Albert Singer

Human papillomavirus genotype as a predictor of persistence and development of high-grade lesions in women with minor cervical abnormalities

Women referred for colposcopy with mild and moderate dyskaryosis and found to have only minor cervical abnormalities were screened for oncogenic human papilloma virus (HPV) types. The natural development of these abnormalities in 42 HPV‐positive women was assessed by cytology and colposcopy at 6‐month intervals for up to 2 years. As is the case with cancers and high‐grade cervical intra‐epithelial neoplasia (CIN), minor cervical abnormalities were frequently found to be associated with HPV16, ‐18, ‐31 and ‐33. Viral persistence and the development of high‐grade lesions were found to be closely associated with HPV16; 56% of HPV16 isolates were persistent compared to 7% of other HPV types, and all 4 subsequent CIN 3 lesions were in women with persistent infection. A striking association of persistence with a variant of HPV16 having a base change at nucleotide 350 was observed. Ten of 12 women with this variant had persistent infection compared to only 1 of 16 women infected with the HPV16 prototype.

Report on consensus conference on cervical cancer screening and management

Anthony B. MILLER*, Saloney NAZEER, Sharon FONN, Assia BRANDUP-LUKANOW, Rakshanda REHMAN, Hennie CRONJE, Rengaswamy SANKARANARAYANAN, Valentin KOROLTCHOUK, Kari SYRJANEN, Albert SINGER and Mathias ONSRUD on behalf of the participants Division of Clinical Epidemiology, German Cancer Research Center, Heidelberg, Germany Department of Gynecology and Obstetrics, Hopitaux Universitaires de Geneve, Geneva, Switzerland Women’s Health Project, Johannesburg, South Africa WHO Regional Office for European Region, Copenhagen, Denmark Department of Gynecology and Obstetrics, Fatimah Jinnah Medical College, Lahore, Pakistan Department of Obstetrics and Gynecology, The University of the Orange Free State, Bloemfontein, South Africa Unit of Descriptive Epidemiology, International Agency for Research on Cancer, Lyon, France Geneva, Switzerland Department of Pathology, Central Hospital, Kuopio, Finland Department of Women’s and Children’s Health, The Whittington Hospital, London, England Department of Gynecology and Obstetrics, University Hospital of Trondheim, Norway

Subpopulations of Langerhans’ cells in cervical neoplasia

Summary. Multiple markers were used to count Langerhans’ cells in the cervix. In the normal cervix, thymocyte antigen (T6) and adenosine triphosphatase (ATPase) demonstrated the largest population of Langerhans’ cells. MHC Class II positive cells were equivalent to 60%, and S100 positive cells were equivalent to 35% of T6 or ATPase positive cells. Whereas Langerhans’ cells demonstrated by T6, ATPase, and MHC Class II antigen were evenly distributed throughout the epithelium, the S100 positive cells were seen predominantly near lymphocytic aggregates and capillaries. In human papillomavirus infection and cervical intraepithelial neoplasia the numbers of T6, ATPase, or MHC Class II positive Langerhans’ cells were reduced by 60% but the S100 positive cells were almost completely depleted. These findings suggested that there were different subpopulations of Langerhans’ cells in the cervical epithelium. The depletion of Langerhans’ cells, particularly the selective depletion of the S100 positive subpopulation, might cause a localized immunodeficiency that impairs immune surveillance and the cell‐mediated immune response to human papillomavirus infection and cervical intraepithelial neoplasia.

Lymphocyte phenotypes in cervical intraepithelial neoplasia and human papillomavirus infection

Summary. Lymphocyte phenotypes in cervical mucosa were studied using a panel of monoclonal antibodies. T lymphocytes were predominant both within the epithelium and in the subepithelial stroma. In the normal cervix, both the T4+ (helper/inducer) and T8+ (suppressor/ cytotoxic) subsets were present in a ratio similar to that in the peripheral circulation. In human papillomavirus (HPV) infection and cervical intraepithelial neoplasia (CIN) there was depletion of intraepithelial lymphocytes, especially of T4+ subset, with reversal of the ratio of T4+ to T8+ subsets to less than one. In contrast, there was no significant reduction in the number of lymphocytes in the subepithelial stroma. Tac+ (antigen primed and clonal expanding) lymphocytes were absent both within the epithelium and in the subepithelial stroma. These findings support our suggestion that there is a localized immunodeficiency in HPV infection and CIN. The aetiological and therapeutic implications are discussed.

Presence of human papillomavirus DNA sequences in cervical intraepithelial neoplasia.

