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Cancer Types   /   Gynecologic Cancers   /   Cervical Cancer   /   NCI Resources

NCI CANCERLIT® Search: Diagnosis-Histopathology-Pathogenesis of Cervical Cancer - September 2001

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Last Modified: November 1, 2001

Table of Contents

CancerMail from the National Cancer Institute

1
UI - 21176236
AU - Cenci M; Chieppa A; Vecchione A
TI - [Controversial categories in cytopathology of the uterine cervix. I. ASCUS: atypical squamous cells of undetermined significance]
SO - Minerva Ginecol 2001 Feb;53(1):49-55
AD - Dipartimento di Medicina Sperimentale e Patologia, Cattedra di Citopatologia, Universita degli Studi di Roma, Rome, Italy.
ASCUS (Atypical Squamous Cells of Undetermined Significance) is a class for reporting cervical cytopathologic diagnoses. The Bethesda System (TBS) introduced ASCUS in 1988 and then defined this cytologic class further. Since the initial subclassification in probably reactive or probably neoplastic , TBS proposed different subgroups for a correct clinical management. At present, the subgroups are the following: ASCUS a) due to compromised specimen (poor processing or obscuring material); b) with mature intermediate-type cytoplasm; c) in postmenopausal women; d) atypical metaplasia; and e) with orangeophilic cytoplasm. Generally, clinical management of ASCUS presents 3 options: 1) cytologic follow-up (colposcopy only in a persistent diagnosis of ASCUS); 2) colposcopy; and 3) both Human papillomavirus testing and Pap-test. These options may be adopted in the ASCUS type b) and e) whereas in the type c) only in postmenopausal women receiving hormone replacement therapy. In the ASCUS type a), Pap-test should be immediately repeated (processing defects) or after therapy (excessive inflammation). In postmenopausal women not receiving hormone replacement therapy, the Pap-test has to be repeated after topical estrogen therapy. In ASCUS type d), a more aggressive follow-up is needed, such as colposcopy and eventual biopsy. Therefore, in the ASCUS diagnosis an effective communication between cytopathologist and clinician is needed for a correct clinical management.

2
UI - 21176237
AU - Cenci M; Chieppa A; Vecchione A
TI - [Controversial categories in cytopathology of the uterine cervix. II. AGUS: atypical glandular cells of undetermined significance]
SO - Minerva Ginecol 2001 Feb;53(1):57-62
AD - Dipartimento di Medicina Sperimentale e Patologia, Cattedra di Citopatologia, Universita degli Studi di Roma, Rome, Italy.
AGUS (Atypical Glandular Cells of Undetermined Significance), or AGCUS, is a category for reporting doubtful or suspicious glandular changes of the uterine cervix. Glandular lesions are not well known by the cytopathologist and their cytologic criteria are not completely reproducible. Only with the introduction of The Bethesda System (TBS) in 1988, the presence of endocervical cells is considered essential to correctly evaluate a cervical specimen. The origin of atypical glandular cells, endometrial or endocervical, should be distinguished. Moreover, endocervical AGUS should be further qualified as favor reactive or favor neoplastic or Adeno-carcinoma in situ (AIS) . Recently, it has been proposed to classify endocervical AGUS in a) AIS; and b) AGUS that cannot rule out AIS when incomplete criteria of AIS are present. Moreover, the origin of AGUS is sometimes impossible to know. In these cases, the diagnosis is AGUS not otherwise specified (NOS). The clinical management of AGUS presents different options depending on its origin or its further qualification: cytologic follow-up, colposcopy and eventual biopsy, endocervical or endometrial curettage, hysteroscopy, human papillomavirus typing, etc. including conization and hysterectomy. In conclusion, an appropriate clinical management is needed to detect glandular or squamous lesions that can be frequently identified in the AGUS follow-up.

3
UI - 21198519
AU - Madeleine MM; Daling JR; Schwartz SM; Shera K; McKnight B; Carter JJ; Wipf GC; Critchlow CW; McDougall JK; Porter P; Galloway DA
TI - Human papillomavirus and long-term oral contraceptive use increase the risk of adenocarcinoma in situ of the cervix.
SO - Cancer Epidemiol Biomarkers Prev 2001 Mar;10(3):171-7
AD - Programs in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
We examined United States Surveillance, Epidemiology, and End Results incidence data and conducted a population-based case-control study to examine the role of human papillomavirus (HPV) and oral contraceptive (OC) use in the etiology of adenocarcinoma in situ of the cervix (ACIS). One hundred and fifty women diagnosed with ACIS and 651 randomly selected control women completed in-person interviews. The presence of HPV DNA in archival ACIS specimens was determined by E6 and L1 consensus PCR. Serum samples from case and control subjects were collected at interview, and antibodies to HPV-16 L1 and HPV-18 L1 were detected by virus-like particle capture assays. The overall prevalence of HPV DNA was 86.6%, with 39.0% positive for HPV-16 DNA, 52.4% positive for HPV-18 DNA, and 13.4% positive for more than one HPV type. The age-adjusted relative risk of ACIS associated with HPV-18 seropositivity was 3.3 (95% confidence interval 2.2-4.9). No increased risk was associated with antibodies to HPV-16 L1. Among women born after 1945, the relative risk increased with duration of OC use, with the highest risk for 12 or more years of use (odds ratio, 5.5; 95% confidence interval, 2.1-14.6) relative to nonusers. The detection of HPV DNA in 86.6% of ACIS and the strong association of ACIS with HPV-18 L1 seropositivity underscore the importance of HPV, particularly HPV-18, in the etiology of ACIS. In addition, long-term OC use may contribute to the pathogenesis of these tumors in some women.

