Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer.

BACKGROUND: Dostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer. METHODS: We conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed. RESULTS: Of the 494 patients who underwent randomization, 118 (23.9%) had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. In the dMMR-MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P<0.001). In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; P<0.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87). The most common adverse events that occurred or worsened during treatment were nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group. CONCLUSIONS: Dostarlimab plus carboplatin-paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR-MSI-H population. (Funded by GSK; RUBY ClinicalTrials.gov number, NCT03981796.).

Olaparib treatment for platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency status: Phase II LIGHT study primary analysis.

OBJECTIVE: Olaparib treatment resulted in significant improvement in objective response rates (ORRs) and progression-free survival (PFS) over non­platinum chemotherapy in patients with BRCA1/BRCA2-mutated (BRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) and ≥2 prior lines of platinum-based chemotherapy in the phase III SOLO3 study. LIGHT (NCT02983799) prospectively evaluated olaparib treatment for patients with PSROC and known BRCAm and homologous recombination deficiency (HRD) status. METHODS: In this phase II open-label multicenter study, patients with PSROC and ≥1 prior line of platinum-based chemotherapy were assigned to cohorts by presence of germline BRCAm (gBRCAm), somatic BRCAm (sBRCAm), HRD-positive tumors without BRCAm, or HRD-negative tumors. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR) and PFS. Tumors were analyzed using Myriad BRACAnalysis CDx and myChoice HRD assays; HRD-positive tumors were defined using a genomic instability score of ≥42. RESULTS: Of 272 enrolled patients, 271 received olaparib and 270 were included in efficacy analyses. At data cut-off, ORRs in the gBRCAm, sBRCAm, HRD-positive, and HRD-negative cohorts were 69.3%, 64.0%, 29.4%, and 10.1%, respectively. DCRs were 96.0%, 100.0%, 79.4%, and 75.3% in each cohort, respectively. Median PFS was 11.0, 10.8, 7.2, and 5.4 months, respectively. The most common (≥ 20%) treatment-emergent adverse events included nausea, fatigue/asthenia, vomiting, anemia, constipation, diarrhea, and decreased appetite. CONCLUSIONS: Olaparib treatment demonstrated activity across all cohorts. The greatest efficacy was observed in the BRCAm cohorts, regardless of gBRCAm/sBRCAm. For patients without a BRCAm, greater efficacy was observed in the HRD-positive than the HRD-negative cohorts. The safety profile was consistent with that established in previous olaparib studies.

The MEMORY Study: MulticentEr study of Minimally invasive surgery versus Open Radical hYsterectomy in the management of early-stage cervical cancer: Survival outcomes.

OBJECTIVE: The Laparoscopic Approach to Cervical Cancer (LACC) trial found that minimally invasive radical hysterectomy compared to open radical hysterectomy compromised oncologic outcomes and was associated with worse progression-free survival (PFS) and overall survival (OS) in early-stage cervical carcinoma. We sought to assess oncologic outcomes at multiple centers between minimally invasive (MIS) radical hysterectomy and OPEN radical hysterectomy. METHODS: This is a multi-institutional, retrospective cohort study of patients with 2009 FIGO stage IA1 (with lymphovascular space invasion) to IB1 cervical carcinoma from 1/2007-12/2016. Patients who underwent preoperative therapy were excluded. Squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinomas were included. Appropriate statistical tests were used. RESULTS: We identified 1093 cases for analysis-715 MIS (558 robotic [78%]) and 378. OPEN procedures. The OPEN cohort had more patients with tumors >2 cm, residual disease in the hysterectomy specimen, and more likely to have had adjuvant therapy. Median follow-up for the MIS and OPEN cohorts were 38.5 months (range, 0.03-149.51) and 54.98 months (range, 0.03-145.20), respectively. Three-year PFS rates were 87.9% (95% CI: 84.9-90.4%) and 89% (95% CI: 84.9-92%), respectively (P = 0.6). On multivariate analysis, the adjusted HR for recurrence/death was 0.70 (95% CI: 0.47-1.03; P = 0.07). Three-year OS rates were 95.8% (95% CI: 93.6-97.2%) and 96.6% (95% CI: 93.8-98.2%), respectively (P = 0.8). On multivariate analysis, the adjusted HR for death was 0.81 (95% CI: 0.43-1.52; P = 0.5). CONCLUSION: This multi-institutional analysis showed that an MIS compared to OPEN radical hysterectomy for cervical cancer did not appear to compromise oncologic outcomes, with similar PFS and OS.

