Head pleomorphic sarcoma showing murine double minute 2 amplification without a well‐differentiated liposarcoma component in a pediatric patient

Abstract Background Murine double minute 2 (MDM2) is an oncogene that inhibits p53, leading to decreased apoptosis. Sarcomas showing MDM2 amplification are rare among pediatric patients. Case A 14‐year‐old boy presented with pleomorphic sarcoma of the head showing MDM2 amplification without a well‐differentiated liposarcoma component. Although chemotherapy was initially performed to reduce the tumor size before surgery, the tumor did not shrink. The patient underwent complete surgical resection. Microscopic examination revealed a positive surgical margin; thus, postoperative proton‐beam radiotherapy was performed. 3 years after the therapy, no sign of recurrence was observed. Conclusion Macroscopic surgical resection combined with adjuvant postoperative radiotherapy was effective against MDM2‐amplified pleomorphic sarcoma refractory to neoadjuvant chemotherapy in a pediatric patient.


| INTRODUCTION
Murine double minute 2 (MDM2), which is located at 12q15, inhibits p53; this results in decreased apoptosis. 1 Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are associated with amplification of the chromosomal 12q13-15 region. 2 WDLPS and DDLPS are genetically characterized by MDM2 amplification. DDLPS is defined as the transition of WDLPS towards nonlipogenic sarcoma. 3 High-grade pleomorphic sarcoma with a WDLPS component is a typical morphology of DDLPS. 2 Liposarcomas are rare among children, representing about 2% of all pediatric soft tissue sarcomas. 4 WDLPS and DDLPS subtypes, associated with MDM2 amplification, comprise approximately 13% of all pediatric liposarcomas. 5 Some peripheral (extremities, trunk wall, head/neck) undifferentiated pleomorphic sarcomas without WDLPS components present MDM2 amplification detected using fluorescence in situ hybridization (FISH) analysis. These were similar to DDLPS in terms of their clinical courses and showed better prognosis than that of MDM2-negative undifferentiated pleomorphic sarcomas. 6 Recently, pleomorphic sarcomas with MDM2 amplification are considered to be DDLPS irrespective of the WDLPS components. [6][7][8] In the study by a French group, patients with peripheral undifferentiated pleomorphic sarcomas harboring MDM2 amplification without WDLPS components were aged >45 years. 6 Sarcomas with MDM2 amplification are rare among pediatric patients. We report a pediatric case of pleomorphic sarcoma of the head showing MDM2 amplification without a WDLPS component. cancers is low, varying between 3.5% and 4.4%. 3 However, its amplification frequency in soft tissue tumors is very high, particularly in WDLPS and DDLPS. 9 CDK4, which is located at 12q13-14, is a key regulator of the G1/S cell cycle checkpoint, and it increases cell proliferation. 1,2 DDLPS is associated with high-amplification of MDM2 and CDK4, which often leads to overexpression of MDM2 and CDK4; therefore, immunohistochemistry staining for MDM2 and CDK4 can also be used for the diagnosis of DDLPS. 10,11 Immunohistochemistry analysis has a sensitivity of 95% and 92% and a specificity of 81% and 95% for MDM2 and CDK4, respectively in the diagnosis of DDLPS. 1 Detection of MDM2 amplification by FISH can be used to confirm the diagnosis of DDLPS, especially in limited biopsy samples. 7 Variable FDG uptake in 18 F-FDG PET/CT is reported in DDLPS. [12][13][14] The mean SUVmax in previous reports was 16.3 ± 11.4 (range 3.4-39.6) 12 and 9.23 ± 7.63 (range 2.3-29.5). 13 Previous studies reported an association between higher FNCLCC grade and higher SUVmax in retroperitoneal DDLPS. [14][15][16] Further, they showed that SUV max >5.3 or 4.8 can be used to predict FNCLCC Grade 3. Increased SUVmax was also associated with poor overall survival. 15,16 In our patient, the SUVmax was 2.14 at diagnosis, with FNLCC Grade 2 tumor following examination of the biopsy specimen.

| CASE PRESENTATION
This was consistent with previous findings regarding the association between SUVmax and pathological grade.
Complete surgical resection remains the primary and most prevalent treatment for DDLPS. 17,18 Primary radiotherapy is commonly used preoperatively to shrink retroperitoneal and intra-abdominal DDLPS, 17 and adjuvant radiotherapy is effective in controlling microscopic residual disease after surgical resection. 4 Radiotherapy (preoperative or postoperative) is associated with better overall survival in patients with retroperitoneal sarcoma than surgery alone. 19 Further, preoperative radiotherapy is associated with a greater risk of wound complications than postoperative radiotherapy in soft tissue sarcoma of the limbs. 20 Some reports indicated minimum benefit of chemotherapy for DDLPS. 21 Other reports revealed that chemotherapy for DDLPS was effective in shrinking tumors. 22 Dose-intensive ifosfamide plus doxorubicin chemotherapy is commonly used for DDLPS. 18,22 This regimen is also used to treat pediatric patients with unresected intermediate-risk and high-risk soft-tissue sarcomas. 23 The partial response rate of this regimen is approximately 30% in patients with DDLPS. 22 In a case report, a patient with retroperitoneal DDLPS underwent six courses of this regimen preoperatively, and the tumor size was considerably reduced. 24 In this report, the pathological findings indicated a 99% disappearance of tumor cells in the resected specimen. 24 We considered complete surgical resection as the best treatment for our patient. However, based on the location, size, and extent of the tumor, we considered that surgical margins might be positive even if macroscopic complete surgical resection was possible. Therefore, we decided to administer postoperative radiotherapy if there was microscopic residual disease. Although the partial response rate of chemotherapy with doxorubicin and ifosfamide is approximately 30%, 22 this regimen may induce the shrinkage of the tumor a little.
Hence, we chose chemotherapy with doxorubicin and ifosfamide to shrink the tumor as much as possible before surgery. However, it was ineffective for our patient, and we subsequently performed the surgery. The surgical margin was positive on microscopic examination.
Generally, 60-70 Gy of external beam radiotherapy is administered for microscopic surgical margin-positive high-grade soft tissue sarcoma of the extremity. 25 Regarding postoperative radiotherapy for DDLPS, 60 Gy is used in patients with a positive surgical margin. 26,27 Considering the tolerable dose of the optic nerve, 50.4 Gy was used in postoperative proton-beam radiotherapy against microscopic residual disease in our patient.
We report a rare pediatric case of pleomorphic sarcoma of the writingreview and editing (equal).

ACKNOWLEDGMENTS
Not applicable.

CONFLICT OF INTEREST
The authors have stated explicitly that there are no conflicts of interest in connection with this article.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.

ETHICS STATEMENT
Informed consent was obtained from the patient for the publication of this case report.

SUPPORTING INFORMATION
Additional supporting information can be found online in the Supporting Information section at the end of this article.