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Background: Worldwide, prostatic adenocarcinoma is the most common tumour type among men. Aim: The aim of the present investigation was to develop a computer program to identify normal prostate biopsies and distinguish them from biopsies showing premalignant alterations (LGPIN, HGPIN) and adenocarcinoma. Method: Prostate biopsies (n = 2094) taken from 191 consecutive men during 2016 were stained with triple immunehistochemisty (antibodies to AMACRA, p63 and CK 5). Digital images of the biopsies were obtained with a scanning microscope and used to develop an automatic computer program (CelldaTM), intended to identify the morphological alterations. Visual microscopic finding was used as a reference. Result: Of the 191 men, 121 (63.4%) were diagnosed as having prostate adenocarcinoma and 70 (36.6%) as having no malignancy on the basis of the visual microscopy. In comparison, computer analysis identified 134 (70.2%) men with malignant disease and 57 (29.8%) with non-malignant disease after exclusion of artifacts, which constituted 10.4% of areas (indicated as malignant disease). Discrepant results were recorded in 15 (7.9%) men, and in 14 of these cases, HGPIN and areas suggestive of early invasion were common. Thus, it was uncertain whether these cases should be regarded as malignant or not. The agreement between the visual examination and the computer analysis was 92.1% (kappa value 0.823, sensitivity 99.2 and specificity was 0.80). Conclusion: It seems that computer analysis could serve as an adjunct to simplify and shorten the diagnostic procedure, first of all by ensuring that normal prostate biopsies are sorted out from those sent for visual microscopic evaluation.

A 50-year-old man developed a pancreatic islet tumor with liver metastases. High levels of islet amyloid polypeptide (IAPP) were recorded in plasma-35,000 pmol/L-concomitant with the occurrence of type II diabetes mellitus (the clinical syndrome has recently been described in detail) [25]. Light microscopically, the tumor contained considerable amounts of amyloid and displayed IAPP immunoreactivity both in the tumor cells and in the amyloid stroma. Electron-microscopical examination of the liver metastases showed presence of round secretory granules in the tumor cells. The granules were immunoreactive to chromogranin A and B and IAPP but not to insulin. The amyloid deposits were mainly accumulated in the extracellular spaces but were also present in the tumor cell cytoplasm. The intracellufar amyloid fibrils were, as revealed by immunogold labeling, IAPP immunoreactive and seemed to emerge from the secretory granules in the shape of radiating threads. The results show that in this particular case, the amyloid formation started already at the intracellular level and in close proximity to the lAPP-storing secretory granules. The findings may have some significance for understanding the development of pancreatic islet B-cell-related amyloidosis in type II diabetes mellitus.

Aim Accurate classification of lung carcinomas is crucial for selecting appropriate and adequate chemotherapy treatment. In this study, glandular (adenocarcinoma), and squamous cell differentiation were examined in non-small cell lung carcinoma (NSCLC) without obvious light-microscopic signs of squamous and glandular differentiation. Materials and methods All lung tumours diagnosed as NSCLC (n=61), without obvious squamous or glandular features, were obtained by bronchial biopsy or core biopsy supported by computed tomography. They were diagnosed during 1996-2009, at the Department of Pathology, Gavle Hospital, Sweden. The tumours were examined immunohistochemically with antibodies against CK5/6, p63 (squamous cell markers) and carcinoembryonic antigen (CEA) (adenocarcinoma cell marker). Double immunostaining (p63/CEA) was also performed on individual tumours. Results The tumours originated from 36 males and 25 females, aged 54-83 years. Pure squamous cell differentiation (CK5/6 positive only) occurred in 34.4% (n=21) tumours and pure adenocarcinoma cell differentiation (CEA positive only) was present in 14.9% (n=9). Tumours with both squamous and adenocarcinoma features (CK5/6 and CEA positive) were most prevalent (47.5%, n=29). Two tumours (3.3%) were negative with both stains (and also synaptophysin negative). Double immunostaining (p63/CEA) revealed that squamous and adenocarcinoma markers were co-localised in cells in certain tumours. Conclusion Co-localisation of squamous and adenocarcinoma markers in the same tumour cell suggests that additional analyses for novel biomarkers of specific lung cancer types may subsequently lead to a refined treatment choice for patients with the goal of improving clinical outcomes.

Human papillomavirus (HPV) 16 is the dominant cofactor in cervical cancer development. The present report investigated the age-specific prevalence of HPV16 in cervical carcinoma in situ (CIS) in females attending organised cervical cancer screening. A retrospective observational study was performed based on individual data from two databases. A total of 162 females aged between 20 and 65 years from Uppsala County, Sweden with CIS and an HPV test conducted between 2010 and 2011, preceding or concomitant to CIS diagnosis, were included. Females with cervical squamous cell carcinoma (SCC; n=35) were used for comparison. In total, 96% (n=156) of females with CIS were positive for high-risk HPV; HPV16 was the most prevalent (44.5%), followed by HPV33/52/58 (19.5%), HPV31 (13.1%) and HPV18/45 (9.5%). HPV16 was most frequently detected in females with CIS aged between 20 and 29 years (73.6%) and least frequently detected in those aged between 50 and 65 years (33.3%), with a statistically significant age-specific difference (P=0.001). Among the HPV16-positive females, multiple infections were most frequent in the younger age groups. The prevalence of HPV16 in females with CIS decreased with age, whereas a high prevalence of HPV16 remained in females with SCC. These results may indicate that HPV16 has increased oncogenic potential in older females.

Background: This study aimed to determine human papillomavirus (HPV) status and to investigate p16INK4A and Ki-67 expression and their correlation with clinical parameters and survival in women with primary carcinoma of the vagina (PCV). Methods: The presence of HPV DNA was evaluated by PCR. Genotyping was performed by Luminex in 68 short-term (⩽2 years) and long-term (⩾8 years) PCV survivors. p16INK4A and Ki-67 expression was evaluated by immunohistochemistry. Results: Human papillomavirus DNA was detected in 43% of patients, the majority (63%) of whom were HPV16 positive. High p16INK4A expression was significantly correlated with low histopathological grade (P=0.004), HPV positivity (P=0.032), and long-term survival (P=0.045). High Ki-67 expression was negatively correlated with histopathological grade (P

Please cite this paper as: Lindell M, Sanner K, Wikstrom I, Wilander E. Self-sampling of vaginal fluid and high-risk human papillomavirus testing in women aged 50 years or older not attending Papan ...

