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Jill Koshiol,
S Terence Dunn,
Joan L Walker, Rosemary E Zuna,
Mark Schiffman,
Mark E Sherman,
Michael A Gold,
Richard A Allen,
Roy Zhang,
Sophia S Wang,
Nicolas Wentzensen
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ABSTRACT: We conducted a Linear Array® test/re-test analysis using cytologic specimens from 198 women. 67.2% of samples had the same HPV types detected in both tests [type-specific positive agreement 83.3% overall (Kappa=0.9), 86.8% for carcinogenic types (Kappa=0.92)]. Discordance was highest with low hybridization signal strength. Overall, Linear Array was highly reproducible.
Journal of clinical microbiology 11/2012; · 4.16 Impact Factor
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Patricia Luhn,
Joan Walker,
Mark Schiffman, Rosemary E Zuna,
S Terence Dunn,
Michael A Gold,
Katherine Smith,
Cara Mathews,
Richard A Allen,
Roy Zhang,
Sophia Wang,
Nicolas Wentzensen
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ABSTRACT: OBJECTIVE: Co-factors for cervical cancer, including oral contraceptive (OC) use, smoking and multiparity have been identified; however, the stage at which they act in cervical carcinogenesis is not clear. We compared established risk factors among women with CIN2 and CIN3 to evaluate the heterogeneity of these factors in precancer and also assessed their role during cervical carcinogenesis. METHODS: The current analysis included 2783 women with various stages of cervical disease who were enrolled in the Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED) and the Biopsy Study. Associations of co-factors within cervical precancer and at different stages of cervical carcinogenesis were estimated using logistic regression. RESULTS: Long-term OC use (10+ years vs. never: OR=2.42, 95% CI: [1.13-5.15]), multiparity (3+ births vs. nulliparous: OR=1.54 [1.04-2.28]), smoking (ever vs. never: OR=1.95 [1.48-2.58]), and no Pap test in the previous five years (2.05 [1.32-3.17]) were positively associated with CIN3 compared to CIN2. We observed that long-term OC use, parity and smoking were associated with an increased risk of CIN3 compared to <CIN2 (1.97 [1.12-3.46]; 2.233 [1.59-3.11]; 2.60 [2.04-3.30], respectively), whereas associations were not significantly different (OC use, parity) or showed decreased risk (smoking) comparing cancer to CIN3. CONCLUSIONS: Differences in established risk factors suggest that CIN3 is a more specific definition of precancer than CIN2. Hormonally-related factors and smoking play a role in the transition from human papillomavirus infection to precancer.
Gynecologic Oncology 11/2012; · 3.89 Impact Factor
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Cara A Mathews,
Julie A Stoner,
Nicolas Wentzensen,
Katherine M Moxley,
Meaghan E Tenney,
Erin R Tuller,
Tashanna Myers,
Lisa M Landrum,
Grainger Lanneau, Rosemary E Zuna,
Michael A Gold,
Sophia S Wang,
Joan L Walker
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ABSTRACT: Infrequent Pap screening is an important risk factor for cervical cancer. We studied the association between contraceptive methods, screening frequency, and cancer.
Women (n=2004) enrolled in the cross-sectional Study to Understand Cervical Cancer Endpoints and Determinants (SUCCEED) underwent colposcopy to evaluate an abnormal Pap test. Questionnaire data were compared between those with cervical intraepithelial neoplasia (CIN) 3/adenocarcinoma in situ (AIS) and those with invasive cancer to identify factors associated with cancer. Logistic regression was used to calculate age-stratified measures of association between contraceptive method and Pap frequency as well as tubal ligation (TL) and cancer risk.
In all age groups, women with TL were more likely to have had no Pap screening in the previous 5years compared to women using other contraception: 26-35years (OR 4.6, 95% CI 2.4-8.6; p<0.001), 36-45years (OR 3.8, 95% CI 2.1-7.0; p<0.001), and 46-55years (OR 2.2, 95% CI 1.0-4.9; p=0.050). Subjects with cancer (n=163) were more likely to have had a TL (41% vs. 21%, p<0.001) than those with CIN 3/AIS (n=370). Age-stratified analyses showed increased odds of tubal ligation in women with cancer versus those with CIN 3/AIS between 25 and 45years, with a significant increase in women 26 to 35years old (OR 3.3, 95% CI 1.4-8.1; p=0.009). Adjusting for Pap frequency changed the effect only slightly, suggesting that increased risk was not fully mediated by lack of screening.
