Low-grade Abnormalities Research Articles

STEROID-INDUCED VERSUS CRYOINSULT-INDUCED FEMORAL HEAD OSTEONECROSIS: STATISTICAL MEASUREMENT OF HISTOLOGIC ABNORMALITY FOCALIZATION

Systematic studies of treatment options for femoral head osteonecrosis have been hindered by the lack of an animal model that mimics the human event of femoral head collapse. The (bipedal) emu model of osteonecrosis has proven to progress to collapse following an external insult. Since osteonecrosis clinically has multiple etiologies, various alternatives are seemingly appropriate to initiate lesions for research purposes. This study compared osteonecrosis initiated by a local cryoinsult, to that initiated by a large systemic dose of steroid (methylprednisolone acetate), and by a combination of steroid and cryoinsult. One year post-insult, the animals were sacrificed and their femoral heads harvested. A custom-written computer program was used to expedite analysis of the global distribution of histologically apparent osteonecrosis, as determined by the Ficat scale. Following whole-head analysis, grade distributions were calculated, and a measure of spatial clustering of histologic abnormality was calculated using Moran's I statistic. Normal femoral heads showed very small amounts of histological abnormality, and no significant spatial clustering. Femoral heads receiving isolated cryoinsult had a greater incidence of high-grade abnormality, as well as statistically significant spatial clustering of that abnormality. Steroid-only animals had a higher percentage of diffuse, low-grade abnormality. The group receiving both steroid and cryoinsult showed the highest overall abnormality, with statistically significant clustering of that high-grade abnormality. Cryoinsult, both in isolation and in combination with a steroid regimen, appeared necessary to mimic the clinically typical focal lesions of osteonecrosis.

A study of Pap test history and histologically determined cervical cancer in NSW women, 1997–2003

To determine the risk of a histological diagnosis of cervical cancer following a given Pap test result and for a given history of Pap test results in a screened population across the full spectrum of possible cytological results. All the Pap screening results held on the New South Wales Pap Test Register for 1997-2003 (five million tests for 1.87 million women) were analysed using Cox proportional hazards regression to estimate the odds of having a histologically determined cervical cancer for a given Pap test result and test result history. The hazard ratios of having cervical cancer in relation to Pap test result histories were estimated: (i) in regard only to the last Pap test result adjusting for age, frequency of Pap testing and proportion of high grade (>or=cervical intraepithelial neoplasia 2 [CIN2]) abnormalities found in a woman's total recorded test result history; and (ii) with regard to the last Pap test result against the highest grade of cytological abnormality found prior to the last Pap test result. The hazard ratios are for a cancer diagnosis occurring before the next Pap test and were adjusted for age, quintile of socioeconomic status of residence, frequency of past Pap testing and proportion of high-grade abnormalities detected in each woman's prior Pap test history. The adjusted hazard ratios were then applied to the tabulated proportions of referent women with negative cytology in each broad age group, and for all women, to estimate the '1 in n' odds of being diagnosed histologically with cervical cancer for a given last Pap test result, and by a given last Pap test result for various prior Pap test result histories. After adjusting for age, socioeconomic status, frequency of previous Pap testing and proportion of past high-grade screen-detected abnormalities, the adjusted hazard ratio of having a subsequent cervical cancer diagnosis for women with a negative Pap test result was 1 in 5,546, compared with 1 in 833 for a low-grade epithelial abnormality (atypia, CIN1), 1 in 56 for a high-grade epithelial abnormality and 1 in seven for a cytological prediction of cervical cancer. These odds estimates were significantly modified by age and by the highest Pap test result prior to the most recent Pap test result: the higher the age and, less consistently, the higher the previous highest Pap test result for a given last Pap test result, the shorter the odds of having a subsequent histological diagnosis of cervical cancer. The results presented here will enable clinicians to inform their patients of their chances of being diagnosed with cervical cancer for a given Pap test result, and for some combinations of the last Pap test result and highest recorded prior Pap test result.

Terms without borders: An international approach to terminology

This article describes the similarities between different terminological systems for reporting the spectrum of abnormalities that comprise pre-cancerous, malignant and equivocal cellular changes in epithelial cells of the uterine cervix. In particular, the new terminology proposed by the British Society for Clinical Cytology (BSCC) is closely aligned with the Bethesda system (TBS) as modified in 2001. Both make a clear distinction between high-grade and low-grade intraepithelial abnormalities and identify certain categories of atypical or borderline changes that are suspicious for high-grade abnormalities.

