Invasive Cervical Cancer

DOI: 10.4236/jct.2018.99061 741 Journal of Cancer Therapy of the most commonly diagnosed cancers during pregnancy (with hematologic malignancy, breast cancer and melanoma). Its incidence, according to the popu- lations, varies between one and ten per 10,000 pregnancies [1]. There are few data available in Africa. These are mostly women with high parity (four to five depending on the studies) [2] [3], patients treated during pregnancy and in im- mediate postpartum are sometimes mixed. There is no currently repository available for the management of invasive cervical cancer during pregnancy. This management depends on the stage (and tumor size), the histological type of the tumor, the term of pregnancy and the desire of the couple to maintain pregnan- cy. The low frequency of this situation did not permit randomized studies. Ac- cording to a recent Swedish study, 1.2% of invasive cervical cancers are discov- ered during pregnancy [4]. Zemlickis et al. [5] showed that cervical cancers di- agnosed during pregnancy were significantly early stages. Stage I: 69% - 83% versus 42% in the non-pregnant group; stage II: 11% - 23% versus 35%; stage III: 3% - 8% versus 21% and stage IV: 0% - 3% versus 2%. About invasive cervical cancer diagnosed during pregnancy, Morice et al. published national recom- mendations [6]. These recommendations are validated by three French learned societies: French Society of Gynecologic Oncology; French Society of Pelvic Surgery and the National College of French Gynecologists and Obstetricians. We conducted a review of the literature to update the management of invasive cer- vical cancers diagnosed during pregnancy.

(Ly, 2009). However, in some countries, there is a low prevalence of those genotypes in cervical cancer; they are preceded by other genotypes (de Sanjose et al., 2007; Bosch et al., 2008). In Burkina Faso, no study has yet focused on the distribution and prevalence of HR-HPV in cases of invasive cervical cancer confirmed histologically. Studies conducted so far focused only on cervical cell samples from women with unknown pathology status and/or HIV (human immunodeficiency virus) positive status. Those studies indicated a predominance of HPV 35, 52, 31 and 39 (Djigma et al., 2011; Zohoncon et al., 2013; Ouedraogo et al., 2015; Traore et al., 2016a; Traore et al., 2016b). In addition, a recent study on the HR-HPV involved in cases of intraepithelial cervical neoplasia in Ouagadougou showed a prevalence of HPV 39, 35 and 45 (Ouédraogo et al., 2016). Based on these findings, we assumed a possible emergence of HR-HPV genotypes other than HPV 16 and 18. Therefore, the objective of this study was to determine the distribution of 14 HR-HPV genotypes in cases of invasive cervical cancer in Ouagadougou (Burkina Faso).

Integration of human papillomavirus type 16 (HPV-16) into the host DNA has been proposed as a potential marker of cervical neoplastic progression. In this study, a quantitative real-time PCR (qRT-PCR) was used to examine the physical status of HPV-16 in 126 cervical carcinoma in situ and 92 invasive cervical cancers. Based on criteria applied to results from this qRT-PCR assay, HPV-16 was characterized in carcinoma in situ cases as episomal (61.9%), mixed (i.e., episomal and integrated; 29.4%), and integrated (8.7%) forms. In invasive cervical cancer samples, HPV-16 was similarly characterized as episomal (39.1%), mixed (45.7%), and inte- grated (15.2%) forms. The difference in the frequency of integrated or episomal status estimated for carcinoma in situ and invasive cervical cancer cases was statistically significant (P ⴝ 0.003). Extensive mapping analysis of HPV-16 E1 and E2 genes in 37 selected tumors demonstrated deletions in both E1 and E2 genes with the maximum number of losses (78.4%) observed within the HPV-16 E2 hinge region. Specifically, deletions within the E2 hinge region were detected most often between nucleotides (nt) 3243 and 3539. The capacity to detect low-frequency HPV-16 integration events was highly limited due to the common presence and abundance of HPV episomal forms. HPV-16 E2 expressed from intact episomes may act in trans to regulate integrated genome expression of E6 and E7.

