Low-grade Squamous Lesion Research Articles

Comparative analysis of Paiteling a traditional Chinese medicine (TCM) and CO2 laser therapy for high-risk HPV-associated with LSIL (CIN1) lesions

ObjectivesThis study aims to evaluate the therapeutic outcomes of Paiteling and CO2 laser therapy on high-risk human papillomavirus. MethodsWe retrospectively analyzed the data of 558 patients with HR-HPV low-grade squamous intraepithelial neoplasia (CIN1) from 2021 to 2023. Patients were selected and put into two groups: Paiteling and CO2 laser. Out of the 558 patients who were included in our final study, 239 (42.8 %) were treated with Paiteling, and 319 (57.2 %) were treated with CO2 laser vaporization. The mean age was 49.55 ± 12.10 years old. We observed that 27 (4.83 %) were younger than 30 years and 531 (95.1 %) were older than 30 years. We reviewed the patient’s results at intervals of 3 months, 6 months, 12 months, and 24 months after each therapy. The results of the recurrence rate, effective viral clearance rate, and the effectiveness of both therapies on low-grade cervical lesions were determined using multivariate and univariate cox-regression analysis. The Kaplan-Meier curve was used to determine the HR-HPV conversion rate of each therapy. ResultsThe median time for HR-HPV clearance was 6.00 months (95 % CI: 4.26–6.89) in the Paiteling group and 9.00 months (95 % CI: 15.92–22.67) in the CO2 laser group. There was a significant difference between the two groups (χ2 = 25.118, p-Value = 0.000). The HR-HPV clearance rate during 6–12 months for Paiteling and CO2 laser was 100 (55.6 %) and 80 (44.4 %), respectively. The clearance rate for both therapies from 6 to 18 months was statistically significant (6–12 months: p < 0.010, 12–18 months: p < 0.011). The Paiteling HR-HPV negative rate over 24 months 214 (89.5 %) is higher than CO2 laser 176 (55.2 %). Paiteling has a 5.4 % re-infection rate, which is marginally lower than the 5.6 % rate for CO2 lasers.The clearance rate for both therapies from 12 to 18 months [Paiteling: 20 (4.7 %) to 10 (3.6 %) and CO2 laser: 22 (8.4 %) to 15 (4.2 %)] was also significant (p < 0.011). The percentage of persistent Hr-HPV clearance rate for Paiteling patients was higher than carbon dioxide laser vaporization. No severe side effects were reported by the Paiteling patients compared to laser vaporization. This is due to the fact that Paiteling, as a traditional Chinese medicine, is a topical, non-invasive medicine, thus preserving the integrity of the cervix. ConclusionsPaiteling is an effective noninvasive therapy that can clear persistent HR-HPV associated with cervical low-grade squamous lesions in a relatively shorter period of time compared to CO2 laser ablation.

The relationship of immunohistochemical SOX-2 staining with histopathological diagnosis in patients with abnormal colposcopic findings.

This study aimed to analyze immunohistochemical staining and pathological data in cervical intraepithelial neoplasia (CIN) and squamous cell cervical carcinoma (SCC) with abnormal colposcopic findings. A histopathological evaluation of 45 low-grade squamous lesions (LSILs), 177 high-grade squamous lesions (HSILs) and 16 SCC biopsy materials from existing slides was obtained from blocks obtained from the archive. In addition, SOX-2 immunohistochemical staining was evaluated. The mean age of the HSIL group was 43.20 ± 8.97years, younger than the mean age of the LSIL group of 51.62 ± 9.64years (p = 0.000). There was no difference between the groups regarding the method of biopsy (p > 0.05). Endocervical gland involvement was not observed in the LSIL group, but was observed in 66 (37.3%) biopsy materials in the HSIL group (p = 0.000). There was a difference between the groups in terms of the level of CIN at the surgical margin (p = 0.000). Ki-67, SOX-2 staining percentage and p16INK4a positivity were higher in the HSIL group than in the LSIL group (respectively, 67.57 ± 19.10 vs. 14.62 ± 7.11, p = 0.000; 27.72 ± 31.56 vs. 10.09 ± 15.38, p = 0.003; 66 (82.5%) vs. 8 (44.4%), p = 0.001). While there was no difference in SOX-2 intensity between the HSIL and LSIL groups (p > 0.05), it was statistically significantly higher in the SCC group (p = 0.000), as was the percentage of SOX-2 (p = 0.000). We have shown that p16INK4a and SOX-2 staining is useful, in addition to Ki-67 immunostaining, which is widely used for SCC, which is one of the preventable cancer types. In addition, SOX-2 may provide a glimmer of hope in the development of SCC treatment modalities, especially since it is aggressively elevated in SCC rather than CIN lesions.

