DOI: https://doi.org/10.21203/rs.3.rs-35753/v1
Background：Tumor morcellation happened to facilitate iatrogenic metastasis for patients with occult uterine sarcoma. The optimal remedial procedure for these patients needed to be established.
Methods：Data were retrospectively collected and analyzed from patients with occult uterine sarcoma undergoing morcellation.
Results：23 consecutive patients with uterine sarcomas undergoing morcellation were accessed between Jan 2008 and Dec 2018, including 15 patients with uterine leiomyosarcoma and 8 with endometrial stromal sarcoma. Cytoreduction as a remedial procedure was significantly associated with better disease-free survival (P=0.031), and none of 7 patients undergoing cytoreduction suffered recurrence, while total hysterectomy (P=0.194) and adjuvant therapy (P=0.159) had no such benefit. There was no significant difference in disease-free survival between laparoscopic and open surgery (p=0.321).
Conclusion：Cytoreduction was considered as the optimal remedial procedure for patients with occult uterine sarcoma undergoing morcellation.
Uterine sarcoma is a rare solid malignant tumor in uterine accounting for less than 3% of all female reproductive system malignancies [1]. The incidence of sarcomatous transformation in benign leiomyoma is 0.13% ~ 0.81% [2]. The major histological types involve uterine leiomyosarcoma (LMS) (accounting for 30 ~ 40% of uterine sarcomas), and endometrial stromal sarcoma (ESS) (10–15%) [3]. Complete tumor resection is the only effective modality, while other modalities, such as radiation therapy, chemotherapy, hormone therapy, targeted therapy, or any of their combinations, are not effective [4].
It is difficult to distinguish occult uterine sarcoma from other benign uterine tumors because of neither specific symptoms nor reliable preoperative diagnostic modality [5]. Therefore, many patients with occult uterine sarcoma underwent laparoscopic surgery with morcellation by accident. A power morcellator is a surgical instrument used for division and removal of large masses of tissues during laparoscopic surgery. In cases of myomectomy or supracervical hysterectomy, the tissue has to be morcellated before extraction. Some studies showed the tumor morcellation utilized in patients with uterine sarcoma increased the rate of pelvic recurrence, facilitated abdominal dissemination and induced poor prognosis [6–11]. In 2014 FDA stated that tumor morcellation used for laparoscopic myomectomy or hysterectomy is associated with increased risk for spreading cancer and so that restrict the usage of tumor morcellation [12]. Some study found the prevalence of occult leiomyosarcoma at surgery for presumed uterine fibroids were 1/8300 [13] or 1/10000-13/10000 [14], lower than the prevalence evaluated by FDA (1/498).
However, which type of remedial procedure should be taken to benefit these patients remained unclear. A previous study indicated patients who underwent cytoreduction and are not upstaged appeared to have a good prognosis [15]. Two questions were tried to answer in this research:
Which kind of surgery can be taken as an effective remedial surgery? According to the 2020 NCCN clinical practice guideline on uterine neoplasms, simple hysterectomy ± oophorectomy was enough for uterine sarcoma. Was it also enough for the patients undergoing morcellation?
Can adjuvant therapy be helpful?
Our study tried to find an optimal option for remedial therapy for these patients.
The data of consecutive patients with LMS and ESS who were treated and followed at Zhejiang Cancer Hospital (Hangzhou, Zhejiang, China) were collected from 2008 to 2018. The data included patient age, menopausal status, and body mass index; clinicopathologic data including International Federation of Obstetrics and Gynecology (FIGO) stage, mitotic count, tumor grade, the interval between the initial surgery and re-operation, residuals after the initial surgery, and adjuvant therapy; and follow-up data including tumor recurrence, location of recurrent tumor, and death. Pathologic slides were all reviewed by two pathologists. We analyzed the data of all patient undergoing morcellation to determine which type of remedial procedure could improve the prognosis. Outcomes included rate of cumulative recurrence, 1-year disease-free survival rate and odd ratio of risk of recurrence.
Means and median values were compared using Student's t-test and frequency distributions were compared using chi-squared and Fisher's exact tests. DFS was calculated as the number of months from the date of surgery to either date of recurrence or date censored. OS was calculated as the number of months from the date of surgery to either date of death or date censored. Survival curves and rates were calculated using the Cox regression analysis. Univariate and multivariate analyses were performed using Cox's proportional hazards model, with multivariate analysis including at least 2 factors significant in univariate analysis. Two-sided P-values less than 0.05 were considered statistically significant. All statistical analyses were performed using SPSS software for Windows (version 17.0; SPSS Inc., Chicago, IL).