Based on the tumor grade, it has been shown that in low-grade lesions, p16 INK4a is diffusely expressed in ~60% of CIN1 and mostly associated with HR-HPV genotypes, but HR-HPV presence was detected in p16 INK4a negative tumors [36, 39]. In addition, high incidence of HR-HPV has been observed among young women and most of these infections were tran- sient and regress spontaneously [39]. We therefore concluded that p16 INK4a overexpression is already in- dicative of advanced viral interference progressing to- wards invasive cancer where aside from active viral replication there is significant morphological change occurring at histology, cellular and molecular level which can be visually scored. However, in invasive cervical cancer, the HPV protein expression was not detectable by IHC and HPV genotyping in FFPE tumor samples.

HPV 16 and 18 are the major aetiological risk factors for cervical carcinoma. Our overall prevalence of the two major HPV types (16 and 18) was over 70%, which is sim- ilar to the IARC multicentric case-control study by Castell- sague et al. [1], the study by Hammouda et al. from Algeria [18] that both used fresh samples and GP5+/6+ PCR assay, as well as the most recently meta analysis of the published literature [9,10]. The study of Castellsague et al. [1], which provides pooled data of eight case control studies conducted in North Africa (Algeria, Morocco), South America (Brazil, Paraguay, Peru) and South East Asia (India, Thailand, Philippines), showed HPV 16 prev- alence of cervical adenocarcinomas of 42.7%, HPV 18 at 31.8% and HPV45 3.8% [1]. However, regional differ- ences were noticeable with a high prevalence of HPV 16 in North Africa and South America, while in South East Asia there was a high prevalence of HPV 18. A recent study from Mozambique [19] on invasive cervical cancer reported a similar prevalence of HPV 16 (about 47%) and of HPV 16 and 18 combined (about 71%) as in our study. Compared with the results of pooled analyses of invasive cervical cancer from different continents [9,10,20], our study presents a lower prevalence of HPV 16 (44.7%) than in Europe, America, Northern Africa and South Asia but comparable with Sub-Saharan Africa, while the HPV 18 prevalence is higher (28.8%) than in all regions [9]. Con- sidering the adenocarcinomas only [1], the prevalence of HPV 16 in our study is lower (35.0%) than in North Africa (72.7%), South America (71.7%) and comparable with

These data provide the first concrete evidence to explore why not all Trusts offer the invasive cervical cancer review to patients and that many of those that do are selective about the women they are offered to. Only 53% of respondents disclose the review results but anecdotal evidence suggests that the true figure is likely to be even lower. For those respondents who did not offer the review, there were four main issues preventing them from doing so: time constraints, lack of awareness or misunderstanding of the guidelines (including the perception that it was someone else’s job) and a fear of causing additional distress to patients; a less identified issue was the fear of litigation. The low awareness or misunderstanding of the guidance found in this study is not easy to understand as it is readily available alongside all other documents of the programme. It could be because the guidelines are not directed at a particular professional group and therefore lack professional ownership, and/or because there has been a lack of emphasis on their implementation in addition to a lack of engagement in the process from some clinicians. The issues raised by those who do not offer the review resonate well with the negative aspects of the review meeting identified by respondents who do conduct them. Causing distress to patients was the most often mentioned issue, with professional anxiety including the fear of litigation coming second. Time constraints were also mentioned.

Human papilloma virus (HPV) is considered as the main sexually transmitted etiological agent for the cause and progression of preneoplastic cervical lesions to cervical cancer. This study is discussing the prevalence of HPV and its genotypes in cervical lesions and invasive cervical cancer tissues and their association with various risk factors in women from Varanasi and its adjoining areas in India. A total of 122 cervical biopsy samples were collected from SS Hospital and Indian Railways Cancer Institute and Research Centre, Varanasi and were screened for HPV infection by PCR using primers from L1 consensus region of the viral genome. HPV positive samples were genotyped by type-specific PCR and sequencing. The association of different risk factors with HPV infection in various grades of cervical lesion was evaluated by chi-square test. A total of 10 different HPV genotypes were observed in women with cervicitis, CIN, invasive squamous cell cervical carcinoma and adenocarcinoma. Increased frequency of HPV infection with increasing lesion grade (p=0.002) was observed. HPV16 being the predominant type was found significantly associated with severity of the disease (p=0.03). Various socio- demographic factors other than HPV including high parity (p<0.0001), rural residential area (p<0.0001), elder age (p<0.0001), low socio-economic status (p<0.0001) and women in postmenopausal group (p<0.0001) were also observed to be associated with cervical cancer.These findings show HPV as a direct cause of cervical cancer suggesting urgent need of screening programs and HPV vaccination in women with low socio- economic status and those residing in rural areas.

