AbstractBackground

: SMARCA4-inactivation induces several malignant tumor types, including the undifferentiated uterine sarcoma, which has recently attracted considerable attention in cancer research. Because this entity is novel, its clinical course and appropriate treatment strategy have not been clarified.

Case

: A 51-year-old female patient presented with massive bleeding from a uterine tumor. Advanced uterine sarcoma was preoperatively diagnosed based on tumor biopsy findings, and a total hysterectomy and lymph node dissection were performed. The definitive pathological diagnosis of the resected tumor was SMARCA4-deficient undifferentiated sarcoma, which showed monotonous rhabdoid tumor cell proliferation with loss of SMARCA4 expression. The tumor had diffusely invaded the uterine cervix, where the surgical margin was positive. Six courses of doxorubicin and ifosfamide were administrated as adjuvant chemotherapy. The tumor relapsed at the postoperative vaginal stump and right obturator lymph node six months after surgery. Despite several courses of systemic treatment, the locally recurrent lesion and metastasis to the iliac lymph nodes progressed, causing bilateral hydronephrosis and renal dysfunction. Also, the patient experienced abdominal distention and liver enzyme elevation due to multiple liver metastases. Palliative radiotherapy at 8 Gy in a single fraction was administered to each site of recurrence. Radiologically, minor and major tumor shrinkage was observed at the site of local recurrence and liver metastases, respectively. The abdominal symptoms remitted, and the blood test findings, including aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase improved from 57 to 21 U/L, 29 to 17 U/L, and 836 to 407 U/L, respectively. The patient received palliative care and died of the disease 12 months after surgery.

Conclusion

: The present case is the first to illustrate the response to radiotherapy in SMARCA4-deficient undifferentiated uterine sarcoma. The response to low-dose radiotherapy observed in the present case suggests that radiotherapy may have a place in treatment strategies for this aggressive sarcoma

IntroductionThe SMARCA4 gene encodes the BRG1 protein, which, as one of the subunits of the SWI/SNF complex, functions as a tumor suppressor.1The SWI/SNF complex—chromatin and cancer. Recently, the SMARCA4-deficiency-related malignant tumor category was expanded to include several tumor types, including thoracic carcinomas and sarcomas, small cell carcinomas of the ovary, hypercalcemic type (SCCOHT), and malignant ovarian rhabdoid tumors.2Jennifer LS Rondell PG Brandon TL Sarah MJ Anja CR Jennifer MB. SMARCA4-deficient thoracic sarcoma: a distinctive clinicopathological entity with undifferentiated rhabdoid morphology and aggressive behavior., 3Rekhtman N Montecalvo J Chang JC et al.SMARCA4-deficient thoracic sarcomatoid tumors represent primarily smoking-related undifferentiated carcinomas rather than primary thoracic sarcomas., 4Witkowski L Carrot-Zhang J Albrecht S et al.Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type., 5Foulkes WD Clarke BA Hasselblatt M Majewski J Albrecht S McCluggage WG. No small surprise–small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour. This category of tumor reportedly shares some common clinicopathological characteristics, such as (1) undifferentiated round cell or rhabdoid morphology and (2) highly aggressive, malignant behavior with a relatively poor clinical course.2Jennifer LS Rondell PG Brandon TL Sarah MJ Anja CR Jennifer MB. SMARCA4-deficient thoracic sarcoma: a distinctive clinicopathological entity with undifferentiated rhabdoid morphology and aggressive behavior., 3Rekhtman N Montecalvo J Chang JC et al.SMARCA4-deficient thoracic sarcomatoid tumors represent primarily smoking-related undifferentiated carcinomas rather than primary thoracic sarcomas., 4Witkowski L Carrot-Zhang J Albrecht S et al.Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type., 5Foulkes WD Clarke BA Hasselblatt M Majewski J Albrecht S McCluggage WG. No small surprise–small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour. Recent studies have proposed a novel entity, the SMARCA4-deficient undifferentiated uterine sarcoma, which is characterized by SMARCA4 inactivation with a few alterations in other oncogenes, the presence of large atypical epithelioid cells with prominent rhabdoid morphology, extensive lymphovascular invasion, extrauterine spread, and marked infiltrative growth with a dismal clinical prognosis.6David LK Fei D Michele B et al.SMARCA4-deficient undifferentiated uterine sarcoma (malignant rhabdoid tumor of the uterus): a clinicopathologic entity distinct from undifferentiated carcinoma.,7Douglas IL Justin MA Jonathan LH et al.Elvin et al. SMARCA4 inactivation defines a subset of undifferentiated uterine sarcomas with rhabdoid and small cell features and germline mutation association. A previous case series of undifferentiated uterine sarcoma is thought to have described some cases of SMARCA4-deficient undifferentiated uterine sarcoma based on the presence of certain overlapping clinicopathological features.8Rios I Rovirosa Á Morales J et al.Undifferentiated uterine sarcoma: a rare, not well known and aggressive disease: report of 13 cases. Malignant rhabdoid tumor, a well-established pediatric tumor entity, is characterized by the complete loss of SMARCB1, a member molecule of the SWI/SNF complex, to which SMARCA4 also belongs.9Geller JI Roth JJ Biegel JA. Biology and Treatment of Rhabdoid Tumor. Because SMARCA4-deficient undifferentiated uterine sarcomas and malignant rhabdoid tumors commonly share an altered SWI/SNF complex as a fundamental pathological abnormality, they have similar clinicopathological features, such as histologically rhabdoid morphology and an aggressive clinical course.6David LK Fei D Michele B et al.SMARCA4-deficient undifferentiated uterine sarcoma (malignant rhabdoid tumor of the uterus): a clinicopathologic entity distinct from undifferentiated carcinoma.,9Geller JI Roth JJ Biegel JA. Biology and Treatment of Rhabdoid Tumor. However, the former is considered to be distinct from the latter because it never occurs in infants and completely lacks a SMARCB1 gene abnormality.6David LK Fei D Michele B et al.SMARCA4-deficient undifferentiated uterine sarcoma (malignant rhabdoid tumor of the uterus): a clinicopathologic entity distinct from undifferentiated carcinoma. Because of its rarity and rapid growth, no studies on specific treatments and outcomes have been done; thus, no standard treatment currently exists.

