Estimation of economic burden throughout course of cervical squamous intraepithelial lesion and cervical cancer in China:A nationwide multicenter cross-sectional study

Objective: Cervical squamous intraepithelial lesion(SIL) and cervical cancer are major threats to females' health and life in China, and we aimed to estimate the economic burden associated with their diagnosis and treatment.Methods: A nationwide multicenter, cross-sectional, hospital-based survey was conducted in 26 qualified hospitals across seven administrative regions of China. We investigated females who had been pathologically diagnosed with SIL and cervical cancer, and included five disease courses(“diagnosis”, “initial treatment”,“chemoradiotherapy”, “follow-up” and “recurrence/progression/metastasis”) to estimate the total costs. The median and interquartile range(IQR) of total costs(including direct medical, direct non-medical, and indirect costs), reimbursement rate by medical insurance, and catastrophic health expenditures in every clinical stage were calculated.Results: A total of 3,471 patients in different clinical stages were analyzed, including low-grade SIL(LSIL)(n=549), high-grade SIL(HSIL)(n=803), cervical cancer stage ⅠA(n=226), ⅠB(n=610), ⅡA(n=487), ⅡB(n=282), Ⅲ(n=452) and Ⅳ(n=62). In urban areas, the estimated total costs of LSIL and HSIL were $1,637.7(IQR:$956.4-$2,669.2) and $2,467.1(IQR:$1,579.1-$3,762.3), while in rural areas the costs were $459.0(IQR:$167.7-$1,330.3) and $1,230.5(IQR:$560.6-$2,104.5), respectively. For patients with cervical cancer stage ⅠA,ⅠB, ⅡA, ⅡB, and Ⅲ-Ⅳ, the total costs were $15,034.9(IQR:$11,083.4-$21,632.4), $19,438.6(IQR:$14,060.0-$26,505.9), $22,968.8(IQR:$16,068.8-$34,615.9), $26,936.0(IQR:$18,176.6-$41,386.0) and $27,332.6(IQR:$17,538.7-$44,897.0), respectively. Medical insurance covered 43%-55% of direct medical costs for cervical cancer patients, while the coverage for SIL patients was 19%-43%. For most cervical cancer patients, the expense was catastrophic, and the extent of catastrophic health expenditure was about twice large for rural patients than that for urban patients in each stage.Conclusions: The economic burden of SIL and cervical cancer in China is substantial, with a significant proportion of the costs being avoidable for patients with LSIL. Even for those with medical insurance, catastrophic health expenditures are also a major concern for patients with cervical cancer, particularly for those living in rural areas.

The Relationship between p53 Expression and Human Papillomavirus in Premalignant and Malignant Uterine Cervical Lesions

Objective: We aimed to retrospectively examine a series of premalignant and malignant cervical tissues to study a high-risk HPV 16 infection that, among cervical tissue lesions, carries the greatest risk of conversion to cancer, and the presence of p53 protein immunoreactivity, a tumor suppressor gene product. Methods: Paraffin blocks were studied via immunohistochemical (IHC) method to explore the presence of HPV 16 in 59 premalignant and malignant cervical lesions as well as immunoreactivity of the p53 oncoprotein, the most common cellular tumor suppressor gene product in human cancers. Results: In our series, mutant p53 positivity rate was 35.3% for low-grade CIL, 40% for high-grade CIL, and 46.8% for invasive carcinoma cases. Immune staining for high-risk HPV 16 type yielded a positive staining rate of 47% in low-grade CIL, 80% in high-grade CIL, and 50% in invasive carcinoma. Conclusion: The results of our study indicate a progressive increase in p53 oncoprotein reactivity from cervical intraepithelial neoplasia to invasive carcinoma. This suggests the clinical importance of p53 immunoreactivity in dysplastic progression and neoplastic transformation. HPV is the most commonly encountered oncogenic type in cervical lesions, especially in high-grade CIL and invasive carcinomas. Results of the previous reports suggest that HPV-positive carcinomas release wild type p53 and HPV-negative ones release mutant type p53 were not confirmed by our results, which indicated a mutant type p53 reactivity in HPV- 16 positive carcinoma cases.