Cervical Dysplasia in Adolescents

Although the incidence of cervical dysplasia in adolescents is increasing, a paucity of data exists regarding the outcomes of adolescents with Pap test abnormalities. We determined the natural history and outcome of adolescents with low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL). A review of all women aged 18 years or younger with a cytologic diagnosis of LSIL or HSIL between 1997 and 2003 was performed. Follow-up cytologic and histologic samples were evaluated. The most significant abnormality was recorded for each patient. Rates of regression, persistence, and progression were calculated. A total of 646 adolescents were identified. Follow-up was available for 477 teenagers with LSIL and for 55 with HSIL. Among adolescents with LSIL, 146 (35%) had negative follow-up. Low-grade abnormalities (atypical squamous cells of undetermined significance, LSIL, and cervical intraepithelial neoplasia grade 1) were seen in 199 (47%), whereas high-grade abnormalities were documented in 77 (18%). After 36 months, 62% had regressed, whereas 31% had progressive dysplasia. For the HSIL cohort, negative follow-up was documented in 12 (21.8%) adolescents, and 15 (27.3%) had low-grade abnormalities, whereas more than one half (50.9%) were found to have a high-grade abnormality. At 36 months, 31% of HSIL subjects had progressed to cervical intraepithelial neoplasia 3. Adolescents with LSIL and HSIL cytology are at significant risk for progression to high-grade cervical abnormalities. The rate of development of high-grade cervical abnormalities in adolescents is similar to adults. Adolescents with cytologic abnormalities mandate close follow-up. II-3.

Outcome after a cervical cytology report of low-grade squamous abnormality in Australia

The current study was undertaken to assist with providing an evidence-based approach to the management of women with cervical cytology reports of low-grade squamous abnormality as used in the Australian organized screening program. Using the Pap Test Registers, an audit was performed of the outcome over 24 months of Australian women who received an index cervical cytology report of low-grade squamous abnormality in 1999. Information was available for 76,709 of the 90,566 women whose first cytology report in 1999 was of a low-grade squamous abnormality. Forty-one cases of histologically confirmed cervical carcinoma were diagnosed during the subsequent 24 months (10 Stage IA, 31 Stage IB or worse). Five of the 10 women who were diagnosed with Stage IA carcinoma during the 24 months of follow-up had an intervening cervical biopsy of high-grade intraepithelial abnormality. The risk of cervical carcinoma diagnosis during the 24 months was 0.05% (95% confidence interval [CI], 0.03-0.07%) for the women with nonspecific minor change index cytology, 0.03% (95% CI, 0.00-0.07%) for the women with human papillomavirus index cytology, and 0.07% (95% CI, 0.03-0.11%) for the women with Grade 1 cervical intraepithelial neoplasia index cytology. Cervical carcinoma was a very rare outcome within 2 years of a cytology report of low-grade squamous abnormality in Australia. A simplified terminology for low-grade squamous cervical cytology reports should be considered by Australia, with uniform management for asymptomatic women.

Adherence to guidelines for follow-up of low-grade cytologic abnormalities among medically underserved women.

To determine whether women in the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) who had findings on a Papanicolaou (Pap) test of atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL) were followed up in accordance with the interim guidelines for management of abnormal cervical cytology. For this study period, the guidelines for a Pap result of ASC-US or LSIL specified follow-up by Pap tests repeated every 4 to 6 months for 2 years. If a second report of ASC-US or LSIL was made, the patient was to have colposcopy. We analyzed data from 10,004 women who had a result of ASC-US or LSIL followed by a second ASC-US or LSIL from 1991-2000. As judged by the guidelines, 44% of women who had 2 low-grade abnormalities were followed up appropriately with colposcopy. Among women with 2 ASC-US results, those aged less than 30 years were more likely to receive colposcopy than the other age groups, while women who were aged 60 years and older were more likely to be followed up with a third Pap test. For each of the 4 result groups, American Indian or Alaska Native women had the highest percentages of a third Pap test, whereas Black or African-American women had a higher percentage of no follow-up. More than one half of the women studied were not followed up in accordance with the established guidelines for managing abnormal cervical cytology. Factors such as age and race or ethnicity influence whether women with cytologic abnormalities receive appropriate follow-up.

