Differential cyclin-E1 expression in CIC-rearranged sarcoma.

CIC-rearranged sarcoma (CRS) is a group of high-grade undifferentiated small round cell sarcomas examined as a separate entity in the current WHO classification; since it shows more aggressive clinical behavior and distinct morphological and molecular features compared to Ewing sarcoma (ES). As CCNE1 expression is associated with tumor growth in CIC::DUX4 sarcomas, we aimed to demonstrate the value of cyclin E1 expression in CRS. Cyclin E1 immunohistochemistry and break-apart FISH for EWSR1 and CIC gene rearrangements were performed on 3-mm tissue microarrays composed of 40 small round cell tumors. Five cases were classified as CRS, whereas 22 were ES and 13 were unclassified (EWSR1-/CIC-). Among all three diagnostic groups, we found cyclin E1 expression level to be higher in CRS (80 %) and unclassified groups (61.5 %) compared to ES (4.5 %, p < 0.001). In addition, high cyclin E1 expression levels were associated with higher mean age at diagnosis, presence of atypical histology and myxoid stroma, low CD99 expression, and presence of metastasis at diagnosis. The sensitivity and specificity of high cyclin E1 expression in detecting non-ES cases were 95.5 % and 66.7 %, respectively. However, the correlation between cyclin E1 expression level and survival was not statistically significant. This is the first study that shows cyclin E1 immunohistochemical expression in EWSR1-negative undifferentiated small cell sarcomas, particularly CRS.

[CIC-rearranged sarcoma: a case report and literature review]. / CIC-perestroennaya sarkoma: klinicheskoe nablyudenie i obzor literatury.

CIC-rearranged sarcoma is a rare and extremely aggressive tumor that occurs mainly in soft tissues. Despite the fact that identification of a characteristic genetic rearrangement is necessary to verify the diagnosis, in most cases, the correct diagnosis can be made by comparing histological signs and a characteristic immunophenotype, which greatly speeds up the diagnosis. The article describes a case of CIC-rearranged sarcoma in a 14-year girl with the successful application of the CWS-2009 treatment protocol.

[Clinical and morphological characteristics of Ewing's sarcoma and the algorithm for diagnosing undifferentiated round cell sarcomas]. / Kliniko-morfologicheskaya kharakteristika sarkomy Yuinga i algoritm diagnostiki nedifferentsirovannykh kruglokletochnykh sarkom.

BACKGROUND: The group of undifferentiated round cell sarcomas, according to the World Health Organization Classification, in addition to Ewing's sarcoma (ES), includes round cell sarcoma with rearrangement of the EWSR1 gene with partners not from the ETS gene family, sarcoma with BCOR gene alterations, CIC -rearranged sarcoma. Despite the fact that all tumors have clear histological and immunological criteria, their diagnosis can be difficult, given the fact that there are overlapping variants of the morphological picture and immunophenotype both within the group and with other round cell tumors. OBJECTIVE: Present a comparative analysis of genetically verified ES, sarcoma with BCOR gene alterations and CIC-rearranged sarcoma. MATERIAL AND METHODS: A comparative study of biopsy specimens of bones, soft tissues and internal organs was carried out in 118 patients with ES, 10 with BCOR gene alterations and 8 with CIC-rearranged sarcomas. All cases were genetically verified. The following research methods were used: histological, immunohistochemical, RT-PCR, RNA sequencing and FISH. RESULTS: Within our cohort, it was shown that ES predominantly affects bones, while soft tissue localization is more typical for the other two undifferentiated round cell sarcomas. Histologically, in the overwhelming majority of cases, ES is characterized by a monomorphic round-cell structure; on the contrary, heterogeneous structure is typical for sarcoma with alterations of the BCOR gene, CIC-rearranged sarcoma. High sensitivity and specificity of CD99/NKX2.2 co-expression for ES, BCOR/SATB2/TLE1 for sarcoma with BCOR gene alterations, high specificity and low sensitivity of WT1/ETV4 co-expression for CIC-rearranged sarcoma was shown. CONCLUSION: For the differential diagnosis of undifferentiated round-cell sarcomas, it is necessary to take into account the clinical, morphology when compared with the data of the IHC study, and verification by molecular genetic methods is necessary to improve the accuracy of diagnosis.