Laparoscopic guided liposomal bupivacaine injection compared to transversus abdominus plane block for postoperative pain after robotic gynecologic oncology surgery.

OBJECTIVE: The purpose of this study was to determine if laparoscopically guided transversus abdominis plane block (Lap-Tap) with liposomal bupivacaine provides superior postoperative pain control when compared to ultrasound-guided block (US-Tap) with liposomal bupivacaine at the time of robotic surgery for gynecology oncology patients. METHODS: This was a prospective randomized controlled trial assigning patients to one of two cohorts: Cohort 1 consisted of US-Tap administered before the procedure using liposomal bupivacaine, Cohort 2 consisted of Lap-Tap administration with laparoscopic visualization using the medication above. Primary outcomes were pain scores and total opioid use in Oral Morphine Equivalents (OME) during the first 72 h after surgery. Secondary outcomes were postoperative pain satisfaction and oral narcotic requirements. RESULTS: There was a significant increase in oral narcotic use in the first 24 h in the US-Tap cohort compared to the Lap-Tap cohort: Lap-Tap mean = 6.73 ± 8.22 OME versus US-Tap mean = 12.69 ± 12.94 p = 0.018 OME. The increase was equivalent to one additional Hydrocodone-Acetaminophen 7.5 mg/325 mg in the first 24 h after surgery. However, total oral narcotic use over the first 72 h was not significantly different between the two cohorts: Lap-Tap mean = 21.73 ± 19.83 OME, US-Tap mean = 32.50 ± 29.47, p = 0.062 OME. In addition, there was no significant difference in satisfaction or pain scores between the US-Tap and Lap-Tap groups at 24, 48, or 72-hours. CONCLUSIONS: Lap-Taps are comparable to US-Tap for postoperative analgesia during the first 72-h after surgery when performing robotic-assisted gynecologic oncology surgery.

Improving the quality of care for patients with advanced epithelial ovarian cancer: Program components, implementation barriers, and recommendations.

The high lethality of ovarian cancer in the United States and associated complexities of the patient journey across the cancer care continuum warrant an assessment of current practices and barriers to quality care in the United States. The objectives of this study were to identify and assess key components in the provision of high-quality care delivery for patients with ovarian cancer, identify challenges in the implementation of best practices, and develop corresponding quality-related recommendations to guide multidisciplinary ovarian cancer programs and practices. This multiphase ovarian cancer quality-care initiative was guided by a multidisciplinary expert steering committee, including gynecologic oncologists, pathologists, a genetic counselor, a nurse navigator, social workers, and cancer center administrators. Key partnerships were also established. A collaborative approach was adopted to develop comprehensive recommendations by identifying ideal quality-of-care program components in advanced epithelial ovarian cancer management. The core program components included: care coordination and patient education, prevention and screening, diagnosis and initial management, treatment planning, disease surveillance, equity in care, and quality of life. Quality-directed recommendations were developed across 7 core program components, with a focus on ensuring high-quality ovarian cancer care delivery for patients through improved patient education and engagement by addressing unmet medical and supportive care needs. Implementation challenges were described, and key recommendations to overcome barriers were provided. The recommendations emerging from this initiative can serve as a comprehensive resource guide for multidisciplinary cancer practices, providers, and other stakeholders working to provide quality-directed cancer care for patients diagnosed with ovarian cancer and their families.

Malignant granular cell tumors: the role of electron microscopy in the definitive diagnosis of an extremely aggressive soft tissue neoplasm.

Granular cell tumors (GCTs) are rare soft tissue neoplasms which may be multicentric. The vast majority are benign, however approximately 100 malignant GCTs have been reported, with only 8 originating in the vulva. Malignant GCTs are very aggressive with very poor survival rates. As the diagnosis of malignant GCT carries an extremely poor prognosis, the utilization of EM ensures that the most accurate diagnosis possible can be rendered.

