The significance of perineural invasion in early-stage cervical cancer

Introduction

Cervical cancer spreads directly and through lymphatic and vascular channels. Perineural invasion is an alternative method of spread. Several risk factors portend poor prognosis and inform management decisions regarding adjuvant therapy.

Objective

To evaluate the incidence and significance of PNI in early cervical cancer.

Methods

Retrospective chart review of early-stage cervical cancer patients (IA-IIA) from 1994 to 2009.

Results

One hundred ninety two patients were included, 24 with perineural invasion in the cervical stroma (cases) and 168 without (controls). The mean age of the cases was 53 years, versus 45.9 in the controls (P = 0.01). PNI was associated with more adjuvant therapy (P = 0.0001), a higher stage (P = 0.005), a larger tumor size (≥ 4 cm) (P < 0.0001), lymphovascular space invasion (P = 0.002), parametrial invasion (P < 0.0001) and more tumor extension to the uterus (P = 0.015). On multivariate analysis using an adjusted hazard ratio, risk factors for recurrence included grade (HR, 95% CI; 3.61, 1.38-9.41) and histopathology (HR, 95% CI; 2.85, 100-8.09). Similarly, risk factors for death included grade (HR, 95% CI; 3.43, 1.24-9.49) and histopathology (HR, 95% CI; 3.71, 1.03-13.33). Perineural invasion was not identified as an independent risk factor for either recurrence or death. The mean follow up time was 56 months. There was no significant difference in recurrence (P = 0.601) or over-all survival (P = 0.529) between cases and controls.

Conclusion

While perineural invasion was found to be associated with multiple high-risk factors, it was not found to be associated with a worse prognosis in early cervical cancer.     

Conizacion con asas diatermias en lesiones premalignas de cuello uterino

Objective

To compare the effectiveness of uterine conization in high-grade cervical squamous intraepithelial lesions (HSIL) by means of surgical electrical excision with Trucone loop or Leep loop.

Subjects and methods

We performed a comparative study that included 150 patients, aged between 20 and 45 years, with a diagnosis of HSIL. All patients underwent uterine conization with diathermy loop. The patients were separated into two groups according to the type of loop used.

Results

Both loops were effective in the management of HSIL but significant differences were found in favor of the Trucone loop in surgical time (X: 3.7 ± 0.52, p < 0.01), lesser margin involvement (100% free margins, p < 0.05) and a lower frequency of residual lesions (94.7%, p > 0.01).

Conclusions

Both diathermy loops were effective in the treatment of HSIL but the frequency of complications and residual lesions was lower with the Trucone loop.     

Is low-grade serous ovarian cancer part of the tumor spectrum of hereditary breast and ovarian cancer?

Objective

To determine whether women with low-grade serous ovarian cancer (LGSOC) have personal and family histories of breast and ovarian cancer that are less suggestive of Hereditary Breast and Ovarian Cancer (HBOC), as compared to women with high-grade serous ovarian cancer (HGSOC).

Methods

A single institution, case-control retrospective review of medical records was conducted. Personal demographics, personal cancer history, and family history of breast and ovarian cancer of women with LGSOC were collected and compared to controls with HGSOC, which is known to be associated with HBOC.

Results

195 cases of LGSOC and 386 controls with HGSOC were included in the analysis. Women with LGSOC were significantly less likely to have a first- or second-degree relative with breast or ovarian cancer (p = 0.0016). Additionally, when the personal and family histories were quantified using the AMyriad BRC mutation prevalence tables, women with LGSOC had lower scores indicative of a less suggestive family history for HBOC (p = 0.027).

Conclusions

In this study, women with LGSOC had family histories that were less suggestive of HBOC compared to women with HGSOC, especially when the degree of relatedness of affected relatives was taken into account. By beginning to determine if LGSOC is part of the tumor spectrum seen in HBOC, this study is an important step towards refining hereditary cancer risk assessment for women with ovarian cancer.     

Immunohistochemical expression of Annexin A2 and S100A proteins in patients with bulky stage IB-IIA cervical cancer treated with neoadjuvant chemotherapy

Objective

Abnormal expression of Annexin A2 and S100A proteins has been reported to induce sensitivity/resistance to chemotherapy in a variety of cancers. The aim of this study was to evaluate the significance of Annexin A2 and S100A protein expression to predict response to neoadjuvant chemotherapy and prognostic significance of these protein expressions in bulky stage IB-IIA cervical cancer patients.

