Human papillomavirus infection and lymphoma incidence using cervical conization as a surrogate marker: a Danish nationwide cohort study.

Persistent human papillomavirus (HPV) infection may promote carcinogenesis by hyperactivation of the immune system. We, therefore, explored the associations between HPV infection and risk of Hodgkin and non-Hodgkin lymphoma in a nationwide cohort study using conization as a surrogate marker. We identified all Danish women who underwent conization between 1978 and 2011. We computed standardized incidence ratios and 95% confidence intervals for Hodgkin and non-Hodgkin lymphoma based on national cancer incidence rates. Among 87 435 women who underwent conization, we noted an increased incidence of Hodgkin (standardized incidence ratio 1.48, 95% confidence interval 1.05-2.02) but only a slight increase for non-Hodgkin lymphoma (standardized incidence ratio 1.10, 95% confidence interval 0.97-1.25). As measured by conization, HPV infection is associated with an increased risk of lymphoma. This association may be attributable to a chronic immune activation induced by persistent HPV infection and/or failure of the immune system both to clear HPV infection and to control lymphoma development. Copyright © 2015 John Wiley & Sons, Ltd.

High performance of combined HPV testing and genotyping for HPV16/18/52/58 in triaging women with minor cervical cytological abnormalities in northern Thailand.

Human papillomavirus (HPV) infection is an important cause of cervical cancer. Screening with cytology or combined cytology and HPV testing helps to detect early cervical cancers and precancerous lesions (high-grade squamous intraepithelial lesion or worse [HSIL+]). Minor cytological abnormalities (atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion) account for the majority of abnormal cervical cytology results, but only 10-20% of women with minor cytological abnormalities have histologic HSIL+. Triage tests are useful to identify the high-risk patients and reduce the colposcopy burden. This study was aimed to evaluate the triage performance of combined HPV DNA testing and genotyping. Cervical samples from women with minor cytological abnormalities, who underwent colposcopy at Chiang Mai University Hospital in northern Thailand between October 2010 and February 2014, were tested for HPV DNA using Hybrid Capture 2 (HC2). Genotyping was performed using Linear Array assay. Of 223 women with cervical histology confirmation, histologic HSIL+ was detected in 25 women (11.2%). The sensitivity, specificity, positive predictive value, and negative predictive value of 3 triage methods for histologic HSIL+ were; 100%, 47.5%, 19.4%, and 100% by HC2 only; 40.0%, 88.4%, 30.3%, and 92.1% by combined HC2 and genotypes HPV16/18; and 96.0%, 75.8%, 33.3%, and 99.3% by combined HC2 and genotypes HPV16/18/52/58. Triage using combined HC2 and genotypes HPV16/18/52/58 showed significantly greater area under the receiver operating curve than the other 2 methods (P < 0.001). Combined HPV DNA testing and genotyping for HPV16/18/52/58 is useful for triaging women with minor cervical cytological abnormalities in northern Thailand.

Prognostic factors for small cell neuroendocrine carcinoma of the uterine cervix: an institutional experience.

OBJECTIVE: This study aimed to determine the clinicopathologic characteristics that affected the survival in patients with small cell neuroendocrine carcinoma of the uterine cervix (SNEC). MATERIALS AND METHODS: All patients with SNEC treated at Chiang Mai University Hospital between January 1995 and October 2011 were retrospectively reviewed with histologic confirmation of SNEC diagnosis. The prognostic predictors for survival were assessed using competing risk regression analysis concerning the probabilities of competing events. RESULTS: One hundred thirty histologically confirmed patients with SNEC met the study criteria. The median overall survival and median cancer-specific survival (CSS) for entire group were 47.8 and 58.1 months, respectively. Five-year CSS for patients with early-stage disease was 62.6% and for patients with advanced-stage disease was 18.1% (P < 0.001). Among the patients with surgically treated early-stage disease, those with adjuvant chemotherapy had a better 5-year survival rate than those with surgery alone, those with adjuvant radiotherapy, and those with adjuvant chemoradiation therapy (P = 0.041). In multivariable analyses, decreased survival in patients with early-stage disease was associated with age older than 60 years at diagnosis (hazards ratio [HR], 4.9; P = 0.007) and deep stromal invasion (HR, 2.9; P = 0.011). Among the patients with advanced-stage disease, decreased survival was associated with age at diagnosis (older than 60 years: HR, 9.9; P < 0.001 and younger than 45 years: HR, 3.4; P = 0.035) and International Federation of Gynecology and Obstetrics stage IV (HR, 7.4; P = 0.024). CONCLUSIONS: International Federation of Gynecology and Obstetrics stage, age at diagnosis, and deep stromal invasion were important prognostic factors for CSS in patients with SNEC. Adjuvant chemotherapy may provide survival benefits in surgically treated patients with early-stage SNEC.