Combining Human Papillomavirus Testing or Cervicography With Cytology to Detect Cervical Neoplasia

Cervicography and oncogenic human papillomavirus (HPV) testing have been proposed for improving the accuracy of cervical cancer screening. To examine whether cervicography and HPV testing can improve beyond chance the detection of cervical intraepithelial neoplasia (CIN) 2 or 3 in women with atypical cells of undetermined significance or low-grade squamous intraepithelial lesions on cytology. Cross-sectional analysis. Oncogenic HPV testing by Hybrid Capture II assay or cervicography combined with cytology was compared with the reference standard of colposcopy with directed biopsy. Community family practices. Three hundred four women with low-grade cytologic abnormality. The gain in accuracy for detecting histologic CIN 2 or 3 or carcinoma. Because an adjunct test may improve sensitivity by chance alone, the sensitivity or specificity if the second test performed randomly was estimated. Cervical intraepithelial neoplasia 2 or 3 was found in 11.8% (36/304) of the women and invasive squamous cell carcinoma in 0.3% (1/304). The sensitivity of cytology for detecting CIN 2 or 3 was 73.0% and increased by 21.6% to 94.6% with the addition of a cervigram showing a low-grade lesion or higher or a positive HPV test result. These gains were reduced to 8.1% and 10.8% above the sensitivities expected if the additional tests performed randomly. The corresponding specificities decreased from 49.1% to 32.2% and 33.0%. There was insufficient power to determine whether observed sensitivities were statistically significantly higher than the expected sensitivities. Adjunctive HPV testing or cervicography may provide similar gains in sensitivity, but they can appear misleadingly large if chance increases are not taken into account.

Combining Human Papillomavirus Testing or Cervicography With Cytology to Detect Cervical Neoplasia

Abstract Context.—Cervicography and oncogenic human papillomavirus (HPV) testing have been proposed for improving the accuracy of cervical cancer screening. Objective.—To examine whether cervicography and HPV testing can improve beyond chance the detection of cervical intraepithelial neoplasia (CIN) 2 or 3 in women with atypical cells of undetermined significance or low-grade squamous intraepithelial lesions on cytology. Design.—Cross-sectional analysis. Oncogenic HPV testing by Hybrid Capture II assay or cervicography combined with cytology was compared with the reference standard of colposcopy with directed biopsy. Setting.—Community family practices. Participants.—Three hundred four women with low-grade cytologic abnormality. Main Outcome Measures.—The gain in accuracy for detecting histologic CIN 2 or 3 or carcinoma. Because an adjunct test may improve sensitivity by chance alone, the sensitivity or specificity if the second test performed randomly was estimated. Results.—Cervical intraepithelial neop...

Cervical screening in adolescents—at least do no harm

91% of low-grade abnormalities on Pap smears in adolescents and young women regress within 36 months and only 3% progress to high-grade disease. This is the main finding from the cohort study in today’s Lancet by Anna- Barbara Moscicki and colleagues from the University of California at San Francisco. These findings are similar to those of a smaller study from Brazil. In the Brazil study which was not restricted to young women an estimated 92.5% of cases regressed within 24 months and 6.5% progressed. The protocol in Moscicki and colleagues’ study called for women with a colposcopic high-grade lesion to be randomly assigned to biopsy or no biopsy. We are told that 17 women were excluded because they had highgrade squamous intraepithelial lesions (HSIL) on histological examination and that 67 of the 187 women included had biopsies taken. If 17 of the 84 (20%) women who had a biopsy had HSIL we can infer that a number of HSILs were missed in the 120 women who did not have a biopsy. Thus Moscicki’s study provides strong indirect evidence that HSIL regresses in adolescents and young women in accord with the findings from another study. (excerpt)

Whipple's disease: multiple hospital admissions of a man with diarrhoea, fever and arthralgia

