Rare case of high-grade endometrial stromal sarcoma metastasising to inferior vena cava and right atrium
- Priyanka Deshmukh and
- Krishnayan Haldar
- Department of Obstetrics and Gynaecology, Addenbrooke's Hospital, Cambridge, UK
- Correspondence to Dr Priyanka Deshmukh; deshpriyanka16220@gmail.com
Abstract
Endometrial stromal sarcomas (ESSs) are a rare form of uterine malignancy representing <10% of all uterine sarcomas and <1% of all primary malignant tumours of the uterus. Invasion of the vascular system by low-grade ESS has been reported in the literature. Here we report the first case of a high-grade ESS invading the pelvic and gonadal vein and extending through the inferior vena cava to the right atrium, the diagnostic challenges and multidisciplinary management of the case.
Background
Uterine sarcomas make up around 3%–7% of all uterine malignancies and are broadly divided into smooth muscle tumours and endometrial stromal tumours.1 The malignant subtype of endometrial stromal tumours, the endometrial stromal sarcoma (ESS), comprises <10% of uterine sarcomas.
The very existence of the high-grade ESSs (HG-ESSs) was debated before they were reintroduced in the classification of ESSs in 2014. Due to the rarity of the condition and complex molecular behaviour, most of the information on these tumours about pathogenesis, spread, diagnostic criteria, prognosis and management protocols is in the form of case reports/series. Also, as compared with low-grade ESS (LG-ESS), cases of HG-ESS are few and far between, making treatment more challenging.
This is a rare case of an HG-ESS invading into pelvic and gonadal vein and extending through the inferior vena cava (IVC) to the right atrium; we present diagnostic challenges and multidisciplinary management.
Case presentation
A premenopausal patient presented to the gynaecology clinic with the main report of menorrhagia. She was known to have a uterine fibroid for around 4 years with a delay in referral due to the COVID-19 pandemic. She was hypothyroid on thyroxine and had bilateral inguinal herniorrhaphy in the past.
On clinical examination, the uterus was bulky, mobile and retroverted. No nodularity was felt in the pouch of Douglas.
Investigations
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An ultrasound scan was done in the community and the patient was diagnosed with fibroid uterus.
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MRI scan showed a grossly abnormal uterus with the prolapsing lesion extending from the endometrial cavity into the endocervical canal with multiple myometrial lesions which were not typical for fibroids. Overall, the appearances were concerning for sarcoma (figure 1).
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A CT scan was performed as part of the preoperative assessment. It was an unenhanced scan as the patient reported contrast allergy and showed no extrauterine spread.
Preoperative MRI.
Differential diagnosis
Based on the investigations, the main differential diagnoses were:
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Fibroid uterus.
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Uterine sarcoma.
Keeping in mind the atypical picture of the fibroids, the patient was seen by the gynaecological-oncology team and was counselled for a total abdominal hysterectomy with bilateral salpingo-oophorectomy.
Treatment
At laparotomy, the uterus was bulky with normal tubes and ovaries. The right infundibulopelvic ligament and paracervical tissues were thickened on touch and intravenous leiomyomatosis was suspected. The upper abdomen was normal; no retroperitoneal lymphadenopathy was noted. Hysterectomy and bilateral salpingo-oophorectomy were completed. Right paracervical abnormal tissue was resected after mobilising the ureter. The tumour noted in the right gonadal vein was felt to be reaching the IVC, after mobilising the caecum and the ascending colon. Imaging was reviewed, but it was difficult to comment on the intravenous extension on unenhanced CT or MRI scans.
Intraoperative sonography was performed and showed an intravascular lesion extending from the right gonadal vein into the hepatic portion of IVC.
The right ovarian pedicle was then traced up above the pelvic brim and transfixed high, and a decision was made not to proceed with resection of gonadal vein tumour any higher up as the upper extent of the lesion could not be defined.
The patient had an uneventful postoperative recovery. She had an allergy test and then a contrast CT and transthoracic echocardiogram. Imaging revealed tumour thrombus extending into IVC extending into the right internal iliac vein and right atrium (figures 2 and 3). The possibility of tumour thrombus in the pulmonary artery was raised. No other features of the distant spread of the disease were seen. It could not be concluded if pulmonary emboli were secondary to tumour or blood clots. On balance, she was started on anticoagulation (apixaban). The case was then discussed at the sarcoma multidisciplinary team (MDT) and vascular MDT meeting.
Tumour thrombus in iliac vein.
Tumour thrombus in inferior vena cava (IVC) and going to the right atrium.
Histology from the uterus shows an endometrial tumour comprising densely cellular islands of spindle cells permeating the myometrium. In the majority of tumour blocks, mitotic activity is relatively low (8–15 mitoses/10 high-power fields). However, focally, there is a more brisk mitotic activity (18–21 mitoses/10 high-power fields). Due to this mixed tumour profile, the specimen was submitted for molecular analyses. Reverse transcription-PCR analysis detected YWHAE/NUTM2A+B gene fusion that is seen in HG-ESS. Right gonadal and paravaginal vessels also showed HG-ESS.
