One Hundred Years of Colposcopy: Reconciling Its Auschwitz Past.

The centennial anniversary of Hans Hinselmann's initial publication describing colposcopy is approaching. In the 100 years since the inventor's seminal paper, colposcopy has become indispensable in the diagnosis and management of cervical cancer. It remains central in diagnosing precancerous and cancerous cervical lesions and has dramatically reduced cervical cancer incidence and mortality since the mid-20th century.Previous descriptions of colposcopy's development in medical literature obscure the dark history of its earliest days, arising within the center of German Nazism. The pioneers of colposcopy benefited from the Nazi government's public health focus and exploited the environment fostered by the Nazi medical establishment. They made use of the apparatus of the Auschwitz concentration camp to position colposcopy for expanded postwar adoption, ultimately accomplishing Hinselmann's stated goal that colposcopy become a routine part of gynecologic examination and care. This historical exposition clarifies the Nazi past of colposcopy, highlights the important role that unethical treatment of victims of Auschwitz played in cementing this procedure within standard cervical cancer screening programs globally, and offers steps to reckon with this tragic legacy.

Patterns of care and outcomes of risk reducing surgery in women with pathogenic variants in non-BRCA and Lynch syndrome ovarian cancer susceptibility genes.

OBJECTIVES: Guidelines recommend risk-reducing bilateral salpingo-oophorectomy (RRSO) for women with pathogenic variants of non-BRCA and Lynch syndrome-associated ovarian cancer susceptibility genes. Optimal timing and findings at the time of RRSO for these women remains unclear. We sought to characterize practice patterns and frequency of occult gynecologic cancers for these women at our two institutions. METHODS: Women with germline ovarian cancer susceptibility gene pathogenic variants who underwent RRSO between 1/2000-9/2019 were reviewed in an IRB-approved study. All patients were asymptomatic with no suspicion for malignancy at time of RRSO. Clinico-pathologic characteristics were extracted from the medical records. RESULTS: 26 Non-BRCA (9 BRIP1, 9 RAD51C, and 8 RAD51D) and 75 Lynch (36 MLH1, 18 MSH2, 21 MSH6) pathogenic variants carriers were identified. Median age at time of RRSO was 47. There were no occurrences of occult ovarian or fallopian tube cancer in either group. Two patients (3%) in the Lynch group had occult endometrial cancer. Median follow up was 18 and 35 months for non-BRCA and Lynch patients, respectively. No patient developed primary peritoneal cancer upon follow up. Post-surgical complications occurred in 9/101 (9%) of patients. Hormone replacement therapy (HRT) was rarely used despite reported post-menopausal symptoms in 6/25 (23%) and 7/75 (37%) patients, respectively. CONCLUSIONS: No occult ovarian or tubal cancers were observed in either group. No recurrent or primary gynecologic-related cancers occurred upon follow-up. Despite frequent menopausal symptoms, HRT use was rare. Both groups experienced surgical complications when hysterectomy and/or concurrent colon surgery was performed suggesting concurrent surgeries should only be performed when indicated.

Opportunities Missed: Cervix Cancer Screening Failures in Women Aged 65 and Older.

OBJECTIVES: This study aimed to determine the screening history and associated outcomes of women diagnosed with cervical cancer after age 65. METHODS: All patients from 2012 to 2021 diagnosed with squamous, adenocarcinoma, neuroendocrine, or adenosquamous cervical cancer after age 65 in a single managed care organization (MCO) were included in this retrospective cohort study. Demographic, medical, screening, pathologic, follow-up, and treatment data were extracted. Statistical analysis was done using chi-square test and logistic regression. Cancer-specific survival was estimated using the Kaplan-Meier method. RESULTS: Of 2,175 patients screened, 209 met inclusion criteria. Only 26.3% of patients had appropriate cervical cancer screening and 41% of patients died of their disease. Managed care organization membership duration of more than 5 years positively correlated with proper cervical cancer screening ( p < .001); however, 64% of the long-term members still did not meet criteria to end screening at age 65, with 42.6% of these patients having more than 25 physician visit opportunities to address screening. Increased physician visits correlated with earlier stage at diagnosis of cervical cancer ( p = .012). Median cancer-specific survival was significantly better in properly screened patients at 68 vs 30 months, respectively ( p = .03). CONCLUSIONS: Most patients diagnosed with cervical cancer after age 65 did not have adequate previous screening, including those who were MCO members for more than 5 years. There were many missed opportunities for screening, despite multiple provider touchpoints. The authors' data suggest that adequate screening confers a survival benefit secondary to earlier stage at diagnosis. Further study in this age group is needed to redefine the criteria to end cervix cancer screening.

