To Örebro University

OBJECTIVES: HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) and head and neck carcinoma of unknown primary (HNCUP) are increasing. Despite good prognosis, recurrence rates range from 10% to 25%. Surveillance with clinical controls and imaging is not always reliable. Circulating tumour human papillomavirus DNA (ctHPV-DNA) has emerged as a potential biomarker for treatment evaluation and detection of recurrence. We aimed to investigate the correlation between ctHPV-DNA in HPV+ OPSCC/HNCUP and radiologic tumour burden. Additionally, we sought to assess whether ctHPV-DNA could serve as a tool in treatment evaluation.

DESIGN: A prospective observational cohort study.

SETTING: This multicenter study involved three otolaryngology units located in central Sweden. We utilised HPV genotype-specific assays for droplet digital PCR (ddPCR) to detect ctHPV-DNA in plasma at diagnosis and follow-up. ctHPV-DNA levels were correlated to radiological tumour burden and radiological response using the Kendall Rank correlation coefficient and the Kruskal-Wallis test.

PARTICIPANTS: Patients with HPV+ OPSCC/HNCUP undergoing definitive (chemo)radiotherapy and enrolled in the CIRCOS study. RESULTS: Out of 54 patients, 51 were eligible for analyses. At baseline, ctHPV-DNA was detectable in 88%. A majority of patients with a favourable radiological evaluation according to RECIST had a corresponding undetectable ctHPV-DNA at follow-up. The levels of ctHPV-DNA at baseline correlated with total tumour volume and nodal volume (rτ = 0.39, p < 0.01, respectively rτ = 0.26, p < 0.01).

CONCLUSION: ctHPV-DNA shows correlation with tumour burden. This study strengthens the role of ctHPV-DNA as a promising biomarker for treatment evaluation in HPV-related OPC/HNCUP. With further research on serial plasma sampling, ctHPV-DNA could complement radiological treatment evaluation in HPV+ OPSCC/HNCUP.

TRIAL REGISTRATION: NCT05904327 [ClinicalTrials.gov].

PURPOSE: To assess the accuracy of conventional MRI with T1- and T2-weighted sequences in detecting lymphatic nodal spread (N1) in intermediate- and high-risk prostate cancer (PCa) patients via morphological criteria alone, extended pelvic lymph node dissection (ePLND) was used as the reference standard.

METHODS: This prospective observational study included patients between 2009 and 2016 with intermediate- and high-risk PCa according to the D'Amico criteria and an estimated risk of N1 > 20% on the basis of the Briganti nomogram. All patients underwent MRI prior to ePLND. Interobserver analysis was conducted across three centers.

RESULTS: Ninety-nine men, mean age 67 (5.7 SD), 93% high-risk PCa patients and 39.4% with N1 disease, according to ePLND, were evaluated. The pooled sensitivity of MRI for detecting N1 was 24.6% (95% CI: 16.3-35.1), whereas the pooled specificity was 95% (95% CI: 85.3-98.8). Interobserver agreement was moderate (Fleiss' κ = 0.56). All readers failed to identify patients with high-volume N1, and the identification of those with a high number of N1 events was inconsistent across readers. The strengths of this study include the high number of N1 cases, with a median of 17 (6-40) harvested lymph nodes per participant. Limitations include the time interval between MRI and ePLND (median of 44 days) and the lack of standardized lymph node evaluation criteria, reflecting real-world clinical practice.

CONCLUSION: MRI using only T1W and T2W sequences has demonstrated limited effectiveness in lymph node staging for intermediate- and high-risk prostate cancer, even in high-volume metastatic disease. Additionally, interobserver analysis shows only moderate agreement.

Inguinal lymph node surgery is a standard treatment for penile cancer patients with intermediate or high risk for lymph node metastasis (LNM) according to European Association of Urology (EAU) risk grading. We are proposing a more objective histological prognostic grading system for inguinal LNM in these patients. We assessed worst pattern of invasion, lymphocytic host response, lymphovascular invasion, and perineural invasion in a population-based cohort of 306 penile cancer patients. Patients were classified into low, intermediate, and high risk for inguinal LNM. There was a significant association both between risk groups and pT stage (p < 0.001) and between risk groups and LNM. Univariate logistic regression showed 25.43 times higher odds of LNM for patients in the intermediate risk group compared with the low risk group (odds ratio (OR) 25.43; 95% confidence interval (CI): 5.94-108.97) and a 177.13 times higher odds in the high risk group compared to the low risk group (OR 177.13; 95% CI: 40.09-782.51). When comparing our histological risk grading with the EAU grading, we found a higher sensitivity, of 51.28% (95% CI: 45.68-56.88) versus 37.09% (95% CI: 31.68-42.50), as well as a higher area under the curve (0.86; 95% CI: 0.81-0.89; versus 0.65; 95% CI: 0.58-0.71) with our grading system. While our grading classified 111 patients as low risk, only 31 were considered low risk for LNM according to the EAU risk classification. The new histological risk grading system shows a higher sensitivity and includes a higher number of patients in the low risk group in whom lymph node surgery could be avoided, reducing morbidity and costs.

