Comparison of human papillomavirus testing strategies for triage of women referred with low-grade cytological abnormalities.

AIM: To compare triage strategies using different human papillomavirus (HPV) consensus and genotyping tests and a p16(INK4a) test. METHODS: 1228 women referred with a borderline or single mildly dyskaryotic smear. Samples were taken at colposcopy using PreservCyt. Tests included Hybrid Capture 2, Abbott RealTime PCR, BD HPV, Cobas 4800, PreTect HPV-Proofer, APTIMA and p16(INK4a). Results were based on the worst histology within 9 months. RESULTS: 97/1228 (7.9%) women had CIN3+ (203/1228 (17%) CIN2+). HPV testing alone using Hybrid Capture 2, Abbott RealTime PCR, BD HPV, Cobas 4800 or APTIMA had a sensitivity for CIN3+ ranging from 99.0% to 100.0% and specificity for

Comparison of seven tests for high-grade cervical intraepithelial neoplasia in women with abnormal smears: the Predictors 2 study.

High-risk human papillomavirus (HPV) DNA/RNA testing provides higher sensitivity but lower specificity than cytology for the identification of high-grade cervical intraepithelial neoplasia (CIN). Several new HPV tests are now available for this purpose, and a direct comparison of their properties is needed. Seven tests were evaluated with samples in liquid PreservCyt transport medium from 1,099 women referred for colposcopy: the Hybrid Capture 2 (Qiagen), Cobas (Roche), PreTect HPV-Proofer (NorChip), Aptima HPV (Gen-Probe), and Abbott RealTime assays, the BD HPV test, and CINtec p16(INK4a) cytology (mtm laboratories) immunocytochemistry. Sensitivity, specificity, and positive predictive value (PPV) were based on the worst histology found on either the biopsy or the treatment specimen after central review. Three hundred fifty-nine women (32.7%) had CIN grade 2+ (CIN2+), with 224 (20.4%) having CIN3+. For detection of CIN2+, Hybrid Capture 2 had 96.3% sensitivity, 19.5% specificity, and 37.4% PPV. Cobas had 95.2% sensitivity, 24.0% specificity, and 37.6% PPV. The BD HPV test had 95.0% sensitivity, 24.2% specificity, and 37.8% PPV. Abbott RealTime had 93.3% sensitivity, 27.3% specificity, and 38.2% PPV. Aptima had 95.3% sensitivity, 28.8% specificity, and 39.3% PPV. PreTect HPV-Proofer had 74.1% sensitivity, 70.8% specificity, and 55.4% PPV. CINtec p16(INK4a) cytology had 85.7% sensitivity, 54.7% specificity, and 49.1% PPV. Cytology of a specimen taken at colposcopy (mild dyskaryosis or worse) had 88.9% sensitivity, 58.1% specificity, and 50.7% PPV. Our study confirms that, in a referral setting, HPV testing by a number of different tests provides high sensitivity for high-grade disease. Further work is needed to confirm these findings in a routine screening setting.

Isolated groin recurrence in vulval squamous cell cancer (VSCC). The importance of node count.

OBJECTIVE: To determine whether there is a node count which can define an adequate inguinofemoral lymphadenectomy (IFL) in primary VSCC. METHODS: A retrospective and prospective review of patients with node negative VSCC who had a full staging IFL. Detection of isolated groin recurrences (IGR) would allow groins with higher risk of groin recurrence to be identified. RESULTS: The median node count of 228 IFLs in 139 patients was eight (0-24). There were six IGR (4.3%). Increased rate of IGR was present in patients with increased age, tumour diameter and depth of invasion, lymphovascular space invasion, unilateral IFL, and moderate/poor tumour grade. In the 138 groins with node counts of eight or greater there were no IGRs compared to six in the patients with either undissected groins or groin node counts less than eight (p = 0.030) Interval to IGR was significantly shorter than other sites of recurrence. Both disease-specific and overall survival were significantly reduced in IGR. CONCLUSIONS: An inadequate IFL is a nodal count of less than eight per groin; both these groins and undissected groins are at increased risk of IGR and should have close surveillance.

