Low-Grade Endometrial Stromal Sarcoma with Intravenous and Intracardiac Extension: A Case Report

Background: Low-grade endometrial stromal sarcoma (ESS) is rare mesenchymal neoplasm, which has an indolent history with late recurrences. ESS usually spread through the lymph nodes and venous system but very seldom involve large vessels or the heart. Case presentation: A 38-year-old Chinese woman was admitted to our department due to pelvic mass found on physical examination. The superior and inferior vena cava CT angiography (CTA) showed an enlarged uterine as well as low density image in the left internal iliac vein, the left common iliac vein, the inferior vena cava, the left renal vein adjacent to the heart and the right atrium, with a range of 110*16mm. The lling defect of right atrium was about 30*14mm. The three-dimensional computed tomography reconstruction showed that the mass originated from the uterine and invaded into the reproductive vein, subsequently extended along the inferior vena cava to the right atrium. Needle biopsy of the pelvic mass was performed and the tissue indicates smooth muscle. The preoperative diagnosis was intravascular leiomyomatosis and the patient underwent radical resection: thrombectomy and total hysterectomy with bilateral salpingo-oophorectomy. Postoperative histopathology revealed low grade endometrial stromal sarcoma. Microscopically, the tumors in both original uterine lesions and intravascular and intracardiac metastases shared morphologic features characterized by neoplastic cells similar to proliferative-phase endometrial stromal cells, in which small spiral artery differentiation was recognized and tumor tissue showed invasive growth pattern by inserting into the surrounding smooth muscle. Immunohistochemistry showed tumor cells were reactive to Estrogen Receptor, Progesterone Receptor,CD10. Primary uterine foci showed cyclin D1(5%+) and Ki-67(20%+),whereas metastatic lesions of the intracardiac and the intravascular component identied cyclin D1(negative) and Ki-67(2%+). The patient is alive without evidence of recurrence 3 months after surgery. Conclusions: Distant metastasis of low-grade endometrial FDG-PET CT maximum standardized uptake value of 14.5 conned to the uterine masses in contrast to elevated uptake value of 8.5 of the intravascular and intracardiac metastatic tumor masses. Segmental curettage was performed to rule out endometrial lesions, In an attempt to clarify the nature of the tumor, needle biopsy of the pelvic mass was performed and the tissue indicates smooth muscle. Immunohistochemistry showed tumor cells were reactive to Ki-67(2%+), Vim, S100, SMA, Desmin, HHF35 and were inactive to CD117, ALK, Dog-1. Preoperative diagnosis of intravascular leiomyomatosis was made. The patient underwent radical resection: thrombectomy and total hysterectomy with bilateral salpingo-oophorectomy. Intraoperative transesophageal echocardiography showed that the atrial tumor was completely removed and the tumors in the vena cava and the left common iliac vein, internal iliac vein, and left renal vein were continued removed. The operation was succesful.


Background
In the differential diagnosis of lesions in inferior vena cava and the heart, in addition to thrombosis, lesions caused by the invasion of malignant tumor should be considered. Common tumors that may transfer to the inferior vena cava and the heart including renal cancer, liver cancer, uterine leiomyomatosis and nephroblastoma [1]. Uterine broids invading the inferior vena cava and the right atrium is also known as intravascular leiomyomatosis [2]. The case described in this paper was admitted to our department due to pelvic mass found on physical examination, other positive ndings including lesions extending from the iliac vein to the inferior vena cava and nally reaching the right atrium. The preoperative PET-CT suggested the possibility of uterine malignancy, and thrombosis was considered of the lesions in the blood vessels and atria. Needle biopsy of the pelvic mass was performed and the tissue indicates smooth muscle. Combined with the patient's medical history, physical examination, preoperative imaging and tumor puncture pathological results, the clinical diagnosis was intended to be intravascular leiomyomatosis. Nevertheless the postoperative pathological results revealed low grade endometrial stromal sarcoma.
In the current WHO classi cation published in 2014, Endometrial stromal tumors were classi ed into three types according to cell morphology and mitosis: benign endometrial stromal nodules (ESN), Endometrial stromal sarcoma (ESS), and Undifferentiated uterine sarcoma(UUS) [3]. ESS was classi ed into high grade(HG-ESS) and low grade(LG-ESS). ESS is a very rare tumor entity, represent only around 0.2% of all uterine malignancies, but they make up approximately 10% of uterine sarcomas [4].Preoperative diagnosis of LG-ESS is di cult as it is often confused with uterine broids [5]. ESS usually spread through the lymph nodes and venous system but very seldom involve large vessels or the heart. Cardiac ESS metastases are extremely rare, and their treatment is very complex [6,7]. Patients with heart involvements are often recurrent cases who had a past history of sugery for endometrial stromal sarcoma [7][8][9][10][11]. To our knowledge, this is the fth patient involving the inferior vena cava and right atrium at initial diagnosis.

