ABSTRACT
Study Objective
Operative hysteroscopy requires elevated intrauterine pressures, which could lead to spread of malignant cells into the peritoneal cavity. Currently, there is paucity of data analyzing clinical outcomes in endometrial cancer following hysteroscopic morcellation with newer equipment. In this study, we sought to determine whether there are increased rates of positive peritoneal cytology, lymphovascular space invasion, or surgical upstaging in patients undergoing hysteroscopic morcellation compared to alternative endometrial biopsy methods.
Design/Setting
Retrospective chart review of patients (2013-2018) was performed at the Karmanos Cancer Institute in Detroit, Michigan. Exclusion criteria included: biopsy at outside institution, stage IV endometrial cancer known prior to biopsy and missing data regarding biopsy method and histology. Peritoneal cytology results, lymphovascular space invasion and surgical staging were compared by method of biopsy and histology using Chi-squared and Krustal-Wallis tests.
Patients
289 patients met the inclusion criteria. 184 patients were classified as low grade (FIGO Grade 1 and 2) and 105 as high grade (FIGO Grade 3, serous, clear cell and carcinosarcoma) endometrial cancer respectively.
Interventions
53 patients (18%) underwent hysteroscopy with morcellation. Alternative biopsy methods included: hysteroscopy without morcellation n=81 (28%), endometrial biopsy n=112 (38.7%), dilation and curettage n=43 (15%).
Measurements/Main Results
Positive peritoneal cytology was noted in 34 cases (12%) and negative cytology in 165 (57%). Cytology was not performed in 90 cases (31%). When comparing outcomes by histologic subtypes, no difference was seen in peritoneal cytology (p=0.704 and 0.727 for Low grade and High grade), stage (p=0.773 and 0.053 for Low Grade and High Grade) or lymphovascular space invasion (p=0.400 and 0.142 Low grade and High grade).
Conclusion
Our study demonstrates that hysteroscopy with morcellation is a safe diagnostic method for Low- and High-Grade endometrial pathologies and does not lead to increased dissemination of malignant cells, lymphovascular space invasion nor upstaging of patients.
INTRODUCTION
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Thus, further scientific efforts are needed in order to better characterize and treat this disease. In more than 70% of cases, diagnosis of endometrial cancer takes place at Stage I, associated with good prognosis and survival rates.
The most common presenting symptom in endometrial malignancy is abnormal uterine bleeding. Diagnostic work up involves imaging by transvaginal ultrasound followed by endometrial sampling. Historically, sampling of the endometrium involved an in-office biopsy or dilation and curettage. More recently, however, hysteroscopic systems have allowed for the concomitant visualization and sampling of the endometrial cavity.
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The elevated intrauterine pressures achieved with modern hysteroscopes, however, raise concern for the dissemination of cells into the peritoneal cavity via a retrograde route.
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Currently, there are no studies analyzing clinical outcomes in endometrial cancer following hysteroscopic morcellation with newer technologies. Given that morcellation-mediated fragmentation of tissue takes place under high intrauterine pressures, this could result in the dissemination of malignant cells into the peritoneal cavity. In this study, therefore, we sought to determine whether hysteroscopic morcellation leads to increased rates of positive peritoneal cytology, lymphovascular space invasion and surgical upstaging in patients with endometrial cancer when compared to alternative biopsy methods.
METHODS
There are currently two outside diameters available for the TruClear hysteroscopic devices (6 and 7.25mm). Both diameters are utilized in our institution for morcellation. Whether polyps or fibroids are present determine if a mini (6mm diameter) or dense tissue shaver (7.25mm diameter), respectively, is used during a procedure. Provider preference is also taken into account. As both are used often, we were unable to retrospectively determine the exact percentage of cases in which each diameter was utilized in this study. In regards to hysteroscopy without morcellation, cavity assessment is often performed followed by visualization of the cavity with a hysteroscope and subsequent tissue sampling with a curette. In the dilation and curettage and endometrial biopsy groups endometrial samples were obtained without prior visualization or assessment of the cavity. Endometrial biopsies were often performed with a pipelle in an outpatient setting.
Biopsy specimens from all procedures were sent for histologic examination and evaluated by a pathologist. Following confirmation of the diagnosis of endometrial cancer or precancerous pathology (hyperplasia with or without atypia with concern for malignancy), patients were referred to and subsequently underwent surgical staging with a gynecologic oncologist. At the time of surgical staging, peritoneal washings were collected and sent for cytopathologic examination along with routine staging per guidelines.