Development of a longitudinal two-biomarker algorithm for early detection of ovarian cancer in women with BRCA mutations.

OBJECTIVE: To develop a longitudinal algorithm combining two biomarkers, CA125 and HE4, for early detection of ovarian cancer in women with BRCA mutations. METHODS: Women with BRCA mutations and intact ovaries were invited to participate in a novel ovarian cancer early detection prospective study. The Risk of Ovarian Cancer Algorithm (ROCA) identifying significant increases above each woman's baseline in serum CA125 and HE4 was performed every four months; abnormal risks triggered a subsequent ultrasound. The study first used a risk algorithm for only CA125, a second algorithm was developed for HE4 and finally a risk algorithm combining the two biomarkers was implemented. The ROCA strategy was compared to Standard of Care (SOC) surveillance strategy. RESULTS: A total of 149 women enrolled in the ROCA arm while 43 women enrolled in the SOC arm. Abnormal scores were found in 24% of ROCA CA125 tests, 16% if ROCA CA125 or the novel ROCA HE4 were used independently and reduced to 8% using the new two-marker ROCA, significantly lower than the 15% of abnormal tests seen in the SOC arm (p = 0.042). The average false positive rate among women without ovarian cancer for two-marker ROCA for referral to ultrasound was 6.6% (specificity 93.4%), and for the two-marker ROCA plus ultrasound for referral to surgical consultation was 1.7% (specificity 98.3%). CONCLUSION: A newly developed two-marker ROCA administered every 4 months had lower call-back rates than SOC surveillance. Having established high specificity, the two-marker ROCA score deserves further evaluation for sensitivity in a larger trial.

Comparison of two Lynch screening strategies in endometrial cancer in a California health system.

OBJECTIVE: Compare detection of Lynch syndrome in endometrial cancer between regions of a health care system with different screening strategies. METHODS: A retrospective study of endometrial cancer (EC) cases from 2 regions of an integrated health care system (Kaiser Permanente Northern (KPNC) and Southern (KPSC) California). Within KPNC, immunohistochemistry tumor screening (IHC) was physician ordered and risk-based; within KPSC, IHC was universal and automated. Clinical risk factors associated with abnormal IHC and Lynch Syndrome (LS) were identified. RESULTS: During the study, there were 2045 endometrial cancers: 1399 in the physician-order group and 646 in the universal testing group. In the physician-order group: among women < age 60, 34% underwent IHC; 9.6% were abnormal, and 3% were possible LS after methylation testing; among women ≥60, 11% underwent IHC, 3% were abnormal and <1% were possible LS. In the universal group, 87% of women age <60 had IHC, 19.4% were abnormal, and 6% were possible LS; Among women age ≥60, 82% underwent IHC, 26% were abnormal, and 2% were possible LS. There were no differences in LS cases between the physician-order group and the universal group in either age strata (<60: 3% vs. 3.6%, p=0.62; ≥60: <1% vs. 1%, p=0.63) Factors associated with LS were younger age (odds ratio (OR) 0.11, 95% confidence interval (CI) 0.04-0.29) and lower body mass index (BMI), (OR 0.38 95% CI 0.18-0.80). CONCLUSIONS: Universal IHC screening did not result in increased LS detection in EC.

Feasibility, patient compliance and acceptability of ovarian cancer surveillance using two serum biomarkers and Risk of Ovarian Cancer Algorithm compared to standard ultrasound and CA 125 among women with BRCA mutations.

