Malignant transformation of mature cystic teratoma of the ovary: 30-year experience of a single tertiary care center.

OBJECTIVE: To review the authors' experience with this rare disease and describe their management modality and the outcome. MATERIAL AND METHODS: From January 1983 to December 2013, 13 patients with malignant transformation arising in ovarian MCT were treated at the Division of Gynecologic Oncology in the University of Manitoba. Demographic characteristics, symptoms, signs, stage, mode of therapy, and results of follow-up were reviewed retrospectively. RESULTS: Median age at diagnosis was 53 years (range 25-65). The most common presenting symptom was a palpable mass in nine cases. Squamous cell carcinoma (SCC) was found in 38% (five cases), adenocarcinoma in 15% (two cases), anaplastic carcinoma in 8% (one case), and papillary thyroid carcinoma in 38% (five cases). Eight cases were Stage I, two cases were Stage II, and three cases were Stage III. All patients underwent surgery. Five patients received adjuvant treatment with platinum-based chemotherapy + pelvic radiation. Four patients had recurrent disease (two SCC and two adenocarcinoma). Three patients died of disease after recurrence. The median follow up period of the entire patient population was 60 months, with a three-year overall survival of 76%. CONCLUSION: Malignant transformation of MCT is large ovarian tumors that mainly occur in patients in their fifth and sixth decades of life. They often present as incidental pathologic findings after surgery for MCT. SCC has traditionally been the most common pathology, however in the present series, the authors found that papillary thyroid carcinoma was equally common. Platinum-based chemotherapy with pelvic radiation in early stage (including Stage IA) and locally recurrent dis- ease should be offered. Advanced stages and mucinous adenocarcinoma represent a poorer prognosis despite adjuvant treatment. In patients with papillary thyroid carcinoma, conservative surveillance in early stage and adjuvant total thyroidectomy with radioactive iodine treatment in advanced stage disease appears to be an effective treatment.

Assessing the impact of mailing self-sampling kits for human papillomavirus testing to unscreened non-responder women in Manitoba.

Background: CervixCheck, Manitoba's cervical cancer screening program, conducted a pilot study to assess whether screening participation could be improved in unscreened women by offering a mailed self-sampling kit for human papillomavirus (hpv) testing instead of a Pap test. Methods: In a prospective cohort study design, a sample of unscreened women (n = 1052) who had been sent an invitation letter from CervixCheck in the past but who did not respond were randomized to either an intervention group or a control group. The intervention group received a mailed hpv self-sampling kit; the control group received no additional communication. Returned hpv self-sampling swabs were analyzed by a provincial laboratory. After 6 months, screening participation in the two study groups was compared using a logistic regression model adjusted for age and area of residence (urban or rural). Secondary outcomes included hpv positivity, specimen inadequacy, compliance with follow-up, and time to colposcopy. Results: Screening participation was significantly higher in the intervention group than in the control group (n = 51, 9.6%, vs. n = 13, 2.5%; odds ratio: 4.7; 95% confidence interval: 2.56 to 8.77). Geographic area of residence (urban or rural) and age were not statistically significant. Conclusions: The study demonstrated that hpv self-sampling kits can enhance screening participation in unscreened non-responder women in the setting of an organized screening program. Next steps should include additional research to determine the best implementation strategy for hpv self-sampling in Manitoba.

Measuring colposcopy quality in Canada: development of population-based indicators.

Background: Colposcopy is a key part of cervical cancer control. As cervical cancer screening and prevention strategies evolve, monitoring colposcopy performance will become even more critical. In the present paper, we describe population-based colposcopy quality indicators that are recommended for ongoing measurement by cervical cancer screening programs in Canada. Methods: The Pan-Canadian Cervical Cancer Screening Network established a multidisciplinary expert working group to identify population-based colposcopy quality indicators. A systematic literature review was conducted to ascertain existing population and program-level colposcopy quality indicators. A systems-level cervical cancer screening pathway describing each step from an abnormal screening test, to colposcopy, and back to screening was developed. Indicators from the literature were assigned a place on the pathway to ensure that all steps were measured. A prioritization matrix scoring system was used to score each indicator based on predetermined criteria. Proposed colposcopy quality indicators were shared with provincial and territorial screening programs and subsequently revised. Results: The 10 population-based colposcopy quality indicators identified as priorities were colposcopy uptake, histologic investigation (biopsy) rate, colposcopy referral rate, failure to attend colposcopy, treatment frequency in women 18-24 years of age, re-treatment proportion, colposcopy exit-test proportion, histologic investigation (biopsy) frequency after low-grade Pap test results, length of colposcopy episode of care, and operating room treatment rate. Two descriptive indicators were also identified: colposcopist volume and number of colposcopists per capita. Summary: High-quality colposcopy services are an essential component of provincial cervical cancer screening programs. The proposed quality and descriptive indicators will permit colposcopy outcomes to be compared between provinces and across Canada so as to identify opportunities for improving colposcopy services.

