Effect of Total Laparoscopic Hysterectomy vs Total Abdominal Hysterectomy on Disease-Free Survival Among Women With Stage I Endometrial Cancer: A Randomized Clinical Trial.

Importance: Standard treatment for endometrial cancer involves removal of the uterus, tubes, ovaries, and lymph nodes. Few randomized trials have compared disease-free survival outcomes for surgical approaches. Objective: To investigate whether total laparoscopic hysterectomy (TLH) is equivalent to total abdominal hysterectomy (TAH) in women with treatment-naive endometrial cancer. Design, Setting, and Participants: The Laparoscopic Approach to Cancer of the Endometrium (LACE) trial was a multinational, randomized equivalence trial conducted between October 7, 2005, and June 30, 2010, in which 27 surgeons from 20 tertiary gynecological cancer centers in Australia, New Zealand, and Hong Kong randomized 760 women with stage I endometrioid endometrial cancer to either TLH or TAH. Follow-up ended on March 3, 2016. Interventions: Patients were randomly assigned to undergo TAH (n = 353) or TLH (n = 407). Main Outcomes and Measures: The primary outcome was disease-free survival, which was measured as the interval between surgery and the date of first recurrence, including disease progression or the development of a new primary cancer or death assessed at 4.5 years after randomization. The prespecified equivalence margin was 7% or less. Secondary outcomes included recurrence of endometrial cancer and overall survival. Results: Patients were followed up for a median of 4.5 years. Of 760 patients who were randomized (mean age, 63 years), 679 (89%) completed the trial. At 4.5 years of follow-up, disease-free survival was 81.3% in the TAH group and 81.6% in the TLH group. The disease-free survival rate difference was 0.3% (favoring TLH; 95% CI, -5.5% to 6.1%; P = .007), meeting criteria for equivalence. There was no statistically significant between-group difference in recurrence of endometrial cancer (28/353 in TAH group [7.9%] vs 33/407 in TLH group [8.1%]; risk difference, 0.2% [95% CI, -3.7% to 4.0%]; P = .93) or in overall survival (24/353 in TAH group [6.8%] vs 30/407 in TLH group [7.4%]; risk difference, 0.6% [95% CI, -3.0% to 4.2%]; P = .76). Conclusions and Relevance: Among women with stage I endometrial cancer, the use of total abdominal hysterectomy compared with total laparoscopic hysterectomy resulted in equivalent disease-free survival at 4.5 years and no difference in overall survival. These findings support the use of laparoscopic hysterectomy for women with stage I endometrial cancer. Trial Registration: clinicaltrials.gov Identifier: NCT00096408; Australian New Zealand Clinical Trials Registry: CTRN12606000261516.

Improved surgical safety after laparoscopic compared to open surgery for apparent early stage endometrial cancer: results from a randomised controlled trial.

AIM: To compare Total Laparoscopic Hysterectomy (TLH) and Total Abdominal Hysterectomy (TAH) with regard to surgical safety. METHODS: Between October 2005 and June 2010, 760 patients with apparent early stage endometrial cancer were enroled in a multicentre, randomised clinical trial (LACE) comparing outcomes following TLH or TAH. The main study end points for this analysis were surgical adverse events (AE), hospital length of stay, conversion from laparoscopy to laparotomy, including 753 patients who completed at least 6 weeks of follow-up. Postoperative AEs were graded according to Common Toxicity Criteria (V3), and those immediately life-threatening, requiring inpatient hospitalisation or prolonged hospitalisation, or resulting in persistent or significant disability/incapacity were regarded as serious AEs. RESULTS: The incidence of intra-operative AEs was comparable in either group. The incidence of post-operative AE CTC grade 3+ (18.6% in TAH, 12.9% in TLH, p 0.03) and serious AE (14.3% in TAH, 8.2% in TLH, p 0.007) was significantly higher in the TAH group compared to the TLH group. Mean operating time was 132 and 107 min, and median length of hospital stay was 2 and 5 days in the TLH and TAH group, respectively (p<0.0001). The decline of haemoglobin from baseline to day 1 postoperatively was 2g/L less in the TLH group (p 0.006). CONCLUSIONS: Compared to TAH, TLH is associated with a significantly decreased risk of major surgical AEs. A laparoscopic surgical approach to early stage endometrial cancer is safe.