Most procedures for self-sampling of cervical cells are based on liquid-based media for transportation and storage. An alternative is to use a solid support, such as dry filter paper media.To evaluate if self-sampling of cervicovaginal fluid using a cytobrush (Viba-brush; Rovers Medical Devices B.V., Oss, The Netherlands) and a solid support such as the Whatman Indicating FTA Elute cartridge (GE Healthcare, United Kingdom) can be used for reliable typing of human papillomavirus (HPV), as compared to cervical samples obtained by a physician using a cytobrush and the indicating FTA Elute Micro card and biopsy analysis.A total of 50 women with a previous high-risk (HR) HPV positive test were invited to perform self-sampling using the Viba-brush and the FTA cartridge and thereafter a physician obtained a cervical sample using the cytobrush and a FTA card, together with a cervical biopsy for histology and HPV typing. Detection of HR-HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59 was performed using three multiplex real-time polymerase chain reaction (PCR) assays.All samples contained sufficient amounts of genomic DNA and the self-samples yielded on average 3.5 times more DNA than those obtained by the physician. All women that were positive for HR-HPV in the biopsy sample also typed positive both by self-sampling and physician-obtained sampling. For women with a histological diagnosis of cervical intraepithelial neoplasia grades 2-3 (CIN 2-3) all three HPV samples showed 100% concordance. A higher number of women were HPV positive by self-sampling than by physician-obtained sampling or by biopsy analysis.The Viba-brush and the FTA cartridge are suitable for self-sampling of vaginal cells and subsequent HR-HPV typing.

Background: Testing for high-risk human papillomavirus (HPV) in primary screening for cervical cancer is considered more sensitive, but less specific, in comparison with Pap-smear cytology. Women with persistent HPV infections have a higher risk of developing cervical intraepithelial neoplasia 2+ (CIN2+) lesions. This study was performed to evaluate the gain in specificity for detection of histologically confirmed CIN2+ lesions achieved by short-time repeat testing for high-risk HPV in women aged 30–65 years, with the primary sample for HPV analysis taken by self-sampling. Methods: A total of 8000 women in Uppsala County, aged 30–65 years, who had not attended organised screening for 6 years or longer, were offered self-sampling of vaginal fluid at home and the samples sent for HPV typing. Of these, 8% (669) were not possible to contact or had performed hysterectomy. Women positive for high-risk HPV in the self-sampling test were invited for a follow-up HPV test and a cervical biopsy on average 3 months after the initial HPV test. Results: In all, 39% (2850/7331) of invited women chose to perform self-sampling of vaginal fluid at home. High-risk HPV infection was found in 6.6% (188) of the women. In all, 89% of the women testing HPV positive performed a follow-up examination, on average 2.7 months, after the first test and 59% of these women were HPV positive in the follow-up test. The prevalence of CIN2+ lesions in women with an initial HPV-positive test was 23% (95% CI 18–30%) and in women with two consecutive HPV-positive tests was 41% (95% CI 31–51%). In women with two positive HPV tests, the prevalence of CIN2+ lesions varied from 49% in women at age 30–39 years to 24% in women at age 50–65 years. Short-time repeat HPV testing increased the specificity for detection of CIN2+ lesions from about 94.2% to 97.8%. The most prevalent HPV types were HPV16 (32%), followed by HPV18/45 (19%) and HPV 33/52/58 (19%). Conclusion: The short-time persistence of high-risk HPV infection in this age group was about 60%. Repeat testing for high-risk HPV using self-sampling of vaginal fluid can be used to increase the specificity in the screening for cervical cancer in women aged 30–65 years.

Background The FTA elute micro card™, which enable the collection, transport, and archiving of DNA could be an attractive alternative to a liquid based collection system for detection of human papillomavirus (HPV). Objectives To develop a method based on the FTA elute micro card™ for dry collection of cervical epithelial cell samples, suitable for subsequent PCR-based HPV testing. Study design The method was evaluated by a comparison of the DNA collected by cytobrush and the regular FTA elute micro card™ from 50 cervical cell samples. The method was then used to estimate the DNA amount in 1040 samples applied to the indicating FTA elute micro card™. Result The agreement in HPV positivity between the cytobrush and FTA samples (94%) was excellent (kappa = 0.88, 95% CI 0.748–1). All the 1040 samples on the indicating FTA card™ had sufficient amounts of genomic DNA (>10 copies of a single copy gene) to be suitable for HPV typing. In 53 of the 1040 women the day in the menstrual cycle was noted, and the copy number during follicular phase day 9–13 was found to be statistically significantly lower than for the other three stages in the menstrual cycle (day 4–8, 14, >14) and during menopause. Conclusion The indicating FTA elute micro card™ represents a suitable medium for collection of cervical cell samples, although follow-up studies are needed to verify the detection of low frequency HPV types.

The argyrophil reaction occurs in the parathyroid cells with the Grimelius silver nitrate stain. In the present study, Bouin's fluid was found to be superior to other tested fixatives (formalin, Karnovsky's fluid, GPA etc) in this respect. A study of the argyrophil reaction on the ultrastructural level showed an accumulation of silver particles in the secretory granules, which means that the Grimelius silver stain can be assumed to be an indicator of the secretory granules stored in the parathyroid cells. Whether the argyrophil reaction can be of help in differential diagnosis between different abnormal parathyroid conditions is not yet clear.

To evaluate the role of the glucose residue of the diabetogenic substance streptozotocin, the effect of its aglucone derivate N-nitrosomethylurea was tested in Chinese hamsters. At a dose of 50 mg/kg body weight of N-nitrosomethylurea a triphasic blood glucose curve was recorded with an initial hyperglycaemic peak after 3 hours followed by a decrease at 6 hours. After 24 hours and during the following days the values were moderately elevated. There was a high mortality in the diabetic animals, about 80 per cent of them dying within one week. The approximate L.D. 50 of N-nitrosomethylurea injected intraperitoneally in non-fasting adult animals was about 125 mg/kg body weight at an observation time of 48 hours. On light microscopy, degenerative changes with nuclear pyknosis were seen after 3 hours in the pancreatic islet cells, followed by cellular disintegration. Both beta-, alpha2- and alpha1-cells were obviously affected. Pretreatment with 500 mg nicotinamide/kg body weight given intraperitoneally 10 minutes before the injection of N-nitrosomethylurea inhibited and hyperglycaemia and seemed to prevent the injurious effects of N-nitrosomethylurea on the islet cells. The results show that the glucose residue of the streptozotocin molecule is not necessary for the induction of diabetes in Chinese hamsters, but it seems to increase the selectivity of the toxic effects for the islet cells. This is a clear advantage in studies of experimental diabetes, especially when longer observation periods are desired.