We aimed to investigate the use of free glycosaminoglycan profiles (GAGomes) and cfDNA in plasma to differentiate between lung cancer and benign lung disease, in a cohort of 113 patients initially suspected of lung cancer. GAGomes were analyzed in all samples using the MIRAM® Free Glycosaminoglycan Kit with ultra-high-performance liquid chromatography and electrospray ionization triple quadrupole mass spectrometry. In a subset of samples, cfDNA concentration and NGS-data was available. We detected two GAGome features, 0S chondroitin sulfate (CS), and 4S CS, with cancer-specific changes. Based on the observed GAGome changes, we devised a model to predict lung cancer. The model, named the GAGome score, could detect lung cancer with 41.2% sensitivity (95% CI: 9.2-54.2%) at 96.4% specificity (95% CI: 95.2-100.0%, n = 113). When we combined the GAGome score with a cfDNA-based model, the sensitivity increased from 42.6% (95% CI: 31.7-60.6%, cfDNA alone) to 70.5% (95% CI: 57.4-81.5%) at 95% specificity (95% CI: 75.1-100%, n = 74). Notably, the combined GAGome and cfDNA testing improved the sensitivity, compared to cfDNA alone, especially in ASCL stage I (55.6% vs 11.1%). Our findings show that plasma GAGome profiles can enhance cfDNA testing performance, highlighting the applicability of a multiomics approach in lung cancer diagnostics.

Urinary bladder cancer (BC) represents a major health issue, and identifying novel biomarkers for early disease detection and outcome prediction is paramount. It has already been established that the immune system plays a role in tumour initiation and progression in which the inflammatory marker pentraxin 3 (PTX3) might be involved, presenting a variety of functions in different cancers. The aim of this study was to investigate whether plasma levels of PTX3 could be used as a biomarker for patients with BC. Plasma levels of PTX3 were determined in 118 BC patients and 50 controls by ELISA. Patients with BC had significantly higher PTX3 levels compared to controls. The value as a diagnostic biomarker is probably limited, however, since no significant difference in PTX3 levels was seen between patients with non-muscle-invasive BC and controls; they were seen only between patients with muscle-invasive disease and controls. However, the potential value of PTX3 as a prognostic biomarker was indicated by significantly higher PTX3 levels in patients who developed metastatic disease during follow-up compared to patients who did not develop metastatic disease. The conclusions from this study are that plasma levels of PTX3 have limited value as a diagnostic biomarker, although they have potential as a prognostic biomarker for patients with BC.

PURPOSE: To assess the long-term risks of infectious and thromboembolic events following inguinal (ILND) and pelvic (PLND) lymph node dissection in men with penile cancer.

MATERIAL AND METHODS: A total of 364 men subjected to ILND with or without PLND for penile cancer between 2000 and 2012 were identified in the Swedish National Penile Cancer Register. Each patient was matched based on age and county of residence with six penile cancer-free men. The Swedish Cancer Register and other population-based registers were used to retrieve information on treatment and hospitalisation for selected infectious and thromboembolic events. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazard models with multiple imputation.

RESULTS: The risk of infectious events remained increased for more than five years postoperatively in men with penile cancer compared with matched controls. The palpable nodal disease was the only predictor of these events, with risk increasing with the cN stage. The HR at one, three and five years and six months postoperatively was 8.60 (95% CI 5.16-14.34), 4.02 (95% CI 2.65-6.09) and 1.93 (95% CI 1.11-3.38), respectively. An increased risk of thromboembolic events persisted for three years postoperatively. The HR at one and three years postoperatively was 13.51 (95% CI 6.53-27.93) and 2.12 (95% CI 1.07-4.20). The results correspond well with the over-prescription of anticoagulants observed during this period. An association with bulky disease (cN3) was observed.

CONCLUSIONS: Lymph node dissection for penile cancer is associated with an increased risk of infectious and thromboembolic events. The findings of this population-based study show that the risks of these events remain increased more than five years for infectious and three years for thromboembolic events. Improved awareness of long-term complications following ILND is of importance both among patients and care givers to ensure early detection and treatment.

