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Cervical Cancer

Cervical cancer is a common type of malignancy accounting for about 6% of all cancers found in women. It is a disease in which cancerous cells develop in the uterine cervix (this is the connecting passage between the uterus and vagina). The human papillomaviruses (HPV) are the principal cause of most cervical cancers. The peak incidence of cervical cancer occurs between the ages of 40 to 55. It is rare before the age of 35, however the incidence of cervical cancer in younger women rose dramatically during the two decades after 1960. Regular Pap smear tests may detect abnormal changes in the cervical tissues, before cancer develops. Symptoms of cervical cancer may include vaginal bleeding after intercourse or bleeding between periods. However, in the early stages of the disease there are often no obvious signs or symptoms, so regular smear tests are important.

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Information for Patients and the Public
Information for Health Professionals / Researchers
Latest Research Publications
Human Papillomavirus (HPV), Vaccination, and Cervical Cancer
Cervical Cancer Screening (including the PAP smear test)
Gynacological Cancers

Information Patients and the Public (22 links)

Information for Health Professionals / Researchers (12 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

van Bogaert LJ
Involved LEEP excision margins as predictor of residual/recurrent disease in HIV-positive and HIV-negative women in a low-resource setting.
Anal Quant Cytopathol Histpathol. 2015; 37(2):105-8 [PubMed] Related Publications
OBJECTIVE: To describe the accuracy of the diagnosis of involved excision margins after loop electrosurgical excision procedure (LEEP) in a low-resource setting.
STUDY DESIGN: Cross-sectional study of 176 LEEPs indicated for a cytological report of high-grade squamous intraepithelial lesion (HGSIL). A total of 72 HIV-positive and 104 HIV-negative women with cervical intraepithelial neoplasia (CIN) ≥ 2 on their LEEP histology report with involved excision margins were enrolled in the study. All patients underwent either a repeat LEEP or a hysterectomy. The specimens were evaluated for residual/recurrent CIN ≥ 2 or less.
RESULTS: Persistent/recurrent CIN ≥ 2 was diagnosed in 139 (79.4%) instances and microinvasive squamous cell carcinoma in 6 (3.4%). Thirty (17.2%) showed CIN1. The persistence/recurrence rate was 72.2% and 88.5% in HIV-positive and HIV-negative women, respectively (χ2 = 7.5, p = 0.006).
CONCLUSION: In > 80% the diagnosis of involved excision margins was confirmed, a positive predictive value of 82.4%. In the absence of more accurate follow-up methods such as HPV testing or co-testing with cytology, a correct diagnosis of margin status, especially when involved, is an important guide to further management and follow-up.

Botha MH, van der Merwe FH, Snyman LC, Dreyer G
The vaccine and cervical cancer screen (VACCS) project: acceptance of human papillomavirus vaccination in a school-based programme in two provinces of South Africa.
S Afr Med J. 2015; 105(1):40-3 [PubMed] Related Publications
BACKGROUND: The incidence of cervical cancer in South Africa (SA) remains high, and the current screening programme has had limited success. New approaches to prevention and screening tactics are needed.
OBJECTIVES: To investigate acceptance of school-based human papillomavirus (HPV) vaccination, as well as the information provided, methods of obtaining consent and assent, and completion rates achieved.
METHODS: Information on cervical cancer and HPV vaccination was provided to 19 primary schools in Western Cape and Gauteng provinces participating in the study. Girls with parental consent and child assent were vaccinated during school hours at their schools.
RESULTS: A total of 3 465 girls were invited to receive HPV vaccine, of whom 2 046 provided written parental consent as well as child assent. At least one dose of vaccine was delivered to 2 030 girls (99.2% of the consented cohort), while a total of 1 782 girls received all three doses. Sufficient vaccination was achieved in 91.6% of the vaccinated cohort. Of all invited girls, 56.9% in Gauteng and 50.7% in the Western Cape were sufficiently vaccinated.
CONCLUSION: This implementation project demonstrated that HPV vaccination is practical and safe in SA schools. Political and community acceptance was good, and positive attitudes towards vaccination were encountered. During the study, which mimicked a governmental vaccine roll-out programme, high completion rates were achieved in spite of several challenges encountered.

Silva-Meléndez PE, Escobar PF, Héctor Silva, et al.
Small cell carcinoma of the uterine cervix: a case report and literature review.
Bol Asoc Med P R. 2015 Jan-Mar; 107(1):55-7 [PubMed] Related Publications
Small cell carcinoma of the uterine cervix is a rare and aggressive extra-pulmonary variant of small cell tumors. This carcinoma of the cervix comprises less than 5% of all cervical carcinomas and is know to be highly undifferentiated. It is associated with a poor prognosis and characterized by premature distant nodal involvement. The survival rate at all stages ranges from 17% to 67%. We describe the case of a 41 year old female patient with a rare, and aggressive, clinical stage IB1 small cell neuroendocrine carcinoma of the cervix. The goal of this case report is to describe this rare pathology and contribute information to the scant available data.

Decker KM, McLachlin CM, Lotocki R,
Performance measures related to colposcopy for canadian cervical cancer screening programs: identifying areas for improvement.
J Obstet Gynaecol Can. 2015; 37(3):245-51 [PubMed] Related Publications
OBJECTIVE: To describe performance measures related to colposcopic examinations in Canadian cervical cancer screening programs; specifically, time to colposcopy, histological investigation rate, and agreement between cytology and histology.
METHODS: As part of a national report on the performance of cervical cancer screening, aggregate provincial cervical cancer screening data provided by provinces to the Pan-Canadian Cervical Screening Network were used to evaluate colposcopy program performance measures for women 20 to 69 years of age who had a Pap test in 2009 and 2010.
RESULTS: A total of 37 523 women had a high-grade or more severe Pap test result. The proportion of women who had a colposcopy ≤ 90 days after their Pap test ranged from 30.9% to 51.5%. Fewer women 60 to 69 years of age had a colposcopy than women in younger age groups. The proportion of women who had a high-grade or more severe Pap test result and colposcopy who had a biopsy within 12 months ranged from 82.1% to 96.5%. The proportion of biopsy results that agreed with the Pap test result ranged from 59.5% to 82.1%.
CONCLUSION: The time from having a high-grade Pap test result to undergoing colposcopy must be reduced to lower the risk of adverse outcomes and the stress associated with delayed follow-up. The agreement between screening cytology and histology meets the national target of ≥ 65%. Although six of 13 provinces and territories provided data for colposcopy-related performance measures, more information is needed to assess colposcopy services accurately at the national level.

