Follow up after LLETZ: could schedules be modified according to risk of recurrence?

OBJECTIVES: To document the pattern of recurrence of disease following large loop excision of the transformation zone (LLETZ) to identify a low risk group of women who might benefit from less intensive cytological surveillance. DESIGN: Analysis of prospectively collected information with retrospective review of follow up smears. POPULATION: Three thousand, five hundred and sixty women who underwent LLETZ (median age 31 years; IQR 12 years). SETTING: Colposcopy clinic at Northern Gynaecological Oncology Centre, Gateshead. METHODS: Women treated with LLETZ from 1988 to 1995 were reviewed. Information on the pathology from LLETZ was collected prospectively and information on the subsequent smears was obtained from the family health authorities. RESULTS: Invasive cancer was detected on the original LLETZ in 134 women who were excluded from the study. Of the remaining 3,426 women, histology of LLETZ showed high grade CIN (II and III) in 2,371 (69%). At least one follow up smear was undertaken in 3,385 women (99%). This constituted 9,765 women years of follow up with a mean duration of 35 months. Four hundred and seventeen women (12.2%) had a dyskaryotic follow up smear. Incomplete excision of the lesion and an age of > or = 50 years at the time of the LLETZ were associated with an increased risk of recurrent CIN. Based on these risk factors the study group was divided into three risk groups: 1. women aged < 50 with no disease at the margins (n = 1680); 2. women aged > or = 50 with disease at the margins (n = 93); and 3. women aged < 50 with positive margins, or aged > or = 50 with negative margins (n = 1653). The cumulative survival without recurrent CIN at five years for these groups were 92%, 57% and 86%, respectively. CONCLUSION: Women aged > or = 50 with CIN at the margins of excision constituted a small minority high risk group (3%). Consideration should be given to repeat treatment of these women rather than surveillance. Women aged < 50 with complete excision of low grade CIN comprised 51% of the study group. These women were at low risk of recurrent CIN and might benefit from less intensive cytological surveillance following LLETZ.

Induction of FGF receptor 2-IIIb expression and response to its ligands in epithelial ovarian cancer.

Epithelial ovarian cancers (EOCs) arise in the Ovarian Surface Epithelium (OSE). This tissue is a simple, poorly committed mesothelium which exhibits characteristics of epithelial and mesenchymal cells when grown in culture. In contrast, EOCs frequently exhibit properties of complex epithelial tissues of the female reproductive tract, such as oviductal, endometrial and cervical epithelia, and show induction of expression of epithelial markers such as E-cadherin. Fibroblast Growth Factor Receptor 2 isoform IIIb (FGF receptor 2-IIIb) is a spliced variant of FGF receptor 2 that binds the ligands FGF-1 and FGF-7 with high affinity, and is expressed exclusively by epithelial cells. We have studied the expression of FGF receptor 2-IIIb and its ligands in primary cultures of normal human OSE, EOC cell lines and snap frozen tissue from EOCs. Expression of FGF receptor 2-IIIb mRNA is undetectable in normal OSE, but is expressed in 16/20 (80%) of EOCs. FGFs 1 and 7 mRNAs are expressed in normal OSE, whilst only 4/20 (20%) and 12/20 (60%) of EOCs demonstrated expression for these ligands respectively. However, FGF-7 protein was detected in 70% (mean level=0.7 ng/ml) of ascitic fluids obtained from patients with EOC. FGFs 1 and 7 stimulate DNA synthesis in EOC cell lines that express FGF receptor 2-IIIb. Moreover, DNA synthesis in these cell lines can be partially blocked by blocking antisera to FGFs 1 and 7. It is suggested that induction of expression of FGF receptor 2-IIIb may play a role in the development of EOCs by rendering the OSE susceptible to paracrine and/or autocrine stimulation by its requisite FGF ligands.

Commencement and maintenance compliance of patients on hormone replacement therapy (HRT) following bilateral oophorectomy.

In a survey in 1989 Spector observed that 70% of women who had had bilateral oophorectomy had never received hormone replacement therapy. Ten years after his survey we decided to audit not only the number of women who started hormone replacement therapy following bilateral oophorectomy, but also to determine long-term compliance, as this is vital if the full benefits of oestrogen replacement are to be obtained. We carried out a survey of 91 women age 45 years and below who had bilateral oophorectomy in a teaching hospital and who were under the care of GPs in 53 general practices in the north-east of England. Of these women, 72.4% were prescribed oestrogen replacement therapy in hospital before discharge. However, within 2 months following bilateral oophorectomy, 97.4% of these women had commenced hormone replacement; 88.4% have maintained hormone replacement for 5 years or more, 11.8% who had started hormone replacement had discontinued within 5 years and 2.6% have never been on hormone replacement therapy, despite the lack of any medical contraindication. This survey shows a marked improvement in the long-term compliance of women on hormone replacement following bilateral oophorectomy. Continuous education of medical staff and patients on the benefits of hormone replacement therapy, preoperative counseling of patients with the opportunity for them to choose the route of administration that best suits them, and regular review of patients on hormone replacement therapy may further enhance long-term compliance.