Contraceptive type is associated with Pap screening. Women with TLs obtain less frequent Pap testing and may be at an increased risk for cervical cancer.
Gynecologic Oncology 07/2012; 127(2):278-82. · 3.89 Impact Factor
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Nicolas Wentzensen,
Lauren Schwartz, Rosemary E Zuna,
Katie Smith,
Cara Mathews,
Michael A Gold,
R Andy Allen,
Roy Zhang,
S Terence Dunn,
Joan L Walker,
Mark Schiffman
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ABSTRACT: Cytology-based screening has limited sensitivity to detect prevalent cervical precancers. Human papilloma virus (HPV) DNA testing is highly sensitive and provides a high, long-term reassurance of low risk of cervical cancer. However, the specificity of HPV DNA testing is limited, requiring additional, more disease-specific markers for efficient screening approaches.
Liquid-based cytology samples were collected from 625 women referred to colposcopy. A slide was stained using the CINtec plus cytology assay. Pap cytology and HPV genotyping were conducted from the same vial. Clinical performance characteristics were calculated for all women, stratified by age, and for women referred with a low-grade squamous intraepithelial lesion (LSIL) Pap.
p16/Ki-67 positivity increased with histologic severity, from 26.8% in normal histology, 46.5% in CIN1, 82.8% in CIN2 to 92.8% in CIN3. Among women with CIN3, p16/Ki-67 positivity increased from 77.8% for women younger than 30 years without HPV16 to 100% for women 30 years and older with HPV16. The sensitivity and specificity to detect CIN3+ were 93.2% and 46.1%, respectively, and increased to 97.2% and 60.0% among women 30 years and older. In women with high-risk (HR)-HPV-positive atypical squamous cells of undetermined significance (ASC-US) and LSIL, sensitivity and specificity for detection of CIN3 were 90.6% and 48.6%, respectively.
p16/Ki-67 testing could reduce referral to colposcopy by almost half while detecting the most severe cases of CIN3. The high sensitivity of p16/Ki-67 with significantly improved specificity compared with HPV testing makes p16/Ki-67 a viable option for LSIL triage. Further studies are required to evaluate p16/Ki-67 as triage marker in HPV-based screening strategies.
Clinical Cancer Research 06/2012; 18(15):4154-62. · 7.74 Impact Factor
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Nicolas Wentzensen,
Joan Walker,
Mark Schiffman,
Hannah P Yang, Rosemary E Zuna,
S Terence Dunn,
R Andy Allen,
Roy Zhang,
Mark Sherman,
Michael A Gold,
Sophia S Wang
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ABSTRACT: Factors associated with progression from cervical intraepithelial neoplasia (CIN) grades 2 and 3 to invasive cancer are not well understood; most CIN2 and CIN3 do not progress to cancer. Among carcinogenic human papillomavirus (HPV) types, infections with HPV16 have the highest risk of progressing to cancer. We evaluated the heterogeneity of risk factors, lesion size, colposcopic impression and colposcopic biopsy results in relation to HPV16 status among 627 women with CIN2 or CIN3 in women referred to colposcopy at the University of Oklahoma. Loop excision specimens were evaluated in 12 radial segments to estimate lesion size. The mean age at CIN3 was 27.7 years for HPV16-positive women (n = 225) and 33.6 years for HPV16-negative women (n = 104). The average lesion size did not differ by HPV16 status (p = 0.83). Among HPV16-positive women with CIN3, lesions were significantly larger in women 30 years and older (p = 0.03). Colposcopic impression was worse in women with HPV16 infections (p = 0.009), but the detection of CIN3 at the preceding biopsy was not improved in HPV16-positive women. CIN3 is detected at the same lesion size, but at much younger age in women with HPV16 infections, suggesting faster growth. CIN2 lesion size in women without HPV16 peaks below 30 years and then decreases, suggesting frequent regression, whereas HPV16-related CIN2 is more likely to persist. Lesion size seems to be an important determinant of colposcopy and biopsy performance. Genotyping for HPV16 in cervical cancer screening can improve risk stratification but may pose challenges to finding small lesions in colposcopy.