Methods

Paired tumor samples (pre- and post-chemotherapy) were obtained from 68 patients who were treated with cisplatin-based neoadjuvant chemotherapy and radical hysterectomy at our hospital from 2006 to 2011. The expression of Annexin A2 and S100A proteins was analyzed by immunohistochemistry.

Results

Thirty-six patients were identified as chemotherapy-response and 32 were non-response. (a). Protein expression in tumor cells: (1). Exposure of tumor cells to chemotherapy results in a change of Annexin A2 and S100A expression (P < 0.05). (2). Annexin A2, S100A8 and S100A9 protein expression correlates with tumor response to chemotherapy (P < 0.05). (b). Protein expression in stromal cells: (1). Expression of Annexin A2, S100A8 and S100A9 was increased, but S100A2 and S100A4 was decreased after exposure to chemotherapy (P < 0.05). (2). Only S100A4 expression was associated with response to chemotherapy (P < 0.05). Multivariate analysis revealed that tumor size (P = 0.022), differentiation (P = 0.000), Annexin A2 expression in stromal cells (P = 0.009), and S100A8 expression in tumor cells (P = 0.008) were independent prognostic factors for progression-free survival of cervical cancer patients.

Conclusions

Expression of some of the measured proteins in tumor and stromal cells correlates with chemotherapy exposure, response to therapy, and progression-free survival.     

Overexpression of gelsolin in human cervical carcinoma and its clinicopathological significance

Objectives.

Cervical carcinoma is the second most common cause of death from gynecological cancers worldwide. Knowledge of the molecular mechanisms underlying the tumorigenesis of cervical cancer cell, except human papilloma virus infection, is limited.

Methods.

A microarray was used to study the differential expression of genes in cancerous tissues to identify new molecular markers for diagnosis and prognosis. Their differential expression was confirmed with Western blotting and immunohistochemical analyses. The clinical correlations and prognostic significance of the aberrantly expressed proteins were evaluated to identify novel biomarkers of cervical cancer.

Results.

The expression of gelsolin was significantly upregulated in 78% of patients with cervical cancer, and gelsolin was selected for further study. Gelsolin expression was stronger in cervical tumor tissues than in the surrounding noncancerous tissues (P < 0.001). Gelsolin expression in the plasma of cervical cancer patients was increased 2.2-fold compared with that of healthy control subjects (P < 0.001). The levels of plasma gelsolin in the early and late stages were significantly different (P = 0.006). According to immunohistochemical analysis, increased gelsolin expression was associated with histological type and FIGO stage II. The 5-year overall survival and recurrence-free survival rates for the low-expression group (cut-off = 115) were significantly higher than those of the high-expression group. Cancer cells with reduced gelsolin expression exhibited reduced migration and proliferation.

Conclusions.

These results provide strong evidence that gelsolin plays an important role in cellular proliferation and migration in cervical cancer and suggest that gelsolin is a promising marker for cervical cancer screening and prognosis.     

Evaluation of Fanconi anaemia genes FANCA, FANCC and FANCL in cervical cancer susceptibility

Objective

Disrupting the function of any of the 13 Fanconi anaemia (FA) genes causes a DNA repair deficiency disorder, with patients being susceptible to a number of cancer types. Variation in the family of FA genes has been suggested to affect risk of cervical cancer. The current study evaluates the influence of three genes in the FA pathway on cervical cancer risk in Swedish women.

Methods

TagSNPs in FANCA, FANCC and FANCL were selected using the Tagger algorithm in Haploview. A total of 81 tagSNPs were genotyped in 782 cases (CIN3 or ICC) and 775 controls using the Illumina GoldenGate Assay and statistically analyzed for association with cervical cancer.

Results

72 SNPs were successfully genotyped in > 98% of the samples. Nominal associations were detected for FANCA rs11649196 (p = 0.05) and rs4128763 in FANCC (p = 0.02). The associations did not withstand correction for multiple testing.

Conclusions

The current study does not support that genetic variation in FANCA, FANCC or FANCL genes affects susceptibility to cervical cancer in the Swedish population.     

