Registry-derived stage (RD-Stage) for capturing cancer stage at diagnosis for endometrial cancer.

BACKGROUND: Capture of cancer stage at diagnosis is important yet poorly reported by health services to population-based cancer registries. In this paper we describe current completeness of stage information for endometrial cancer available in Australian cancer registries; and develop and validate a set of rules to enable cancer registry medical coders to calculate stage using data available to them (registry-derived stage or 'RD-Stage'). METHODOLOGY: Rules for deriving RD-stage (Endometrial carcinoma) were developed using the American Joint Commission on Cancer (AJCC) TNM (tumour, nodes, metastasis) Staging System (8th Edition). An expert working group comprising cancer specialists responsible for delivering cancer care, epidemiologists and medical coders reviewed and endorsed the rules. Baseline completeness of data fields required to calculate RD-Stage, and calculation of the proportion of cases for whom an RD stage could be assigned, was assessed across each Australian jurisdiction. RD-Stage (Endometrial cancer) was calculated by Victorian Cancer Registry (VCR) medical coders and compared with clinical stage recorded by the patient's treating clinician and captured in the National Gynae-Oncology Registry (NGOR). RESULTS: The necessary data completeness level for calculating RD-Stage (Endometrial carcinoma) across various Australian jurisdictions varied from 0 to 89%. Three jurisdictions captured degree of spread of cancer, rendering RD-Stage unable to be calculated. RD-Stage (Endometrial carcinoma) could not be derived for 64/485 (13%) cases and was not captured for 44/485 (9%) cases in NGOR. At stage category level (I, II, III, IV), there was concordance between RD-Stage and NGOR captured stage in 393/410 (96%) of cases (95.8%, Kendall's coefficient = 0.95). CONCLUSION: A lack of consistency in data captured by, and data sources reporting to, population-based cancer registries meant that it was not possible to provide national endometrial carcinoma stage data at diagnosis. In a sample of Victorian cases, where surgical pathology was available, there was very good concordance between RD-Stage (Endometrial carcinoma) and clinician-recorded stage data available from NGOR. RD-Stage offers promise in capturing endometrial cancer stage at diagnosis for population epidemiological purposes when it is not provided by health services, but requires more extensive validation.

An overview of Clinical Quality Registries (CQRs) on gynecological oncology worldwide.

INTRODUCTION: Clinical Quality Registries (CQRs) were initiated in order to compare clinical outcomes between hospitals or regions within a country. To get an overview of these CQRs worldwide the aim of this study was to identify these CQRs for gynecological oncology and to summarize their characteristics, processes and QI's and to establish whether it is feasible to make an international comparison in the future. METHODS: To identify CQRs in gynecological oncology a literature search in Pubmed was performed. All papers describing the use of a CQR were included. Administrative, epidemiological and cancer registries were excluded as these registries do not primarily serve to measure quality of care through QI's. The taskforce or contact person of the included CQR were asked to participate and share information on registered items, processes and indicators. RESULTS: Five nations agreed to collaborate: Australia, Denmark, Italy, the Netherlands and Sweden. Denmark, Netherlands and Sweden established a nationwide registry, collecting data on multiple tumor types, and various QI's. Australia and Italy included patients with ovarian cancer only. All nations had a different process to report feedback results to participating hospitals. CONCLUSION: CQRs serve the same purpose to improve quality of care but vary on different aspects. Although similarities are observed in the topics measured by the QI's, an international comparison was not feasible as numerators or denominators differ between registries. In order to compare on an international level it would be useful to harmonize these registries and to set an international standard to measure the quality of care with similar indicators.

Dietary folate and related micronutrients, folate-metabolising genes, and ovarian cancer survival.