International Journal of Cancer 04/2012; · 5.44 Impact Factor
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Jacolien van der Marel,
Wim G V Quint,
Mark Schiffman,
Miekel M van de Sandt, Rosemary E Zuna,
S Terence Dunn,
Katherine Smith,
Cara A Mathews,
Michael A Gold,
Joan Walker,
Nicolas Wentzensen
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ABSTRACT: Women with high-grade cervical intraepithelial neoplasia (HGCIN) frequently present with multiple cervical lesions and multiple concomitant Human papillomavirus (HPV) genotype infections. To elucidate HPV genotype attribution in different regions on the cervix, we performed molecular mapping of cervical disease in women with HGCIN. Thirteen subjects referred to colposcopy for abnormal cervical cancer screening results were included. A cervical smear and biopsies from 4 different areas on the cervix were collected. HPV genotyping using Linear Array (for cytology) or SPF(10) LiPA(25) (for histology) were performed in 13 smears, 52 whole sections from biopsies and 138 tissue regions isolated with laser capture microdissection (LCM). Twelve subjects had a diagnosis of CIN3 and one subject had a diagnosis of CIN2 based on the worst histology found in 4 biopsies. Eight of the 13 smears (62%) showed multiple genotype infections. Four of 13 women (31%) had multiple HPV infections in their biopsies. After performing LCM-PCR, only one woman (8%) had two different carcinogenic HPV types in morphologically distinct, but colliding HGCIN lesions. HPV16 was identified as the causal type in all women with HPV16 in cytology. A large proportion of other HPV types found in cervical smears were not detected at the tissue level. Using tissue-based genotyping and LCM-PCR analysis, we were able to attribute an individual HPV type to each area of CIN lesions. We demonstrate that HPV16 is even more etiologically dominant than previously thought, based on various genotype attribution models.
International Journal of Cancer 03/2012; 131(6):E946-53. · 5.44 Impact Factor
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Nicolas Wentzensen,
Patti E Gravitt,
Rodney Long,
Mark Schiffman,
S Terence Dunn,
J Daniel Carreon,
Richard A Allen,
Munira Gunja, Rosemary E Zuna,
Mark E Sherman,
Michael A Gold,
Joan L Walker,
Sophia S Wang
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ABSTRACT: Carcinogenic human papillomavirus (HPV) infections are necessary causes of most anogenital cancers. Viral load has been proposed as a marker for progression to cancer precursors but has been confirmed only for HPV16. Challenges in studying viral load are related to the lack of validated assays for a large number of genotypes. We compared viral load measured by Linear Array (LA) HPV genotyping with the gold standard, quantitative PCR (Q-PCR). LA genotyping and Q-PCR were performed in 143 cytology specimens from women referred to colposcopy. LA signal strength was measured by densitometry. Correlation coefficients and receiver operating characteristic (ROC) analyses were used to evaluate analytical and clinical performance. We observed a moderate to strong correlation between the two quantitative viral load measurements, ranging from an R value of 0.61 for HPV31 to an R value of 0.86 for HPV52. We also observed agreement between visual LA signal strength evaluation and Q-PCR. Both quantifications agreed on the disease stages with highest viral load, which varied by type (cervical intraepithelial neoplasia grade 2 [CIN2] for HPV52, CIN3 for HPV16 and HPV33, and cancer for HPV18 and HPV31). The area under the curve (AUC) for HPV16 Q-PCR at the CIN3 cutoff was 0.72 (P = 0.004), and the AUC for HPV18 LA at the CIN2 cutoff was 0.78 (P = 0.04). Quantification of LA signals correlates with the current gold standard for viral load, Q-PCR. Analyses of viral load need to address multiple infections and type attribution to evaluate whether viral load has clinical value beyond the established HPV16 finding. Our findings support conducting comprehensive studies of viral load and cervical cancer precursors using quantitative LA genotyping data.
Journal of clinical microbiology 02/2012; 50(5):1564-70. · 4.16 Impact Factor
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Hannah P Yang, Rosemary E Zuna,
Mark Schiffman,
Joan L Walker,
Mark E Sherman,
Lisa M Landrum,
Katherine Moxley,
Michael A Gold,
S Terence Dunn,
Richard A Allen,
Roy Zhang,
Rodney Long,
Sophia S Wang,
Nicolas Wentzensen
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ABSTRACT: Cervical intraepithelial neoplasia grade 3 (CIN3), the immediate cervical cancer precursor, is a target of cervical cancer prevention. However, less than half of CIN3s will progress to cancer. Routine treatment of all CIN3s and the majority of CIN2s may lead to overtreatment of many lesions that would not progress. To improve our understanding of CIN3 natural history, we performed a detailed characterization of CIN3 heterogeneity in a large referral population in the US.
We examined 309 CIN3 cases in the SUCCEED, a large population-based study of women with abnormal cervical cancer screening results. Histology information for 12 individual loop electrosurgical excision procedure (LEEP) segments was evaluated for each woman. We performed case-case comparisons of CIN3s to analyze determinants of heterogeneity and screening test performance.