Performance of the Abbott RealTime high-risk HPV test in women with abnormal cervical cytology smears.

HPV DNA testing is known to be much more sensitive than cytology, but less specific. A range of HPV and related tests in 858 women referred for colposcopy because of an abnormal smear were evaluated to compare the performances of these tests. This article compared the Abbott test to other tests which had been previously evaluated. This test was a real true test for 14 high-risk HPV types. The Abbott test was found to be highly sensitive for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) (98.9%) with a specificity of 31.5%. These numbers were comparable with the Qiagen HC2 test, the Roche Linear Array and Amplicor tests, and the Gen-Probe APTIMA test. Differences between these tests appeared to be related mostly to the choice of cutoff level. An added feature of the Abbott test was the provision of type specific results for HPV 16 and 18.

A long-term study of women with normal colposcopy after referral with low-grade cytological abnormalities.

BACKGROUND: About 50,000 women are referred annually to colposcopy in England because of a low-grade smear. About 35% of these women have no colposcopic abnormality but are followed up in the colposcopy clinic because of uncertainty about the risk of significant pathology. OBJECTIVE: This study determined the 5-year rate of disease when initial colposcopy was normal and smear was non-dyskaryotic. DESIGN: Retrospective study. SETTING: Colposcopy clinic of an inner city postgraduate teaching hospital. Population Two thousand one hundred and fifty seven women referred between January 1990 and December 2001 with mild dyskaryosis (Low Grade Squamous Intraepithelial Lesion [LSIL]) or borderline nuclear changes (Abnormal Squamous Changes of Uncertain Significance [ASCUS]). METHODS: Information was obtained from the colposcopy clinic database and Open-Exeter. Time plots of the disease-free rates were generated using the Kaplan-Meier method, and statistical comparisons were performed using Cox regression. MAIN OUTCOME MEASURES: Cumulative rates of cytological and histological abnormalities. RESULTS: High-grade or invasive disease was diagnosed histologically in 12.8% of 805 women referred with borderline nuclear changes and in 35.8% of 1352 referred with mild dyskaryosis. Among 620 women with normal colposcopy and a negative or borderline repeat smear, high-grade disease was found after 5 years of follow up in 1.3% of women originally referred with a borderline smear and in 8.5% referred because of mild dyskaryosis. CONCLUSION: Women referred to colposcopy with borderline nuclear changes or mild dyskaryosis whose colposcopy findings are normal and whose repeat smear in the clinic is non-dyskaryotic may be discharged for routine 3-yearly screening in the community because the risk of high-grade disease in the next 5 years is small.

The role of colposcopy in the follow up of women treated for cervical intraepithelial neoplasia.

OBJECTIVE: To determine the effect of colposcopy on the sensitivity and specificity of follow-up procedures in the detection of residual or recurrent disease after treatment for cervical intraepithelial neoplasia (CIN). DESIGN: A retrospective study of information held in a colposcopy database. SETTING: A teaching hospital colposcopy clinic. POPULATION: A total of 2244 women treated in Hammersmith Hospital for histologically confirmed CIN between 1 January 1988 and 31 December 2002. METHODS: Data from the records of women treated with some form of local conservative therapy for CIN1-CIN3 between January 1988 and December 2002 were extracted from the colposcopy database. Women with histological confirmation of post-treatment disease were identified. MAIN OUTCOME MEASURES: The sensitivity and specificity of cytology alone was compared with the sensitivity and specificity of the combination of colposcopy and cytology. RESULTS: Colposcopy improved the sensitivity of cytology for the detection of high-grade disease from 64 to 91% but reduced the specificity from 95 to 88%. With a 3% rate of post-treatment high-grade disease, colposcopy detected 8 extra cases per 1000 women but resulted in 88 more false alarms per 1000 women. Among women in whom the treatment margins were involved or uncertain, colposcopy detected 13 extra cases per 1000 women but resulted in 12 fewer false alarms per 1000 women because the prevalence of post-treatment disease was higher. CONCLUSIONS: Colposcopy does improve the detection rate of post-treatment disease but at a cost of additional false alarms. The benefit of colposcopy will be greater in high-risk groups of women with higher rates of treatment failure.