From the ashes of "Ewing-like" sarcoma: A contemporary update of the classification, immunohistochemistry, and molecular genetics of round cell sarcomas.

Round cell sarcomas include a diverse group of bone and soft tissue tumors, which comprise well-defined entities as well as several nascent categories presented in the 2020 World Health Organization classification. The morphologic overlap yet disparate nosology, prognostic implications, and management strategies places a high value on ancillary testing, including a strategic immunohistochemical approach and directed confirmation by cytogenetic and molecular genetic methods. We review the diagnostic categories that have emerged from the former wastebasket "undifferentiated round cell sarcoma" ("Ewing-like" sarcomas), with an emphasis on algorithmic exclusion of nonsarcomatous entities, diagnostic stratification of well-defined entities (Ewing sarcoma, rhabdomyosarcomas, poorly differentiated synovial sarcoma), and a discussion of the new categories with novel genetic alterations (CIC-rearranged sarcomas, sarcomas with BCOR genetic alterations, and round cell sarcomas with EWSR1-non-ETS fusions).

Primary capicua transcriptional repressor-rearranged sarcoma of the lung.

A 60-year-old man had a malignant left lower lung tumour with no metastases and underwent video-assisted thoracoscopic left lower lobectomy and lymphadenectomy. Pathological examination led to a diagnosis of capicua transcriptional repressor (CIC)-rearranged sarcoma. He has had 3.5 years of recurrence-free survival. CIC-rearranged sarcoma is a Ewing-like sarcoma that shows pathological findings similar to Ewing sarcoma. Most of CIC-rearranged sarcoma is CIC-double homeobox 4 protein (DUX4) fusion. Pulmonary CIC-rearranged sarcoma is extremely rare and has an unfavourable prognosis. However, complete resection can produce prognosis of long-term survival, and thus, surgery is an important option.

Modeling fusion gene-associated sarcoma: Advantages for understanding sarcoma biology and pathology.

Disease-specific gene fusions are reportedly major driver mutations in approximately 30% of bone and soft tissue sarcomas. Most fusion genes encode transcription factors or co-factors that regulate downstream target genes, altering cell growth, lineage commitment, and differentiation. Given the limitations of investigating their functions in vitro, the generation of mouse models expressing fusion genes in the appropriate cellular lineages is pivotal. Therefore, we generated a series of mouse models by introducing fusion genes into embryonic mesenchymal progenitors. This review describes mouse models of Ewing, synovial, alveolar soft part, and CIC-rearranged sarcomas. Furthermore, we describe the similarities between these models and their human counterparts. These models provide remarkable advantages to identify cells-of-origin, specific collaborators of fusion genes, angiogenesis key factors, or diagnostic biomarkers. Finally, we discuss the relationship between fusion proteins and the epigenetic background as well as the possible role of the super-enhancers.

Pancreaticoduodenectomy for a primary duodenal capicua transcriptional repressor (CIC) -rearranged sarcoma with severe bleeding: a case report.

BACKGROUND: Capicua transcriptional repressor (CIC) -rearranged sarcoma is characterized by small round cells, histologically similar to Ewing sarcoma. However, CIC-rearranged sarcoma has different clinical, histological, and immunohistochemical features from Ewing sarcoma. It is important to differentiate between these tumors. CASE PRESENTATION: The patient is a 44-year-old man with a duodenal tumor diagnosed in another hospital who presented with a history of melena. Laboratory studies showed anemia with a serum hemoglobin of 6.0 g/dL. He was hospitalized and gastrointestinal bleeding was controlled successfully with endoscopy. However, he suffered from appetite loss and vomiting and progression of anemia a few weeks after presentation. Upper gastrointestinal endoscopy showed a circumferential soft tumor in the second portion of the duodenum and the endoscope could not pass distally. Computed tomography scan showed a greater than 10 cm tumor in the duodenum, with compression of the inferior vena cava and infiltrating the ascending colon. A definitive pathologic diagnosis could not be established despite four biopsies from the tumor edge. Due to gastrointestinal obstruction and progression of anemia, a pylorus-preserving pancreaticoduodenectomy with partial resection of the inferior vena cava and right hemicolectomy was performed as a complete tumor resection. The tumor was diagnosed as a CIC-rearranged sarcoma, but 2 months postoperatively local recurrence and distant metastases to the liver and lung were found. The patient died 3 months after surgery. CONCLUSIONS: Although the only definitive treatment for CIC-rearranged sarcoma is surgical resection, the CIC-rearranged sarcoma is highly malignant with a poor prognosis even after radical resection. More research is needed to establish optimal treatment strategies.