Whipple's disease is a rare chronic multi-systemic infectious disorder caused by the Gram-positive bacillus, Tropheryma whippelii. Infection may involve any organ in the body, and most commonly affects white men in the fourth to sixth decades of life. The most common presenting symptoms are gastrointestinal and include abdominal pain, diarrhoea, anorexia and associated weight loss. However, the variability in presentation is considerable and some patients may present with intermittent low-grade fever, neurological abnormalities (nystagmus, ophthalmoplegia, cranial nerve defects), migratory arthralgia, lymphadenopathy, or involvement of the cardiovascular system. In typical Whipple's disease, the most severe changes are seen in the proximal small intestine and biopsy reveals mucosal and lymph node infiltration with large, foamy histocytes, containing granules that stain positive with periodic acid-Schiff (PAS) reagent and represent intact or partially degraded bacteria. Extended antibiotic treatment (up to 1-year) is indicated. Life-long surveillance for recurrence is essential, once primary treatment has been completed. We report the case of a 58-year-old man who developed a rare infection with the actinobacterium, T. whippelii. The patient had suffered intermittent episodes of varying clinical symptoms associated with multiple hospital admissions and clinical diagnoses, spanning a period of 22 years. Historically, arthralgia was the primary manifestation in this patient and also was the chief complaint for which he was first hospitalized 22 years ago. At his most recent admission to our hospital department, his presenting symptoms were persistent fatigue, weight loss, arthralgia and diarrhoea. Thus, it is essential that clinicians retain a high index of suspicion for T. whippelii infection in patients who have a long-term history of arthritis, fever and diarrhoea.

Guidelines for screening and treatment of cervical disease in the adolescent

Background The last decade has seen a significant increase in our knowledge of HPV infection and its natural history. The advent of liquid-based cytology and HPV testing has changed the way we approach patients with abnormal Pap tests. The objective is to summarize some of the key evidence that lead to the American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines for the management of abnormal cytology and histology and the American Cancer Society (ACS) cervical cancer screening guideline as they pertain to adolescents. Methods The critical publications responsible for the recent ASCCP guidelines as well as the ACS recommendations for cervical cancer screening were reviewed. Results Sexually active adolescents are frequently infected by HPV. The natural history of these infections is one with a high rate of resolution. The typical HPV infection will resolve in approximately one year. The ACS has recommended that Pap test screening begin at 21, or 3 years after the onset of sexual activity. The ASCCP guidelines for the management of CIN 1 conclude that observation is the preferred therapy. These recommendations reflect our improved understanding of the natural history of HPV infection. Conclusions Adolescents frequently experience transient HPV infections. As our understanding of the natural history of these infections has improved major national organizations have changed the recommendations for the screening of cervical disease and treatment of low-grade cervical abnormalities. The health care community servicing adolescents should incorporate these recommendations into daily practice.

Adenocarcinoma in situ of the uterine cervix: screening and diagnostic errors in Papanicolaou smears.

Little attention has been given to the reasons for failure to detect adenocarcinoma in situ (AIS) of the uterine cervix in Papanicolaou (Pap) smears. In the current study, the authors examined a series of screening or diagnostic errors in cases in which the final histologic diagnosis was either AIS or AIS combined with a high-grade squamous intraepithelial lesion (AIS + HSIL). Smears obtained in the 3 years before histologically proven AIS or AIS + HSIL was diagnosed and within a specified 6-year period (1993-1998) were reviewed and reclassified. All were conventional Pap smears. The smears studied were those with a review diagnosis of possible or definite high-grade epithelial abnormality that initially were reported by a cytotechnologist to be negative (screening error) or that were reported by a pathologist to be negative, unsatisfactory, or indicative of a low-grade epithelial abnormality (diagnostic error). A semiquantitative, blinded assessment of the frequency of cytologic criteria for the diagnosis of AIS was made for smears with erroneous diagnoses compared with a series of smears that yielded true-positive findings. Sampling errors, which were defined as cases in which smears did not have sufficient evidence for a diagnosis of possible or definite AIS or HSIL on review, accounted for 35.1% and 36% of all smears from patients with a biopsy diagnosis of AIS and patients with a biopsy diagnosis of AIS + HSIL, respectively. With regard to AIS, there were 3 screening errors and 5 diagnostic errors, accounting for 10.4% of 77 smears. Minimal, poorly preserved material was evident in four smears, including three smears with only one sheet of abnormal glandular cells. In four other smears, there was a moderate amount of adequately preserved glandular material, mainly in large sheets, with varying degrees of crowding and hyperchromasia. With regard to AIS + HSIL, there were 6 screening errors and 6 diagnostic errors, accounting for 13.5% of 89 smears. In those smears, there generally was a moderate amount of abnormal material in the form of crowded groups of suboptimally preserved, hyperchromatic squamous cells. Only two of those smears yielded findings of possible abnormal glandular cells. Only 3 of 20 errors occurred in smears that were examined during the last 3 years of the study. In the semiquantitative assessment, smears with erroneous findings were shown to contain far less abnormal material than true-positive smears and to exhibit a corresponding paucity of diagnostic criteria. Sampling errors were the main cause of false-negative reports in cases of AIS and AIS + HSIL. The primary factors that contributed to screening or diagnostic errors in AIS were minimal, poorly preserved abnormal material and an overly conservative approach to the assessment of unusual large sheets or aggregates of glandular cells. With regard to AIS + HSIL, most laboratory errors were related to the presence of crowded groups of squamous epithelial cells. There were fewer errors in the last 3 years of the study, raising the possibility of improvement over time.

