Early epidemiological studies of cervical neoplasia suggested a causal relation with sexual activity and human papillomaviruses (HPVs) have emerged as prime suspects as venerally transmitted carcinogens. HPVs fall into two broad camps: low risk types, associated with cervical condylomas and CIN 1; and high risk types (mostly 16 and 18), found in 50-80% of CIN 2 and CIN 3 lesions, and 90% of cancers. This association with cancer is very strong, with odds ratios of > 15 (often much higher) in case-control studies that are methodologically sound. An infrequently detected third group of intermediate risk type HPVs is associated with all grades of CIN and occasionally with cancers. HPVs have also been detected in a wide range of asymptomatic controls, indicating that other events are required for development of neoplasia such as viral persistence and/or altered expression of viral genes, often following integration of the viral genome. This leaves the two major viral oncogenes, E6 and E7, directly coupled to viral enhancers and promoters, allowing their continued expression after integration. High risk HPV E7 proteins bind and inactivate the Rb protein, whereas E6 proteins bind p53 and direct its rapid degradation. A range of putative cofactors has been implicated in progression: HLA type, immunosuppression, sex steroid hormones, and smoking; most of these cofactors appear to influence progression to CIN 3. The natural history includes progression to CIN 3 in 10% of CIN 1 and 20% of CIN 2 cases, whereas at least 12% of CIN 3 cases progress to invasive carcinoma. Cervical glandular intraepithelial neoplasia (CGIN) often coexists with squamous CIN, and the premalignant potential of high grade CGIN is not in doubt, but the natural history of low grade CGIN remains uncertain. A high proportion of CGIN lesions and adenocarcinomas are HPV positive, and HPV18 has been implicated more in glandular than in squamous lesions. A strong clinical case for the application of HPV typing of cells recovered from cervical scrapes can be made; however, a rigorous cost-benefit analysis of introducing HPV typing into the cervical screening programme is required. Prophylactic and therapeutic HPV vaccines are under development. This article reviews the aetiology, pathogenesis, and pathology of cervical neoplasia, emphasising the role of HPVs. (J Clin Pathol 1998;51:96-103) Keywords: human papillomavirus; cervical neoplasia This review is based on three presentations by the authors to the first National Cervical Screening Conference organised by Marie Curie Cancer Care and held in Oxford, UK in September 1996. It also includes several more recent developments. It is important to emphasise that the cervical screening programme aims to detect women who have an epithelial abnormality that might, if untreated, lead to the development of cervical carcinoma. The screening programme is not designed to detect small or early invasive carcinomas, but no screening system will detect all women at risk and it is inevitable that in a small prop...

Purpose: Colposcopy occupies a key role in the prevention of cervical cancer by identifying preinvasive or invasive lesions. However, colposcopy is subjective and is responsible for 52% of screening failures. Dynamic spectral imaging (DSI) is based on the objective, quantitative assessment of the acetowhitening effect. This study compared DSI with colposcopy. Experimental Design: Women referred for colposcopy were examined simultaneously with colposcopy and DSI using a precommercial DySIS model (FPC-03) in an international, multicenter trial. The colposcopy impression and DySIS values were compared with consensus histology reports of biopsies. Subjects were recruited to a training group and subsequently to a test group. Measures were taken to avoid verification bias. Results: The training and test groups comprised 82 and 308 eligible women, respectively. A cutoff value to identify high-grade disease was selected from the results of the training group and data from previous work. Receiver operator curve analysis of the test data showed an area under the curve of 0.844. DySIS detected 62.9% more high-grade cases than colposcopy (57 versus 35, P = 0.0001). DySIS exceeded end points approved by the Food and Drug Administration for similar studies, with increments in the true positive rate of 22/308 (7.1%; lower 95% CL, 4.5% versus 2%) and in the false positive rate of 32/308 (10.4%; upper 95% CL, 14.7% versus 15%). Conclusions: DySIS is more sensitive than colposcopy in detecting high-grade lesions and can provide improved guidance for biopsy. The results are obtained in a user-independent fashion, making it suitable for use by nursing personnel.

Aim: Vascular risk factors, and particularly vasospasm, are thought to play a part in the pathogenesis of normal pressure glaucoma (NPG). This study aimed to determine whether the function of systemic resistance arteries was altered in patients with NPG. Methods: Contractile and relaxant function was assessed in arteries dissected from gluteal fat biopsies (11 NPG, 12 control) using small vessel myography. Results: Responses to K + and noradrenaline were similar in patients and controls and were unaffected by endothelial removal. In contrast, responses to 5-hydroxytryptamine (5-HT; pD 2 ; 7.29 (SD 0.16) v 6.66 (0.19); p=0.03) and endothelin-1 (ET-1; pD 2 , 9.12 (0.10) v 8.72 (0.13); p=0.03) were enhanced in arteries from patients with NPG. Removal of the endothelium enhanced responses to 5-HT (pD 2 , 6.66 (0.19) v 7.66 (0.08); p=0.003) and ET-1 (pD 2 , 8.72 (0.13) v 9.66 (0.39); p=0.02) in control arteries but not in those from patients. ET-1 mediated contraction in control and patient arteries was reduced in the presence of (10 −5 M) nifedipine. Endothelium dependent and independent relaxation was not impaired in arteries from patients. Conclusions: This study has identified dysfunction of the systemic vascular endothelial cell in patients with normal pressure glaucoma. The vascular endothelium modulates contractile responses to 5-HT and ET-1 in human subcutaneous resistance arteries but this effect is lost in patients with NPG, indicating a selective defect in agonist mediated release of endothelium derived vasodilators. Selective antagonists of 5-HT and ET-1 may, therefore, help to prevent vasospasm in patients with NPG.