Risk factors to predict the incidence of surgical adverse events following open or laparoscopic surgery for apparent early stage endometrial cancer: results from a randomised controlled trial.

AIMS: To identify risk factors for major adverse events (AEs) and to develop a nomogram to predict the probability of such AEs in patients who have surgery for apparent early stage endometrial cancer. METHODS: We used data from 753 patients who were randomised to either total laparoscopic hysterectomy or total abdominal hysterectomy in the LACE trial. Serious adverse events that prolonged hospital stay or postoperative adverse events (using common terminology criteria 3+, CTCAE V3) were considered major AEs. We analysed pre-surgical characteristics that were associated with the risk of developing major AEs by multivariate logistic regression. We identified a parsimonious model by backward stepwise logistic regression. The six most significant or clinically important variables were included in the nomogram to predict the risk of major AEs within 6weeks of surgery and the nomogram was internally validated. RESULTS: Overall, 132 (17.5%) patients had at least one major AE. An open surgical approach (laparotomy), higher Charlson's medical co-morbidities score, moderately differentiated tumours on curettings, higher baseline Eastern Cooperative Oncology Group (ECOG) score, higher body mass index and low haemoglobin levels were associated with AE and were used in the nomogram. The bootstrap corrected concordance index of the nomogram was 0.63 and it showed good calibration. CONCLUSIONS: Six pre-surgical factors independently predicted the risk of major AEs. This research might form the basis to develop risk reduction strategies to minimise the risk of AEs among patients undergoing surgery for apparent early stage endometrial cancer.

The utility of serum CA-125 in predicting extra-uterine disease in apparent early-stage endometrial cancer.

Surgical staging in early-stage uterine cancer is controversial. Preoperative serum CA-125 may be of clinical value in predicting the presence of extra-uterine disease in patients with apparent early-stage endometrial cancer. Between October 6, 2005, and June 17, 2010, 760 patients were enrolled in an international, multicentre, prospective randomized trial (LACE) comparing laparotomy with laparoscopy in the management of endometrial cancer apparently confined to the uterus. Of these, 657 patients with endometrial adenocarcinoma had a preoperative serum CA-125 value recorded. Multiple cross-validation analysis was undertaken to correlate preoperative serum CA-125 with stage of disease (Stage I vs. Stage II+) after surgery. Patients' median preoperative serum CA-125 was 14 U/ml. A cutoff point of 30 U/ml was associated with the smallest misclassification error, and using this cutoff, 98 patients (14.9%) had elevated CA-125 levels. Of those, 36 (36.7%) had evidence of extra-uterine disease. Of the 116 patients (17.7%) with evidence of extra-uterine disease, 31.0% had an elevated CA-125 level. On univariate and multivariable logistic regression analysis, only preoperative CA-125 level, but no other preoperative clinical characteristics were found to be associated with extra-uterine spread of disease. Utilizing a cutoff point of 30 U/ml achieved a sensitivity, specificity, positive predictive value and negative predictive value of 31.0, 88.5, 36.7 and 85.7%, respectively. Elevated CA-125 above 30 U/ml in patients with apparent early-stage disease is a risk factor for the presence of extra-uterine disease and may assist clinicians in the management of patients with clinical Stage I endometrial cancer.

Quality of life after total laparoscopic hysterectomy versus total abdominal hysterectomy for stage I endometrial cancer (LACE): a randomised trial.