Smith GL, Jiang J, Giordano SH, et al.
Trends in the quality of treatment for patients with intact cervical cancer in the United States, 1999 through 2011.
Int J Radiat Oncol Biol Phys. 2015; 92(2):260-7 [PubMed] Related Publications
PURPOSE: High-quality treatment for intact cervical cancer requires external radiation therapy, brachytherapy, and chemotherapy, carefully sequenced and completed without delays. We sought to determine how frequently current treatment meets quality benchmarks and whether new technologies have influenced patterns of care.
METHODS AND MATERIALS: By searching diagnosis and procedure claims in MarketScan, an employment-based health care claims database, we identified 1508 patients with nonmetastatic, intact cervical cancer treated from 1999 to 2011, who were <65 years of age and received >10 fractions of radiation. Treatments received were identified using procedure codes and compared with 3 quality benchmarks: receipt of brachytherapy, receipt of chemotherapy, and radiation treatment duration not exceeding 63 days. The Cochran-Armitage test was used to evaluate temporal trends.
RESULTS: Seventy-eight percent of patients (n=1182) received brachytherapy, with brachytherapy receipt stable over time (Cochran-Armitage Ptrend=.15). Among patients who received brachytherapy, 66% had high-dose rate and 34% had low-dose rate treatment, although use of high-dose rate brachytherapy steadily increased to 75% by 2011 (Ptrend<.001). Eighteen percent of patients (n=278) received intensity modulated radiation therapy (IMRT), and IMRT receipt increased to 37% by 2011 (Ptrend<.001). Only 2.5% of patients (n=38) received IMRT in the setting of brachytherapy omission. Overall, 79% of patients (n=1185) received chemotherapy, and chemotherapy receipt increased to 84% by 2011 (Ptrend<.001). Median radiation treatment duration was 56 days (interquartile range, 47-65 days); however, duration exceeded 63 days in 36% of patients (n=543). Although 98% of patients received at least 1 benchmark treatment, only 44% received treatment that met all 3 benchmarks. With more stringent indicators (brachytherapy, ≥4 chemotherapy cycles, and duration not exceeding 56 days), only 25% of patients received treatment that met all benchmarks.
CONCLUSION: In this cohort, most cervical cancer patients received treatment that did not comply with all 3 benchmarks for quality treatment. In contrast to increasing receipt of newer radiation technologies, there was little improvement in receipt of essential treatment benchmarks.

Beaber EF, Kim JJ, Schapira MM, et al.
Unifying screening processes within the PROSPR consortium: a conceptual model for breast, cervical, and colorectal cancer screening.
J Natl Cancer Inst. 2015; 107(6):djv120 [PubMed] Related Publications
General frameworks of the cancer screening process are available, but none directly compare the process in detail across different organ sites. This limits the ability of medical and public health professionals to develop and evaluate coordinated screening programs that apply resources and population management strategies available for one cancer site to other sites. We present a trans-organ conceptual model that incorporates a single screening episode for breast, cervical, and colorectal cancers into a unified framework based on clinical guidelines and protocols; the model concepts could be expanded to other organ sites. The model covers four types of care in the screening process: risk assessment, detection, diagnosis, and treatment. Interfaces between different provider teams (eg, primary care and specialty care), including communication and transfer of responsibility, may occur when transitioning between types of care. Our model highlights across each organ site similarities and differences in steps, interfaces, and transitions in the screening process and documents the conclusion of a screening episode. This model was developed within the National Cancer Institute-funded consortium Population-based Research Optimizing Screening through Personalized Regimens (PROSPR). PROSPR aims to optimize the screening process for breast, cervical, and colorectal cancer and includes seven research centers and a statistical coordinating center. Given current health care reform initiatives in the United States, this conceptual model can facilitate the development of comprehensive quality metrics for cancer screening and promote trans-organ comparative cancer screening research. PROSPR findings will support the design of interventions that improve screening outcomes across multiple cancer sites.

Sabatino SA, White MC, Thompson TD, et al.
Cancer screening test use - United States, 2013.
MMWR Morb Mortal Wkly Rep. 2015; 64(17):464-8 [PubMed] Related Publications
Regular breast, cervical, and colorectal cancer (CRC) screening with timely and appropriate follow-up and treatment reduces deaths from these cancers. Healthy People 2020 targets for cancer screening test use have been established, based on the most recent U.S. Preventive Services Task Force (USPSTF) guidelines. National Health Interview Survey (NHIS) data are used to monitor progress toward the targets. CDC used the 2013 NHIS, the most recent data available, to examine breast, cervical, and CRC screening use. Although some demographic subgroups attained targets, screening use overall was below the targets with no improvements from 2010 to 2013 in breast, cervical, or CRC screening use. Cervical cancer screening declined from 2010 to 2013. Increased efforts are needed to achieve targets and reduce screening disparities.

Lowy DR, Herrero R, Hildesheim A,
Primary endpoints for future prophylactic human papillomavirus vaccine trials: towards infection and immunobridging.
Lancet Oncol. 2015; 16(5):e226-33 [PubMed] Related Publications
Although available human papillomavirus (HPV) vaccines have high efficacy against incident infection and disease caused by HPV types that they specifically target, new vaccine trials continue to be needed. The goals of these trials could include change of vaccine dose or route of administration (or both), development of second-generation vaccines, and the regional manufacture of biosimilar vaccines. We summarise present thinking about primary endpoints for HPV vaccine trials as developed at an experts workshop convened by the International Agency for Research on Cancer and the US National Cancer Institute in September, 2013. Efficacy trials that have led to licensure for cervical cancer prevention have used the disease endpoint of cervical intraepithelial neoplasia grade 2 or worse (CIN2+). However, on the basis of experience from the trials and present knowledge of HPV infection, future efficacy trials for new vaccines can be safely streamlined by the use of persistent HPV infection, which occurs more frequently than CIN2+, and can be more reproducibly measured as a primary endpoint. Immunobridging trials can be sufficient to ascertain immunological non-inferiority for licensure for alternate dosing schedules, bridging to age 26 years or younger, and biosimilar vaccines, with post-licensure surveillance confirming effectiveness. These recommendations are intended to help stimulate continued vaccine development while ensuring appropriate assessment of safety and efficacy.