The decision to do a thrombectomy was taken independently by two tertiary referral sarcoma centres at the MDT meeting based on tumour response to chemotherapy. A plan was made for neoadjuvant chemotherapy as there was a concern that there is disease elsewhere that is not visible on CT. As this was going to be a major vascular surgery, the team wanted to be assured that there was no progression/no new metastasis before considering surgery. If a good response to chemotherapy was to be seen, then the plan was for adjuvant chemotherapy post-surgery.
The patient received three cycles of chemotherapy, and post-chemotherapy imaging showed residual tumour only in the right gonadal vein, right iliac vein and distal IVC. She had surgery with the vascular team for excision of the right gonadal vein, right iliac vein with branches and IVC intravenous thrombus.
Post-surgery, she received doxorubicin and eventually was put on letrozole maintenance.
A summary of the treatment timeline from the index surgery to the follow-up 1 year later is shown in table 1.
Timeline in the management of the case
| Index surgery | Surgery | Total abdominal hysterectomy, bilateral salpingo-oophorectomy, excision of right paracervical/paravaginal veins and right gonadal vessels above pelvic brim |
| Histology | High-grade endometrial stromal sarcoma (YWHAE–NUTM2A/B fusion gene detected), measuring 100 mm in maximum dimension; ER(Estrogen Receptor) positive | |
| Post-initial surgery imaging for staging | Echocardiogram: linear, thin echogenic structure seen all the way up the IVC and extending to the right atrium CT with Iomeron contrast: tumour thrombus seen within the pulmonary arteries, IVC, right internal iliac vein and possibly right atrium. No other features to suggest distant spread of disease |
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| Started on anticoagulation (apixaban) | ||
| Started on hormonal treatment | Letrozole 2.5 mg once daily | |
| Repeat CT scan | Interval reduction of pulmonary artery and right iliac vein confluence thrombus. Persistent tumour thrombus in IVC and right internal iliac vein | |
| Chemotherapy ×3 cycles | Doxorubicin | |
| Response post-chemotherapy | Echocardiogram: no mass seen in IVC, hepatic vein or right atrium. Tumour thrombus in distal IVC much smaller in size CT after 2 cycles of doxorubicin: reduction in PE, slight reduction in IVC, right gonadal vein and right internal iliac tumour thrombus. No new site of disease |
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| Repeat imaging | Echocardiogram: no mass seen in IVC, hepatic vein or right atrium | |
| Six months after index surgery | Surgery with the vascular team | Excision of right gonadal vein with IVC intravenous thrombus and right iliac vein with branches |
| Postoperative chemotherapy ×3 cycles | Doxorubicin | |
| Post-chemotherapy imaging | CT: no evidence of recurrent or metastatic disease (figure 4) | |
| Hormonal therapy | Letrozole 2.5 mg once daily | |
| One year after index surgery | Surveillance imaging: CT scan | No evidence of recurrence |
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IVC, inferior vena cava; PE, pulmonary emboli.
Resolution of tumour post-surgery and chemotherapy.
Outcome and follow-up
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Following complete surgical treatment, the patient was started on adjuvant chemotherapy and eventually hormonal therapy.
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One year after the complete surgical cure, the patient remains tumour-free and on radiological surveillance with three monthly CT scans.
Discussion
ESSs are the second most common pure mesenchymal tumours of the uterus, and they account for 10% of all uterine sarcomas.2
The highlight of the latest WHO classification of ESSs 20143 is the reintroduction of the HG-ESS subtype based on the recent discovery of a subset of ESSs with a unique YWHAE–FAM22. FAM22A/B was renamed NUTM2A/B due to its sequence homology with NUT (NUTM1)4 gene rearrangement. This subset of ESSs has distinct morphological features and a prognosis intermediate between LG-ESS and undifferentiated uterine sarcoma.5
Among the ESSs, the HG-ESSs form a very small subset and hence little is known about their natural course, prognostic factors and optimal management.
HG-ESS is usually seen in the premenopausal age group with a mean age of diagnosis of 50 years. It most commonly presents with abnormal vaginal bleeding and often has an extrauterine disease at the time of presentation.6 All these features were noted in our patient.