Cancerous inhibitor of protein phosphatase 2A is overexpressed in cervical cancer and upregulated by human papillomavirus 16 E7 oncoprotein

Objectives

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified oncoprotein stabilizing c-Myc and promoting cell proliferation and transformation. Here we investigated the role of CIP2A in cervical cancer in vivo and in vitro.

Methods

CIP2A expression was assessed in normal cervical, cervical intraepithelial neoplasia (CIN) I to III and cervical cancer tissues by immunohistochemistry and RT-PCR. Cell growth was explored by cell proliferation assay, colony formation assay and anchorage-independent growth in soft agar after inhibition of CIP2A by siRNA in HeLa, SiHa and Caski cells. Crosstalk of CIP2A and HPV16 E7 was investigated by immunohistochemistry in cervical cancer tissues and by real-time PCR and western blot analysis after HPV16 E7 inhibition by siRNA in SiHa cells.

Results

CIP2A was transcribed in 73.3% of cervical cancer tissues (n = 15) but not in normal cervical tissues (n = 8). CIP2A protein was detected in 52.8% of cervical cancer (n = 72) and 12.5% of CIN III tissues (n = 24) but not in normal (n = 15), CIN I (n = 21) or CIN II samples (n = 25). CIP2A protein level was positively associated with HPV16 E7 level in cervical cancer tissues. CIP2A expression was markedly reduced after E7 depletion. Moreover, CIP2A depletion reduced c-Myc protein level and impaired proliferation and growth of cervical cancer cells.

Conclusions

CIP2A is overexpressed in cervical cancer and promotes the malignant growth of cervical cancer cells. Its expression is upregulated by HPV16 E7. Therefore, CIP2A plays an important role in carcinogenisis of cervical cancer and shows promise for the diagnosis and treatment of cervical cancer.     

Prevalence and genotype distribution of human papillomavirus in women with cervical cancer or high-grade precancerous lesions in Chengdu, western China

Objective

To study the prevalence and genotype distribution of human papillomavirus (HPV) among women with cervical cancer or high-grade squamous intraepithelial lesions (HSIL) in western China.

Methods

Cervical cast-off cells from 144 women with cervical cancer and 63 women with HSIL were tested for HPV genotypes using an oligonucleotide microarray.

Results

The overall HPV prevalence was 80.6% in cases of carcinoma and 61.9% in cases of HSIL. The most common genotypes were HPV-16 (carcinoma, 68.1%; HSIL, 34.9%) and HPV-58 (carcinoma, 8.3%; HSIL, 17.5%). Other high-risk types included HPV-18, -31, -33, -35, -45, and -52, with HPV-18 more common in adenocarcinomas than in squamous cell carcinomas (21.4% vs 3.1%; P < 0.02). The HPV prevalence was lower among patients older than 49 years (P < 0.02).

Conclusion

The prevalence of HPV-16 and HPV-58 was high. This finding may help to improve HPV vaccination and cervical cancer prevention programs in western China.     

Cervical dysplasia in Nigerian women infected with HIV

Objective

To determine the prevalence of and risk factors for cervical dysplasia in HIV-positive women receiving care at the Jos University Teaching Hospital in Nigeria.

Methods

A total of 369 HIV-positive women had cervical cytology performed; HIV-1 RNA viral load and CD4 counts were measured.

Results

Of 369 participants, cervical dysplasia was present in 107 (29.0%) women. However, cervical cytology was abnormal in 252 (68.3%). Among those with abnormal cytology, 145 (57.5%) women had ASCUS, 56 (22.2%) had LSIL, and 51 (20.2%) had HSIL. Median CD4 lymphocyte count was lower in women with dysplasia compared with those without (142 vs 170 cells/mm³; P = 0.04), while median HIV RNA viral load was higher in women with dysplasia (101 781 vs 77 479 copies/mL; P = 0.002). Low CD4 count (< 200 cells/mm³) and evidence of HPV infection were significantly associated with cervical dysplasia.

Conclusion

A high prevalence of cervical dysplasia was found among HIV-positive Nigerian women, which was associated with increased immune suppression.     

Effect of cervical mucus aspiration before intrauterine insemination

Objective

To determine whether cervical mucus aspiration before intrauterine insemination (IUI) has any effect on clinical pregnancy rates.