We described herein a case of SMARCA4-deficient undifferentiated uterine sarcoma, which progressed aggressively despite several courses of systemic therapy but showed a remarkable response to low-dose radiotherapy, especially in its diffuse liver metastases. Also presented is a hypothesis explaining the sensitivity of SMARCA4-deficient undifferentiated uterine sarcoma to radiotherapy.

Case presentation

A 51-year-old female patient presented with massive irregular bleeding of several months’ duration. An internal examination revealed a uterine mass protruding into the vagina. The initial laboratory assessment found hemoglobin 9.6 mg/dL (normal rage: 11.6 -14.8 g/dL), lactate dehydrogenase 224 IU/L (normal range: 124 - 222 U/L), and CA125 108.4 mg/dL (normal range: 0.0 - 35.0 U/mL). Other tumor markers, such as CA19-9, CEA, SCC, and NSE were negative, and a blood test revealed no other abnormal findings. She had a history of dyslipidemia and colorectal polyps and a family history of colorectal cancer.

Computed tomography (CT) revealed a large tumor (maximum diameter 15 cm) occupying the uterine cervix to the corpus and a metastasis to the left common iliac lymph node (Fig. 1A). The tumor appeared as an area of moderate intensity on T2-weighted magnetic resonance imaging (Fig. 1B, C) and as an area of intermediate to high intensity on T1-weighted imaging, suggesting the presence of an intra-tumoral hemorrhage. Diffusion-weighted imaging revealed an area of high signal intensity with a very low diffusion coefficient value (0.766 × 10−3) indicating malignant potential. A biopsy of the uterine lesion revealed a non-epithelial malignancy. Based on the diagnosis of advanced uterine sarcoma, a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and low para-aortic lymph node dissection were performed with curative intent. The resected tumor was pathologically diagnosed as SMARCA4-deficient undifferentiated sarcoma based on the presence of a fairly monotonous proliferation of rhabdoid tumor cells resembling a malignant rhabdoid tumor with complete loss of SMARCA4 expression. The tumor had diffusely invaded the uterine cervix, where the surgical margin was positive due to diffuse intramural extension of the tumor and lymphatic invasion. The right external iliac and left common iliac nodes were positive for metastasis.

Figure 1Axial contrast-enhanced computed tomography (CT) imaging showing the uterine mass (A) and the area of moderate intensity on T2-weighted magnetic resonance imaging (MRI) (B). Sagittal T2-weighted MRI showing the uterine mass protruding into the vagina (C).