4
UI - 21261307
AU - Anonymous
TI - Cervical cancer vaccine trials started.
SO - AIDS Patient Care STDS 2001 Apr;15(4):229-30

5
UI - 21263773
AU - Pickel H; Winter R
TI - [Colposcopy of CIN and microinvasive cervical carcinoma]
SO - Zentralbl Gynakol 2001 Apr;123(4):211-5
AD - Universitatsfrauenklinik Graz/Osterreich. pickelh@kfunigraz.ac.at
The colposcopist must distinguish between two patterns: nonsuspicious findings and suspicious findings. With experience, the colposcopist will succeed more and more in distinguishing between the two, thereby markedly reducing the number of biopsies. Suspicious findings are not synonymous with abnormal findings because the latter are not always due to premalignant lesions. A number of features are of value in the different diagnosis of colposcopic findings: sharp borders, response to acetic acid (white epithelium), surface contour, appearance of blood vessels, surface extent (size), combinations of abnormalities, iodine uptake, and keratinization. The diagnostic features described above can be expressed to varying degrees, and can be found singly or in combination. The more distinct a feature is and the greater the variety of features seen in combination, the higher the index of suspicion. Attempting to differentiate between the various grades of CIN (SIL) colposcopically is more questionable, as these lesions are regarded now as forming a spectrum of the same biologic process.

6
UI - 21395267
AU - Genova NJ
TI - Evidence-based medicine--in real time. Comparing methods of cervical Ca screening.
SO - JAAPA 2000 Jan;13(1):55-6, 59-60, 63
AD - Mercy Family Practice, Portland, Me., USA.

7
UI - 21398874
AU - Yokoyama M; Nakao Y; Iwasaka T; Pater A; Sugimori H
TI - Retinoic acid and interferon-alpha effects on cell growth and differentiation in cervical carcinoma cell lines.
SO - Obstet Gynecol 2001 Aug;98(2):332-40
AD - Department of Obstetrics and Gynecology, Saga Medical School, Saga, Japan. yokoyam1@post.saga-med.ac.jp
OBJECTIVE: To investigate and compare the efficacy of all-trans retinoic acid (RA) and/or interferon-alpha (IFN-alpha) on premalignant and malignant models of cervical cancer. METHODS: Cell growth rate was examined after treatment for 4, 7, and 10 days with RA and/or IFN-alpha of human papillomavirus type 18 (HPV 18)-immortalized endo- and ectocervical cells, nontransformed serum-adapted cells, transformed cells, three adenocarcinoma, and three squamous cell carcinoma cell lines. The effect on epithelial differentiation by RA and IFN-alpha was examined in organotypic culture. Induction of apoptosis was examined by modified terminal transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) and DNA fragmentation. RESULTS: Cell growth rate was inhibited by RA, 84-96% in HPV 18-immortalized endocervical cells, SiHa, and ME180, 0% in OMC-4, and 18-62% in other cell lines; and by IFN-alpha about 75% in SiHa and ME180 and 14-40% in the other cell lines. Combining RA and IFN-alpha increased the antiproliferative effect in premalignant cell lines and some cancer cell lines except OMC-4, SiHa, and HT-3. In rafts, RA treatment reversed human endocervical cell metaplasia and HPV 18-immortalized endo- and ectocervical cell dysplastic epithelial differentiation. Interferon-alpha, not RA, treatment of HPV 18-immortalized endo- and ectocervical cells induced apoptosis. CONCLUSION: Cell growth inhibition by treatment with RA, IFN-alpha, and their combination differentially depends on treatment type and time, cell origin, cell line, and oncogenic state. In a premalignant model of cervical carcinoma, RA reduces dysplastic differentiation and IFN-alpha induces apoptosis. These data confirm that these treatments may be effective for preventing or treating premalignant cervical lesions.

8
UI - 21412306
AU - Ndisang D; Budhram-Mahadeo V; Pedley B; Latchman DS
TI - The Brn-3a transcription factor plays a key role in regulating the growth of cervical cancer cells in vivo.
SO - Oncogene 2001 Aug 9;20(35):4899-903
AD - Medical Molecular Biology Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
The cellular Brn-3a transcription factor is known to activate transcription of the genes encoding the human papilloma virus E6 and E7 proteins and is over-expressed in women with cervical neoplasia. We show that cervical cell lines with reduced Brn-3a expression show a greatly reduced ability to form tumours in nude mice compared to control cells and also show reduced expression of the HPV E6 and cellular Bcl-2 oncogenes. These effects are also observed in cervical cells over-expressing the related Brn-3b factor, which is known to antagonize activation of HPV gene expression by Brn-3a. These results demonstrate, for the first time, that inhibition of Brn-3a expression or enhanced Brn-3b expression can inhibit cervical cell-derived tumour growth in vivo as well as in vitro. Hence they establish Brn-3a as a key factor in cervical tumorigenesis and as a potential therapeutic target in human cervical neoplasia.