S71 Role of High-Resolution Anoscopy in Inflammatory Bowel Disease

Background: Anal squamous cell carcinoma is rare, but its incidence and mortality have been increasing worldwide, and 90% of cases are related to HPV infection. Patients with Inflamatory Bowel disease (IBD), have a higher risk than the general population, It has been identified: 5.5 per 100,000 patients in the IBD group vs 1.8 in the non-IBD group. This is due to the prolonged inflammatory state, which decreases viral clearance of HPV; and the persistence of HPV in the transition zone in the anal canal, increases the possibility of developing premalignant lesions and consequently anal cancer. Likewise, prolonged management with anti-TNF and steroids, generates loss of cell cycle regulation, altering viral clearance. Should we add a new risk population group to the literature? Currently, there are no recommendations for anal canal HPV screening in patients with IBD, so we conducted a study with the purpose of confirming the presence of HPV-related premalignant lesions in the anal canal that could explain the high risk of anal cancer development in these patients, and to develop a screening algorithm in which high-resolution anoscopy is the cornerstone for the diagnosis and treatment of premalignant lesions Methods: A prospective cohort study was conducted in which we included patients under follow-up for IBD, without perianal symptoms, between January 2022 and July 2022 at the Instituto de Coloproctology in Medellín, who underwent anal cytology, genotyping of hHPV and high-resolution anoscopy, after explanation and acceptance of the procedure. If lesions were found, ablative treatment was performed. Results: A total of 21 patients with IBD were included. Six percent presented failure of the first line of management and were under anti-TNF management; 23% had low-grade squamous lesions, while 14.2% had high-grade lesions with changes of dysplasia at the time of anoscopy; 90.4% had positive genotyping for HPV of which 76.1% were high-grade; 76.1% patients had dysplasia which was 87% associated with high-risk HPV. Conclusion(s): Our study demonstrates that IBD patients behave as a high risk group for developing premalignant lesions in association with HPV, such as, high grade lesion which was found in 14.2% of patients and dysplasia in 76%. The persistent inflammatory state, the use of steroids and anti-TNF play an important role in decreasing the viral clearance of HPV, so a more exhaustive study should be performed in patients with IBD; to establish the frequency of lesions and the viral genetic profile that could be related to the development of anal cancer. High resolution anoscopy is a cost effective, painless and affordable method that in expert hands can efficiently diagnose and treat premalignant lesions and decrease the incidence of anal cancer in patients with IBD.

Inter- and intraobserver agreement in whole-slide digital ThinPrep samples of low-grade squamous lesions of the cervix uteri with known high-risk HPV status: A multicentric international study.

High-risk human papilloma virus (HR HPV) testing and liquid-based cytology are used for primary cervical screening. Digital cytology, based on whole-slide scanned samples, is a promising technique for teaching and diagnostic purposes. The aim of our study was to evaluate the interobserver and intraobserver variation in low-grade squamous lesions, HR HPV status bias, and the use of whole-slide scanned digital cervical cytology slides. Fifteen expert cytopathologists evaluated 71 digitalized ThinPrep slides (31 atypical squamous cells of undetermined significance [ASC-US], 21 negative for intraepithelial lesion or malignancy, and 19 low-grade squamous intraepithelial lesion cases). HR HPV data were accessible only in the second round. In interobserver analysis, Kendall's coefficient of concordance was 0.52 in the first round and 0.58 in the second round. Fleiss' kappa values were 0.29 in the first round and 0.31 in the second round. In the ASC-US category, Fleiss kappa increased from 0.19 to 0.22 in the second round and the increase was even higher expressed by Kendall's coefficient: from 0.42 to 0.52. In intraobserver analysis, personal scores were higher in the second round. The interobserver and intraobserver variability in low-grade squamous lesions was within fair agreement values in the present study, in line with previous works. The comparison of two rounds showed that expert cytopathologists are generally unbiased by the knowledge of HR HPV data, but that being informed of the HR HPV status leads to a better agreement. Stain quality and back discomfort were highlighted as factors affecting digital cytopathology use.

