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 &lt; 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.</p

HPV is an essential driver in recurrence of cervical cancer

INTRODUCTION: High-risk human papillomavirus (HPV) has been detected in distant metastases from cervical cancer (CC) patients, suggesting a role of HPV. MATERIAL AND METHODS: Here, we included 26 patients with recurrence of CC (2019-2023). With next generation sequencing (NGS) and immunohistochemical staining, primary and recurrent tissues were analyzed for HPV DNA and HPV RNA, p16INK4a expression, and somatic TP53 and RB1 mutations. RESULTS: All primary and corresponding recurrent tissues were HPV DNA and HPV RNA positive. Within the same tissue, we found complete DNA/RNA agreement in 25/26 (96.2 %) primary and 25/25 (100 %) recurrent tissues, and partial agreement in the remaining sample. There was complete agreement between primary and recurrent tissue in 23/26 (88.5 %) and 23/25 (92.0 %) patients on DNA and RNA, respectively, whereas the remaining showed partial agreement with two genotypes detected in primary and only one of these in recurrent tissue. Except for one sample, all samples from high-risk HPV-positive patients were p16INK4a positive. The low-risk HPV11-positive patient was p16INK4a negative and had a pathogenic TP53 mutation, while the remaining samples were TP53/RB1 mutation negative. CONCLUSION: In high-risk HPV-positive CC patients, HPV seems to play a role in recurrent disease. Our findings support ongoing research on targeting HPV oncogenes in CC, also in metastatic disease.</p

Coronary artery calcification progression and renal involvement in patients with systemic lupus erythematosus:a longitudinal cohort study

To investigate if progression of coronary artery calcification (CAC) in patients with systemic lupus erythematosus (SLE) is associated with renal and traditional cardiovascular risk factors as well as incidence of myocardial infarctions. CAC progression was evaluated by cardiac computed tomography (CT) at baseline and after 5 years. Multivariable Poisson regression was applied to investigate associations between CAC progression and baseline values for traditional cardiovascular risk factors, CAC, SLE disease duration, lupus nephritis, and renal function. Regarding renal function, three groups were defined based on eGFR. Further, we analysed association between CAC progression and myocardial infarction during follow-up. Of the 147 SLE patients, 99 had cardiac CT at baseline and 5-year follow-up, with a total of 502 patient-years. At baseline, their median age was 47 years, median SLE disease duration was 14 years, 88% were women, 58% had lupus nephritis, and the median eGFR was 99 mL/min/1.73m2. 38/99 (39%) had CAC progression. CAC progression was associated with smoking (ever) (relative risk [RR] 1.69, CI95% 1.19-2.40), SLE disease duration (RR per year 1.03, CI95% 1.01-1.04), and CAC presence (RR 2.52, CI95% 1.68-3.78) at baseline. During follow-up, myocardial infarction occurred in three (7.9%) CAC progressors and in two (3.3%) patients who did not have CAC at any time (RR 2.1, CI95% 0.0-5.5). In this study, progression of CAC was associated with smoking, SLE disease duration and the prior presence of CAC, but it was inconclusive as to associations with renal involvement and incidence of MI.</p

Residual tumor and primary debulking surgery vs interval debulking surgery in stage IV epithelial ovarian cancer

INTRODUCTION: It is debated whether women with FIGO (International Federation of Gynecology and Obstetrics) Stage IV epithelial ovarian cancer should be offered primary debulking surgery (PDS) or interval debulking surgery (IDS). Furthermore, the impact of complete resection of intra‐abdominal disease (R0) despite their extra‐abdominal metastases is questioned. The objective of this study was to investigate the impact of intra‐abdominal residual tumor, Stage IVA vs IVB, the localization and number of metastases defining Stage IV disease on overall survival (OS) comparing PDS and IDS in FIGO Stage IV epithelial ovarian cancer. MATERIAL AND METHODS: We included 2091 women registered with Stage IIIC–IV ovarian cancer in the Danish Gynecological Cancer Database during 2009–2016. The impact of residual tumor was evaluated using univariate and multivariate analyses. RESULTS: In total, 681 patients had stage IV disease, of whom 26% underwent PDS, 38% IDS, and 36% chemotherapy only. Overall survival for PDS and IDS were similar. Patients achieving R0 at PDS showed a tendency towards a higher OS than patients achieving R0 at IDS, though the difference was non‐significant. In women with Stage IVA and IVB disease there was a survival benefit in achieving R0 both when treated with PDS and IDS. Women with Stage IVB disease treated with chemotherapy only had a significantly lower OS than patients achieving R0 at both PDS and IDS. Malignant pleural effusion and having five metastatic sites compared with having one was associated with a poorer OS. CONCLUSIONS: Our study shows similar OS in patients with Stage IV disease treated with IDS compared with PDS. Complete intra‐abdominal tumor resection improves the prognosis in both PDS and IDS in Stage IV ovarian cancer. Malignant pleural effusion seems to be a negative prognostic factor and should have more focus in future studies

