Cervical cancer is a complex disease caused by both genetic susceptibility and environmental factors. Inherited genomic variance, high-risk human papilloma virus (HPV) infection/integration, genome methylation and somatic mutation could all constitute one machine learning model, laying the ground for molecular classification and the precision medicine of cervical cancer. Therefore, for cervical screening, next generation sequencing (NGS)-based HPV DNA and other molecular tests as well as dynamic machine learning models would accurately predict patients with potential to develop the cancer, thereby reducing the burden of repeated screening. Meantime, genome-editing tools targeting HPV would emerge as the next generation gene therapy for HPV-related cervical lesions. In this article, we review the substantial progress on molecular mechanism of cervical cancer development and suggest the future for precise prevention and early treatment of cervical cancer.
Early Detection of Cancer ; Female ; Humans ; Mass Screening ; Papillomaviridae ; Uterine Cervical Neoplasms ; diagnosis ; prevention & control ; therapy ; virology

Cervical cancer is the most common malignancy of the female genital tract. Its incidence is still increasing with lower average onset age. Mass screening should be above prevention and treatment, and three screening programs, including the optimal program, the general program, and the basic program, are currently adopted in China. Cervical intraepithelial neoplasia (CIN) , a precancerous lesion, can be confirmed by the combined use of cytology, colposcopy, and histology and then managed with standardized approach. Human papillomavirus (HPV) infection is an essential factor during the development of cervical cancer, and persistent infection of high-risk HPVs may lead to CIN and subsequently develop to cervical cancer. High-risk HPV detection can be used for screening, differentiation of the atypical squamous cells of undetermined significance/ low-grade squamous intraepithelial lesion (ASCUS/LSIL) triage, and follow-up after treatment. The modern strategy of HPV infection is "to treat the disease, CIN, means to treat the virus, HPV". The licensing of HPV vaccine is an important event in cancer prevention, and this vaccine can be used for the primary prevention. However, early diagnosis and early treatment are still the most basic strategies for cervical cancer prevention and treatment.
Cervical Intraepithelial Neoplasia ; diagnosis ; therapy ; virology ; Early Diagnosis ; Female ; Humans ; Papillomavirus Infections ; diagnosis ; prevention & control ; therapy ; Papillomavirus Vaccines ; Uterine Cervical Neoplasms ; diagnosis ; prevention & control ; virology

OBJECTIVETo observe the correlation between human papillomavirus (HPV) infection and cervical lesion among women living in community of Beijing.

METHODSA total of 795 women at age 20-54, living in Zhanlanlu District of Beijing were screened for cervical lesion. Samples of cervical cytology (LCT) and HPV test (hc2) were collected. Colposcopy and biopsy were conducted in women with positive LCT.

RESULTSIn those 795 women, the infection rate of HPV was 14.1% (112/795). In 40 women who were LCT positive 1 early invasive cervical cancer, 4 cervical intra-epithelial neoplasia (CIN3), 3 CIN2 and 7 CIN1 were noticed. In 750 women with negative LCT, 5 CIN1 and 1 low-grade CGIN were diagnosed. In those women who were Cyto(+) and HPV(+), 15 cases (55.6%, 15/27) were diagnosed with > or = CIN1 (including 7 CIN1, 3 CIN2, 4 CIN3 and 1 early invasive cancer).

CONCLUSIONThe risk of cervical lesion significantly increased in women showing positive in cytology and HPV test.

Adult ; Biopsy ; Cervical Intraepithelial Neoplasia ; diagnosis ; epidemiology ; virology ; Cervix Uteri ; virology ; China ; epidemiology ; Colposcopy ; Female ; Humans ; Middle Aged ; Papillomavirus Infections ; epidemiology ; Risk Factors ; Uterine Cervical Diseases ; epidemiology ; Uterine Cervical Neoplasms ; diagnosis ; epidemiology ; virology ; Vaginal Smears ; Young Adult

PURPOSETo investigate the clinical significance and management of ASCUS/LSIL.

METHODS254 patients who were examined with cervical cytology in the Cancer Institute and Hospital Chinese Academy of Medical Sciences were ASCUS/LSIL, of whom 136 cases underwent colposcopy, Data were analyzed retrospectively according to the golden criterion of pathology outcome.