The condition may often be misdiagnosed as uterine leiomyoma or endometrial carcinoma preoperatively because of a lack of characteristic imaging and clinical manifestations. Imaging and diagnostic tests, including endometrial biopsies, may not always be helpful, especially if the lesion is completely within the myometrium. Due to the similarity of ESS with normal endometrium, it may be impossible to diagnose it with certainty on curettage fragments, and the definitive diagnosis can be made only on a hysterectomy specimen.7 Also, in suspected and symptomatic stage 1 sarcoma, a hysterectomy is usually the first treatment. Neoadjuvant treatment is not considered even with a preoperative diagnosis of stage 1 sarcoma, especially with no contraindications to surgery. As the imaging said there was only suspicion of sarcoma with no extrauterine disease on the imaging done, a biopsy was not done preoperatively. If there was any extrauterine disease suspected, a biopsy would have been warranted and done.
A preoperative MRI and a CT scan were done as part of the investigations. However, as the patient had reported an allergy to contrast medium and hence a non-contrast CT was done, it, unfortunately, could not comment on the intravascular pathology. An MRI with contrast should have been done at this stage as it would have helped in the evaluation of the extrauterine spread. ESS is known to metastasise and recur in lymph nodes, bone, peritoneum, retroperitoneum, lung, bowel, heart and skin.8–10 There have been numerous case reports and case series about the extension of LG-ESS tumour thrombus into the IVC, extending to the heart and even to the pulmonary vasculature.11–13 However, there are no cases of HG-ESS showing such a pattern of spread. This could also represent a lack of molecular analysis done in previous cases. Our patient had tumour extension that involved the internal iliac veins and the gonadal vein extending into the IVC and right atrium. The diagnosis of the extent of the tumour was made difficult by a concurrent pulmonary embolism. It was only on treatment and resolution on repeat imaging with anticoagulants that we could make out that the pulmonary embolus was not tumour embolus but blood clots. This case, along with the previously reported cases of LG-ESS in the major vessels, reiterates the importance of attempting complete imaging before operating cases of suspected uterine sarcomas. In cases showing vascular involvement, there should be a low threshold for cardiac imaging.
Diagnostic dilemmas concerning immunohistochemistry (IHC) are not uncommon while differentiating LG-ESS from HG-ESS. LG-ESS is known to be ER, PR and CD10 positive and cyclin D1 negative. HG-ESS is generally ER, PR negative (positive staining has also been reported) with CD10 variable expression and cyclin D1 positive. If, however, they have the low-grade spindle cell component, they may display positive staining with ER, PR, and CD10 or demonstrate positive staining with cyclin D1.14 The IHC profile of our case was as follows: ER and PR positive, CD10—diffuse strong positivity, h-caldesmon negative, cyclin D1—focal weak positivity. Also, some atypical areas of very high mitotic activity (18–21 mitoses/10 high-power fields) were picked up, unlike what is expected in LG-ESS. The tumour thus showed some of the features that are characteristically associated with HG-ESS as reported by Nucci15 and some of LG-ESS. This made molecular diagnosis all the more important. Eventually, it was diagnosed as HG-ESS with YWHAE/NUTM2A+B gene fusion.
Thus, correct diagnosis may not always be straightforward and needs to be confirmed with molecular tests if doubt exists. The difference in diagnosis affects the treatment and eventual prognosis of the patient. In this case, it was the confirmation of the HG-ESS on molecular studies that prompted the use of neoadjuvant chemotherapy before considering radical surgery to remove the intravascular tumour. Although the role of neoadjuvant chemotherapy in ESS is still debated, the MDT opted for this mode of treatment to ensure the correctness and completion of the surgical mode of treatment going forward.
Because of the multimodal approach used in this case, it becomes evident that in addition to surgery, chemotherapy, radiotherapy and hormone therapy should be considered in these rare tumours. More research is needed in this direction. Hormonal therapy has been confirmed effective for recurrent, metastatic or unresectable LG-ESS and ER+/PR+ uterine leiomyosarcoma, with favourable tolerance and compliance.16 A successful response to aromatase inhibitors in our case suggests they can be an option for ER+/PR+ HG-ESS as well. Newer therapies like apatinib (antiangiogenic agents) and pazopanib in treating HG-ESS need further evaluation.17
It is evident from this case that due to the rarity and heterogeneity of the condition, it is difficult to define the right treatment approach and the role of adjuvant chemotherapy, radiotherapy or hormone therapy. In complex cases like ours, multidisciplinary care involving gynaecological-oncology, medical oncology and vascular surgery with good imaging will give the patient the best chance for optimum treatment.
Learning points
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Proper and thorough pretreatment vascular imaging is essential in cases where there is a suspicion of uterine sarcomas.
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Molecular techniques are of paramount importance when differentiating low-grade endometrial stromal sarcoma (ESS) from high-grade ESS as the treatment and prognosis are very different for both.
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A multimodal treatment approach with surgery, chemotherapy and hormonal therapy is needed for the complete management of these tumours.
Ethics statements
Patient consent for publication
Footnotes
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Contributors PD—planning, conduct, reporting, conception and design, acquisition of data or analysis and interpretation of data. KH—planning, conduct, reporting, conception and design, acquisition of data or analysis and interpretation of data.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.
References
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