Evidence of latent HPV infection in older Danish women with a previous history of cervical dysplasia.

INTRODUCTION: Understanding whether human papillomavirus (HPV) may establish latency in the uterine cervix is important. A better understanding of HPV natural history is useful for clinical counseling of women attending screening and to accurately inform health prevention strategies such as screening and HPV vaccination. We evaluated the extent of latent HPV infections in older women with a history of abnormal cytology. MATERIAL AND METHODS: We conducted a cross-sectional study in Aarhus, Denmark, from March 2013 through April 2015. Women were enrolled if they underwent cervical amputation or total hysterectomy because of benign disease. Prior to surgery, women completed a questionnaire and a cervical smear was collected for HPV testing and morphological assessment. For evaluation of latency (i.e., no evidence of active HPV infection, but HPV detected in the tissue), we selected women with a history of abnormal cervical cytology or histology, as these women were considered at increased risk of harboring a latent infection. Cervical tissue underwent extensive HPV testing using the SPF10-DEIA-LipA25 assay. RESULTS: Of 103 women enrolled, 26 were included in this analysis. Median age was 55 years (interquartile range [IQR] 52-65), and most women were postmenopausal and parous. The median number of sexual partners over the lifetime was six (IQR 3-10), and 85% reported no recent new sexual partner. Five women (19.2%) had evidence of active infection at the time of surgery, and 19 underwent latency evaluation. Of these, a latent infection was detected in 11 (57.9%), with HPV16 being the most prevalent type (50%). Nearly 80% (n = 14) of the 18 women with a history of previous low-grade or high-grade cytology with no treatment had an active or latent HPV infection, with latent infections predominating. HPV was detected in two of the six women with a history of high-grade cytology and subsequent excisional treatment, both as latent infections. CONCLUSIONS: HPV can be detected in cervical tissue specimens without any evidence of an active HPV infection, indicative of a latent, immunologically controlled infection. Modeling studies should consider including a latent state in their model when estimating the appropriate age to stop screening and when evaluating the impact of HPV vaccination.

Trends in hysterectomy-corrected uterine cancer mortality rates during 2002 to 2015: mortality of nonendometrioid cancer on the rise?

Corpus uteri cancer is the most common gynecological malignancy in most developed countries. The disease is typically diagnosed at an early stage, is of endometrioid histologic subtype, and has a fairly good prognosis. Here, we describe hysterectomy-corrected mortality rates of corpus uteri cancer, overall and stratified by age, stage and histologic subtype. Using data from nationwide Danish registries, we calculated uncorrected and hysterectomy-corrected age-standardized mortality rates of corpus uteri cancer among women ≥35 years during 2002 to 2015. Individual-level hysterectomy status was obtained from national registries; hysterectomy-corrected mortality rates were calculated by subtracting posthysterectomy person-years from the denominator, unless hysterectomy was performed due to corpus uteri cancer. Correction for hysterectomy resulted in a 25.5% higher mortality rate (12.3/100000 person-years vs 9.8/100000 person-years). Mortality rates were highest in women aged 70+, irrespective of year of death, histologic subtype and stage. A significant decline was observed in overall hysterectomy-corrected mortality rates from 2002 to 2015, particularly among women aged 70+. Mortality rates of endometrioid cancer declined significantly over time (annual percent change [APC]: -2.32, 95% CI -3.9, -0.7, P = .01), whereas rates of nonendometrioid cancer increased (APC: 5.90, 95% CI: 3.0, 8.9, P < .001). With respect to stage, mortality rates increased significantly over time for FIGOI-IIa (APC: 6.18 [95% CI: 1.9, 10.7] P = .01) but remained unchanged for FIGO IIb-IV. In conclusion, increasing mortality rates of nonendometrioid cancer paralleled the previously observed rise in incidence rates of this histologic subtype. Given the poor prognosis of nonendometrioid cancer, more studies are needed to clarify the underlying reason for these findings.

Impact of PD-L1 and T-cell inflamed gene expression profile on survival in advanced ovarian cancer.

