Subtypes of endocervical cancer: A retrospective, observational study at Charlotte Maxeke Johannesburg Academic Hospital

Objective We analyzed subtypes of human papilloma virus (HPV) infection in Papanicolaou (Pap) smear results of women in Jeju island, Korea. Methods We investigated the distribution of HPV subtypes according to Pap smear results among 635 women in Jeju island, Korea between October 2005 and October 2010. Results The most prevalent HPV subtypes were HPV 16, 52, 53, 58 in negative Pap smear result and HPV 16, 52, 31, 53, 66 in atypical squamous cell, HPV 52, 53, 56, 66 in low grade squamous intraepithelial lesion, HPV 16, 58, 52, 33, 33 in high grade squamous intraepithelial lesion/squamous cell carcinoma each other. The subtypes of HPV 16, 52, 53, 58, 31 were common in all women participated in study from Jeju island, Korea. And multiple infections were more common in women under 30 years of age than above age as previous study and the majority of HPV multiple infections were high risk types (94.5%). Conclusion This prevalence was some different from previous study of Korean other region, but more similar to Japanese study data. We think this result shows that Jeju island women maybe have the genetic, regional or environmental close relationship with Japanese because of close distance and culture irrespective of different national race.

ObjectiveAlthough the prognostic role of human papilloma virus (HPV) status in oropharyngeal head and neck squamous cell carcinoma (SCC) is well established, growing evidence shows that there may be a prognostic role for HPV status in hypopharyngeal SCC. The objective of this study was to determine the prognostic role of HPV status in hypopharyngeal SCC.MethodsWe performed a retrospective, population‐based analysis of 1934 adult patients with HNSCC diagnosed between 2010‐2016 and treated with a combination of surgery and/or radiotherapy, with or without chemotherapy, and a subset of 641 patients with hypopharyngeal SCC and known HPV status included in the Surveillance, Epidemiology, and End Results (SEER) Head and Neck with HPV Status Database. Patient data were used to determine the adjusted 2‐year cancer‐specific survival (CSS) and overall survival (OS) for the entire cohort and the specific subgroup of hypopharyngeal cancer patients with known HPV status.ResultsOf the 1934 hypopharynx SCC cases, HPV status was unknown in 1294 (66.9%), and 167 (8.6%) were HPV positive; among hypopharynx cases with known HPV status, 21.6% were HPV positive. In models adjusting for sex, age, race/ethnicity, marital status and stage, patients with HPV‐positive hypopharyngeal tumors had improved CSS compared with patients with HPV‐negative tumors (CSS: HR: .57, 95% CI = .38 to .86, P = .008; OS: HR: .49, 95% CI = .34 to .71, P = <.001).ConclusionOur findings in a large cohort of hypopharyngeal SCC with known HPV status and cancer‐specific survival support the hypothesis that HPV has a prognostic role in hypopharyngeal cancer. Consideration should be given to increased testing for HPV in hypopharyngeal SCC.Level of Evidence4

To estimate the association between human papillomavirus (HPV) status and the expression of p53, Ki-67 and bcl-2 in cases of endocervical adenocarcinoma, and the relation with squamous intraepithelial lesions (SIL) and age, 229 cases were selected, treated between 1995 and 2003 in the Hospital Nossa Senhora da Conceiçao. All samples were evaluated by polymerase chain reaction to determine HPV status. Immunohistochemical technique was used to investigate the expression of p53, Ki-67 and bcl-2. The joint occurrence of endocervical adenocarcinoma and SIL were estimated too. In the 229 evaluated cases, 182 cases (79.48%) were associated with the presence of the HPV. The most common types were HPV18 (93 cases - 51.09%) and HPV16 (62 cases - 34.06%). Expression of Ki-67 (p=0.009) and the presence of SIL (p=0.018) were associated to HPV infection. Expression of p53 (p=0.647) and bcl-2 (p=0.671) were not related to HPV status. The mean age of the patients was 53.2 years, without clear correlation between age group and HPV (p=0.095). The presence of HPV, especially type 18 in endocervical adenocarcinoma suggests that this agent can be an important cofactor in the development and progression of glandular neoplasms of the uterine cervix. The joint occurrence of endocervical adenocarcinoma and SIL may support this hypothesis. HPV may promote an increased proliferation index in endocervical adenocarcinoma, shown by the expression of Ki-67.