Schiller JT, Müller M
Next generation prophylactic human papillomavirus vaccines.
Lancet Oncol. 2015; 16(5):e217-25 [PubMed] Related Publications
The two licensed bivalent and quadrivalent human papillomavirus (HPV) L1 (the major papillomavirus virion protein) virus-like particle (VLP) vaccines are regarded as safe, effective, and well established prophylactic vaccines. However, they have some inherent limitations, including a fairly high production and delivery cost, virus-type restricted protection, and no reported therapeutic activity, which might be addressed with the development of alternative dosing schedules and vaccine products. A change from a three-dose to a two-dose protocol for the licensed HPV vaccines, especially in younger adolescents (aged 9-13 years), is underway in several countries and is likely to become the future norm. Preliminary evidence suggests that recipients of HPV vaccines might derive prophylactic benefits from one dose of the bivalent vaccine. Substantial interest exists in both the academic and industrial sectors in the development of second-generation L1 VLP vaccines in terms of cost reduction-eg, by production in Escherichia coli or alternative types of yeast. However, Merck's nonavalent vaccine, produced via the Saccharomyces cerevisiae production system that is also used for their quadrivalent vaccine, is the first second-generation HPV VLP vaccine to be available on the market. By contrast, other pharmaceutical companies are developing microbial vectors that deliver L1 genes. These two approaches would add an HPV component to existing live attenuated vaccines for measles and typhoid fever. Prophylactic vaccines that are based on induction of broadly cross-neutralising antibodies to L2, the minor HPV capsid protein, are also being developed both as simple monomeric fusion proteins and as virus-like display vaccines. The strong interest in developing the next generation of vaccines, particularly by manufacturers in middle-to-high income countries, increases the likelihood that vaccine production will become decentralised with the hope that effective HPV vaccines will be made increasingly available in low-resource settings where they are most needed.

Herrero R, González P, Markowitz LE
Present status of human papillomavirus vaccine development and implementation.
Lancet Oncol. 2015; 16(5):e206-16 [PubMed] Related Publications
Oncogenic human papillomavirus (HPV) infection is the cause of nearly all cervical cancers and a proportion of other anogenital and oropharyngeal cancers. A bivalent vaccine containing HPV 16 and 18 and a quadrivalent vaccine containing HPV 6, 11, 16, and 18 antigens are in use in vaccination programmes around the world. In clinical trials, three vaccine doses provided 90-100% protection against cervical infection and pre-cancer related to HPV 16 and 18 in women aged 15-26 years who were not infected at vaccination. Partial cross-protection against other HPV types has been reported but its duration is unknown. The vaccines were also efficacious at the prevention of HPV 16 and 18 infections at other anatomical sites in both sexes. Immunobridging studies allowed licensing of the vaccines for use starting at age 9 years for both sexes. Two-dose schedules elicit high antibody concentrations, leading to the recommendation of two-dose schedules for girls aged 9-14 years. Pre-licensure and post-licensure studies have provided data supporting vaccine safety. In 2014, a nonavalent vaccine containing HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 antigens was licensed by the US Food and Drug Administration. HPV vaccination was first introduced in high-income countries owing to vaccine cost, logistic challenges, and competing health priorities. Since 2011, vaccine prices have lowered, allowing the introduction of the vaccine in some middle-income countries. Funding of the vaccine by the GAVI Alliance in 2012 led to demonstration projects in some low-income countries. By 2014, more than 57 countries had included the HPV vaccine in their national health programmes. Data from several countries have shown the effect of vaccination on HPV infection and associated disease, and provided evidence of herd immunity. Expansion of programmes to countries with the highest burden of disease is beginning, but further efforts are needed to realise the potential of HPV vaccines.

Wang S, Sun H, Jia Y, et al.
Association of 42 SNPs with genetic risk for cervical cancer: an extensive meta-analysis.
BMC Med Genet. 2015; 16:25 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A large number of single nucleotide polymorphisms (SNPs) associated with cervical cancer have been identified through candidate gene association studies and genome-wide association studies (GWAs). However, some studies have yielded different results for the same SNP. To obtain a more comprehensive understanding, we performed a meta-analysis on previously published case-control studies involving the SNPs associated with cervical cancer.
METHODS: Electronic searches of PubMed and Embase were conducted for all publications about the association between gene polymorphisms and cervical cancer. One-hundred and sixty-seven association studies were included in our research. For each SNP, three models (the allele, dominant and recessive effect models) were adopted in the meta-analysis. For each model, the effect summary odds ratio (OR) and 95% CI were calculated. Heterogeneity between studies was evaluated by Cochran's Q test. If the p value of Q test was less than 0.01, a random effect model was used; otherwise, a fixed effect model was used.
RESULTS: The results of our meta-analysis showed that: (1) There were 8, 2 and 8 SNPs that were significantly associated with cervical cancer (P < 0.01) in the allele, dominant and recessive effect models, respectively. (2) rs1048943 (CYP1A1 A4889G) showed the strongest association with cervical cancer in the allele effect model (1.83[1.57, 2.13]); in addition, rs1048943 (CYP1A1 A4889G) had a very strong association in the dominant and recessive effect model. (3) 15, 11 and 10 SNPs had high heterogeneity (P < 0.01) in the three models, respectively. (4) There was no published bias for most of the SNPs according to Egger's test (P < 0.01) and Funnel plot analysis. For some SNPs, their association with cervical cancer was only tested in a few studies and, therefore, might have been subjected to published bias. More studies on these loci are required.
CONCLUSION: Our meta-analysis provides a comprehensive evaluation of cervical cancer association studies.