Comparison of non-invasive sampling methods for detection of HPV in rural African women.

BACKGROUND: The prevalence of cervical cancer is extremely high in low income countries, primarily because of a lack of cytological screening. The link between human papillomavirus (HPV) and cervical cancer has long been recognised, and it has been suggested that isolated HPV testing in women who do not participate in existing screening programmes may be used to identify women at higher risk of developing cervical cancer. This community based study compares two self administered techniques for detecting HPV (tampons and self administered swabs) with a clinician directed technique, the cervical cytobrush. METHODS: 377 rural women were interviewed and of these 210 women had full gynaecological examination, and accepted all three sampling methods for HPV. HPV typing of DNA extracts was performed using polymerase chain reaction and enzyme linked immunosorbent assay techniques. RESULTS: Using the cervical cytobrush as the gold standard, self administered swabs (SAS) showed a sensitivity of 63.9%, and tampons showed a sensitivity of 72.4%. The acceptability of these two tests was 97.1% and 84.6% respectively. When combining acceptability with sensitivity, the SAS detected 61.9% and the tampons detected 60.9% of the true positives. CONCLUSION: In a setting where women are at a considerable risk of developing cervical cancer, with no access to a formal screening programme, self directed HPV testing could be a useful screening tool in identifying those women at increased risk who may require further investigation.

Ovarian cancer detected non-invasively by contrast-enhanced power Doppler ultrasound.

Overall, about one-third of women operated upon because of suspected ovarian cancer turn out to have benign disease. This proportion will be even higher when the tumours are small. A more accurate method of determining which are malignant would reduce the number of unnecessary referrals to the cancer centre and increase the scope for conservative management. This pilot study of ultrasound and intravenous microbubble contrast in 20 women with small ovarian tumours enabled the identification of all four malignant lesions with good inter-observer agreement. These preliminary findings suggest that intravenous contrast improves the ultrasound identification of small ovarian malignancies and may provide an accurate way of selecting women who require to be referred urgently for surgery under the auspices of a gynaecological oncologist. The remainder might be considered for laparoscopic surgery or even for observation in some cases.

Use of neoadjuvant chemotherapy prior to radical hysterectomy in cervical cancer: monitoring tumour shrinkage and molecular profile on magnetic resonance and assessment of 3-year outcome.

The objective of this study is to assess tumour response to neoadjuvant chemotherapy prior to radical hysterectomy in cervical cancer using magnetic resonance (MR) to monitor tumour volume and changes in molecular profile and to compare the survival to that of a control group. Eligibility included Stage Ib-IIb previously untreated cervical tumours >10 cm(3). Neoadjuvant chemotherapy in 22 patients (methotrexate 300 mg x m(-2) (with folinic acid rescue), bleomycin 30 mg x m(-2), cisplatin 60 mg m(-2)) was repeated twice weekly for three courses and followed by radical hysterectomy. Post-operative radiotherapy was given in 14 cases. A total of 23 patients treated either with radical surgery or chemoradiotherapy over the same time period comprised the nonrandomised control group. MR scans before and after neoadjuvant chemotherapy and in the control group documented tumour volume on imaging and metabolites on in vivo spectroscopy. Changes were compared using a paired t-test. Survival was calculated using the Kaplan-Meier method. There were no significant differences between the neoadjuvant chemotherapy and control groups in age (mean, s.d. 43.3+/-10, 44.7+/-8.5 years, respectively, P=0.63) or tumour volume (medians, quartiles 35.8, 17.8, 57.7 cm(3) vs 23.0, 15.0, 37.0 cm(3), respectively, P=0.068). The reduction in tumour volume post-chemotherapy (median, quartiles 7.5, 3.0, 19.0 cm(3)) was significant (P=0.002). The reduction in -CH(2) triglyceride approached significance (P=0.05), but other metabolites were unchanged. The 3-year survival in the chemotherapy group (49.1%) was not significantly different from the control group (46%, P=0.94). There is a significant reduction in tumour volume and -CH(2) triglyceride levels after neoadjuvant chemotherapy, but there is no survival advantage.