Effectiveness of AutoPap system location-guided screening in the evaluation of cervical cytology smears.

Location-guided screening is a feature of the AutoPap primary screening software. Areas of the smear most likely to contain an abnormality are identified for prompt review by the cytotechnologist, thereby facilitating diagnostic accuracy and reducing laboratory workload. A two-armed retrospective study comprising 6,000 conventional smears was undertaken to compare this approach with the current practice of full manual screening of conventional smears. Discrepant diagnoses between the two study arms were subject to an internal discrepancy review process to determine the final truth diagnosis. Analysis of the results show that AutoPap location-guided screening is at least equivalent to current practice when detecting high-grade or suspected high-grade smears. However, the device does not detect low-grade abnormalities, unsatisfactory smears, an endocervical component or organisms, as well as standard screening. The device also assigns a numerical score to each slide, with abnormal smears allocated a higher rank. Slide ranking was found to be of value in triaging abnormal smears for prompt screening and reporting. The performance of the primary screening software was found to be comparable to previous studies, with the majority of abnormal smears being selected by the instrument for manual review.

Sexual health issues after lung transplantation: importance of cervical screening

To determine the incidence and outcomes of human papillomavirus infection and cervical abnormalities after lung transplantation, we performed a retrospective cross-sectional study of all 166 female recipients who underwent transplantation between February 1989 and June 2001 at our institution. The incidence of low-grade epithelial abnormality of the cervix, cervical intra-epithelial neoplasia (CIN) 1, and the earliest pre-cancerous changes of the cervical epithelial cells, CIN 3, in the post-transplant cohort was 42.2 and 30, respectively, per 1,000 women screened compared with 8.3 and 6.2 per 1,000 women screened (20–69 years old) in a large reference population. We conclude that the incidence of cervical abnormalities in lung transplant recipients is significantly greater than in the general population. The importance of regular surveillance in immunosuppressed patients to decrease the burden of disease from this potentially fatal but treatable condition is emphasized.

Rapid review in cervical cytology: a retrospective review of cases detected on rapid review within a DGH cytology department and subsequent outcome.

We retrospectively reviewed smears detected by rapid review within a district general hospital (DGH) laboratory over a period of 33 months and the subsequent histological or cytological outcome. Sixty-three cases had adequate follow-up data: 32 subsequently had two negative smears and 31 had a histological abnormality on subsequent biopsy. Twenty were high-grade lesions (CIN2, CIN3 or a glandular lesion) and eight of these were preceded by a low-grade smear abnormality. We reviewed and compared the pattern and distribution of smear abnormalities in these 63 cases. Abnormalities were often present within few cells (76%, n = 48 with 50 abnormal cells or less) or in micro-biopsies (27%, n = 17). There was no statistical difference in the pattern and distribution of smear abnormality between the rapid review-detected smears with a biopsy-proven abnormality and those with negative follow-up smears. Overall, the positive predictive value for high-grade CIN detected by rapid review (75%) was within NHSCSP achievable standards targets. This review of rapid review-detected abnormalities and the biopsy and cytological follow-up reiterates the importance of the method in cervical screening.