Method

The outcomes of 186 IUI cycles in 95 consecutive patients in whom mucus was aspired prior to IUI were compared retrospectively with those of 1057 IUI cycles in 505 women.

Results

The pregnancy rate was 15.1% (28 pregnancies for 186 cycles) in the cervical mucus aspiration group and 9.9% (105 pregnancies for 1057 cycles) in the control group (P = 0.05). Mucus aspiration led to significantly increased pregnancy rates for women with unexplained infertility (24% in the aspiration group vs 9.5% in the control group; P = 0.04).

Conclusion

Cervical mucus aspiration before IUI might improve clinical pregnancy rates by yet-to-be-defined mechanisms.     

Knowledge about cervical cancer among Polish and Finnish female students

Objectives

The purpose of the study was to assess the knowledge of Polish and Finnish students about cervical cancer prevention and the factors influencing it.

Study design

427 women took part in the research, 175 of whom were Finns and 252 Poles. The questionnaire had 20 questions. The survey had three parts: (1) socio-metric, (2) a knowledge test-13 questions, (3) questions about the sources of knowledge and their evaluation. Statistical analysis was made using the SPSS 18.0 program. The impact of variables such as socio-metric values or knowledge sources on answers to individual questions was verified using the χ² test, while significance of these variables on the total score was assessed using ANOVA. The significance level was p < 0.05.

Results

Respondents’ knowledge was low. On average both groups got just above 50% of the maximum of 13 points (Polish M = 7.1, SD = 2.24, Finnish M = 6.85, SD = 2.42, p < 0.05). In both groups the percentage of correct answers was highest in the case of questions concerning cytological examination procedures. Factors such as major subject studied, whether or not cytological examination had been undergone had an important influence on respondents’ answers.

Conclusions

There were differences between the studied groups of Polish and Finnish female students in levels of knowledge about cervical cancer, however, in both samples the levels were low. Due to Finns’ marginal performance in the test, together with differences in the sources of knowledge and diverse cervical cancer prevention methods in studied countries, we concluded that knowledge in these domains is not indispensable for a successful cancer prevention programme. What is required, is trust in clinicians and implementation of recommended cancer prevention measures.     

Differentiation of metastatic from non-metastatic lymph nodes in patients with uterine cervical cancer using diffusion-weighted imaging

Objective

This study aims to determine the diagnostic value of diffusion-weighted imaging (DWI) in the differentiation of metastatic lymph nodes from non-metastatic lymph nodes in uterine cervical cancer.

Methods

In 42 patients who underwent lymph node dissection for uterine cervical cancer, conventional MRI and DWI examinations were performed before surgery. Of the 1109 total dissected pelvic lymph nodes, 188 enlarged nodes with a short-axis diameter of 5 mm or greater were included for further analysis. Each of the size-based criteria (i.e., short-axis diameter and long-axis diameter) and ADC-based criteria (i.e., mean ADC, minimum ADC, mean rADC (relative ADC) and minimum rADC) were compared between metastatic lymph nodes and non-metastatic lymph nodes.

Results

There were statistically significant differences between metastatic and non-metastatic lymph nodes in the short-axis diameter, long-axis diameter, mean ADC, minimum ADC, mean rADC and minimum rADC (P < 0.001). The Az of the minimum ADC (0.990) was greater than that of the other ADC-based criteria (0.974, 0.939, 0.976 for mean ADC, mean rADC and minimum rADC, respectively) and all size-based criteria (0.878 for short-axis diameter and 0.858 for long-axis diameter) (P < 0.05). Using the minimum ADC criteria (≤ 0.881 × 10^− 3mm²/s), the sensitivity and specificity for differentiating metastatic from non-metastatic lymph nodes were 95.7% and 96.5%, respectively.

Conclusions

DWI is feasible for differentiating metastatic from non-metastatic pelvic lymph nodes in patients with uterine cervical cancer and minimum ADC could be served as a representative marker.     

Chemoradiation and adjuvant chemotherapy in advanced cervical adenocarcinoma

Purpose

The optimal treatment of women with advanced adenocarcinoma of uterine cervix is still undefined. We compared concurrent chemoradiation (CCRT) and adjuvant cisplatin-based chemotherapy with CCRT alone for advanced cervical adenocarcinoma in a randomized trial at the Hunan Provincial Tumor Hospital in China.

