). In contrast, NGS, particularly RNA-seq, provides a more comprehensive fusion analysis but requires more tissue and comes at a higher cost and longer turnaround time. Moreover, NGS fusion discovery algorithms may fail to identify CIC fusions due to the DUX4/DUX4L sequence similarities, which may lead them to be filtered out during data analysis. This limitation can be mitigated by manual review of the RNA-seq data, though NGS may still miss CIC fusions that are detectable by FISH. Considering these factors, CIC break-apart FISH may be a reasonable first-line test in many instances. However, given the possibility for false-negatives by either approach, a combination of FISH and NGS (with manual data review) may be warranted, particularly when there is strong suspicion for CIC-rearranged sarcoma. While no single test is perfect, a multimodal approach integrating morphologic assessment, immunohistochemistry, and cytogenetic and molecular tools should allow for identification of CIC-rearranged sarcoma in most cases.

Although immunohistochemistry and molecular tools have improved the recognition of CIC-rearranged sarcoma, diagnostic challenges persist. A notable pitfall is the expression of vascular markers, such as ERG and CD31, in a subset of CIC-rearranged sarcoma, which can lead to misclassification as angiosarcoma.7,24,48,49 Interestingly, CIC rearrangements and mutations have also been reported in approximately 10% of angiosarcomas, particularly those with round to epithelioid morphology in younger patients.50 These cases lacked definitive vasoformative areas and their transcriptional profiles overlapped with CIC-rearranged sarcomas, complicating precise classification.50

A recent study by Kojima et al. highlighted some features to distinguish CIC-rearranged sarcomas with CD31/ERG expression from angiosarcomas.48 In their cohort, angiosarcomas were diffusely and strongly positive for both CD31 and ERG but were consistently negative for ETV4 and nuclear WT1. Most cases also showed at least focal vascular channel formation. Conversely, CIC-rearranged sarcomas typically demonstrated heterogeneous or multifocal expression of ERG and CD31 and were negative for CD34. DNA methylation profiling also showed potential in distinguishing these entities, revealing that a CD31-positive CIC-rearranged sarcoma clustered with CD31-negative cases, forming a group distinct from angiosarcomas.48 Accurately distinguishing CIC-rearranged sarcoma from angiosarcoma is important, as treatment strategies for these tumors often differ significantly.

Future diagnostic advancements for CIC-rearranged sarcoma will likely depend on the development of more sensitive molecular assays and the refinement of existing techniques. One potential direction involves whole transcriptomic analysis, which enables the identification of a unique gene expression signature associated with CIC-rearranged sarcoma, including upregulation of ETV1, ETV4, ETV5.19 More targeted approaches, including mRNA in situ hybridization using probes targeting these upregulated genes, have also shown potential as ancillary diagnostic tools (Fig. 3).51

Figure 3.

Figure 3.

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ETV4 chromogenic in situ hybridization in CIC-rearranged sarcoma. (A) Multinodular round cell tumor with necrosis and thick fibrous septa (H&E, 40× magnification). (B, C) ETV4 in situ hybridization showing diffuse expression of ETV4, manifesting as cytoplasmic puncta and aggregates of red chromogen in tumor cells (B, 40× magnification; C, 400× magnification). Images courtesy of Steven C. Smith, MD, PhD, Virginia Commonwealth University.

Recently, large-scale proteomic studies have uncovered an array of overexpressed proteins in CIC-rearranged sarcoma, presenting new opportunities to expand the repertoire of immunohistochemical markers.52 Additionally, DNA methylation profiling is emerging as a powerful tool for sarcoma classification, including CIC-rearranged sarcoma.48,49,53 These advanced methodologies hold significant potential to improve diagnostic sensitivity and specificity beyond current approaches. However, they remain largely confined to research settings and have yet to be adopted into widespread clinical practice.

Acknowledgments:

The authors would like to thank the members of the Appropriate Use Criteria Committee, especially Dr. Maxwell Fung, and the administrative staff of the American Society of Dermatopathology for supporting this work.

Funding:

Supported by: MSK NIH Funded Grant# P30 CA08748

Footnotes

Conflict of interests:

The authors have no conflicts of interests relevant to this manuscript.

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