In a histopathological and immunocytochemical study of biopsy and/or operation specimens from 27 patients with endocrine tumors of the colon and rectum ("hind-gut carcinoids") enkephalin-immunoreactive tumor cells were observed in two cases. Both patients were obese women, about 50 years of age, with a history of constipation. The tumors were situated near the anus in the dorsal wall of the rectum. One tumor had metastasized to a lymph node, and the other showed vascular invasion. The tumor cells were non-argentaffin; some were argyrophil. One tumor contained only few enkephalin-immunoreactive cells but had numerous beta-endorphin-immunoreactive cells, which were distinct from the former. The other contained large numbers of enkephalin-immunoreactive cells but no beta-endorphin cells. Both tumors also harboured glucagon-immunoreactive cells; in one there were also cells containing immunoreactive pancreatic polypeptide. These cells were distinct from the enkephalin-storing ones. No 5-hydroxytryptamine could be detected in the two tumors.

One day after injection of 200 mg streptozotocin/kg body weight in Chinese hamsters, necrotic cell debris or marked degenerative changes were seen in the pancreatic islets light microscopically. Both β-, α2- and α1-cells seemed to be affected. During the first weeks, in particular, signs of regeneration and neoformation of islet tissue were evident in the pancreatic tissue. Labelling with 3H-thymidine revealed an increased incorporation of this isotope in islets of diabetic animals. Tubular structures and proliferating buds consisting mostly of “clear cells” were seen. “Clear cells” were also observed sometimes in aggregates in islets with degenerative changes. The high incorporation of labelled thymidine at the same time as “clear cells” were observed in the islet tissue suggest that these cells are involved in islet cell regeneration. After one week, up to about one month, large islets containing hypertrophied cells with a large nucleus and a prominent nucleolus were found. Hydropic degeneration and even necrosis sometimes occurred in these islets. The regenerative activity as well as the hypertrophic islets disappeared at the end of the observation period (3 months) at which time relatively small islets with degranulated β-cells and irregularly distributed α2- and α1-cells with variable staining properties and nuclear sizes were seen.

Twenty typical mid-gut carcinoid tumours were examined for the presence of gastrin immuno-reactivity to antisera specific to the C-terminal pentapeptide or to the mid-portion of gastrin-17. Pentagastrin immuno-reactivity was found in seven cases, and in one of these reactivity to antiserum against the mid-portion of gastrin-17 was also observed. The results are in accordance with the previous observation that argyrophil tumour cells are present in mid-gut carcinoid tumours and may explain why peptic ulcer disease is sometimes seen in association with the carcinoid syndrome.

The Grimelius argyrophil reaction was studied in 27 rectal carcinoids. A majority of the tumour cells were silver-reactive in 16 tumours and a minority in 11 tumours. Both weakly and strongly stained tumours were found, as well as tumour cells with variable staining properties within the same tumour. Re-staining resulted in potentiation of the reaction, but this was most obvious in tumours with an initially easily identified argyrophilia. It is suggested that evaluation of the Grimelius argyrophil reaction in combination with routine histology increases the accuracy of the diagnosis of rectal carcinoids.

An ultrastructural study of the early effects of intraperitoneal injection of 50 mg/kg body weight of N-nitrosomethylurea on the pancreatic islet tissue in Chinese hamsters was performed. Thirty minutes after injection there was slight dilatation of the endoplasmic reticulum and mitochondrial swelling in a few peripheral alpha2-cells near to capillaries and also in some beta-cells. After 1 hour these changes were more pronounced. After 3 hours, distinct nuclear pyknosis was seen in endocrine islet cells of all types together with beta-cells granular irregularities, disruption of granular cores and autophagy of alpha2-cell granules. During the following hours, marked derangement of intracellular structures, ending in obvious cellular destruction, was observed. The results indicate that N-nitrosomethylurea has a direct cytotoxic effect on the beta-, alpha2- and alpha1-cells of the islet tissue. The similarity between the ultrastructure of the pancreatic islets after injection of N-nitrosomethylurea and streptozotocin is discussed.

Background: Around 65% of women with cervical carcinoma in Sweden have not attended an organised screening. We therefore investigated the value of using self-sampling at home in combination with a test for high-risk human papilloma virus (HPV) to increase participation. Methods: A total of 2829 women 30–58 years old, who had not attended the organised screening for ⩾6 years, were recruited. They were offered self-sampling at home (Qvintip) and recommended to send the collected vaginal fluid to a laboratory for analysis of the presence of high-risk HPV (Hybrid Capture 2 method). Results: A total of 39.1% of the women accepted home sampling. These women disclosed a relatively high prevalence of high-risk HPV, which decreased with age, from 11.1% in women 30–39 years old to 2.9% in women ⩾50 years . Follow-up disclosed histological cervical intraepithelial neoplasm (CIN) 2–3 lesions in 43.2% of the women with a persistent HPV infection, corresponding to 2.0% of the total number of participating women. The sensitivity of a single smear to detect the histological CIN 2–3 lesions were only 52.6%, even if all abnormal smears (atypical squamous cells of unknown significance (ASCUS)–CIN 3)) were included. Conclusion: The use of self-sampling at home in combination with testing for high-risk HPV increases the participation rate of the organised screening and detects almost twice as many women with pre-malignant cell alterations (CIN 2–3) in comparison those with a single cytological smear.

Background Human papillomavirus (HPV) testing is an important part of cervical carcinoma screening, and the most widely used assay for detection of HPV is Hybrid Capture 2 ( HC2 ). Objectives We compare the HC2 with the real-time PCR hpVIR assay for detection of HPV in follow-up smears of 398 women diagnosed with atypical squamous cells of unknown significance (ASCUS) or low grade cervical intraepithelial neoplasia (CIN 1) in their initial smear. Study design The two assays target the same set of high-risk (HR) HPVs with exception of HPV68. hpVIR identify individual or groups of HPV types as well as their viral load, while HC2 identify HR HPVs without specification of type. Results 34% (131/391) of the women were positive with HC2 and 45% (175/391) with hpVIR . 16% (63/391) were positive only with hpVIR and among those with cytology available 6% (3/52) had a CIN 2. The 3% (13/391) of women positive only with HC2 either contained low-risk HPVs or copy numbers below the cut-off for the hpVIR assay. Conclusion The hpVIR assay has a similar sensitivity and specificity as HC2 , but hpVIR detect a higher frequency of high-risk HPV infections.