Case Presentation
A 38-year-old woman (gravida 3, para2) was admitted to the Second XiangYa Hospital due to pelvic mass found on physical examination. Further abdominal and pelvic ultrasound as well as the cardiac echocardiography showed inferior vena cava and right atrium lumps. The past history included fallopian tube ligation 12 years ago and hysteroscopic submucosal myomectomy 7 years ago. She had no family history of cancer. Blood testing showed hyperlipemia, cholesterol 6.28 mmol/L(normal range: 2.9-5.2 mmol/L) and triglycerides 1.79 mmol/L(normal range: <1.7 mmol/L).Blood testing also showed slightly elevated levels of trioxypurine 366 U/L(normal range: 155-357 U/L) and cancer antigen (CA)125 and CA 19-9 level was within normal limits. The pelvic examination and transvaginal ultrasonography revealed a three months pregnant-sized uterine without abnormalities in other reproductive organs. The cervical cytology was normal. The superior and inferior vena cava CTA showed an enlarged uterine as well as low density image in the left internal iliac vein, the left common iliac vein, the inferior vena cava, the left renal vein adjacent to the heart and the right atrium, with a range of 110*16 mm. The lling defect of right atrium was about 30*14 mm.The tumor grows along the veins, and the venous system shows low-density shadows ( Fig. 1A-F). The threedimensional computed tomography reconstruction showed that the mass originated from the uterine and invaded into the reproductive vein, subsequently extended along the inferior vena cava to the right atrium( Fig. 2A-D). FDG-PET CT demonstrated maximum standardized uptake value of 14.5 con ned to the uterine masses in contrast to elevated uptake value of 8.5 of the intravascular and intracardiac metastatic tumor masses. Segmental curettage was performed to rule out endometrial lesions, In an attempt to clarify the nature of the tumor, needle biopsy of the pelvic mass was performed and the tissue indicates smooth muscle. Immunohistochemistry showed tumor cells were reactive to Ki-67(2%+), Vim, S100, SMA, Desmin, HHF35 and were inactive to CD117, ALK, Dog-1. Preoperative diagnosis of intravascular leiomyomatosis was made. The patient underwent radical resection: thrombectomy and total hysterectomy with bilateral salpingo-oophorectomy. Intraoperative transesophageal echocardiography showed that the atrial tumor was completely removed and the tumors in the vena cava and the left common iliac vein, internal iliac vein, and left renal vein were continued removed. The operation was succesful.
structures.The longest tumor segment (from the inferior vena cava and right atrium) is 14.5 cm (Fig. 3A-C). Postoperative histological morphology showed a group of small and consistent round-oval cells, little-medium eosinophilic cytoplasm, 1 mitosis /HPF, small spiral artery differentiation was recognized and tumor tissue showed invasive growth pattern by inserting into the surrounding smooth muscle. Immunohistochemistry showed ER, PR, CD10 positive( Fig. 4A-H). the primary uterine foci showed cyclin D1(5%+) and Ki-67(20%+), whereas metastatic lesions of the intracardiac and the intravascular component identi ed cyclin D1(< 1%) and Ki-67(2%+) (Fig. 5A-D).Overall histomorphology and immunohistochemistry con rmed the diagnosis of a low-grade endometrial stromal sarcoma. The patient was discharged 12 days after surgery. Treatment with aromatase inhibitor letrozole 2.5 mg everyday. 3 months after the operation, the patient has fully recovered from the operation and can engage in normal activities. MRI showed no obvious signs of tumor recurrence 3 months after surgery.