Small Round Blue Cell Sarcoma Other Than Ewing Sarcoma: What Should an Oncologist Know?

OPINION STATEMENT: The diagnosis of round cell sarcomas has changed rapidly over the last decade, causing much diagnostic confusion for pathologists and oncologists. The advances in diagnosis are largely due to the advent of next-generation sequencing techniques, which allowed the recognition of novel gene fusions in round cell sarcomas. The new 5th edition of the WHO Classification of Tumors of Soft Tissue and Bone recognizes four subgroups of undifferentiated round cell sarcomas: Ewing sarcoma, CIC-rearranged sarcomas, BCOR-altered sarcomas, and sarcomas with EWSR1-non-ETS fusions, in addition to desmoplastic small round cell tumor. This classification is based on a variety of publications showing that each of these molecular subtypes has unique clinical and prognostic characteristics distinct from Ewing sarcoma, therefore supporting the validity of recognizing these as discrete diagnostic entities. Despite our improved ability to diagnose these new round cell sarcomas, there remains confusion on how best to identify and treat these tumors. However, several key clinicopathologic features can point the physician toward the correct diagnosis. The goal of the following article is to emphasize the key clinical, pathologic, molecular, and prognostic differences between Ewing sarcoma and these non-Ewing round cell malignancies to improve recognition of these rare diseases.

MUC5AC immunoreactivity in scattered tumor cells is useful for diagnosing CIC-rearranged sarcoma.

CIC-rearranged sarcoma is an aggressive round cell sarcoma, and an alternative ATXN1/ATXN1L fusion has been reported. Diagnosis may be difficult, and molecular assays may suffer from imperfect sensitivity. Characteristic histology and ETV4 immunohistochemical positivity are diagnostically helpful. However, ETV4 staining is unavailable in most laboratories. Here, we explored the diagnostic utility of MUC5AC immunohistochemistry in CIC-rearranged sarcomas. All 30 cases, except one, of CIC-rearranged sarcomas and 2 ATXN1-rearranged sarcomas were positive for MUC5AC, although the number of immunopositive cells was generally low (< 5%) in most samples, representing a characteristic scattered pattern. The only MUC5AC-negative case had the lowest tumor volume. Among the 110 mimicking round cell malignancies, 12 tumors showed MUC5AC positivity, including occasional cases of synovial sarcoma and small cell carcinoma, whereas the remaining 98 samples were negative. Despite its lower specificity than that of ETV4 and sparse reactivity that requires careful interpretation, MUC5AC may serve as a useful marker for CIC/ATXN1-rearranged sarcoma because of its wider accessibility.

CIC-DUX4 Rearranged Sarcoma Presenting in the Skin: Case Report.

Introduction: Capicua transcriptional repressor (CIC)-DUX4 rearranged sarcoma is a subtype of CIC-rearranged sarcomas composed of undifferentiated Wilms' tumor 1 (WT1)+, CD99+ round cells with recurrent CIC gene rearrangement. The diagnosis of CIC-rearranged sarcoma remains challenging, and the prognosis of CIC-rearranged sarcomas is poor. Case Presentation: In this report, we described a case of CIC-DUX4 rearranged sarcoma presenting in the skin, expressing WT1 and CD99 in a dot-like pattern. In addition, the assessment of genomic alterations using genome panel testing was useful to confirm the accurate diagnosis. Conclusion: Our present case suggests that widespread use of genomic panel testing in the future may lead to early treatment and improve the prognosis of CIC-rearranged sarcomas.

Molecular and therapeutic advancements in Capicua (CIC)-rearranged sarcoma.

Capicua (CIC)-rearranged sarcomas are an aggressive subset of undifferentiated round cell sarcomas. CIC::DUX4, the proto-typical CIC fusion oncoprotein is associated with rapid clinical progression and chemotherapy resistance leading to poor clinical outcomes. Recent studies have identified additional CIC fusions (CIC::NUTM1, CIC::FOXO4, and CIC::LEUTX) that largely retain CIC-binding specificity but leverage C-terminal binding partners (NUTM1, FOXO4, and LEUTX) to potentially activate transcriptional programs that drive oncogenesis. Moreover, the recent development of preclinical models to study CIC::DUX4 sarcoma have advanced our understanding of the underlying biological mechanisms and uncovered key dependencies that can be translated into rational therapies. In this review, we will highlight these recent advancements in CIC-rearranged sarcoma biology with a vision for clinical translation to improve patient outcomes.