BACKGROUND: This two-stage randomised controlled trial, comparing total laparoscopic hysterectomy (TLH) with total abdominal hysterectomy (TAH) for stage I endometrial cancer (LACE), began in 2005. The primary objective of stage 1 was to assess whether TLH results in equivalent or improved quality of life (QoL) up to 6 months after surgery compared with TAH. The primary objective of stage 2 was to test the hypothesis that disease-free survival at 4.5 years is equivalent for TLH and TAH. Here, we present the results of stage 1. METHODS: Between Oct 7, 2005, and April 16, 2008, 361 participants were enrolled in the QoL substudy at 19 centres across Australia, New Zealand, and Hong Kong; 332 completed the QoL analysis. Randomisation was done centrally and independently from other study procedures via a computer-generated, web-based system (providing concealment of the next assigned treatment), using stratified permuted blocks of three and six patients. Patients with histologically confirmed stage I endometrioid adenocarcinoma and Eastern Cooperative Oncology Group performance status less than 2 were randomly assigned to TLH (n=190) or TAH (n=142), stratified by histological grade and study centre. Patients and study personnel were not masked to treatment assignment. QoL was measured at baseline, 1 and 4 weeks (early), and 3 and 6 months (late) after surgery, using the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire. The primary endpoint was the difference between groups in QoL change from baseline at early and late timepoints (a 5% difference was considered clinically significant). Analysis was done according to the intention-to-treat principle. Patients for both stages of the trial have now been recruited and are being followed up for disease-specific outcomes. The LACE trial is registered with ClinicalTrials.gov, number NCT00096408. FINDINGS: Eight of 332 patients (2.4%) had treatment conversion-seven from TLH to TAH and one from TAH to TLH (patient preference). In the early phase of recovery, patients who had TLH reported significantly greater improvement in QoL from baseline compared with those who had TAH, in all subscales apart from emotional and social wellbeing. Improvements in QoL up to 6 months after surgery continued to favour TLH, except in the emotional and social wellbeing measures of FACT and the visual analogue scale of the EuroQoL five dimensions (EuroQoL-VAS). Operating time was significantly longer in the TLH group (138 min [SD 43]) than in the TAH group (109 min [34]; p=0.001). Although the proportion of intraoperative adverse events was similar between groups (TAH eight of 142 [5.6%] vs TLH 14 of 190 [7.4%]; p=0.53); postoperatively, twice as many patients in the TAH group experienced adverse events of grade 3 or higher (33 of 142 [23.2%] vs 22 of 190 [11.6%] in the TLH group; p=0.004). Postoperative serious adverse events occurred more in the TAH group (27 of 142 [19.0%]) than in the TLH group (16 of 190 [7.9%]; p=0.002). INTERPRETATION: QoL improvements from baseline during early and later phases of recovery, and the adverse event profile, favour TLH compared with TAH for treatment of stage I endometrial cancer. FUNDING: Cancer Council Queensland, Cancer Council New South Wales, Cancer Council Victoria, Cancer Council Western Australia; NHMRC project grant 456110; Cancer Australia project grant 631523; The Women and Infants Research Foundation, Western Australia; Royal Brisbane and Women's Hospital Foundation; Wesley Research Institute; Gallipoli Research Foundation; Gynetech; TYCO Healthcare, Australia; Johnson and Johnson Medical, Australia; Hunter New England Centre for Gynaecological Cancer; Genesis Oncology Trust; and Smart Health Research Grant QLD Health.

Extrauterine adenomyoma with atypical (symplastic) smooth muscle cells: a report of 2 cases.

Adenomyomas are circumscribed tumorlike masses most often involving the uterus and consisting of endometrioid glands, stroma, and smooth muscle tissue. They are uncommon in extrauterine sites and in this situation it may be unclear whether such lesions represent foci of endometriosis with marked smooth muscle hyperplasia/metaplasia, uteruslike mass lesions, or leiomyomas with entrapped endometriotic glandular and stromal elements. In this report 2 cases of extrauterine adenomyoma are presented in which the smooth muscle component showed focal atypical (symplastic) cytologic appearances.

