High-Grade Undifferentiated Small Round Cell Sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 Fusion: Emerging Entities of Soft Tissue Tumors with Unique Histopathologic Features – A Case Report and Literature Review

Background

Undifferentiated small round cell sarcomas (USRCS), also called small blue round cell tumors (SBRCTs), comprise a rare subset of highly aggressive EWSR1-negative sarcomas that occur in younger populations. This subset of undifferentiated small round blue cells sarcomas are also referred to as ‘Ewing’s-like tumors’ [1]. When viewed under a microscope, they share similar morphological features with the Ewing sarcoma family of tumors (EST). “They demonstrate small to medium-sized round to oval cells, packed in solid sheets with minimal or absent intervening collagen” [2], and they share with them an aggressive clinical course [2]. Upon conducting next-generation sequencing, unique mutations are being recognized: recurrent BCOR-CCNB3 fusion (in primitive bone and soft tissue sarcoma) [3]; CIC-FOXO4 fusion (in soft tissue sarcoma) [4] Or CICDUX4 fusion as a result of either t(4;19) or t(10;19) translocations (in primitive soft tissue sarcoma) [2]. The clinical features in our case harboring t(4;19) are compatible with those described in the literature.

Case Report

A healthy 36-year-old African-American nonsmoker nonalcoholic woman presented to the hospital 11 months ago with pain and swelling in her right groin. Two weeks prior to that, she noticed a small boil which rapidly increased to an “orangesize”. Physical exam revealed a tender, fluctuant mass on the right upper medial thigh. An incision and drainage was performed and it revealed blood clots. Ultrasound showed a complex 4.8×3.5×6 cm heterogeneous swelling consistent with hematoma. A CT scan of the right femur, (Figure 1A), revealed a complex mass with hematoma suspicious for malignancy. The patient subsequently underwent an elective wide local excision (>10 cm). Pathology (Figure 2A, 2B), revealed a high-grade un-differentiated small round cell sarcoma. Immunohistochemical staining (Figure 3A–3E) showed very focally positive staining for CD 99, and positive staining for CD 31; Pan-Cytokeratin, and Bcl-2 was strongly and diffusely positive. FISH studies for EWSR1 (Ewing sarcoma) and SYT (synovial sarcoma) rearrangements were negative. t(4: 19)(q35;q13.1) CIC-DUX4 gene fusion was confirmed by FISH (Figure 4). Margins were clear, with no lymph node involvement. Within a few weeks, the patient began adjuvant radiation treatment. She received 45 Gy to the tumor bed plus a wide margin followed by a cone down to a total dose of 66.6Gy. Radiation treatment was delivered using intensity modulation (IMRT) to maximize dose to the coverage of the tumor volume, while minimizing dose to the perineal skin and femur/femoral neck. Subsequently chemotherapy was started; where the patient was given 4 cycles of Doxorubicin and ifosfamide along with mesna. During the fourth and the final cycle, the patient was unable to receive ifosfamide secondary to the adverse effects during the third cycle. She reported that her tongue was “swollen and twisted” and that she had some memory problems. Otherwise, the patient was clinically stable. A follow-up MRI femur with contrast performed 11 months later (Figure 1B) and CT abdomen/pelvis showed no convincing evidence of residual neoplasm or metastatic disease.

Discussion

CIC-DUX4 FUSION – MECHANISM OF ACTION:

The gene capicua transcriptional repressor (CIC), located on the chromosome 19q13.2, is usually fused to copies of the DUX4 gene (double homeobox 4), which are found on either chromosome 4 (4q35) or chromosome 10 (10q26.3) [2]. CIC-DUX4 fusion, in particular, is known to potentiate the NIH/3T3 fibro-blasts transformation. This potentiation has been suggested by an enhanced CIC transcriptional activity, with resultant deregulation of the CIC downstream targets. Further gene expression analysis shows that CIC-DUX4 fusion recognizes a novel target sequence on the EMR/ETV5 promoter; and it binds directly to it, leading to an up-regulation to its expression [7].

CIC-DUX4 FUSION:

CIC-DUX4 fusion has been reported in 44 cases of EWSR1-negative undifferentiated small round cell sarcomas, including our patient (Table.1). Age, sex, location, metastasis status, treatment used if reported, life span based on last follow-up, and the source of information were all merged and are detailed in Table 1. Noticeably, t(4;19)(q35;q13.1) translocation has been the most prevalent gene mutation reported (33 cases) compared to t(10,19)(q26.3;q13) translocation (11 cases). The first case ever reported with CIC-DUX4 fusion with t(4;19)(q35;q13.1) was in 1996 by Richkind et al. [5]. Age range for CIC-DUX4 cases was 6–62 years, with a mean age of 27, affecting younger age groups. General, the sex distribution for CIC-DUX4 fusion was slightly in favor of females: (M:F ratio is 1:1.31); however, among cases with t(4;19) translocation M: F ratio was similar (1:1.08). In contrast, t(10;19) is more common among males (M: F ratio of 1.75:1). The most commonly affected body site is the limbs (including groin) 22/44 cases (50%). Unusual primary cerebral localization was reported in 1 case 1/44 (0.02%). Metastasis rate was high in 26/44 reported cases (59%), and the most common place to metastasize was to the lungs 18/44 cases (∼41%), in addition to other body areas like bone, brain, and peritoneum. Treatment modalities vary based on staging, and there is minimal literature available with which to determine a standard therapy for this rare disease. In general, surgery and radiation therapy remain the main treatments for sarcomas. Combinations of doxorubicin and Ifosfamide, or doxorubicin, vincristine, and cyclophosphamide are used (Table 1). Average life span after diagnosis was around 15.4 months and only 6 cases had prolonged survival (22–48 months (Table 1).

ROLE OF RADIATION:

Studies showed that patients with high-grade soft tissue sarcomas who were randomized to amputation versus limb-sparing surgery plus adjuvant radiation had no differences in 5-year disease-free survival and overall survival, establishing limb preservation plus radiation as the standard of care [18].

Patients who underwent limb-sparing surgery were randomized to adjuvant radiation or observation. In patients with high-grade tumors, adjuvant radiation was associated with decreased local failure (0% vs. 19%, SS) [19].

Given the inner thigh location of our patient’s tumor, we decided to use radiation in the post-operative setting to decrease the likelihood of a wound complication, this decision was supported by a randomized trial [20].

Conclusions

High-grade undifferentiated small round cell sarcomas are very aggressive tumors, and quickly develop resistance to traditional chemotherapy regimens. Treatment includes surgery, chemotherapy, and radiation. Despite aggressive treatment, they exhibit high rates of metastasis to lung and brain, often with a poor prognosis, and median survival is less than 2 years. Next-generation sequencing techniques help in identifying subsets of previously unclassifiable sarcoma with distinct mutations and unique histopathology features, and are promising diagnostic and possibly prognostic tools.