A pilot study of topical imiquimod therapy for the treatment of recurrent extramammary Paget's disease.

OBJECTIVE: The objective of this prospective pilot study was to assess the clinical and histologic effects of topical imiquimod therapy on recurrent extramammary Paget's disease of the vulva. METHODS: Patients with biopsy-proven recurrent extramammary Paget's disease presenting to the gynecology outpatient services at two participating institutions were recruited for conservative treatment with 5% imiquimod cream from 2007 to 2011. The topical cream was to be applied 3 times per week for 12weeks. Punch biopsy and photography were performed at baseline and at the 12-week time point. RESULTS: Eight patients from two institutions were enrolled. Complete clinical and histologic response was achieved in 6 (75%) patients by the 12-week follow-up appointment. Of the two remaining patients, one had a complete clinical response but no significant histologic response; the other patient was removed from the study protocol secondary to intolerable local irritation. Two patients continue to have no evidence of disease after a median follow-up of 35months. Five are alive with disease. No patients progressed to invasive cancer while receiving therapy. CONCLUSION: Topical 5% imiquimod cream is a safe and feasible option for women suffering from recurrent extramammary Paget's disease of the vulva, and should be considered as a viable alternative to surgical management. Given the rare nature of this disease, additional multi-institutional prospective studies should be conducted to explore the efficacy of this treatment regime.

Neuroendocrine tumors in the ovary: histogenesis, pathologic differentiation, and clinical presentation.

OBJECTIVE: Primary neuroendocrine tumors in the ovary are rare. These tumors arise from the neuroendocrine cell system of ovarian stroma and surface epithelium, and may also arise from teratoma. We present four primary ovarian neuroendocrine tumors and compare clinicopathologic findings based on tumor histogenesis and site of origin. DESIGN: Four primary ovarian neuroendocrine tumors were identified from our 10-year departmental archives. H&E slides and immunostains were reviewed and the diagnoses were confirmed. Clinical history, imaging studies, and follow-up data were obtained from medical records. RESULTS: Patients' ages ranged from 26 to 63. All patients presented with abdominal discomfort and unilateral or bilateral ovarian masses. MRI and CT scans from cases 1 and 2 revealed a solid ovarian mass with no extra-ovarian extension. In case 1, the patient also had a cystic mass in the opposite ovary and an elevated urine 5-HIAA. Microscopically, case 1 revealed a well-differentiated carcinoid tumor with no surface epithelial involvement, and a mature teratoma in the contralateral ovary. Case 2 revealed a stromal carcinoid within the ovarian parenchyma. Imaging studies from cases 3 and 4 showed large complex masses with peritoneal implants and ascites. In both cases 3 and 4, tumor grossly involved both ovarian parenchyma and surface epithelium with multiple pelvic implants. In addition, liver metastases were present in case 4. Microscopically, these tumors were poorly differentiated carcinoma with neuroendocrine differentiation. Histologic sections revealed extensive necrosis, and both cases showed positivity for neuroendocrine markers. CONCLUSIONS: Primary neuroendocrine tumors in the ovary are rare and consist of a group of heterogeneous malignancies that express similar immunohistochemical markers. Primary neuroendocrine tumors that are limited to the ovarian parenchyma often arise from ovarian stroma and teratoma, and are carcinoid tumors with a good prognosis. Neuroendocrine tumors that arise from surface epithelium or dedifferentiate from de novo carcinoma often involve both ovarian stroma and surface epithelium and clinically present as aggressive malignancies with poor prognoses.

Management of Persistent Postpartum Hemorrhage Caused by Inner Myometrial Lacerations.

BACKGROUND: Postpartum hemorrhage management must involve rapid recognition of the source of bleeding. Inner myometrial laceration is an uncommonly recognized cause; most cases are demonstrated only by evaluation of peripartum hysterectomy specimens. The exact cause of this laceration is unknown; however, it can be identified by uterine cavity exploration and managed with conservative surgery that preserves fertility. CASE: Postpartum hemorrhage caused by inner myometrial lacerations is presented. We explored the uterine cavity through laparotomy and uterine hysterotomy to identify and repair the source of bleeding. CONCLUSION: In persistent hemorrhage that fails initial interventions, inner myometrial laceration should be considered. Uterine cavity exploration with laparotomy incision and hysterotomy to directly visualize the source are essential steps to manage postpartum hemorrhage while avoiding maternal morbidity, peripartum hysterectomy, and potential mortality.