OBJECTIVE. Atypical squamous cells of undetermined significance (ASCUS) cells, occurring in organized cytological screening, may be either high-risk human papillomavirus (HPV) positive or negative. To refine the assessment of women with ASCUS, a high-risk HPV-DNA test is recommended as triage in Sweden.A total of 197 consecutive women (mean age 39 years, range 21-60) with a diagnosis of ASCUS from the primary screening were selected for triage. Their cervical smears were collected and evaluated by using conventional cytological examination in combination with a high-risk HPV-DNA test (hybrid capture 2). The women were categorized into four groups: Group A, Cytology + /HPV + ; Group B, Cytology-/HPV + ; Group C, Cytology + /HPV-; and Group D, Cytology-/ HPV-. Women within Groups A-C were admitted for colposcopy and cervical biopsy. The women in Group D were considered as a low-risk group for tumor development, and were re-examined after three years in the next round of the organized screening.In women in Group A (n=58) the prevalence of histological verified CIN2-3 was 41%, in Group B (n=41) 20%, and in Group C (n=9) 0%. In Group D (n=89), repeated primary screening three years later revealed CIN2-3 in two biopsies from 74 women studied (3%). The prevalence of a high-risk HPV infection decreased with age in women with ASCUS. It was 74% in women30 years and 19% in womenor =50 years.Adding a high-risk HPV test in secondary screening increased the identification of women with CIN2-3 lesions by 33% in comparison with repeat cytology (p=0.01). The clinical significance of the ASCUS diagnosis varied with age of the women.

The aim of the study was to investigate long-term trends in the incidence of borderline tumors and ovarian cancer in Sweden during 1960-2005, based on data from the population-based Swedish Cancer Register. We identified 6,288 patients with borderline ovarian tumors and a total of 34,977 cases of ovarian cancer during the study period. The age-standardized incidence of borderline ovarian tumors increased from 1.0 to 5.3 per 100,000 women-years from 1960-1964 to 2000-2005 and the incidence of ovarian cancer increased from 16.4 to 19.7 per 100,000 women-years from 1960-1964 to 1980-1989 and then declined to 16.6 per 100,000 women-years to the period 2000-2005. Borderline ovarian tumors comprised 15% of all primary ovarian neoplasms and the proportion increased from 8.3 to 23.6% during the study period. The median age at diagnosis for patients with borderline ovarian tumors and ovarian cancer was 55.2 and 61.6 years, respectively. In women younger than 40 years, 34% of all primary ovarian malignancies consisted of borderline ovarian tumors. For the 5 birth cohorts evaluated, the peaks of incidence occurred in stepwise younger age for each younger birth cohort for both borderline tumors and ovarian cancer. The increasing incidence of borderline ovarian tumors could be explained by an increase in diagnostic activity and by a lack of protective effect of oral contraceptive use. The decline in invasive tumors could be explained by a combination of factors, where the contribution of each is uncertain: shifting exposure to risk factors, a protective effect of oral contraceptive use, and increased detection of and removal of precancerous lesions.

After drinking water, the fluid quickly leaves the stomach thereby creating a hypotonic luminal environment in the duodenum. This in turn constitutes a potential threat to the integrity of the duodenal epithelium. It therefore seems highly likely that luminal hypotonicity activates physiological mechanisms that aim to increase luminal osmolality. One such physiological mechanism may be to increase mucosal permeability thereby facilitating the transport of osmolytes into the lumen.A draw-back of performing experiments in anesthetized animals is that surgery per se depresses gut functions, such as peristalsis, by mechanisms involving endogenous prostaglandins. In this thesis it is shown that inhibition of cyclooxygenase-2 (COX-2), in animals subjected to an abdominal operation, restore and/or improve duodenal functions such as motility, mucosal bicarbonate secretion, hypotonicity-induced increase in mucosal permeability and the osmolality-adjusting capability.Experiments revealed that the stomach is resistant to hypotonic challenge while the jejunum is more sensitive to hypotonicity-induced increase in mucosal permeability than the duodenum. The hypotonicity-induced increase in duodenal mucosal permeability is not due to injury but possibly reflects physiological dilatation of paracellular shunts.Luminal perfusion of the duodenum with an isotonic solution lacking Cl- decreased bicarbonate secretion while the lack of luminal Na+ increased mucosal permeability. Stimulation of bicarbonate secretion by COX-2 inhibition is to a large extent dependent on luminal Cl- while that induced by vasoactive intestinal peptide is not.The hypotonicity-induced increase in mucosal permeability involves the release and action of serotonin (5-HT) on 5-HT3 and 5-HT4 receptors and stimulation of enteric nerves strongly implicating physiological regulation of this process.

Time trends in the incidence of malignant neoplasms of the thyroid were examined for Sweden for the period 1958-81, 5,838 cases being studied. Autopsy-diagnosed cases were excluded. Mean annual changes in the age-standardized rates over this period were 1.9% and 1.2% for women and men, respectively, for all thyroid carcinomas combined; 4.9% and 2.1% for papillary carcinoma; 0.9% and 2.1% for follicular carcinoma; and -1.0% and -2.1% for anaplastic carcinoma. Age, period and cohort models were fitted. There was a progressive increase in papillary cancer incidence for cohorts born since 1919. This increase cannot be satisfactorily explained as an artefact of trends in classification, and probably reflects a real increase in incidence. A less marked increase was seen for follicular cancer, and there was a decline for cohorts born since 1939. While the risk of papillary and anaplastic carcinoma was lower in iodine-deficient areas, follicular cancer risk was twice as high in these areas, for men only. There was a steady decline of anaplastic cancer in both sexes after 1965, largely attributable to a decline in cohorts born since 1924.

Background Self-sampling for HPV as part of primary screening is a well-tolerated method for women not attending organized Pap smear screening and could increase coverage of cervical cancer screening. Objective To investigate if the prevalence of HR-HPV varies from day to day in infected women and if one single sample is reliable for detecting an ongoing infection. Study design This is a prospective cohort study on 12 premenopausal and 13 postmenopausal women performing daily self-sampling for HR-HPV testing. They were all HR-HPV-positive 1–3 months ago. Postmenopausal women were sampled for 28 days and premenopausal women sampled during bleeding-free days in one menstrual cycle. A possible difference in viral load between the estrogen-dominated proliferative phase and the progesterone-dominated secretory phase was analyzed. Results and conclusions Consistent results throughout the sampling period were observed for 19 women, with either a daily presence of HPV (14 women) or no HPV at all during the sampling period (5 women). Of 607 samples from 25 women, 596 were consistently positive or negative for HPV during the sampling period and 11 were inconsistent (2%). There was no difference in HPV copy number between the estrogen dominated proliferative or progesterone dominated secretory menstrual cycle phases. The major finding was a high degree of consistency concerning HR-HPV positivity and negativity of HR-HPV in vaginal fluid during a sustained period of daily self-sampling. It does not appear to matter whether the sample is collected in the proliferative or secretory phase.