OBJECTIVE: We assessed the feasibility, patient acceptability of and compliance of a new surveillance strategy for ovarian cancer surveillance in women with BRCA mutations, based on assessments of serum CA125 and HE4 every 4 months (Risk of Ovarian Cancer Algorithm (ROCA) arm), compared to Standard of Care (SOC) surveillance with CA125 blood tests and pelvic ultrasounds every 6 months. METHODS: Women were recruited 6/13/16-9/11/17 from an integrated health care system in California for this non-randomized prospective cohort study. Women were invited to participate in a novel serum biomarker surveillance strategy using ROCA or they could opt to be in the standard of care control arm with ultrasound and CA 125 every 6 months. Outcomes assessed included compliance, self-reported distress using the Impact of Event Scale (IES) and cancer anxiety using the Cancer Worry Scale. RESULTS: There were 159 women in the ROCA arm and 43 in the SOC arm. Overall, compliance was higher in the ROCA arm (83.2%) than in SOC (51.9%), p < 0.0001. Based on the IES, ROCA arm women reported less feelings about intrusion and avoidance at 12 months compared to baseline; the difference approached significance for intrusion (7.6% vs 4.1% severe, p = 0.057) and was statistically significant for avoidance (20.8% vs 9.9% severe, p = 0.034). CONCLUSIONS: This pilot demonstrated that compliance was high with blood tests performed every four months for ovarian cancer surveillance. Moreover, ROCA women had lower stress scores over time than SOC women. Given the lack of clinical utility and poor compliance shown with traditional ultrasound and CA125 tests, further investigation is warranted of longitudinal biomarker surveillance for early detection of ovarian cancer.

Prediction of Occult Uterine Sarcoma before Hysterectomy for Women with Leiomyoma or Abnormal Bleeding.

STUDY OBJECTIVE: To develop a risk prediction model for occult uterine sarcoma using preoperative clinical characteristics in women undergoing hysterectomy for presumed uterine leiomyomata. DESIGN: Cases of uterine sarcoma were identified from the electronic medical records. Age/race-matched controls were selected at a 2:1 ratio (controls:cases) from a cohort of 45 188 women who underwent hysterectomy for uterine leiomyomata or abnormal bleeding during the same time interval. Unadjusted conditional logistic regression was performed to identify risk factors for occult uterine sarcomas, defined as no preoperative suspicion for malignancy. A risk prediction model was developed using a weighted logistic regression model, and the performance of the model was assessed using the receiver operator characteristic curve and corresponding area under the curve. SETTING: A large integrated health care system in California PATIENTS: Women 18 years of age and older who underwent a hysterectomy and were diagnosed with a uterine sarcoma and matched controls from 2006 to 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 117 cases of occult uterine sarcomas that met inclusion criteria during the study period. The final risk prediction model included age, race/ethnicity, number of myomas, uterine weight, uterine size increase, degree of pelvic pain, and recent history of blood transfusion. The risk prediction model showed high accuracy based on the receiver operating characteristic curve method (area under the curve = 0.83; 95% confidence interval, 0.77-0.90); however, the positive predictive values were low (0.048 or less) at all risk thresholds. CONCLUSION: Multiple clinical features are associated with the presence of a uterine sarcoma, but when incorporated into a prediction model, they fail to provide significantly more information about women who may have an unrecognized sarcoma and only marginally improve the certainty about women who are not likely to have sarcoma.

Non-malignant Sequelae after Unconfined Power Morcellation.

STUDY OBJECTIVE: To identify the incidence of repeat surgery and subsequent findings after the performance of unconfined uterine power morcellation. DESIGN: A retrospective descriptive study (Canadian Task Force classification II-2). SETTING: Southern California Kaiser Permanente Medical Centers. PATIENTS: Women (N = 5154) who underwent laparoscopic supracervical hysterectomy with unconfined power morcellation. MEASUREMENTS AND MAIN RESULTS: Of the 5154 cases, 279 (5.41%) underwent subsequent reoperation with a median of 24 months after index surgery. The most common clinical complaint leading to laparoscopic supracervical hysterectomy was symptomatic leiomyoma (n = 135, 48.4%) and abnormal uterine bleeding (n = 94, 33.7%). The most common indication for reoperation was a symptomatic adnexal mass (n = 87, 31.2%) followed by pelvic pain (n = 83, 29.7%). The majority (n = 128, 60.4%) of subsequent non-urogynecologic-related reoperations resulted in benign pathology. Endometriosis was the primary pathologic diagnosis in 65 of 279 (23.3%) of the reoperative cases; this was not previously documented in 86% (n = 57/65) of these cases. The overall frequency of subsequent pathology was endometriosis (65/5154, 1.26%), disseminated leiomyomatosis (18/5154, 0.35%), and new malignancy (11/5154, 0.21%). CONCLUSION: Morcellation of nonmalignant tissue is not without consequence. Pathology confirmed endometriosis was documented for the first time in 20.4% of patients who underwent a second surgery. This finding raises the suspicion that morcellation and dispersion of the uterine specimen may be associated in the development of endometriosis.