Detection of pelvic lymph node metastases in gynecologic malignancy: a comparison of CT, MR imaging, and positron emission tomography.

OBJECTIVE: Accurate assessment of lymph node status before treatment is critical in the treatment of gynecologic cancers because the 5-year survival and treatment of women is influenced by lymph node involvement. The aims of this study were to investigate the ability of X-ray CT, MR imaging, and (18)F-FDG positron emission tomography (PET) to detect pelvic lymph node metastases by comparing imaging with histopathologic findings after lymph node dissection. MATERIALS AND METHODS: Eighteen patients with gynecologic cancers were studied by all three imaging methods before surgery. The images were initially reviewed with routine diagnostic conditions and then, subsequently, by two observers who were unaware of the clinical and histopathologic findings of the patients. The nodal sites were split into upper (aortic to common iliac bifurcations) and lower (common iliac bifurcations to inguinal ligament) iliac chains. All observers' results were statistically analyzed with specificity, sensitivity, positive and negative predictive values, Fisher's exact test (individual observers) or chi-square test (combined observers), and Cohen's kappa test. RESULTS: Eight of 18 patients had lymph node metastases at histology. Findings of all three modalities agreed in full in only one patient. CT correctly revealed 10 node-negative patients, whereas MR imaging was correct in eight of these patients. (18)F-FDG PET correctly depicted one patient with lymph nodes negative for tumor. CT was the most specific imaging modality (97.0%), with MR imaging and PET rendering values of 90.7% and 77.3%, respectively, but sensitivity of all modalities was low (CT, 48.1%; MR imaging, 53.7%; PET, 24.5%). Observer agreement for each modality was good; kappa values among all observers were 0.88 for CT, 0.85 for MR imaging, and 0.72 for PET. CONCLUSION: CT is the most specific modality for detecting lymph nodes positive for tumor in gynecologic cancers, whereas MR imaging is the most sensitive. The poor results of PET in the pelvis are attributed to urinary (18)F-FDG in the ureters or bladder, which may mask or imitate lymph node metastases.

The frequency of significant pathology in women attending a general gynaecological service for postcoital bleeding.

OBJECTIVES: To document the frequency of pathology in women who complain of postcoital bleeding. To determine whether negative cervical cytology excludes serious pathology in women with postcoital bleeding. To determine whether postcoital bleeding increases the risk of serious pathology in women with an abnormal smear. DESIGN: A retrospective study. SETTING: A university teaching hospital. POPULATION: 314 women with postcoital bleeding seen in the gynaecology service from first January 1988 to 31 December 1994. METHODS: Women were identified from the computerised records of the colposcopy service and copies of correspondence, which was routinely retained on computer. The latter was searched for the text strings coital and intercourse. MAIN OUTCOME MEASURE: Histopathological diagnosis. RESULTS: Twelve women (4%) had invasive cancer: 10 were cervical or vaginal cancers and two endometrial cancers. Eight of the 10 cervical or vaginal cancers were clinically apparent. Four women of these 10 had had a normal smear before being referred for further investigation of postcoital bleeding. Two of these cancers were visible only with the aid of the colposcope. Thus, 0.6% of women attending a gynaecology service with postcoital bleeding, a normal looking cervix and a normal smear had invasive cancer of the cervix. Cervical intraepithelial neoplasia were found in 54 women (17.%) and 15 women (5%) had cervical polyps. Nineteen of the 63 women (30%) with significant pathology had a normal or inflammatory cervical smear. No explanation for the postcoital bleeding was found in 155 women (49 %). CONCLUSIONS: Although invasive cancer is rare in women with postcoital bleeding, it is much commoner than in the general population. It seems likely that cervical intraepithelial neoplasia is also associated with postcoital bleeding, perhaps because the fragile cervical epithelium becomes detached during intercourse. Postcoital bleeding should continue to be regarded as an indication of high risk for invasive cervical cancer and for cervical intraepithelial neoplasia. Prompt referral to a colposcopy clinic is indicated, but most women with postcoital bleeding will have no serious abnormality.

Is conservative treatment for adenocarcinoma in situ of the cervix safe?