Typical lung carcinoids are usually relatively benign tumors, but distant metastases are seen in up to 12% of the patients. In contrast, atypical carcinoids are more aggressive tumors, displaying metastases in up to 70%. The current treatment of metastatic lung carcinoids is discouraging. New therapies, such as inhibitors of the tyrosine kinase receptor family c-kit, platelet-derived growth factor receptors (PDGFR) alpha and beta and epidermal growth factor receptor (EGFR) have shown promising results in other malignancies and might be of value in malignant lung carcinoids.Tumor tissue from 51 patients with typical lung carcinoids were immunostained with polyclonal antibodies against c-kit, PDGFRalpha, PDGFRbeta and EGFR. Of the 24 patients who had metastatic disease, 17 had distant metastases. Fifteen of the patients had died from their disease.Twelve of the tumors stained positive for c-kit, 44 expressed PDGFRalpha, 30 showed positive immunoreactivity for PDGFRbeta and 26 were EGFR immunoreactive. Among the 17 patients with distant metastases, 5 tumors expressed c-kit, 12 were PDGFRalpha immunoreactive, 9 stained positive for PDGFRbeta, and 7 showed positive immunoreactivity for EGFR. There was no correlation to distant metastases or survival for c-kit, PDGFRbeta or EGFR.Tyrosine kinase receptors such as c-kit, PDGFRalpha, PDGFRbeta and EGFR are expressed in a significant number of patients with metastatic lung carcinoids. Treatment with inhibitors of the tyrosine kinase receptors expressed may be considered.

In a substantial proportion of cases with endocrine malignant disease the primary lesion cannot be localised and the pathologist hesitates upon the origin of the tumour. Well differentiated neuroendocrine carcinomas of the small bowel can usually be identified by the strong serotonin immunoreactivity, but foregut carcinoids may also stain positive for serotonin and the differential diagnosis between the various foregut tumours may be difficult. We examined if immunostaining for gastrin-releasing-peptide (GRP) may aid in establishing the origin of an unknown neuroendocrine tumour. Tumour tissue from 79 patients (27 lung carcinoids, 4 thymic carcinoids, 4 gastric neuroendocrine tumours, 17 pancreatic well differentiated neuroendocrine carcinomas, 1 duodenal well differentiated neuroendocrine tumour and 26 well differentiated neuroendocrine carcinomas of the small bowel) were immunostained with antibodies against GRP and serotonin. Positive staining for GRP was found in 12/27 lung carcinoids. All other tumour types were consistently GRP-negative (p?0.0001). We conclude that immunostaining for GRP may aid in defining the origin of the tumour, and that GRP-immunoreactivity increases the suspicion of a lung carcinoid.

Background. The relationship between the human papillomavirus (HPV) tests and the cytological findings was evaluated. Methods. Totally, 161 women participating in the organized cytological screening in the County of Uppsala and showing atypical squamous cells of uncertain significance (ASCUS) in their cervical smears were identified during 2002 and 2003. Those women were invited for a repeated examination about 3 months later. At that occasion, a smear sample was collected and used for cytological examination and a concomitant HPV test. Oncogenic HPV was identified by polymerase chain reaction and HPV deoxyribonucleoside acid (DNA) sequence analysis in 50 cases and by Hybrid Capture II in 111 cases. Results. Women with an ASCUS diagnosis showed a normal cytology and a negative HPV test in 30% of the cases, abnormal cytology and a positive HPV test in 32% of the cases; in 26% of the women, the HPV test was positive, whereas cytology was normal; and in 11% of the women, the HPV test was negative, whereas cy...

High loads of human papillomavirus (HPV) 16 and HPV 18/45 increase the risk of developing invasive cervical carcinoma, revealing higher risk in percentiles of highest viral loads for HPV 16 (odds ratio (OR) 58.7, 95% confidence interval (CI) 21.9–151.4) compared to HPV 18/45 (OR 3.3, 95% CI 1.5–7.2). Thus, HPV load is a type-dependent risk marker for invasive carcinoma.

Objective To examine the effect of Papanicolaou staining of cervical smears on the sensitivity of molecular biologic HPV tests. Study Design Two sensitive HPV tests were used, HPV DNA sequence analysis after polymerase chain reaction (PCR) amplification and the Hybrid Capture II method (HC II) (Digene Diagnostics Inc., Silver Spring, Mainland, U.S.A.). Papanicolaou-stained and unstained smears taken simultaneoulsy were examined from 265 women readmitted for examination due to an atypical squamous cells of undetermined significance diagnosis. Results After an HPV test with the PCR method on unstained slides, 66% of the women were HPV positive, whereas the same women were HPV positive in 54% when Papanicolaou-stained slides were analyzed. However, this difference was not statistically significant (p>0.1). With the HC II method, 55% of unstained smears were HPV positive whereas 29% were HPV positive, when Papanicolaonstained slides were examined. This difference was significant (p < 0.001). The same strong differences in sensitivity were observed when both the PCR and HC II methods were studied on the same Papanicolaou stained glass slides. whereas on unstained slides no significant difference was found. Conclusion The results demonstrate that Papanicolaou staining of a cervical smear significantly decreases the sensitivity of an HPV test performed with the HC II method, whereas the PCR method is less affected. With the Papanicolaou method, the bematoxylin bath is followed by HCl treatment, and strong acid treatment destroys DNA.

The aim of the present investigation was to define the spectrum of oncogenic types of human papillomavirus (HPV) present in benign, pre-malignant (low-grade and high-grade squamous intraepithelial lesions, LSIL and HSIL) and malignant cervical lesions. The study comprises 215 HPV-positive biopsies, analysed with PCR, followed by sequence analyses of the HPV DNA. Fifeteen oncogenic types of HPV were identified. In 170 benign or pre-maligant alterations, the most common being HPV 16 (51%), HPV 31 (8%), HPV 18 (7%) and HPV 45 (6%). HPV 33, 35, 51, 56, 58, 66, and 70 occurred in about 1–4%. The prevalence of HPV 39, 52, 56, 59 and 73 was In conclusion, a total of 15 different oncogenic HPV types were identified, of which 13 types were present in pre-malignant cervical lesions and 9 in malignant lesions. This information may have some relevance when HPV analyses are considered as an adjunct to the organised screening of cervical cancer and for those working with the development of HPV vaccines for the prevention of cervical cancer.