Adjuvant gemcitabine-docetaxel chemotherapy for stage I uterine leiomyosarcoma: Trends and survival outcomes.

OBJECTIVE: To assess recent trends of administering adjuvant gemcitabine-docetaxel (GD) chemotherapy for Stage I uterine leiomyosarcoma, and to compare disease-free and overall survival between women who received and did not receive adjuvant GD chemotherapy. METHODS: All patients diagnosed with Stage I uterine leiomyosarcoma in a California-Colorado population-based health plan inclusive of 2006-2013 were included in a retrospective cohort. Adjuvant GD chemotherapy rates, clinico-pathologic characteristics and survival estimates were assessed. RESULTS: Of 111 women with Stage I uterine leiomyosarcoma, 33 received adjuvant GD (median 4cycles), 77 received no chemotherapy, and 1 patient excluded for non-GD chemotherapy. GD-chemotherapy and no-chemotherapy groups were similar with respect to age, stage (IA/IB), uterine weight, mitotic index, body mass index, and Charlson comorbidity score. Non-Hispanic white women were twice as likely to receive adjuvant chemotherapy as non-white or Hispanic women (37.7 vs. 17.1%, P=0.02). The proportion of women receiving adjuvant GD chemotherapy increased from 6.5% in 2006-2008 to 46.9% in 2009-2013 (P<0.001). There was no significance difference in unadjusted Kaplan-Meyer estimated disease-free (P=0.95) or overall survival (P=0.43) between GD-chemotherapy and no-chemotherapy cohorts. Corresponding adjusted Cox proportional hazard ratios for adjuvant GD chemotherapy compared to no chemotherapy were 1.01 (95% confidence interval [CI] 0.57-1.80, P=0.97) for recurrence and 1.28 (95% CI 0.69-2.36, P-0.48) for mortality. CONCLUSIONS: Use of adjuvant GD chemotherapy for Stage I uterine leiomyosarcoma has increased significantly in the last decade, despite unclear benefit. Compared to no chemotherapy, 4-6cycles of adjuvant GD chemotherapy does not appear to alter survival outcomes.

Preoperative Vaginal Metronidazole Decreases the Risk of Pelvic Infections After Radical Robotic Hysterectomy.

OBJECTIVES: Risk factors and infection rates of radical robotic procedures have yet to be described in gynecology. A practice improvement strategy using a solitary dose of vaginal metronidazole the night before surgery was initiated to determine if it decreased the risk of pelvic infection. METHODS: A retrospective chart review of robotic radical hysterectomies for gynecologic malignancy at our institution from April 2010 through April 2016 was performed. Demographic data, operative data, and data on use of metronidazole before surgery were collected. χ Statistical analysis, Student t test, and multivariate analysis were performed to analyze the data. RESULTS: Ninety-four patients met the inclusion criteria, and 46 patients received vaginal metronidazole. Demographic and clinical factors were similar between the 2 groups. The pelvic infection rate was significantly higher in nonusers at 13% (6/46) compared with users at 0% (0/42) (P ≤ 0.05). The genitourinary infection rate was also significantly higher in nonusers at 20% as compared with users at 2.2% (P = 0.02). Operative risk factors found to be associated with pelvic infection included hospital length of stay, blood loss, and metronidazole use. Multivariate regression analysis determined that only vaginal metronidazole had a clinically significant reduction of pelvic and genitourinary infection. DISCUSSION: A single dose of preoperative vaginal metronidazole reduces the risk of pelvic and genitourinary infection after robotic radical hysterectomy.

Same-day discharge is feasible and safe in patients undergoing minimally invasive staging for gynecologic malignancies.