9
UI - 21410095
AU - Chen HY; Hsu CT; Lin WC; Tsai HD; Chang WC
TI - Prognostic value of nm23 expression in stage IB1 cervical carcinoma.
SO - Jpn J Clin Oncol 2001 Jul;31(7):327-32
AD - Department of Obstetrics and Gynecology, China Medical College Hospital, Taichung, Taiwan.
BACKGROUND: The purpose of this retrospective study was to evaluate the patterns of nm23 expression in stage IB1 squamous cell carcinoma of the uterine cervix, to compare nm23 expression with clinicopathological findings and to assess its prognostic value. METHODS: Twenty-seven patients with stage IB1 squamous cell carcinoma of the uterine cervix underwent abdominal radical hysterectomy and pelvic lymph node dissection. Expression of nm23 was studied immunohistochemically, followed by amplification and direct sequencing of exons 4 and 5 of the nm23 gene. RESULTS: Overexpression of nm23 was detected in 18.5% of the tumors and low expression was seen in 33.3%, while negative expression was found in 48.1% of the tumors. Deep cervical stromal invasion (> or =1/2) was found to be associated with the increased risk of lymph node metastases (odds ratio = 17.5). A significantly lower percentage of patients survived when nm23 overexpression was observed (p = 0.0063). Univariate analysis revealed that tumor size (2-3.9 cm), lymph node metastasis, tumor invasion into parametria, tumor invasion into blood/lymph vessel, squamous cell carcinoma (> or =2 ng/ml) and nm23 overexpression had a significantly lower recurrence-free survival rate of the patients. None of the above factors was significant according to multivariate analysis. There were no mutations in exons 4 and 5 of the nm23 gene in stage IB1 squamous cell carcinoma of the uterine cervix. CONCLUSIONS: This study suggests that expression of nm23 may be indicative of an unfavorable prognosis in patients with stage IB1 squamous cell carcinoma of the uterine cervix.

10
UI - 21230099
AU - Monsonego J
TI - Global challenges of cervical cancer prevention.
SO - Clin Exp Obstet Gynecol 2001;28(1):5-13

11
UI - 21241493
AU - Stoler MH
TI - HPV testing is not useful for LSIL Triage--but stay tuned.
SO - Adv Anat Pathol 2001 May;8(3):160-4
AD - Department of Pathology, University of Virginia, Charlottesville, USA.

12
UI - 21345028
AU - Tjalma WA; Weyler JJ; Bogers JJ; Pollefliet C; Baay M; Goovaerts GC; Vermorken JB; van Dam PA; van Marck EA; Buytaert PM
TI - The importance of biological factors (bcl-2, bax, p53, PCNA, MI, HPV and angiogenesis) in invasive cervical cancer.
SO - Eur J Obstet Gynecol Reprod Biol 2001 Aug;97(2):223-30
AD - Laboratory of Cancer Research and Clinical Oncology, Antwerp University, Antwerp, Belgium. wiebren.tjalma@uza.uia.ac.be
OBJECTIVE: The present study was designed to analyse the relationship between apoptosis related proteins (bcl-2 and bax), tumour suppressor protein p53, proliferation markers (PCNA and mitotic index), human papillomavirus (HPV) and angiogenesis in cervical cancer and their impact on clinical outcome. STUDY DESIGN: Tumours from 111 patients were assessed by immunohistochemistry for the expression of bcl-2, bax, p53 and PCNA, by PCR for the presence of HPV-DNA, for the quantification of the mitotic index and the microvessel density (CD 31). The results were correlated with various histopathologic characteristics and survival. RESULTS: The multiple Cox's regression analysis for overall survival of all prognostic variables gave as best model: bcl-2 (P<0.001), lymphovascular permeation (P=0.004), mitotic index (P=0.019), tumour grade (P=0.048) and FIGO stage (P=0.070). Subanalysis was performed for the patients where the lymph node status was known (n=79). Adding the lymph node status gave as best model for overall survival bcl-2 (P=0.001), lymphovascular permeation (P=0.003) and mitotic index (P=0.044). However, they hardly influenced the association. CONCLUSION: In the apoptotic pathway of cervical cancer, bcl-2 is one of most important proteins. It can probably not only mediate cell death but also regulate cell growth. A better understanding of their relations will probably provide the basis for more rational cancer therapies in the future.

13
UI - 21423697
AU - Lo KW; Cheung TH; Yim SF; Chung TK
TI - Preoperative hysteroscopic assessment of cervical invasion by endometrial carcinoma: a retrospective study.
SO - Gynecol Oncol 2001 Aug;82(2):279-82
AD - Division of Gynecologic Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong.
OBJECTIVE: The aim of this study was to evaluate the efficacy of hysteroscopy, using normal saline (NS) or carbon dioxide (CO2) as the distention medium, in assessing tumor invasion of the uterine cervix by endometrial carcinoma. METHODS: A retrospective study was conducted in 200 consecutive patients with endometrial carcinoma diagnosed from 1993 to 2000. Prior to definitive surgical treatment, hysteroscopy was performed using either NS or CO2 as the distention medium to determine whether the tumor had spread to the cervix. The uterine specimens obtained after hysterectomies were cut open for gross examination. Tumor invasion of the cervix as determined by hysteroscopy and gross examinations was compared with the pathological findings. RESULTS: Tumor invasion of the cervix was found in 41 (20.5%) cases on pathological examination. Hysteroscopy has an accuracy of 92.5% (185/200), a sensitivity of 68.3% (28/41), and a specificity of 98.7% (157/159), with a PPV of 93.3% (28/30) and a NPV of 92.4% (157/170) in determining cervical involvement. Assessment by gross inspection had 93.0% (186/200) accuracy, 68.3% (28/41) sensitivity, 99.4% (158/159) specificity, 96.6% (28/29) PPV, and 92.4% (158/171) NPV. There was no significant difference between the two assessment methods. When the results of hysteroscopy performed with different distention mediums were compared, the use of NS had a higher accuracy in determining tumor spread to the cervix (96.8% vs 88.7%, P = 0.03) and NPV (96.4% vs 88.4%, P < 0.05) than the use of CO2. CONCLUSIONS: Hysteroscopic assessment and gross examination of the uterine specimen had similar efficacy in detecting cervical invasion by endometrial carcinoma. Hysteroscopic examination using NS is more accurate than that which uses CO2. Copyright 2001 Academic Press.

