Abstract
Background: Low-grade endometrial stromal sarcoma (LG-ESS) is an indolent tumor harboring gene fusion involving polycomb family genes. While early LG-ESS has a good clinical course, some tumors have pelvic recurrence. The etiology and genetic alterations involved in the process remain unknown. Case Report: A 44-year-old nulliparous woman underwent hysteroscopic surgery for a 2.5 cm submucosal uterine tumor with negative endometrial cytology. Pathological evaluation revealed LG-ESS. On the 31st day, total laparoscopic hysterectomy was indicated. She was diagnosed with stage IA (pT1aNXM0) LG-ESS without lymphovascular invasion. At 4 years, positron-emission tomography showed multiple pelvic masses. Secondary debulking surgery was performed, which revealed severe intra-abdominal recurrence of LG-ESS with JAZF1–SUZ12 fusion. Conclusion: Hysteroscopic surgery is a convenient tool for benign uterine submucosal diseases. However, intrauterine morcellation with fluid can lead to unexpected recurrence of occult LG-ESS. It is important when seeking consent for surgery to inform patients about the possible risk of dissemination of uterine mesenchymal tumors.
Hysteroscopic surgery is convenient for qualitative diagnosis of uterine submucosal tumors. Since such lesions can be accessed and excised transcervically, office-based hysteroscopy has become widespread. It has been used to treat conditions such as endometrial polyp, submucosal leiomyoma, and isthmocele (1). We typically use a monopolar resectoscope with a non-electrolyte reflux solution or a bipolar resectoscope with electrolyte-containing fluid after cervical dilation. Recently, hysteroscopic tissue removal systems that cut tissue with rotational motion and no energization have become widespread. According to the American College of Obstetricians and Gynecologists, clinicians should be aware of specific complications such as uterine perforation, water intoxication and intrauterine adhesions in hysteroscopic surgery (1). Although a rare event, unexpected cancer can be found postoperatively, which might worsen prognosis. Endometrial cancer has been reported to be associated with a risk of intraperitoneal dissemination due to hysteroscopy (2). However, the risk of dissemination of mesenchymal uterine tumors remains unknown.
Uterine mesenchymal tumors are neoplasms for which it is difficult to predict preoperative diagnosis based on cytology, endometrial tissue sampling and imaging. Malignant mesenchymal tumors may be diagnosed incidentally in histological specimens (3, 4). One type of these tumors is low-grade endometrial stromal sarcoma (LG-ESS), which is the second most common malignant uterine mesenchymal tumor after leiomyosarcoma (5). Although there are often diagnostic discrepancies in hematoxylin–eosin and immunohistochemistry-based histological examination, genetic testing with next-generation sequencing (NGS) is a powerful auxiliary tool that enhances diagnostic accuracy. Genetic abnormalities characteristic of LG-ESS include the fusion gene JAZF zinc finger 1 (JAZF1)–SUZ12 polycomb repressive complex 2 subunit (SUZ12) and genes such as JAZF1–PHD finger protein 1 (PHF1), enhancer of polycomb homolog 1 (EPC1)–PHF1, and EPC1–SUZ12 (6).
We treated a case of multiple abdominal recurrence of LG-ESS harboring JAZF1–SUZ12 after hysteroscopic surgery. This case highlights the possibility that disruption of LG-ESS with hysteroscopic surgery may facilitate iatrogenic dissemination.
Case Report
Ethical approval was obtained from the respective Institutional Review Boards (reference no. 1211 of Akita University and reference no. 858 of Osaka University).
A 44-year-old nulliparous Japanese woman consulted with complaints of dysmenorrhea. Transvaginal ultrasound revealed a 2.5 cm submucosal uterine tumor. She was treated with low-dose estrogen-progestin therapy for 9 months. No abnormalities were detected with cervical and endometrial cytology; however, irregular genital bleeding relapsed. Magnetic resonance imaging revealed a submucosal tumor reaching approximately 50% into the uterine muscle (Figure 1), which was clinically diagnosed as submucosal leiomyoma. Since she desired to preserve the uterus, we decided to perform hysteroscopic surgery.
Hysteroscopic resection was performed after administration of three cycles of a gonadotropin-releasing hormone analog. An Olympus 26 Fr monopolar resectoscope was used. The intrauterine perfusate was 3% D-sorbitol (Uromatic S®). The solution bag was placed at approximately 100 cm height from the uterus. Hysteroscopy revealed a broad-based, slightly irregular white mass on the anterior wall of the uterine body. The elevated mass was cauterized with a loop electrode for excision and collected after being cut into multiple pieces. We used 4,000 ml of reflux liquid with a fluid deficit of approximately 200 ml. Transvaginal ultrasound showed retention of 3 cm of reflux fluid in the Douglas fossa, which was not observed before the operation.