The patients’ charts were retrospectively reviewed and classified based on their initial method of biopsy. Pathology and cytology reports were examined to identify the presence or absence of positive peritoneal cytology. In addition, histologic type, surgical staging, and presence of lymphovascular space invasion (LVSI) were evaluated. Comparisons between biopsy histology and post-surgical histology also took place. Histology was classified as low grade (LG-FIGO Grade 1 and 2) and high grade (HG-FIGO Grade 3 and serous, clear cell and carcinosarcoma). Surgical stage was determined based on the 2009 FIGO staging criteria. Pathology reports were also reviewed for the presence or absence of LVSI. Exclusion criteria included: biopsy at outside institution, stage IV endometrial cancer known prior to biopsy, and missing data regarding biopsy method and histology. Demographics and other patient characteristics at time of diagnosis, including race, age (years), weight (kg), BMI (kg/m2) and menopausal status, were also analyzed. Peritoneal cytology results, lymphovascular space invasion (LVSI) and surgical staging were compared by method of biopsy and histology using Chi-squared tests. Time elapsed from the initial biopsy to the subsequent staging surgery was also obtained and compared by method of biopsy and histology using Kruskal-Wallis (KW) tests. Stratified analyses were further performed to adjust the effect of pathology histology using Cochran-Mantel-Haenszel (CMH) test and stratified KW tests. A p-value of less than 0.05 was considered statistically significant. Of note, in accordance with the journal’s guidelines, we will provide our data for the reproducibility of this study in other centers if such is requested.
RESULTS
Table 1Demographics by type of biopsy
Table 2Association between pathology and surgical histology
Figure 1Outcomes by histologic subtype regarding differences in LVSI, positive cytology, and stage for LG and HG groups.
Table 3Association between pathology and surgical histology
Table 4Patients characteristics by method of biopsy for those with high grade histology
Table 5Patients characteristics by method of biopsy for those with high grade histology
DISCUSSION
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This raises concern for higher intrauterine pressures and the theoretical increased extravasation of malignant cells into the peritoneal cavity and adjacent tissue. In addition, high pressures and the hypothetical dissemination of malignant cells could also lead to high rates of positive peritoneal cytology and lymphovascular space invasion, an isolated poor prognostic factor for both recurrence/relapse and survival in endometrial cancer patients.
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, endometrial tissue can disseminate in a retrograde manner through patent fallopian tubes. Subsequently, deposits can implant themselves in the peritoneal cavity. This phenomenon has been observed in patients with endometriosis, in which chocolate cysts or gun powder lesions have been noted in the lymphovascular and peritoneal environment during laparoscopic or open procedures. For example, in a study by Halmes et al
, blood was noted in the peritoneal fluid of 90% of patients with patent fallopian tubes. Contrarily, in patients proven to have occluded fallopian tubes, blood was noted in the peritoneal cavity in only 15% of cases. While retrograde menstruation can be a common physiologic event and contribute to endometriosis, the overall risk of an endometriosis-associated cancer remains low. In regards to hysteroscopic procedures, it has been previously hypothesized that increased intra-uterine pressures promoted by distending media could contribute to circulation of malignant cells in the peritoneal cavity in a retrograde manner through the fallopian tubes. One could theorize, therefore, the hysteroscopic morcellation can further contribute to retrograde dissemination of malignant cell into the peritoneal cavity, by provoking shedding and resection of cells in a high-pressure system.
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In studies demonstrating an increased incidence in positive peritoneal cytology with the use of hysteroscopy alone compared to conventional methods of endometrial biopsy, results suggested that preoperative hysteroscopy did not lead to worse outcomes or prognosis.
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For example, in a study by Ben-Arie et al., after a twenty-five month follow-up of patients who were initially diagnosed with endometrial cancer by hysteroscopy, the overall survival and recurrence rates proved to be similar to that of patients undergoing other diagnostic methods.
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Lymphovascular space invasion, on the other hand, has been implicated as an independent predictor of poor outcomes with an associated decrease in overall survival, increased rates of recurrence or relapse and nodal metastasis.
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No studies to date, however, have investigated if the use of modern hysteroscopy with morcellation has been associated with increased rates of positive peritoneal cytology and lymphovascular space invasion in endometrial cancer patients.