Expert Cytopathologists Were Not Biased by HPV Data in Interobserver and Intraobserver Study in Low Grade Squamous Lesions in Thin Prep Liquid-based Cytology

Expert Cytopathologists Were Not Biased by HPV Data in Interobserver and Intraobserver Study in Low Grade Squamous Lesions in Thin Prep Liquid-based Cytology

Cervical Cancer Screening: Is the Age Group 30-65 Years Optimum for Screening in Low-Resource Settings?

An Operational Framework document for population-wide screening of common cancers in India was launched in 2016. The target age for screening is 30-65years for cervical, breast and oral cancers. This study was designed to review the frequency and distribution of cervical lesions among women aged 21-29, 30-65 and > 65years. A retrospective review of all satisfactory cervical smears (n = 79,896) received over a ten-year period (2010-2019) was conducted. Three age bands were defined: 21-29years, 30-65years and > 65years. The frequency and distribution of the various epithelial cell abnormalities (ECAs) across the three age bands were calculated. Cytohistologic correlation was performed wherever available. Of the 1357 ECAs (1.7% of all smears), about 16.9% were seen in the age band 21-29years, while 4.5% presented in > 65years of age. About 80% of the ECAs seen in younger women were low-grade squamous lesions, while 75% of lesions in women > 65years were high-grade squamous abnormalities. Among the total 512significant high-gradeand malignant(squamous and glandular) lesions, 5.6% presented in women 21-29years, while 10.1% were seen in > 65years of age. Majority of the significant cervical lesions would be detected if the screening focuses on the 30-65years age group. However, about 19% of high-grade squamous preneoplasticlesions(ASC-H/ HSIL) and 13% of preneoplasticglandular lesions(AGC-N) are likely to be missed if women 21-29years and > 65years are excluded. The cost of screening incurred by including these age groups has to be weighed against the benefits derived, especially in low-resource settings. In the absence of universal implementation of HPV immunization, there is a felt need to enhance cervical cancer awareness and encourage screening, more so in high-risk category and symptomatic females beyond the selected age group.

Difference Between Cryotherapy and Follow Up Low Grade Squamous Lesion of Cervix Uteri.

Introduction:Cervical cancer can be successfully prevented by effective treatment.Aim:Analyse of success of cryotherapy in LSIL and ASCUS.Materials et methods:In retrospective study between January 2016 to March 2017, 3244 PAP test were analysed. 257 patients who had been diagnosed with LSIL and ASCUS from PAP smear were divided in two groups: women who had HPV positive, colposcopic positive and cytologic finding of LSIL or ASCUS treathed with cryotherapy and women with LSIL, ASCUS and negative colposcopy. χ2 test was used for statistical analysis of data.Results:Analysis of 3244 PAP smears showed negative for intraepithelial lesion or malignancy (NILM) in 90,10% (N-2923), and abnormal in 9,8% (N-321) of women. ASCUS was found in 4,8% (N-156) and ASC-H in 0,2% (N-6), LSIL in 3,1% (N-101), HSIL in 0,64% (N-21). The average age of patients with ASCUS lesion was 41 ± 12 years. After cryotherapy, HSIL had progression in 1,5% (N-1), persistence in 6,3% (N-4) and regression in 91,7% (N-58). Progression occured in 10,5% (N-4) of HSIL, persistence in 52,6% (N-20) and regression in 36,7% (N-14) in 38 women with LSIL lesion after repeated PAP test. Progression occured in 8% (N-10) of LSIL and 4% HSIL (N-5), persistence in 58% (N-72) and regression in 29,8% (N-37) in 124 women with ASCUS lesion after treatment and repeated PAP test. Difference in progression lesions in HSIL between women with cryotherapy (1,5%) and follow-up (10,5%) after LSIL is not significant, but progression to CIN II occured after cryotherapy. CIN III or cervical cancer was not found.Conclusion:Cryotherapy prevents progression of LSIL in HSIL and in cervical cancer. Because of that cryotherapy is successful method in prevention of cervical cancer.

Experience with colposcopy at Aminu Kano Teaching Hospital, Kano, North-Western Nigeria