On examination, the tumor was similar to endometrial stromal cells with a round nucleus and grew solidly. Nuclear atypia was scarce and no mitosis was observed (Figure 2A). Immunohistochemically, the tumor cells were positive for CD10 (Figure 2B), estrogen receptor, and progesterone receptor. The patient was diagnosed as having LG-ESS. On the 31st day after hysteroscopic surgery, she underwent total laparoscopic hysterectomy (TLH). In order to prevent tumor spillage into the abdominal cavity, the origins of both fallopian tubes were first double-cauterized. TLH was performed to avoid uterine manipulation. Both adnexa were preserved. The uterus was collected transvaginally to avoid exposure to the abdominal cavity. Washing ascites cytology was negative. Histopathological examination revealed LG-ESS that had infiltrated approximately half of the myometrium (Figure 2C and D). Lymphovascular invasion was not evident. She was diagnosed with stage1A (pT1aNXM0). Adjuvant therapy was not indicated.
At 4 years after TLH, positron-emission tomography showed localized accumulation of fluorodeoxyglucose at pelvic sites, which was considered to be abdominal recurrence. Secondary debulking surgery (SDS) consisting of abdominal bilateral adnexectomy, omentectomy, and intraperitoneal dissemination resection was performed. Washing ascites cytology was negative. Intraoperative findings included disseminated nodules on the bladder surface, rectal serosa, left pelvic wall, and omentum. They were histologically diagnosed as recurrence of LG-ESS with morphological features similar to those of the initially resected tumor (Figure 2E). In order to assess the background genetic alterations of the tumor, RNA was extracted from formalin-fixed paraffin-embedded tissues of the recurrent lesion located in the pelvic wall and the TLH specimen. Written-informed consent was obtained from the patient. A novel NGS-based gene fusion panel, SMART Fusion-Seq (Takara Bio, Kusatsu, Japan), was used as reported previously (7). As a result, JAZF1-SUZ12 genetic fusion was detected in the recurrent tumor (Figure 2F) and the same fusion product was identified in the TLH specimen. The patient is currently undergoing medroxyprogesterone acetate therapy and has been followed up for 2 years after SDS.
Discussion
LG-ESS is an indolent tumor, most commonly harboring JAZF1–SUZ12. The overall survival for early LG-ESS is very good (8). Many cases of LG-ESS are diagnosed accidentally after conservative, minimally invasive surgery for fertility preservation (3, 4). In cases of intra-abdominal morcellation, recurrence occurs frequently, and the prognosis is worsened (9). These facts suggest that fragmented and residual mesenchymal tumors engraft in intra-abdominal tissue. Therefore, to avoid unexpected recurrence, in February 2020, the Food and Drug Administration released an updated Safety Communication which recommend power morcellation should be performed for certain appropriately selected women only with a legally marketed tissue containment system (10). There is some consensus about the use of power morcellation in the abdominal cavity, however, morcellation in hysteroscopic surgery is not well documented (11). Koskas et al. reported multiple postpartum intraperitoneal recurrences in patients requiring fertility preservation who were found to have LG-ESS after hysteroscopic surgery (12). Generally, possible routes for dissemination of malignant uterine tumors into the abdominal cavity, excluding the retroperitoneum, are direct infiltration from the uterine serosa or trans-tubal spillage. The latter includes menstrual regurgitation or mechanical manipulation with inflatable media. In our patient, TLH was performed with the utmost care after hysteroscopic surgery but multiple recurrences occurred in the abdominal cavity. Genetically, the fusion gene JAZF1–SUZ12 was found in a recurrent tumor in the pelvis. The same product was confirmed in the previous TLH sample. Given these facts, the tumor most likely spread through the fallopian tubes and recurred in the abdominal cavity. Due to difficulties in cytodiagnosis of LG-ESS, which has bland morphological features (13), cytology of intraoperative ascites was carried out but was negative during TLH and even at SDS when intraperitoneal dissemination had occurred. Although there are some reports of LG-ESS occurring intraperitoneally due to ectopic endometriosis (14), in our case, there were no lesions suggestive of endometriosis in the uterine specimen and intraperitoneal cavity. Therefore, morcellation during hysteroscopic surgery may have carried the tumor transtubally along with the perfusate and promoted abdominal recurrence. This suggests that during hysteroscopic surgery with perfusion fluid, the act of crushing tissue in the uterine cavity while fragmenting it into small pieces may cause a process similar to tissue morcellation in the abdominal cavity during minimally invasive surgery.
In conclusion, hysteroscopic surgery is a convenient tool for therapy of benign uterine submucosal diseases. However, intrauterine crushing with reflux fluid can lead to unexpected iatrogenic recurrence of LG-ESS. It is important for clinicians to inform patents about the possible risk of dissemination of occult uterine mesenchymal tumors, and to share decision-making for appropriate hysteroscopic surgery.
Acknowledgements
The Authors are grateful to Dr. Masafumi Horie, Dr. Yohei Yamamoto and Tomoyuki Asari for their help in interpreting the significance of the data. This work was supported by a JSPS KAKENHI grant [grant number: 19K07433 (DM)].
Footnotes
Authors’ Contributions
DT, DM and HS performed the research. KE provided clinicopathological information. DT and DM wrote the article. All Authors approved the final article.
Conflicts of Interest
Research by DM was partly supported by Takara Bio.
- Received June 9, 2021.
- Revision received June 28, 2021.
- Accepted July 5, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.