Advanced-stage cervix cancer: rapid tumour growth rather than late diagnosis.

Either diagnostic delay or tumour biology are possible factors governing the degree of spread at diagnosis of cervical cancer. To try to identify the most important parameter contributing to advanced stage, the duration of symptoms were recorded from patients scheduled for radiotherapy (n = 141) or radical hysterectomy (n = 36). In 146 cases tumour proliferation rates were evaluated following in vivo labelling with the DNA precursor BrdUrd. For symptomatic patients there was no association between duration of symptoms and stage at presentation. There was a significant trend for patients with increasing tumour stage to have more rapidly proliferating tumours with higher mean labelling index (LI) measurements (P = 0.001) and a shorter mean potential doubling time (Tpot) (P = 0.023). Socio economic deprivation may be associated with shorter Tpot values. The conclusion from this data is that stage at diagnosis is more dependent on the biological behaviour of the tumour, as expressed by proliferation rates, than delay in presentation.

Apoptosis in cervical squamous carcinoma: predictive value for survival following radiotherapy.

BACKGROUND: Apoptosis, or programmed cell death, can be induced by radiotherapy. The extent of apoptosis in a tumour before treatment may have important implications for response to radiotherapy and long term survival. AIM: To examine the extent of apoptosis in tumour tissue from patients with squamous carcinoma of the cervix before radiotherapy, and to correlate this with response to treatment and prognosis. METHODS: The percentage of apoptotic cells was assessed in 146 carcinomas of the cervix from patients scheduled to receive radiotherapy. The CAS 200 static image analysis system was used to count the number of tumour nuclei per high power field, while the numbers of apoptotic cells in the same field were visualised simultaneously on the image analyser and recorded manually. RESULTS: The median apoptotic level was 0.73%. Patients were divided into two groups around the median. There was no statistically significant difference in outcome between the two groups as determined by long term survival following radiotherapy. CONCLUSIONS: The CAS 200 static image analyser system can be used to assist in the rapid semiautomated assessment of apoptosis in conventionally prepared tissue. The results suggest that the apoptotic state of a tumour before treatment is of no value in predicting response to radiotherapy and subsequent prognosis. Tumour stage, size, and BrdU labelling index, as a measure of proliferation rate, remain the most important prognostic factors in terms of predicting local tumour control.

The role of laparoscopic surgery in the management of endometrial cancer.

OBJECTIVE: To assess the place of laparoscopically assisted vaginal hysterectomy in the treatment of endometrial cancer. DESIGN: A retrospective uncontrolled case series. SETTING: Gynaecological Oncology Department, Queen Elizabeth Hospital, Gateshead. POPULATION: Women with endometrial cancer referred to this centre from August 1992 to August 1997. MAIN OUTCOME MEASURES: Success of laparoscopically assisted vaginal hysterectomy, operative morbidity, and the length of hospital stay. RESULTS: Laparoscopically assisted vaginal hysterectomy was successful in 35 of 40 women (88%). Five women required laparotomy. Two women sustained injury to the inferior epigastric vessels. One sustained injury to the small intestine requiring later laparotomy and three women required a blood transfusion. The mean hospital stay was 3 x 3 days (SD 1 x 5). Three women died of the disease within one year of their operation. CONCLUSION: Laparoscopically assisted vaginal hysterectomy is a feasible treatment for endometrial cancer. It can be performed successfully in high risk population who are medically unfit and overweight. However, a larger randomised study is required to assess the morbidity compared with the traditional open approach.

Thrombocytosis in women with vulvar carcinoma.