RESULTS140 cases were ASCUS, and 114 cases were LSIL. Cervical intra-epithelial neoplasia (CIN) were diagnosed in 51.5% of patients with ASCUS, compared with 59.6% of patients with LSIL (P>0.05). High-grade cervical intraepithelial neoplasia were diagnosed in 22.9% of patients with ASCUS, compared with 30.7% of patients with LSIL (P >0.05). In the 136 patients examined with colposcopy, inflammation was found in 47 cases, low-grade intraepithelial lesion in 53 cases, High-grade intraepithelial lesion in 36 cases. The pathological results show inflammation in 55 cases, low-grade intraepithelial lesion in 41 cases, High-grade intraepithelial lesion in 40 cases (Kappa=0.314, U=0.064, P less than 0.05). CIN were diagnosed in 79% (67/84) of HPV-positive patients identified by pathology, compared with 43.5% (74/170) of HPV-negative patients (chi2=29.88 P less than 0.05). 83.5% of 254 patients were between 35 to 55 years old, and that was consistent with HPV-positive women age peak.

CONCLUSIONPatients with ASCUS should be paid the same attention with LSIL patients and colposcopy examination should be done immediately to avoid missed diagnosis and missed follow-up examination, especially for HPV positive patients between 35 to 55 years old.

Adult ; Cervical Intraepithelial Neoplasia ; diagnosis ; therapy ; virology ; Colposcopy ; Cytodiagnosis ; instrumentation ; methods ; Female ; Humans ; Middle Aged ; Neoplasms, Squamous Cell ; diagnosis ; therapy ; virology ; Papillomaviridae ; isolation & purification ; Papillomavirus Infections ; diagnosis ; therapy ; virology ; Retrospective Studies ; Uterine Cervical Neoplasms ; diagnosis ; therapy ; virology ; Young Adult

OBJECTIVETo evaluate the diagnostic performance of different specimens for detecting CIN2(+), and to find the solution of the problem that why the performance of self-collected specimen is worse than cervical specimen collected by physician.

METHODSThe cervix, lower 1/3 vagina, upper 1/3 vagina and self-collected specimens from each of the 806 women who took part in this multi-center screening program from May 2006 to April 2007 were tested by hybrid capture 2 (HC2) technique. The diagnostic performance of HC2 on the four specimens for detecting CIN2(+) lesions was calculated. Linear array was performed on the four specimens from 489 out of the 806 women and the diagnostic performance of linear array on the four specimens for detecting CIN2(+) lesions was also calculated. Z test was used to compare the area under ROC and McNemar or χ(2) test was used to compare the sensitivity and specificity of different specimens.

RESULTSThe area under ROC of the cervix, 1/3 upper vagina, 1/3 lower vagina and self-collected samples testing by HC2 for detecting CIN2(+) lesions were 0.902, 0.793, 0.769 and 0.773, respectively (P < 0.001). Using 1 RUL/CO as the cut-point of HC2, the sensitivity of the cervix, upper vagina, lower vagina and self-collected samples were 98.0%, 91.8%, 83.7% and 81.6%. Compared with the cervical specimen, the sensitivity of self-collected specimen for detecting CIN2(+) lesions was significantly lower (P = 0.008). Lowering the cutoff value for HC2 test could improve the sensitivity of self-collected specimen, but it significantly compromised the specificity. The sensitivity of self-collected specimen tested by linear array for detecting CIN2(+) lesions was 95.7% and it was not significantly different compared with the sensitivity of cervical specimen (97.9%) tested by HC2.

CONCLUSIONSThe performance of self-collected specimen tested by HC2 for detecting CIN2(+) lesions is lower than that of physician-collected cervical specimen, and lowering the cutoff value can't improve its diagnostic performance. Using linear array as the HPV DNA test can significantly improve the screening diagnostic performance of self-collected specimens.

Adolescent ; Cervical Intraepithelial Neoplasia ; diagnosis ; virology ; Cervix Uteri ; virology ; DNA, Viral ; analysis ; Female ; Human Papillomavirus DNA Tests ; Humans ; Mass Screening ; Papillomaviridae ; isolation & purification ; Papillomavirus Infections ; diagnosis ; virology ; Self-Examination ; Specimen Handling ; methods ; Uterine Cervical Neoplasms ; diagnosis ; virology ; Vagina ; virology

OBJECTIVETo study the diagnostic value of p16(INK4a) in squamous intraepithelial lesion in gynecologic cytology and its relationship with types of human papillomavirus (HPV).

METHODS88 liquid-based gynecologic cytology cases with histologic correlation, including 20 cases of cervicitis, 18 cases of low-grade squamous intraepithelial lesion (LSIL), 34 cases of high-grade squamous intraepithelial lesion (HSIL) and 16 cases of squamous cell carcinoma (SCC), were enrolled into the study. Immunocytochemistry for p16(INK4a) protein and polymerase chain reaction-based HPV DNA testing (for HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66 and 68, as well as HPV types 6, 11, 42, 43 and 44) were performed.