Background: The first 2 years' experience of a colposcopy clinic at our teaching hospital was analyzed. Establishment of the clinic was supervised by consultants trained in colposcopy. Objective: To review the performance of the clinic from its inception in 2010. Materials and Methods: A study of 90 patients who were referred for colposcopy was conducted. Data were extracted from patients' folders and records in the colposcopy and histopathology register and analyzed using EPI INFOTM 7. Results: Fifty-one women were referred on account of abnormal Papanicolaou (Pap) smears indicating either low grade squamous lesion (44%) or high grade lesion (12.2%). Thirteen patients (14.4%) had persistent inflammatory smears while 26 patients (28.9%) where referred on account of suspicious cervix. Abnormal colposcopic findings were reported in 48 patients who subsequently had colposcopically directed punch biopsy. The result of the biopsy showed that 18 patients had cervical intraepithelial neoplasia (CIN) I. Only two of these had high grade lesion; the remaining had low grade lesion (81% concordance). Nineteen women had either CIN II or CIN III. Only two cases were reported as low grade lesions and one case as suspected invasive cervical cancer on colposcopy. The remaining had high grade lesion (85% concordance %). Overall, the colposcopic impression was in agreement with the histological diagnosis in 87% of the cases. Conclusion: Our initial experience with colposcopy shows good correlation/agreement between colposcopic impression and histological diagnosis. This has improved the detection rate of premalignant and malignant disease of the cervix in our center.

Frecuencia de infecciones vaginales y lesiones intraepiteliales en las usuarias de los laboratorios clínicos de Dinámica IPS de la ciudad de Medellín (Colombia), 2005-2010: estudio descriptivo

Objetivo: determinar la frecuencia de infecciones vaginales y lesiones intraepiteliales los resultados de laboratorio de las usuarias de los laboratorios clínicos de Dinámica IPS de la ciudad de Medellín atendidas entre el 2005 y el 2010.Materiales y Método: estudio descriptivo transversal con fuentes secundarias de los resultados de pruebas realizadas a usuarias de Dinámica IPS atendidas en el periodo de estudio en el que se evaluaron variables como la edad y los resultados de citología vaginal (n= 261 789), Gram (n= 70 447) y directo de flujo vaginal (n= 89 527). Se excluyeron registros con información incompleta. Se realizó análisis estadístico con medianas y proporciones.Resultados: del total de muestras analizadas(n=261 789), el 1,99% correspondían a lesiones escamosas, de éstas el 0,038% corresponde a muestras positivas de cáncer de cuello uterino confirmada por patólogo; el 8,01% corresponde a lesiones intraepiteliales de alto grado y el 36,13% a lesiones escamosas de bajo grado. En el examen de flujo vaginal por directo se encontraron 14 803 pruebas positivas (16,51%) para vaginitis por hongos, 19 079 (21,31%) para vaginosis bacteriana y 414 (0,46%) para vaginitis por Trichomona; en el Gram se observó que las infecciones vaginales generadas por Gardnerella ocupan la mayor frecuencia con 19 186 resultados positivos (27,23%).Conclusiones: los datos encontrados con relación a las frecuencias de lesiones escamosas intraepiteliales y para las infecciones vaginales guardan relación con lo reportado en la Literatura nacional; sin embargo, para el casos del ASCUS se encuentra variación, probablemente por las características mismas de este tipo de atipias.

Human papillomavirus (HPV) E6/E7 mRNA as a triage test after detection of HPV 16 and HPV 18 DNA

High-risk human papillomavirus (HPV) DNA detection provides high sensitivity but low specificity for moderate-grade cervical intraepithelial neoplasia or worse histological identification. A prospective study evaluated mRNA testing efficacy for predicting this histological diagnosis in case of HPV 16 and/or 18 DNA detection. A total of 165 endocervical samples harboring HPV 16 and/or 18 DNA were tested with NucliSENS-EasyQ® HPV E6/E7-mRNA-assay (Biomerieux, Marcy l´Etoile, France). Women with cytological alterations were referred to colposcopy (n = 111). Moderate-grade cervical intraepithelial neoplasia or worse was diagnosed in 25.8% of women presenting atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions and in 89.8% of women with high-grade squamous intraepithelial lesions. mRNA sensitivity was 81.3% and 84.1%, respectively. Specificity was 52.2%, and 80.0%, respectively. Negative predictive value (NPV) was 88.9% in undetermined or low-grade squamous lesions. Positive predictive value (PPV) was 97.4% in high-grade squamous lesions. mRNA reduced colposcopies by 44.3% in undetermined or low-grade squamous lesions. Direct treatment of mRNA-positive cases reduced 77.5% of colposcopies in high-grade squamous lesions. Women without cytological alterations were followed for 18 months (n = 35), and moderate-grade cervical intraepithelial neoplasia or worse was diagnosed in 34.3%; mRNA sensitivity and specificity were 83.3% and 86.9%, respectively. PPV and NPV were 76.9% and 90.9%, respectively for predicting moderate-grade cervical intraepithelial neoplasia or worse in 18 months. mRNA reduced the number of visits for follow-up in 62.2%. In conclusion, NucliSENS-EasyQ® HPV E6/E7-mRNA-assay (Biomerieux) can serve as a triage test in case of HPV 16 and/or 18 DNA detection.