14
UI - 21423698
AU - Liu FS; Hsieh YT; Chen JT; Ho ES; Hung MJ; Lin AJ
TI - FHIT (fragile histidine triad) gene analysis in cervical intraepithelial neoplasia.
SO - Gynecol Oncol 2001 Aug;82(2):283-90
AD - Division of Gynecologic Oncology, Taichung Veterans General Hospital, Taichung, Taiwan, Republic of China. fsliu@vghtc.vghtc.gov.tw
OBJECTIVE: Recently a candidate tumor suppressor gene, FHIT (fragile histidine triad), was identified at chromosome 3p14.2. Abnormality of this gene has been observed in a variety of human tumors. Although aberrant FHIT transcripts in a substantial percentage of cervical cancer cell lines and primary cervical tumors were also noted, some other studies revealed different results. Therefore, its association with the development of cervical cancer is still debatable. Because allelic loss in chromosome 3p is also a frequent finding in cervical intraepithelial neoplasia (CIN), we compared the transcription pattern and expression of FHIT in the preinvasive cervical lesions and normal cervical epithelia to investigate its possible role in cervical carcinogenesis. METHODS: Thirty-five consecutive CIN lesions taken from conization specimens and 33 normal cervical epithelial tissues taken from hysterectomy for benign diseases were included in this study. Total RNA was extracted from the pathology-confirmed tissue samples and first-strand cDNA was synthesized. It was amplified using a nested reverse transcription polymerase chain reaction (RT-PCR) method. The PCR products were then subjected to subcloned sequence analysis. Paraffin blocks from all of the samples were selected and prepared for immunohistochemical study with an anti-FHIT polyclonal antibody. RESULTS: All the cDNAs of CIN and normal cervical epithelial tissues showed the expected size of RT-PCR product. However, 7 of the 35 (20%) CIN lesions and 5 of the 33 (15%) normal cervical epithelia also presented aberrant transcripts in addition to the normal-sized transcript of FHIT. Deletion of the cDNA segment covering exon 4 to exon 8 was the most frequent finding in the cases that showed abnormal FHIT transcripts. FHIT protein was intermediately or strongly expressed in most of the CIN lesions and normal squamous epithelia. However, reduced or absent FHIT expression was observed heterogeneously in the 7 CIN lesions and 5 normal cervices in which aberrant FHIT transcripts were detected. CONCLUSION: Because the normal-sized FHIT transcript was present robustly in all of the CIN lesions and the abnormal FHIT transcripts occurred with similar frequency and pattern in the CIN lesions and normal cervical tissues, we suggest that abnormal FHIT transcription might not be causal in the early process of cervical carcinogenesis. Copyright 2001 Academic Press.

15
UI - 21423702
AU - Yamamoto R; Okamoto K; Yukiharu T; Kaneuchi M; Negishi H; Sakuragi N; Fujimoto S
TI - A study of risk factors for ovarian metastases in stage Ib-IIIb cervical carcinoma and analysis of ovarian function after a transposition.
SO - Gynecol Oncol 2001 Aug;82(2):312-6
AD - Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-8638, Japan.
OBJECTIVE: The objective of the present study was to examine the incidence and risk factors of ovarian metastases in cervical carcinoma. The function of transposed ovaries was also studied. METHODS: In order to analyze the risk factors of ovarian metastases, 255 slides of pathological specimens were reassessed by multivariate logistic regression analysis. Fifty-six patients were studied prospectively on the basis of the function of transposed ovaries. Basal body temperature and serum hormone levels were analyzed. RESULTS: Ovarian metastasis was identified in 2 of 485 (0.4%) patients with squamous cell carcinoma and in 12 of 146 (8.2%) patients with nonsquamous tumors of the cervix. Histologic type (P = 0.0014) and blood vessel invasion (P = 0.0433) were significant independent risk factors for ovarian metastases, as revealed by multivariate logistic regression analysis. Cumulative survival curves of preserved ovaries showed a significant (P < 0.005) decline in the group with postoperative radiotherapy. CONCLUSION: Preservation of ovarian function should be pursued in patients with squamous cell carcinoma of the cervix, provided that the patient has no other risk factor (blood vessel invasion) for ovarian metastases. Moreover, sufficient attention should be paid to the proper handling of ovarian blood vessels during surgery, in order to shield and protect them from exposure to scattered radiation administered during postoperative radiotherapy. Copyright 2001 Academic Press.

16
UI - 21423710
AU - Paraskevaidis E; Malamou-Mitsi V; Koliopoulos G; Pappa L; Lolis E; Georgiou I; Agnantis NJ
TI - Expanded cytological referral criteria for colposcopy in cervical screening: comparison with human papillomavirus testing.
SO - Gynecol Oncol 2001 Aug;82(2):355-9
AD - Department of Obstetrics and Gynecology, Ioannina University Hospital, Ioannina, 45500, Greece. koliops@ath.forthnet.gr
OBJECTIVE: The goal of this study was to investigate whether expanded cytologic referral criteria for colposcopy or the addition of human papillomavirus (HPV) testing on cervical screening could improve the rates of detection of cervical intraepithelial neoplasia (CIN). METHODS: HPV testing by semiquantitative polymerase chain reaction/ELISA was performed in 1000 women who were self-referred for routine Pap smear. They underwent colposcopy following an abnormal smear result or a positive HPV test. As abnormal smear results were considered reports of low- or high-grade squamous intraepithelial lesion, atypical squamous cells of undetermined significance, and even HPV-associated reactive cellular changes (mild koilocytosis, mild dyskeratocytosis, hyperchromatic nuclei, bimultinucleation, and cleared cytoplasm). Loop excision of the transformation zone was performed in women with cytology and colposcopy indicative of CIN, as well as in women with normal cytology but positive HPV test and colposcopic impression of CIN. RESULTS: The Pap test was abnormal in 89% of the cases of CIN 1 (34/38) and 96% of CIN 2/3 (27/28) diagnosed in our population. HPV testing picked up four additional cases of CIN 1 (11%) and one case of CIN 2/3 (4%). Overall the HPV test detected 95% of the cases of CIN 1 (36/38) and 89% of the cases of CIN 2/3 (25/28). CONCLUSION: HPV testing does not appear to add significantly to cytology in terms of positive predictive value or detection rate, if extended cytologic indications for colposcopy are used. Copyright 2001 Academic Press.