OBJECTIVE: Folate is essential for DNA synthesis and methylation and is implicated in tumour progression. Few studies have examined its role in ovarian cancer survival. Our objective was to determine relationships between intake of folate, related one-carbon nutrients, single nucleotide polymorphisms (SNPs) in folate-metabolising genes and survival following ovarian cancer diagnosis. METHODS: This analysis included 1270 women with invasive epithelial ovarian cancer diagnosed in 2002-2006. Pre-diagnostic and some post-diagnostic lifestyle, dietary, and sociodemographic information was collected via self-administered questionnaires. DNA samples were genotyped for SNPs in methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and methionine synthase reductase (MTRR) genes. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression. RESULTS: Multivariate analyses did not identify associations between higher pre-diagnostic intake of folate, folic acid, vitamins B2, B6, and B12, methionine, betaine or choline and survival overall. In stratified analyses, higher folic acid and folate intake was associated with significantly worse survival among women with mucinous tumours (HRs per 100 µg 1.30 and 1.43, respectively) and smokers (HRs per 100 µg 1.23 and 1.16 respectively). There was also a suggestion that higher supplemental folic acid use post-diagnosis was associated with worse survival (HR per 100 µg 1.03, 95%CI 1.00-1.05). MTHFR SNP rs2066470 was significantly associated with survival (per allele HR 0.81, 95%CI 0.67-0.98). CONCLUSIONS: Our data provide little evidence that folate intake affects ovarian cancer survival. However, combined effects with smoking, and findings within the mucinous subtype and for post-diagnosis folic acid, warrant further investigation.

Progestogen treatment options for early endometrial cancer.

OBJECTIVE: Premenopausal women with early endometrial cancer may wish to maintain their fertility, and for some patients non-surgical treatment options may be attractive. We have examined our own experience with such patients, as there are limited published data so far to support clear guidelines in this area. DESIGN: Retrospective analysis of a case series. SETTING: Case series from a specialist gynaecological oncology unit in a major tertiary referral hospital. SAMPLE: Sixteen patients receiving progestogen therapy for stage-1 endometrial cancer. METHODS: We reviewed our experience of all patients receiving progestogen therapy for stage-1 endometrial cancer, and we particularly examined their cancer-free outcome and fertility potential. MAIN OUTCOME MEASURES: Response to treatment, duration of response, and subsequent pregnancies. RESULTS: Of the 16 patients investigated, four received an oral progestogen, five received the levonorgestrel-releasing intrauterine system (Mirena), and seven received both forms of treatment. Ten patients (63%) responded to treatment, with a median time to response of 5.5 months. Six patients did not respond to treatment, but all were either early in treatment or opted for surgical management before the average time of response. No patient who responded had a later recurrence. The mean total follow-up time was 27 months (range 3-134 months), with no patient deaths. Three patients had successful pregnancies, with one patient having two children. CONCLUSIONS: This form of treatment appears to be a realistic treatment option in selected patients in the closely supervised environment of a specialist gynaecological oncology unit.

Prognostic factors for recurrence in patients with FIGO stage I and II, intermediate or high risk endometrial cancer.

BACKGROUND: The aim of this study was to determine predictors for loco-regional or distant recurrence of disease in a subgroup of intermediate or high risk stage I and II endometrial cancer. METHODS: A retrospective analysis of 295 patients with histopathological stage I and II, intermediate or high risk endometrial cancer is reported. The following factors were studied: stage, grade, age, histologic diagnosis, lymphadenectomy, lymphovascular space invasion, and adjuvant radiotherapy. The Log-Rank test was used for statistical analyses and the Kaplan-Meyer method was used for time-to-event analysis. Multivariate analysis was also performed. RESULTS: Thirty-four (11.5%) patients developed a recurrence; 20 (59%) developed loco-regional recurrence, and 14 (41%) developed distant recurrence. In 20 women (59%), recurrence appeared within 3 years of surgery, and the actuarial survival at 3 years after recurrence was 29%. Multivariate analysis showed that for recurrence, age >60 years was a significant unfavourable prognostic factor (p < 0.05). CONCLUSIONS: We found low rates of recurrence in patients with early stage intermediate or high risk endometrial cancer. Only age was identified as an independent significant predictor for recurrence.