23 patients with uterine sarcoma were treated and followed at Zhejiang Cancer Hospital, including 15 patients with LMS and 8 with ESS. The median follow-up times were 23 months (range, 5-106 months) for all patients. The characteristics of patients were present in Table 1.
| Characteristics of patients | Value | |
|---|---|---|
| Age | Mean ± SD | 44.9 ± 7.2 |
| Menopause, n (%) | No | 19(82.6) |
| Yes | 4(17.4) | |
| Body mass index | Mean ± SD | 22.6 ± 2.3 |
| Initial symptoms, n (%) | Asymptomatic | 14(60.9) |
| Palpable mass | 4(17.4) | |
| Vaginal bleeding | 4(17.4) | |
| Abdominal pain | 2(8.7) | |
| Preoperative presumptive diagnosis, n (%) | Uterine sarcoma | 0(0) |
| Uterine leiomyoma | 23(100) | |
| Initial operation was performed at, n(%) | Zhejiang Cancer Hospital | 0(0) |
| Other hospital | 23(100) | |
| Initial operation, n(%) | Myomectomy | 18(78.3) |
| Supracervical hysterectomy | 4(17.4) | |
| Hysterectomy | 1(4.3) | |
| Pathological type, n (%) | Uterine leiomyosarcoma | 15(65.2) |
| Endometrial stromal sarcoma | 8(34.8) | |
| FIGO stage, n (%) | I | 17(73.9) |
| II | 2(8.7) | |
| III | 4(17.4) | |
| Mitotic count, n (%) | < 5/10HPF | 18(78.3) |
| ≥ 5/10HPF | 5(21.7) | |
| Grade of tumor, n (%) | Low | 18(78.3) |
| High | 5(21.7) | |
| SD, standard deviation; PLND, pelvic lymph node dissection; PALND, para-aortic lymph node dissection. | ||
According to Table 2, there were no significant differences between groups in age, menopausal status, and FIGO stage.
Cytoreduction involved total hysterectomy ± oophorectomy, omentectomy and additional surgical resection for intraoperative discovery of extrauterine disease. Adjuvant therapy involved in our study contained chemotherapy, radiotherapy and hormone therapy.
We found that cytoreduction could improve the disease-free survival compared with the no re-operation group (OR, 0.17; 95% CI, 0.03–0.85; P = 0.031) (Table 2). None of 7 patients undergoing cytoreduction suffered recurrence. However, simple hysterectomy ± oophorectomy (P = 0.194), residuals after the initial surgery (p = 0.115) and adjuvant therapy (P = 0.159) seemed not to impact the DFS. 6 of 12 patients undergoing simple hysterectomy ± oophorectomy suffered recurrence. Whether to take Laparoscopic surgery or abdominal surgery also seem no significant difference between each other (p = 0.321).
| Total, n | Recur, n(%) | 1-year DFS(%) | Odd ratio(95%CI) | P-value | ||
|---|---|---|---|---|---|---|
| Age | ≤ 47 years | 10 | 5(50.0) | 48.5 | 1 | |
| ༞47 years | 13 | 5(38.5) | 80 | 0.74(0.20–2.80) | 0.662 | |
| Menopause | No | 19 | 7(36.8) | 82.5 | 1 | |
| Yes | 4 | 3(75.0) | 50 | 0.97(0.19–4.87) | 0.968 | |
| FIGO stage | I | 17 | 5(29.4) | 86.2 | 1 | |
| II and III | 6 | 5(83.3) | 50 | 3.58(0.93–13.77) | 0.063 | |
| Histological types | LMS | 15 | 8(53.3) | 71.8 | 1 | |
| ESS | 8 | 2(25.0) | 57.1 | 0.60(0.12–3.07) | 0.539 | |
| Interval between first operation and re-operation | ༜30 days | 14 | 5(35.7) | 91.7 | 1 | |
| ≥ 30 days | 5 | 1(20.0) | 75 | 1.07(0.12–9.75) | 0.95 | |
| no re-operation | 4 | 4(100.0) | 25 | 4.81(1.12–20.64) | 0.035※ | |
| Types of re-operation | no re-operation | 4 | 4(100.0) | 25 | 1 | |
| Simply hysterectomy ± oophorectomy | 12 | 6(50.0) | 75 | 0.31(0.05–1.83) | 0.194 | |
| Cytoreduction | 7 | 0(0) | 91.7 | 0.17(0.03–0.85) | 0.031※ | |
| Adjuvant therapy | No | 13 | 9(69.2) | 61.5 | 1 | |
| Yes | 10 | 1(10.0) | 100 | 0.22(0.03–1.81) | 0.159 | |
| DFS, disease-free survival; CI, confidence interval; FIGO, International Federation of Obstetrics and Gynecology; ※, p < 0.05 | ||||||
Our study summarized the data of every recurrence of patients in Table 3. About 47.8% patients experienced the recurrence 14 months (4–56 months) after the initial surgery. The disease-free intervals between recurrence became shorter and shorter. The recurrence was the most likely to occur in the pelvis. Peritoneal and gastrointestinal implantation was the most common form of cancer metastasis, while pelvic and para-aortic lymph metastasis was rare.