CIN3 cases varied substantially by size (1-10 LEEP segments) and by presentation with concomitant CIN2 and CIN1. All grades of CINs were equally distributed over the cervical surface. In half of the women, CIN3 lesions were found as multiple distinct lesions on the cervix. Women with large and solitary CIN3 lesions were more likely to be older, have longer sexual activity span, and have fewer multiple high risk HPV infections. Screening frequency, but not HPV16 positivity, was an important predictor of CIN3 size. Large CIN3 lesions were also characterized by high-grade clinical test results.
We demonstrate substantial heterogeneity in clinical and pathological presentation of CIN3 in a US population. Time since sexual debut and participation in screening were predictors of CIN3 size. We did not observe a preferential site of CIN3 on the cervical surface that could serve as a target for cervical biopsy. Cervical cancer screening procedures were more likely to detect larger CIN3s, suggesting that CIN3s detected by multiple independent diagnostic tests may represent cases with increased risk of invasion.
PLoS ONE 01/2012; 7(1):e29051. · 4.09 Impact Factor
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Rosemary E Zuna,
Erin Tuller,
Nicolas Wentzensen,
Cara Mathews,
Richard A Allen,
Rebecca Shanesmith,
S Terence Dunn,
Michael A Gold,
Sophia S Wang,
Joan Walker,
Mark Schiffman
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ABSTRACT: HPV16 variants are associated with different risks for development of CIN3 and invasive cancer, although all are carcinogenic. The relationship of HPV 16 variants to cancer survival has not been studied.
155 HPV16-positive cervical cancers were categorized according to European and non-European variant patterns by DNA sequencing of the E6 open reading frame. Clinico-pathologic parameters and clinical outcome were collected by chart review and death registry data.
Of the 155 women (mean age 44.7 years; median follow-up 26.7 months), 85.2% harbored European variants while 14.8% had non-European sequences. HPV16 variants differed by histologic cell type (p = 0.03) and stage (1 vs. 2+; p = 0.03). Overall, 107 women (68.0%) were alive with no evidence of cancer, 42 (27.1%) died from cervical cancer, 2 (1.3%) were alive with cervical cancer, and 4 (2.6%) died of other causes. Death due to cervical cancer was associated with European variant status (p < 0.01). While 31% of women harboring tumors with European variants died from cervical cancer during follow-up, only 1 of 23 (4.4%) non-European cases died of cancer. The better survival for non-European cases was partly mediated by lower stage at diagnosis.
Overall, invasive cervical cancers with non-European variants showed a less aggressive behavior than those with European variants. These findings should be replicated in a population with more non-European cases.
Infectious Agents and Cancer 01/2011; 6:19.
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ABSTRACT: We developed a protocol to collect representative cervical specimens based on colposcopic evaluation from women treated with loop electrosurgical excision procedure (LEEP).
We analyzed the histology of biopsies targeting the worst and a normal area on the cervical surface in 74 women referred for LEEP because of cervical intraepithelial neoplasia grade 3 (CIN3) detected in a previous biopsy. Lesions and normal tissue were identified in colposcopy, marked, and removed after LEEP. Cervical cytology specimens collected at the same time were analyzed using Pap cytology and human papillomavirus (HPV) genotyping.
All but two women had an abnormal colposcopic impression with 59 of 68 (87%) showing an impression of CIN2 or greater. In 19 of 58 (33%) women, the histology result of the frozen specimen targeting the worst lesion was < or =CIN1. In 18 of 46 (40%) women, the histology of the frozen specimen targeting normal tissue was CIN2+. A concordant histology result in specimens targeting the worst lesion was associated with a greater extension of the CIN3 in the LEEP (p trend=0.002) and a HSIL cytology result (p trend=0.02).
It is challenging to sample representative cervical tissue. Even in women with confirmed CIN3, colposcopy performance to identify the worst lesion on the cervix was limited. Correctly identified CIN3s were more likely to be larger lesions that may have a higher risk of progression to cancer.