The relationship between the human papillomavirus (HPV) tests and the cytological findings was evaluated.Totally, 161 women participating in the organized cytological screening in the County of Uppsala and showing atypical squamous cells of uncertain significance (ASCUS) in their cervical smears were identified during 2002 and 2003. Those women were invited for a repeated examination about 3 months later. At that occasion, a smear sample was collected and used for cytological examination and a concomitant HPV test. Oncogenic HPV was identified by polymerase chain reaction and HPV deoxyribonucleoside acid (DNA) sequence analysis in 50 cases and by Hybrid Capture II in 111 cases.Women with an ASCUS diagnosis showed a normal cytology and a negative HPV test in 30% of the cases, abnormal cytology and a positive HPV test in 32% of the cases; in 26% of the women, the HPV test was positive, whereas cytology was normal; and in 11% of the women, the HPV test was negative, whereas cytology was abnormal (ASCUS or more).The results show that HPV tests identify a larger group of women at risk to develop cervical cancer in comparison with cytological examination. As the HPV tests have a higher sensitivity than the cytological screening, it is suggested that an HPV test in conjunction with a diagnosis of ASCUS can be employed to more efficiently select women, to whom further follow up is recommended.

Acta Obstet Gynecol Scand 2002; 81: 949-953. © Acta Obstet Gynecol Scand 2002 Background. Infertile women in Sweden are offered in vitro fertilization (IVF) within the frame of the social security system. The present investigation was undertaken to evaluate the prevalence of genital human papilloma virus (HPV) infection in relation to the results of cytologic screening and to the infertility in these women. Material and methods. Two hundred and fourteen women, mean age 32 years (range 20-40), admitted to the Center for Reproduction at Uppsala University Hospital for investigation of infertility and IVF were studied. Human papilloma virus tests were performed by a sensitive polymerase chain reaction-based technique in cervical smears obtained at a medical examination or during oocyte retrieval. Cytologic screening results were obtained from medical records or at the time of investigation. The infertile women were compared with 197 healthy female controls. Results. Infertility resulted from female factors i...

Antibodies to six specific regions of the chromogranin A (CgA) molecule were used to study their immunoreactivity in human neuroendocrine (NE) tumors. Tissue specimens from endocrine pancreatic tumors (n = 14), duodenal carcinoids (n = 2), bronchial carcinoids (n = 5), ileal carcinoids (n = 5) appendix carcinoids (n = 2), medullary thyroid carcinomas (n = 6), parathyroid adenomas (n = 2), and pheochromocytomas (n = 8) were analyzed. The results showed that the NE tumor types expressed varying numbers of CgA fragments. A variation in frequency of the expression of immunoreactive cells was sometimes seen also within the same tumor type. The midportion fragment CgA 176-195 (chromacin) was the only fragment expressed in all tumors. Benign and malignant tumors expressed different patterns, being especially true of insulinomas and pheochromocytomas. These findings suggest that region-specific antibodies to CgA fragments can be used as a diagnostic tool for the characterization of NE tumors.

Infection with the human papillomavirus is an important co-factor in the development of cervical carcinomas. Accordingly, HPV DNA is recognised in most of these tumours. Polymorphism of the p53 gene, codon 72, is also considered a risk factor in the development of cervical carcinoma. However, this finding is contradicted by several observers. In the present investigation, 111 cases of adenocarcinoma of the cervix collected through the Swedish Cancer Registry and 188 controls (females with normal cytology at organised gynaecological screening) were analysed with regard to p53, codon 72, polymorphism using a PCR- and SSCP-based technique. In the controls, 9% showed pro/pro, 44% pro/arg and 47% arg/arg, whereas in the invasive adenocarcinomas, the corresponding figures were 0%, 29% and 71%, respectively. The difference was statistically significant (P = 0.001). HPV DNA was identified in 86 tumours (HPV 18 in 48, HPV 16 in 31 and HPV of unknown type in 7 cases) and 25 tumours were HPV negative. The p53, codon 72, genotypes observed in HPV-positive and HPV-negative cervical adenocarcinomas were not statistically different (P = 0.690). The results indicate that women homozygotic for arg/arg in codon 72 of the p53 gene are at an increased risk for the development of cervical adenocarcinomas. However, this genetic disposition seems to be unrelated to the HPV infection. © 2001 Cancer Research Campaign http://www.bjcancer.com

Investigation on intratumoral genetic heterogeneity provides an important insight into the roles of genetic alterations in human carcinogenesis and clues to clonal origin of tumors. Intratumoral heterogeneity of genetic changes of cervical cancer has not been described so far. In this study, we analyzed the intratumoral heterogeneity of chromosome 3p deletions and X-chromosome inactivation patterns in multiple microdissected samples from each individual cervical cancer, attempting to understand the roles of 3p deletions in development of cervical cancer and its clonal origin. Totally, 120 normal and lesional samples from 14 cases of fresh cervical cancers were analyzed. Frequency and patterns of allelic losses of 3p were assessed by polymerase chain reaction (PCR) amplification of 12 microsatellite markers flanking the frequently deleted regions of 3p, followed by Genescan analysis in an ABI 377 DNA sequencer. Loss of heterozygosity was recorded as heterogeneous pattern (LOH present in parts of samples or LOH involving different alleles among different samples) and homogeneous pattern (LOH involving identical alleles in all samples from the tumor). Allelic loss affecting at least one marker was detected in 8 of 14 cases (57%). Allelic losses, both homogeneous and heterogeneous, were frequently detected at FHIT gene region (D3S1300, 40% and 60%; D3S4103, 27.3% and 54.6%), 3p21.3–21.2 (D3S1478, 27.3% and 45.5%), and 3p24.2–22 (D3S1283, 30% and 50%). Seven of eight LOH-positive tumors exhibited homogeneous allelic loss involving at least one of these three 3p loci. Allelic losses were present in the CIN lesions synchronous with invasive lesions positive for LOH. Our findings suggest essential roles of genes on these 3p loci, particularly the FHIT gene in participating in clonal selection and early development of cervical cancer. Most interestingly, with the combination of LOH analysis and X-chromosome inactivation analysis, we provided the first clear genetic evidence of polyclonal origin of cervical invasive cancer in two of eight cases. This finding strongly suggests the importance of field defect (possible human papilloma virus) in cervical carcinogenesis.

