Jette Junge

Population‐based prevalence, type‐ and age‐specific distribution of HPV in women before introduction of an HPV‐vaccination program in Denmark

Knowledge about the prevalence of human papillomavirus (HPV) on a population level is important. We conducted a large population‐based study in Denmark to determine the overall and age‐specific HPV prevalence, and HPV type distribution in women. Liquid‐based cytology samples (SurePath®) were collected consecutively. HPV testing was performed with Hybrid Capture 2 (HC2; Digene) (high‐risk and low‐risk probes), and LiPA (Innogenetics) was used for genotyping. We analyzed samples from 11,617 women; 94.0% had normal cytology, 4.3% atypical squamous cells of undetermined significance or low‐grade squamous intraepithelial lesion and 1.6% had high‐grade squamous intraepithelial lesion (HSIL). The HPV prevalence was 26.4% with a peak in women 20–24 years (50.2%) and then decreased without a second peak in older women. Among the youngest women (15–19 years), 14% had HPV 16/18 and 16% had HPV 6/11. Prevalence of high‐risk HPV types increased from 19.2% in women with normal cytology to 100% in women with cervical intraepithelial neoplasia grade 3 (CIN3)/cervical cancer. HPV 16 was the most prevalent type (6.0% of all women), and was also the most prevalent in women with HSIL (35.1%) and CIN3 (53.2%). Other common HPV types in women with CIN3 included HPV 52, 51, 31, 33 and 18. HPV 16/18 alone was present in 23% of CIN3 lesions and 67% of cervical cancers, and HPV 16/18 together with other high‐risk HPV types was present in 41% of CIN3 lesions. This suggests that an efficacious HPV 16/18 vaccine will have a substantial preventive potential in the general female population.

Early alcoholic liver injury: Activation of lipocytes in acinar zone 3 and correlation to degree of collagen formation in the disse space

Acinar zone 3 areas in liver biopsy specimens from 23 alcoholics and 47 non-alcoholics were investigated by light microscopy and transmission electron microscopy to asses fibrosis in the perisinusoidal space and to evaluate the role of the lipocytes. Quantitative analysis by light microscopy on toluidine blue-stained sections showed a significant reduction in number of lipocytes--median values of 2.7 and 1.2 lipocytes per 100 hepatocytes in biopsies from chronic alcoholics showing no or varying degrees of zone 3 fibrosis, respectively, as compared to 3.6 lipocytes per 100 hepatocytes in non-alcoholic livers. By transmission electron microscopy, the reduction in number of lipocytes was related to a corresponding increase in number of cells rich in rough endoplasmic reticulum and microfilaments (activated lipocytes). The occurrence of activated cells was significantly correlated to fibrosis of the perisinusoidal space. Activation of lipocytes and collagenization of the perisinusoidal space appeared before light microscopic evidence of fibrosis and were topographically not related to Mallory bodies or alcoholic hepatitis.

Papillary tubal hyperplasia: the putative precursor of ovarian atypical proliferative (borderline) serous tumors, noninvasive implants, and endosalpingiosis.

In contrast to the controversy regarding the terminology and behavior of ovarian noninvasive low-grade serous tumors [atypical proliferative serous tumor (APST) and serous borderline tumor], little attention has been directed to their origin. Similarly, until recently, proliferative lesions in the fallopian tube had not been extensively studied. The recent proposal that ovarian high-grade serous carcinomas are derived from intraepithelial carcinoma in the fallopian tube prompted us to evaluate the possible role of fallopian tube in the genesis of low-grade serous tumors. We have identified a lesion, designated “papillary tubal hyperplasia (PTH),” characterized by small rounded clusters of tubal epithelial cells and small papillae, with or without associated psammoma bodies, that are present within the tubal lumen and which are frequently associated with APSTs. Twenty-two cases in this study were selected from a population-based study in Denmark of approximately 1000 patients with low-grade ovarian serous tumors in whom implants were identified on the fallopian tube. Seven additional cases were seen recently in consultation at The Johns Hopkins Hospital (JHH). These 7 cases were not associated with an ovarian tumor. PTH was found in 20 (91%) of the 22 cases in the Danish study. On the basis of this association of PTH with APSTs with implants and the close morphologic resemblance of PTH, not only to primary ovarian APSTs but also to noninvasive epithelial implants and endosalpingiosis, we speculate that the small papillae and clusters of cells from the fallopian tube implant on ovarian and peritoneal surfaces to produce these lesions. The 7 JHH cases of PTH that were not associated with an ovarian tumor support the view that PTH is the likely precursor lesion. We propose a model for the development of ovarian and extraovarian low-grade serous proliferations (APST, noninvasive epithelial implants, and endosalpingiosis) that postulates that all of these lesions are derived from PTH, which appears to be induced by chronic inflammation. If this hypothesis is confirmed, it can be concluded that low-grade and high-grade ovarian tumors develop from tubal epithelium and involve the ovary secondarily.