17
UI - 21403063
AU - Stoler MH
TI - HPV for cervical cancer screening: is the era of the molecular pap smear upon us?
SO - J Histochem Cytochem 2001 Sep;49(9):1197-8
AD - Pathology, University of Virginia Health System, Jefferson Park Ave., Charlottesville, VA 22908, USA.
Based on the best estimates of the prevalence of human Papillomavirus infection in the United States, the overall HPV prevalence in the target population is approximately 20%. The prevalence varies greatly with age, being as high as approximately 50% in the third decade to less than 5% in the sixth. These data have implications for a discussion about the utility of human Papillomavirus testing as a screening procedure.(J Histochem Cytochem 49:1197-1198, 2001)

18
UI - 21415206
AU - Smith ED; Phillips JM; Price MM
TI - Screening and early detection among racial and ethnic minority women.
SO - Semin Oncol Nurs 2001 Aug;17(3):159-70
AD - University of Illinois, Chicago College of Nursing, Chicago, IL, USA.
OBJECTIVES: To highlight sociocultural factors reported to influence and strategies to promote breast and cervical cancer screening and early detection behaviors of racial and ethnic minority women. DATA SOURCES: Published articles, book chapters, and reports. CONCLUSIONS: The most successful strategies for promoting screening and early detection among racial and ethnic minority women are collaborative and include approaches that are culturally sensitive and appropriate. NURSING IMPLICATIONS: Intercultural and intracultural differences in racial and ethnic minority women challenge nurses to explore strategies that focus on the health care provider, the health care delivery system, and the individual woman within the context of the woman's culture.

19
UI - 20531235
AU - Check W
TI - Opening the door to HPV testing.
SO - CAP Today 2000 Oct;14(10):1, 58, 62-4, passim

20
UI - 20279854
AU - Wilson RM
TI - Screening for breast and cervical cancer as a common cause for litigation. A false negative result may be one of an irreducible minimum of errors.
SO - BMJ 2000 May 20;320(7246):1352-3

21
UI - 20455468
AU - Benson JR; Purushotham AD; Warren R
TI - Screening and litigation. The rate of interval cancers is too high.
SO - BMJ 2000 Sep 23;321(7263):760; discussion 761

22
UI - 20455469
AU - Rooney CI; Rodrigues LC; Campbell OM
TI - Screening and litigation. Measures of validity need to be clear.
SO - BMJ 2000 Sep 23;321(7263):760; discussion 761

23
UI - 20455470
AU - Coleman DV
TI - Screening and litigation. Some false negatives arise from negligence.
SO - BMJ 2000 Sep 23;321(7263):761

24
UI - 20386418
AU - Giroux J; Welty TK; Oliver FK; Kaur JS; Leonardson G; Cobb N
TI - Low national breast and cervical cancer-screening rates in American Indian and Alaska Native women with diabetes.
SO - J Am Board Fam Pract 2000 Jul-Aug;13(4):239-45
AD - Epidemiology Program, Aberdeen Indian Health Service Area, Rapid City, SD, USA.
BACKGROUND: The cervical cancer mortality rate for American Indian and Alaska Native women is twice that of all races in the United States. To date the only published national breast and cervical cancer-screening rates for American Indian and Alaska Native women are based on self-reported data. When the Indian Health Service (IHS) conducts an annual audit on patients with diabetes, it includes cancer screening. This observational study presents national breast and cervical cancer-screening rates for American Indian and Alaska Native women with diabetes. METHODS: Cancer-screening rates were extracted from the 1995 diabetic audit for the 12 IHS areas. These rates were compared with rates for women without diabetes of the same age, 50 to 69 years, by chart review, at four IHS hospitals in the Aberdeen IHS area. RESULTS: Screening rates for women with diabetes in the 12 areas varied: mammogram (ever) 35% to 78%; clinical breast examination (last year) 28% to 70%, and Papanicolaou smear (last year) 26% to 69%. The Aberdeen IHS area women with diabetes had 51% more clinic visits per year than women without diabetes, but the groups had similar screening rates. CONCLUSION: Cancer-screening rates for American Indian and Alaska Native women vary by region. In the Aberdeen IHS area, women with diabetes had more visits (missed opportunities) but similar screening rates as women without diabetes. The diabetic audit could be used to monitor national IHS cancer-screening trends for women with diabetes and in the Aberdeen IHS area for all women aged 50 to 69 years.