OBJECTIVE: Programmed death ligand 1 (PD-L1) expression affects tumor evasion of immune surveillance. The prognostic value and relationship of PD-L1 expression to T-cell-inflamed immune signatures in ovarian cancer are unclear. The purpose of this study is to evaluate the impact of PD-L1 on overall survival and its correlation with an immune-mediated gene expression profile in patients with advanced ovarian cancer. METHODS: PD-L1 expression in tumor and immune cells was assessed by immunohistochemistry, and PD-L1-positive expression was defined as a combined positive score ≥1; a T-cell-inflamed gene expression profile containing interferon γ response genes was evaluated using extracted RNA from surgical samples. Associations between PD-L1 expression, gene expression profile status, and overall survival were analyzed using the Kaplan-Meier method, log-rank test, and multivariate Cox proportional hazards regression models. RESULTS: A total of 376 patients with advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer treated by cytoreductive surgery and platinum-based therapy were included. PD-L1-positive expression was observed in 50.5% of patients and associated with more advanced stage (p=0.047), more aggressive histologic subtype (p=0.001), and platinum sensitivity defined by increasing treatment-free interval from first platinum-based chemotherapy to next systemic treatment (p=0.027). PD-L1-positive expression was associated with longer overall survival in multivariate analyses (adjusted HR 0.72, 95% CI 0.56 to 0.93). In subgroup analyses, this association was most pronounced in patients with partially platinum-sensitive disease (treatment-free interval ≥6 to <12 months). T-cell-inflamed gene expression profile status correlated with PD-L1 expression (Spearman, ρ=0.712) but was not an independent predictor of overall survival. CONCLUSION: PD-L1 expression is associated with longer overall survival among advanced ovarian cancer patients. PD-L1 expression may be an independent prognostic biomarker.

HPV genotype distribution in older Danish women undergoing surgery due to cervical cancer.

INTRODUCTION: The prevalence of human papillomavirus (HPV)16/18 in cervical cancer may decrease with age. This study aimed to describe the HPV genotype distribution in Danish women aged 55 years or older with cervical cancer. MATERIAL AND METHODS: In this cross-sectional study we identified 153 cases of cervical cancer diagnosed at Aarhus University Hospital, Denmark (1990-2012) and Copenhagen University Hospital Herlev, Denmark (2007-2012). All women had surgery to treat the disease. HPV genotyping was performed on cervical cancer tissue using the INNO LiPA HPV genotyping extra (Fujirebio, Belgium) at the Department of Pathology, Aarhus University Hospital, Denmark. The main outcome was to estimate the age-specific prevalence of high-risk HPV genotypes included in the bivalent, the quadrivalent, and the nonavalent vaccine. RESULTS: Of 121 cases of cervical cancer included in this study, 113 were HPV-positive (93.4%). Although HPV16 and 18 were the most common genotypes overall, the prevalence of HPV16/18 decreased significantly from 78.1% in women aged 55-59 years to 45.5% in women aged 75 or older (p < 0.001), whereas the prevalence of other HPV types and HPV-negative cases tended to increase with age (p = 0.1). The prevalence of HPV types included in the nonavalent vaccine was stable around 90% until the age of 75 years and then dropped to 63%. CONCLUSION: In the absence of waning immunity, the nonavalent HPV vaccine would be predicted to reduce cervical cancer burden in Denmark across a broader age-range compared with the reduced type-spectrum vaccines.

Acid hypersensitivity in patients with eosinophilic oesophagitis.

OBJECTIVE: Painful symptoms are prevalent in patients with eosinophilic oesophagitis but experimental data are sparse. The aim of this study was to compare the pain response to experimental oesophageal stimulation in 14 patients with eosinophilic oesophagitis and 15 healthy volunteers. MATERIAL AND METHODS: A multimodal probe was placed in the oesophagus. The participants were subjected to mechanical, thermal and electrical pain stimuli followed by perfusion with 0.1 M HCl. Pain scores, referred pain areas and evoked brain potentials to electrical stimulation of the oesophagus were recorded. RESULTS: Patients tolerated significantly less acid perfused in the oesophagus (median 123 versus 200 ml; P = 0.02) and felt the burning sensation evoked by the acid earlier (median 2.0 versus 5.0 min; P = 0.01). Eight patients had coexisting gastro-oesophageal reflux disease. Six patients had pure eosinophilic oesophagitis, and this group felt the acid earlier than those with concomitant reflux or the healthy volunteers (median 0.8 versus 2.0 and 5.0 min; P = 0.03). There were no differences between patients and controls in the responses to mechanical or thermal stimulation (P > 0.4). Furthermore, no differences were found for the proxies of central nervous system sensitization (response to electrical stimulations, referred pain areas or evoked brain potentials; P > 0.1). CONCLUSIONS: Patients with eosinophilic oesophagitis are hypersensitive to acid perfused in the oesophagus, and pathophysiologic findings are likely confined to the peripheral tissue. Reflux from physiological acid may play a role in the symptoms of eosinophilic oesophagitis.

18F-FDG Uptake in a Mesonephric Carcinoma.