CIC-Rearranged Sarcoma.

CIC-rearranged sarcoma is a rare type of small round cell sarcoma. The tumors often affect the deep soft tissues of patients in a wide age range. They are highly aggressive, respond poorly to chemotherapy, and have a worse outcome than Ewing sarcoma. CIC-rearranged sarcoma has characteristic and recognizable histology, including lobulated growth, focal myxoid changes, round to epithelioid cells, and minimal variation of nuclear size and shape. Nuclear ETV4 and WT1 expression are useful immunohistochemical findings. CIC fusion can be demonstrated using various methods; however, even next-generation sequencing suffers from imperfect sensitivity, especially for CIC::DUX4.

Patched Homolog 1 (PTCH1) Mutation in a CIC-Rearranged Sarcoma: Lack of Response to the Smoothened (SMO) Vismodegib.

Next-generation sequencing (NGS) to identify potential targets is becoming a common approach to refractory tumors. We describe a patient with a CIC-DUX4 sarcoma that harbored a patched homolog 1 (PTCH1) mutation, a mutation not previously reported in so-called Ewing family tumors. PTCH1 is part of the hedgehog signaling pathway. Basal cell carcinomas (BCC) commonly have PTCH1 mutations, and those with PTCH1 mutations are often responsive to therapy with the hedgehog pathway inhibitor vismodegib. The effect of any mutation in a gene important in cell growth and division is likely dependent upon the background biochemistry of the cell. In the current case, vismodegib was not effective. This case is the first report of a PTCH1 mutation in an Ewing family tumor and demonstrates that the utility of targeting a potential mutation may depend upon many factors, including other mutations in the signaling pathway, and importantly, also the background biochemistry of the malignant cell that may prevent effective treatment targeting.

Novel ATXN1/ATXN1L::NUTM2A fusions identified in aggressive infant sarcomas with gene expression and methylation patterns similar to CIC-rearranged sarcoma.

CIC-rearranged sarcomas are newly defined undifferentiated soft tissue tumors with CIC-associated fusions, and dismal prognosis. CIC fusions activate PEA3 family genes, ETV1/4/5, leading to tumorigenesis and progression. We report two high-grade CNS sarcomas of unclear histological diagnosis and one disseminated tumor of unknown origin with novel fusions and similar gene-expression/methylation patterns without CIC rearrangement. All three patients were infants with aggressive diseases, and two experienced rapid disease deterioration and death. Whole-transcriptome sequencing identified an ATXN1-NUTM2A fusion in the two CNS tumors and an ATXN1L-NUTM2A fusion in case 3. ETV1/4/5 and WT1 overexpression were observed in all three cases. Methylation analyses predicted CIC-rearranged sarcoma for all cases. Retrospective IHC staining on case 2 demonstrated ETV4 and WT1 overexpression. ATXN1 and ATXN1L interact with CIC forming a transcription repressor complex. We propose that ATXN1/ATXN1L-associated fusions disrupt their interaction with CIC and decrease the transcription repressor complex, leading to downstream PEA3 family gene overexpression. These three cases with novel ATXN1/ATXN1L-associated fusions and features of CIC-rearranged sarcomas may further expand the scope of "CIC-rearranged" sarcomas to include non-CIC rearrangements. Additional cases are needed to demonstrate if ATXN1/ATXN1L-NUTM2A fusions are associated with younger age and more aggressive diseases.

CIC-Rearranged Sarcomas: An Intriguing Entity That May Lead the Way to the Comprehension of More Common Cancers.