Patterns of first recurrence following adjuvant intraperitoneal chemotherapy for stage IIIC ovarian cancer.

OBJECTIVE: Adjuvant intraperitoneal (IP) platinum-based chemotherapy has been shown to improve outcome for patients with advanced ovarian cancer. We hypothesize that patients who have received adjuvant IP chemotherapy more commonly recur first at extraperitoneal sites than patients who have received adjuvant intravenous (IV) chemotherapy. METHODS: Patients with newly diagnosed stage IIIC optimally debulked serous ovarian cancer were identified from institutional databases. Patterns of recurrence were compared between patients who received IV and IP chemotherapy using standard two-sided statistical tests. RESULTS: Of the 104 patients who met inclusion criteria, 60 received IV chemotherapy and 44 received IP chemotherapy. Patients in the IV group had a first recurrence more commonly in the lower abdomen or pelvis than the IP group. Patients in the IP group more commonly recurred in the upper abdomen and extra-abdominal lymph nodes. More patients in the IP group than the IV group recurred at extra-abdominal sites (45.5% versus 23.3%, P=0.018). CONCLUSIONS: Patients receiving adjuvant IP chemotherapy are less likely to first recur in the lower abdomen or pelvis and more likely to recur outside of the abdominal cavity. The data suggest that IP chemotherapy is highly effective in the anatomic areas of peritoneal distribution.

Low risk of complications associated with the fenestrated peritoneal catheter used for intraperitoneal chemotherapy in ovarian cancer.

OBJECTIVES: We previously reported a 10% rate of catheter complications, including inflow obstruction and infection, using a fenestrated catheter to administer intraperitoneal (i.p.) chemotherapy for ovarian cancer. Because of recent reports of higher rates of catheter complications, we performed this study to update our experience with the fenestrated catheter. METHODS: We reviewed the medical records of all patients who had a fenestrated catheter placed at our institution from 5/97-5/06. Data were collected regarding patient demographics, surgical procedure, timing of catheter insertion, and reasons for discontinuing i.p. chemotherapy. RESULTS: We identified 342 patients who had fenestrated catheters placed and for whom follow-up data were available. Nine patients (3%) required discontinuation of chemotherapy due to catheter complications. Three patients experienced catheter infection, 5 patients had inflow obstruction, and 1 patient's port could not be accessed. Seventy-one patients (21%) discontinued i.p. chemotherapy for reasons unrelated to the catheter. The percentage of patients who completed the intended chemotherapy regimen was similar for patients who underwent a bowel resection (22/30 [73%]) compared to those who had not (226/312 [72%]) (P=1.0). CONCLUSIONS: The fenestrated catheter for i.p. chemotherapy continues to be associated with a low risk of catheter-related complications. The low rate of complications, even in the setting of bowel resection and increase in utilization during upfront chemotherapy, suggest that the fenestrated catheter is still a feasible method for the administration of i.p. chemotherapy.

Routinely assessed morphological features correlate with microsatellite instability status in endometrial cancer.