The incidence of oropharyngeal squamous cell carcinoma (OpSCC) is increasing worldwide. In British Columbia, similar trend is observed. High-risk HPV and p16 have been used as prognostic markers in OpSCC; however, due to the difference in HPV detection methods, the results have been indeterminate. In BC, we do not routinely stain for p16 or investigate tumoral HPV status. This is the first time to link these data with treatment and outcome information. Objectives: To determine HPV status and expression of cyclin D1, p16 and EGFR of OpSCC and their impact on survival. Methods: Patients (N = 151) with primary OpSCC and treated with intent-to-cure at the Vancouver Centre from 2001 to 2007 were retrospectively identified from Pathology database. Outcome data was collected through electronic chart review. Among these patients, 100 (66 %) patients had no recurrence or died without disease at last follow-up (better outcome, Group1) and 50 (33%) patients had persistent disease or died of disease (poorer outcome, Group 2). The high-risk HPV status was determined using Chromogenic in situ hybridization (CISH) (DAKO, Denmark) and expression of p16, EGFR, and cyclin D1 were analyzed using immunohistochemistry. Results: There was no difference in gender, smoking habit, and tumor staging between Groups 1 and 2. However, Group 1 had a significant longer follow-up time comparing to those of Group 2 (50 ± 20 vs. 29 ± 21 months; P &amp;lt; 0.0001). Group1 was 5 years younger than Group 2 (55.5 ± 9.4 vs. 60.1 ± 9.7 years, P= 0.001). HR-HPV had been found in 70% of all cases (N = 105). Group 1 showed significantly higher HR-HPV infection (77% vs. 54%, P = 0.005), more p16 overexpression (80% vs. 64%, P = 0.05), and less cyclin D1 overexpression (16% vs. 36%, P = 0.007). There was no difference observed in EGFR expression. Using Cox Proportional Hazard model for age, sex, treatment type (Surgery and/or radiation, radiation only, combined chemo and radiation therapy), tumor staging (early and late), HPV status, p16, cyclin D1, and EGFR expression, only HPV status (p = 0.0003) and age (p = 0.011) were found to be significant predictors of 5- year survival. After adjusting the age variable, HPV positive patients were 65% less likely to die compared to those HPV negative patients. Those patients with cyclinD1 positive tumors have a 2.8 time elevated risk to die of disease. Conclusion: High frequency of high-risk HPV is identified in OpSCC in British Columbia. Presence of HPV and younger ages have better outcome. The presence of high-risk HPV is an independent factor to long-term survival. (Canadian Cancer Society CCSRI-20336 and BC Cancer Foundation) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-445. doi:1538-7445.AM2012-LB-445