Gynecologic Oncology 09/2009; 115(3):493-6. · 3.89 Impact Factor
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ABSTRACT: It has been suggested that DNA sequence variants of HPV16 contribute to differences in the behavior of individual cervical lesions. To address this question, we have analyzed the association of HPV16 variants with diagnostic severity in 354 HPV16-positive Oklahoman women. HPV16 variant status was determined by PCR amplification and DNA sequencing of the E6 open reading frame. European sequences were identified in 86% of samples and 14% were non-European. Of the 51 non-European cases, 61% were Asian-American, 23% African and 16% were Native American variants. European prototype and related variants were present in comparable numbers (43% each) but the relative proportion of each differed with diagnostic category. In general, the proportion of European variants and non-European variants increased with diagnostic severity while the European prototype decreased. When adjusted for age and race (white, black or Hispanic), the increased risk for carcinoma/severe dysplasia for non-European variants was statistically significant with an odds ratio of 3.8 (1.3-10.7). However, the analogous comparison for the European variants, although also showing increased association with carcinoma/severe dysplasia, did not reach statistical significance (OR = 1.6 (95% CI 0.7-3.6). Overall, HPV16 European sequences (both prototype and related variants), were predominant in Oklahoman women including those with cancers. This suggests that while there appear to be differences among the HPV16-variant categories in risk for progression to invasive cancer, all variant categories are associated with the development of invasive cancer.
International Journal of Cancer 07/2009; 125(11):2609-13. · 5.44 Impact Factor
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Nicolas Wentzensen,
Mark Schiffman,
Terence Dunn, Rosemary E Zuna,
Michael A Gold,
Richard A Allen,
Roy Zhang,
Mark E Sherman,
Sholom Wacholder,
Joan Walker,
Sophia S Wang
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ABSTRACT: Determining the causal attribution of human papillomavirus (HPV) genotypes to cervical disease is important to estimate the effect of HPV vaccination and to establish a type spectrum for HPV-based screening. We analyzed the prevalence of HPV infections and their attribution to cervical disease in a population of 1,670 women referred to colposcopy for abnormal cytology at the University of Oklahoma. HPV genotyping was performed from cytology specimens using the Linear Array assay that detects 37 HPV genotypes. We used different methods of type attribution to revised cervical disease categories. We found very high prevalence of multiple HPV infections with up to 14 genotypes detected in single specimens. In all disease categories except for cancers, there was a significant trend of having more infections at a younger age. We did not see type interactions in multiple genotype infections. HPV16 was the most frequent genotype at all disease categories. Based on different attribution strategies, the attribution of vaccine genotypes (6, 11, 16, 18) ranged from 50.5 to 67.3% in cancers (n = 107), from 25.6 to 74.8% in CIN3 (n = 305), from 15.2 to 52.2% in CIN2 (n = 427), and from 6.6 to 26.0% in <CIN2 (n = 708). In the HSIL cytology group (n = 651), attribution ranged from 26.1 to 64.7%. The attribution of vaccine types to HSIL was substantially higher compared to the lower cytology categories. The potential range of HPV genotype attribution is wide at the disease categories <CIN2 to CIN3. Genotyping from cervical lesions and analyzing viral oncogene expression can improve estimates of HPV genotype attribution.
International Journal of Cancer 05/2009; 125(9):2151-8. · 5.44 Impact Factor
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Sophia S Wang, Rosemary E Zuna,
Nicolas Wentzensen,
S Terence Dunn,
Mark E Sherman,
Michael A Gold,
Mark Schiffman,
Sholom Wacholder,
Richard A Allen,
Ingrid Block,
Kim Downing,
Jose Jeronimo,
J Daniel Carreon,
Mahboobeh Safaeian,
David Brown,
Joan L Walker
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ABSTRACT: Human papillomavirus (HPV) cofactors for cervical cancer include smoking, multiparity, and oral contraceptive use, but their mechanisms of action are not fully understood. It is also unknown whether cofactors vary by HPV genotypes. The Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED) is a cross-sectional study comprising women referred to the University of Oklahoma from November 2003 to September 2007 for abnormal cervical screening results. Detailed questionnaire data and liquid cytology specimens were collected and the latter was genotyped for HPV using the LINEAR ARRAY HPV Genotyping Test. The present analysis includes women with both questionnaire and HPV data and diagnosed with <CIN1 (n = 535), CIN1 (n = 497), CIN2 (n = 336), CIN3 (n = 292), and cancer (n = 80). We evaluated HPV types and cofactors among HPV-infected women by calculating odds ratios (OR) and 95% confidence intervals (95% CI) for CIN3 and CIN2 separately compared with <CIN2 using a polytomous logistic regression model; cancers were excluded from further analysis due to the substantially higher ages of these women. We found that HPV-infected women with minor histologic or cytologic abnormalities (e.g., CIN1, ASCUS, and LSIL) were indistinguishable from those with normal histology/cytology and were thus combined to form the referent group (<CIN2). Among women positive for oncogenic HPV, current smokers had a 2.5-fold increased risk for CIN3 (95% CI, 1.8-3.6) compared with nonsmokers. Among HPV16-infected women, current smokers had elevated risk for both CIN2 (OR, 1.9; 95% CI, 1.1-3.2) and CIN3 (OR, 2.7; 95% CI, 1.6-4.6). Our data suggest that non-HPV16-related CIN2 likely reflects a combination of CIN1 and CIN3 diagnosis, whereas HPV16-related CIN2 may indicate a precancerous state. Investigations on the molecular distinctions along the disease continuum of cervical pathogenesis by HPV type are needed.
