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Cytology and histology records and cervical samples for HPV assay were obtained from a prospective cohort of 49 655 women attending clinics for routine cervical cytology in or near Manchester between 1988 and 1993. The women were followed up for cytological abnormality and neoplasia through the cytology laboratory's records. HPV at entry was assayed in an age-and periodstratified random sample of 7278 women and in prevalent and incident CIN3 cases. The prevalence of newly diagnosed CIN3 increased with time since last normal smear, indicating that most cases persist for several years. CIN3 prevalence did not increase further for screening intervals exceeding 5 years, however, suggesting that CIN3 eventually regresses cytologically. CIN2 prevalence increased less steeply with screening interval, while the prevalence of lesser abnormality was almost independent of screening interval. The prevalence of oncogenic HPV at entry declined from 19% among women aged under 25 to less than 3% at age 40 or above. Oncogenic HPV infection was strongly predictive of subsequent CIN3 (OR 17.2, 95% CI 10.4 -28.4), but only weakly related to CIN2 (OR 2.3, 95% CI 0.5 -10.7) and lesser abnormality (OR 1.4, 95% CI 0.8 -2.5). At current incidence rates, the lifetime risk of developing CIN3 will be 9% in this population. The cumulative risk of CIN3 diagnosis among cytologically normal women with oncogenic HPV detected at entry was 28% (CI 18 -43%) after 14 years. Persistence of oncogenic HPV may be more sensitive and specific than cytology for early detection of CIN3 and invasive cancer. Population-based prospective data on cervical neoplasia rates in relation to age, screening interval and history of type-specific HPV infection are still limited. Few cohorts are representative of regularly screened women in the general population, and those using the Bethesda system under which the high-grade category (HSIL) includes both CIN2 and CIN3 (Solomon et al, 2002) have often not analysed CIN2 and CIN3 separately. There is a strong and consistent association of genital HPV infection with cervical intraepithelial neoplasia (CIN) and cancer. CIN3 is almost always preceded by persistently detectable oncogenic HPV (Nobbenhuis et al, 1999), and HPV DNA was present in virtually all (99.7%) of a large sample of cervical cancers obtained from populations worldwide . Uninfected women, including those with abnormal cytology, are thus at negligible risk of invasive cancer. Follow-up studies indicate that most HPV infections are transient (Hildesheim et al, 1994;Remmink et al, 1995;Ho et al, 1998;Liaw et al, 1999;Nobbenhuis et al, 1999), but women with persistent HPV are at high risk of developing CIN3 (Nobbenhuis et al, 1999(Nobbenhuis et al, , 2001. HPV testing could thus be superior to cytology in routine cervical screening (Nobbenhuis et al, 1999;Cuzick et al, 2003).This report describes the relationship between HPV detection at entry and cytological and histological follow-up based on routine laboratory records in a prospective population-based cohort...