We present the case of a 39-year-old woman with vaginal bleeding and abdominal pain. An F-FDG PET/CT showed high F-FDG uptake in a tumor in the pouch of Douglas, in 3 lymph nodes in the pelvis, and in the left tuber ischiadicum. Biopsies revealed a mesonephric carcinoma with metastases. Six series of empiric chemotherapy with carboplatin, paclitaxel, and bevacizumab were not sufficient to treat the cancer, and checkpoint immunotherapy with nivolumab and ipilimumab was initialized.

Detection of high-risk human papillomavirus DNA in tissue from primary cervical cancer tumor, pelvic lymph nodes and recurrent disease.

OBJECTIVES: The present study investigated Human Papillomavirus (HPV) DNA genotyping in primary tumor, pelvic lymph nodes (PLN) and recurrence in early-stage cervical cancer patients. METHODS: We conducted a hospital-based case-control study. From 2003 to 2015, 282 patients underwent surgery for cervical cancer in the Department of Gynecology, Aarhus University Hospital, Denmark. Twenty-nine recurrent cases were identified. HPV DNA genotyping was performed on formalin-fixed, paraffin-embedded tissue specimens from the primary tumor, PLN, and recurrent disease. RESULTS: In the primary tumor, HPV DNA was detectable in 18(72%) of 25 tissue specimens from recurrent cases and in 15(83%) of 18 controls. HPV DNA-positive PLN was significantly associated with recurrence, 83%(95%CI: 52-98%), compared to patients with HPV-negative PLN, 38%(95%CI: 18-62%)(p < 0.05). HPV DNA genotyping was positive in eight of 12(67%) patients with recurrent disease. The genotype was identical in all three tissues types. The positive predictive value for recurrence was the same for detection of HPV-DNA and metastases in the PLN, with reasonable sensitivity. The negative predictive value for recurrence, however, was best for HPV-DNA, 62%(95%CI: 38-98%). CONCLUSIONS: In conclusion, our data suggest that the presence of HPV in pelvic lymph nodes is associated with an increased risk of recurrence.

Whole tissue cervical mapping of HPV infection: Molecular evidence for focal latent HPV infection in humans.

In this study, we aimed to provide molecular evidence of HPV latency in humans and discuss potential challenges of conducting studies on latency. We analyzed the entire cervix of two women who underwent hysterectomy unrelated to cervical abnormality. The cervices were sectioned into 242 and 186 sets respectively, and each set was tested separately for HPV using the SPF10-PCR-DEIA-LiPA25 system. To identify whether there was any evidence of transforming or productive infection, we used the biomarkers E4 and P16INK4a to stain slides immediately adjacent to HPV-positive sections. HPV was detected in both cervices. In patient 1, 1/242 sets was positive for HPV31. In patient 2, 13/186 sets were positive for HPV18 and 1/186 was positive for HPV53. The infection was very focal in both patients, and there was no sign of a transforming or productive infection, as evaluated by the markers E4 and P16INK4a. Had we only analyzed one set from each block, the probability of detecting the infection would have been 32.3% and 2%, respectively.Our findings support the idea that HPV may be able to establish latency in the human cervix; however, the risk associated with a latent HPV infection remains unclear.

A Rare Case of Embryonal Carcinoma in a Patient with Turner Syndrome without Y Chromosomal Material but Mutations in KIT, AKT1, and ZNF358 Demonstrated Using Exome Sequencing.

Gonadoblastoma and malignant transformations thereof can occur in females with Turner syndrome (TS) and Y chromosomal material. However, in females with TS and no Y chromosomal material, this is rarely seen. We report a female with an apparent 45,X karyotype (in blood and tumor) who was diagnosed with a metastatic embryonal carcinoma. Exome sequencing of blood and the tumor was done, and no Y chromosomal material was detected, while predicted deleterious mutations in KIT (likely driver), AKT1, and ZNF358 were identified in the tumor. The patient was treated with chemotherapy (first-line: cisplatin, etoposide, and bleomycin; second-line: paclitaxel and gemcitabine), and after that surgical debulking was performed. She is currently well and without signs of relapse. We conclude that embryonal carcinoma can apparently occur in 45,X TS without signs of Y chromosomal material.

[Primary malignant melanoma of the vagina]. / Primært malignt melanom i vagina.

We describe a case of malignant melanoma (MM) of the vagina in a 77-year-old woman. The type was nodular, measuring 2,5 × 1,8 cm and located in close relation to the urethra. The patient underwent pelvic exenteration and received no kind of adjuvant therapy. Seven months later, the patient locally had recurrence of the disease. The vagina is a rare location of MM, and the literature in this regard is mostly based on case reports. There is a need for better registration of these patients in order to identify factors that predict prognosis and in order to determine the optimal treatment.