Cancer Epidemiology Biomarkers & Prevention 01/2009; 18(1):113-20. · 4.12 Impact Factor
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ABSTRACT: Human papillomaviruses (HPV) 16 is a DNA virus encoding three oncogenes--E5, E6, and E7. The E6 and E7 proteins have well-established roles as inhibitors of tumor suppression, but the contribution of E5 to malignant transformation is controversial. Using spontaneously immortalized human keratinocytes (HaCaT cells), we demonstrate that expression of HPV16 E5 is necessary and sufficient for the formation of bi-nucleated cells, a common characteristic of precancerous cervical lesions. Expression of E5 from non-carcinogenic HPV6b does not produce bi-nucleate cells. Video microscopy and biochemical analyses reveal that bi-nucleates arise through cell-cell fusion. Although most E5-induced bi-nucleates fail to propagate, co-expression of HPV16 E6/E7 enhances the proliferation of these cells. Expression of HPV16 E6/E7 also increases bi-nucleated cell colony formation. These findings identify a new role for HPV16 E5 and support a model in which complementary roles of the HPV16 oncogenes lead to the induction of carcinogenesis.
Virology 12/2008; 384(1):125-34. · 3.35 Impact Factor
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Nicolas Wentzensen,
Mark Schiffman,
S Terence Dunn, Rosemary E Zuna,
Joan Walker,
Richard A Allen,
Roy Zhang,
Mark E Sherman,
Sholom Wacholder,
Jose Jeronimo,
Michael A Gold,
Sophia S Wang
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ABSTRACT: Diagnosis and treatment of cervical cancer precursors rely on colposcopic biopsy, which is sometimes hampered by incorrect biopsy placement and the unclear prognostic value of poorly reproducible diagnoses such as cervical intraepithelial neoplasia (CIN) Grade 1 and 2. Searching for discrete disease categories that incorporate the value of cytology and that reflect the causal role of particular HPV types, we analyzed histology, cytology and HPV genotype distributions in the Study to Understand Cervical Cancer Endpoints and Early Determinants (SUCCEED). This cross-sectional study comprises approximately 1,700 women referred to colposcopy or treatment for the spectrum of cervical disease, including 439 women with <CIN1, 429 CIN1, 322 CIN2, 297 CIN3 and 107 with cancer. Using hierarchical clustering of histology-cytology groups based on HPV genotype distributions, we could plainly distinguish in this referral population 5 increasingly severe diagnostic groups of HPV-positive women: (i) HPV-positive women with <CIN2 histology and normal cytology, (ii) HPV positive women with <CIN2 histology and ASC or LSIL cytology; (iii) CIN2, including histologic CIN2 and HSIL cytology with any histology <CIN2; (iv) CIN3; and (v) invasive cervical cancer. The grouping of women with HSIL cytology, but without histological abnormalities to women with CIN2 suggests that in these cases the worst lesion was missed during colposcopy-biopsy. We are now using these sharpened diagnostic categories to search for novel biomarkers predicting the risk of progression and invasion.
International Journal of Cancer 10/2008; 124(4):964-9. · 5.44 Impact Factor
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ABSTRACT: The objective of the study was to review the cytologic and histopathologic features among women 35 years of age or older with cervical dysplasia.
Patients presenting between 2001 and 2005 were included. Patients were labeled as pre- (PRE) or postmenopausal (POST) based on age younger than or 50 years old or older. Statistics were performed using SAS 8.0.
Three hundred fifty-nine patients were identified: 270 PRE and 89 POST. PRE and POST patients had similar referral cytology with atypical cells of undetermined significance (ASC)/low-grade squamous intraepithelial lesion (LSIL) in 60% and 65% and high-grade squamous intraepithelial lesion (HSIL) in 35% and 27%, respectively. Among patients with ASC/LSIL, POST had significantly more cervical intraepithelial neoplasia (CIN) 3 (41% vs 29%; P = .027) as well as more malignancies (17 vs 0%; P = .002). Among patients referred for loop electrical excisional procedure secondary to HSIL cytology not explained by colposcopy, CIN 2 or greater was identified more often in POST (71 vs 32%; P = .03).