OBJECTIVE: The objective of the study was to evaluate the feasibility and safety of same-day discharge of patients undergoing minimally invasive comprehensive surgical staging for endometrial and cervical cancer. STUDY DESIGN: We performed a retrospective review of consecutive patients from January 2008 to December 2011 undergoing comprehensive staging for endometrial or cervical cancer by traditional laparoscopy or robotic-assisted laparoscopy and intended for same-day discharge. Patients accomplishing same-day discharge were compared with those who required admission. Clinical and demographic data, perioperative outcomes, and postoperative patient contacts within 6 weeks were collected. Multivariate logistic regression modeling was used to determine factors associated with admission and unscheduled patient contacts within 2 weeks of surgery. RESULTS: A total of 141 patients were identified. One hundred eighteen patients (83.7%) underwent same-day discharge and 23 (16.3%) required overnight admission. The variables that significantly predicted overnight admission were severe pain in the postanesthesia care unit (odds ratio [OR], 6.81; 95% confidence interval [CI], 1.74-26.6; P = .006), delayed ability to tolerate oral intake (OR, 9.3; 95% CI, 2.25-38.6, P = .002), traditional laparoscopic vs robotic-assisted surgical approach (OR, 9.05; 95% CI, 2.34-35.1; P = .001), and surgery start time at 2:00 pm or later (OR, 36.8; 95% CI, 6.19-219.3; P < .0001). There was no difference in the readmission rate between patients undergoing same-day discharge compared with overnight admission (11% vs 17%, P = .48). No variables significantly predicted unscheduled patient contact within 2 weeks of surgery at P < .01. CONCLUSION: Same-day discharge for patients undergoing laparoscopic or robotic-assisted laparoscopic staging for endometrial or cervical cancer is feasible and safe. There are low complication rates and few readmissions or unscheduled patient contacts within 2 weeks of surgery.

Lymph Node Micrometastases in Early-Stage Cervical Cancer are Not Predictive of Survival.

Although patients with early-stage cervical cancer have in general a favorable prognosis, 10% to 40% patients still recur depending on pathologic risk factors. The objective of this study was to evaluate if the presence of lymph node micrometastasis (LNmM) had an impact on patient's survival. We performed a multi-institutional retrospective review on patients with early-stage cervical cancer, with histologically negative lymph nodes, treated with radical hysterectomy and pelvic lymphadenectomy for the study period 1994 to 2004. Tissue blocks of lymph nodes from the patient's original surgery were recut and then evaluated for the presence of micrometastases. One hundred twenty-nine patients were identified who met inclusion criteria. LNmM were found in 26 patients (20%). In an average follow-up time of 70 mo, there were 11 recurrences (8.5%). Of the 11 recurrences, 2 (18%) patients had LNmM. Patients with LNmM were more likely to have received adjuvant radiation and chemotherapy. In stratified log-rank analysis, LNmM were not associated with any other high-risk clinical or pathologic variables. Survival data analysis did not demonstrate an association between the presence of LNmM and recurrence or overall survival. The presence of LNmM was not associated with an unfavorable prognosis nor was it associated with other high-risk clinical or pathologic variables predicting recurrence. Further study is warranted to understand the role of micrometastases in cervical cancer.

Is older age a poor prognostic factor in stage I and II endometrioid endometrial adenocarcinoma?

OBJECTIVE: Prior studies have shown that age ≥70 years is associated with more aggressive non-endometrioid histology and worse survival in endometrial cancer. The purpose of this study is to assess if age is an independent poor prognostic factor in endometrioid histologies. METHODS: Under an IRB-approved protocol, we identified patients with surgical stage I to II endometrioid endometrial adenocarcinoma from 1995 to 2008 at two institutions. Patients were divided into two groups based on age at diagnosis: Group A (age 50-69 years) and Group B (age≥70 years). All patients underwent hysterectomy, bilateral salpingoophorectomy, +/-pelvic/aortic lymphadenectomy and adjuvant therapy. Prognostic factors were evaluated by univariate and multivariate analyses. RESULTS: We identified 338 patients with stage IA to IIB endometrioid endometrial adenocarcinoma. The median age in Group A was 59 years (range 50-69) and Group B was 75 years (range 70-92). Patients in Group B were more likely to have hypertension (51% vs. 68%, p=0.006) and coronary artery disease (9% vs. 18%, p=0.03). There were no differences in progression-free or disease-specific survival, however, Group B had a worse overall survival (OS) (50.1 vs. 62.6 months, p=0.03). On univariate analysis, age (p=0.04), grade (p=0.006), and coronary artery disease (p=0.01) were associated with worse OS. After adjusting for grade and coronary artery disease, age was no longer a significant variable for OS (p=0.17). CONCLUSIONS: After adjusting for other poor prognostic factors, age ≥70 years alone may not be a significant variable affecting overall survival in patients with early stage endometrioid endometrial adenocarcinoma.