Human papillomaviruses and multifocal genital neoplasia.

In 143 patients with vulvar carcinoma (76 cases) or vulvar intraepithelial neoplasia (VIN III, 67 cases), cervical cancer or cervical intraepithelial neoplasia CIN III lesions developed in 39 patients (27%) at some time during their life. In patients with classic keratinizing squamous cell carcinoma (KSC) of the vulva, cervical neoplasia developed in only one of 51 (2%), whereas the frequency was 10 of 25 (40%) in patients with vulvar carcinoma of the basaloid or warty type and 28 of 67 (42%) in patients with VIN III lesions. The original, paraffin-embedded surgical specimens were examined by polymerase chain reaction and type-specific molecular hybridization for human papillomavirus (HPV) DNA of the types 6, 11, 16, 18, and 33. DNA of the oncogenic types HPV 16 or HPV 33 was found in 4% of the KSCs, in 84% of the basaloid or warty carcinomas, in 90% of VIN III lesions, and in 89% of the cervical lesions. The same HPV type was found in both lesions in 81% of the patients with double primary tumors. The results support the concept that VIN III and a subgroup of vulvar carcinomas are HPV-related lesions, that they are frequently associated with another HPV-related genital primary tumor, and that these multiprimary tumors are secondary to an HPV infection involving the entire genital tract.

Human papillomavirus prevalence and type distribution in 3603 HIV-positive and HIV-negative women in the general population of Tanzania: the PROTECT study.

Objective: The aim of the Prevention of Cervical Cancer in Tanzania (PROTECT) study is to assess the prevalence of oncogenic human papillomavirus (HPV) and to determine the type distribution among women in the general population according to human immunodeficiency virus (HIV) status, in preparation for a potential HPV immunization program. Methods: We included 3603 women from the general population in urban and rural areas of Tanzania. All women underwent a gynecological examination where a Pap smear was obtained and cervical cells were collected to assess the presence of high-risk (HR) HPV DNA by hybrid capture 2 test. Genotyping was performed by the LiPaExtra method. These women were also tested for HIV. Results: The prevalence of HR HPV types was 20.1%, ranging from 14.8% in women with normal cytology to 94.2% in women with high grade squamous intraepithelial lesion (HSIL) or worse (100% in 5 cancers). In women with normal cytology or low-grade lesions, the most common type was HPV52 (3.2%), followed by HPV16 (2.1%). In contrast, HPV16 was the dominating type in HSIL or worse (32.8%). No cancers contained HPV52. The HR HPV prevalence was higher in HIV-positive women (46.7%) than in HIV-negative women (17.2%). No specific HR HPV types were significantly more common in HIV-positive women. Conclusion: The HPV type distribution is similar in HIV-positive and HIV-negative women. These results suggest that the HPV vaccines that are currently available could protect women from HPV infection independently of their HIV status.

Comparison of conventional Papanicolaou smear and SurePath® liquid-based cytology in the Copenhagen population screening programme for cervical cancer

Objective:  To compare diagnostic performance of conventional Papanicolaou smear with SurePath® liquid‐based cytology in a population screening programme.

Interleukin-8 and eicosanoid production in the lung during moderate to severe Pneumocystis carinii pneumonia in AIDS: a role of interleukin-8 in the pathogenesis of P. carinii pneumonia

Pneumocystis carinii pneumonia (PCP) may cause severe respiratory distress. This is believed to be partly caused by the accumulation of neutrophils in the lung. Interleukin-8 (IL-8) and leukotriene B4 (LTB4) are potent neutrophil chemo-attractants and activators. Eicosanoids [i.e. prostaglandins (PG) and leukotrienes (LT)] are pro-inflammatory mediators released from arachidonic acid by action of phospholipase A2 (PLA2) and have been implicated in the host response to micro-organisms. Bronchoalveolar lavage (BAL) was performed on patients with PCP as part of a randomized study of adjuvant corticosteroids vs. placebo, in addition to standard antimicrobial therapy. Re-bronchoscopy was offered at day 10. BAL fluid was available for 26 patients who had follow-up bronchoscopy performed. At diagnosis, IL-8 levels were elevated in patients with PCP, compared to healthy controls, and correlated with relative BAL neutrophilia and P(A-a)O2. LTB4 was also elevated in PCP, but failed to correlate with either BAL neutrophilia or P(A-a)O2. PLA2 activity in patients correlated with IL-8 levels and BAL neutrophilia, but not with P(A-a)O2. A trend towards a decrease in IL-8 levels in BAL fluid was detected in the corticosteroid-treated patients from days 0-10, whereas no change was detected in the placebo group. No change in levels of LTB4, LTC4, PGE2, PGF2a and PLA2 were detected cover time in either treatment group. This study establishes a correlation between IL-8, BAL neutrophilia and P(A-a)O2, and suggests a role of IL-8 as a mediator in the pathogenesis of PCP, whereas the role of eicosanoids seems less clear.