Twenty two patients referred to a district colposcopy clinic because of an abnormal cervical cytology report or a suspicious cervix and found to have a cervical epithelial abnormality were studied. The techniques of cytology, histology, immunohistochemistry, and DNA-DNA hybridisation were used to detect infection by human papillomavirus. Using an indirect immunoalkaline phosphatase technique human papillomavirus antigen was found in biopsy specimens from six of the 22 patients and DNA of papillomavirus type 6 in biopsy specimens from 13 of these women, including four out of six whose histological diagnosis was cervical intraepithelial neoplasia grade 3. In eight cases where cytological, colposcopical, and histological investigations all indicated the presence of wart virus infection, papillomavirus type 6 DNA was found in seven. Papillomavirus type 6 DNA was found in more than half of the proved cases of cervical intraepithelial neoplasia. The presence of this viral DNA in women with no cervical abnormality is to be studied.

CIN 3: the role of lesion size in invasion

Objective To define the relation between the size of a CIN 3 lesion (measured histologically) and invasive squamous carcinoma.

Cytological status and lesion size: a further dimension in cervical intraepithelial neoplasia

Summary. Quantitative histological study of 84 laser cone biopsies showed a highly significant correlation between the grade of a cervical smear and the size of the lesion for all grades of cervical intraepithelial neoplasia (CIN) (CIN 1 P= 0·004; CIN II P= 0·0001; C1N 111 P= 0·003; total CIN P< 0·0001); 10 of 34 (29%) of women with CIN III and mild dyskaryosis or less had significantly smaller lesions than 23 of 36 (63%) of women with CIN III and moderate or severe dyskaryosis. Repeat cytology identified as severe dyskaryosis all those with large CIN III lesions. Lesion size has been neglected in studies of the natural history of CIN and in the assessment of cytological screening, but offers an explanation for the apparent discrepancies between cytological, colposcopic and histological assessment of progression of CIN.

Case-control study of risk factors for cervical intraepithelial neoplasia in young women

A case-control study of 497 women under age 40 diagnosed with cervical intraepithelial neoplasia (CIN) and 833 controls was done in the London area between 1984 and 1988 to examine whether known risk factors for invasive cervical cancer produced similar risks for CIN of different grades in young women. Cases of CIN III had a risk profile similar to that seen for invasive disease whereas CIN I cases were similar to the controls in all risk factors examined except a history of genital warts. Cases of CIN II were intermediate between the two. Among several indicators of sexual and reproductive behaviour, age at first childbirth and a history of multiple sexual partners were the strongest risk factors for CIN II and CIN III. Smoking had a strong and independent effect on the risk of CIN II and CIN III, but had only a limited effect for CIN I. Use of oral contraceptives was widespread in cases and controls, but length of use of oral contraceptives was not found to be a risk factor. A small protective effect of barrier contraception was observed.

The HPV-activating cellular transcription factor Brn-3a is overexpressed in CIN3 cervical lesions.

The cervical cellular transcription factors Brn-3a and Brn-3b have antagonistic effects on transcription of the human papilloma virus types 16 and 18 E6 and E7 oncogenes, with Brn-3a activating expression and Brn-3b repressing it. We therefore measured expression of Brn-3a and Brn-3b mRNAs in biopsies from 16 women with no detectable cervical abnormality, and in 14 women with cervical intraepithelial neoplasia grade 3 (CIN3) lesions. Although the mean level of Brn-3b expression was similar in both groups, the mean level of Brn-3a expression was over 300-fold higher in the CIN3 samples when compared with normals. Elevated expression of Brn-3a was also detected in 16 histologically normal regions of the cervix adjacent to the CIN3 lesions, indicating that elevation of Brn-3a levels is not confined to the lesion in women with CIN3, and is thus not a consequence of the oncogenic process. The elevated levels of Brn-3a in the CIN3 patient samples, together with the activating effect of Brn-3a on HPV-16 and -18 oncogene expression, suggest that induction of this factor is involved in activating HPV-16 and -18 oncogene expression in the cervix, and hence in the production of cervical cancers induced by HPV.

Tissue macrophage response in human papillomavirus infection and cervical intraepithelial neoplasia

Summary. Tissue macrophages in the uterine cervix were studied immunocytochemically with monoclonal antibody (MoAb) 3.9 which reacts with the majority of macrophages, and Ell which is specific for the C3b receptor, CR1. Samples from five normal women, six with human papillomavirus (HPV) infection and 10 with cervical intraepithelial neoplasia (CIN) were tested. A small population of MoAb 3.9 positive and only occasional MoAb Ell positive macrophages were found in the normal cervix. In HPV infection and CIN there was a significant infiltration of MoAb 3.9 positive and MoAb Ell positive macrophages in both the epithelium and the stroma. The pattern of infiltration in these groups of women suggests that these macrophages were most likely to be functioning as the first line of defence against the spread of the virus infection, either through a direct anti‐virus mechanism or non‐specific phagocytosis.