25
UI - 21003411
AU - Samuelson P
TI - Cancer screening rates.
SO - J Am Board Fam Pract 2000 Nov-Dec;13(6):468-9

26
UI - 21111276
AU - Harima Y; Sawada S; Nagata K; Sougawa M; Ostapenko V; Ohnishi T
TI - Polymorphism of the WAF1 gene is related to susceptibility to cervical cancer in Japanese women.
SO - Int J Mol Med 2001 Mar;7(3):261-4
AD - Department of Radiology, Kansai Medical University, Moriguchi City, Osaka 570-8507, Japan. harima@takii.kmu.ac.jp
The WAF1 gene, located on chromosome 6p21.2, has been cloned and identified as a p53 mediator and an inhibitor of G1 cyclin-dependent kinases (CDKs). The present study was performed to investigate the possible role of the WAF1 gene in the pathogenesis of human cervical carcinoma. Matched venous blood and cancer tissues from 66 patients with cervical cancer were screened for WAF1 mutation by reverse transcription-polymerase chain reaction (RT-PCR) and DNA sequencing. A polymorphism in the WAF1 gene involving a cytosine (C) to an adenine (A) transversion at the third base of codon 31 was observed in 52 of 66 (78.8%) patients with cervical carcinoma and 68 of 108 (63%) normal individuals (P=0.02). A total of 7 patients (10.6%) were found to have a change of the WAF1 gene at codon 31 on comparison of blood and tumor specimens. An A-->C transversion in 5 tumors and a C-->A transversion in 2 tumors, that were not found in matching normal specimens, were observed. In addition, the presence of loss of heterozygosity (LOH) on chromosome 6p21.2 in tumor and normal tissue DNA were analyzed by PCR at three polymorphic microsatellite loci (D6S276, D6S1624, D6S1583). In two cases, there was a change of Arg/Ser in blood to Ser/Ser in the tumor, which did not involve LOH on 6p21.2. Therefore, somatic mutation of the WAF1 gene was detected in 3% (2 of 66) of patients with cervical cancer in this series. In conclusion, the increased frequency of WAF1 polymorphism in the patients studied implied that codon 31 Arg allele of the WAF1 gene may be associated with a tendency to develop cervical carcinoma. To our knowledge, this is the first report of WAF1 somatic mutations in primary human cervical cancer.

27
UI - 21236223
AU - Fasanmade AA; Owuor ED; Ee RP; Qato D; Heller M; Kong AN
TI - Quinacrine induces cytochrome c-dependent apoptotic signaling in human cervical carcinoma cells.
SO - Arch Pharm Res 2001 Apr;24(2):126-35
AD - Department of Pharmaceutics and Pharmacodynamics, Center for Pharmaceutical Biotechnology, College of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA.
Quinacrine (QU), a phospholipase-A2 (PLA-2) inhibitor has been used clinically as a chemotherapeutic adjuvant. To understand the mechanisms leading to its chemotherapeutic effect, we have investigated QU-induced apoptotic signaling pathways in human cervical squamous carcinoma HeLa cells. In this study, we found that QU induced cytochrome c-dependent apoptotic signaling. The release of pro-apoptotic cytochrome c was QU concentration- and time-dependent, and preceded activation of caspase-9 and -3. Flow cytometric FACScan analysis using fluorescence intensities of DiOC6 demonstrated that QU-induced cytochrome c release was independent of mitochondrial permeability transition (MPT), since the concentrations of QU that induced cytochrome c release did not alter mitochondrial membrane potential (delta pai(m)). Moreover, kinetic analysis of caspase activities showed that cytochrome c release led to the activation of caspase-9 and downstream death effector, caspase-3. Caspase-3 inhibitor (Ac-DEVD-CHO) partially blocked QU-induced apoptosis, suggesting the importance of caspase-3 in this apoptotic signaling mechanism. Supplementation with arachidonic acid (AA) sustained caspase-3 activation induced by QU. Using inhibitors against cellular arachidonate metabolism of lipooxygenase (Nordihydroxyguaiaretic Acid, NDGA) and cyclooxygenase (5,8,11,14-Eicosatetraynoic Acid, ETYA) demonstrated that QU-induced apoptotic signaling may be dependent on its role as a PLA-2 inhibitor. Interestingly, NDGA attenuated QU-induced cytochrome c release, caspase activity as well as apoptotic cell death. The blockade of cytochrome c release by NDGA was much more effective than that attained with cyclosporin A (CsA), a MPT inhibitor. ETYA was not effective in blocking cytochrome c release, except under very high concentrations. Caspase inhibitor z-VAD blocked the release of cytochrome c suggesting that this signaling event is caspase dependent, and caspase-8 activation may be upstream of the mitochondrial events. In summary, we report that QU induced cytochrome c-dependent apoptotic signaling cascade, which may be dependent on its role as a PLA-2 inhibitor. This apoptotic mechanism induced by QU may contribute to its known chemotherapeutic effects.

28
UI - 21323102
AU - Twinn S
TI - The evaluation of the effectiveness of health education interventions in clinical practice: a continuing methodological challenge.
SO - J Adv Nurs 2001 Apr;34(2):230-7
AD - Department of Nursing, Chinese University of Hong Kong, Shatin, China. sftwinn@cuhk.edu.hk
AIM: This paper examines the methodological issues arising from an evaluation of the effectiveness of a health education project undertaken to increase Hong Kong Chinese women's knowledge of the prevention of cervical cancer and the uptake of screening. BACKGROUND: The significance of health promotion to the prevention of diseases currently affecting contemporary society has become increasingly recognized. Within the context of health promotion health education continues to provide an important preventive strategy. Indeed the leading causes of mortality such as coronary heart disease and cancer lend themselves well to health education interventions. However the evaluation of the effectiveness of health education remains complex and raises some important methodological issues. DESIGN: The project used a health education intervention as the major preventive strategy and employed multiple methods of evaluation to assess its effectiveness. Outcome evaluation consisted of a confidential questionnaire administered at two points in time to measure changes in health-related behaviour and knowledge. It also included the collection of data from service providers to assess changes in the uptake of cervical cancer screening. Process evaluation involved the use of focus groups with randomly selected groups of women who had participated in the health education intervention and a diary kept by the project nurse. FINDINGS: Methodological issues identified in the evaluation of the project included the extent to which changes in health-related knowledge and behaviour could be attributed to the intervention, the sensitivity of outcome measures and challenges in developing methods of process evaluation appropriate to the target population. CONCLUSIONS: The findings highlight the complexity of designing effective evaluation strategies for health education and the need to consider these issues in the development of both process and outcome evaluation.