Capicua transcriptional repressor (CIC)-rearranged sarcoma, belonging to the undifferentiated round cells sarcoma family, is characterized by high metastatic rate and poor chemo response. CIC sarcoma represents a new entity harboring the recurrent chromosomal translocation between CIC and, in most of the cases, DUX4. CIC-DUX4 imposes a CIC-specific transcriptional signature, which drives cell transformation, proliferation, and migration. While the discovery of the fusion represented the first evidence of a role of CIC in cancer, a complete comprehension of CIC-rearranged activity is still required before providing new potential avenues for therapy. To date, a specific and effective treatment for CIC sarcoma has yet to be defined. In this review, we initially highlight the clinical features and pathogenesis of CIC-rearranged sarcomas along with current therapeutic approaches and then focus on the specific oncogenic mechanisms driven by the CIC-rearrangement. We discuss novel therapeutic options evoked by the aberrant relations of CIC-DUX4 with the IGF system, DUSP6, P300/CBP, and CCNE1. We also discuss how different mutations involving CIC might converge on a common upregulation of CIC-target genes across human cancers. A deeper understanding of the oncogenic mechanisms driven by the chimera CIC-DUX4 might provide novel therapeutic opportunities with a general impact in cancer.

Complete Spontaneous Regression of Lung Metastases after Resection of CIC-Rearranged Sarcoma: A Case Report.

The vast majority of patients with soft tissue sarcomas (STS) of the trunk and bilateral lung metastases at diagnosis are considered incurable. These tumors have poor prognosis as only a palliative therapeutic approach can be offered to patients. We report on an extremely rare case in which bilateral lung metastases disappeared spontaneously following surgical resection of the primary CIC-rearranged sarcoma with no addition of chemotherapy or any other systemic therapy. A 53-year-old female presented with a rapidly swelling mass on her back. A magnetic resonance imaging scan of the chest revealed a large soft tissue mass on the posterior chest wall and bilateral lung metastases. Soon after stereotactic core-needle biopsy confirmation of round-cell sarcoma, the patient underwent surgery of the primary tumor as it started to be increasingly symptomatic. The resected specimen was pathologically diagnosed a poorly differentiated grade 3 sarcoma. Approximately 1 month later, a new CT scan revealed that the lung metastases were smaller and some of them had completely disappeared. Shortly afterward, the patient started adjuvant external beam radiotherapy of the tumor bed for 14 months. During the last follow-up visit, the patient confirmed no evidence of disease for 35 months postoperatively. In parallel, a histological study of pulmonary nodules, molecular analyses of the tumor, and a comprehensive study of the patient's immunophenotype were performed to gain some additional insights in the potential causes of this rare phenomenon.

Secondary CIC-rearranged sarcoma responsive to chemotherapy regimens for Ewing sarcoma: A case report.

Capicua transcriptional repressor (CIC)-rearranged sarcoma is an Ewing-like sarcoma with an aggressive clinical course and poor prognosis. No standard treatment has been established. The present study describes a case of CIC-rearranged sarcoma with lung metastases developing in a 24-year-old woman as a therapy-associated malignancy following chemotherapy for anaplastic large cell lymphoma at nine years old. This was treated with palliative regimens used for Ewing sarcoma. The patient achieved disease control for one year. Of note, ifosfamide and etoposide (IE), which were used as a second line treatment lead to a partial response. The case described in the present study indicated that treatment with Ewing regimens is a reasonable option for patients with metastatic CIC-rearranged sarcoma, including those with a second malignant case.

Update on Cutaneous Soft Tissue Tumors.

This article focuses on various recently described or emerging cutaneous soft tissue neoplasms. These entities encompass a wide range of clinical and histologic characteristics. Emphasis is placed on their distinguishing morphologic and immunophenotypic features compared with entities that enter into their differential diagnosis, as well as novel immunophenotypic and molecular tests that are often necessary for accurate diagnosis of these entities. Entities discussed include EWSR1-SMAD3-rearranged fibroblastic tumor, superficial CD34-positive fibroblastic tumor, epithelioid fibrous histiocytoma, CIC-rearranged sarcomas, and NTRK-rearranged spindle cell tumors.

Round Cell Sarcomas: Newcomers and Diagnostic Approaches.

Undifferentiated sarcomas of soft tissue and bone have been defined as tumors with no identifiable morphologic, immunohistochemical, or molecular features indicating tumor cell origin. In young patients, these tumors frequently have a round or spindle cell morphology. Recently described recurrent translocations within this category have led to the recognition of new molecular subtypes of round cell sarcomas, and several of them have a more aggressive clinical course and less chemosensitivity. Because these "newcomers" are diagnosed based on their molecular characteristics, molecular investigation is key in the diagnosis and optimal treatment of these challenging tumors.