Treatment of recurrent and metastatic adenocarcinoma of the endometrium with cisplatin, doxorubicin, cyclophosphamide, and medroxyprogesterone acetate.

We conducted a retrospective review of 44 patients with metastatic or recurrent endometrial carcinoma treated with cisplatin, doxorubicin, cyclophosphamide, and medroxyprogesterone acetate. Thirty-six women had metastatic disease; eight had recurrent disease. In the metastatic group, 12 women had positive peritoneal cytology as the only criterion for metastatic disease. Grade 1 tumors represented 25%, grade 2, 47.7%, and grade 3, 27.3%. The series was divided into four groups based on disease volume before chemotherapy: positive peritoneal cytology only (N = 12), microscopic (N = 11), macroscopic less than 2 cm (N = 6), and macroscopic greater than 2 cm (N = 15). Fifteen patients had measurable disease and eight (53%) had an objective response. The median survival was 31 months for the whole group. Median survivals were not reached for the positive peritoneal cytology only and the microscopic groups. Median survival for the macroscopic less than 2 cm and greater than 2 cm groups were 15 and 10 months, respectively (P less than .0001). The volume of disease was the most important factor in determining survival as well as the time to progression (P less than .0001). The distribution of grade was similar in all groups (P = .88), and grade did not predict survival (P = .80) or recurrence (P = .87). The significant number of low-grade lesions in our series as well as the importance of positive cytology as a predictor of survival underscore the need for surgical pathologic staging in an effort to identify those patients in need of adjuvant therapy.

Papillary serous adenocarcinoma of the endometrium.

The clinical outcome of 15 women with papillary serous adenocarcinoma of the endometrium is presented. In 14 instances the diagnosis was made by uterine curettage. Eight cases (53.3%) were clinically understaged based on laparotomy findings. Intraoperative assessment for extrauterine spread of disease was infrequently performed. Recurrent disease developed in 12 patients (80.0%) with ten arising within the abdomen either alone or in conjunction with another site. Eleven patients (73.3%) have died of disease and two of the four alive have been treated for a recurrence. The need to determine appropriate adjuvant therapy for patients with this disease exists. A protocol for patient management is proposed.

Peritoneovenous shunt for palliation of gynecologic malignant ascites.

BACKGROUND: Ascites is a common sequela of advanced or recurrent gynecologic malignancies, such as carcinoma of the ovary, fallopian tube, or endometrium. Symptomatic treatment with repeated paracentesis is the initial management after failure of chemotherapy. STUDY DESIGN: This study was done to evaluate the safety and effectiveness of a peritoneovenous shunt (PVS) in the palliation of these patients with recurrent ascites. A retrospective review of 25 patients having a PVS between 1982 and 1992 was performed. RESULTS: The 25 patients consisted of 21 patients with carcinoma of the ovary, two with primary carcinoma of the peritoneum, one with carcinoma of the endometrium, and one patient with carcinoma of the fallopian tube. The mean weight and abdominal girth decreased after shunt insertion (p < 0.001). Gastrointestinal dysfunction and dyspnea also improved with PVS insertion. There was no change in mean Karnofsky score after placement of a PVS. Two patients died within ten days postoperatively. The median survival period was 80 days and shunt occlusion occurred in four patients. CONCLUSIONS: The insertion of a PVS is effective in relieving refractory malignant ascites in gynecologic malignancies. The impact on quality of life requires further study.

Antiestrogens affect both pathways of killer cell-mediated oncolysis.