VIN 3: a clinicopathologic review.

A retrospective review of the management of vulvar intraepithelial neoplasia 3 (VIN 3) over a 16-year period from 1981 to 1997 was conducted. Complete information was available for analysis on 101 patients. The mean age was 53.9 years (range 14-102 years). The mean duration of follow-up was 36 months (range 2-184 months). Fifty-eight percent of patients presented with pruritus. The disease was multifocal in 51% and unifocal in 49% of cases and the left labium majus was the most frequently affected site (27%). Co-existent or previous genital disease was identified in 39% of patients and 8% had a history of invasive gynecological cancer. Histologic evidence of human papillomavirus (HPV) infection was found in 31% of patients. Wide local excision was the most frequently used treatment modality (78%). Thirty-eight percent of patients required at least one further treatment for recurrent disease. Smoking, multifocality, HPV effect, and positive surgical margins were not found to be significant predictors of recurrence. There were three (3%) cases of progression to invasive squamous cell carcinoma of the vulva, one at 6, 7, and 7 years after initial treatment.

Adenocarcinoma in situ of the uterine cervix: an experience with 100 cases.

OBJECTIVE: The aim of this study was to ascertain whether cold knife conization alone for cervical adenocarcinoma in situ is safe. METHODS: One hundred consecutive patients with a histologically proven adenocarcinoma in situ (AIS) of the cervix were studied from 1970 to 1992. RESULTS: Ninety-two women presented with abnormal smears, and of these 56% contained abnormal glandular cells. Sixty-seven (74%) of 90 women who underwent colposcopy had an abnormal examination, but a glandular abnormality was suspected in only 19 (28%). In all, 80 cold knife conizations were performed. In 7, no abnormality was found following punch biopsy. The margins were free of disease in 55 (75%). The most commonly involved margin in the remainder was the apical. Conization was followed by hysterectomy in 20 women: in 8 of these the cone margins were free and residual disease was found in 2 of the extirpated uteri: as these were extramural cases, inadequate sampling could not be excluded. Of the 12 women where hysterectomy followed conization with diseased margins, 9 had residual disease in the hysterectomy specimen. The definitive therapy was cold knife conization in 56 patients, hysterectomy in 38, and electrocoagulation diathermy in 6. Follow-up of the 53 patients treated by conization alone ranging from 1 to 16 years, with a mean of 8 years (3 have been lost to follow-up) revealed no recurrence of AIS or adenocarcinoma to date. CONCLUSION: It is concluded that cold knife conization is a safe therapeutic modality, provided that the cone biopsy has been adequately sampled and the margins are free.

Management of vaginal intraepithelial neoplasia: A series of 132 cases with long-term follow-up.

A series of 132 cases of vaginal intraepithelial neoplasia (VAIN) is presented, including nine (6.8%) where early invasive carcinoma of the vagina was found in the course of initial management of the VAIN. The majority of patients (75%) had high-grade VAIN (two or three). Seventy-two (55%) had undergone a prior hysterectomy; 22 for preinvasive disease (CIN), 33 for invasive gynecological cancer, 13 for benign reasons, and in 4 the reason for the hysterectomy and/or the Pap smear history was not known. Twenty-one (16%) had received prior pelvic radiotherapy. VAIN was noted to involve either the vaginal vault (in the post-hysterectomy group) or the upper vagina (in the no hysterectomy group) in more than 80% cases. A variety of treatment modalities was used with varying degrees of success. For high-grade VAIN excisional treatments had an overall (first-line plus subsequent) cure rate of 69% (53/77). The state of the surgical margins did not correlate with the risk of residual disease. CO2 laser ablation was curative in 69% (18/26) of cases and was significantly better than electrocoagulation diathermy which was curative in only 25% (3/12) of cases (P = 0.013). Five-fluorouracil cream was curative in 46% (5/11) of cases, including four patients who had received prior radiotherapy. Radiotherapy was effective in eradicating VAIN in the two cases where it was used as the primary treatment modality. Progression of high-grade VAIN to invasive cancer occurred in eight (8%) cases; after no treatment in two cases, after treatment failure in five cases, and as a late recurrence in one case. For low-grade VAIN an observational approach after biopsy was initially adopted in eight patients and regression occurred in seven (88%) of these patients. Other miscellaneous treatments were also effective in low-grade VAIN. These data provide evidence that high-grade VAIN is a precursor to invasive cancer of the vagina and every attempt should be made to eradicate it. Based on our experience and a review of the literature we have proposed a plan for optimal management of this condition.