Methods

From 1998 to 2007, 880 patients with clinical FIGO stages IIB-IVA cervical adenocarcinoma were randomized to receive either CCRT or chemoradiation with one cycle of neo-adjuvant chemotherapy with Paclitaxel (135 mg/m²) + Cisplatin (75 mg/m²) before receiving radiation and two cycles of consolidation chemotherapy with the same drugs after radiotherapy in 3-week intervals. The disease control and survival rates were calculated using the Kaplan-Meier method.

Results

All patients completed the treatment plan. 340 patients have relapsed, with a median follow-up duration of 60 months. Patients who received chemoradiation with adjuvant chemotherapy showed a significantly longer disease-free (P < .05), cumulative survival (P < .05) and long-term local tumor control (P < .05). Patients who received CCRT alone had significantly more distant metastasis and pelvic failure than those who received chemoradiation with adjuvant chemotherapy (P < .05).

Conclusion

Incorporating neo-adjuvant and consolidation chemotherapy with Paclitaxel and Cisplatin into concomitant chemoradiation is highly effective, safe and may be a very promising treatment protocol for advanced cervical adenocarcinoma.     

Aggressive characteristics of cervical cancer in young women in Taiwan

Objective

To compare the characteristics and prognosis of cervical cancer in young women (under 30 years) with those of older women (over 30 years).

Methods

A retrospective study of 2443 patients diagnosed with FIGO stage IA-IIA cervical cancer who underwent surgical procedures between January 1983 and December 2007.

Results

Thirty patients (1.2%) were 30 years or younger. The proportion of non-squamous cell carcinoma was higher in patients 30 years or younger compared with in patients over 30 years (14/30, 46.7% vs 10/30, 33.3%; P = 0.001). A higher rate of parametrial involvement was found in the younger group of patients compared with those over 30 years (10/30, 33.3% vs 289/2413, 12.0%; P = 0.001). Patients under 30 years had a higher rate of distant metastases compared with older patients (60% vs 49.7%; P = 0.036).

Conclusions

Non-squamous histology, parametrial involvement, a higher rate of distant metastases, and poorer prognosis are more common in women aged 30 or younger with cervical cancer than in older women with the disease.     

Relevance of gamma-glutamyltransferase--a marker for apoptotic balance--in predicting tumor stage and prognosis in cervical cancer

Introduction

Recent large epidemiologic population-based studies identified gamma-glutamyltransferase (GGT) as a marker for increased cervical cancer incidence. Furthermore, high levels of GGT seem to increase the risk of progression of high-grade cervical dysplasia to invasive carcinoma. Therefore, we evaluated the association between pre-therapeutic serum GGT levels, tumor stage and prognosis in patients with cervical cancer.

Materials and methods

In this multi-center trial, pre-therapeutic GGT levels were examined in 692 patients with cervical cancer. GGT levels were correlated with clinico-pathological parameters. Patients were assigned to previously described GGT risk groups and uni- and multivariable survival analyses were performed.

Results

GGT serum levels were associated with FIGO stage (p < 0.0001) and age (r = 0.2, p < 0.0001) but not with lymph node involvement (p = 0.85), and histological type (p = 0.98). High-risk GGT group affiliation (p = 0.01 and p < 0.0001) was associated with poor disease-free and overall survival in a univariate analysis, but not in a multivariable Cox-regression model (p = 0.59 and p = 0.171). We further investigated the association between prognosis and GGT and observed a linear correlation between GGT and prognosis. Therefore we were not able to identify a clear prognostic cut-off value for GGT in patients with cervical cancer.

Conclusions

High GGT - a marker for apoptosis and cervical cancer risk - is associated with advanced tumor stage in patients with cervical cancer.     

Estrogen decrease coronary artery disease risk in patients with cervical cancer after treatment

Background

The purpose of this study was to explore the possible association between coronary artery disease (CAD) risk and cervical cancer.

Methods

We used data from the National Health Insurance system of Taiwan to address the research topic. The exposure cohort contained 728 patients with cervical cancer. Each cancer patient was randomly frequency-matched with 4 participants by age, index-month, and index-year from the general population who did not have a cancer history before the index date (control group). Cox's proportion hazard regression analyses were conducted to estimate the relationship between cervical cancer and CAD risk.