BACKGROUND: Our previous studies indicate that antiestrogenic drugs tamoxifen (TX) and toremifene (TO) augment immune oncolysis induced by various killer cells. The underlying mechanism(s), however, have not been fully elucidated. MATERIALS AND METHODS: Ovarian carcinoma cells freshly isolated from cancer patients and the human erythroleukemia cell line, K562 were used as targets for killer cells and/or the anti-Fas monoclonal antibody, CH-11 in 51Cr release assays. In a number of experiments, extracellular Ca++ was chelated by EGTA/MgCl2 to distinguish Ca(++)-dependent perforin/granzyme pathway from Fas/FasL pathway. Fas expression was studied by flow cytometry. RESULTS: Ovarian carcinoma cells were sensitized by antiestrogens towards enhanced cytolysis mediated by autologous cytotoxic lymphocytes. Antiestrogens also significantly augmented the killing of ovarian carcinoma cells triggered by anti-Fas monoclonal antibody. Flow cytometry analyses showed an upregulation of Fas (CD 95/Apo-1) upon TX or TO treatment in a number of cases. By contrast, antiestrogen treatment did not induce Fas expression in the Fas-negative K562 cells; yet, natural killer cell-mediated cytotoxicity against K562 was augmented by antiestrogens and maximal lysis was achieved when both target and effector cells were treated. The presence of Ca++ chelator (EGTA/MgCl2) in the assay abrogated killing of K562 and its antiestrogen--mediated augmentation. This indicates the involvement of the perforin/granzyme pathway. CONCLUSION: Antiestrogens can influence both Fas/FasL and perforin/granzyme pathways of killer cell--mediated oncolysis.

Antiestrogens sensitize human ovarian and lung carcinomas for lysis by autologous killer cells.

BACKGROUND: The antiestrogens tamoxifen (TX) and toremifene (TO) were shown previously to enhance the lysis of target cells by natural killer cells (NK), lymphokine activated killer (LAK) cells, and by cytotoxic T lymphocytes (CTL). MATERIALS AND METHODS: CTL were cultured from lung cancer tissue and from ascites fluid of ovarian carcinoma patients with the aid of human recombinant interleukin-2 (hrIL-2). The target, effector or both cell populations were pretreated by TX, TO and/or with human recombinant interferon-alpha (IFN-alpha). RESULTS: Significant enhancement of cytotoxicity occurred when the tumor targets or both the target and effector cells were treated with TX, TO or when these drugs were used in combination with IFN-alpha. The lytic activity of CTL cultured from draining lymph nodes of lung cancer patients, was also observed after similar treatment. The lytic effect of autologous LAK cells derived from peripheral blood was increased to a lesser extent, which could be amplified by additional treatment with IFN-alpha. CONCLUSIONS: The antiestrogens TX and TO and IFN-alpha enhance the lysis of autologous tumor cells by CTL and LAK effectors.

Early ovarian cancer: what is the staging impact of retroperitoneal node sampling?

BACKGROUND: Comprehensive surgical staging of apparent early-stage epithelial ovarian cancer includes peritoneal washings, biopsies, and retroperitoneal lymph node dissection. Unresolved is the relative frequency or importance of the lymph node dissection. OBJECTIVES: (1) To determine the site(s) of microscopic metastatic disease in women undergoing a comprehensive staging for apparent early-stage cancer of the ovary; (2) to identify those women with metastases in the retroperitoneal lymph nodes alone. METHODS: Between 1985 and 2000, we reviewed all records of women at cancer centres in Winnipeg, Ottawa, and Saskatoon who had undergone a "staging laparotomy" for an apparent early-stage IA epithelial cancer of the ovary. Histology, tumour grade, initial and final surgical stage, and the site(s) of metastatic disease were recorded for all cases. RESULTS: Forty-three of the 128 women (34%) had a final surgical stage of II or III. Sixteen women had positive pelvic biopsies, while 19 had microscopic upper abdominal disease. Eight women had positive retroperitoneal nodes, and in only 2 of these women, disease was found in the retroperitoneal nodes alone. In the 8 women with nodal disease, 5 had grade 3 tumours and 6 had serous histology tumours. CONCLUSION: Comprehensive staging is important to identify women with metastatic disease. Solitary nodal metastases are predominantly found in grade 3 and serous tumours.