RESULTSThe rate of expression of p16(INK4a) protein was 0, 27.8%, 100% and 100% in the cervicitis group, LSIL group, HSIL group and SCC group, respectively. The expression was significantly higher in the latter 3 groups than that in the cervicitis group (P < 0.01). Besides, the expression was significantly higher in cases associated with high-risk HPV genotypes (96.4%) than in cases associated with low-risk HPV genotypes (7.7%).

CONCLUSIONp16(INK4a) is a valuable biomarker for detection of HPV-related dysplastic squamous cells, with high sensitivity and specificity.

Carcinoma, Squamous Cell ; diagnosis ; metabolism ; virology ; Cervical Intraepithelial Neoplasia ; diagnosis ; metabolism ; virology ; Cyclin-Dependent Kinase Inhibitor p16 ; metabolism ; Diagnosis, Differential ; Female ; Genotype ; Humans ; Immunohistochemistry ; Papillomaviridae ; genetics ; isolation & purification ; Papillomavirus Infections ; Polymerase Chain Reaction ; Sensitivity and Specificity ; Uterine Cervical Dysplasia ; diagnosis ; metabolism ; virology ; Uterine Cervical Neoplasms ; diagnosis ; metabolism ; virology ; Uterine Cervicitis ; diagnosis ; metabolism ; virology

Human papillomavirus (HPV) infection is an essential cause of cervical cancer. HPV testing therefore may maximize the clinical benefits of cervical screening and abnormal cervical cytology management. A negative HPV test in combination with a normal Pap test result in women age 30 years or older allows the safe extension of the cervical screening interval to 3 years. However, because HPV infection is common in young women and is usually transient, HPV testing is not recommended as part of primary cervical screening for women younger than 30 years. HPV testing is recommended for women of any age as a triage test with atypical squamous cells of undetermined significance (ASC-US) results and as an option for follow-up of women with HPV-positive ASC-US, atypical squamous cells "cannot rule out high-grade", low-grade squamous intraepithelial lesions, or atypical granular cells not found to have CIN 2/3. HPV testing is also recommended as an alternative to colposcopy and/or cytology for follow-up of treated cases. Proper use of HPV testing improves the management of women with cytologic abnormalities.
Age Factors ; Cervical Intraepithelial Neoplasia ; diagnosis ; pathology ; virology ; Early Detection of Cancer ; Female ; Humans ; Papillomaviridae ; isolation & purification ; Papillomavirus Infections ; diagnosis ; Precancerous Conditions ; diagnosis ; pathology ; virology ; Uterine Cervical Neoplasms ; diagnosis ; pathology ; virology ; Vaginal Smears ; Virology ; methods

OBJECTIVETo detect the high-risk human papillomavirus (HPV) infectious condition in women with abnormal cytology and evaluate its values in the screening of high grade squamous intraepithelial lesion.

METHODSWe used hybrid capture 2 (hc2) method to examine 949 patients with abnormal cervical cytology results [ > or =atypical squamous cells of undetermined significance (ASC-US) according to the 2001 The Bethesda System diagnosis criteria]. All subjects also received colposcopy for tissue studies.

RESULTSAmong 949 patients with abnormal cytology, the diagnoses of atypical squamous cells (ASC), low grade squamous intraepithelial lesion (LSIL), and high grade squamous intraepithelial lesion (HSIL) were made in 432, 310, and 207 patients, respectively. The high-risk HPV positive rate in ASC, LSIL, and HSIL were 40.3%, 44.8%, and 89.4%, respectively. The numbers of patients with pathologically confirmed results of negative intraepithelial lesion or malignancy (NILM), cervical intraepithelial neoplasia 1, 2, 3 (CIN 1, 2, 3), and squamous cell carcinoma (SCC) were 335, 388, 118, 101, and 7, and the high-risk HPV positive rate was 17.3%, 66.2%, 92.4%, 97.0%, and 100%, respectively. Among patients with atypical squamous cells of undetermined significance (ASC-US), rate of HSIL in high-risk HPV positive group and negative group were 10.2% and 0.8%, respectively (P < 0.01). In screening HSIL, the sensitivities of cytology [ > or = ASC cannot exclude HSIL (ASC-H)] and cytology ( > or = ASC-H) plus high-risk HPV testing were 0.925 and 0.991, and the specificities were 0.510 and 0.748, respectively (P < 0.01). Sensitivitives of cytology ( > or = LSIL) and cytology (> or = LSIL) plus high risk HPV in detecting HSIL were 0.898 and 0.982, respectively, while the specificitives were 0. 567 and 0.779, respectively (P < 0.01).