Six cycles of doxorubicin and ifosfamide were administrated as adjuvant chemotherapy. Radiotherapy was not administered as an adjuvant treatment due to the lack of supporting evidence. The tumor relapsed at the postoperative vaginal stump and right obturator lymph node at postoperative month 6. The patient received one cycle of gemcitabine and docetaxel as a second-line treatment, but the locally recurrent lesion and metastasis progressed to the iliac lymph nodes, causing bilateral hydronephrosis and renal dysfunction. The patient complained of pain and vaginal discharge; therefore, after considering the tumor's aggressiveness and the need for continued systemic treatment, palliative radiotherapy at 8 Gy was administered in single fraction for the locally recurrent lesion. Radiotherapy led to symptom improvement and tumor shrinkage on CT, with the diameter of the locally recurrent lesion decreasing from 8.3 × 8.1 cm to 6.1 × 6.8 cm at two months after the treatment (Figure 2 A–C). Pazopanib hydrochloride and eribulin mesylate were administered as third- and fourth-line systemic treatments, but the tumor progressed rapidly via hematogenous and lymphatic spread. Because the patient complained of abdominal distension due to multiple diffuse liver metastases (Figure 2D) with elevated liver enzymes, whole-liver irradiation (8 Gy in a single fraction) was administered with palliative intent. After radiotherapy, the liver metastases decreased markedly, and the abdominal distension completely resolved (Figures 2E, F). Manual tumor delineation using a radiotherapy treatment planning system revealed a decrease in the total tumor volume from 45% (722/1,718 mL) to 2% (32/1,573 mL) of the total liver volume. Blood tests revealed an improvement in the values for aspartate aminotransferase (57 to 21 U/L), alanine aminotransferase (29 to 17 U/L), alkaline phosphatase (836 to 407 U/L), lactate dehydrogenase (974 to 638 U/L), and C-reactive protein (12.89 to 3.71 mg/dL) two weeks after radiotherapy. The patient received palliative care after treatment termination, and her general condition gradually deteriorated. Renal dysfunction resulted from hydronephrosis caused by the malignancies, and the patient died of the disease at postoperative 12 months.

Figure 2Axial CT of the locally recurrent lesion before (A), and two months after, radiotherapy (B). Axial CT of the liver three weeks before (D), and two weeks after, whole-liver radiotherapy (E). Radiotherapy plan for the locally recurrent lesion (C) and the liver metastases (F).

Discussion

Because SMARCA4-deficient undifferentiated uterine sarcoma is a relatively new entity, to the best of our knowledge, no study has yet described a treatment for the disease. The present case is unique in that it demonstrated aggressive tumor behavior with a remarkable response to radiotherapy.

Whole-liver irradiation is often used to ameliorate abdominal symptoms caused by a primary liver malignancy and liver metastasis and focuses on symptom management. Thus, a radiological response to low-dose intensity is not necessarily expected.10Soliman H Ringash J Jiang H et al.Phase II trial of palliative radiotherapy for hepatocellular carcinoma and liver metastases. Several small studies have evaluated the response of diffuse liver tumors to radiotherapy, and reports of whole-liver irradiation of primary and metastatic liver tumors at doses as low as 21.6 to 40 Gy have shown a predictably low objective response rate.11Feng M Smith DE Normolle DP et al.A phase I clinical and pharmacology study using amifostine as a radioprotector in dose-escalated whole liver radiation therapy.,12Goody RB Brade AM Wang L et al.Phase I trial of radiation therapy and sorafenib in unresectable liver metastases. Furthermore, sarcomas are generally treated with doses of 50 Gy or more in a definitive or adjuvant setting, and the treatment effect at lower doses is not well understood.13

National Comprehensive Cancer Network (NCCN). Soft Tissue Sarcoma. https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. 2.2020 version. Accessed August 1, 2020.

In view of the findings in the present case, the remarkable response of the liver metastases to radiotherapy was noteworthy and suggested that SMARCA4-deficient undifferentiated uterine sarcoma may be sensitive to radiotherapy.

The response of a locally recurrent tumor to radiotherapy at a dose of 8 Gy in a single fraction was minor compared to the response of the liver metastasis. Local oxygenation status may explain this discrepancy. Since surgery caused the pelvic lesions to become more hypoxic than in the original state, the recurrent tumors were possibly resistant to the radiotherapy. However, the abundant blood flow in the liver from the portal vein and the hepatic artery may have conferred some protection against ischemia.