Sentinel lymph node mapping for endometrial and cervical cancer in Denmark

INTRODUCTION: This was a surgical pilot study to systematically introduce the technique of sentinel lymph node (SLN) mapping in women with early-stage stage cervical cancer (CC) and endometrial cancer (EC) in Denmark. The study aimed to facilitate structured surgical training to ensure surgeon proficiency in SLN mapping. The study precedes two national prospective studies on the oncological safety and correct patient selection for SLN mapping in CC and EC. METHODS: The study was conducted at four gynaecological cancer centres at Odense and Aarhus University Hospital, Rigshospitalet and Herlev Hospital, between September 2016 and August 2019. All centres went through a protocolled introduction to the surgical technique, pelvic lymphatic drainage, pathological ultra-staging and data entry. A criterion of a total (uni- and bilateral) SLN detection of &gt; 80%, based on 30 SLN mappings was set. RESULTS: The four centres performed 140 (range: 30-46) procedures. The total SLN detection rate was 91.3% with bilateral SLN detection in 68.8% and unilateral SLN detection in 22.5% of cases. The cumulated total SLN detection rate at three centres was above the pre-set 80% criterion from the beginning of inclusion, whereas one centre reached the criterion after 20 procedures. CONCLUSIONS: In this study, all centres demonstrated international-level SLN detection rates within 30 procedures. Hence, all centres met the study criterion regarding surgeon proficiency and were eligible for the national studies. Funding: Eva &amp; Henry Frænkels Fond, Frimodt-Heineke Fonden, Kong Christian X Fond. TRIAL REGISTRATION: The study was approved by the Danish Data Protection Agency (R. no.15/52037). The SENTIREC studies including this pilot study are registered with clinicaltrials.gov (NCT02825355 and NCT02820506)

From FIGO-2009 to FIGO-2018 in women with early-stage cervical cancer; Does the revised staging reflect risk groups?

Objectives: We aimed to evaluate if the revised staging according to FIGO-2018 in early-stage cervical cancer correctly predicts the risk for nodal metastases. Methods: We reallocated 245 women with early-stage cervical cancer from FIGO-2009 to FIGO-2018 stages using data from a national, prospective cohort study on sentinel lymph node (SLN) mapping. We used univariate and multivariate binary regression models to investigate the association between FIGO-2018 stages, tumor characteristics, and nodal metastases. Results: Stage migration occurred in 54.7% (134/245) (95% CI 48.2–61.0), due to tumor size or depth of invasion (71.6%, 96/134) and nodal metastases (28.4%, 38/134). Imaging preoperatively upstaged 7.3% (18/245); seven had nodal metastatic disease on final pathology. Upstaging occurred in 49.8% (122/245) (95% CI 43.4–56.2%) and downstaging to FIGO-2018 IA stages in 4.9% (12/245) (95% CI 2.6–8.4). The tumor size ranged from 3.0–19.0 mm in women with FIGO-2018 IA tumor characteristics, and none of the 14 women had nodal metastases. In multivariate analysis, risk factors significantly associated with nodal metastases were FIGO-2018 ≥ IB2 (RR 5.01, 95% CI 2.30–10.93, p &lt; 0.001), proportionate depth of invasion &gt;2/3 (RR 1.88, 95% CI 1.05–3.35, p = 0.033), and lymphovascular space invasion (RR 5.56, 95% CI 2.92–10.62, p &lt; 0.001). Conclusions: The FIGO-2018 revised staging system causes stage migration for a large proportion of women with early-stage cervical cancer. Women who were downstaged to FIGO-2018 IA stages did not have nodal metastatic disease. The attention on depth of invasion rather than horizontal dimension seems to correctly reflect the risk of nodal metastases.</p