Intraoperative assessment of clear cell carcinoma of the ovary.

Frozen section is a reliable technique in gynecologic pathology and is widely used to guide intraoperative management in patients presenting with ovarian masses. However, there are limited data regarding the diagnostic accuracy of frozen section in specific subtypes of ovarian neoplasia. Our impression that primary clear cell carcinoma (CCC) causes disproportionate diagnostic difficulty led us to review the intraoperative and final histopathologic reports from a consecutive series of 44 CCC that were subject to frozen-section assessment and to compare the results with a similar number of primary serous and endometrioid carcinomas. The original intraoperative slides from those CCC with discordant diagnoses were also reviewed. Review of the diagnostic reports showed that CCC was less frequently specifically identified than serous or endometrioid carcinomas on frozen section (44% cases compared with 55% and 65%, respectively), although the differences were not statistically significant. Difficulties in distinguishing primary ovarian carcinoma from tumors metastatic to the ovary occurred in a minority of cases of all histologic subtypes, but was slightly more frequent in CCC. Two CCC were misdiagnosed as borderline epithelial tumors and 1 case as a dysgerminoma. Review of the frozen-section slides from the CCC with discrepant intraoperative diagnoses showed features suggestive or indicative of the correct diagnosis in 7 (39%) of 18 cases.

Intraoperative assessment of ovarian tumors: a 5-year review with assessment of discrepant diagnostic cases.

Frozen section is often requested in the intraoperative assessment of patients, presenting with ovarian masses, to provide guidance for appropriate surgical management. To assess the accuracy of frozen section and identify causes of diagnostic error, we reviewed 914 consecutive ovarian frozen sections performed over a 5-year period in 2 laboratories; one of which provides a general surgical pathology service and, the other, a specialist gynecologic pathology service. Cases, in which there were significant diagnostic discrepancies between the intraoperative and the final histological diagnoses, were reviewed. The series included 552 benign lesions (60.4%), 96 borderline (atypical proliferating) epithelial tumors (10.5%), and 266 malignancies (29.1%). The overall accuracy of frozen section diagnosis was 95.3%. There were 43 cases with diagnostic discrepancy; 20 (3.8% cases) of which were reported in the specialist laboratory and 23 (5.9% cases) in the general laboratory. Underdiagnosis of tumor type accounted for 32 of 43 discrepant cases and was most frequent in borderline mucinous tumors. The most common cause of overdiagnosis was the misinterpretation of serous cystadenofibroma as borderline serous tumor. Slide review of the 41 assessable cases indicated that sampling error, pathologist misinterpretation, and suboptimal slide preparations contributed to misdiagnoses in 17, 23, and 9 tumors, respectively (in 9 cases, 2 factors were contributory), whereas no specific error was identified in the remaining case. Technical factors and pathologist misinterpretation were more common in the general pathology laboratory. This study confirms that ovarian frozen section is a generally reliable technique, but there are problematic areas, particularly involving the assessment of borderline tumors.

Accuracy of frozen section in distinguishing primary ovarian neoplasia from tumors metastatic to the ovary.