Screening for gynaecological conditions

Well organised cervical screening programmes have reduced the mortality from cervical cancer by up to 50% in the developed world. Despite this, questions remain over: high false negative rates; the role of Human Papillama Virus (HPV) testing; and the management of low grade abnormalities. In contrast, the value of mass screening for ovarian cancer remains unproven, although current screening methods can detect early stage disease in asymptomatic individuals. Breast screening does appear to be associated with a reduction in mortality in the long term but paradoxically may increase death rates in young women in the short term. Testing for sexually transmitted infections is effective in reducing morbidity, but tends to be selective at present because of concerns over the cost and psychosocial implications of general population screening.

Adjunctive human papillomavirus testing in the 2-year follow-up of women with low-grade cervical cytologic abnormalities: A randomized trial and economic evaluation

Abstract Context.—Although human papillomavirus (HPV) testing may aid in managing low-grade abnormality on screening cervical cytology, patient compliance with repeat testing programs requires cons...

Risk Factors for Low-Grade Cervical Abnormalities Differ from Those for Human Papillomavirus Infection

A prospective study was conducted among 13-20 year old women attending family planning clinics in San Francisco California to assess the factors associated with acquisition of human papillomavirus (HPV). Follow-up visits were scheduled every 4 months for women with HPV infection and every 6 months for those who were HPV-negative. In univariate analyses the risk of acquiring HPV increased as a womans number of lifetime partners number of recent partners and monthly number of new partners increased. When the researchers conducted multivariate analyses most of the factors remained significant predictors of risk. The results indicated that HPV risk was influenced by sexual behavior infection history and pill use. On the other hand the risk of developing low-grade squamous intraepithelial lesions was associated with HPV infection and cigarette smoking.

Management of atypical squamous cells of undetermined significance and low-grade squamous intra-epithelial lesion by human papillomavirus testing

Cervical cytological terminology varies from country to country. In the USA, the Pap smear is reported using the Bethesda system. The abnormal morphological changes described by this system include two very problematic categories: atypical squamous cells of undetermined significance (ASCUS) and atypical glandular cells of undetermined significance (AGUS). The management of ASCUS, which is similar to the British system ‘borderline’ smear, has been most problematic because the majority of women with this Pap result are normal, although approximately 5–11% have high-grade cervical intraepithelial neoplasia and 1 per 1000 has cervical cancer. Because AGUS is far less common and a significantly greater risk for high-grade cervical intraepithelial neoplasia, adenocarcinoma in situ and cancer, its management is far less controversial, but it is problematic because of clinical confusion with the ASCUS terminology. Low-grade squamous intraepithelial neoplasia is almost entirely related to human papillomavirus. Documentation that certain high-risk types of human papillomavirus are necessary in the aetiology of cervical cancer has led to investigations into the management of these equivocal and low-grade Pap smear abnormalities by testing for these human papillomavirus types.

The feasibility of a one-stop colposcopy clinic in the management of women with low grade smear abnormalities: a prospective study

Objectives: To assess the feasibility of a one-stop colposcopy clinic for the management of women with low-grade smear abnormalities. Secondly, to determine whether the approach of immediate information of biopsy results combined with treatment if indicated helps to reduce patient anxiety and improve overall patient satisfaction with the colposcopy process. Design: Prospective study following the introduction of a “one-stop” process for the management of women with low grade smear abnormalities. Subjects: First 118 women managed in a “one-stop” clinic during an 8-month period. Methods: Assessment of patient anxiety via self-completed questionnaires and comparison of anxiety scores with a control group managed via a standard clinic. Results: The median waiting time for results in the one-stop clinic was 120min (range: 100–165). All women in both groups felt anxious at the time of the clinic visit. However, after 1 week the majority of patients managed via the one-stop process felt slight anxiety only (P=0.0001) as opposed to those patients in the control group who remained anxious (P=NS). In addition, all women said they would prefer the one-stop approach for further smear abnormalities if a further colposcopic examination was warranted. Conclusion: A one-stop colposcopy clinic is feasible for the management of women with low-grade smear abnormalities. In addition, it delivers a quality service, optimises patient management, reduces anxiety and is the patient’s choice.