A previous Swedish study revealed that both prototype and variant HPV16 E6 oncoprotein, occur in about equal numbers in high-grade cervical intraepithelial neoplasia (HCIN), whereas variant HPV16 predominates in invasive cervical squamous carcinoma. Most of the malignant HPV16 variants contain a common mutation, L83V, in the E6 oncoprotein. In the present investigation, 28 HPV16 positive, invasive cervical adenocarcinomas were collected from a total number of 131 adenocarcinomas. These HPV16-positive cases were evaluated with analysis of the E6 gene, using a recently described PCR-SSCP method for identification of the specific mutation (L83V) in the E6 gene. The results obtained were correlated to findings in 103 preinvasive, HCIN, and 31 invasive cervical squamous carcinomas also infected with HPV16. The HPV16 E6 variant L83V was present in 40% of the HCIN lesions, in 54% of the invasive adenocarcinomas, in comparison to 81% of the invasive squamous carcinomas. The difference between HCIN and squamous carcinomas was statistically significant, P< 0.001, whereas the difference between HCIN and invasive adenocarcinomas was not statistically significant, P = 0.604. Prototype HPV16 and its E6 variant L83V are both prevalent in preinvasive and invasive cervical lesions in Swedish women. However, the obvious predominance of HPV16 variant in squamous carcinomas was not seen in adenocarcinomas. A single amino-acid shift in the HPV16 E6 gene appears to result in a different transforming potential in squamous and glandular cervical lesions. © 2000 Cancer Research Campaign

Two problems were the focus of this study. (1) Is precancer and/or invasive cancer of the human cervix a poly- or monoclonal proliferation of neoplastic cells? (2) Are simultaneously present precancers and cancers of the cervix clonally related, or do they arise independently? Microdissection of 37 neoplastic lesions with different degrees of histologic severity in 22 patients followed by polymerase chain reaction-based analysis of X-chromosome inactivation was used as a principal method. Invasive cancers were interpreted as monoclonal because samples invariably showed monoclonal signals. In two thirds of these cases, simultaneously present precursors had the identical X-chromosome inactivation pattern, but in one third the pattern was different. Polyclonality was seen in a subgroup of precursors, where there was no simultaneous presence of invasive cancer. In contrast, when invasive cancer was present, no precursor signaled polyclonality. Data taken together indicate that the pathogenesis of cervical cancer is probably even more complicated than that of other cancers involving selection of subclones from originally polyclonal precursors and possibility of coexistence of precursors of different monoclonal composition. The study also observed that a large field of normal cervical squamous epithelium (approximately 500 basal squamous epithelial cells) with nonrandom X-chromosome inactivation was present. It remains to be further investigated whether this phenomenon represents an embryologic lyonization pattern of X-chromosome inactivation or postembryologic clonal expansion of submorphologically transformed cells.

Cervical cancers are considered to originate from a series of pre-malignant lesions (cervical intra-epithelial neoplasia, CIN). The mechanisms behind these events are unknown. In addition to HPV infection, deletions of chromosome 3p have been found to be a frequent event in cervical cancer and likely play an important role in the transition of CIN to invasive cancer. To classify the potential role of 3p deletions in early-stage cervical carcinogenesis, we analyzed LOH of 3p in cervical precancers. Thirty cases with single or multiple CIN lesions were selected for the study, including 20 cases without and 10 cases with synchronous invasive cancers. Allelic losses on 1 or more 3p loci were recorded in 33% (3/9) of CIN II and 36% (5/14) of CIN III lesions from 20 cases without co-existing invasive cancer, whereas an increasing percentage of LOH was observed in the 10 precancerous lesions synchronous with invasive cancer, with 71% (5/7) CIN II and 76% (13/17) CIN III lesions. This result implies that 3p deletions have selective roles in early transition of pre-malignancy to invasive cancer. Comparing the LOH patterns between the 2 groups, genetic deletions in cases with invasive cancers involved extensive regions of 3p but were more localized in precancer cases without concomitant invasive cancer. Two interstitial regions, 3p22-21.3 around marker D3S1260 and 3p21.1 around markers D3S1289 and D3S1076, were most frequently deleted in both groups, suggesting that these 2 regions are novel tumor-suppressor loci which may play a role in early transition of cervical precancer to invasive cancer. Identical LOH patterns between multiple CIN lesions and synchronous invasive cancer in the same case suggests that different cervical precancers and invasive cancer are genetically linked and most likely originate from a single precursor cell.

The clonality of intestinal carcinoids and the relationship between different tumour deposits of multiple intestinal carcinoids were investigated in this study. Six cases of multiple ileal carcinoids were selected for analysis and three independent carcinoid lesions from each case were microdissected. Clonality of the lesions was determined by polymerase chain reaction (PCR)-based X-chromosome inactivation of the human androgen receptor gene. Four out of six cases were heterozygous for microsatellite repeats within the androgen receptor gene and thus informative for the study. The results showed that all 12 lesions analysed had non-random X-chromosome inactivation (monoclonal) patterns, compared with the background normal intestinal mucosal tissues. This finding proves for the first time the monoclonal origin of human intestinal carcinoids, by X-chromosome inactivation analysis. More interestingly, identical X-chromosome inactivation patterns were found in different carcinoid lesions from each individual case. This evidence strongly indicates that multiple carcinoids of the small intestine were generated by metastasis of a primary tumour to different locations in the intestine, rather than being of multiple origin. This study provides an important insight into the carcinogenesis of intestinal carcinoids.

A case of rapidly fatal bronchial adenocarcinoma in an 18-year-old woman is reported. Remarkable features of the case included early metastasis to bone and development of leucoerythroblastic anaemia with thrombocytopenia and eosinophilia.

Tumor tissues from 43 patients with typical bronchial carcinoids have been immunostained with monoclonal antibodies (mAbs) against the standard form (CD44s) and the splice variants v4, v5, v6, v7, v7-8, v9 and v10 of the adhesion molecule CD44. The staining results were correlated with clinical data. Ten patients (23%) had regional lymph node metastases at diagnosis. Distant metastases have occurred in 12% of the patients; 9% died during the observation period of median 65 months (14-325). Positive staining for CD44s was correlated with decreased risk for distant metastases and disease related death. All patients with distant metastases were v6-negative. Patients with CD44v7-8-positive tumors had decreased risk for distant metastases, but the differences in mortality did not reach statistical significance. CD44v9 correlated significantly with decreased risk for distant metastases and death. The remaining CD44 variants (v4, v5 and v10) did not correlate significantly with clinical outcome. Our results confirm earlier observations that typical bronchial carcinoids are potentially malignant. However, positive staining for CD44s, v7-8 and v9 seems to be associated with a more favorable outcome, and may be taken into consideration in prognostic evaluation.