Darwish-Yassine M, Garvin AD, Johnston CM, et al.
An assessment of gynecological cytology screening practices among health care providers nationwide.
Arch Pathol Lab Med. 2015; 139(5):650-5 [PubMed] Related Publications
CONTEXT: The Michigan Public Health Institute and the Michigan Cancer Consortium's Cervical Cancer Committee conducted a national survey of health care providers, thanks to funding from the Centers for Disease Control Cooperative Agreement 5U47CI000743-02. Papanicolaou test screening practices were examined, emphasizing the relationship between clinical and laboratory practices. This survey found differing screening practices among providers of women's health care.
OBJECTIVES: To collect information from family medicine practitioners, women's nurse practitioners, obstetricians and gynecologists, and certified nurse-midwives on Papanicolaou and human papillomavirus testing; to discuss how those practices align with current cytology screening and follow-up recommendations from professional organizations (US Preventive Services Task Force, American Cancer Society, American College of Obstetricians and Gynecologists, and American Society for Colposcopy, and Cervical Pathology); and ultimately, to make recommendations aimed at standardizing practice performance.
DESIGN: This survey was conducted in part to examine clinicians' practices and their perceptions of laboratory performance, to evaluate items that are known to enhance quality of care, and to examine factors that may prohibit universal implementation of best standards of care. The survey used a self-administered questionnaire, distributed to 9366 clinicians, with 1601 (17.1%) completed surveys.
RESULTS: This assessment shows a clear lack of consensus among practitioners in performing Papanicolaou testing. It demonstrates how differently patients are tested, based on the providers' screening practices, and demonstrates specific cervical cancer screening practice disparities between and among the 4 provider groups, both in Papanicolaou testing and in the use of human papillomavirus testing.
CONCLUSION: A unified mandate for screening is needed to standardize screening practices.

Chacko S
Effect of structured teaching programme on VIA test for early detection and diagnosis of cervical cancer.
Nurs J India. 2014 Sep-Oct; 105(5):221-4 [PubMed] Related Publications
The conceptual framework of the study, undertaken in select health centres of New Delhi, was based on General System Model. The research approach was evaluative with one group pre-test and post-test design. The study population comprised of Community Health Workers working in selected centres in Najafgarh, Delhi. Purposive sampling technique was used to select a sample of 30 Community Health Workers. A structured knowledge questionnaire was developed to assess the knowledge of subjects. A Structured Teaching Programme was developed to enhance the knowledge of Community Health Workers. Pre-test was given on day 1 and Structured Teaching Programme administered on same day. Post-test was conducted on day 7. Most of the Community Health Workers were in the age group of 21-30 years with academic qualification up to Higher Secondary level. Maximum Community Health Workers had professional qualification as ANM/MPHW (female). Majority of the Community Health Workers had experience up to 5 years. Initially there was deficit in scores of knowledge of Community Health Workers regarding Visual Inspection with Acetic Acid (VIA) test. Mean post-test knowledge scores of Community Health Workers were found to be signifi- cantly higher than their mean pre-test knowledge score. The Community Health Workers after expo- sure to Structured Teaching Programme gained a significant positive relationship between post-test knowledge scores. The study reveals the efficacy of Structured Teaching Programme in enhancing the knowledge of Community Health Workers regarding VIA test and a need for conducting a regular and well planned health teaching programme on VIA test for improving their knowledge on VIA test for the early detection and diagnosis of cervical cancer.

Lin Y, Li H, Chen Z, et al.
Correlation of histogram analysis of apparent diffusion coefficient with uterine cervical pathologic finding.
AJR Am J Roentgenol. 2015; 204(5):1125-31 [PubMed] Related Publications
OBJECTIVE: The purpose of this study was to investigate the application of histogram analysis of apparent diffusion coefficient (ADC) in characterizing pathologic features of cervical cancer and benign cervical lesions.
SUBJECTS AND METHODS: This prospective study was approved by the institutional review board, and written informed consent was obtained. Seventy-three patients with cervical cancer (33-69 years old; 35 patients with International Federation of Gynecology and Obstetrics stage IB cervical cancer) and 38 patients (38-61 years old) with normal cervix or cervical benign lesions (control group) were enrolled. All patients underwent 3-T diffusion-weighted imaging (DWI) with b values of 0 and 800 s/mm(2). ADC values of the entire tumor in the patient group and the whole cervix volume in the control group were assessed. Mean ADC, median ADC, 25th and 75th percentiles of ADC, skewness, and kurtosis were calculated. Histogram parameters were compared between different pathologic features, as well as between stage IB cervical cancer and control groups.
RESULTS: Mean ADC, median ADC, and 25th percentile of ADC were significantly higher for adenocarcinoma (p = 0.021, 0.006, and 0.004, respectively), and skewness was significantly higher for squamous cell carcinoma (p = 0.011). Median ADC was statistically significantly higher for well or moderately differentiated tumors (p = 0.044), and skewness was statistically significantly higher for poorly differentiated tumors (p = 0.004). No statistically significant difference of ADC histogram was observed between lymphovascular space invasion subgroups. All histogram parameters differed significantly between stage IB cervical cancer and control groups (p < 0.05).
CONCLUSION: Distribution of ADCs characterized by histogram analysis may help to distinguish early-stage cervical cancer from normal cervix or cervical benign lesions and may be useful for evaluating the different pathologic features of cervical cancer.