Considering the above, our study aimed at evaluating the impact of modern hysteroscopy with morcellation on positive peritoneal cytology, lymphovascular space invasion and clinical upstaging. Theoretically, hysteroscopy with morcellation would lead to the dissemination of malignant cells by promoting tissue breakdown in a high-pressure uterine setting when compared to alternative biopsy methods. However, when compared to hysteroscopy without morcellation, endometrial biopsy, and dilation and curettage, hysteroscopic morcellation was shown in this study to be a safe method of biopsy. Our results showed no statistically significant differences in terms of increased positive peritoneal cytology amongst these diagnostic modalities. These findings were representative and consistent across both low-grade (FIGO Grade 1 and 2) and high-grade (Grade 3, serous, clear cell and carcinosarcoma) histology. Additionally, our data demonstrates that hysteroscopic morcellation does not result in an increased incidence of lymphovascular space invasion or surgical upstaging of disease in comparison to additional methods of biopsy. Therefore, when utilizing modern hysteroscopy with morcellation, gynecologists should be reassured that increased intrauterine pressures is not associated with retrograde dissemination of occult malignant endometrial cells into the peritoneal cavity in comparison to alternative methods of biopsy. Our results further confirm that newer technologies of hysteroscopy with morcellation can confidently be used in the evaluation of patients suspected of having endometrial cancer.
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Interestingly, studies have demonstrated that hysteroscopy has a high correlation (greater than 97%) with the final hysterectomy histopathological grade than that of D&C alone. Therefore, hysteroscopic morcellation can guide gynecologists and gynecologic oncologists in establishing a more accurate staging plan in endometrial cancer patients. Finally, hysteroscopic morcellation can decrease operative time if used optimally, given that cutting speeds are relatively fixed by design characteristics and procedure time is dependent on tissue contact.
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To our knowledge, this is the first study to date to investigate the incidence of positive peritoneal cytology, lymphovascular space invasion and upstaging of disease in patients with endometrial cancer after undergoing modern hysteroscopic morcellation. We recognize that this was a single-center study in a large urban hospital that provides care to a low-resource patient population and that inter-operator variability and experience can affect biopsy results. For example, method of biopsy in our institution is mainly guided by provider preference and comfort level with biopsy methods. While some attendings feel comfortable with performing hysteroscopy with morcellation in patients with polyps or a thickened endometrial stripe, others prefer using hysteroscopy followed by a dilation and curettage or an additional method of biopsy. Another limitation of our study was the fact that positive peritoneal cytology was not performed in some cases. Peritoneal cytology is no longer part of the diagnostic criteria for endometrial cancer, however it is recommended that peritoneal fluid should be obtained and evaluated during staging surgery, as it can provide prognostic information on patients and perhaps guide future management. As this is a retrospective study, we were unable to identify the specific reasons for the lack of this information in some cases. We suspect that surgeon preference and judgement determined lack of peritoneal cytology in these circumstances. Given that our institution includes a wide variety of clinicians and residents performing the above endometrial sampling techniques, sampling adequacy can potentially be affected or subjected to provider preference. Therefore, future directions for this study would include analyzing data across multiple centers, including academic and community hospitals, creating a larger sample size and a better representation of the general patient population affected by endometrial cancer. Additionally, developing a prospective study to control for inter-operator variability regarding different methods of endometrial biopsy as well as risk-factor exposure status would allow for long term follow up of further prognostic outcomes including disease-free survival and overall survival in endometrial cancer patients.
STATEMENT OF CONTRIBUTION
Rebeca Kelly: Conceptualization, methodology, investigation, data curation, writing – original draft, writing – review and editing, visualization; Christopher Walker: Conceptualization, methodology, data curation, investigation, writing – original draft, writing – review and editing; George Contos: Conceptualization, methodology, data curation, investigation, writing – original draft, writing – review and editing; Martins Ayoola-Adeola: data curation, investigation, writing – review and editing; Kim Seongho: Formal analysis, Visualization, writing – review and editing; Ira Winer: Conceptualization, methodology, investigation, supervision, resources, writing – review and editing.
Article Info
Publication History
Accepted:
February 4,
2021
Received in revised form:
February 2,
2021
Received:
October 22,
2020
Publication stage
In Press Journal Pre-Proof
Footnotes
DISCLOSURE STATEMENT: The authors report no conflict of interest. Financial Disclosure: None of the authors of this paper have a financial or personal relationship with other people or organizations that could inappropriately influence or bias the content of the paper.
Results from this study were accepted and released in a poster format at the Society for Gynecology Oncology (SGO) meeting in Toronto, March 2020. This study is suitable for publication at JMIG. This study is a retrospective chart review approved for Exemption by the Institutional Review Board at Wayne State University on July 11, 2018 (IRB #032618M1X). No funding to be declared.
Identification
Copyright
© 2021 Published by Elsevier Inc. on behalf of AAGL.
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