We microdissected 15 specimens of invasive cervical cancer co-existing with some of its precursors. Out of 15 cases, 10 carried HPV16, 2 HPV31, 1 HPV18 and 2 were HPV-negative. We found 3 HPV16 E6 variants among the 10 cases; one was A --G in nt 131 (one case) and a second was A --G in nt 276. The third, T;--G in nt 350, was common, and was found in 5 of the 10 patients infected by HPV16. The type of HPV and the E6 variant were identical in all lesions within the same patient. Viral DNA present in normal epithelium was identical in type and E6 variant to HPV in the same patient's lesions. Multiple samples from invasive cancers with HPV were consistently positive. The data suggest that the originally infecting HPV, including its variant type in the E6 gene, persists unaltered in the whole series of CIN that precedes invasive cancer. Our data are compatible with an essential role of HPV manifested by persistence of the viral genome during the entire natural life history of cervical cancer. We did not confirm previous data on the specific association of invasive cancer with an HPV E6 variant (G at nt 350 rather than T). The discrepancy may depend on the relatively few cases investigated or selection of a special sub-set with progression from CIN to invasive cancer already manifest.

A variant of human papillomavirus (HPV) 16 has been shown recently to be more prevalent in invasive cervical carcinoma than in preinvasive lesions. This HPV 16 variant possesses a common mutation (T to G) in nucleotide 350 (codon 83) of the E6 gene, resulting in an amino acid shift, L83V, in the E6 protein. This mutation was believed to signify preinvasive cervical lesions with a high probability of progression to invasive carcinoma. The purpose of the present investigation is to describe a rapid method for the detection of this variant HPV 16, E6 (L83V). Paraffin blocks of 18 gynecologic biopsy specimens were collected, all displaying the morphology of cervical intraepithelial neoplasia (CIN I-III) and a positive HPV 16 test. Sections from these blocks were used for DNA extraction. A DNA sequence of the E6 gene containing 176 bases (including codon 83) was amplified by polymerase chain reaction (PCR) and analyzed by non-radioactive single-strand conformational polymorphism (SSCP) analysis. A divergent SSCP pattern was observed in 7 of the HPV 16 positive biopsy specimens. A DNA sequence analysis of the PCR products revealed the conversion of Leu to Val in codon 83 of the E6 gene, correlating to the divergent band pattern. This PCR-SSCP method can be used to test for HPV 16 in women who are at serious risk of developing invasive cervical carcinoma.

Anal warts are, from an aetiological point of view, a diverse category of lesions including condylomata acuminata, fibroepithelial polyps and seborrhoeic keratosis. Human papillomavirus induced anal warts, in contrast to other types of warts, are contagious and not infrequently sexually transmitted, they therefore need to be accurately identified. A total of 24 anal warts were randomly collected and the histopathological diagnoses based on microscopy, alone or in combination with a sensitive PCR-based human papillomavirus test, were compared using the SHARP Signal system for detection. Three lesions were identified as condyloma acuminatum by morphology alone due to the obvious presence of koiloytotic atypia; 11 warts without koilocytes were identified only after a positive test for anogenital human papillomavirus. One additional lesion contained human papillomavirus DNA of cutaneous type and 9 papillomas were human papillomavirus-negative and tentatively diagnosed as fibroepithelial polyps or seborrhoeic keratosis. All 14 condylomas contained human papillomavirus of low-risk type. Of these, 12 warts showed a positive human papillomavirus reaction with in situ hybridization. Morphology alone cannot reveal the true nature of most anal papillomas, even when koilocytotic atypia is considered as a diagnostic hallmark. An optimal diagnosis of anal warts requires a sensitive PCR-based human papillomavirus DNA test. A test for identification of cutaneous human papillomavirus DNA is also worthwhile.

Background—Type 1 gastric carcinoids are associated with hypergastrinaemia and chronic atrophic gastritis, type 2 occur in patients with multiple endocrine neoplasia type 1 combined with Zollinger-Ellison syndrome, and type 3 lack any relation to hypergastrinaemia. Type 1 tumours are usually benign whereas type 3 are highly malignant.Aims—To identify possible tumour markers in patients with gastric carcinoids.Patients/method—Nine patients with type 1, one with type 2, and five with type 3 were evaluated with regard to symptoms, hormone profile, and prognosis.Results—Plasma chromogranin A was increased in all patients but was higher (pConclusions—Plasma chromogranin A appears to be a valuable tumour marker for all types of gastric carcinoid. Combination therapy with interferon α and octreotide may be beneficial in patients with metastasising type 1 gastric carcinoids.

Squamous carcinoma of the uterine cervix accounts for a considerable mortality among gynecological malignancies, although both the incidence of and mortality from cervical cancer have decreased in the Nordic countries since 1970. The reduction is a result of the cytologic screening program, through which precursor lesions can be detected and removed. Our aim was to determine why women in the county of Uppsala get cervical cancer despite extensive gynecological screening. A retrospective study of all women (43 cases) who developed histologically verified cervical squamous carcinoma in the county of Uppsala during the years 1991 to 1994 was undertaken. A central computer database covering all histopathological and cytological material made it possible to compare each woman's previous smears or lack of smears with her cancer diagnosis. Twenty women (47%, mean age at diagnosis 64.4 years) had not undergone cytological screening. Twenty-three women (53%) had been screened at least once within 6 years before tumor diagnosis. Of these, 11 (mean age 47.5 years) had had normal smears for the last 6 years, 8 (mean age 44.3 years) had shown abnormal cytology for less than one year and 4 (mean age 39.0 years) had shown abnormal cytology for more than one year and up to 6 years before their cervical cancer diagnosis. Women with cervical squamous carcinoma, who are not covered by the gynecological screening program (47%) are at increased risk of developing cervical cancer compared with other women. Consequently the average age of non-screened women developing cancer is considerably higher (64.4 years) than that of women with cancer screened previously (44.9 years). In 26% of the total group of women with cervical squamous carcinoma previous cytology displayed normal features.

Summary Background Little is known about factors related to prognosis in patients with carcinoid disease. In this study we have tried to identify such factors. Patients and methods We have evaluated 301 consecutive carcinoid patients (256 midgut, 39 foregut and six hindgut) referred during 15 years for medical treatment with respect to tumor distribution, hormone production, prognostic factors and survival. Results Survival was significantly shorter in midgut carcinoid patients with ≥ 5 liver metastases or with high levels of urinary 5-hydroxyindoleacetic acid, plasma chromogranin A or neuropeptide K. By univariate analysis, these variables together with the presence of carcinoid syndrome were related to a higher risk of dying. In multivariate analyses, performed in the 71 patients with full information on all variables, advanced age and plasma chromogranin A > 5000 μg/1 were independent predictors of overall survival. Conclusions Poor prognostic factors for midgut carcinoid patients were multiple liver metastases, presence of carcinoid syndrome and high levels of the tumor markers studied. In this study the only independent predictors of bad prognosis in midgut carcinoid patients were advanced age, which however is inherently related to overall survival, and plasma chromogranin A > 5000 μg/1. Thus, chromogranin A may prove to be an important prognostic marker for patients with carcinoid tumors.