Chen J, Solomides C, Parekh H, et al.
Cisplatin resistance in human cervical, ovarian and lung cancer cells.
Cancer Chemother Pharmacol. 2015; 75(6):1217-27 [PubMed] Related Publications
PURPOSE: This study was performed to determine whether or not in cervical, ovarian and lung cancer cell lines, free radicals (ROS) play a role in cisplatin cytotoxicity and activation of the mitochondrial and JNK/p38 pathways. The role of the enzyme, dihydrodiol dehydrogenase (DDH1), in the activation/deactivation of this pathway and how this may be related to the development of resistance was also investigated.
METHODS: Mitochondrial membrane potential and ROS analysis were performed by flow cytometry, P-JNK and P-p38 by western blotting and mRNA by RT-PCR. Dihydrodiol dehydrogenase (DDH1) and thioredoxin knockdowns were prepared by standard techniques.
RESULTS: Cisplatin treatment of a cervical cancer cell line resulted in ROS production with mitochondrial membrane depolarization and phosphorylation of JNK and p38. N-acetyl-cysteine, a free radical scavenger, ameliorated these effects. Treatment of the sensitive cells with H2O2 produced similar effects but at shorter incubation times. Similar results were observed with an ovarian cell line. Downregulation of dihydrodiol dehydrogenase in the cisplatin-resistant cervical and lung cancer cell lines resulted in increased drug sensitivity with detectable production of ROS and activation of the JNK/p38 pathways; however, downregulation of thioredoxin in the cervical cells had minimal effect.
CONCLUSION: Dihydrodiol dehydrogenase appears to play a role in cisplatin resistance in cervical, ovarian and lung cancer cells which includes mitochondrial membrane depolarization, ROS production and activation of the JNK pathway. However, its mode of action cannot be mimicked by an ROS scavenger so its mechanism of action is more complex (a not unexpected finding considering its role in xenobiotic activation/countering oxidative stress).

Weissferdt A, Kalhor N, Moran CA
Ewing sarcoma with extensive neural differentiation: a clinicopathologic, immunohistochemical, and molecular analysis of three cases.
Am J Clin Pathol. 2015; 143(5):659-64 [PubMed] Related Publications
OBJECTIVES: Three patients with Ewing sarcomas showing extensive neural differentiation are presented.
METHODS: The patients were two women and one man between the ages of 15 and 35 years. Anatomically, one tumor was in the lung, one in the testis, and one in the cervix uteri. The symptoms were determined by the location of the neoplasm and included respiratory symptoms, testicular pain, and pelvic manifestations, respectively. Complete surgical resection of the tumors was performed.
RESULTS: Histologically, all neoplasms showed similar characteristics-namely, a neoplastic cellular proliferation arranged in sheets and composed of small blue cells with round to oval nuclei and inconspicuous nucleoli typical for Ewing sarcoma. In addition, in two cases, there were areas characterized by the presence of neuropil, ganglion cells, and small cells most compatible with ganglioneuroblastoma, while in one tumor, the neural component was characterized by the presence of small cells with prominent perivascular pseudorosettes more closely resembling ependymoma. Immunohistochemical studies in all cases and molecular analysis in two tumors were in keeping with a diagnosis of Ewing sarcoma.
CONCLUSIONS: The recognition of such histologic variants is important in the diagnostic assessment of these tumors to avoid misinterpretation, especially in small biopsy specimens.

Yang L, He Z, Huang XY, et al.
Prevalence of human papillomavirus and the correlation of HPV infection with cervical disease in Weihai, China.
Eur J Gynaecol Oncol. 2015; 36(1):73-7 [PubMed] Related Publications
OBJECTIVE: This study investigates the human papillomavirus (HPV) infection rate in female genital tracts, as well as the HPV genotype distribution and HPV correlation with cervical disease in Weihai, Shandong Province, China.
MATERIALS AND METHODS: A random sample of 9,460 volunteers was simultaneously screened using gene chips and examined by ThinPrep liquid-based cytology test (TCT). Cervical biopsy samples were collected from women with positive HPV-DNA and abnormal TCT for pathological diagnosis.
RESULTS: The overall HPV prevalence was 6.93% (656 of 9,460). A total of 753 subjects were infected with HPV subtypes (including multiple HPV infections). Of those with infections, 688 were infected with high-risk (HR) types (91.37%), and 65 were infected with low-risk subtypes (8.63%). The single-infection rate was 63.1%.The prevalence rates of HPV in women aged 20 to 39 years and 40 to 59 years were 7.29% and 6.71%, respectively. The most common genotype was HPV16. The HR genotypes were associated with cervical diseases such as atypical squamous cells of undetermined significance (ASCUS) (37.9%), atypical squamous cells high grade (ASC-H) (42.5%), low grade squamous intraepithelial lesion (LSIL) (50%), and high grade squamous intraepithelial lesion HSIL (66.7%). Cervical biopsy results show that the HPV detection rate increased in the following biopsy samples: cervical intraepithelial neoplasia (CIN) I (74.11%), CIN II (84.31%), CIN III (90.32%), and squamous-cell carcinoma (SCC) (100%).
CONCLUSIONS: The HPV infection rate with associated cervical disease in Weihai is equal to those in foreign countries but is lower than the average rate in China. The prevalence of HPV was higher in young people. The most common HPV genotype was 16, followed by 52 and 58. HR HPV is the most probable infection factor for cervical diseases.

Zhou WQ, Sheng QY, Sheng YH, et al.
Expressions of survivin, P16(INK4a), COX-2, and Ki-67 in cervical cancer progression reveal the potential clinical application.
Eur J Gynaecol Oncol. 2015; 36(1):62-8 [PubMed] Related Publications
PURPOSE OF INVESTIGATION: To explore the significance of survivin, P16(INK4a), COX-2, and Ki-67 expressions for prediction of cervical cancer progression.
MATERIALS AND METHODS: A retrospective study was performed in 129 cases including 24 squamous carcinoma of the cervix (SCC), 70 cervical intraepithelial neoplasias (CIN), 15 cervical condyloma acuminatum (CCA), ten chronic cervicitis (CC), and ten normal cervix (NC). Protein expressions were evaluated using immunohistochemistry.
RESULTS: Survivin, P16(INK4a); COX-2, and Ki-67 were highly expressed in SCC and CIN compared with others. Their expression rates were gradually increased in CIN I, CIN II, CIN III, and SCC groups, showing 72.00%, 88.00%, 90.00%, and 95.83% for P16(INK4a), 68.00%, 84.00%, 95.00% and 100.00% for COX-2, 76.00%, 96.00%, 100.00%, and 100.00 for Ki-67, respectively. There were significant correlations between survivin and P16(INK4a), COX-2, Ki-67, as well as P16(INK4a) and Ki-67.
CONCLUSION: Survivin, P16(INK4a), COX-2 and Ki-67 play critical roles for development and progression of cervical cancer.