SUMMARY Human polyomavirus (BK) was detected in two renal allograft recipients as a result of routine examination of Papanicolaou-stained smears of urinary sediment in the light microscope. Infection with this recently identified virus was confirmed by virus isolation and electron microscopy. The cytological, histological, and ultrastructural changes due to the virus are described, and virus excretion is correlated with the clinical progress of the patients and the pathological findings. The transplant ureters in both patients were found to be ulcerated and stenosed, and virus-infected cells were observed in the ureteric epithelium. We suggest that the administration of high-dose steroids in transplantation may permit active infection with human polyomavirus to occur in ureteric epithelium which has been damaged by ischaemia or inflammation.Infection with human polyomavirus (BK) was first described by Gardner et al. (1971), who isolated the virus from the urinary tract of a renal allograft recipient. The patient (BK) developed clinical evidence of ureteric obstruction coincident with the virus infection, and at laparotomy a segment ofdonor ureter was found to be ulcerated and stenosed. Since this initial observation was made, serological studies have shown that reactivation of latent BK virus is common in renal allograft recipients (Coleman et al., 1973b) and polyomavirus particles have been observed in the urine of 44% of transplant patients (Lecatsas et al., 1973); but, despite the frequency of infection, there have been no further case reports of BK virus infection associated with ureteric stenosis or obstruction.In this paper we report pathological changes in two patients who were found to have active infection with human polyomavirus (BK) after renal transplantation. BK virus infection was suspected when numerous large inclusion-bearing cells were seen in routine Papanicolaou smears of the urinary sediment, and the cytological diagnosis was confirmed by electron microscopy and virus isolation. Examination of postmortem material and surgical specimens revealed that, in both cases, BK virus infection was associated with narrowing, fibrosis, and ulceration of the donor ureter.Received for publication 20 October 1977 Special methods of investigation CYTOLOGY Ten millilitres of freshly voided urine were concentrated by centrifugation and the deposit was resuspended in 1 ml of the supernatant urine. Three slides were made from the cell suspension by cytocentrifugation (Shandon-Elliot). Two slides were stained by the Papanicolaou method and the third by methyl green pyronin. The slides were screened by light microscopy for activated lymphocytes, inclusionbearing cells, renal tubular cells, and casts. ELECTRON MICROSCOPYTen millilitres of urine were concentrated by centrifugation and the deposit was resuspended in 0 5 ml of supernatant placed in a conical polyethylene embedding capsule and centrifuged again. The supernatant in the capsule was discarded, leaving a button of cells in the point of the capsule. A 1 ...

Urine samples from 1,235 pregnant women were examined by light microscopy for cytologic evidence of virus infection. Smears of urine sediment from 40 women (3.2%) were observed to contain inclusion-bearing cells; polyomavirus infection was confirmed by virologic methods in 24 (60%). A polyomavirus was isolated from 12 women. Five isolates were identified as JC virus and one as BK virus. Another isolate designated AS virus appeared to be unique. Serologic studies on the 40 women were consistent with a high frequency of reactivation of JC virus, and virus excretion was related to gestation. The evidence suggests that selective excretion of JC virus may occur in pregnancy. Among 390 pregnant women without inclusion-bearing cells in their urine, 78 (20%) had a high or rising titer of serum antibody to JC or BK virus or both, a result suggesting virus reactivation, but virus excretion was not detected. In contrast to other reports, no evidence was found for transmission of BK virus to the fetus.

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Human cervical cancer is an immunogenic tumor with a defined pattern of histopathological and clinical progression. Tumor-infiltrating T cells contribute to immune control of this tumor; however, cervical cancer dysregulates this immune response both through its association with human papillomavirus (HPV) infection and by producing cytokines and chemokines. Animal tumor models have revealed associations between overproduction of the chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12) and dysregulation of tumor-specific immunity. We therefore proposed that CXCL12 expression by cervical precancerous and cancerous lesions correlates with histopathological progression, loss of immune control of the tumor, and HPV infection. We found a significant association between cancer stage and CXCL12 expression for squamous and glandular lesions as well as with the HPV16؉ (high-risk) status of the neoplastic lesions. Cancer progression was correlated with increasing levels of FoxP3 T-cell infiltration in the tumor.

Human polyomaviruses produce characteristic large basophilic nuclear inclusions in urothelial cells. Cytologic screening of urinary sediment for inclusion-bearing cells permits the identification of persons who are actively excreting these viruses. The human polyomavirus-induced changes may be differentiated from changes induced by other viruses and from cancer by transmission electron microscopy of infected cells. Cytologic evidence of virus infection was detected in five of 37 cancer patients receiving various treatments, two of whom were also diabetic, and in two of 84 adult patients who had diabetes mellitus. The monitoring of 3,648 urine samples sent for routine cytologic examination revealed 12 additional patients to have cytologic changes of human polyomavirus infection. Electron microscopy confirmed the presence of polyomavirus particles in seven of the 19 cytologically positive specimens. Previous reports of human polyomavirus excretion have been confined to describing patients whose immunity may have been impaired by drug therapy, congenital disease, or pregnancy. This study indicates that cytologic evidence of active human polyomavirus infection may be found among patients receiving various treatments for a number of medical disorders not usually associated with immunologic defects. Further studies to identify factors concerned in the reactivation of human polyomavirus are indicated.

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