Sentinel lymph node mapping in early-stage cervical cancer – A national prospective multicenter study (SENTIREC trial)

Objectives: Sentinel lymph node (SLN) mapping may replace staging radical pelvic lymphadenectomy in women with early-stage cervical cancer. In a national multicenter setting, we evaluated SLN mapping in women with early-stage cervical cancer and investigated the accuracy of SLN mapping and FDG-PET/CT in tumors &gt;20 mm. Methods: We prospectively included women with early-stage cervical cancer from March 2017–January 2021 to undergo SLN mapping. Women with tumors &gt;20 mm underwent completion pelvic lymphadenectomy and removal of FDG-PET/CT positive nodes. We determined SLN detection rates, incidence of nodal disease, sensitivity and negative predictive value (NPV) of SLN mapping, and the sensitivity, specificity, NPV, and positive predictive value (PPV) of FDG-PET/CT. Results: We included 245 women, and 38 (15.5%) had nodal metastasis. The SLN detection rate was 96.3% (236/245), with 82.0% (201/245) bilateral detection. In a stratified analysis of 103 women with tumors &gt;20 mm, 27 (26.2%) had nodal metastases. The sensitivity of SLN mapping adhering to the algorithm was 96.3% (95% CI 81.0–99.9%) and the NPV 98.7% (95% CI 93.0–100%). For FDG-PET/CT imaging the sensitivity was 14.8% (95% CI 4.2–33.7%), the specificity 85.5% (95% CI 75.6–92.5%), the NPV 73.9% (95% CI 63.4–82.7%), and the PPV 26.7% (95% CI 7.8–55.1%). Conclusions: SLN mapping seems to be an adequate staging procedure in early-stage cervical cancer tumors ≤20 mm. In tumors &gt;20 mm, SLN mapping is highly sensitive but demands full adherence to the SLN algorithm. We recommend completion pelvic lymphadenectomy in tumors &gt;20 mm until the oncological safety is established. FDG-PET/CT for nodal staging of women with early-stage cervical cancer seems limited.</p

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.</p

SENTIREC - The sentinel node mapping in women with cervical cancer study:Patient-reported early lymphedema and its impact on quality of life

Objective:  To evaluate patient-reported incidence and severity of early lymphedema and its impact on quality of life (QoL) after sentinel lymph node (SLN) mapping only and after SLN and pelvic lymphadenectomy (PL) in women undergoing surgery for early-stage cervical cancer. Methods:  In a national prospective multicenter study, we included women with early-stage cervical cancer from March 2017-January 2021 to undergo radical surgery including SLN mapping. Women with tumors >20 mm underwent completion PL. The incidence and severity of early lymphedema and its influence on QoL were evaluated using validated patient-reported outcome measures before surgery and three months postoperative. We investigated changes over time using linear regression. Results:  Two hundred of 245 (81.6%) included women completed questionnaires at baseline and three months postoperatively. The incidence of early lymphedema was 5.6% (95% CI 2.1-11.8%) and 32.3% (95% CI 22.9-42.7%) in women who underwent SLN mapping only and SLN + PL, respectively. Lymphedema symptoms in the legs, genitals, and groins increased in both groups postoperatively but three times more in women who underwent PL. Lymphedema symptoms after SLN + PL significantly impaired physical performance (p = 0.001) and appearance (p = 0.007). Reporting lymphedema was significantly associated with impaired body image, physical-, role-, and social functioning, and a high level of fatigue. Conclusions:  SLN mapping alone carries a low risk of lymphedema in women undergoing surgery for early-stage cervical cancer. In contrast, completion PL is associated with a high incidence of early lymphedema. Reporting lymphedema is associated with significant impairment of several physical, psychological, and social aspects of QoL