Abnormal cervical cytology in pregnancy: experience of 811 cases.

This paper reviews our hospital's experience spanning 15 years and involving 811 women referred with abnormal cervical cytology in pregnancy. It supports the safety and accuracy of managing dysplasia in pregnancy with colposcopy, directed punch biopsy and deferral of treatment until the postpartum period. The histologically-proven progression in pregnancy to a higher grade of dysplasia postpartum was 7%. None of the women are known to have developed microinvasive or invasive cancer between antenatal assessment and postpartum review. Of these 811 women, 16% were lost to follow-up, 1 of whom subsequently represented 4 years later with invasive cervical cancer.

Determination of benzalkonium chloride in drug formulations by capillary electrophoresis (CE).

A Capillary Electrophoresis method was developed and applied successfully to test the quality of different drug formulations for release and stability studies. In the method an uncoated fused-silica capillary was employed containing a phosphoric acid buffer electrolyte which was brought to pH by triethylamine. The benzalkonium chlorides (BAC-C12 and BAC-C14) present in the standard were completely separated from each other and from the peaks of the main compound. Performance results of the method in terms of system repeatability, precision and accuracy are discussed.

A phase II trial of carboplatin and etoposide for relapsed or metastatic carcinoma of the cervix.

This study reports the results of a phase II trial of carboplatin 100 mg/m2 combined with etoposide 120 mg/m2 each given for 3 consecutive days every 28 days in women with recurrent or metastatic carcinoma of the cervix. Seventeen eligible patients were treated between August, 1990 and May, 1993. In the 16 evaluable patients, there were 2 complete responses, and no partial responses with an overall objective response rate of 12.5% (95% confidence interval 1.6%-38%). The main toxicities of this regimen related to myelosuppression and emesis. The combination of carboplatin and etoposide did not achieve either a better response rate or a substantially improved toxicity profile than is seen with single agent cisplatin.

Microinvasive adenocarcinoma of the cervix: a clinicopathologic study of 77 women.

OBJECTIVE: To prove that microinvasive adenocarcinoma of the cervix exists and, like its squamous counterpart, carries an excellent prognosis. METHODS: Seventy-seven women with microinvasive adenocarcinoma of the cervix were seen from 1971 to 1995. Microinvasion was defined as depth of invasion or tumor thickness of at most 5 mm. Microscopic assessment was made on punch biopsies, serially sectioned conization specimens, and extensively sampled hysterectomy specimens. RESULTS: Most of the women had abnormal Papanicolaou smears. We made definitive diagnoses on conization specimens in 49 women, hysterectomy specimens in 22, and colposcopically directed punch biopsies in six (three being no residual disease in the subsequent conization-hysterectomy specimens). The length of microinvasive adenocarcinomas ranged from 0.8 to 21 mm, and the volume was between 3 and 1000 mm. The tumors were multicentric in 21 cases, but no true "skip" lesions were found. Overall, 58 cold-knife conizations were performed: the margins were free in 39 cases, involved in 18, and inconclusive in one. The one loop conization had involved margins. Definitive therapy included cold-knife conization in 16 women, combined with pelvic-node dissection in four. In the remainder of the women, we performed some type of hysterectomy. None of the 26 women who had radical hysterectomy had parametrial spread, and none of the 48 who had pelvic-node dissection or the 23 in whom one or both adnexa were removed had metastases. There have been two "recurrences" to date; one was an adenocarcinoma and the other a squamous cell carcinoma, both at the vault. CONCLUSION: Microinvasive adenocarcinoma of the cervix is a clinicopathologic entity that appears to have the same prognosis, and should be treated in the same way, as its squamous counterpart.