Microsatellite instability (MSI) has been shown to be important in the molecular pathogenesis of both sporadic and inherited endometrial carcinomas of endometrioid type. It is likely prognostically significant as well. The aim of this study was to determine whether MSI phenotype in endometrial carcinoma was associated with specific morphologic patterns and therefore predictable by tumor morphology. The study subjects consisted of 102 patients with nearly equal representation of MSI high (MSI-H; n = 52) and non-MSI-H (n = 50) endometrial tumors. Microsatellite instability was determined by the standard polymerase chain reaction method using the National Cancer Institute-recommended set of 5 markers. The MSI-H and non-MSI-H groups were matched for patient age, race, histologic type (all endometrioid), International Federation of Gynecology and Obstetrics grade, and disease stage. Assessed morphological features included host inflammatory response (tumor infiltrating lymphocytes [TILs], peritumoral lymphocytes, peritumoral lymphoid follicles, and neutrophilic infiltration), tumor characteristics (cytologic grade, growth pattern, tumor heterogeneity, invasion pattern, metaplastic changes, necrosis, and lymphovascular invasion), and background endometrium (hyperplasia, atrophy, and polyp). Of all the features examined, TIL counts and peritumoral lymphocytes correlated significantly with MSI-H status. Their statistical relationship was strengthened in the presence of a nonpapillary growth pattern and endometrial hyperplasia. On multivariate analysis, TIL counts and peritumoral lymphocytes remained independent predictors for MSI-H status. At a cutoff point of 40 TILs/10 high power fields, TIL counts had a sensitivity of 85% in predicting MSI status in endometrioid endometrial carcinoma, with a specificity of 46%. This specificity increased as higher cutoff points were selected, but sensitivity decreased. Given that analogous features have been encountered in MSI-H colorectal cancers, our findings suggest a similar relationship between tumor phenotype and DNA mismatch repair abnormalities in both endometrial and colorectal tumors. Therefore, morphological patterns encountered in endometrial carcinoma may prove useful in screening tumors under consideration for MSI testing and identifying appropriate patients for referral to a genetic counseling service.

Effect of perioperative venous thromboembolism on survival in ovarian, primary peritoneal, and fallopian tube cancer.

OBJECTIVES: Venous thromboembolism (VTE) affects 15% of cancer patients and is the second leading cause of death in hospitalized cancer patients. The purpose of this study was to describe the overall survival of patients with ovarian, primary peritoneal, and fallopian tube cancers treated for VTE within 30 days of initial surgery. METHODS: We reviewed the medical records of all patients who developed VTE within 30 days of primary surgery for stage I-IV epithelial ovarian, tubal, or primary peritoneal cancer at our institution from 1/99 to 4/05. Standard statistical tests were used. RESULTS: Fifty-seven (10%) of 559 patients developed VTE within 30 days of initial surgery. There were no deaths from VTE within 30 days of surgery. With a median follow-up of 2.8 years (range, 0.11-7.3 years), the median overall survival for the entire cohort was 5.9 years (95% CI, 4.6-NR). The proportion of advanced-stage (III-IV) patients within the VTE group compared to the group with no VTE was higher (90% versus 72%; P=0.0078), as was the proportion of patients with ascites compared to those with none (74% versus 54%; P=0.0045), and the proportion of patients with residual disease >1 cm compared to those with 1 cm (P<0.0001) were significant predictors of poorer overall survival. VTE within 30 days of surgery was not found to be independently associated with overall survival (hazard ratio, 1.1; 95% CI, 0.71-1.7); P=0.65). CONCLUSIONS: Previous studies have shown that a significant number of patients undergoing primary surgery for ovarian cancer will develop postoperative VTE, especially those undergoing extensive cytoreductive procedures. In this large cohort of patients with ovarian, tubal, or primary peritoneal cancer, we found no detrimental effects of perioperative VTE on overall survival.

Difficulties in assessing the depth of myometrial invasion in endometrial carcinoma.

The depth of myometrial invasion (DMI) is one of the most important prognostic indicators and determinants of therapy in endometrial cancer. There are well-documented problems in recognizing DMI. We examined 100 previously diagnosed endometrioid endometrial carcinomas in hysterectomy specimens, reassessed DMI, and explored morphological features that complicated appraisal of myometrial invasion. The DMI was different from the original measurement in 29% of cases. Twelve percent of all cases (40% of cases with measurement discrepancies) involved differences in the assignment of invasion categories (noninvasive, < or =50% myometrial invasion, and >50% myometrial invasion). Nearly all endometrial cancers originally diagnosed as invasive were considered noninvasive on review. We examined whether the distribution of stromal metaplasia, noninvasive patterns (exophytic tumors, irregular endomyometrial junctions, and adenomyosis), and myometrial invasion patterns were different in cases with and without measurement discrepancies. Irregular endomyometrial junctions, exophytic tumors, and adenomyosis tended to coexist and were more common in the cases with DMI discrepancies. Although there seemed to be a relationship between smooth muscle metaplasia and exophytic tumors, it did not appear that smooth muscle metaplasia was significantly more common in cases with measurement difficulties. However, cases with extensive smooth muscle metaplasia posed problems with assessment of myometrial invasion. Patterns of myometrial invasion other than the conventional destructive pattern were sufficiently uncommon as to not impact on DMI measurement in large numbers of cases. Measuring the DMI is usually uncomplicated, but additional scrutiny should be paid to cases involving exophytic tumors, irregular endomyometrial junctions, adenomyosis, and extensive stromal smooth muscle metaplasia.