Kerimoglu OS, Pekin A, Yilmaz SA, et al.
Pyometra in elderly post-menopausal women: a sign of malignity.
Eur J Gynaecol Oncol. 2015; 36(1):59-61 [PubMed] Related Publications
PURPOSE: To describe the clinical and histopathological characteristics of 12 patients with pyometra and highlight the increased incidence of gynecological malignancy in these patients.
MATERIALS AND METHODS: The authors examined the medical records of 12 patients with pyometra, who were treated between 2009 and 2013.
RESULTS: All patients were post-menopausal, and their mean age was 70.83 ± 6.978 years (min = 61, max = 82). To remove purulent fluid via dilation and because of the probability of malignancy, three patients (25%) underwent cervical biopsy and endometrial curettage; the other nine patients (75%) underwent curettage alone, with suitable antibiotic therapy. Of the 12 patients, nine (75%) had gynecologic malignancy [(endometrial cancer, n = 5, 41.6%), (cervical cancer, n = 3, 25%), (uterine leiomyosarcoma, n = 1, 8.3%)]. In three (25%) patients, the cause of pyometra was benign pathologies, among which the most common were leiomyomas (n = 2, 66.6%).
CONCLUSION: Pyometra diagnosed during the post-menopausal period should be considered a complication caused by gynecological malignancy until proven otherwise.

Li Y, Wang X, Li J, Ding W
Combination therapy of liposomal paclitaxel and cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer.
Eur J Gynaecol Oncol. 2015; 36(1):54-8 [PubMed] Related Publications
OBJECTIVES: To investigate the efficacy and toxicities of combination therapy of liposomal paclitaxel and cisplatin as neoadjuvant chemotherapy (NACT) in locally advanced cervical cancer.
MATERIALS AND METHODS: The authors retrospectively reviewed the clinical records of patients with cervical cancer who received NACT with liposomal paclitaxel and cisplatin at Sun Yat-sen University Cancer Center from April 1, 2008 to December 31, 2012. Liposomal paclitaxel and cisplatin was administrated intravenously at a dose of 175 mg/m2 and 75 mg/m2, respectively.
RESULTS: The total response rate was 86.1% (62/72) including a complete response and partial response rate of 27.8% (20/72) and 58.3% (42/72), respectively. Stable disease was observed in 12.5% (9/72) of patients and progressive disease in 1.4% (1/72). Hematological toxicities were the major dose-limiting toxicities. Grade 3/4 neutropenia and anemia developed in 18.1% (13/72) and 6.9% (5/72) of patients, respectively. Peripheral neuropathy occurred in 6.9% (5/72) of patients (all grade 1).
CONCLUSION: The study findings support further evaluation of liposomal paclitaxel with cisplatin as an additional chemotherapy regimen which may be efficacious and tolerable in the NACT of cervical cancer.

Andrikopoulou M, Salakos N, Deligeoroglou E, et al.
The role of mTOR signaling pathway in premalignant and malignant cervical lesions.
Eur J Gynaecol Oncol. 2015; 36(1):36-43 [PubMed] Related Publications
PURPOSE OF THE STUDY: Aberrant activation of the Akt/mTOR/pS6 signaling pathway has been identified in various types of cancer and is under investigation in cervical cancer. The purpose of this study was to assess the expression of the phosphorylated/activated forms of Akt (upstream molecule), 4E-BP1 and pS6 (downstream molecules) in biopsy samples of cervical low grade squamous intraepithelial lesions (LSIL), high grade squamous intraepithelial lesions (HSIL), and squamous cell carcinoma (Ca) compared to normal cervical epithelium.
MATERIAL AND METHODS: The study included 38 cases diagnosed as LSIL, 31 cases as HSIL, 29 cases as Ca, and eight control cases from normal cervix. Immunohistochemistry was used to assess the expression of pAkt, p4E-BP1 and pS6.
RESULTS: Statistical analysis revealed significant differences between HSIL and Ca groups compared to controls regarding intensity, positivity, and total scores for all three molecules (p < 0.001). A trend for higher expression with increasing grade of dysplasia was demonstrated.
CONCLUSION: These results strongly support the view that the mTOR signaling pathway is involved in cervical carcinogenesis.

Cho SH, Lim JY, Kim SN, et al.
The prognostic significance of pretreatment [18F]FDG-PET/CT imaging in patients with uterine cervical cancer: preliminary results.
Eur J Gynaecol Oncol. 2015; 36(1):30-5 [PubMed] Related Publications
PURPOSE OF INVESTIGATION: To evaluate the prognostic significance of positron emission tomography/computed tomography (PET/CT) in patients diagnosed with cervical cancer.
MATERIALS AND METHODS: Patients with cervical cancer in FIGO Stages IB1 to IVB were imaged with PET/CT prior to treatment during one of the staging work-ups. The patients were observed for a median of 31.4 months (range, six to 89 months) after the initial treatment. The standardized uptake value (SUV) max of the primary cervical tumor mass was compared with the prognostic factors. RESULTs: A total of 81 patients who were primarily treated with radical hysterectomy (RH, n = 45) or concurrent chemoradiation (CCRT, n = 36) were analyzed. Multivariate analysis indicated that larger tumor size (> 4 cm, OR 8.694, 95% CI, 1.638-46.146), deep stromal invasion (≥ 1 cm, OR 7.249, 95% CI, 1.141-46.039) by the primary tumor, and pathologically confirmed pelvic lymph node involvement (positive, OR 14.586, 95% CI, 2.072-102.674) were significantly associated with recurrence after treatment. However, pretreatment SUVmax was not a significant independent predictor of disease recurrence (OR 1.058, 95% CI, 0.255-4.398).
CONCLUSION: [18F]Fluorodeoxyglucose (FDG) uptake by the primary tumor showed a significant association with several risk factors that have been identified as treatment predictors. However, a high pretreatment SUVmax was not predictive of recurrence in uter- ine cervical cancer patients.