Introduction: The objectives of this study were to describe the diagnostic and therapeutic aspects, identify problems and evaluate the survival rate of inva- sive cervical cancer patients. Patients and method: It was a retrospective de- scriptive study of 7 years from 1 January 2006 to 31 December 2012. Records of invasive cervical cancer were histologically confirmed. The clinical and therapeutic data collected were transferred to Epi info 7 and SSPS version 18 software with a significance level p < 0.05. The telephone network was used to provide information on the vital condition after confidential agreement. Kap- lan Meier was used to assess the overall survival rate. Results: Invasive cancer of the cervix was frequent (58.79%) with an annual median rate of 16.7%, with extremes of 5.8% and 20.6%. 88.70% of the patients was referred from regions of the country (54.02%); the median age was 50 years with extremes of 16 and 84 years and a peak of 29.6% between 35 and 44 years; 76.20% were house- wives; uneducated women were about 60.12%; Stage III was about 45.3%. Most of the patients were confirmed histologically after 30 days (68%). The means of treatment were surgery about 91 (29.26%), palliation 75 (24.12%), radiotherapy 59 (18.97%) and chemotherapy 41 (13.18%) with surgery (9, 65%) or radiotherapy (4.82%). The main complication was metrorrhagia, 164 cases (56.55%), with overall survival rate of 51.8% at 2 years and 5.1% at 5 years. Conclusion: Invasive cervical cancer in later stages is treated for low survival in the context of our work. Early detection and treatment of precan- How to cite this paper: Camara, M.K.,

This study was supported by grants from the Oklahoma Center for the Advancement of Science and Technology (OCAST HR05-136) and from the National Cancer Institute (03-A117523) as well as from contract N02-CP- 31102 from the National Cancer Institute. Drs. Wentzensen and Schiffman are supported by the Intramural Research Program of the National Institutes of Health. Special thanks are due to Greg Rydzak, Information Management Services, Silver Spring, MD for his assistance in data analysis as well as to Tracey Young and her associates in the Department of Obstetrics and Gynecology and Susan Nagelhout, CTR of the OU Medical Center Tumor Registry for their efforts in obtaining patient follow-up information.

a high viral load, were suggested to be strong risk factors for incident-abnormal Pap smear results during monitoring. Hence, assessment of the viral load might be helpful in iden- tifying women at risk for high-grade dysplasia, as reported by Schlecht et al who measured viral burden using PCR, and by Sun et al who measured RLUs using HC2. Schlecht et al concluded that the risk of incident lesions increased with viral load at enrolment and that viral burden appears to have an independent effect on dysplasia incidence. Measurement of viral load, as a surrogate for HPV persistence, may identify women at risk of developing cervical cancer precursors. The recognition of HR HPVs as etiological agents of cervi- cal cancer has increased the demand for testing for HPV, to detect abnormal cervical smears, and for cervical cancer screening, supporting the concept of HPV vaccination against an important subtype.

Notably, our results provide insights into the oncogenic potentials of several genotypes currently IARC-classified as probably oncogenic in humans. Our meta-analytic assessment of the oncogenic potentials of HPV-69 and -82 (both α-5 species), -30 (α-6), -67 (α-9), and -34 and -73 (α-11) was based on small numbers of cases, which yielded particularly wide CIs. However, they ranked among carcinogenic HPV genotypes, which could sug- gest stronger oncogenic potentials than assumed so far. To date, evidence for HPV-30, -34 and -69 has relied on their phylogenetic analogy to other HPV genotypes, while HPV-67, -73 and -82 were positively associated with cancer but lack strong mechanistic evi- dence [8,11]. In contrast, HPV-53, -66 and -70, also placed in the probably carcinogenic subgroup [8,11], had lower relative ORs in our analyses. Hence, overall, our analysis of available epidemiologic data provided more discrepant results for the probably carcinogenic genotype distribution.