The fourth edition of the World Health Organization classification set up new entities of endocervical adenocarcinoma (ECA), namely the "usual type" and "gastric type." These 2 types are considered to be distinct histogenetically because of their differing immunophenotypes, human papillomavirus (HPV) status, and prognoses. Usual-type ECAs (U-ECAs) are virtually always associated with high-risk human papillomavirus (HR-HPV) infection. Gastric-type ECAs (G-ECAs) are believed not to be associated with HR-HPV infection. Morphologically, U-ECA cells are characterized by mucin-poor and eosinophilic cytoplasm, resembling endometrioid carcinoma (a pseudoendometrioid feature). G-ECA cells are characterized by abundant clear or pale, mucinous cytoplasm and distinct cell borders. However, in routine practice we noticed that some ECAs contain morphologically usual type-like components and gastric type-like components in a single tumor; we have named these "G+U" ECAs. The histogenesis of such tumors has not been investigated. We conducted the present study to clarify the clinicopathologic and immunohistochemical features and HPV status of G+U ECAs, and to determine whether G+U ECAs are genuine G-ECAs mimicking U-ECAs or genuine U-ECAs with gastric type-like morphology. We retrospectively analyzed a series of 70 consecutive cases of ECA diagnosed as mucinous ECA, endocervical type, and we reclassified them on the basis of the latest World Health Organization classification. We identified 48 (69%) pure U-ECAs, 9 pure G-ECAs, and 13 G+U ECAs. Ten of the 13 G+U ECAs (77%) showed no HR-HPV infection by in situ hybridization (HPV-unrelated G+U ECAs) and showed frequent HIK1083 expression and aberrant p53 expression in both usual type-like and gastric type-like components. The other 3 G+U ECAs showed HR-HPV infection (HPV-related G+U EACs) and frequent p16+/p53-/HIK1083- immunophenotype in both usual type-like and gastric type-like components. The U-ECAs were characterized by HR-HPV infection detected by in situ hybridization and frequent p16+/p53-/HIK1083- immunophenotype, similar to that of the HPV-related G+U ECAs. In contrast, the pure G-ECAs were characterized by the absence of HPV infection and frequent HIK1083 expression and aberrant p53 expression, similar to that of HPV-unrelated G+U ECAs. G+U ECAs thus represent a heterogenous group composed of genuine G-ECAs and genuine U-ECAs. Most of the G+U ECAs we examined were genuine HPV-unrelated G-ECAs with usual type-like components showing mucin-poor, eosinophilic cytoplasm (pseudoendometrioid morphology). A small population of G+U ECAs was genuine HPV-related U-ECAs with gastric type-like components showing mucin-rich, voluminous cytoplasm. Thus, both types of ECAs can occasionally display patterns of differentiation suggesting a component of the other type but true mixed tumors do not appear to exist. Ancillary techniques (immunohistochemical analysis of p16, p53, and HPV DNA detection assays) should be used to assure proper classification of tumors with mixed morphologic features.

Cervical cancer screening, involving Papanicolaou (PAP) smear and assessment of p53 expression, is crucial for early detection and prevention of cervical cancer. The aim is to evaluate the concordance between Papanicolaou (PAP) smears and P53 expression in detecting cervical abnormalities in Osogbo women southwest, Nigeria. This cross-sectional study involved 221 women aged 18–65 attending Uniosun teaching hospital for cervical screening between January 2023 and December 2023. Cervical cytology was performed using PAP smears, and P53 expression was assessed through immunohistochemistry of the smear samples. The agreement between cytology, PAP smear results, and P53 expression were analyzed. Of the 221 women, 86 (38.9%) had abnormal Pap smear results, categorized as ASC-US, LSIL, or HSIL. P53 overexpression was observed in 86 (38.9%) cases. A statistically significant association was found between age group and Pap smear results, with a higher proportion of abnormal results among the 30–39 age groups. Additionally, a significant association was observed between miscarriage history and Pap smear results, with a higher proportion of abnormal results among those with more than two miscarriages. The relationship between PAP smear results and p53 expression revealed a statistically significant association (p=0.047), with a higher proportion of normal PAP smear results having negative p53 expression (99.3%) compared to abnormal PAP smear results (100% negative P53 expression). The concordance rate between Pap smear findings and P53 expression, indicating that there is no substantial agreement. The highest concordance was observed in normal cases (95.6%). This study suggests that p53 expression can be used as a complementary negative marker to Pap smear in cervical cancer screening although there was no concordance substantial between PAP smears and P53 expression in detecting cervical abnormalities. This could help in enhancing the accuracy of cervical cancer screening or for monitoring of the disease but not for diagnosis.