OBJECTIVE: To determine the long term results of treatment of adenocarcinoma in situ by conisation of the cervix using survival analysis. DESIGN: A retrospective study in six teaching hospitals in North West Thames. POPULATION: Eighty-five women with a histological diagnosis of adenocarcinoma in situ of the cervix in punch or cone biopsy were identified from pathology and clinical databases. RESULTS: In one patient a small focus of adenocarcinoma in situ was found in a cervical polyp. Subsequent cytology was normal and no further treatment was undertaken. The 84 remaining women underwent diathermy loop, cold knife cone biopsy, laser cone biopsy, or needle excision of the transformation zone. A hysterectomy or second conisation was performed in 31/84 women (36.9%) as part of the initial treatment. In all, nine (10.6%) had early invasive lesions of which four were squamous. Fifty-nine patients were treated conservatively following one or two conisations (median follow up 78 weeks, range 0-543 weeks). One had a subsequent hysterectomy for menorrhagia. Five women have undergone treatment for suspected recurrence, a 21.5% cumulative rate of further treatment by four years. The cumulative rate of histologically proven recurrence after conservative management was 4.3% at one year and 15% at four years. CONCLUSIONS: In those cases with clear margins in the cone biopsy, there is a place for conservative management of a selected group of patients who wish to preserve fertility. However, 16.7% of these will require further treatment after four years because of recurrent cytological abnormalities. Women who opt for conservative management should undergo regular, long term surveillance in a colposcopy clinic. Among those women with involved margins in the initial cone biopsy, there is a high incidence of residual disease. A second cone biopsy may be appropriate 'definitive treatment' for young women who wish to preserve their fertility if the margins of the second biopsy are clear and there is no evidence of invasion. Even among those for whom a hysterectomy is the proposed 'definitive treatment', a second cone biopsy may be required before hysterectomy to avoid inappropriate treatment of an occult invasive lesion.

Magnetic resonance imaging of the primary site in stage I cervical carcinoma: A comparison of endovaginal coil with external phased array coil techniques at 0.5T.

OBJECTIVE: To compare endovaginal with pelvic phased array coil magnetic resonance imaging (MRI) in detection of Stage I cervical carcinoma by correlating the findings with histopathology. PATIENTS AND METHODS: Forty consecutive patients with Stage I cervical carcinoma confirmed histologically were studied using an endovaginal coil alone immediately followed by a pelvic phased array coil. T1-W transverse and T2-W FSE sagittal images made with each coil were analyzed independently by two radiologists noting the presence and size of a mass within the cervix and any parametrial extension or involvement of adjacent organs. Tumor volumes were measured using the electronic calliper to compute tumor area on each slice and multiplying by the slice thickness. Thirty patients underwent radical hysterectomy, one a trachylectomy, one simple hysterectomy and four extended cone biopsies. Four patients had radiotherapy to the primary tumor. Following surgery, histopathologic findings were recorded and tumor volumes measured. RESULTS: Tumor volumes ranged from 0-106 cm(3)(median 1.4 cm(3), mean 9 +/- 19.4 cm(3)). Thirty-six patients had correlation of the primary site with the surgical specimen. Agreement between observers was excellent for both endovaginal (k = 0.90) and pelvic phased array (k = 0.96) techniques. Combined sensitivity and specificity for both observers of endovaginal MR imaging for detection of tumor was 96% and 70%, respectively; for pelvic phased array imaging sensitivity was substantially less at 54%. Specificity was higher at 83.7%, probably because small abnormalities were seldom visible. In patients treated surgically, early parametrial involvement in four women on endovaginal MRI was confirmed histologically in two. Pelvic phased array imaging showed early parametrial involvement in four women and was confirmed in one. CONCLUSION: Endovaginal MRI adds substantially to information from pelvic phased array images in the preoperative assessment of patients with early cervical cancer. J. Magn. Reson. Imaging 2000;12:1020-1026.

Standards for the management of cervical and vulval carcinoma.