Our data demonstrate a high proportion of severe cervical dysplasia in age groups traditionally thought to have less risk than younger patients.
American journal of obstetrics and gynecology 06/2008; 199(5):471.e1-5. · 3.28 Impact Factor
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Tongzhong Ju,
Grainger S Lanneau,
Tripti Gautam,
Yingchun Wang,
Baoyun Xia,
Sean R Stowell,
Margaret T Willard,
Wenyi Wang,
Jonathan Y Xia, Rosemary E Zuna,
Zoltan Laszik,
Doris M Benbrook,
Marie H Hanigan,
Richard D Cummings
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ABSTRACT: Neoplastic lesions typically express specific carbohydrate antigens on glycolipids, mucins, and other glycoproteins. Such antigens are often under epigenetic control and are subject to reversion and loss upon therapeutic selective pressure. We report here that two of the most common tumor-associated carbohydrate antigens, Tn and sialyl Tn (STn), result from somatic mutations in the gene Cosmc that encodes a molecular chaperone required for formation of the active T-synthase. Diverse neoplastic lesions, including colon cancer and melanoma-derived cells lines, expressed both Tn and STn antigen due to loss-of-function mutations in Cosmc. In addition, two human cervical cancer specimens that showed expression of the Tn/STn antigens were also found to have mutations in Cosmc and loss of heterozygosity for the cross-linked Cosmc locus. This is the first example of somatic mutations in multiple types of cancers that cause global alterations in cell surface carbohydrate antigen expression.
Cancer Research 04/2008; 68(6):1636-46. · 7.86 Impact Factor
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ABSTRACT: Previously we found differences in the distribution of the individual human papillomavirus types in cervical cancers and high-grade squamous intraepithelial lesions. This suggested that there were differences in risk for progression of high-grade squamous intraepithelial lesions that were related to human papillomavirus type within the category of oncogenic genotypes. In this work, we add additional cases including low-grade squamous intraepithelial lesions. ThinPrep samples from 282 squamous intraepithelial lesions and invasive cervical cancers were categorized morphologically by consensus interpretation and genotyped for 27 individual human papillomavirus types by polymerase chain reaction-based reverse line blot analysis using PGMY09/PGMY11 consensus primers for the L1 open reading frame. The 27 human papillomavirus types were divided into three categories: high risk 16, 18, 31, 45; intermediate risk 33, 35, 39, 51, 52, 56, 58, 59, 68, 73, 82, 83; and low risk: 6, 11, 26, 40, 42, 53, 54, 55, 57, 66, and 84. Of the 282 cases of cancer and squamous intraepithelial lesions, 95.7% were positive for one or more of 27 human papillomavirus types and 38.7% had two or more genotypes. Three major categories of squamous intraepithelial lesions were identified based upon the combination of consensus diagnosis and human papillomavirus category: (1) high-grade squamous intraepithelial lesions associated with high-risk human papillomavirus types that appear to be at increased risk for progression to carcinoma; (2) squamous intraepithelial lesions (typically low-grade intraepithelial lesions and high-grade lesions consistent with moderate dysplasia) associated with intermediate risk human papillomavirus types with limited or indeterminate risk for progression; (3) low-grade squamous intraepithelial lesions associated with low-risk human papillomavirus types with little or no risk for progression. Only a subset of human papillomavirus genotypes commonly considered to be oncogenic were closely associated with invasive cervical cancer and high-grade squamous intraepithelial lesions classed as severe dysplasia. Other oncogenic types were closely associated with high-grade squamous intraepithelial lesions of moderate dysplasia and low-grade squamous intraepithelial lesions. This suggests that risk for progression to invasion in squamous intraepithelial lesions is closely related to human papillomavirus genotype. Knowledge of the associated human papillomavirus type in women with morphologic squamous intraepithelial lesions may help to clarify risk for progression.
Modern Pathology 03/2007; 20(2):167-74. · 4.79 Impact Factor
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ABSTRACT: Low-grade squamous intraepithelial lesion (LSIL) subsumes the formerly delineated cytologic categories of human papillomavirus (HPV)-associated cell changes (koilocytotic atypia) and low-grade dysplasia/cervical intraepithelial neoplasia (CIN) Grade 1 (CIN1). In this study, the objective was to determine whether these 2 morphologic subcategories are characterized by differences in risk for CIN3 and/or HPV type distribution.