Mixed Mullerian tumors of the uterus: clinical and pathologic correlations.

The 10-year experience at The Johns Hopkins Hospital with 61 cases of mixed Mullerian tumors were reviewed. The patients had a mean age of 63.7 years and the similar constitutional factors of diabetes mellitus, hypertension and nulliparity of endometrial adenocarcinoma. Only one patient had estrogen exposure. Eighteen percent had had prior exposure to pelvic radiation. The life table survival of the 61 patients was 41.1% at 5 years. The 2-year life table survival was 76% for disease confined to the uterus and 16.5% for extrauterine disease. There was no difference in survival between homologous and heterologous tumors. The surgical staging and the autopsies reviewed documented widely disseminated disease even when the tumor appeared to be confined to the uterus. It thus appears essential in order to improve survival these patients require aggressive staging and consideration of systemic adjuvant chemotherapy.

Early ovarian cancer: value of a negative staging laparotomy.

OBJECTIVE: To assess the risk of recurrence in patients with stage I (negative cytology) epithelial ovarian cancer receiving no adjuvant therapy. METHODS: Between 1976 and 1991, 51 patients with apparent stage I ovarian cancer underwent a comprehensive surgical staging that included: peritoneal cytology, omentectomy, pelvic and para-aortic lumphadenectomy, peritoneal biopsies and either unilateral salpingo-oophorectomy or TAH and BSO. RESULTS: Eleven of 51 patients (22%) were found to have stage II or III disease based on a positive staging laparotomy. Thirty-seven of 40 patients with stage I disease received no further therapy. There was one recurrence (stage 1C - grade 1) in patients with surgical stage 1C while there were no recurrences in patients with either stage 1A or 1B disease. CONCLUSION: This study concludes that surgical staging in apparent early stage ovarian cancer can identify a group of patients that require surgical therapy alone.

Changes in cervical cancer screening behavior for women attending Pap Test Week clinics.

OBJECTIVE: This retrospective study of all women who accessed the 2006 Manitoba Pap Test Week clinics was designed to determine factors associated with inadequate cervical cancer screening and changes in cervical cancer screening behavior. METHODS: Data were acquired using the CervixCheck Manitoba registry and an ancillary database of demographic information collected from clinic attendees. RESULTS: The study included 1124 women. Of these, 53% (n = 598) were under-screened (no Pap test in the previous 2 years) prior to accessing the clinics. Logistic regression analyses demonstrated that older age (odds ratio [OR] = 1.02, 95% confidence interval [CI] 1.01-1.03), no doctor (OR = 1.4, 95% CI 1.05-1.54), and living in Canada < 1 year (OR = 5.5, 95% CI 2.73-11.12) were associated with being under-screened prior to accessing the Pap Test Week clinics. Thirty-seven percent (n = 223) of under-screened women demonstrated improved screening status subsequent to the 2006 Pap Test Week (had a subsequent Papanicolaou [Pap] test performed within 2 years) and these women were more likely to live in an urban setting (P = 0.003), be younger (P < 0.001), originate outside Canada (P = 0.006), have lived in Canada for less than 1 year (P = 0.006), and have had an abnormal Pap test result in 2006 (P < 0.001). Previously under-screened women were less likely to become adequately-screened subsequent to 2006 if they had a Pap test performed at a Pap Test Week clinic compared to having a Pap test performed elsewhere (37% versus 60%, P < 0.001). CONCLUSION: This study identified a subset of under-screened women accessing Pap Test Week clinics whose screening status might be most modifiable.

Distribution of human papillomavirus types, cervical cancer screening history, and risk factors for infection in Manitoba.