Human Papillomavirus Type 16 Causes Larger Colposcopic Lesions Than Other HPV Types in Patients With Grade 3 Cervical Intraepithelial Neoplasia

Recent studies have shown that human papillomavirus (HPV) type 16 causes more definite visual abnormalities on cervigram than other HPV types and is thus easier to evaluate colposcopically. We examined factors, including HPV-16, related to colposcopic lesions in patients with grade 3 cervical intraepithelial neoplasia (CIN 3). A retrospective chart review included 108 women with CIN 3 who underwent the loop electrosurgical excision procedure (LEEP). Lesions were assessed according to the number of cervical quadrant(s) involved by colposcopy, dichotomized as 2 or fewer or 3 or more quadrants involved. The Hybrid Capture 2 (HC2) test and HPV DNA chip assay (MyGene Co, Seoul, Korea) were used to detect HPV before punch biopsy or loop electrosurgical excision procedure. The type of HPV was dichotomized as HPV-16 or other (including negative cases). The HC2 viral load cutoff was 300 relative light units. Cytology was dichotomized as (1) low grade, less than, or equal to low-grade squamous lesions; or (2) high-grade, with high-grade squamous lesions or worse. Age and menopausal status were also assessed. The mean (SD) age of the 108 women was 41.9 (10.7) years (range = 22-76 y). Seventy-one (65.7%) had lesions involving 2 quadrants or fewer and 37 (34.3%) had lesions involving 3 quadrants or more. Multiple logistic regression revealed that larger lesions (≥3 quadrants involved) were significantly associated with HPV-16 (p = .032, odds ratio [OR] = 2.552, 95% confidence interval = 1.085-6.000) but not with age, menopausal status, cytologic grade, or HPV HC2 viral load. Our data suggest that colposcopic lesions differ according to HPV type and that HPV-16 is associated with larger lesions, facilitating lesion detection by colposcopy.

Broom versus broom-and-brush: A comparison of Surepath® liquid-based Papanicolaou test (LBPT) collection devices

Broom versus broom-and-brush: A comparison of Surepath^® liquid-based Papanicolaou test (LBPT) collection devices

Value of Cytology in Papillary Condylomatous Lesions of the Cervix

To determine the value of cytology in detecting mature and immature papillary condylomas of the uterine cervix.We evaluated 240 cases of plane cervical intraepithelial neoplasia, grade 1 (CIN 1), and 23 papillary condylomas by Pap smear and biopsy and classified histologic sections according to maturity and keratinization. We reevaluated corresponding cytologic smears and identified criteria of low grade squamous lesion (LSIL) and human papillomavirus (HPV) infection.Thirteen (56.5%) papillary lesions were histologically classified as mature, 6 (26%) as immature and 4 (17.3%) as mixed. Fifteen lesions (65.2%) were nonkeratinized, 2 (8.6%) keratinized and 6 (26%) partially keratinized. Corresponding smears were cytologically diagnosed as LSIL (6, 26%), atypical squamous cells of undetermined significance (ASCUS) (7, 30.4%) and negative (10, 43.4%). Careful cytologic review diagnosed only two of the 13 mature lesions; few cytological criteria of LSIL and HPV infection were observed. Koilocytes were seen in just 1 case. Sample limiting factors occurred in 4 cases: 2 cytologically diagnosed as LSIL, 1 asASCUS and 1 as negative for lesion.Cytology was not effective in the detection of cervical condyloma acuminatum, independent of limitations in sample adequacy and of the degree of maturity or keratinization of the lesions.

P16INK4a expression and progression risk of low-grade intraepithelial neoplasia of the cervix uteri.