Within the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study, all cytologic interpretations of HPV cellular changes and CIN1 rendered by any of the pathology reviewers (community laboratory, clinical center, or Pathology Quality-Control Group) on referral Papanicolaou (Pap) tests or enrollment ThinPrep Pap tests were included for analysis. HPV testing was performed by Hybrid Capture 2 (HC2) and by polymerase chain reaction based reverse-line blot analysis for 27 HPV types. The absolute risks of cumulative detection of CIN3 or cancer (CIN3 +) and CIN2 or worse (CIN2 +) over 2 years of follow-up were calculated for the various cytologic interpretations.
For each review group and cytology preparation, most LSIL interpretations (from approximately 2 of 3 interpretations to 3 of 4 interpretations) were subcategorized as CIN1 rather than HPV cellular changes. HPV type 16 (HPV-16) was the most common HPV type and was identified in 21% to 24% of CIN1 and in 14% to 18% of HPV cellular changes. Nononcogenic types were identified alone in from 9% to 11% of CIN1 compared with 17% to 20% of HPV cellular change. The absolute risks of CIN1 and HPV cellular changes for cumulatively detected CIN3 + ranged from 12% to 16% for CIN1 and from 6% to 9% for HPV cellular changes.
Both cytologic subcategories of LSIL were associated predominantly with oncogenic HPV types; however, the proportion of nononcogenic HPV types was lower and the absolute risks for CIN3 + were higher for CIN1 compared with HPV cellular changes. The concordance in subcategorizing LSIL was low, and the authors concluded that the diagnostic distinction is of limited clinical utility for individual patient management.
Cancer 11/2006; 108(5):288-97. · 4.77 Impact Factor
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Itzel E Calleja-Macias,
Luisa L Villa,
Jose C Prado,
Mina Kalantari,
Bruce Allan,
Anna-Lise Williamson,
Lap-Ping Chung,
Robert J Collins, Rosemary E Zuna,
S Terence Dunn,
Tang-Yuan Chu,
Heather A Cubie,
Kate Cuschieri,
Magnus von Knebel-Doeberitz,
Claudia R Martins,
Gloria I Sanchez,
F Xavier Bosch,
Nubia Munoz,
Hans-Ulrich Bernard
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ABSTRACT: Among the more than one hundred formally described human papillomavirus (HPV) types, 18 are referred to as high-risk HPV types due to their association with anogenital cancer. Despite pathogenic similarities, these types form three remotely related taxonomic groups. One of these groups is called HPV species 9 and is formed by HPV-16, the most common and best-studied type, together with HPV-31, -33, -35, -52, -58, and -67. Previous worldwide comparisons of HPV-16 samples showed about 2% nucleotide diversity between isolates, which were subsequently termed variants. The distribution of divergent variants has been found to correlate frequently with the geographic origin and the ethnicity of the infected patients and led to the concept of unique African, European, Asian, and Native American HPV-16 variants. In the current study, we address the question of whether geography and ethnicity also correlate with sequence variations found for HPV-31, -35, -52, and -58. This was done by sequencing the long control region in samples derived from Europe, Asia, and Africa, and from immigrant populations in North and South America. We observed maximal divergence between any two variants within each of these four HPV types ranging from 1.8 to 3.6% based on nucleotide exchanges and, occasionally, on insertions and deletions. Similar to the case with HPV-16, these mutations are not random but indicate a relationship between the variants in form of phylogenetic trees. An interesting example is presented by a 16-bp insert in select variants of HPV-35, which appears to have given rise to additional variants by nucleotide exchanges within the insert. All trees showed distinct phylogenetic topologies, ranging from dichotomic branching in the case of HPV-31 to star phylogenies of the other three types. No clear similarities between these types or between these types and HPV-16 exist. While variant branches in some types were specific for Europe, Africa, or East Asia, none of the four trees reflected human evolution and spread to the extent illustrated by HPV-16. One possible explanation is that the rare HPV types that we studied spread and thereby diversified more slowly than the more abundant HPV-16 and may have established much of today's variant diversity already before the worldwide spread of humans 100,000 years ago. Most variants had prototypic amino acid sequences within the E6 oncoprotein and a segment of the L1 capsid protein. Some had one, two, or three amino acid substitutions in these regions, which might indicate biological and pathogenic diversity between the variants of each HPV type.
Journal of Virology 12/2005; 79(21):13630-40. · 5.40 Impact Factor