High-resolution anoscopy:Unchartered territory for gastroenterologists?

High-resolution anoscopy(HRA) is a procedure where patients with an increased risk of anal cancer, like men who have sex with men, human immunodeficiency virus infected individuals, transplant patients and women with a history of lower genital tract neoplasia, with abnormal anal cytology results, are submitted to anal and perianal visualization under magnification. This willallow for a better detection of anal high-grade lesions that can be treated, in an effort to prevent anal cancer. Anal cancer screening follows the same principles that cervical cancer screening. During this procedure, an anoscope is inserted and a colposcope is used to examine systematically the squamocolumnar junction, the transformation zone and the perianal skin. Initially the observation is done with no staining and then with the application of acetic acid and Lugol's iodine solution, allowing for better lesion identification and characterization. Any suspicious lesion seen should be carefully evaluated and biopsied. Without HRA only a small percentage of suspicious lesions are identified. High-grade lesions that are detected can be ablated under HRA. This is a challenging exam to perform, with a long learning curve and the number of clinicians performing it is limited, although the growing number of patients that need to been screened. Specific equipment is required, with these patients ideally been followed by a multidisciplinary team, in a reference centre. HRA remains unfamiliar for many gastroenterologists.

Large pelvic mass arising from the cervical stump: A case report

BACKGROUND A large cervical cyst with a cervical high-grade squamous intraepithelial lesion arising from the cervical stump is rare.After supracervical hysterectomy,there is a risk of various lesions occurring in the cervical stump.We review the types and characteristics of cervical stump lesions and compare total hysterectomy with subtotal hysterectomy.Gynecologists should choose the most suitable surgical method based on both the patient’s condition and wishes.If the cervix is retained,patients require a close follow-up.CASE SUMMARY A 57-year-old woman was admitted to the Gynecology Department for a large pelvic mass.Her chief complaint was abdominal distention for two months.She had undergone subtotal supracervical hysterectomy for leiomyoma 14 years prior.Abdominal ultrasonography detected a 9.1 cm×8.5 cm×8.4 cm anechoic mass with silvery fluid in the pelvic cavity and high-risk human papilloma virus 53(HPV53)was positive.The admission diagnosis we first considered was a pelvic mass mimicking carcinoma of the cervical stump.We performed a laparotomy and a rapid frozen biopsy was suggestive of a fibrous cyst wall coated with a high squamous intraepithelial lesion.The pelvic mass was removed,and a bilateral adnexectomy was implemented.Final pathology confirmed that the pelvic mass was a large inflammatory cyst with a cervical high-grade squamous intraepithelial lesion.After successful intervention,the patient was discharged one week after surgery and there was no recurrence of the vaginal stump at 43 mo.CONCLUSION When addressing benign uterine diseases,gynecologists should pay adequate attention to retaining the cervix.If the cervix is retained,patients require a close follow-up.

Invasive stratified mucin-producing carcinoma (ISMC) of the uterinecervix: An analysis of 6 cases with distinctive clinicopathologicalfeatures

Invasive stratified mucin-producing carcinoma(ISMC)is a recently described histologic variant of high-risk human papillomavirus(HPV)-associated endocervical adenocarcinoma,as the putative invasive counterpart of the stratified mucin-producing intraepithelial lesion(SMILE).ISMC can display variable architectural patterns and usually coexists with other more conventional types of HPV-associated carcinomas,which makes diagnosis and differential diagnosis of ISMC is difficult for pathologists.Moreover,the prognosis of ISMC is still controversial.We analyzed 6 ISMCs with detailed pathological and clinical information.Intraepithelial lesion,including 1 high-grade squamous intraepithelial lesion and 1 SMILE,was found.Various architectures were observed(including nest,glandular,solid,trabecular,and single cell).Nuclear peripheral palisading,apoptotic bodies and mitoses,and variable cytoplasmic mucin vacuoles were seen in all of our cases.The predominance of neutrophils infiltration was seen in only 1 tumor.All the tumors infiltrated the cervical stroma in Silva pattern C manner.p63 and/or p40 was characteristically expressed in the peripheral cells in only 2 cases.High-risk HPV infection was observed in 3/3 detected cases.All the patients were alive during the follow-up time.Recognition of this infrequent tumor may help pathologists and oncologists for an accurate diagnosis and a better understanding of the clinicopathological behavior.