Utility of immunohistochemistry in predicting microsatellite instability in endometrial carcinoma.

Identification of the microsatellite instability (MSI) phenotype in endometrial carcinoma is important given that such tumors are the most common noncolorectal tumors to occur in hereditary nonpolyposis colorectal cancer syndrome, and may bear prognostic relevance. The objective of this study was to assess the utility of immunohistochemistry (IHC), a simple and fast technique, in detecting MSI in endometrial carcinoma. The study subjects consisted of 90 endometrial carcinoma patients with equal representation of MSI-high (MSI-H) and non-MSI-H tumors. MSI was tested using the standard polymerase chain reaction-based method and the 5 NCI-recommended markers. Overall, IHC with MLH1 and MSH2 antibodies detected 69% of MSI-H tumors with a specificity of 100%. Adding PMS2 and MSH6 to the antibody panel increased the sensitivity to 91% but decreased the specificity to 83%. The most common IHC abnormality in MSI tumors was concurrent loss of MLH1/PMS2. Assessment of staining was straightforward in most cases but not in all. Staining inadequacies existed. Five stains (4 MLH1 and 1 MSH6) were not interpretable because of the lack of any internal positive control. Two percent to 10% of the cases (depending on the antibody assessed) had only focal weak staining; the highest frequency (10%) occurred with MLH1 antibody. PMS2 staining detected 7 MLH1-staining present MSI-H cases, thus partly accounting for the increased sensitivity with the 4-antibody panel. MSH6 staining identified 9 cases with loss of MSH6 alone, 6 of 9 were non-MSI-H, thus partly accounting for the decreased specificity with the 4-antibody panel. In conclusion, our results suggest that IHC is useful in detecting MSI in endometrial carcinoma. Although IHC has a lower sensitivity with more apparent staining inadequacies in detecting MSI in endometrial carcinoma than it does in colorectal carcinoma, its use in endometrial carcinoma may be an important adjunct when screening for hereditary cases. In the future, as prognostic and therapeutic implications of MSI phenotype become better defined, it may be reasonable to perform IHC for mismatch repair proteins in large numbers of endometrial carcinomas.

The outcomes of patients with positive margins after excision for intraepithelial Paget's disease of the vulva.

OBJECTIVES: Vulvar Paget's disease is a rare neoplasm that usually occurs in postmenopausal women. Treatment with surgical excision can be complicated by extension of microscopic disease in an irregular manner well beyond the visible margins of the lesion. The objective or our study was to analyze the outcomes of patients with primary vulvar intraepithelial Paget's disease who had positive microscopic margins after primary excision. METHODS: We reviewed the records of all patients with Paget's disease of the vulva treated at our institution from 1/80 to 9/02. Patients whose sample showed stromal invasion or an underlying carcinoma were excluded. Data were collected regarding patient demographics, disease location, treatment, surgical margin status, additional treatment, and clinical outcome. RESULTS: The medical records and histopathologic specimens of 28 women with intraepithelial Paget's disease of the vulva were evaluated. Surgical treatment consisted of radical vulvectomy in 3 patients (11%), simple vulvectomy in 18 patients (64%), and wide local excision in the other 7 patients (25%). Of the 20 patients with microscopically positive margins, 14 (70%) developed recurrent disease and the remaining 6 (30%) are disease free. Of the 8 patients with negative margins, 3 (38%) developed disease recurrence and the remaining 5 (63%) are disease free. With a median follow-up of 49 months (range, 3-186 months), there was no correlation between disease recurrence and margin status (P=0.20). Of the 17 patients who recurred, 14 (82%) underwent additional surgical excision and 1 patient was treated with Retin-A. The remaining 2 patients refused further treatment and were lost to follow-up. In those patients who underwent surgery for recurrence, between 1 and 3 re-excisions were performed. Of the 15 evaluable patients who were treated for recurrent disease, 12 (80%) had no evidence of persistent disease and 3 (20%) had persistent disease at a median follow-up of 63.7 months (range, 18.5-186 months). CONCLUSIONS: Microscopically positive margins following surgical excision of vulvar intraepithelial Paget's disease is a frequent finding, and disease recurrence is common regardless of surgical margin status. Long-term monitoring of patients is recommended, and repeat surgical excision is often necessary.