29
UI - 21254125
AU - Marino JF; Fremont-Smith M
TI - Direct-to-vial experience with AutoCyte PREP in a small New England regional cytology practice.
SO - J Reprod Med 2001 Apr;46(4):353-8
AD - Seacoast Pathology P.A., 1 Hampton Road, Suite 108, Exeter, NH 03833, USA.
OBJECTIVE: To evaluate and assess the efficiency and efficacy of the AutoCyte PREP thin-layer Pap test method (TriPath Imaging, Inc., Burlington, North Carolina) in a privately owned cytology laboratory. STUDY DESIGN: Data from 35,496 conventional Pap smear preparations performed in 1999 were compared to 6,357 conventional Pap smears and 15,534 AutoCyte PREP cases that were collected, prepared and processed from January 1 to July 31, 2000. RESULTS: The AutoCyte PREP demonstrated a statistically significant increased detection of low grade squamous intraepithelial lesions (LSIL) (47%) (P = .0011) and high grade squamous intraepithelial lesions (HSIL) (116%) (P = .0002) when compared to conventional Pap smears processed during the same time period. When compared to the conventional Pap smears from 1999, the LSIL lesions increased by 57% (P < .00001), and the HSIL lesions increased by 55% (P = .0002). Both increases are statistically significant. The atypical squamous cells of undetermined significance (ASCUS)/LSIL ratio was reduced by 48% (P < .00001) using AutoCyte PREP when compared to the 1999 conventional Pap smear experience. The unsatisfactory rate was reduced by 70%. AutoCyte PREP demonstrated improved histologic correlation in HSIL cases. CONCLUSION: AutoCyte PREP was significantly more effective than the conventional Pap smear for the detection of both LSIL and HSIL. The ASCUS/LSIL ratio and unsatisfactory cases were also significantly reduced.

30
UI - 21253992
AU - Valdini A; Vaccaro C; Pechinsky G; Abernathy V
TI - Incidence and evaluation of an AGUS Papanicolaou smear in primary care.
SO - J Am Board Fam Pract 2001 May-Jun;14(3):172-7
AD - Department of Family Medicine and Community Health, Tufts University School of Medicine, Boston, Mass, USA.
BACKGROUND: The category atypical glandular cells of undetermined significance (AGUS) occurs in about 0.5% of Papanicolaou smears. Although recent case series report a great many dysplastic, cancerous, and precancerous lesions of the cervix and endometrium associated with AGUS, little attention has been focused on this issue in primary care literature. METHODS: We report a case series of 52 women with AGUS Papanicolaou smears in a family health center during 2 years (1997 to 1998), along with colposcopy and biopsy results and 18 months of follow-up findings. These results were compared with findings of recent reports. RESULTS: The incidence of AGUS was 0.5%, 52 of 10,564 Papanicolaou smears. Colposcopy was performed in 45. Biopsy (n = 46) showed 2 adenocarcinomas of the endometrium, and 6 high-grade dysplastic lesions, including 1 squamous cell carcinoma in situ. Nineteen women had cervical intraepithelial neoplasia stage I-changes of human papillomavirus effect, and 4 had endocervical polyps. Three women were lost to follow-up. The frequency of dysplastic and cancerous lesions in our population (17.4%) is consistent with series findings from cytology and obstetrics and gynecology literature, reporting that 19.5% of women with AGUS have either cancer--adenocarcinoma of the endometrium, squamous cell carcinoma, or extrauterine (8%)--or high-grade lesions--cervical intraepithelial neoplasia II-III, carcinoma in situ, or cervical adenocarcinoma in situ, (11.5%). CONCLUSIONS: A relatively large percentage of women with AGUS on Papanicolaou smears have cancerous and dysplastic squamous and glandular lesions of the exocervix, endocervix, and endometrium. Clinical practice guidelines recommend patients with AGUS should be evaluated with colposcopy and endocervical curettage. Consensus supports endometrial sampling in women 35 years and older and in those with a laboratory report of AGUS, favors neoplasia or suggests an endometrial source.

31
UI - 21430216
AU - Moore KJ
TI - Medicare expands preventive screening benefits.
SO - Fam Pract Manag 2001 Jun;8(6):16

32
UI - 21320829
AU - Goldie SJ; Kuhn L; Denny L; Pollack A; Wright TC
TI - Policy analysis of cervical cancer screening strategies in low-resource settings: clinical benefits and cost-effectiveness.
SO - JAMA 2001 Jun 27;285(24):3107-15
AD - Center for Risk Analysis, Department of Health Policy and Management, Harvard School of Public Health, 718 Huntington Ave, Suite 2, Boston, MA 02115-5924, USA. sgoldie@hsph.harvard.edu
CONTEXT: Cervical cancer is a leading cause of cancer-related death among women in developing countries. In such low-resource settings, cytology-based screening is difficult to implement, and less complex strategies may offer additional options. OBJECTIVE: To assess the cost-effectiveness of several cervical cancer screening strategies using population-specific data. DESIGN AND SETTING: Cost-effectiveness analysis using a mathematical model and a hypothetical cohort of previously unscreened 30-year-old black South African women. Screening tests included direct visual inspection (DVI) of the cervix, cytologic methods, and testing for high-risk types of human papillomavirus (HPV) DNA. Strategies differed by number of clinical visits, screening frequency, and response to a positive test result. Data sources included a South African screening study, national surveys and fee schedules, and published literature. MAIN OUTCOME MEASURES: Years of life saved (YLS), lifetime costs in US dollars, and incremental cost-effectiveness ratios (cost per YLS). RESULTS: When analyzing all strategies performed as a single lifetime screen at age 35 years compared with no screening, HPV testing followed by treatment of screen-positive women at a second visit, cost $39/YLS (27% cancer incidence reduction); DVI, coupled with immediate treatment of screen-positive women at the first visit was next most effective (26% cancer incidence reduction) and was cost saving; cytology, followed by treatment of screen-positive women at a second visit was least effective (19% cancer incidence reduction) at a cost of $81/YLS. For any given screening frequency, when strategies were compared incrementally, HPV DNA testing generally was more effective but also more costly than DVI, and always was more effective and less costly than cytology. When comparing all strategies simultaneously across screening frequencies, DVI was the nondominated strategy up to a frequency of every 3 years (incremental cost-effectiveness ratio, $460/YLS), and HPV testing every 3 years (incremental cost-effectiveness ratio, $11 500/YLS) was the most effective strategy. CONCLUSION: Cervical cancer screening strategies that incorporate DVI or HPV DNA testing and eliminate colposcopy may offer attractive alternatives to cytology-based screening programs in low-resource settings.