Results

Among patients with cervical cancer, the overall risk for developing CADs was significantly lower than that of the control group [adjusted hazard ratio (aHR): 0.57, 95% confidence interval (95% CI): 0.41-0.79]. Further analyses revealed that the lower risk was observed only in patients with older age (aHR: 0.57, 95% CI: 0.40-0.82), a shorter follow-up duration (aHR: 0.47, 95% CI: 0.31-0.72), or with estrogen supplements (aHR: 0.39, 95% CI: 0.22-0.68).

Conclusions

The findings from this population-based study suggest that estrogen supplements are associated with a decreased CAD risk in patients with cervical cancer.     

Type-specific human papillomavirus DNA testing with the genotyping array: a comparison of cervical and vaginal sampling

Objective

To compare the detection and typing of human papillomavirus (HPV) between vaginal and cervical specimens by using polymerase chain reaction (PCR)-based reverse-blot genotyping arrays.

Study design

Two hundred and fifty-two women were referred to colposcopy clinics because of suspicious or positive results in a community-based cervical cancer-screening program. Genital tract cells were sampled from the cervix and self-collected from the vagina and tested with the HPV Blot kit.

Results

The HPV Blot kit identified HPV infection in 24.7% of vaginal specimens and in 30.2% of cervical collections. Cervical sampling detected significantly more infections compared to vaginal sampling only for HPV type 52; cervical sampling also detected significantly more high-risk HPV infection overall. The sensitivities of detecting histology ≥cervical intraepithelial neoplasia (CIN) grade 3 using the HPV Blot in vaginal and cervical specimens were 75.0% (95% CI, 47.6-92.7%) and 87.5% (95% CI, 61.6-98.4%), respectively (P = 0.48). Both sampling methods were thus statistically effective at detecting high-grade lesions and cervical cancer (P < 0.0001).

Conclusions

The HPV Blot yielded similar results for both vaginal sampling and cervical sampling in the detection of CIN grade 3 or worse. These findings indicate that self-sampling for HPV testing is a viable cervical cancer screening option.     

Non-uptake of colposcopy in a resource-poor setting

Objective

To determine the rate of acceptance/refusal of colposcopy and the reasons for refusal by women referred for the procedure in southeast Nigeria.

Methods

An audit was performed of the computerized database for all women referred for colposcopy at the University of Nigeria Teaching Hospital, Enugu, from August 1, 2009, to July 31, 2010. The characteristics of those who accepted colposcopy were compared with those who refused the procedure. An interviewer-administered questionnaire was used to assess reasons for refusal and the subsequent treatment chosen.

Results

During the study period, 154 women were referred for colposcopy: 103 (66.9%) accepted and 51 (33.1%) refused. Those who refused were younger and tended to be nulliparous (P = 0.029 and P = 0.004, respectively). The most common reasons for refusal were fears of possible diagnosis of cervical cancer and compromise of future fertility. Most women who refused resorted to spiritual healing.

Conclusion

The rate of refusal of colposcopy in southeast Nigeria was high, indicating an urgent need for appropriate remedial measures instituted through intensive education of women regarding cervical cancer and its prevention. Targeted counseling should be initiated early as part of prescreening counseling.     

Genetic variations of interleukin-1 and -6 genes and risk of cervical intraepithelial neoplasia

Objective

To evaluate the association between five interleukin-1 (IL-1) and -6 gene polymorphisms and risk of high grade cervical intraepithelial neoplasia (CIN 2-3).

Methods

This case-control study investigates five common IL-1 and IL-6 gene polymorphisms in 131 women with CIN 2-3 and 209 controls by pyrosequencing and polymerase chain reaction. Associations between gene polymorphisms and risk of CIN 2-3 are analysed by univariate and multivariable models. Their combined effect on the risk of CIN is evaluated by haplotype analysis.

Results

In a multivariable regression model IL1A −889 (odds ratio 0.3 [95% confidence interval 0.1-0.8], p = 0.01) and smoking (4.0 [1.7-9.1], p = 0.001) are independently associated with the risk of high grade CIN. Haplotype analysis does not reveal any high-risk combinations for the susceptibility of CIN.

Conclusion

The single nucleotide polymorphism IL1A −889 is independently associated with risk of high grade CIN.