Pap smear, colposcopy, and biopsy results were collected from 1988-1993 at a group of family planning clinics. Positive predictive values and likelihood ratios were calculated for diagnosis of high-grade lesions based on age and Pap smear results. One thousand and forty-seven colposcopies were logged; 771 had a biopsy or endocervical curettage. Seventy-nine (10%) were high-grade lesions. If only human papillomavirus (HPV) was reported on the Pap smear, the likelihood of a high-grade biopsy was lowest (positive predictive value, 4.5%; likelihood ratio, 0.4). Women under age 25 were less likely to have high-grade biopsies (positive predictive value, 7.3%; likelihood ratio 0.7). Repeat Pap smears for atypical cells of undetermined significance (ASCUS) and low grade squamous intra-epithelial lesion (LGSIL) showing only HPV in women under age 30 would have reduced the immediate colposcopy rate by 60% and delayed diagnosis by 23% of high-grade lesions. Consideration of patient age and whether HPV is the only Pap smear finding may reduce referral for immediate colposcopy.

Background:Although the role of human papilloma virus (HPV) in cervical squamous cell carcinoma (CSCC) is well established, the role in head and neck SCC (HNSCC) is less clear. MicroRNAs (miRNAs) have a role in the cancer development, and HPV status may affect the miRNA expression pattern in HNSCC. To explore the influence of HPV in HNSCC, we made a comparative miRNA profile of HPV-positive (HPV+) and HPV-negative (HPV−) HNSCC against CSCC.Methods:Fresh frozen and laser microdissected-paraffin-embedded samples obtained from patients with HPV+/HPV− HNSCC, CSCC and controls were used for microarray analysis. Differentially expressed miRNAs in the HPV+ and HPV− HNSCC samples were compared with the differentially expressed miRNAs in the CSCC samples.Results:Human papilloma virus positive (+) HNSCC had a distinct miRNA profile compared with HPV− HNSCC. Significantly more similarity was seen between HPV+ HNSCC and CSCC than HPV− and CSCC. A set of HPV core miRNAs were identified. Of these especially the miR-15a/miR-16/miR195/miR-497 family, miR-143/miR-145 and the miR-106-363 cluster appear to be important within the known HPV pathogenesis.Conclusion:This study adds new knowledge to the known pathogenic pathways of HPV and substantiates the oncogenic role of HPV in subsets of HNSCCs.

The value of HPV DNA typing in the distinction between adenocarcinoma of endocervical and endometrial origin

ABSTRACTThe aim of this study was to assess the correlation between human papilloma virus (HPV) infections and cervical intraepithelial neoplasia (CIN). The study included 421 women (aged 18–45 years) who were examined gynecologicaly; their medical history and Pap smear results were collected and colposcopy and HPV tests were performed. In those cases where colposcopy and cytological evidence of atypism was found, biopsy or abrasion from the uterine cervix was performed. The GenoFlow HPV Array Test Kit was used to analyse the HPV status in cervical samples collected during the study. The obtained results showed that, one/more HPV genotypes were identified in 42% (177/421) and HPV(−) in 58% (244/421) of the examined women. In the HPV(+) group, CIN was diagnosed in 57 (13.5%) women, whereas, in the HPV(−) group, in 44 (10.5%) women. There was a significant dependence between HPV(+) status and development of CIN (p = 0.001), but the statistical analysis did not reveal sufficient positive predictive value or precision (p > 0.05), i.e. probability that (randomly selected) HPV(+) patients have CIN; neither sensitivity (p > 0.05), i.e. probability that (randomly selected) CIN patients are HPV(+); nor specificity (p > 0.05), i.e. probability that (randomly selected) women without CIN are HPV(−). These results indicate that infection with HPV is probably not the only cause for development of CIN.

HPV Association and the Increasing Incidence of Unknown Primary Head-and-Neck Squamous Cell Carcinoma: Epidemiology and Prevention

CDKN2A/p16 evaluation in cytology specimens.