Role of adjuvant chemotherapy in patients with early stage uterine papillary serous cancer.

OBJECTIVE: Uterine papillary serous carcinoma (UPSC) is an aggressive subtype of endometrial cancer. We studied survival outcomes in patients with stages I/II UPSC. MATERIALS: A retrospective, multi-institutional study of patients with stages I/II UPSC was conducted. Patients underwent surgical staging followed by observation, adjuvant platinum-based chemotherapy (CT), or radiation therapy (RT). Continuous variables were compared via Wilcoxon rank sum test; Fisher exact test was used for the unordered categorical variables. Kaplan-Meier curves were used to estimate survival. RESULTS: Thirty-nine women were diagnosed with stage I (n = 30) or II (n = 9) UPSC, with a median follow-up of 52 months. Of the 26 patients who did not receive adjuvant CT, 9 developed recurrences and 8 died of their disease. Of the 10 patients with no myometrial invasion who did not receive adjuvant CT, 3 developed recurrences and died. Of the 7 patients who underwent RT, 2 developed distant recurrences and died. Of the 13 patients who underwent CT, 1 developed vaginal recurrence. The 5-year overall (OS) and progression-free survival (PFS) rates for the adjuvant CT group were 100% and 92%, respectively, compared with 69% and 65% for those who did not receive CT (P = 0.002 OS, P = 0.002 PFS). The 5-year OS and PFS rates for RT group were both 71%. CONCLUSIONS: Patients with stages I/II UPSC are at significant risk for distant recurrence and poor survival. Platinum-based adjuvant CT may decrease recurrence rate and improve survival in women with early and well-staged UPSC.

Occult Uterine Sarcoma and Leiomyosarcoma: Incidence of and Survival Associated With Morcellation.

OBJECTIVE: To estimate the incidence of occult uterine sarcoma and leiomyosarcoma in hysterectomies for leiomyomas and the risk associated with their morcellation. METHODS: We conducted a population-based cohort study. All uterine sarcomas from 2006-2013 in an integrated health care system were identified. Age- and race-specific incidences of occult uterine sarcoma were calculated. Kaplan-Meier survival analysis was performed. Crude and adjusted risk ratios of recurrence and death associated with morcellation at 1, 2, and 3 years were estimated using Poisson regression with inverse probability weighting. RESULTS: There were 125 hysterectomies with occult uterine sarcomas identified among 34,728 hysterectomies performed for leiomyomas. The incidence of occult uterine sarcoma and leiomyosarcoma was 1 of 278 or 3.60 (95% confidence interval [CI] 2.97-4.23) and 1 of 429 or 2.33 (95% CI 1.83-2.84) per 1,000 hysterectomies. For stage I leiomyosarcoma (n=111), eight (7.2%) were power and 27 (24.3%) nonpower-morcellated. The unadjusted 3-year probability of disease-free survival for no morcellation, power and nonpower morcellation was 0.54, 0.19, and 0.51, respectively (P=.15); overall survival was 0.64, 0.75, and 0.68, respectively (P=.97). None of the adjusted risk ratios for recurrence or death were significant except for death at 1 year for power and nonpower morcellation groups combined (6/33) compared with no morcellation (4/76) (5.12, 95% CI 1.33-19.76, P=.02). We had inadequate power to infer differences for all other comparisons including 3-year survival and power morcellation. CONCLUSION: Morcellation is associated with decreased early survival of women with occult leiomyosarcomas. We could not accurately assess associations between power morcellation and 3-year survival as a result of small numbers.