Struma ovarii presenting as acute pseudo-Meigs syndrome with an elevated CA 125 level.

A 62-year-old woman presented with acute hydrothoraces and ascites. The CA 125 level was greatly elevated and pelvic ultrasound revealed an adnexal mass with solid and cystic components. At surgery a benign pure struma ovarii was diagnosed and following removal of the tumour the patient had immediate and complete resolution of her symptoms. This is the first report of struma ovarii causing both pseudo-Meigs syndrome and a marked elevation of CA 125.

Screening for ovarian cancer using serum CA125 and vaginal examination: report on 2550 females.

This study was undertaken to assess the effectiveness of using serum CA125 and vaginal examination as a screening test for ovarian cancer in apparently healthy females. Two thousand five hundred and fifty healthy females aged 40 and over were recruited to participate in a screening study involving a questionnaire, serum CA125 measurement and vaginal examination. Females with either an elevated CA125 level or abnormal vaginal examination had a pelvic ultrasound performed as a secondary procedure. The positive predictive values of an elevated serum CA125 level, and a combination of CA125 level measurement and vaginal examination for ovarian cancer, were 1/100 and 1/3, respectively. The specificities of serum CA125 levels, vaginal examination and both in combination were 96.1%, 98.5% and 99.9%, respectively. In postmenopausal females the positive predictive values were improved with CA125 measurement alone, giving a positive predictive value of 1/24. Seventeen females underwent operative procedure as a result of the screening-only one of these was for an ovarian cancer. The combination of serum CA125 measurement and vaginal examination is not an effective screening test in the general population, although in postmenopausal females it does achieve acceptable specificities and positive predictive values.

Primary vulvar sarcomas.

Vulvar sarcomas are uncommon, comprising only approximately 2% of all vulvar malignancies. Consequently, most reported series contain only a few cases. We add to the literature 10 cases of various primary sarcomas of the vulva, including previously unreported cases of angiosarcoma and a neoplasm resembling Ewing's sarcoma. The only histologic feature helpful in determining prognosis was tumor necrosis.

A prospective study of inhibin in granulosa cell tumors of the ovary.

Elevated preoperative serum inhibin concentrations have been reported in patients with granulosa cell tumor of the ovary. The aim of this study was to determine if elevations in serum inhibin predated clinical recurrence in patients with a diagnosis of granulosa cell tumor. Twenty-seven consecutive patients with granulosa cell tumor were followed prospectively to assess the relationship between serum inhibin concentrations and disease status. The serum inhibin concentrations in normal postmenopausal women were < 77-130 U/liter. In patients with granulosa cell tumor at initial surgery, mean inhibin concentrations preoperatively were 2831 U/liter in 4 postmenopausal subjects (range 2130-3323 U/liter) and 3680 U/liter in each of 2 premenopausal women. In 5 postmenopausal subjects with a histological diagnosis of granulosa cell tumor who underwent secondary surgery because of a recurrent palpable mass, mean inhibin concentrations were 4216 U/liter (range 2672-7360). In 3 patients with known or suspected residual disease despite a secondary debulking operation the serum inhibin concentrations were 475, 1000, and 2541 U/liter. In 13 subjects who were clinically disease free with a previous diagnosis of granulosa cell tumor, serum inhibin concentrations remained within the normal range for reproductive status. We conclude: (1) Preoperative serum inhibin concentrations are typically elevated sevenfold above the normal premenopausal follicular phase levels in women with granulosa cell tumor; (2) after surgery, serum inhibin levels may become elevated up to 2 years before further surgery is undertaken; and (3) serum inhibin concentrations appear to be a valuable tumor marker for the diagnosis of primary or recurrent granulosa cell tumor.