Shou H, Chen Y, Chen Z, et al.
Laparoscopic ovarian transposition in young women with cervical squamous cell carcinoma treated by primary pelvic irradiation.
Eur J Gynaecol Oncol. 2015; 36(1):25-9 [PubMed] Related Publications
OBJECTIVE: To report the authors' experience with laparoscopic ovarian transposition and ovarian function preservation in young women with cervical squamous cell carcinoma treated by primary pelvic irradiation.
MATERIALS AND METHODS: Twenty-seven premenopausal patients were treated with radiotherapy for a cervical squamous cell carcinoma. Laparoscopic ovarian transposition to paracolic gutters with uterine conservation with pelvic common iliac lymph node and para-aortic lymph node sampling were performed in ten patients at the same time of laparoscopic ovarian transposition. Preservation of ovarian function was assessed by patients' symptoms and serum follicle-stimulating hormone level.
RESULTS: Bilateral or unilateral laparoscopic ovarian transposition was performed in 27 patients: 22 cases Stage IIB, one case Stage IIIA, and four cases Stage IIIB. No immediate intraoperative or postoperative complications were observed. Two of the ten patients were confirmed by lymph node metastases. One patient was lost to follow-up. Ovarian preservation was achieved in 18 (69.2%) of 26 patients. No patient was detected with ovarian metastasis at follow-up.
CONCLUSIONS: Laparoscopic ovarian transposition is a safe and effective procedure for preserving ovarian function. This procedure may be considered in premenopausal women who need to undergo pelvic irradiation for cervical squamous cell carcinoma, especially for those less than 40 years of age. Otherwise, para-aortic lymph node or common iliac lymph nods sampling at the same time of laparoscopic ovarian transposition may preferably guide radiation therapy.

Kavallaris A, Zygouris D, Dafopoulos A, et al.
Nerve sparing radical hysterectomy in early stage cervical cancer. Latest developments and review of the literature.
Eur J Gynaecol Oncol. 2015; 36(1):5-9 [PubMed] Related Publications
BACKGROUND: Cervical cancer is the second most common malignancy of the female genital tract worldwide. Radical hysterectomy with pelvic lymphadenectomy exemplifies the treatment of choice for early stage disease, whereas even if it is performed by gynaecologist-oncologist, still has the drawback of significant postoperative morbidity, especially for urinary bladder function. Nerve-sparing radical hysterectomy (NSRH) is a technique in which the neural part of the cardinal ligament which encloses the inferior hypogastric plexus, as well as the bladder branch (distal part of the plexus), remains intact. By this way, the bladder's innervation is safe and its functional recovery is more rapid. There is sufficient data to support the feasibility of the technique via laparotomy and laparoscopy, as well as the effectiveness related to the postoperative bladder dysfunction compared to conventional radical hysterectomy. On the other hand, the evidence related to survival outcomes is weak and derives from non-randomized trials. However, the low rate of local relapses after NSRH in early stage disease (IA2-IB1) with tumor diameter less than two cm makes the procedure suitable for this group of patients.
CONCLUSION: According to the current evidence NSRH seems to be a suitable technique for gynaecologist-oncologist familiar with the method in early stage cervical cancer. It is a technique which improves significantly postoperative bladder recovery and the patients' quality of life (QoL), without compromising the oncological standard.

Im H, Castro CM, Shao H, et al.
Digital diffraction analysis enables low-cost molecular diagnostics on a smartphone.
Proc Natl Acad Sci U S A. 2015; 112(18):5613-8 [PubMed] Article available free on PMC after 05/11/2015 Related Publications
The widespread distribution of smartphones, with their integrated sensors and communication capabilities, makes them an ideal platform for point-of-care (POC) diagnosis, especially in resource-limited settings. Molecular diagnostics, however, have been difficult to implement in smartphones. We herein report a diffraction-based approach that enables molecular and cellular diagnostics. The D3 (digital diffraction diagnosis) system uses microbeads to generate unique diffraction patterns which can be acquired by smartphones and processed by a remote server. We applied the D3 platform to screen for precancerous or cancerous cells in cervical specimens and to detect human papillomavirus (HPV) DNA. The D3 assay generated readouts within 45 min and showed excellent agreement with gold-standard pathology or HPV testing, respectively. This approach could have favorable global health applications where medical access is limited or when pathology bottlenecks challenge prompt diagnostic readouts.

Choi CH, Chung JY, Park HS, et al.
Pancreatic adenocarcinoma up-regulated factor expression is associated with disease-specific survival in cervical cancer patients.
Hum Pathol. 2015; 46(6):884-93 [PubMed] Related Publications
Pancreatic adenocarcinoma up-regulated factor (PAUF) is a novel soluble protein involved in tumor development and metastases. This study was to investigate the PAUF expression and its prognostic value in cervical cancer patients. The expression of PAUF was immunohistochemically determined in 345 formalin-fixed, paraffin-embedded cervical cancer tissues and 107 normal cervical epitheliums. Subsequently, its associations with clinicopathological characteristics and patient survival were assessed. PAUF protein was expressed both in cytoplasm and nucleus, and cytoplasmic expression was more frequent in cancers than normal tissues (32% versus 17%, P = .002), and the difference was prominent in glandular cells. Notably, the expression was more frequent in adenocarcinoma than in squamous cell carcinoma (57% versus 25%, respectively; P < .001), and the differential expression was also seen at the messenger RNA level (P = .014). Cox regression analysis showed that the cytoplasmic expression of PAUF protein was independently associated with poor disease-free (hazard ratio = 2.3; 95% confidence interval, 1.2-4.3; P = .008) and overall survival (hazard ratio = 2.9; 95% confidence interval, 1.2-7.5; P = .020). Detection of PAUF expression may aid current evaluation of prognosis in cervical adenocarcinoma.