Thrombocytosis (platelet count >400 x 10(9)/L) is frequently found in association with malignant disease. Although the pathogenesis of thrombocytosis in malignancy is currently unclear, it appears to be a poor prognostic factor in patients with lung, colon, breast, and cervical carcinoma. The current study was initiated to assess the incidence of thrombocytosis in vulvar carcinoma and to evaluate its prognostic significance for patients with vulvar carcinoma. The pretreatment platelet counts of 201 women treated for vulvar cancer were reviewed and correlated to the patient's age, stage of disease, node status, histologic type, and outcome. Differences between categories were analyzed by means of the ANOVA test, and survival was compared using the log-rank test on the Kaplan-Meier life table. Thrombocytosis was presented in 14.92% of patients with vulvar malignancies and in 15.46% of patients with squamous cell carcinoma of the vulva. No correlation was found between thrombocytosis and tumor size, incidence of lymph node metastases, or stage of the disease. The 5-year survival rate for patients with thrombocytosis was 89.29%, which was not significantly different from the 76.47% 5-year survival of patients with normal platelet counts (P = 0.586). When adjusted for age, histological differentiation, number of tumors, staging, incidence of nodal metastases, platelet count, hemoglobin, and white blood count, only the staging, number of tumors, and histological differentiation were associated with an unfavorable prognosis (P = 0.0001, P = 0.003, P = 0.03, respectively). Thrombocytosis was not found to be a prognostic factor in patients with carcinoma of the vulva in this series of 201 patients.

Virtual environments. Surgical simulation in otolaryngology.

Advanced technology in the form of computer-generated surgical simulation has tremendous potential as an adjunctive training aid to residents in training and experienced surgeons. This article explores the state-of-the-art in surgical simulation for otolaryngologists and future directions in this area.

Prognostic factors in surgically treated stage IB-IIB carcinoma of the cervix with negative lymph nodes.

Comerci G, Bolger BS, Flannelly G, Maini M, de Barros Lopes A, Monaghan JM. Prognostic factors in surgically treated stage IB-IIB carcinoma of the cervix with negative lymph nodes. Int J Gynecol Cancer 1998; 8: 23-26. Two hundred and seventy-five females with stage IB-IIB negative lymph node cervical cancer, treated between January 1988 and December 1994 by radical hysterectomy and pelvic lymph node dissection, form the basis of this analysis. The clinical records were reviewed for all patients including histopathology, clinical features at presentation, and follow-up. Tumors were re-staged according to the 1995 FIGO classification. Median follow-up was 55 months and 85.8% were followed for longer than two years. There were 21 recurrences, 12 of which were true central recurrence (disease-free survival at 5 years: 91.66%). Fifteen of 25 deaths were due to cervical cancer (crude survival at 5 years: 93.27%). In univariate log-rank analysis, stage (P = 0.005), tumor size (P = 0.0002), and lymph-vascular space involvement (LVSI) (P = 0.01) appeared to be statistically significant factors for tumor recurrence. Other factors including age, histology type, differentiation, adjacent cervical intraepithelial neoplasia or cervical glandular intraepithelial neoplasia, and presence of intraepithelial disease at resection margin were not found to be statistically significant. In multivariate analysis (Cox regression) tumor size (P = 0.02) and LVSI (P = 0.03) were the only independent variables. In the presence of negative lymph nodes and complete surgical excision, tumor size and LVSI are important predictors of local recurrence.

Prognostic value of preoperative squamous cell carcinoma antigen level in patients surgically treated for cervical carcinoma.

Preoperative evaluation of squamous cell carcinoma antigen (SCCa) was performed in 220 patients with surgically treated early-stage carcinoma of the cervix. The median duration of follow-up was 1.9 years. SCCa was significantly higher in tumors with a squamous element (P < 0.001). There was a squamous element in 171 tumors. SCCa was elevated (>2 ng/ml) in 21.6%. Significantly higher levels were associated with stage II disease (P < 0.001), tumors >4-cm size (P < 0.001), and lymph node metastases (P < 0.001). The positive predictive value for lymph node metastases at >2, >4, and >8.6 ng/ml SCCa is 51.4, 70.0, and 100% and the sensitivity is 58.1, 45.2, and 22.6%, respectively. Low SCCa is a poor predictor of absence of lymph node metastasis. The median SCCa for patients who developed tumor recurrence was greater than those who remained disease free (1.7 and 1.0 ng/ml, respectively, P = 0.009); however, in a multivariate analysis only lymph node metastasis and tumor size were of independent prognostic significance (P = 0.002 and P = 0.004, respectively). SCCa level >8.6 ng/ml is highly predictive of lymph nodal disease. There is no independent prognostic significance in patients with early-stage surgically treated cervical carcinoma.

E-cadherin and integrin cell adhesion molecule expression in invasive and in situ carcinoma of the cervix.