OBJECTIVES: We conducted a study to investigate the prevalence of human papillomavirus (HPV) infections in an opportunistic sample of women in Manitoba, Canada. We inquired about risk factors associated with HPV infections and linked the HPV typing results with the cervical cancer screening history of the participants. METHODS: The study population included 592 women attending Papanicolaou (Pap) test clinics. After signing a consent form, participants were given a self-administered questionnaire on risk factors and received a conventional Pap test. Residual cells from the Pap tests were collected and sent for HPV typing. RESULTS: The mean age of the population was 43 years. A total of 115 participants (19.4%) had an HPV infection, 89 of whom had a normal Pap test. Of those who were HPV-positive, 61 (10.3%) had high-risk (Group 1) HPV. HPV-16 was the most prevalent type (15/115: 13.0% of infections). The most consistent risk factors for HPV infection were young age, Aboriginal ethnicity, higher lifetime number of sexual partners and higher number of sexual partners in the previous year. CONCLUSION: The prevalence of HPV types in Manitoba is consistent with the distributions reported in other jurisdictions. These data provide baseline information on type-specific HPV prevalence in an unvaccinated population and can be useful in evaluating the effectiveness of the HPV immunization program. An added benefit is in the validation of a proof of concept which links a population-based Pap registry to laboratory test results and a risk behaviour survey to assess early and late outcomes of HPV infection. This methodology could be applied to other jurisdictions across Canada where such capacities exist.

Prognostic significance of positive peritoneal cytology in endometrial carcinoma.

A retrospective review of 280 patients with endometrial carcinoma who had peritoneal cytologic examination done at the time of laparotomy was undertaken. A positive cytologic finding was the only manifestation of extrauterine disease in 16 patients (6%). Four (25%) of these patients had a recurrence. Only 13 (5%) of 237 patients with negative cytologic findings had a recurrence. Positive peritoneal cytology is a marker for potential recurrence.

Staging laparotomy in early epithelial ovarian carcinoma.

It is well known that ovarian carcinoma may have subclinically metastasized at the time of the initial surgical operation when all tumor seemed to be confined to the ovary. A retrospective review of 650 ovarian carcinoma patients from 1976 to 1984 revealed 25 staging laparotomies for early epithelial ovarian carcinoma. Sixteen patients had invasive epithelial ovarian carcinoma, and nine had borderline ovarian carcinomas. Five patients had the stage of their disease changed whereas 20 remained unchanged. Among the staging laparotomy patients, 50% of cases of ovarian carcinoma with ruptured capsules were upstaged as were 33% with those with ascites. Twenty-five percent of cases with invasive epithelial ovarian carcinoma and 12% with borderline ovarian carcinoma were upstaged by a staging laparotomy. As a result of staging laparotomy, 72% of patients were spared treatment. No patient with disease truly confined to the ovaries showed recurrence in spite of receiving no treatment. All patients with disease apparently confined to the ovaries should undergo a staging laparotomy. Only disease remote from the ovary need be treated. If a staging laparotomy is not done, treatment is recommended for apparent Stage I disease.

Should selective paraaortic lymphadenectomy be part of surgical staging for endometrial cancer?

Surgical staging of adenocarcinoma of the endometrium attempts to identify the true distribution of disease. The survival value of paraaortic lymphadenectomy selectively performed in patients with histologic risk factors is unproven. The objective of this study was to determine if a staging procedure that did not include paraaortic lymphadenectomy predicted recurrence-free survival in disease surgically confined to the uterus. Between 1978 and 1990, 273 patients underwent surgical staging. Two hundred and sixty-nine were clinical stage I and 4 were stage II. The staging procedure included peritoneal cytology, TAH and BSO, and pelvic lymphadenectomy. Postoperative therapy, if any, consisted of whole pelvis and vault radiotherapy in disease confined to the uterus and systemic chemotherapy in patients with extrauterine disease. Surgical staging resulted in 220 (81%) stage I, 20 (7%) stage II, 27 (10%) stage III, and 6 (2%) stage IV. Eighty-eight patients in stages I and II had deep myometrial invasion or a grade 3 tumor. There were 12 recurrences, 8 in stage I and 4 in stage II, in patients with disease confined to the uterus. Four patients (1.7%) recurred outside the pelvis. Had paraaortic lymphadenectomy been performed in patients with risk factors, this would have mandated 88 dissections to potentially benefit 4 patients. We conclude that paraaortic lymphadenectomy would have been of small benefit to these surgically staged patients.

Results of prior cytologic screening in patients with a diagnosis of Stage I carcinoma of the cervix.