OBJECTIVE: To examine the feasibility of achieving designated target standards for the management of women with cervical and vulval cancer. DESIGN: Retrospective casenote review. SETTING: The Gynaecological Oncology Centre at Hammersmith Hospital, London. POPULATION: Sixty-one women with cervical and vulval cancer presenting to the gynaecological oncology clinic at the Hammersmith Hospital during 1996 and 1997. Various aspects of the management of those women were compared with standards suggested by a multidisciplinary panel of local experts. Targets included the referral and treatment process, the accuracy of staging, and measures of surgical performance. RESULT: The target interval of seven days between receipt of the referral and the first visit at the cancer centre was achieved in 93% of women. Surgical treatment was administered to 92% of the women within the target of 20 working days from the first clinic appointment. Tumour close to or involving the margins of the specimen was noted in 13% of cervical and 9% of vulval cancers. The node count fell below the target standards in 13% of pelvic and 10% of groin dissections. Appropriate imaging investigations for staging were not undertaken in 15 of 39 cases (38%) of cervical cancer and in 5 out of 22 (23%) of vulval cancers. CONCLUSION: The suggested targets of process and surgical performance are reasonable and achievable. These standards would be appropriate for national use. The area most clearly identified where these targets were not achieved was the requesting of complementary staging investigations. This could be addressed by the use of a simple investigation protocol to be included in each patient's notes and available at specialist clinics and gynaecology wards.

The growth response to tumour necrosis factor alpha of human gynaecological cancer cell lines.

The cytokine tumour necrosis factor alpha (TNF-alpha) is implicated in the regulation of diverse gynaecological cell types, its biological activity being potentially mediated by two distinct cell surface receptors (TNFR) of molecular weight 55 and 75 kDa, respectively. In this study the sensitivity to the growth regulatory properties of TNF-alpha of a panel of human cervical, endometrial and ovarian cancer cell lines was investigated in relation to the expression and biological activity of the 55- and 75-kDa receptor. There was no evidence of expression or function of the 75-kDa receptor in any of the cell lines tested. The expression and biological activity of the 55-kDa receptor was demonstrated in each TNF sensitive cell line, with one exception, the HOG-1 cervical cancer cell line. The data suggest that the 55-kDa receptor mediates the cellular response to TNF-alpha in sensitive gynaecological cancer cell lines but raises the possibility of the presence of a distinct receptor in HOG-1 cells.

Value of magnetic resonance imaging with an endovaginal receiver coil in the pre-operative assessment of Stage I and IIa cervical neoplasia.

OBJECTIVE: To assess the value of high resolution endovaginal magnetic resonance images (MRI) of the uterine cervix in planning management of early cervical cancer. DESIGN: Prospective cross-sectional study. SETTING: Specialist gynaecological oncology unit of a postgraduate teaching hospital. PARTICIPANTS: Thirty nine women aged 25-76 years old (mean 42.5 years) with invasive carcinoma Stage I or IIa of the cervix. METHODS: A ring coil was positioned endovaginally around the cervix. Imaging was performed on a 1.0 T HPQ Vista or 0.5 T Asset (Picker, Highland Heights, Ohio, USA) using T1 weighted and T2 weighted sequences in transverse and sagittal planes with thin slices (2.5 mm) and small fields of view (12 cm). Tumour volumes were measured and any extension into adjacent organs and parametrium was noted. The patients were followed up after treatment and the outcome related to the MRI findings. RESULTS: There was one false positive and one false negative result among five Stage Ia patients being assessed for residual disease after cone biopsy or LLETZ. The MRI assessment of the size and distribution of the tumour was confirmed histologically in all 31 patients with Stage Ib or IIa disease who were treated surgically. One of these patients in whom no endocervical tumour was visible on MRI underwent radical trachelectomy. Three patients had radiotherapy as primary treatment. Patients with Stage Ib or IIa disease who had tumour volumes > 10 cm3 with early parametrial extension on MRI had a substantially worse prognosis at 24 months (disease-free survival 58.3% vs 95.5%, P = 0.003). CONCLUSION: High resolution MRI with an endovaginal coil allows precise measurement of tumour volume and identifies patients with small volume disease who might be considered for more conservative therapy. This technique also reveals early parametrial invasion that cannot be identified reliably by any other method. Early parametrial invasion in women with large tumours appears to have a very much worse prognosis.