CONCLUSIONSThe positive rate of high-risk HPV increases with the gravity of cervical lesions. In patients with abnormal cervical cytology, high-risk HPV testing can improve the sensitivity and specificity in the screening of HSIL.

Carcinoma, Squamous Cell ; diagnosis ; pathology ; virology ; Cervical Intraepithelial Neoplasia ; diagnosis ; pathology ; virology ; Female ; Humans ; Papillomaviridae ; genetics ; isolation & purification ; Papillomavirus Infections ; diagnosis ; pathology ; virology ; Risk Assessment ; Uterine Cervical Neoplasms ; diagnosis ; pathology ; virology

OBJECTIVETo investigate the clinic value of combination of high-risk human papillomavirus test and cervical cytology test in diagnosis of cervical lesions.

METHODSPatients underwent physical examination at our department were checked by high-risk human papillomavirus test, cervical cytology test and colposcope from October 2004 to December 2006. Abnormal patients with cervical abnormalities were asked for pathological test.The diagnostic value of cervical lesions among these different methods were compared.

RESULTSBased on the criteria of histopathology, the sensitivity, specificity, positive-predictive value and negative-predictive value of high-risk human papillomavirus test for detecting all cases of CIN II and CIN III were 94.83%, 31.06%, 55.22% and 87.02% respectively, and those of the cervical cytology were 92.10%, 31.06%, 54.50% and 81.43% respectively.Those values changed to 99.65%, 18.55%, 61.46% and 97.62% respectively if two methods were combined.

CONCLUSIONSHuman papillomavirus test and cervical cytology test combined with pathological test can improve the detective rate of cervical lesions and facilitate the treatment.

Adolescent ; Adult ; Aged ; Cervical Intraepithelial Neoplasia ; diagnosis ; virology ; Cytodiagnosis ; Female ; Humans ; Middle Aged ; Papillomaviridae ; isolation & purification ; Papillomavirus Infections ; diagnosis ; Pregnancy ; Reagent Kits, Diagnostic ; Uterine Cervical Diseases ; diagnosis ; Uterine Cervical Neoplasms ; diagnosis ; Vaginal Smears ; Young Adult

OBJECTIVETo evaluate the value of p16INK4a immuncytochemical examination in cytological screening of cervical carcinoma and precancerous lesions.

METHODSp16JNK4a immuncytochemical detection was performed on 220 specimens remaining from liquid-based cytology, followed up by biopsy histology , and compared with the results of high-risk human papillomavirus ( HR - HPV ) DNA tests . Results In patients with cytological diagnosis of squamous cell carcinoma( SCC) , high-grade squamous intraepithelial lesion (HSIL) , low-grade squamous intraepithelial lesion (LSIL) , atypical squamous cells-cannot exclude HSIL (ASC-H) , and atypical squamous cells of undetermined significance (ASC-US) , the positive rates of p16INK4a were 100.0% (7/7), 92. 2% (107/116) , 24. 3% (17/70) , 100. 0% (14/14) and 36.4% (4/ 11) , respectively. In 111 of the 150 p6INK4a positive cases, we found 97 (87.4% ) cases which had biopsy diagnosises of > or =CIN2, but none in 18 of 70 p16INK4a negative cases was. The difference in the positive rates for p16INK4a between cervical intraepithelial neoplasia (CIN) 1 and > or =CIN2 lesions had statistical significance (P < 0. 01) , whereas for HR-HPV DNA test it was not.

CONCLUSIONp16LNK4a is over-expressed in a HSIL, and it may be useful in cytological screening of high risk patients.

Carcinoma, Squamous Cell ; diagnosis ; metabolism ; virology ; Cervical Intraepithelial Neoplasia ; diagnosis ; metabolism ; virology ; Cyclin-Dependent Kinase Inhibitor p16 ; analysis ; Cytodiagnosis ; DNA, Viral ; analysis ; Female ; Humans ; Immunohistochemistry ; Papillomaviridae ; genetics ; isolation & purification ; Papillomavirus Infections ; diagnosis ; metabolism ; virology ; Predictive Value of Tests ; Uterine Cervical Dysplasia ; diagnosis ; metabolism ; virology ; Uterine Cervical Neoplasms ; diagnosis ; metabolism ; virology