Frozen section is widely used in the intra-operative assessment of patients with ovarian tumors. The diagnosis of malignancy is usually straightforward but in some cases it may be difficult to distinguish whether tumors are of ovarian origin or represent matastases from other sites. Recently, Seidman and colleagues presented a simple algorithm based on tumor size and unilateral versus bilateral involvement to aid in intra-operative assessment of ovarian mucinous neoplasms. In this study we have reviewed the accuracy of frozen section in distinguishing primary ovarian malignancies from tumors metastatic to the ovaries encountered in two hospitals over a 5-year period. The algorithm was also applied to our cases retrospectively irrespective of histological type. Nine hundred fourteen ovarian frozen sections were performed in the study period including 266 cases with a final diagnosis of malignancy. Thirty-seven malignancies (13.9%) were of metastatic origin (exclusing one lymphoma), 21 of which (58.8%) were correctly identified on frozen section. In 5 additional cases metastatic origin was included in the differential diagnosis while a primary ovarian tumor was favored un 11 cases (29.7%). Application of the algorithm to the metastatic tumors led to correct classification in 26/33 (78.8%) assessable cases. Conversely, 195/228 primary ovarian malignancies were correctly identified intra-operatively but the possibility of extra-ovarian malignancy was considered or not excluded in 33 cases (14.5%). Application of the algorithm to the latter problematic primary ovarian tumors overall was not helpful in distinguishing primary or metastatic origin. However if only low-grade primary adenocarcinomas were considered then 10/12 assessable cases were correctly assigned. In conclusion frozen section is only moderately successful in distinguishing primary ovarian malignancies fron tumors metastatic to the ovaries. The simple algorithm proposed by Seidman and colleagues for assessment of ovarian mucinous tumors is helpful and can be applied to low-grade adenocarcinomas of other histological types.

Total laparoscopic hysterectomy with a transvaginal tube.

Several techniques of laparoscopic hysterectomies have been described, but loss of carbon dioxide (CO(2)) pneumoperitoneum is still a problem when the vagina is incised and the specimen has been removed. Our technique allows maintenance of CO(2) pneumoperitoneum by inserting a silicone tube into the vagina. The McCartney tube is open at its vaginal (proximal) end and a cap covers the outer distal end. The total hysterectomy specimen, adnexa, and, if necessary, lymph nodes can be easily removed through the tube.

Total laparoscopic hysterectomy for endometrial cancer: patterns of recurrence and survival.

OBJECTIVE: The impact of laparoscopic surgery on the patterns of recurrence and on prognosis in patients with endometrial cancer remains unclear. The objective of the current study was to evaluate the effect of the laparoscopic approach on patterns of recurrence, disease-free (DFS), and overall survival (OS) in patients with endometrial cancer. METHODS: A retrospective review of patients presenting with stages 1-4 endometrial cancer who had a hysterectomy, bilateral salpingo-oophorectomy with or without surgical staging was performed. Patients either had a total laparoscopic hysterectomy (TLH) or a total abdominal hysterectomy (TAH). Patterns of recurrence, DFS and OS were the study endpoints. RESULTS: The surgical intent was TLH in 226 patients (44.3%) and TAH in 284 patients (55.7%). TLH was converted to laparotomy in 11 patients. Patients for TLH were younger, heavier, and had a higher ASA score and were more likely to present with early-stage, well-differentiated tumors and were less likely to have undergone lymphadenectomy. Median follow-up was 29.4 months. DFS and OS were adversely and independently affected by increasing age, higher stage, higher grade, and by deeper myometrial invasion, whereas the intention to treat (TLH vs. TAH) did not influence DFS or OS. Patterns of recurrence were similar in both groups and no port-site metastasis was noted in the TLH group. CONCLUSIONS: The incidence of port-site metastasis in early-stage endometrial cancer treated by TLH is low. Laparoscopic management does not seem to worsen the prognosis of patients with endometrial cancer.

Feasibility and safety of total laparoscopic radical hysterectomy.