HPV type 16 or 18 infections are responsible for approximately 60-80% of all invasive cancers, varying according to the patient ’ s socioeconomic status [6]. Of all new HPV infections, both oncogenic and non-onco- genic type infections last between eight and five months, respectively, and the large majority of initially HPV- infected women show clearance within two years [7]. Pre-invasive surrogate lesions of squamous cervical can- cer would be those of grade II and III, with the lowest potential of regression being that for grade III cervical intra-epithelial neoplasia [8]. Since our patient refused histopathological verification of the first cytological abnormalities in 1993, we were unable to determine whether a single, persistent HPV type 18 infection gave rise to her cervical cancer, which was diagnosed in 2003. The assumption that this was the case is highly likely to be true, since progression from HPV infection to invasive cancer is believed to take place during the course of several years, although we cannot exclude HPV type 18 reinfection after initial clearance. Cervical

Cervical cancer is a major cause of morbidity and mortality among women in sub-Saharan countries and about 70% of cervical cancers are caused by Human Papillomavirus (HPV) types 16 and 18 which are transmitted sexually through body contact. Some studies have shown that HIV-infected women after being infected with HPV infection have a high risk to progress to HPV-related cervical diseases and invasive cervical cancer than women without having HIV infection [1, 2, 3].

Background: Organized cervical cancer screening services are presently lacking in Nigeria contributing to late presentation and diagnosis of invasive cervical cancer cases (ICCs) at advanced stages in most gynecologic units in Nigeria. We evaluated outcomes of ICCs diagnosed at Jos University Teaching Hospital (JUTH) to better understand factors associated with cervical cancer survival in similar resource limited settings. Methods: We performed a retrospective cohort study with a prospective follow up data to estimate time from diagnosis to mortality among women diagnosed with ICCs at JUTH. Women who were diagnosed with ICCs between January 2011 and May 2013 were followed up after initial evaluation at JUTH and subsequent referral for specialized treatment in one of the national oncology treatment centers in Nigeria. The main outcome measured was all-cause mortality rate and overall survival (OS) after diagnosis of ICC. The follow up data were updated and observations were censored March 31, 2015. The overall death rate was estimated using the total number of death events and the cumulative follow-up time from diagnosis to death. We conducted Cox proportional hazard regression to assess factors associated with death.

Abstract: Programmed cell death 4 (PDCD4) is a tumor suppressor, and it inhibits tumor progression and metasta- sis. Even though down-regulation of PDCD4 has been implicated with many different types of human cancers, its roles in the progression of cervical cancer remain unexplored. Here, we have systematically examined the expres- sion pattern of PDCD4 in cervical tissues. 15 cervical normal tissues, 14 cervical intraepithelial neoplasia (CIN) or carcinoma in situ (CIS) of cervix tissues and 78 invasive cervical cancer (ICC) tissues were analyzed by immuno- histochemistry. Compared with the cervical normal tissues, the expression of PDCD4 was significantly reduced in all cancerous tissues. The extent of PDCD4 reduction can be correlated with the cervical cancer progression and severity. Furthermore, the decreasing of PDCD4 expression correlated with lymph node metastasis, histological type and p53 status. Thus, our study demonstrated that the reduction of PDCD4 was closely associated with the progres- sion of cervical cancer and it might serve as a potential diagnosis marker.

In Nigeria, the sad and devastating situation of cervical cancer is not just the high incidence and prevalence of the disease, but of greater concern is the limited infrastructure for effective treatment for invasive cervical cancer particularly when diagnosed in late stages. A recently published data from a federal tertiary academic medical center in Nigeria 11 showed that majority of these cancers are detected at advanced stages with low survival probability. Additionally, there are several related social factors affecting access to treatment of cervical cancer, even in settings where treatment facilities are available within the country. The National Health Insurance Scheme (NHIS) in Nigeria does not provide coverage for cervical cancer prevention or treatment services and most patients incur heavy out-of-pocket payments 12 . Leaving individuals to bear the cost for such lifesaving preventive and therapeutic services, implicitly limits the utilization of cervical cancer services which could contribute to the late presentation in advanced stages with dismal survival probability. Even in developed societies were treatment facilities are available, cost related factors, health insurance, low levels of health literacy, lack of social support and transportation barriers have limiting effects on patients receiving care in a timely fashion 4,13- 17 . It is therefore imperative to look closely at the options for improving cervical cancer health outcomes in Nigeria and similar settings in Africa in the perspective of societal rather than individual investments.