Somatic CDKN2A copy number variations are associated with the prognosis of esophageal squamous cell dysplasia

Background:Somatic copy number variations(SCNVs)in the CDKN2A gene are among the most frequent events in the dysplasia-carcinoma sequence of esophageal squamous cell carcinoma.However,whether CDKN2A SCNVs are useful biomarkers for the risk stratification and management of patients with esophageal squamous cell dysplasia(ESCdys)is unknown.This study aimed to investigate the characteristics and prognostic value of CDKN2A SCNVs in patients with mild or moderate(m/M)ESCdys.Methods:This study conducted a prospective multicenter study of 205 patients with a baseline diagnosis of m/M ESCdys in five high-risk regions of China(Ci County,Hebei Province;Yanting,Sichuan Province;Linzhou,Henan Province;Yangzhong,Jiangsu Province;and Feicheng,Shandong Province)from 2005 to 2019.Genomic DNA was extracted from paraffin biopsy samples and paired peripheral white blood cells from patients,and a quantitative polymerase chain reaction assay,P16-Light,was used to detect CDKN2A copy number.The cumulative regression and progression rates of ESCdys were evaluated using competing risk models.Results:A total of 205 patients with baseline m/M ESCdys were enrolled.The proportion of ESCdys regression was significantly lower in the CDKN2A deletion cohort than in the diploid and amplification cohorts(18.8%[13/69]vs.35.0%[28/80]vs.51.8%[29/56],P<0.001).In the univariable competing risk analysis,the cumulative regression rate was statistically significantly lower(P=0.008),while the cumulative progression rate was higher(P=0.017)in ESCdys patients with CDKN2A deletion than in those without CDKN2A deletion.CDKN2A deletion was also an independent predictor of prognosis in ESCdys(P=0.004)in the multivariable analysis.Conclusion:The results indicated that CDKN2A SCNVs are associated with the prognosis of ESCdys and may serve as potential biomarkers for risk stratification.

Diagnostic Accuracy of Colposcopically Directed Biopsy and Loop Electrosurgical Excision Procedure for Cervical Lesions

Objective:The aim of this study is to evaluate the diagnostic accuracy of colposcopically directed biopsy(CDB)and loop electrosurgical excision procedure(LEEP)for cervical lesions and assess their ability to detect glandular involvement.Methods:This retrospective study reviewed 4689 cervical lesions that were tested by CDB and LEEP at a tertiary hospital.The sensitivity,specificity,and predictive value of CDB and LEEP and the ratio of glandular involvement detected by these two methods were analyzed.Results:CDB and LEEP had sensitivities of 95.4%and 80.0%,respectively,for diagnosing high-grade intraepithelial or more severe lesions(HSIL+)(P=0.000)and 31.8%and 87.9%,respectively,for diagnosing adenocarcinoma in situ or more severe lesions(AIS+)(P=0.001).CDB and LEEP had sensitivities of 18.1%and 90.2%,respectively,for diagnosing invasive squamous cell carcinoma(P=0.000)and 5.9%and 98.0%,respectively,for diagnosing invasive adenocarcinoma(P=0.000).The negative predictive values of CDB and LEEP for diagnosing HSIL+were 88.6%and 64.4%,respectively(P=0.000).The ratios of glandular involvement were 0.2%(CDB)and 2.4%(LEEP)in low-grade intraepithelial lesions(LSILs)and 8.9%(CDB)and 59.0%(LEEP)(P=0.000)in HSIL+.Conclusions:LEEP is superior to CDB for diagnosing AIS and detecting early invasive cancer.It should be offered as an additional investigation to all patients with AIS,HSIL,or LSIL with glandular involvement on CDB.