Oropharyngeal Squamous Cell Carcinoma Treated With Radiotherapy or Radiochemotherapy: Prognostic Role of TP53 and HPV Status

Background Oropharyngeal squamous cell carcinoma (OPSCC) incidence is rising worldwide, especially human papillomavirus (HPV)-associated disease. Historically, high levels of protein kinase CK2 were linked with poor outcomes in head and neck squamous cell carcinoma (HNSCC), without consideration of HPV status. This retrospective study examined tumor CK2α protein expression levels and related clinical outcomes in a cohort of Veteran OPSCC patient tumors which were determined to be predominantly HPV(+). Methods Patients at the Minneapolis VA Health Care System with newly diagnosed primary OPSCC from January 2005 to December 2015 were identified. A total of 119 OPSCC patient tumors were stained for CK2α, p16 and Ki-67 proteins and E6/E7 RNA. CK2α protein levels in tumors and correlations with HPV status and Ki-67 index were assessed. Overall survival (OS) analysis was performed stratified by CK2α protein score and separately by HPV status, followed by Cox regression controlling for smoking status. To strengthen the limited HPV(−) data, survival analysis for HPV(−) HNSCC patients in the publicly available The Cancer Genome Atlas (TCGA) PanCancer RNA-seq dataset was determined for CSNK2A1. Results The patients in the study population were all male and had a predominant history of tobacco and alcohol use. This cohort comprised 84 HPV(+) and 35 HPV(−) tumors. CK2α levels were higher in HPV(+) tumors compared to HPV(−) tumors. Higher CK2α scores positively correlated with higher Ki-67 index. OS improved with increasing CK2α score and separately OS was significantly better for those with HPV(+) as opposed to HPV(−) OPSCC. Both remained significant after controlling for smoking status. High CSNK2A1 mRNA levels from TCGA data associated with worse patient survival in HPV(−) HNSCC. Conclusions High CK2α protein levels are detected in HPV(+) OPSCC tumors and demonstrate an unexpected association with improved survival in a strongly HPV(+) OPSCC cohort. Worse survival outcomes for high CSNK2A1 mRNA levels in HPV(−) HNSCC are consistent with historical data. Given these surprising findings and the rising incidence of HPV(+) OPSCC, further study is needed to understand the biological roles of CK2 in HPV(+) and HPV(−) HNSCC and the potential utility for therapeutic targeting of CK2 in these two disease states.

Insulin-like growth factor-1 receptor (IGF1R) plays a key role in cell growth and transformation. It is overexpressed in several solid tumors. This study evaluates IGF1R immunoexpression in penile squamous cell carcinoma (SCC). Four tissue microarrays were built from formalin-fixed, paraffin-embedded blocks of 112 penile SCC from Paraguay. Membranous IGF1R expression was evaluated by immunohistochemistry using two different approaches. An H-score was calculated in each spot (stain intensity by extent), and a median score per tumor was obtained. The second approach consisted of a score similar to the scoring system that was used for evaluating HER2 immunoexpression. For each case, the highest category obtained at any spot was used for statistical analyses. IGF1R expression was compared by histologic subtype, grade, and human papillomavirus (HPV) status. Median H-score was 22.5. The distribution of IGF1R expression by HER2 approach was as follows: 0 in 33.0% cases, 1+ in 46.4%, 2+ in 14.3%, and 3+ in 6.2%. IGF1R H-scores were associated with basaloid and warty/basaloid subtypes (p=0.0026) and higher grade (p=0.00052). Although weaker when using the HER2 approach, the association of IGF1R expression with subtype (p=0.015) and grade (p=0.015) remained significant. Furthermore, there was an association between IGF1R expression by HER2 approach and HPV status (p=0.012). IGF1R was expressed in about two thirds of penile SCC cases, showing a strong positive association with histologic grade, subtype, and HPV status. Considering that grade is a predictor of outcome IGF1R expression may have prognostic relevance and could point to a potential role for IGF1R inhibitors in treating penile SCC.