Use of Risk Factors To Select Adjuvant Therapy Versus Surveillance for Testicular Nonseminoma and Seminoma Germ Cell Tumors.

New risk factors associated with relapse of stage I testicular cancer have been identified. These new factors reflect the risk of recurrence much better than previous parameters and can be used to assess the possible effect of adjuvant chemotherapy.

Prognostic factors for relapse in patients with clinical stage I testicular non-seminoma: A nationwide, population-based cohort study.

BACKGROUND: Approximately 30% of patients with clinical stage I non-seminoma (CSI-NS) relapse. Current risk stratification is based on lymphovascular invasion (LVI) alone. The extent to which additional tumor characteristics can improve risk prediction remains unclear. OBJECTIVE: To determine the most important prognostic factors for relapse in CSI-NS patients. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study including all patients with CSI-NS diagnosed in Denmark between 2013 and 2018 with follow-up until 2022. Patients were identified in the prospective Danish Testicular Cancer database. By linkage to the Danish National Pathology Registry, histological slides from the orchiectomy specimens were retrieved. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Histological slides were reviewed blinded to the clinical outcome. Clinical data were obtained from medical records. The association between prespecified potential prognostic factors and relapse was assessed using Cox regression analysis. Model performance was evaluated by discrimination (Harrell's C-index) and calibration. RESULTS: Of 453 patients included, 139 patients (30.6%) relapsed during a median follow-up of 6.3 years. Tumor invasion into the hilar soft tissue of the testicular hilum, tumor size, LVI and embryonal carcinoma were independent predictors of relapse. The estimated 5-year risk of relapse ranged from < 5% to > 85%, depending on the number of risk factors. After internal model validation, the model had an overall concordance statistic of 0.75. Model calibration was excellent. CONCLUSION AND RELEVANCE: The identified prognostic factors provide a much more accurate risk stratification than current clinical practice, potentially aiding clinical decision-making.

Prognostic Factors for Relapse in Patients With Clinical Stage I Testicular Seminoma: A Nationwide, Population-Based Cohort Study.

PURPOSE: Approximately 20% of patients with clinical stage I seminoma relapse. Tumor size and rete testis invasion have been identified as risk factors for relapse. However, the level of evidence supporting the use of these risk factors in clinical decision making is low. Previous studies have been hampered by selection bias and variable pathology reporting that limit interpretation and generalization of results. We assessed prognostic factors for relapse in an unselected nationwide population-based setting with centralized pathology review. METHODS: Patients with clinical stage I seminoma diagnosed from January 2013 to December 2018 were identified in the prospective Danish Testicular Cancer database. By linkage to the Danish National Pathology Registry, histologic slides from the orchiectomy specimens were retrieved and reviewed blinded to the clinical outcome. Clinical data were obtained from medical records with follow-up until July 2022. The association between prespecified potential clinical and histopathologic prognostic factors and relapse was assessed by the use of Cox regression analysis. RESULTS: Of 924 patients included, 148 (16%) patients relapsed during a median follow-up of 6.3 years. Invasion of the testicular hilum (rete testis and hilar soft tissue), lymphovascular invasion, and elevated preorchiectomy levels of ß-human chorionic gonadotropin and lactate dehydrogenase were independent predictors of relapse. The estimated 5-year risk of relapse ranged from 6% in patients with no risk factors to 62% in patients with all four risk factors with tumor extension into the hilar soft tissue of the testicular hilum. After internal model validation, the prognostic model had an overall concordance statistic of 0.70. CONCLUSION: The provided prognostic factors could replace current risk factors in guidelines and be used in future studies investigating risk-adapted follow-up and treatment strategies.

A Validated Algorithm for Register-Based Identification of Patients with Relapse of Clinical Stage I Testicular Cancer.

Purpose: The Danish Testicular Cancer (DaTeCa) database aims to monitor and improve quality of care for testicular cancer patients. Relapse data registered in the DaTeCa database rely on manual registration. Currently, some safeguarding against missing registrations is attempted by a non-validated register-based algorithm. However, this algorithm is inaccurate and entails time-consuming medical record reviews. We aimed (1) to validate relapse data as registered in the DaTeCa database, and (2) to develop and validate an improved register-based algorithm identifying patients diagnosed with relapse of clinical stage I testicular cancer. Patients and Methods: Patients registered in the DaTeCa database with clinical stage I testicular cancer from 2013 to 2018 were included. Medical record information on relapse data served as a gold standard. A pre-specified algorithm to identify relapse was tested and optimized on a random sample of 250 patients. Indicators of relapse were obtained from pathology codes in the Danish National Pathology Register and from diagnosis and procedure codes in the Danish National Patient Register. We applied the final algorithm to the remaining study population to validate its performance. Results: Of the 1377 included patients, 284 patients relapsed according to the gold standard during a median follow-up time of 5.9 years. The completeness of relapse data registered in the DaTeCa database was 97.2% (95% confidence interval (CI): 95.2-99.1). The algorithm achieved a sensitivity of 99.6% (95% CI: 98.7-100), a specificity of 98.9% (95% CI: 98.2-99.6), and a positive predictive value of 95.9% (95% CI: 93.4-98.4) in the validation cohort (n = 1127, 233 relapses). Conclusion: The registration of relapse data in the DaTeCa database is accurate, confirming the database as a reliable source for ongoing clinical quality assessments. Applying the provided algorithm to the DaTeCa database will optimize the accuracy of relapse data further, decrease time-consuming medical record review and contribute to important future clinical research.