SUMMARY The theoretical and practical reasons for replacing the terms "cervical dysplasia" and "cervical carcinoma in situ" by the single diagnostic entity of "cervical intraepithelial neoplasia" are reviewed and the advantages and drawbacks of this newer terminology discussed. The histological characteristics and cytological features of the various grades of cervical intraepithelial neoplasia are described and the differential diagnosis of this lesion is considered.

Irregular bleeding remains a common reason for the discontinuation of progestin-only contraception. The levonorgestrel releasing intrauterine system (LNG-IUS) has profound morphological effects upon the endometrium. Specific features are gland atrophy and extensive decidual transformation of the stroma. Morphological changes in the endometrium may be associated with perturbation of mechanisms regulating normal endometrial function. This study describes endometrial stromal and glandular features prior to and up to 12 months following insertion of the LNG-IUS. Comparison is made with first trimester decidua. In order to elucidate further mechanisms governing endometrial function with local intrauterine delivery of LNG, we here report histological features consistent with decidualization; a significant increase in granulocyte-macrophage colony stimulating factor (GM-CSF) immunoreactivity in decidualized stromal cells; glandular and stromal prolactin receptor expression and an infiltrate of CD56 + large granular lymphocytes and CD68 + macrophages. We are unaware of previous reports which have documented longitudinally both morphological and functional observations in endometrium exposed to local intrauterine levonorgestrel delivery. These studies demonstrate that long-term administration of intrauterine levonorgestrel results in features of altered morphology and function. No correlation was apparent between the end points in the study and the bleeding patterns described by the subjects. Further evaluation of these features in the context of menstrual bleeding experience may contribute to a better understanding of this troublesome side-effect which often leads to dissatisfaction and discontinuation of the intrauterine system.

Objective To assess the efficacy of cervical conization as primary management of cervical intraepithelial glandular neoplasia (CIGN). Design A multicentre prospective cohort study. Setting CRC Clinical Trials Unit, Birmingham. Subjects 84 women registered with the Unit between May 1986 and January 1989. After excluding 33 women, 51 who had been managed in accordance with the described protocol and had the presence of CIGN confirmed by central review of diagnostic histopathological material were included in the study. Intervention/Protocol Women with CIGN diagnosed on a cervical cone specimen were managed in accordance with a specific protocol: (a) women with negative cone margins were managed conservatively and followed up with regular cervical cytological and colposcopic examinations; (b) women with involved cone margins were managed by hysterectomy. Main outcome measures Presence or absence of CIGN at cone margins, results of cervical cytological examinations following conization, results of histopathological assessment of any surgical specimens taken after initial cone biopsy. Results Of the 51 women with confirmed CIGN, managed by conization, 14 (27%) were aged 30 or less and 15 (29%) were nulliparous. Thirty five women who had a cone biopsy showing margins free of CIGN have been managed by conization alone. After a median follow‐up period of 12 months there is no apparent residual CIGN or invasive disease in this group. Thirteen women have had further surgical procedures (according to protocol) and two have had a hysterectomy for benign gynaecological disorders. Eight further procedures were carried out because the original cone biopsy had margins involved with CIGN, and only one of them was found to have residual CIGN. The other five procedures were carried out solely because of abnormal cytology, only one of them had a diagnosis of CIN 1. A total of 10 women had cytological abnormality following cone biopsy, one had CIGN, one had CIN 1 and a third had CIN 3. Conclusions Our preliminary data suggests that when a diagnosis of CIGN is made upon a cone biopsy, further surgery is unnecessary in those women in whom the margins of the cone specimen are free of disease. Cytological and colposcopic follow up, including cytological sampling of the endocervical canal, is recommended for these women.

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Following an ovulatory control cycle, six women took 2 mg of mifepristone daily for 30 days. Endometrial biopsies were collected in the control cycle between 7 and 11 days after the plasma luteinizing hormone (LH) surge and on the corresponding day of the treatment cycle (days 19-28). In order to investigate the effects of unopposed oestrogen on the endometrium, persistent proliferative endometrium was obtained from six women with anovulatory infertility due to polycystic ovarian syndrome (PCOS) on a similar cycle day (days 21-23) following a progestogen-induced withdrawal bleed. Endometrium was evaluated for histology and immunolocalization of oestrogen receptors (ER), progesterone receptors (PR) and the cell proliferation markers [proliferating cell nuclear antigen (PCNA) and Ki67]. Treatment with mifepristone inhibited ovulation in four of the six subjects. In the two subjects in whom ovulation did occur, secretory transformation was delayed, suggesting that successful implantation of a blastocyst would be unlikely. In subjects who remained anovulatory during treatment, the histology and pattern of steroid receptor expression was similar to proliferative phase endometrium. In women with PCOS, mitoses and intense immunostaining for ER, PR and cell proliferation markers were observed in both glands and stroma. Although PCNA and Ki67 immunostaining were also present in mifepristone-treated endometrium from subjects who did not ovulate, there were no mitoses and significantly less ER immunostaining in spite of exposure to unopposed oestrogen for a similar duration. Since PCNA and Ki67 detect cells throughout all stages of the cell cycle this would suggest that mifepristone might affect the entry of cells into the mitotic phase of the cell cycle and, therefore, might prevent endometrial hyperplasia. These findings add further evidence to support the contraceptive potential and antiproliferative activity of daily low dose mifepristone.