Micro-invasive squamous cell carcinoma of the cervix: a clinico-pathologic study of 200 cases with long-term follow-up.

The clinico-pathologic details of 200 patients with micro-invasive squamous-cell carcinoma of the cervix have been analyzed. All tumors invaded 5 mm or less below the basement membrane. One hundred and nine were categorized as FIGO stage 1a1 (early stromal invasion) and 91 as FIGO stage 1a2 (micro-carcinoma). The horizontal spread (length) of 12 micro-carcinomas exceeded 7 mm. Twenty-three had stromal invasion 3 mm or more, and 22 had capillary-like space involvement. Fifty-eight patients underwent pelvic lymphadenectomy in addition to hysterectomy and none had positive nodes. Univariate and multivariate analyses of possible prognostic factors including depth, horizontal spread, width, area, volume, grade, growth pattern, capillary-like space involvement, and stromal reaction failed to show any to be significantly associated with recurrence. The median duration of follow-up is now 8 years (0-22 years). Despite complete resection, seven (3.5%) patients developed recurrence of in situ or invasive carcinoma (three after early stromal invasion and four after micro-carcinoma), all of which were located at the vaginal vault. There were two deaths, one due to pulmonary squamous-cell carcinomatosis 21 years after early stromal invasion, the connection being tenuous, and the other due to local recurrence. There have been no recurrences to date in 23 patients treated by conization alone. The uniformly good prognosis of patients in this study is attributed to meticulous sampling of operative specimens resulting in accurate diagnosis and appropriate treatment, which may be conization alone provided the margins are free, there is no capillary-like space involvement, and the depth of penetration is less than 3 mm.

Cisplatin-based chemotherapy for ovarian germ cell malignancies: the Australian experience.

PURPOSE: This study was performed to evaluate the Australian experience with cisplatin-based treatment of ovarian germ cell tumors (OGCT) with respect to survival and toxicity of treatment. PATIENTS AND METHODS: A retrospective review was undertaken based on a standardized questionnaire, which was sent to all major gynecologic oncology centers in Australia. RESULTS: Data on 58 patients were obtained. Overall survival at 5 years for all patients was 87%. There was one death from disease among 14 patients with dysgerminoma, and four deaths from disease among 44 patients with nondysgerminomas. Cisplatin-based chemotherapy was associated with a low incidence of serious complications, with only one treatment-related death (from bleomycin-induced respiratory failure). CONCLUSION: Our large series demonstrates that cisplatin-based chemotherapy is highly effective for patients with OGCT. Although direct comparisons cannot be made, the survival of our patients with advanced tumors was comparable to that seen in male germ cell tumors, rather than inferior as is commonly believed. Future studies should aim to refine treatment to minimize toxicity, while further increasing curability.

Women with a pelvic mass--when to perform an ultrasound.

A retrospective study of 264 patients with a pelvic mass who had a preoperative serum CA 125 level performed was undertaken to compare the sensitivity, specificity and predictive values of this test as a predictor of malignancy, compared with clinical impression and ultrasonography (USG). The values were calculated for each parameter alone and in combination, and the effect of menopausal status, histological type and stage of disease was also assessed. The results indicate that in postmenopausal women with a pelvic mass, a CA 125 level should be performed and the patient referred to a gynaecological oncologist if the value is raised. In contrast both CA 125 and USG should be performed in the premenopausal woman to allow appropriate referral. In this study a CA 125 level of 35 u/ml or more correctly identified malignancy in 90% of postmenopausal women.