Differentiation between penile squamous cell carcinoma patients who can benefit from limited organ-sparing surgery and those at significant risk of lymph node metastasis is based on histopathological prognostic factors including histological grade and tumor histological subtype. We examined levels of interobserver and intraobserver agreement in assessment of histological subtype and grade in 207 patients with penile squamous cell carcinoma. The cases were assessed by seven pathologists from three hospitals located in Sweden and Italy. There was poor to moderate concordance in assessing both histological subtype and grade, with Fleiss kappas of 0.25 (range: 0.02-0.48) and 0.23 (range: 0.07-0.55), respectively. When choosing HPV-associated and non-HPV-associated subtypes, interobserver concordance ranged from poor to good, with a Fleiss kappa value of 0.36 (range: 0.02-0.79). A re-review of the slides by two of the pathologists showed very good intraobserver concordance in assessing histological grade and subtype, with Cohen's kappa values of 0.94 and 0.91 for grade and 0.95 and 0.84 for subtype. Low interobserver concordance could lead to undertreatment and overtreatment of many patients with penile cancer, and brings into question the utility of tumor histological subtype and tumor grade in determining patient treatment in pT1 tumors. 

Background: The International Society of Urological Pathology (ISUP) revised the Gleason system in 2005 and 2014. The impact of these changes on prostate cancer (PCa) prognostication remains unclear.

Objective: To evaluate if the ISUP 2014 Gleason score (GS) predicts PCa death better than the pre-2005 GS, and if additional histopathological information can further improve PCa death prediction.

Patients and Methods: We conducted a case-control study nested among men in the National Prostate Cancer Register of Sweden diagnosed with non-metastatic PCa 1998-2015. We included 369 men who died from PCa (cases) and 369 men who did not (controls). Two uro-pathologists centrally re-reviewed biopsy ISUP 2014 Gleason grading, poorly formed glands, cribriform pattern, comedonecrosis, perineural invasion, intraductal, ductal and mucinous carcinoma, percentage Gleason 4, inflammation, high-grade prostatic intraepithelial neoplasia (HGPIN) and post-atrophic hyperplasia. Pre-2005 GS was back-transformed using i) information on cribriform pattern and/or poorly formed glands and ii) the diagnostic GS from the registry. Models were developed using Firth logistic regression and compared in terms of discrimination (AUC).

Results: The ISUP 2014 GS (AUC = 0.808) performed better than the pre-2005 GS when back-transformed using only cribriform pattern (AUC = 0.785) or both cribriform and poorly formed glands (AUC = 0.792), but not when back-transformed using only poorly formed glands (AUC = 0.800). Similarly, the ISUP 2014 GS performed better than the diagnostic GS (AUC = 0.808 vs 0.781). Comedonecrosis (AUC = 0.811), HGPIN (AUC = 0.810) and number of cores with ≥50% cancer (AUC = 0.810) predicted PCa death independently of the ISUP 2014 GS.

Conclusion: The Gleason Grading revisions have improved PCa death prediction, likely due to classifying cribriform patterns, rather than poorly formed glands, as Gleason 4. Comedonecrosis, HGPIN and number of cores with ≥50% cancer further improve PCa death discrimination slightly.

BACKGROUND: Studies suggest that a hybrid indocyanine green (ICG)-^99mTc-nanocolloid tracer improves sentinel node (SN) identification compared to conventional dynamic sentinel node biopsy (DSNB).

OBJECTIVE: To investigate hybrid tracer-guided SN identification in a multicentre setting and determine false-negative (FN) and complication rates.

DESIGN, SETTING, AND PARTICIPANTS: A total of 130 patients with penile cancer scheduled for DSNB were prospectively included between February 2016 and December 2017 at two national Swedish referral centres. ICG-^99mTc-nanocolloid hybrid tracer was used in the standard DSNB protocol.

INTERVENTION: SNs were identified intraoperatively using radioguidance, fluorescence imaging, and blue dye.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The number of SNs identified by each tracer and the rates of complications and nodal recurrence during median follow-up of 34 mo were recorded. Differences in proportions between groups were compared using χ² and McNemar's tests.

RESULTS AND LIMITATIONS: Overall, 453 SNs were identified preoperatively via single-photon emission computed tomography/computed tomography. Among the 425 SNs excised, radioguidance, fluorescence, and blue dye identified 414 (97%), 363 (85%), and 349 (82%), respectively. Fluorescence imaging helped to detect six SNs that were negative using the other tracers, two of which were from the same patient and contained metastases. Histopathological examination detected 33 metastatic SNs in 20/130 patients (15%). The FN rate was 12% per groin (95% confidence interval 8-16%).

CONCLUSIONS: Identification of SNs in patients with penile cancer relies mainly on radioguidance, while fluorescence (ICG) and blue dye methods for optical SN identification are comparable. However, the value of fluorescence imaging should be further evaluated in studies with long-term follow-up.

PATIENT SUMMARY: In this study, we investigated addition of a dye called indocyanine green (ICG) for assessment of lymph nodes in patients with cancer of the penis. ICG did not improve the rate of detection of nodes most likely to harbour cancer because of their location in the drainage pathway for lymphatic fluid, but did help in identifying additional metastases.