Despite the absence of reports describing the treatment of SMARCA4-deficient undifferentiated uterine sarcoma, some previous studies have reported the treatment and response of SMARCA4-deficient malignancies.14Erica HB Arup RC Xiaokui M et al.SMARCA4/BRG1 is a novel prognostic biomarker predictive of cisplatin-based chemotherapy outcomes in resected non–small cell lung cancer.,15Callegaro-Filho D Gershenson DM Nick AM et al.Small Cell Carcinoma of the Ovary – Hypercalcemic Type (SCCOHT): A Review of 47 Cases. Lower SMARCA4 expression was associated with increased sensitivity to cisplatin-based chemotherapy despite the poor survival outcomes.14Erica HB Arup RC Xiaokui M et al.SMARCA4/BRG1 is a novel prognostic biomarker predictive of cisplatin-based chemotherapy outcomes in resected non–small cell lung cancer. A case series of 47 cases of SCCOHT showed a trend toward lower recurrence rates in patients receiving radiotherapy as part of their primary adjuvant therapy.15Callegaro-Filho D Gershenson DM Nick AM et al.Small Cell Carcinoma of the Ovary – Hypercalcemic Type (SCCOHT): A Review of 47 Cases. Although generalizability across primary sites is an important issue, findings related to SMARCA4 expression in other malignancies might provide clues to the development of a treatment for SMARCA4-deficient undifferentiated uterine sarcomas. Although the proportion of SMARCA4-deficient undifferentiated uterine sarcoma cases among the malignancies formerly described as undifferentiated uterine sarcomas is uncertain, a previous report of 13 undifferentiated uterine sarcoma cases demonstrated the treatment benefits of radiotherapy; eight patients with adjuvant radiotherapy did not experience a local relapse while three of five patients without adjuvant radiotherapy experienced a local recurrence.8Rios I Rovirosa Á Morales J et al.Undifferentiated uterine sarcoma: a rare, not well known and aggressive disease: report of 13 cases.

Palliative radiotherapy seems to be a good treatment option for metastatic SMARCA4-deficient undifferentiated uterine sarcoma showing aggressive progression and a tumor response to radiotherapy as in the present case. Moreover, perioperative radiotherapy, including external beam pelvic radiotherapy and brachytherapy (which were not administered in the present case), may have the potential to improve the outcomes, given a favorable response to radiotherapy and local recurrence at the site of the initial recurrence.

Several basic studies of molecular cell biology have demonstrated that SWI/SNF function loss compromises DNA damage repair, leading to tumor radiosensitivity. A large-scale study examining cell survival after DNA damage reported that SMARCA4 was one of 19 genes implicated in high radiation sensitivity after radiation exposure among a diverse array of 533 genetically annotated human tumor cell lines.16Brian DY Drew JA Eui KC et al.A genetic basis for the variation in the vulnerability of cancer to DNA damage. BRG1 and its combined protein modifications are the targets of research on radiosensitivity and sensitizing agents.17Zernickel E Sak A Riaz A Klein D Groneberg M Stuschke M. Targeting of BRM Sensitizes BRG1-mutant lung cancer cell lines to radiotherapy.,18Kwon SJ Lee SK Na J et al.Targeting BRG1 chromatin remodeler via its bromodomain for enhanced tumor cell radiosensitivity in vitro and in vivo. The suppression of ARID1A and ARID1B, which are also components of the SWI/SNF complex, as well as defects in these proteins, which have been found in several malignancies, inhibit the repair of DNA double-strand breaks and cause sensitivity to ionizing radiation.19Watanabe R Ui A Kanno S et al.SWI/SNF Factors Required for Cellular Resistance to DNA Damage Include ARID1A and ARID1B and Show Interdependent Protein Stability. Although these basic findings do not directly explain the remarkable response to radiotherapy observed in the liver metastases in the present case, future research might clarify the relationship between SMARCA4 deficiency and radiosensitivity. Malignant rhabdoid tumors are similarly characterized by SWI/SNF function loss. The treatments available for this disease, including perioperative radiotherapy and the multidisciplinary treatment approach, are well-established. Given the shared pathological features between malignant rhabdoid tumors and SMARCA4-deficient undifferentiated uterine sarcoma, the treatment strategy for the former might be applied with good effect to the latter.9Geller JI Roth JJ Biegel JA. Biology and Treatment of Rhabdoid Tumor.

Our study demonstrated rapid progression of the SMARCA4-deficient undifferentiated uterine sarcoma in the present case via both hematogenous and lymphatic spread. Because this disease entity is relatively new, only a few details on appropriate treatment are currently available. In the present case, low-dose radiotherapy not only ameliorated the symptoms but also resulted in a significant radiological response, indicating the potential for radiotherapy as an effective treatment option for SMARCA4-deficient undifferentiated uterine sarcoma.