The aim of the study was to evaluate the immunohistochemical expression of p16INK4a as a marker of progression risk in low-grade dysplastic lesions of the cervix uteri. p16INK4a immunohistochemistry was performed on 32 CIN1 with proven spontaneous regression of the lesion in the follow-up (group A), 31 (group B) with progression to CIN3 and 33 (group C) that were randomly chosen irrespective of the natural history of the lesion. p16INK4a staining pattern was scored as negative (less than 5% cells in the lower third of dysplastic epithelium stained), as focally positive (< or = 25%) and as diffuse positive (> 25%). A diffuse staining pattern was detected in 43.8% of CIN1 of group A, 74.2% of group B and 56.3% of group C. No p16INK4a staining was detected in 31.3% and 12.9% CIN1 lesions of groups A and B, respectively. Overall, 71.4% and 37.8% of p16INK4a-negative and diffusely positive CIN1 had regressed at follow-up, whereas 28.6% and 62.2% negative and diffusely positive CIN1 were progressed to CIN3, respectively (P < 0.05). All CIN3 lesions analyzed during follow-up of group B were diffusely stained for p16INK4a. Although p16INK4a may be expressed in low-grade squamous lesions that undergo spontaneous regression, in this study, CIN1 cases with diffuse p16INK4a staining had a significantly higher tendency to progress to a high-grade lesion than p16INK4a-negative cases. p16INK4a may have the potential to support the interpretation of low-grade dysplastic lesions of the cervix uteri.

P53, Bcl-2, PCNA expression and apoptotic rates during cervical tumorigenesis

5068 Background: In order to estimate the apoptotic rates during the development of cervical cancer, we investigated apoptosis by morphological criteria and by the TUNEL assay, as well as by the expression of proteins related to this process such as p53, Bcl-2 and PCNA in lesions of all phases of tumor progression in the cervical epithelium. Methods: The expression of p53, Bcl-2 and PCNA proteins were immunohistochemically examined using 31 normal cervical epithelium, 10 low grade squamous lesions (CIN I), 28 high grade squamous lesions (CIN II/III) and 36 invasive squamous cell carcinomas (ISCC). The same samples were used for TUNEL assays and HPV detection by polymerase chain reaction (PCR) and sequence. Results:Human papillomavirus (HPV) presence is necessary but not sufficient for cervical cancer development, suggesting that cellular genes participate in tumor progression. PCNA protein expression was significantly increased as the grade of cervical lesion becomes higher from normal epithelium to ISCC. Surprisingly, p53 levels also increased with lesion degree. Apoptosis as determined by TUNEL assay, and PCNA protein expression show a significant positive correlation with increasing histological abnormality. Statistical analysis showed a positive correlation between p53 and PCNA expression in CIN I (r=0.378, P=0.016). A similar correlation was found between p53 and Bcl-2 expression in CIN II/III (r=0.385, P=0.023). A total of 76 of 105 (71.4%) cervical samples were HPV positive, with HPV 16 being the most common high-risk type detected (72.4%). Conclusions:Our results suggest that p53 protein overexpression during cervical tumorigenesis could be playing a pivotal role in cervical tumor progression as a late event. Although a stronger p53 than Bcl-2 expression in CIN II/III was detected, the up-regulation of Bcl-2 in ISCC suggests that protection against apoptosis is important for maintaining cervical neoplasia. PCNA protein expression increase may be a useful marker for diagnosis of various dysplasia grades and cervical cancer. No significant financial relationships to disclose.

P53, Bcl-2, PCNA expression and apoptotic rates during cervical tumorigenesis

5068 Background: In order to estimate the apoptotic rates during the development of cervical cancer, we investigated apoptosis by morphological criteria and by the TUNEL assay, as well as by the expression of proteins related to this process such as p53, Bcl-2 and PCNA in lesions of all phases of tumor progression in the cervical epithelium. Methods: The expression of p53, Bcl-2 and PCNA proteins were immunohistochemically examined using 31 normal cervical epithelium, 10 low grade squamous lesions (CIN I), 28 high grade squamous lesions (CIN II/III) and 36 invasive squamous cell carcinomas (ISCC). The same samples were used for TUNEL assays and HPV detection by polymerase chain reaction (PCR) and sequence. Results:Human papillomavirus (HPV) presence is necessary but not sufficient for cervical cancer development, suggesting that cellular genes participate in tumor progression. PCNA protein expression was significantly increased as the grade of cervical lesion becomes higher from normal epithelium to ISCC. Surprisingly, p53 levels also increased with lesion degree. Apoptosis as determined by TUNEL assay, and PCNA protein expression show a significant positive correlation with increasing histological abnormality. Statistical analysis showed a positive correlation between p53 and PCNA expression in CIN I (r=0.378, P=0.016). A similar correlation was found between p53 and Bcl-2 expression in CIN II/III (r=0.385, P=0.023). A total of 76 of 105 (71.4%) cervical samples were HPV positive, with HPV 16 being the most common high-risk type detected (72.4%). Conclusions:Our results suggest that p53 protein overexpression during cervical tumorigenesis could be playing a pivotal role in cervical tumor progression as a late event. Although a stronger p53 than Bcl-2 expression in CIN II/III was detected, the up-regulation of Bcl-2 in ISCC suggests that protection against apoptosis is important for maintaining cervical neoplasia. PCNA protein expression increase may be a useful marker for diagnosis of various dysplasia grades and cervical cancer. No significant financial relationships to disclose.