STUDY OBJECTIVE: To evaluate feasibility and morbidity of a total laparoscopic radical hysterectomy (TLRH). DESIGN: Retrospective chart review (Canadian Task Force classification II-3). SETTING: Gynecologic cancer center. PATIENTS: Fifty-five women with cervical (39), endometrial (8), vaginal (2), or recurrent colon cancer (1), or severe pelvic endometriosis (5) followed for 3 years. INTERVENTION: TLRH in 55 women, converted to laparotomy in 3 (5.5%). MEASUREMENTS AND MAIN RESULTS: Feasibility, safety, patterns of recurrence, and survival were assessed. Estimated blood loss was 200 ml (range 50-2000 ml), median total operating time was 210 minutes, and median hospital stay was 5 days. Intraoperative complications were three vascular injuries and one obturator nerve palsy, all of which occurred in the first half of the series. Early postoperative morbidity included deep vein thrombosis, pulmonary embolism, bladder infection and dysfunction, and vaginal fistula. These events occurred less frequently in the second half of the series. Late postoperative morbidity consisted of lymphedema, pelvic abscess and lymphocyst formation, pelvic cellulitis, hyperesthesia of the leg, and small bowel obstruction. The only fatality was a patient who developed a pulmonary embolus on postoperative day 3. Median follow-up was 36.5 months. Of 39 women with cervical cancer, 34 were alive and disease free at their last visit. No case of port site metastasis occurred during follow-up. CONCLUSION: TLRH carries acceptably low morbidity that can be reduced with experience with the technique.

Total laparoscopic hysterectomy in the management of endometrial carcinoma.

STUDY OBJECTIVE: To compare total laparoscopic hysterectomy (TLH) with open hysterectomy in the management of endometrial carcinoma. DESIGN: Retrospective chart review (Canadian Task Force classification II-3). SETTING: Gynecologic cancer center. PATIENTS: All women with endometrial carcinoma managed between January 1, 1993, and June 30, 1999. INTERVENTIONS: Of 403 patients reviewed, in 161 (40%) the surgical intention was laparoscopic management, in 230 (57%) the intention was open management, and in 12 (3%) it was vaginal hysterectomy. Total laparoscopic hysterectomy was successfully completed in 153 (95%) of the laparoscopic group. MEASUREMENTS AND MAIN RESULTS: Mean weight of women in the laparoscopic group (80.1 kg) was greater than that in the open group (73.3 kg, p = 0.002), and included 27 patients weighing over 100 kg (maximum individual weight 170 kg). Mean operating times were 138 minutes for laparoscopy and 121 minutes for the open procedure (p = 0.002). Complications differed, with significantly more occurring in the open group (43%, 100) than in the laparoscopic group (17%, 27, p <0.00001). Mean postoperative hospital stay was significantly shorter for the laparoscopic group (4.3 days) than for the open group (8.5 days, p = 0.0001). Conclusion. TLH combined with laparoscopic surgical staging has many advantages over the open approach, especially in obese women.

The prognostic value of immunohistochemically detected CD44v3 and CD44v6 expression in patients with surgically staged vulvar carcinoma: a multicenter study.

BACKGROUND: Isoforms of the adhesion molecule CD44 are involved in carcinogenesis and the metastatic cascade of tumor cells by increasing the affinity of malignant cells to their extracellular matrix. Preliminary data with respect to the prognostic value of the CD44 isoforms CD44v3 and CD44v6 in patients with vulvar carcinoma showed promising results. The current multicenter study aimed to determine the prognostic value of CD44v3 and CD44v6 in patients with surgically staged vulvar carcinoma. METHODS: Expression of CD44v3 and CD44v6 in vulvar carcinoma tissue was assessed by immunohistochemistry. Immunohistochemical staining was performed according to established protocols. Results were correlated to clinical data. RESULTS: A positive CD44v3 and CD44v6 staining was detected in 33.3% (33 out of 99) and 39.4% (39 out of 99) of the tumor samples, respectively. Overexpression of CD44v6 was associated with an impaired prognosis with respect to disease-free survival (P = 0.01) and overall survival (P = 0.04). Multivariate analysis showed that CD44v6 provided prognostic information with respect to disease-free survival (P = 0.001) and overall survival (P = 0.005) independently of the two established prognosticators, tumor stage and groin lymph node involvement. Overexpression of CD44v3 had no impact on patient survival. CONCLUSIONS: The current multicenter study, involving a large series of patients with surgically staged vulvar carcinoma, allowed for multivariate survival analysis and showed that CD44v6 confers prognostic information in addition to that provided by the established clinicopathologic parameters of tumor stage and lymph node status.