Detection of residual subclinical ovarian carcinoma after completion of adjuvant chemotherapy.

PURPOSE: We sought to test the hypothesis that the presence of telomerase activity in peritoneal washings of patients treated for ovarian carcinoma is a sensitive and specific indicator of the presence of residual disease. We hypothesized that this test, if added to second-look procedure protocols, could help determine whether residual disease is present or not in patients who have completed their adjuvant chemotherapy for ovarian carcinoma. EXPERIMENTAL DESIGN: Peritoneal washings were obtained from 100 consecutive patients undergoing a second-look procedure after treatment for ovarian carcinoma (cases) and from 100 patients undergoing surgery for benign gynecological conditions (controls). The washings were assayed for telomerase activity using the telomerase repeat amplification protocol. The results were compared to the histological and cytological findings. RESULTS: Among our 100 cases, 82 (82%) had either positive second-look procedures or expressed telomerase in their peritoneal washings. Fifty-three (53%) had positive second-look procedures, whereas 66 (66%) tested positive for telomerase. Twenty-nine of the 47 patients (62%) with negative second-look procedures tested positive for telomerase. Of the 53 patients with positive second-look procedures, 37 (70%) tested positive for telomerase. None of the 100 controls (0%) expressed telomerase in their peritoneal washings. CONCLUSIONS: Telomerase activity in peritoneal washings of patients treated for ovarian carcinoma and undergoing a second-look procedure may provide a means of increasing the sensitivity of such procedures for the detection of residual disease while maintaining a high level of specificity.

Metformin and breast and gynecological cancer risk among women with diabetes.

OBJECTIVE: We investigated if metformin lowers breast, endometrial, and ovarian cancer risk in women with type 2 diabetes mellitus compared with women who used other antidiabetic medications. RESEARCH DESIGN AND METHODS: We followed a cohort of 66 778 female patients with diabetes for a maximum of 12 years (median 6 years). We examined breast, endometrial, and ovarian cancer risk, and the composite cancer risk. We examined drug categories using pharmacy records: metformin only; metformin combination regimens; non-metformin regimens; and non-users. We used χ(2) analyses to examine categorical variables. We conducted multivariable Cox regression models with time-dependent drug use status. RESULTS: Women who used metformin combination regimens versus metformin only had a 15% lower breast cancer risk (adjusted HR=0.85, 95% CI 0.69 to 1.04). After stratifying by glycated hemoglobin (HbA1c), the association attenuated in those who had poorly controlled HbA1c (adjusted HR=1.06, 95% CI 0.73 to 1.55). Given the small numbers of ovarian and endometrial cancer outcomes, we examined these as a composite. The risk of all cancers combined was similar in those who used metformin combination regimens versus metformin only (adjusted HR=0.92, 95% CI 0.78 to 1.10). We found no significant differences for breast cancer or all cancers combined when we compared risks in non-metformin users versus metformin only users. CONCLUSIONS: Women who used metformin and other antidiabetic drugs had a lower breast cancer risk compared with women who used metformin only, but the results were not significant. We also found no difference in overall cancer risks when we compared women who used other antidiabetic drugs (no metformin) versus metformin users.

Identification of micrometastases in histologically negative lymph nodes of early-stage cervical cancer patients.