Integrin and E-cadherin cell adhesion molecules are important in the maintenance of normal epithelial structures, and altered expression of these molecules may be important in epithelial tumors, particularly in the processes of invasion and metastasis. This study examines the immunohistochemical expression of the alpha2beta1, alpha3beta1, alpha6, and beta4 integrins and of E-cadherin in high-grade cervical intraepithelial neoplasia (CIN) and in invasive carcinoma of the cervix. Abnormal expression of E-cadherin and of all of the integrin subunits examined was detected in the dysplastic epithelium in CIN in the majority of cases, but in a minority of cases this expression was lost in the superficial layers of the dysplastic epithelium. Diffuse expression of E-cadherin and of all of the integrins was seen in the majority of cases of invasive cervical carcinoma. Abnormal expression of integrin cell adhesion molecules occurs in the majority of cases of high-grade CIN, and E-cadherin expression is retained in the dysplastic epithelium. Diffuse expression of integrins and of E-cadherin also occurs in invasive carcinoma, but as the expression pattern was similar in all cases of carcinoma, no correlation with outcome is possible and the significance of this expression is unclear.

Role of appendicectomy in the surgical management of ovarian cancer.

There is a paucity of literature on the role of appendicectomy in the staging and cytoreductive procedures for ovarian cancer. In this series of 129 patients with ovarian carcinoma over a period of 9 years. (June 1985-June 1995) at the Northern Regional Department of Gynaecological Oncology, Gateshead, appendicectomy was performed in 31 patients. 11/31 were found to have metastases to the appendix. The concept of appendicectomy of a macroscopically abnormal appendix to achieve optimum debulking is accepted. The need for a prospective evaluation of the histological findings from macroscopically normal appendices removed in the presence of clinically staged early and advanced disease is required to define the role of appendicectomy in this group of patients.

Prediction of radiotherapy response of cervical carcinoma through measurement of proliferation rate.

Estimation of tumour proliferation may allow the design of individualised radiotherapy schedules to optimise response. This prospective study correlates the tumour proliferation rate of cervical carcinoma with response to conventional radiotherapy. The potential tumour cell doubling rate (Tpot) was estimated following flash labelling of the tumours in vivo using the DNA precursor, bromodeoxyuridine (BrdUrd); samples were analysed by flow cytometry. Tumour ploidy, DNA index and mitotic count were also assessed as was histological grade and type. Multiple biopsies from each tumour were obtained from 121 women. The median Tpot was 4.0 days, median S-phase duration 12.8 h and median adjusted labelling index 9.8%. Higher BrdUrd labelling was seen in patients who developed pelvic tumour recurrence following radiotherapy. This was the only biological/histological parameter with univariate and multivariate significance in relation to locoregional recurrence (P = 0.006 and P = 0.034 respectively). This study represents the first assessment of Tpot in relation to long-term response of cervical tumours treated by radiotherapy treatment. The association of high BrdUrd labelling and poor pelvic disease-free survival indicates the need for further research into the potential of radiotherapy schedule alteration to reflect tumour proliferation. The predictive value may be enhanced by combination with other biological parameters.

Measurement of cell kinetics in cervical tumours using bromodeoxyuridine.

The pre-treatment cell kinetics of 120 cervical tumours were assessed following the in vivo labelling with the thymidine analogue Bromodeoxyuridine (BrdUrd). In 89% both static and temporal kinetic parameters could be measured. Through the analysis of multiple biopsies from each tumour marked intra tumour heterogeneity was demonstrated. The median values for the most highly labelled sample analysed for each tumour were; S-phase duration (Ts) 12.1 h, BrdUrd labelling index (CLI) 9.5% and potential tumour doubling time 4.4 days. There was a significant elevation in CLI, but no difference in Ts, between tumour and non-neoplastic cervical tissue. There was a significant elevation in CLI, advanced stage and large size tumours. Although a significant elevation in CLI was found in aneuploid tumours this is likely to represent the systemic bias of the calculation methods, with no difference being seen between aneuploid and diploid tumours when BrdUrd labelling was measured with-out reference to the nuclei DNA content. The majority of these patients were treated with radiotherapy and cell kinetic data will be correlated with treatment response when adequate follow up has been achieved.

A prospective study of colposcopy in women with mild dyskaryosis or koilocytosis.

Colposcopy was performed in 91 women who had cervical cytology suggesting mild dyskaryosis or showing koilocytosis, all previous cytology having been normal. The final histological diagnosis was CIN III in 22%, CIN II in 18%, CIN I in 31%, koilocytosis alone in 14% and no abnormality in 15%. These results indicate that even with mild cytological atypia, a high proportion of patients will have more advanced disease when colposcopy-directed punch biopsy is performed.