Cervical squamous and glandular intraepithelial neoplasia: identification and current management approaches.

Certain types of human papillomaviruses (HPV) are associated with squamous intraepithelial lesions and cancer and these are termed high-risk. HPV type 16 is detected in approximately half of the high-grade squamous intraepithelial lesions and cancer. Because of the high rate of spontaneous regression of low-grade squamous lesions, follow-up by cytology, colposcopy and possible biopsy appears preferable. Due to the higher rate of progression to malignancy of the high-grade lesions conservative treatment is recommended. One of the most common reasons for persistence relates to the human immunodeficiency virus. Adenocarcinoma in situ is an uncommon disorder and not well identified by cytologic sampling or colposcopic inspection. The diagnosis is made by cone biopsy, the specimen having negative margins for disease. Hysterectomy is the treatment procedure of choice unless fertility is an issue. Excisional methods (particularly electrosurgical loop) can interfere with accurate histological interpretation in some cases of both squamous disease and adenocarcinoma in situ. This paper is available too at: http://www.insp.mx/salud/index.html.

Spotlight on gynecology

OBJECTIVE: Our purpose was to evaluate the cost-effectiveness of the use of a Food and Drug Administration–approved human papillomavirus test in triaging patients with Papanicolaou smears showing atypical squamous cells of undetermined significance or a low-grade squamous intraepithelial lesion for colposcopy compared with an algorithm that used cytologic follow-up.STUDY DESIGN: Four hundred sixty-two women referred to our Colposcopy Clinic with a Papanicolaou smear report of atypical squamous cells of undetermined significance or a low-grade squamous intraepithelial lesion underwent repeat Papanicolaou smear, cervical colposcopy, directed cervical biopsy, and endocervical curettage. In addition, human papillomavirus testing by the Food and Drug Administration–approved HPV Profile (Digene Diagnostics, Silver Spring, Md.) test was done. A comparision of sensitivity, specificity, and cost-effectiveness of an algorithm determining the need for colposcopy on the basis of repeat cytologic testing versus an algorithm that incorporated repeat cytologic testing and human papillomavirus screening was done. The cost-effectiveness of both of these triage algorithms was also compared.RESULTS: As expected, high-risk human papillomavirus deoxyribonucleic acid was detected with greater frequency in relation to increasing severity of cervical intraepithelial neoplasia. In 268 women, the follow-up smear obtained in our clinic was reported as negative. High-risk human papillomavirus types were found in 23.5% of these women. In the human papillomavirus–negative women, 5.9% had grade 2 or 3 cervical intraepithelial neoplasia confirmed on cervical biopsy. In comparison, 20.6% of those with a positive result of the human papillomavirus test had grade 2 or 3 cervical intraepithelial neoplasia on biopsy (p < 0.001). Despite this difference, the sensitivity of a positive result of a high-risk human papillomavirus test in predicting the presence of grade 2 or 3 cervical intraepithelial neoplasia was only 52%. Among the women for whom a follow-up clinic Papanicolaou smear was reported as showing atypical squamous cells of undetermined significance or a low-grade squamous intraepithelial lesion, there was no difference in the frequency of biopsy-proved grade 2 or 3 cervical intraepithelial neoplasia between those women with a positive human papillomavirus test result and those with a negative test result. Colposcopy would have been recommended for 194 women because of a repeat clinic smear revealing atypical squamous cells of undetermined significance, a low-grade squamous intraepithelial lesion, or a high-grade squamous intraepithelial lesion, and in 21.6% of these women grade 2 or 3 cervical intraepithelial neoplasia was shown on biopsy (sensitivity 63%, specificity 62%). Colposcopy would have been recommended for 180 women because high-risk human papillomavirus or a high-grade squamous intraepithelial lesion was detected at the clinic visit, and in 25% of this group grade 2 or 3 cervical intraepithelial neoplasia was evident on biopsy (sensitivity 67%, specificity 66%). Sensitivity and specificity were virtually identical for the two algorithms, but the cost of human papillomavirus testing was nearly double that of triage based on repeat cytologic testing alone ($692 vs $1246 per case).CONCLUSION: The Food and Drug Administration–approved HPV Profile test is not a cost-effective triage for patients referred with Papanicolaou smears reported as showing atypical squamous cells of undetermined significance or low-grade squamous lesions. (Am J Obstet Gynecol 1997;177:930-6.)