Cervical cancer (CC) is the second leading cause of can- cer deaths in women, with more than 80% of these oc- curring in developing countries that have limited access to screening programs. It is estimated that 12,170 women will develop cervical cancer and about 4,220 women will die from cervical cancer in the United States during 2012 [1]. And in China, the mortality rate of cer- vical cancer ranged from 2 to 4 per 105 population in urban areas, 0 to 7 per 105 population in rural areas during the period of 1996 to 2005 [2]. Remarkably, it al- ways takes about ten years to arise from precancerous lesion to invasive cervical cancer. For this reason, the ef- fective screening of precursor lesion is of great import- ance, which makes cervical cancer preventable and curable. Cytological examination and HPV test are the most widely applied screening methods for CC and its precursor (cervical intraepithelial neoplasia, CIN) lesion. Although the implementation of the Papanicolaou test has been in routine, the test has limited accuracy not likely to be improved with enhanced collection and screening procedures. Specifically, the inability to dis- tinguish high-grade CIN with potential possibility of progression to invasive cancer from pathologically insig- nificant or regressing dysplasia contributes to overtreat- ment, whereas false-negative results could not been eliminated. Furthermore, although 95% of patients with precancerous lesions harbour oncogenic HPV, only a small fraction of these eventually progresses to invasive carcinoma (invCA) [3]. Progression of a high-risk HPV infected CIN lesion to invCA is a result of further spe- cific genetic alterations within the host cell genome. One of the consequences that are crucial for tumor de- velopment is an increased activity of telomerase.

Background: Uterine cervical cancer (UCC) represents a public health prob- lem in many part of the world. The use of new technologies is leading to in- creased treatment costs, resulting in a substantial economic impact world- wide. Standardization of economic evaluation methods is needed to improve comparisons between jurisdictions. Objective: To identify the methods used to measure the cost of treating invasive UCC, and to search for correlations between cancer treatment expenditures and local economies. Methods: We searched articles in MEDLINE, LILACS, and SciELO with no language re- strictions, and included publications from January 01, 2007 to December 31, 2016. Studies were included if they described the annual direct cost of inva- sive cervical cancer and detailed the costing method. Complete economic evaluations were excluded. Results were described in 2016 international dol- lars. Results: Of 1581 studies initially reviewed, 13 articles were included in the analysis. Six articles used a bottom-up; six used a top-down approach and one used both. Annual cost per patient varied from I$ 2146.22 (Poland) to 34,351.54 (Sweden). Middle-income countries (MIC) spent median 72.52% of its GDP per capita on the treatment of invasive cervical cancer, while high-income countries (HIC) spent median 30.12% (p = 0.032). No sig- nificant difference was found when separated by costing method. Conclu- sions: We found that, for the treatment costs of invasive UCC, the percen- tages of GDP per capita were statistically higher in MIC than in HIC. How- ever, no significant difference was found between costing methods, and the top-down approach could be used.

The relatively high risk level of invasive cervical cancer in Taiwan implies the urgency to improve the compli- ance rate of cervical screening to the early detection of SIL and cervical cancer, even though the ICER of pro- phylactic vaccination would rise accordingly because the marginal effectiveness of vaccination would be dimin- ished as improvement in cytological screening would decrease the baseline incidence of invasive cervical can- cer without adding HPV vaccination. Moreover, during the model calibration process, we discovered an upward trend of cervical cancer incidence by age that reflected inadequate compliance with cervical screening among older women, particularly those older than 60 years (Figure 2). Had the cervical screening compliance for older women improved to be comparable with those of younger women, the cumulative incident cases with cer- vical cancer would have decreased in both cohorts with or without vaccination, while the ICER of HPV vaccine would go up slightly to US$14,120 per QALY gained.

In the present study, the overexpression of p16INK4a in the cervical cancer samples deter- mining by the percentage of positive squamous cells per category was reported. Moreover, to test the predictive power of p16INK4a as a diagnos- tic marker for precancer and invasive cervical cancer, ROC curves were applied. ROC analysis and calculation of AUC specified the variance of sensitivity and specificity (17). A cut-off value of 54.43% was established and relatively high sensi- tivity (100%), specificity (100%) were obtained, Accordingly, p16INK4a could be an applicable surrogate marker to discern CIN from other similar tumors and assess the risk of CIN 2-3. These findings are agreement with previous re- ports regarding the marker potential of p16INK4a for prediction of CINs (18-21). A