There were 4 patients in our study never undergoing any remedial procedures after taking morcellation by accident. The reasons include misdiagnosis of pathology and personal rejection. All these patients suffered at least 2 times of recurrence. 1 of 4 patients died of uncontrolled abdominal tumor bleeding after 4 times of recurrence.
| Recurrence | First recurrence | Second recurrence | Third recurrence | Forth recurrence | |
|---|---|---|---|---|---|
| n (%) | 11(47.8) | 8(34.8) | 4(17.4) | 1(4.3) | |
| Death, n | 1 | 0 | 2 | 1 | |
| Disease-free interval before recurrence(month) | Median(range) | 14(4–56) | 3.5(2–31) | 7.5(7–21) | 12 |
| Pathological type | Uterine leiomyosarcoma(n = 15) | 9 | 7 | 3 | 1 |
| Endometrial stromal sarcoma(n = 8) | 2 | 1 | 1 | 0 | |
| Anatomical location of recurrence | Pelvis (without rectum and lymph nodes) | 6 | 7 | 3 | 1 |
| Pelvic lymph nodes | 1 | 0 | 1 | 0 | |
| Rectum | 2 | 4 | 0 | 0 | |
| Colon(without rectum) | 3 | 3 | 0 | 0 | |
| Small intestine | 4 | 2 | 0 | 0 | |
| Peritoneum (not in the pelvis) | 2 | 2 | 0 | 0 | |
| Omentum | 0 | 1 | 0 | 0 | |
| Pancreas | 0 | 1 | 0 | 0 | |
| Liver | 0 | 0 | 1 | 0 | |
| Abdominal wound | 0 | 1 | 0 | 0 | |
| Lung | 1 | 1 | 1 | 0 |
To our knowledge, the FDA stated that tumor morcellation promoted an adverse effect on the prognosis of patients with LMS [12]. Jeong-Yeol Park et al confirmed that tumor morcellation facilitated recurrence in peritoneal cavity and adversely affected DFS(OR, 2.59; 95% CI, 1.03–6.50; P = 0.043)and OS༈OR, 3.07; 95% CI, 1.05–8.93; P = 0.040༉ in patients with uterine LMS [6]. They also found tumor morcellation was associated with a significantly higher rate of abdominopelvic recurrence and significantly poorer DFS (OR, 4.03; 95% CI, 1.06–15.30; P = 0.040) in patients with ESS, but OS was not significantly compromised [8]. Another research with 123 patients found the rate of pelvic recurrence 3 months after surgery was higher in the morcellation group than in the non-morcellation group, but the difference was not statistically significant (8.8% vs. 3.6%, P = 0.25) [7].
Our study found 47.8% of patients suffered sarcoma recurring. Patients with no remedial procedures seemed to experience recurrence probably and have worse prognosis. It was much frequently that the recurrence occurred in the pelvis where former primary lesion was located. The peritoneal and gastrointestinal implantation in upper abdomen were also common.
In our study, cytoreduction as remedial re-operation was very important for those patients to improve DFS (OR, 0.17; 95% CI, 0.03–0.85; P = 0.031), no matter how long between the initial surgery and re-operation (༜30 days vs. ≥30 days, P = 0.950). Cytoreduction after the initial incomplete surgery may be the optimal option, which could eliminate all iatrogenic implantation metastasis caused by morcellation, especially the metastasis on omentum, according to our study. Cytoreduction we mentioned should contain total hysterectomy and oophorectomy, and additional surgical resection for intraoperative discovery of extrauterine disease should be individualized.
None of 7 patients undergoing cytoreduction suffered recurrence while 6 of 12 patients undergoing simple hysterectomy ± oophorectomy suffered recurrence. Simple hysterectomy ± oophorectomy (P = 0.194) and adjuvant therapy (P = 0.159) seemed not to impact the DFS. A previous retrospective study showed that 2 of 13 patients with uterine malignancy underwent paracervical hysterectomy during the initial surgery was upstaged by re-exploration; both had LMS originally resected with morcellation. Patients who underwent completion surgery with restaging appeared to have a good prognosis [15]. Moreover, re-operation long after the initial surgery (≥ 30 days) with morcellation can still be valuable. Cao H et al also confirmed that the time interval between initial treatment and secondary definitive surgery was not shown to impact prognosis[16].
The limitation of our study included the retrospective design and the relatively small number of patients.
Cytoreduction as a remedial procedure decrease the DFS of all patients with occult uterine sarcoma undergoing morcellation by accident.
confidence interval
disease-free survival
Uterine endometrial stromal sarcoma.
International Federation of Obstetrics and Gynecology
high power filed
Uterine leiomyosarcoma
not applicable
overall survival
The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This research was approved by the ethics committee of Zhejiang Cancer Hospital. The reference number was IRB-2019-199.
Consent for publication
Not applicable.
Competing interests
All authors report no conflict for interest for this research paper.
None.
Guarantor of integrity of the entire study: Jianqing Zhu. Study concepts: Jianqing Zhu, Chao Ding. Study design: Jianqing Zhu, Chao Ding. Collection of data: Chao Ding. Data analysis: Chao Ding. Statistical analysis: Chao Ding. Manuscript preparation: Chao Ding. Manuscript editing: Chao Ding. Manuscript review: Jianqing Zhu. The authors read and approved the final manuscript.
None.
Authors’ information
Affiliations
Department of Gynecological Oncology, Hospital of the University of Chinese Academy of Sciences（Zhejiang Cancer Hospital）,Institute of Cancer and Basic Medicine（IBMC）, Chinese Academy of Sciences, Hangzhou 310022, China.
Chao Ding, Jianqing Zhu