Prognostic Value of Tumor Budding in Early-Stage Cervical Adenocarcinomas

Background: Tumor budding has recently been reported as an independent adverse prognostic factor for colorectal adenocarcinomas and other types of carcinoma in the digestive tract. This study aimed to evaluate the prognostic value of tumor budding in patients with early-stage cervical adenocarcinomas and any associations with other clinical and pathological features. Methods: Histological slides of patients with early-stage (IB-IIA) usual-type endocervical adenocarcinoma who underwent radical hysterectomy and pelvic lymph node dissection, without preoperative chemotherapy, between January 2006 and December 2012 were reviewed. Tumor budding was evaluated in routinely-stained sections and defined as detached single cells or clusters of fewer than 5 cells in a tumor invasive front and was stratified based on the number of bud counts in 10-high-power fields as low (<15 buds) and high (≥15 buds). Correlations between tumor bud count and other clinical and pathological variables including follow-up outcomes were assessed. Results: Of 129 patients, a high tumor bud count was observed in 15 (11.6%), positively associated with histologic grade 3 (p<0.001), invasive pattern C (Silva System) (p=0.004), lymph node metastasis (p=0.008), stage IB2-IIA (p=0.016), and tumor size >2 cm (p=0.036). Kaplan-Meyer analysis showed a significant decrease in both disease-free survival and cancer-specific survival for patients with a high tumor bud count (p=0.027 and 0.031, respectively). On multivariate analysis, histologic grade 3 was the only independent predictor for decreased disease-free survival (p=0.004) and cancer-specific survival (p=0.003). Conclusions: A high tumor budding count based on assessment of routinely-stained sections was found to be associated with decreased disease-free and cancer-specific survival in patients with early-stage cervical adenocarcinomas. However, it was not found to be an independent prognostic predictor in this study.

Genotyping for Human Papillomavirus (HPV) 16/18/52/58 Has a Higher Performance than HPV16/18 Genotyping in Triaging Women with Positive High-risk HPV Test in Northern Thailand.

BACKGROUND: Testing for high-risk human papillomavirus DNA (HPV test) has gained increasing acceptance as an alternative method to cytology in cervical cancer screening. Compared to cytology, HPV test has a higher sensitivity for the detection of histologic high-grade squamous intraepithelial lesion or worse (HSIL+), but this could lead to a large colposcopy burden. Genotyping for HPV16/18 has been recommended in triaging HPV-positive women. This study was aimed to evaluate the screening performance of HPV testing and the role of genotyping triage in Northern Thailand. METHODS: A population-based cervical screening program was performed in Chiang Mai (Northern Thailand) using cytology (conventional Pap test) and HPV test (Hybrid Capture 2). Women who had abnormal cytology or were HPV-positive were referred for colposcopy. Cervical samples from these women were genotyped using the Linear Array assay. RESULTS: Of 5,456 women, 2.0% had abnormal Pap test results and 6.5% tested positive with Hybrid Capture 2. Of 5,433 women eligible for analysis, 355 with any positive test had histologic confirmation and 57 of these had histologic HSIL+. The sensitivity for histologic HSIL+ detection was 64.9% for Pap test and 100% for Hybrid Capture 2, but the ratio of colposcopy per detection of each HSIL+ was more than two-fold higher with Hybrid Capture 2 than Pap test (5.9 versus 2.8). Genotyping results were available in 316 samples. HPV52, HPV16, and HPV58 were the three most common genotypes among women with histologic HSIL+. Performance of genotyping triage using HPV16/18/52/58 was superior to that of HPV16/18, with a higher sensitivity (85.7% versus 28.6%) and negative predictive value (94.2% versus 83.9%). CONCLUSIONS: In Northern Thailand, HPV testing with genotyping triage shows better screening performance than cervical cytology alone. In this region, the addition of genotyping for HPV52/58 to HPV16/18 is deemed necessary in triaging women with positive HPV test.

Prognostic evaluation of tumor-stroma ratio in patients with early stage cervical adenocarcinoma treated by surgery.

BACKGROUND: The tumor-stroma ratio (TSR) represents the percentage of neoplastic cell components compared to the combined area of neoplastic cells and the surrounding tumor-induced stroma. A low TSR (predomination of stromal component) has been demonstrated to be an independent adverse prognostic factor in cancers of several organs. In cervical carcinoma patients, TSR has been evaluated in only one previous study with different histological types. The present study aimed to assess the prognostic value of TSR in early stage cervical cancer patients with adenocarcinoma histology only. MATERIALS AND METHODS: Histological slides of patients with early stage (IB-IIA) cervical adenocarcinoma who underwent surgical treatment between January 2003 and December 2011 were reviewed. Patients who had received preoperative chemotherapy were excluded. TSR was categorized as low (<50%) and high (≥50%). Correlations between TSR and clinicopathological variables were evaluated. Prognostic values of TSR and other variables were estimated using Cox's regression. RESULTS: Of 131 patients; 38 (29.0%) had low TSR and 93 (71.0%) had high TSR. The patients with low TSR had significantly higher proportions of deep cervical stromal invasion (outer third of wall, p=0.011; residual stroma less than 3 mm, p=0.008) and parametrial involvement (p=0.026). Compared to the patients with high TSR, those with low TSR tended to have lower 5-year disease-free survival rate (83.8% versus 88.9%) and overall survival rate (85.6% versus 90.3%), although the differences were not statistically significant. Low TSR was significantly associated with decreased overall survival in univariate analysis (HR 2.7; 95% CI 1.0-7.0; p=0.041), but not in multivariate analysis. TSR was not significantly associated with decreased disease-free survival. CONCLUSIONS: Low TSR is associated with decreased overall survival in patients with early stage cervical adenocarcinoma treated by surgery. However, it was not found to be an independent prognostic predictor in this study.