Coffey K, Beral V, Green J, et al.
Lifestyle and reproductive risk factors associated with anal cancer in women aged over 50 years.
Br J Cancer. 2015; 112(9):1568-74 [PubMed] Article available free on PMC after 28/04/2016 Related Publications
BACKGROUND: Anal cancer incidence increases with age and is higher in women than men. Risk factors in this group other than high-risk human papillomavirus infection are unclear.
METHODS: In all, 1.3 million women were recruited in 1996-2001 and followed for incident anal cancer. Cox regression models were used to calculate relative risks (RRs) for anal cancer by various potential risk factors.
RESULTS: Five hundred and seventeen incident anal cancers were registered over 13 years of follow-up. The largest RR was associated with a history of cervical intraepithelial neoplasia grade 3 (CIN 3; RR=4.03, 95% CI 2.59-6.28). Other factors associated with significantly increased risks in multivariate analyses were: ever smoking (RR=1.49, 1.24-1.80); previous use of oral contraceptives (RR=1.51, 1.24-1.83); nulliparity (RR=1.61, 1.24-2.07); tubal ligation (RR=1.39, 1.13-1.70) and not living with a partner (RR=1.82, 1.40-2.38). The association with smoking was significantly greater for squamous cell carcinoma than adenocarcinoma of the anus (RR 1.66 vs 0.89, P for heterogeneity=0.04).
CONCLUSIONS: History of CIN 3, smoking, past oral contraceptive use, nulliparity, tubal ligation and not living with a partner are risk factors for anal cancer in women. There was a significant increase in risk associated with smoking for squamous cell anal cancers but not adenocarcinomas.

Blatt AJ, Kennedy R, Luff RD, et al.
Comparison of cervical cancer screening results among 256,648 women in multiple clinical practices.
Cancer Cytopathol. 2015; 123(5):282-8 [PubMed] Related Publications
BACKGROUND: In the United States, human papillomavirus (HPV) and Papanicolaou (Pap) testing (cotesting) for cervical screening in women ages 30 to 65 years is the preferred strategy, and cytology alone is acceptable. Recently, a proprietary automated test for identifying high-risk HPV types for primary cervical screening was approved by the US Food and Drug Administration. The objective of the current study was to document extensive cervical screening among these screening options.
METHODS: To investigate the sensitivity of various testing options for biopsy-proven cervical intraepithelial neoplasia grade 3 or worse (≥ CIN3) and cancer, the authors reviewed 256,648 deidentified results from women ages 30 to 65 years at the time of cotest who had a cervical biopsy specimen obtained within 1 year of the cotest.
RESULTS: A positive cotest result was more sensitive (98.8%; 4040 of 4090 cotests) for diagnosing ≥ CIN3 than either a positive HPV-only test (94%; 3845 of 4090 HPV-only tests) or a positive Pap-only test (91.3%; 3734 of 4090 Pap-only tests; P < .0001). A positive Pap-only result was more specific (26.3%; 66,145 of 251,715 Pap-only tests) for diagnosing ≥ CIN3 than a positive HPV-only test (25.6%; 64,625 of 252,556 HPV-only tests) or a positive cotest (10.9%; 27,578 of 252,558 cotests; P < .0001). Of 526 cervical cancers, 98 (18.6%) were HPV-only negative, 64 (12.2%) were Pap-only negative, and 29 (5.5%) were cotest negative.
CONCLUSIONS: Compared with HPV-only testing, cotesting was more sensitive for the detection of ≥ CIN3 in women ages 30 to 65 years. The current data suggest that approximately 19% of women with cervical cancer may be misdiagnosed by an HPV-only cervical screen. It is important to consider these data as the guidelines for cervical cancer screening undergo revision. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Hoogendam JP, Veldhuis WB, Hobbelink MG, et al.
99mTc SPECT/CT Versus Planar Lymphoscintigraphy for Preoperative Sentinel Lymph Node Detection in Cervical Cancer: A Systematic Review and Metaanalysis.
J Nucl Med. 2015; 56(5):675-80 [PubMed] Related Publications
UNLABELLED: We aimed to compare SPECT/CT and lymphoscintigraphy on overall and bilateral sentinel lymph node (SLN) detection in cervical cancer patients.
METHODS: A systematic search was performed on August 1, 2014, in PubMed, Embase, Scopus, and the Cochrane library. The syntax was based on synonyms of the terms cervical cancer, SPECT/CT, and lymphoscintigraphy. Retrieved articles were screened on their title/abstract and considered eligible when an SLN procedure was performed using both imaging modalities and if detection results were reported. Two independent reviewers assessed all included studies on methodologic quality using QUADAS-2. Studies were pooled on their odds ratios (ORs) with a random-effects model.
RESULTS: The search yielded 962 unique articles, of which 8 were ultimately included. The studies were recent retrospective or prospective cohort studies of limited size (n = 7-51) but sufficient methodologic quality. The median overall detection (≥1 SLN in a patient) was 98.6% for SPECT/CT (range, 92.2%-100.0%) and 85.3% for lymphoscintigraphy (range, 70.0%-100.0%). This corresponded to a pooled overall SLN detection OR of 2.5 (95% CI, 1.2-5.3) in favor of SPECT/CT. The reported median bilateral detection (≥1 SLN in each hemipelvis) was 69.0% for SPECT/CT (range, 62.7%-79.3%) and 66.7% for lymphoscintigraphy (range, 56.9%-75.8%), yielding a pooled OR of 1.2 (95% CI, 0.7-2.1). No significant difference in the number of visualized SLNs was observed at a pooled ratio of 1.2 (95% CI, 0.9-1.6).
CONCLUSION: In cervical cancer patients, preoperative SLN imaging with SPECT/CT results in superior overall SLN detection in comparison with planar lymphoscintigraphy.

Knegt Y
Audit of cervical cancer screening and colposcopy attendance in rural South Africa.
Afr J Reprod Health. 2014; 18(4):70-8 [PubMed] Related Publications
Women in developing countries generally lack access to cervical cancer preventive services. An audit was performed in rural South Africa to test the hypothesis that women do not follow (pre-)cancerous cervical disease treatment sufficiently, to understand the possible reasons for this non-attendance behavior, and to evaluate other published diagnostic and treatment initiatives. Based on Pap smear and colposcopy attendance data, including age, HIV status, month of attendance, and cervical intraepithelial neoplasia (CIN) staging, relatively few patients (54% of 928 patients) visited a colposcopy clinic following an abnormal Pap smear. Although these co-factors do not explain this high non-attendance rate, HIV status was an important co-factor; percentage-wise, HIV positivity correlated with a higher attendance rate. Screening methods that use mobile teams to successfully deliver cost-effective on-the-spot treatment warrant further attention.

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