Fertility-sparing radical abdominal trachelectomy for cervical carcinoma: technique and review of the literature.

OBJECTIVES: Radical trachelectomy has emerged as a reasonable fertility-sparing operation for selected patients with stage I cervical cancer. The purpose of this report is to describe our technique of radical abdominal trachelectomy, a fertility-sparing operation in women with cervical cancer, and review the current literature on this procedure. METHODS: A review of a prospectively maintained database of all fertility-sparing radical trachelectomy procedures performed at our institution. RESULTS: Between 11/01 and 3/06, we performed a total of 42 fertility-preserving radical trachelectomies with pelvic lymphadenectomy for women with invasive cervical cancer. We had previously reported on 2 pediatric abdominal trachelectomies, which are excluded from this report. Five of the remaining 40 cases had undergone a radical abdominal trachelectomy, and 35 cases were performed laparoscopically with a radical vaginal approach. The characteristics of the 5 adult patients who underwent abdominal radical trachelectomy included stage IB1 disease in all cases, a mean age of 36 years (range, 33-39), and a mean estimated blood loss of 280 ml (range, 50-400); 1 patient with squamous cell carcinoma needed completion radical hysterectomy at the time of trachelectomy due to disease extending into the endometrium, and 1 patient needed postoperative chemoradiation due to a positive parametrial lymph node. The remaining 3 patients resumed normal menstruation postoperatively. All patients remain disease-free at the time of this report. The only remaining uterine blood supply in these patients are the utero-ovarian vessels. There were no postoperative complications, and transurethral Foley catheters were removed in all cases within 2 weeks. CONCLUSIONS: Radical abdominal trachelectomy with pelvic lymphadenectomy is a feasible operation for selected women with stage I cervical cancer who desire to preserve reproductive function. Menstruation and reproductive function may be preserved after bilateral uterine vessel ligation. The procedure expands the inclusion criteria of radical vaginal trachelectomy to patients with distorted cervicovaginal anatomy in which the vaginal approach may not be feasible.

Cystoscopic temporary ureteral catheterization during radical vaginal and abdominal trachelectomy.

OBJECTIVES: To describe the role of temporary retrograde ureteral catheterization at the time of fertility-sparing radical vaginal or abdominal trachelectomy in women with early-stage cervical cancer. METHODS: We analyzed a prospectively maintained database of all patients with cervical cancer who were explored for radical vaginal or abdominal trachelectomy at our institution. Cystourethroscopy and ureteral catheterization were performed prior to the vaginal or abdominal operation in all patients, except two pediatric ones. Temporary bilateral retrograde ureteral catheters were planned for all patients as part of our routine procedure to facilitate identification of the distal ureters. 5Fr whistle-tip or open-ended catheters were used and usually advanced to approximately 20 cm. Catheters were removed at the end of the operation in all cases. All catheters were inserted by a gynecologic oncology fellow or attending. RESULTS: Between 11/01 and 12/05, 40 patients were taken to the operating room for planned fertility-sparing radical vaginal or abdominal trachelectomy. We previously reported on two pediatric patients; they are excluded from this report. The median age for adult patients was 32 years (mean, 31.6; range, 23-40). International Federation of Gynecology and Obstetrics (FIGO) stage included IB1 (26), IA2 (6), and IA1 with lymphovascular invasion (6). Thirty-four patients underwent radical vaginal trachelectomy and four underwent a radical abdominal trachelectomy. Two (5%) of 38 patients required immediate completion radical hysterectomy due to extensive endocervical disease (one in the vaginal group and one in the abdominal group). Bilateral ureteral catheters were inserted successfully in 37 (97%) of 38 patients and facilitated identification of the distal ureter during the dissection. In one case, the right ureteral orifice could not be successfully catheterized, and the case was completed with unilateral catheterization. The estimated time to perform this part of the operation was approximately 15-20 min. Twenty-eight patients (74%) had 5Fr whistle-tip ureteral catheters inserted, and 10 had open-ended catheters inserted. There were no intraoperative complications. Median hospital stay was 3 days (range, 3-7). Hematuria, evident in the drainage bag attached to the Foley catheter, usually resolved in 24-48 h. Two (20%) of 10 patients who had open-ended catheters inserted developed a transient rise in postoperative creatinine (1.7 and 3.5 mg/dl, respectively) compared to 0/28 patients who had whistle-tip catheters placed (P<0.001). Both were attributed to postoperative distal ureteral edema, and only one patient required reinsertion of temporary ureteral stents. No patient developed long-term urinary complications or fistulae. CONCLUSIONS: Cystourethroscopy and bilateral retrograde ureteral catheterization by gynecologic oncologists is a simple and quick procedure that may facilitate identifying the distal ureter during radical vaginal or abdominal trachelectomy. We favor using 5Fr whistle-tip catheters as they may be associated with less ureteral mucosal trauma and subsequent postoperative edema. The skills needed for this procedure should be available to fellows in gynecologic oncology training.