OBJECTIVE: Despite histologically negative lymph nodes, approximately 15% of patients with early-stage cervical cancer will develop recurrence. Micrometastases have been shown to be important in staging and treatment of breast cancers and melanoma and have been identified by polymerase chain reaction analysis in cervical cancers. This study sought to estimate the frequency of micrometastases identified by immunohistochemistry in histologically negative lymph nodes and compare this to other known risk factors for recurrence of cervical cancer. METHODS: Early-stage (stages IA2, IB1, and IB2) cervical cancer patients of all histologic subtypes were identified from the surgical logs of the Los Angeles County-University of Southern California Medical Center for the period 1994-2000. One hundred thirty-two patients had histologically negative lymph nodes. Immunohistochemical assay was performed on 3,106 lymph nodes by using antibodies against cytokeratins AE-1 and CAM 5.2 in combination according to standard protocols. The stained nodes were then evaluated for the presence of micrometastases and compared against the respective clinicopathologic information in each case. RESULTS: Micrometastases were detected in 19 of 132 (15%, 95% confidence interval [CI] 9%, 22%) patients, found in 29 of the 3,106 (0.9%) lymph nodes evaluated. Vascular space invasion was seen in 50 of 132 cases (38%, 95% CI 30%, 47%) and in 8 of 19 (42%, 95% CI 21%, 66%) cases with micrometastases. Surgical margins of the resected specimen were negative in 120 of 132 cases (91%, 95% CI 84%, 95%) and in 16 of 19 (84%, 95%CI 60%, 96%) of those cases with micrometastases. Micrometastases were seen most frequently in pelvic lymph nodes (25 of 29, 86%). Patients with more than 20 lymph nodes removed were more likely to demonstrate metastasis (P <.001). There was no statistically significant association between micrometastasis and vascular space invasion or tumor volume. CONCLUSION: Micrometastases are identifiable in histologically negative lymph nodes in 15% (95% CI 9%, 22%) of early-stage cancer patients, a frequency which approximates the recurrence rate for patients with negative nodes. In this series, patients with greater numbers of lymph nodes analyzed were more likely to have lymph node micrometastasis identified. There appears to be no relationship between tumor volume and the identification of micrometastases. Although micrometastases can be identified in histologically negative lymph nodes, their presence is not strongly associated with other known factors of cervical cancer recurrence. Further research is needed to determine whether the presence of lymph node micrometastases is associated with an unfavorable prognosis. LEVEL OF EVIDENCE: II-3

Lymphovascular and perineural invasion in the parametria: a prognostic factor for early-stage cervical cancer.

OBJECTIVE: To estimate the impact of parametrial lymphovascular and perineural involvement on nodal metastasis and failure pattern of women with early-stage, surgically treated cervical cancer. METHODS: Clinical records and pathologic slides of 93 patients with early-stage cervical cancer (2 IA2, 52 IB1, 31 IB2, and 8 IIA) treated with radical hysterectomy and pelvic lymphadenectomy with or without paraaortic lymphadenectomy were reviewed. The study group comprised 80 patients with squamous cell carcinoma and 13 patients with adenocarcinoma of the cervix. Median follow-up time was 33 months. The association among the various histopathologic predictors of outcome was determined with chi2 analysis. The influence of the predictors on outcome was examined with log rank survival methods and the Cox regression model. RESULTS: The presence of parametrial lymphovascular space invasion is a predictor of disease in the pelvic (P<.001) and paraaortic (P<.05) lymphatics independently. Large tumor size (greater than 4 cm), parametrial perineural invasion, cervical lymphovascular space invasion, and tumor depth (greater than two thirds) were found to be simultaneous predictors of recurrence on multivariate analysis (P<.05). Using these four binary predictor variables, we have computed a model-based relative risk. Based on this model, the presence of perineural invasion in the parametria more than doubles the risk of recurrence in the cohort of patients with large (greater than 4 cm) tumors (P<.05). In a subset analysis of patients with negative nodal disease, parametrial perineural invasion and tumor size were independent predictors of poor outcome (P<.05). CONCLUSION: Presence of parametrial lymphovascular space invasion correlates significantly with the risk of nodal metastasis in women with early-stage cervical cancer. Parametrial perineural invasion is an independent poor prognostic factor. Histopathologic findings within the parametria are a valuable independent predictor of recurrence and thus may influence the selection of patients for adjuvant treatment.

Abdominal aortic resection and Y-graft placement to achieve complete cytoreduction in stage IIIc ovarian carcinoma.

BACKGROUND: Major vascular resection with reconstruction in patients with gynecologic malignancy is rarely performed and infrequently reported. CASE: A 40-year-old woman undergoing surgery for stage IIIc ovarian papillary serous adenocarcinoma was left with a 7-cm aortic metastasis not separable from the infrarenal abdominal aorta. An aortic resection with prosthetic graft placement was performed to achieve complete tumor resection. She remains disease-free in excess of 10 years with no evidence of graft complication. CONCLUSION: Major vascular reconstructive procedures for the management of malignancy need not be precluded in properly selected circumstances.