Histological type-specific prognostic factors of cervical small cell neuroendocrine carcinoma, adenocarcinoma, and squamous cell carcinoma.

BACKGROUND: The study aimed to determine the prognostic impact of clinical and pathological factors on survival among patients with small cell neuroendocrine carcinoma (SNEC), adenocarcinoma (ADC), and squamous cell carcinoma (SCC). METHODS: Eligible participants were all patients with histologically confirmed cervical cancer treated at Chiang Mai University Hospital between 1995 and 2011. We included all patients with SNEC and randomly enrolled patients with ADC and SCC. We used competing-risk regression analysis to examine the risk of cancer-related death by histological type. RESULTS: We included 130 (6.2%) women with SNEC, 346 (16.4%) with ADC, and 1,632 (77.4%) with SCC. Age >60 years (hazard ratio [HR] 4.9, 95% confidence interval [CI] 2.0-12.0) and lymph node involvement (HR 3.0, 95% CI 1.2-7.4) were prognostic factors among surgically-treated patients with SNEC. Deeper stromal invasion (HR 3.6, 95% CI 1.6-8.3) was a prognostic factor in patients with SCC. In patients with advanced SNEC, age >60 years had a strong prognostic impact (HR 2.6, 95% CI 1.0-6.5) while the International Federation of Gynecology and Obstetrics stages III and IV were prognostic factors for patients with advanced stage ADC (HR 2.9, 95% CI 2.0-4.4 and HR 4.5, 95% CI 2.6-7.9, respectively) and SCC (HR 1.7, 95% CI 1.4-2.0 and HR 3.7, 95% CI 2.8-4.9, respectively) compared with the International Federation of Gynecology and Obstetrics stage IIB. CONCLUSION: Clinical and pathological prognostic factors in cervical cancer differed according to histological type. Taking the important prognostic factors for each histological type into consideration may be beneficial for tailored treatment and follow-up planning.

Prognostic impact of histology in patients with cervical squamous cell carcinoma, adenocarcinoma and small cell neuroendocrine carcinoma.

BACKGROUND: Clarifying the prognostic impact of histological type is an essential issue that may influence the treatment and follow-up planning of newly diagnosed cervical cancer cases. This study aimed to evaluate the prognostic impact of histological type on survival and mortality in patients with cervical squamous cell carcinoma (SCC), adenocarcinoma (ADC) and small cell neuroendocrine carcinoma (SNEC). MATERIALS AND METHODS: All patients with cervical cancer diagnosed and treated at Chiang Mai University Hospital between January 1995 and October 2011 were eligible. We included all patients with SNEC and a random weighted sample of patients with SCC and ADC. We used competing-risks regression analysis to evaluate the association between histological type and cancer-specific survival and mortality. RESULTS: Of all 2,108 patients, 1,632 (77.4%) had SCC, 346 (16.4%) had ADC and 130 (6.2%) had SNEC. Overall, five-year cancer-specific survival was 60.0%, 54.7%, and 48.4% in patients with SCC, ADC and SNEC, respectively. After adjusting for other clinical and pathological factors, patients with SNEC and ADC had higher risk of cancer-related death compared with SCC patients (hazard ratio [HR] 2.6; 95% CI, 1.9-3.5 and HR 1.3; 95% CI, 1.1-1.5, respectively). Patients with SNEC were younger and had higher risk of cancer-related death in both early and advanced stages compared with SCC patients (HR 4.9; 95% CI, 2.7-9.1 and HR 2.5; 95% CI, 1.7-3.5, respectively). Those with advanced-stage ADC had a greater risk of cancer-related death (HR 1.4; 95% CI, 1.2-1.7) compared with those with advanced-stage SCC, while no significant difference was observed in patients with early stage lesions. CONCLUSION: Histological type is an important prognostic factor among patients with cervical cancer in Thailand. Though patients with SNEC were younger and more often had a diagnosis of early stage compared with ADC and SCC, SNEC was associated with poorest survival. ADC was associated with poorer survival compared with SCC in advanced stages, while no difference was observed at early stages. Further tailored treatment-strategies and follow-up planning among patients with different histological types should be considered.