Endocervical intraepithelial glandular atypia (dysplasia): a histopathologic, human papillomavirus, and MIB-1 analysis of 25 cases

The purpose of this study was to determine the likelihood thatintraepithelial endocervical glandular atypias that are less severe than adenocarcinoma in situ (AIS) are precursors to AIS and, if so, whether they can be recognized by morphological or other means. We first assessed the frequency of atypias found in association with either AIS or invasive adenocarcinoma (ACA) and then tested these cases and additional randomly encountered cases for the presence of human papillomavirus (HPV) and for their proliferative (G-67) index. Lesions not fulfilling the classic criteria for AIS were subdivided into high-grade (HGGA) and low-grade glandular atypias (LGGA). Atypias and controls were microdissected and tested for HPV by the polymerase chain reaction. Serial sections were labeled for Ki-67 by immunohistochemistry with the MIB-1 antibody. Eight cases (6.8%) containing glandular atypia were found in a search of 117 consecutive cone biopsy or hysterectomy specimens that also had either AIS, ACA, or both. An additional 17 cases were either randomly encountered or were received in consultation. In 3 cases, both HGGA and LGGA were present, yielding a total of 28 lesions for study. Of the 9 HGGA cases that were associated with either AIS, ACA, or CIN II/III, 6 were positive for HPV; M1B-1 reactivity in all 6 was present in greater than 25% of the nudei. Of the 3 HPV negative HGGA cases in this group, the 2 that were tested showed low MM-1 reactivity. All 3 cases of HGGA that were not associated with a diagnostic lesion were HPV negative and had low MM-1 reactivity. Of the 6 LGGAs associated with either AIS, ACA, or CIN II/III, 1 was positive for HPV, MIB-1 was nonreactive in this case and was low in all of the HPV negative cases in this group that were tested. Of 10 LGGAs not associated with a diagnostic lesion, or with a low-grade squamous lesion as the only other abnormality, 2 were positive for HPV. Of these 2, one had an MIB-1 reactivity of greater than 25% and also had intestinal differentiation. MIB-1 reactivity was elevated in 2 of the 8 HPV negative LGGAs from this group. All 10 ciliated atypias (3 HGGA, 7 LGGA) were HPV negative and had low MIB-1 reactivity. One HPVpositive AIS control case was focally ciliated. Six of 7 foci with apoptotic bodies (5 HGGA, 2 LGGA) were HIM positive. The infrequent occurrence of glandular atypias with AIS and ACA and the low rate of HPV DNA positivity when they are found in isolation are evidence that most AIS lesions do not evolve through morphologically identifiable antecedents and that most isolated atypias are not AIS precursors. HGGAs associated with AIS or CIN II/III may be either precursors to or subtle variants of AIS. However, LGGAs similarly encountered are unlikely to be either. Elevated MIB-1 reactivity may be helpful diagnostically in selected cases, but it is not reliable as an independent criterion. The presence of cilia in isolated glandular atypias favors a onneoplastic process, whereas intestinal differentiation and apoptotic bodies each suggest neoplasia.

Polymorphism at Codon 72 of p53 Is Not Associated with Cervical Cancer Risk

P53 allelic polymorphism at codon 72 has been studied as a possible predisposing factor for cervical carcinogenesis with inconsistent results. Storey and colleagues recently published the interesting finding of a 7-fold increased risk for cervical cancer in women homozygous for the arginine allele at codon 72. This stimulated a number of independent investigations, the majority of which found no association of cervical cancer and arginine homozygosity.With the use of a modified Storey method for determining codon 72 allelotypes, DNA was examined from 431 microdissected, formalin-fixed, archival cervical conization specimens ranging from low-grade squamous lesions to invasive cancer. An alternative independent method using restriction fragment length polymorphism analysis was performed on all arginine homozygotes and all indeterminate cases for confirmation and final allelotype assignment.With the use of Storey's method alone, logistic regression suggested an association (odds ratio, 1.42) between arginine homozygosity and invasive disease. However, with the use of the combined method for accurate allelotyping, this trend disappeared (odds ratio, 1.00), the discordance was clearly resolvable as being due to methodologic variables.With the use of two separate methods for codon 72 allelotyping and accounting for a number of the issues raised in previously published reports, there is no increased risk for invasive cervical cancer associated with arginine homozygosity at codon 72 of p53.