Clinicopathologic significance of defective DNA mismatch repair in endometrial carcinoma.

PURPOSE: Defective DNA mismatch repair is commonly present in sporadic manifestations of gastrointestinal, endometrial, and other cancers. The pathognomonic molecular manifestation of this repair defect is microsatellite instability (MSI). Here, we test the hypothesis that MSI predicts the clinicopathologic features of endometrial carcinoma. PATIENTS AND METHODS: A retrospective cohort of 473 patients treated for endometrial carcinoma at this institution was identified. All cases were reviewed by a gynecologic pathologist, and clinical information was abstracted from medical records. Using consensus criteria, DNA samples from nontumor and tumor tissue pairs were genotyped for MSI. Associations between MSI status and pathologic and clinical variables were assessed. RESULTS: Ninety-three (20%) of 473 tumors were MSI+. In the MSI+ tumor group compared with the MSI- tumor group, the proportion of advanced compared with early-stage tumors was higher (92% v 81%; P = .01), as was the proportion of tumors of endometrioid compared with nonendometrioid histologic subtype (94% v 23%; P = .001), and the proportion of tumors with myometrial invasion compared with those with none (92% v 78%; P = .01). By multivariate analyses, disease-free survival (hazard ratio, 0.3; 95% CI, 0.2 to 0.7) and disease-specific survival (hazard ratio, 0.3; 95% CI, 0.1 to 0.8) were significantly improved in patients with MSI+ tumors. CONCLUSION: In endometrial carcinoma, the presence of MSI was independently associated with a more favorable clinical outcome.

Evaluation of germline PTEN mutations in endometrial cancer patients.

BACKGROUND AND OBJECTIVE: Cowden Syndrome is a rare autosomal dominant disorder characterized by multiple hamartomas, increased risks of breast and thyroid cancers, and possibly endometrial carcinoma. Susceptibility to Cowden syndrome is conferred by germline mutation of the PTEN tumor suppressor gene, and somatic mutations of PTEN are common in sporadic endometrial carcinomas. The aim of this study was to test whether a substantial proportion of endometrial cancers are associated with germline mutations of the PTEN gene, not necessarily in association with clinically overt Cowden syndrome. METHODS: A retrospective cohort of 240 consecutive patients with pathologically confirmed endometrial carcinoma diagnosed at our institution from 1999 to 2002 was ascertained for study. Genomic DNA was isolated from peripheral blood lymphocytes and the entire PTEN coding region and exon-intron junctions were screened for mutations by single strand conformation polymorphism analysis. Potential variants were subjected to direct sequence analysis. RESULTS: No clearly deleterious PTEN sequence variant was identified in this screened cohort of endometrial cancer patients. One patient harbored a 5-bp deletion in the intronic region adjacent to the splice acceptor site of PTEN exon 4, but this variant has been previously classified as a rare polymorphism. CONCLUSIONS: Although these data do not preclude the possibility of an increased risk of endometrial cancer in association with the Cowden syndrome, they indicate that germline PTEN mutations do not account for a significant proportion of genetic attributable risk for endometrial carcinoma.