33
UI - 21346370
AU - Asai S; Miyachi H; Oshima S; Kawakami C; Kubota M; Ando Y
TI - A scoring system for ultrasonographic differentiation between cervical malignant lymphoma and benign lymphadenitis.
SO - Rinsho Byori 2001 Jun;49(6):613-9
AD - Department of Laboratory Medicine, Tokai University School of Medicine, Isehara, Japan.
The purpose of our study is to assess the usefulness of a scoring system for ultrasonography using a high-frequency transducer as a non-invasive examination in the differential diagnosis of cervical malignant lymphoma from benign lymphadenitis. Ultrasonography was performed with a real-time linear scanner using 7.5 and/or 11 MHz probes in 66 patients who were presented with cervical lymphadenopathy and were suspected to have malignant lymphoma. Thereafter, a surgical biopsy was performed for histopathological diagnosis, revealing 49 cases of malignant lymphoma and 17 cases of benign lymphadenitis. Ultrasonographic findings were reviewed retrospectively. The incidence of following ultrasonographic features was found to be significantly higher in malignant lymphoma than in benign lymphadenitis. These were; (1) longitudinal and transverse diameter ratio(L/T) < 2.0, (2) a delineation of multiple nodes, (3) a tendency of fusion, (4) an irregular margin, (5) hypoechoic masses with heterogeneous internal echoes, (6) a presence of line echoes and (7) an absence of hilum. These 7 ultrasonographic features were used in combination for a scoring system to discriminate malignant lymphoma from benign lymphadenitis. When ultrasonographic findings of lymph nodes fulfilled more than 3 of the 7 features, malignant lymphoma was diagnosed with a sensitivity of 98.0% and a specificity of 76.5%. Ultrasonographic evaluation of swollen cervical lymph nodes using a high-frequency transducer would be informative and should be performed prior to a surgical biopsy.

34
UI - 21381632
AU - Weiderpass E; Ye W; Tamimi R; Trichopolous D; Nyren O; Vainio H; Adami HO
TI - Alcoholism and risk for cancer of the cervix uteri, vagina, and vulva.
SO - Cancer Epidemiol Biomarkers Prev 2001 Aug;10(8):899-901
AD - International Agency for Research on Cancer, Lyon, France. Weiderpass@iarc.fr
We conducted a population-based cohort study to analyze the risk of developing cancers of the female genitals among 36,856 patients with a hospital discharge diagnosis of alcoholism (ICD-7: 307, 322; ICD-8: 291, 303; ICD-9: 291, 303, 305A) in Sweden between 1965 and 1995. The follow-up was done by linkages of national registries. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were computed based on nationwide specific cancer rates. The first year of follow-up was excluded from all analyses to minimize the impact of selection bias. We found that alcoholic women had excess risks for in situ cervical cancer (SIR, 1.7; 95% CI, 1.6-1.9), for invasive cervical cancer (SIR, 2.9; 95% CI, 2.4-3.5), and for cancer of the vagina (SIR, 4.6; 95% CI, 2.2-8.5) but not for cancer of the vulva (SIR, 1.0; 95% CI, 0.4-2.0). The fact that alcoholics had an excess risk also for the in situ cancer suggests that the observed excess in invasive cervical cancer may not only be attributable to less use of Pap smear screening among them. The alcoholic women may be at higher risk for the progression from human papillomavirus infection to a malignant lesion for lifestyle-related reasons (promiscuity, smoking, use of contraceptive hormones, and dietary deficiencies). We conclude that alcoholic women are at high risk for in situ and invasive cervical cancer and for cancer of the vagina.

35
UI - 21402820
AU - Stein MD; Cunningham WE; Nakazono T; Turner BJ; Andersen RM; Bozzette SA; Shapiro MF; HCSUS Consortium
TI - Screening for cervical cancer in HIV-infected women receiving care in the United States.
SO - J Acquir Immune Defic Syndr 2001 Aug 15;27(5):463-6
AD - Division of General Internal Medicine, Rhode Island Hospital, Brown University, 593 Eddy Street, Providence, RI 02903, USA. mstein@lifespan.org
OBJECTIVE: We examined the sociodemographic, clinical and provider factors associated with screening for cervical cancer among HIV-infected women. METHODS: We studied a national sample representing 43,490 women receiving treatment of HIV infection who completed first follow-up surveys of the HIV Cost and Service Utilization Study (HCSUS). All women were asked, "In the past 12 months, have you had a Pap test?" Women reporting an abnormal Pap test result were asked whether they had been told antibiotics could cure abnormal cells, and whether they were scheduled for another Pap test or for a colposcopy within 3 months. RESULTS: Of the population represented, 81% had had a Pap test in the past 12 months. Women who reported having a gynecologist and primary care physician at the same clinical site were almost twice as likely (odds ratio, 1.9; 95% confidence interval, 1.3-3.0) as other women to report Pap testing. Among women who reported abnormal Pap test results and were not told antibiotics could cure abnormal cells, 95% were scheduled for a repeat Pap test or colposcopy, but 15% of the women had not received their repeat Pap test or colposcopy. CONCLUS

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