Discussion
As a very rare malignant gynecological neoplasm, the annual incidence of ESS is 0.19 per 100,000 women [8].Tumor stage is the most important prognostic factor in LG-ESS [12], which are staged along with uterine leiomyosarcomas in accordance with the FIGO and TNM classi cations [13,14]. In patients with tumor stage I-II, the 5-year survival rate is over 90%,while with stages III-IV it is around 50% [15]. LG-ESS have an indolent history with recurrence rate of 10-20% that often happen many years after the diagnosis and initial surgery [6,16]. Therefore, they have better prognosis than other uterine sarcomas [17]. In most cases, the recurrence period varied from 3 months to 23 years, with a median interval of 3 years [18]. Long-term follow-up is critical due to the high longterm recurrence rate.
Preoperative diagnosis of LG-ESS can be di cult and is often confused with uterine broids on account of the absence of speci c clinical manifestations [5], Imageological procedures such as ultrasound, computed tomography and magnetic resonance imaging are not able to display any speci c characteristics of LG-ESS [19]. In contrast to carcinomas of the endometrium, a diagnosis of LG-ESS as a mesenchymal tumor cannot be securely established using hysteroscopy and fractional curettage, in our case no abnormal endometrium was observed during preoperative curettage. Pathologically, a clear distinction from benign ESN can only be reliably made after histological analysis of the tumor's entire interface with the neighboring myometrium [20]. Therefore most diagnosis of LG-ESS were made after surgery. According to the literature, the most frequently reported sites of metastases of the LG-ESS are the vagina, pelvis, and peritoneal cavity. Cardiac metastases are rare because ESS commonly spreads through the lymph nodes and venous system [6].To our knowledge, 18 LG-ESS patients with heart involvement have been reported to date, and their clinical characteristics are summarized as shown in Table 1.
The age of the 18 patients with heart involvement ranged from 24 years old to 71 years old (average age 46 years), 66.7% had a history of surgery for LG-ESS and only 33.3% without de nite history and were diagnosed for the rst time. Our patient had a history of "submucosal myomectomy" 7 years ago, the diagnosis of ESN was determined, when reassessing the pathological sections from the last operation, ESN was still considered due to the limited amount of specimens. It is not possible to know the fact back then. In this case we predict it is likely that the patient already had LG-ESS 7 years ago, and the tumor relapsed this time. Therefore, whether surgery is a cause of LG-ESS invasion into the great vessels and the heart remains to be further explored. For patients with a history of LG-ESS, it is not di cult to predicate the recurrence. However, for patients with no relevant history, when tumors in the atrium and inferior vena cava were discovered for the rst time, the differential diagnosis of uterine malignant tumor metastasis should also be considered in addition to thrombi and venous leiomyomatosis. The clinical symptoms of LG-ESS involving the heart and great vessels vary from asymptomatic to obvious dyspnea and right heart failure. CT and MRI examinations are of value for early detection of cardiac and vascular involvement. In our case, the three-dimensional CT reconstruction imaging was used to simulate tumor route and scope, which was of great signi cance for comprehensive evaluation of the range of the lesion and complete resection of the tumors. Several cases pointed out that transesophageal ultrasound(TEE) is useful for diagnosis of cardiac involvement before operation and can also guide the doctor to determine whether the cardiac mass is removed completely during the surgery [21][22].Moreover there were patients whose intracardiac lesions were detected accidently by TEE [23], suggesting that for patients with possible great vascular metastasis, TEE should be stressed and applied as the important means.
The primary treatment for LG-ESS is surgery with total hysterectomy (without morcellation) and bilateral salpingo-oophorectomy [18], It has been shown that LG-ESS are hormone-dependent, It is not clear whether the ovaries can be preserved in young, premenopausal women [24].There is no evidence that cytoreduction and lymphadenectomy are bene cial for long-term survival [25]. All 18 patients with cardiac involvement were stage IV LG-ESS and radical resection were performed in 14 cases, the perioperative mortality rate was zero. All patients recovered uneventfully after the operation. Except for one case, all 13 patients showed no signs of recurrence by the end of the follow-up. Although the long-term effects of surgery on patients cannot be proved, the surgery can prevent patients from developing into severe complications such as heart failure and pulmonary embolism even sudden death.
The nal diagnosis of this disease mainly depends on histopathology, the pathological diagnosis of our case is certain. Interestingly, immunohistochemistry of cyclin D1 and Ki-67 in the primary uterine foci and the metastatic lesions of the intracardiac and the intravascular component are different. This result is consistent with the study of Koto Fujiishi et al [26]. In their study, a patient with LG-ESS whose uterine lesions composed of three components, all of which meet the criterion of LG-ESS, However, PET-CT indicated high uptake of uorodeoxyglucose in 2 lesions (subserosal tumors with SUV value 13.28) and no uptake of uorodeoxyglucose in 1 lesion (intramural tumor with SUV value 0) before surgery. Postoperative nuclear cyclin D1 immunostaining was identi ed  [27]. There are no valid data to show that adjuvant chemotherapy leads to any improvement in survival in patients with LG-ESS [18]. Postoperative radiotherapy in patients with ESS only appears to improve locoregional control, so that the medium-term and long-term side effects of pelvic irradiation need to be weighed carefully against what is in any case a good prognosis in relation to locoregional recurrences [28]. The expression of steroid receptors and aromatases in LG-ESS suggests that adjuvant therapy with gestagens, GnRH analogues, or aromatase inhibitors should be effective [18]. Whether PET-CT as well as the immunohistochemical results of CyclinD1 and KI-67 can also guide subsequent treatment, such as chemotherapy and radiotherapy, remains to be further explored.

Conclusions
Despite its well-known good prognostic nature, low-grade ESS may behave as an aggressive malignancy. The differential diagnosis of malignant tumor metastasis should be considered in the lump of great vessels and the heart. Complete resection of tumor requires multidisciplinary cooperation. The perioperative mortality is low and the risk of fatal complications such as heart failure and pulmonary embolism can be reduced.

Consent for publication
Written consent was obtained from the patient to publish this case report.

Availability of data and materials
All data generated or analysed during this study are included in this published article.

Competing interests
The authors declare that they have no competing interests. All authors read and approved the nal manuscript.

No. Authors
Age P/R Symptoms Heart   The three-dimensional computed tomography reconstruction of the whole path of the mass originating from the uterine and invaded into the venous system and eventually to the right atrium. A. Positive view B. Back view C.D. Endovascular imaging of the tumor.Red represents the mass Blue represents the blood vessel.

Figure 3
Imaging of the operation and gross specimen.

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