Mutational analysis of BRAF and KRAS in ovarian serous borderline (atypical proliferative) tumours and associated peritoneal implants

There is debate as to whether peritoneal implants associated with serous borderline tumours/atypical proliferative serous tumours (SBT/APSTs) of the ovary are derived from the primary ovarian tumour or arise independently in the peritoneum. We analysed 57 SBT/APSTs from 45 patients with advanced‐stage disease identified from a nation‐wide tumour registry in Denmark. Mutational analysis for hotspots in KRAS and BRAF was successful in 55 APSTs and demonstrated KRAS mutations in 34 (61.8%) and BRAF mutations in eight (14.5%). Mutational analysis was successful in 56 peritoneal implants and revealed KRAS mutations in 34 (60.7%) and BRAF mutations in seven (12.5%). Mutational analysis could not be performed in two primary tumours and in nine implants, either because DNA amplification failed or because there was insufficient tissue for mutational analysis. For these specimens we performed VE1 immunohistochemistry, which was shown to be a specific and sensitive surrogate marker for a V600E BRAF mutation. VE1 staining was positive in one of two APSTs and seven of nine implants. Thus, among 63 implants for which mutation status was known (either by direct mutational analysis or by VE1 immunohistochemistry), 34 (53.9%) had KRAS mutations and 14 (22%) had BRAF mutations, of which identical KRAS mutations were found in 34 (91%) of 37 SBT/APST–implant pairs and identical BRAF mutations in 14 (100%) of 14 SBT/APST–implant pairs. Wild‐type KRAS and BRAF (at the loci investigated) were found in 11 (100%) of 11 SBT/APST–implant pairs. Overall concordance of KRAS and BRAF mutations was 95% in 59 of 62 SBT/APST–implant (non‐invasive and invasive) pairs (p < 0.00001). This study provides cogent evidence that the vast majority of peritoneal implants, non‐invasive and invasive, harbour the identical KRAS or BRAF mutations that are present in the associated SBT/APST, supporting the view that peritoneal implants are derived from the primary ovarian tumour. Copyright

Screening history in women with cervical cancer in a Danish population-based screening program

OBJECTIVE The aim of this study was to explore the screening histories of all cervical cancers in a Danish screening population. The intention was to decide suboptimal sides of the screening program and to evaluate the significance of routine screening in the development of cervical cancer. METHODS The study describes the results of a quality control audit, performed on all new cervical cancer cases diagnosed in the years 2008-2009 at two major Danish screening-centers. All relevant cytological and histological cervical samples were reviewed. RESULTS 202.534 cytological samples were evaluated in the study period, while 112 women were diagnosed with cervical cancer. The histological diagnoses comprised: 62 (55.4%) squamous cell carcinomas, 20 (17.9%) microinvasive squamous cell carcinomas, 25 (22.3%) adenocarcinomas and 5 cancers of different histology. The mean age of study subjects was 46.6 years. 51 (45.5%) women had deficient screening histories, while 45 (40.2%) women had followed the screening recommendations and had normal cervical samples in review. 11 (9.8%) women were diagnosed with false negative cytology, 2 women had false negative histological tests, while pathological review was not feasible for 3 subjects. CONCLUSIONS More than 45% of the cervical cancer cases in our study were due to deficient cervical screening, stressing the importance of increasing the screening-uptake and coverage. 40% interval cancers emphasize the relevance of further cervical testing of women with relevant symptoms, despite of prior normal cervical samples. Finally, 9.8% false negative cytological samples are consistent with previous reports, but still a part of the screening program that should be improved.

Pituitary adenylate cyclase activating polypeptide (PACAP): occurrence and vasodilatory effect in the human uteroplacental unit

UNLABELLED Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide which was originally isolated from ovine hypothalamus. PACAP exists in at least two biologically active forms, PACAP-38 and PACAP-27. The aim of this study was to establish the distribution, localization and smooth muscle effects of PACAP-38 and PACAP-27 in the human uteroplacental unit. For this purpose we used radioimmunoassay, immunocytochemistry and in vitro studies of the effect of the peptides on smooth muscle activity. RESULTS By radioimmunoassay both peptides were detected throughout the uteroplacental unit. The concentrations of PACAP-27 were in general low, ranging from 1/6-1/25 of the corresponding PACAP-38 concentrations. PACAP-immunoreactivity was localized in nerve fibres of the lower segment of the pregnant uterus, but the number of PACAP-immunoreactive nerves was very clearly reduced compared to the corresponding isthmic region of non-pregnant myometrial tissue. PACAP-immunoreactive fibres were not observed in placenta or in the umbilical cord. Both PACAP-38 and PACAP-27 caused a concentration-dependent relaxation on stem villous arteries and on the intramyometrial arteries. Neither of the peptides displayed any effect on non-vascular smooth muscle specimens from the term pregnant myometrium. In conclusion the findings suggest a vasoregulator role of PACAP in the human uteroplacental unit.