Triage for management of cervical high-grade squamous intraepithelial lesion patients with positive margin by conization： a retrospective analysis

The objective of this study is to guide a triage for the management of cervical high-grade squamous intraepithelial lesion （HSIL） patients with positive margin by conization. Clinico-pathological data of HSIL patients with positive margin by conization were retrospectively collected from January 2009 to December 2014. All patients underwent secondary conization or hysterectomy within 6 months. The rate of residual lesion was calculated, and the factors associated with residual lesion were analyzed by univariate and multivariate analyses. Among a total of 119 patients, 56 （47.06%） patients presented residual HSIL in their subsequent surgical specimens, including 4 cases of invasive cervical carcinoma （3 stage IA1 and 1 stage IA2 patients）. Univariate analysis showed that patient age 〉 35 years （P = 0.005）, menopausal period 〉 5 years （P = 0.0035）, and multiple- quadrant involvement （P=0.001） were significantly correlated with residual disease; however, multivariate analysis revealed that multiple-quadrant involvement （P=0.001; OR, 3.701; 95%CI, 1.496-9.154） was an independent risk factor for residua! disease. Nearly half of HSIL patients with positive margin by conization were disease-free in subsequent surgical specimens, and those with multiple positive margins may consider re- conization or re-assessment.

Prognostic value of human papillomavirus 16/18 genotyping in low-grade cervical lesions preceded by mildly abnormal cytology

Histological low-grade squamous intraepithelial lesion/cervical intraepithelial neoplasia grade 1 （LSIL/CIN1） preceded by normal or mildly abnormal cytology is recommended for conservative follow-up, with no separated management. In this study, we assessed the triage value of human papillomavirus （HPV） 16/18 genotyping in 273 patients with LSIL/CINI. HPV16/18 genotyping was performed at baseline and follow-up was at 6-monthly intervals for up to 2 years. At each follow-up, women positive for cytology or high-risk HPV （hrHPV） were referred for colposcopy. Enrollment cytology, HPV16/18 genotyping, and questionnaire-obtained factors were linked to the 2-year cumulative progression rate. Univariate and multivariate analyses were performed taking into account time-to-event with Cox proportional hazard regression. The results showed that 190 cases （69.6%） regressed, 37 （13.6%） persisted, and 46 （16.8%） progressed. HPV16/18 positivity （hazard ratio （HR）, 2.708; 95% confidence interval （CI）, 1.432-5.121; P=-0.002） is significantly associated with higher 2-year cumulative progression rate. Sub-analysis by enrollment cytology and age restricted the positive association among patients preceded by mildly abnormal cytology and aged 30 years or older. Immediate treatment is a rational recommendation for the high-risk subgroup, when good compliance is not assured.

Clinical Value of Human Papillomavirus E6/E7 mRNA Testing in Patients with Atypical Squamous Cells of Undetermined Significance and Low-Grade Squamous Intraepithelial Lesion