Cervical carcinoma is a disease which lends itself to prevention and diagnosis by cytologic screening. The results of previous Papanicolaou smears were obtained in 84 patients. Of 197 Papanicolaou smear results obtained prior to diagnosis of Stage I carcinoma, 63 (31%) were positive; and of 51 such smears obtained 1 year prior to diagnosis, 30 (59%) were positive. Possible explanations for negative screening prior to development of carcinoma are given. The need for centralized cytologic screening programs on a provincial basis is stressed.

Factor analysis of false-negative second-look laparotomy.

From January 1976 through December 1987, 155 patients with ovarian epithelial malignancy underwent a second-look laparotomy. Seventy-seven (50%) had a negative second-look. Recurrence after negative second-look occurred in 15 patients (19.5%). Of the factors analyzed, serous histology and residual disease after initial laparotomy were found to be of significance. Grade of tumor, stage, and ascites were not found to be of significance.

The benefits of comprehensive surgical staging in the management of early-stage epithelial ovarian carcinoma.

OBJECTIVE: The management of understaged patients with apparent clinically early ovarian cancer is difficult. Options include offering chemotherapy based on histopathologic factors or reoperation to obtain the necessary information needed to assign an accurate surgical stage. This study aims to compare these two approaches and to define the role of staging surgery in this common patient population. METHODS: Retrospective chart reviews were carried out at the Universities of Manitoba and Saskatchewan over the period 1975 to 1999. Demographic data and surgical findings were abstracted and entered into a computerized database for analysis. Patients not having surgical staging procedures were offered platinum-based chemotherapy based on high tumor grades, dense adhesions, and presence of surface excrescences or large necrotic areas. Patients with surgically proven stage I disease were treated with no further therapy regardless of histopathologic factors. Descriptive statistics are used to summarize the data. Logistic and Cox regression models are used to identify significant predicting factors for recurrences and progression-free intervals. RESULTS: One hundred and thirty-eight patients presented with tumor macroscopically confined to the ovary at the time of laparotomy. The median age at presentation is 56.5 (18-90). The histology distribution was serous tumor in 28.3%, mucinous in 26.1%, endometrioid in 23.2%, clear cell in 14.5%, anaplastic in 2.2%, and mixed types in 5.8%. The grade distribution was 47.1% grade 1, 27.5% Grade 2, and 25.4% Grade 3. Sixty-eight percent of the patients had a comprehensive surgical staging procedure initially. Thirty-six percent of these patients were found to have extraovarian metastases and were subsequently treated with adjuvant chemotherapy. Forty-three percent of those not having staging laparotomy were offered chemotherapy based on high risk factors only. At a median follow-up of 58 months. 77% of patients remained disease-free and 23% had recurrent disease. Of 60 patients with surgically proven stage I treated expectantly, 6 (10%) recurred, whereas of 25 unstaged patients treated expectantly due to lack of risk factors 7 (28%) recurred (P = 0.036). In patients treated expectantly, a significant survival advantage was noted in the staged group. Logistic regression showed age (OR 1.032, P = 0.043), high grade (OR 4.16, P = 0.003), and lack of a proper staging surgery (OR 2.62, P = 0.032) to be important factors predicting recurrence. In terms of progression-free interval, only age (OR 1.027, P = 0.048) and tumor grade (OR 3.62, P = 0.05) are significant predictors. CONCLUSION: Absence of surgical pathologic high-risk factors is inferior to comprehensive staging laparotomy findings in guiding recommendations for subsequent adjuvant therapy. Patients who have not been properly staged stand a significant risk of recurrent disease despite more frequent use of chemotherapy. All clinically early-stage ovarian cancer patients should be considered for comprehensive staging surgery prior to further treatment recommendations.

Tubular Krukenberg tumor in pregnancy with virilization.

A case of tubular Krukenberg tumor in pregnancy with virilization is presented. The pathology is reviewed. This rare tumor must be distinguished from a Sertoli-Leydig tumor. The index case adds to the previously recorded eight cases. All nine cases reviewed presented with progressive virilization between the third and eighth month of gestation, which regressed after surgery. The fetal outcomes of seven cases have been recorded. The fetuses were all female and of these five were virilized. A gastric primary was found in five cases. A primary breast carcinoma was postulated in another. In the remaining cases either no autopsy was performed or no primary tumor was found.