Objective: To explore the clinical significance of the quantitative detection of human papillomavirus(HPV) E6/E7 mRN A in triage of patients with atypical squamous cells of undetermined significance(ASC-US) and low-grade squamous intraepithelial lesion(LSIL).Methods: A cross-sectional screening study was conducted among women who underwent outpatient gynecological screening at the Obstetrics and Gynecology Hospital of Fudan University from September 2015 to July 2016. A total of 500 patients from our hospital with ASC-US or LSIL based on cytology testing were subjected to HPV DNA and HPV E6/E7 mRNA quantitative analysis.Results: The specificity of the HPV E6/E7 mRNA test for detecting ≥high-grade squamous intraepithelial lesion(HSIL+) was statistically higher than that of the HPV DNA test(61.3% vs. 40.0%, P< 0.05), whereas there was no significant difference in the sensitivity of HPV E6/E7 mRNA test and HPV DNA test(90.0% vs. 95.0%, P > 0.05). The positive rates of HPV in the participants tested by HPV E6/E7 mRNA and HPV DNA were, respectively, 42.8%(214/500) and 62.8%(314/500), with statistical significance(P < 0.05).Conclusions: The HPV E6/E7 mRNA test was slightly less sensitivity than that of the HPV DNA test for diagnosing HSIL+ in patients with ASC-US and LSIL, but the difference was not significant, although the specificity of the former was significantly higher. HPV E6/E7 mRNA detection can effectively reduce overdiagnosis and overtreatment of patients with ASC-US and LSIL and has important clinical value in triage of patients with ASC-US and LSIL.

Selective applications of excisional surgical treatments of cervical precancers

Cervical precancers encompass high-grade squamous intraepithelial lesion and adenocarcinoma in situ.Treatment of precancerous lesions can reduce cervical cancer mortality and prevent the development of invasive cervical cancer.The choice of treatment regimen needs to follow the principle of individualization and should be based on a combination of factors,including the patient's age,fertility requirements,pregnancy status,pathological type,type of colposcopic transformation zone,patient's follow-up conditions,and the experience of the treating provider.This article presents an opinion regarding the appropriate indications for excisional surgery and total hysterectomy in the management of precancerous lesions of the cervix,with the aim of establishing standardized therapeutic approaches for the treatment of precancerous lesions of the cervix.

Human papillomavirus(HPV) E6/E7 mRNA detection in cervical exfoliated cells:a potential triage for HPV-positive women

Cytology triage has been generally recommended for human papillomavirus （HPV）-positive women, but is highly dependent on well-trained cytologists. The present study was designed to explore whether HPV E6/E7 mRNA detection in cervical exfoliated cells can be a potential triage for HPV-positive women from a clinic-based population. Both the primary HPV testing and Papanicolaou （Pap） test were performed on all eligible HPV-positive women. HPV E6/E7 mRNA was detected by QuantiVirus HPV E6/E7 mRNA assay in cervical exfoliated cells. All HPV-positive women underwent colposcopy and further biopsy if indicated. The data were assessed by Pearson＇s Chi-squared test and the receiver operating characteristic curve. A total of 404 eligible HPV-positive women were enrolled. Positive rate of E6/E7 mRNA in high-grade squamous intraepithelial lesion （HSIL） cases was higher than that in low-grade squamous intraepithelial lesion （LSIL） or normal cases. There was no statistical difference found between mRNA and cytological testing with sensitivity （89.52% vs. 86.67%, P=0.671）, specificity （48.96% vs. 48.96%, P=1.000）, positive predictive value （39.00% vs. 38.24%, P=1.000）, and negative predictive value （92.76% vs. 90.97%, P=-0.678） for detecting ≥HSIL. HPV E6/E7 mRNA detection in cervical exfoliated cells shows the same performance as Pap triage for HSIL identification for HPV-positive women. Detection of HPV E6/E7 mRNA may be used as a new triage option for HPV-positive women.

The Importance of Endocervical Curettage in an Old Post-Loop Electrosurgical Excision Procedure Woman with Abnormal Cervical Cytology and a Normal Punch Biopsy Histology:A Case Report and Literature Review

Endocervical curettage(ECC)is an optional practice during colposcopy,and the indication for endocervical curettage(ECC)is controversial between Europe and the USA.Here,we explored the value of ECC in a specific situation.An elderly post-loop electrosurgical excision procedure woman,who had undergone a colposcopy 4 months before,went for her follow-up and abnormal cytology was found,and both the ECC and punch biopsy showed negative results.Then,a second ECC was performed,which led to the diagnosis of a high-grade squamous intraepithelial lesion.This case report shows that ECC is useful for diagnosing elderly women with Type 3 squamocolumnar junction.