Multiparametric magnetic resonance imaging for characterizing renal tumors: A validation study of the algorithm presented by Cornelis et al.

Objectives: In the last decade, the incidence of renal cell carcinoma (RCC) has been rising, with the greatest increase observed for solid tumors. Magnetic resonance imaging (MRI) protocols and algorithms have recently been available for classifying RCC subtypes and benign subtypes. The objective of this study was to prospectively validate the MRI algorithm presented by Cornelis et al. for RCC classification. Material and Methods: Over a 7-month period, 38 patients with 44 renal tumors were prospectively included in the study and received an MRI examination in addition to the conventional investigation program. The MRI sequences were: T2-weighted, dual chemical shift MRI, diffusion-weighted imaging (DWI), and dynamic contrast-enhanced T1-weighted in wash-in and wash-out phases. The images were evaluated according to the algorithm by two experienced, blinded radiologists, and the histopathological diagnosis served as the gold standard. Results: Of 44 tumors in 38 patients, only 8 tumors (18.2%) received the same MRI diagnosis according to the algorithm as the histopathological diagnosis. MRI diagnosed 16 angiomyolipoma, 14 clear cell RCC (ccRCC), 12 chromophobe RCC (chRCC), and two papillary RCC (pRCC), while histopathological examination diagnosed 24 ccRCC, four pRCC, one chRCC, and one mixed tumor of both pRCC and chRCC. Malignant tumors were statistically significantly larger than the benign (3.16 ± 1.34 cm vs. 2.00 ± 1.04 cm, P = 0.006). Conclusion: This prospective study could not reproduce Cornelis et al.'s results and does not support differentiating renal masses using multiparametric MRI without percutaneous biopsy in the future. The MRI algorithm showed few promising results to categorize renal tumors, indicating histopathology for clinical decisions and follow-up regimes of renal masses are still required.

Prevalence of CBAVD in azoospermic men carrying pathogenic CFTR mutations - Evaluated in a cohort of 639 non-vasectomized azoospermic men.

BACKGROUND: Men with obstructive azoospermia (OA) due to impaired development of the genital tract often carry at least one Cystic Fibrosis Transmembrane Conductance Regulator CFTR mutation. OBJECTIVE: To determine the frequency of Congenital Bilateral Absence of Vas deferens (CBAVD) in men with azoospermia carrying CFTR gene mutations. MATERIALS AND METHODS: Non-vasectomized men with azoospermia referred to our andrological center were consecutively included. All men underwent palpation of the scrotal parts of the Vasa deferentia, ultrasonography of the testicles and hormone profile, and genetic analyses. Testicular biopsy was usually performed. A panel of 32 of the most important CFTR mutations was examined from genomic DNA isolated from blood lymphocytes. Either multiplex PCR analysis or a next-generation sequencing technique was performed. RESULTS: Among the 639 men with azoospermia, 69 (10.8%) had at least one CFTR mutation. Of the 43 patients with at least one of the two CFTR mutations, ΔF508 and R117H, 19 (44.2%) showed CBAVD, 2 (4.7%) Congenital Unilateral Absence of Vas deferens (CUAVD), and 22 (51.2%) presence of the scrotal parts of the Vasa deferentia. In contrast, only 1/21 men (4.8%) with an isolated IVS8-5T variant showed CBAVD. Among the further 20 men with an isolated IVS8-5T variant, 11 had a history of cryptorchidism. Among the 570 men without CFTR mutations, CBAVD was found in only two men and CUAVD in one. FSH level was higher and testicular volume lower in men with present Vasa deferentia compared to those without (P < .001; Student's t test). Thirty-one men with either ΔF508 or R117H mutations, or both, had a testicular biopsy. Motile spermatozoa were found in 100% of 16 cases with CBAVD but in only 6 out of 15 cases with present Vasa deferentia (P < .01; Fisher's exact test). DISCUSSION AND CONCLUSIONS: CBAVD was found in ~ 44% of men with ΔF508/R117H mutations. The data may support that CFTR mutations might affect male fertility through other mechanisms than obstruction of the genital tract. For a practical, clinical purpose analysis for only ΔF508, R117H and IVS8-5T seems sufficient until further research shows anything else.

Prognostic factors for relapse in patients with clinical stage I testicular cancer: protocol for a Danish nationwide cohort study.

INTRODUCTION: Approximately one-fourth of patients with clinical stage I testicular germ cell cancer will relapse within 5 years of follow-up. Certain histopathological features in the primary tumour have been associated with an increased risk of relapse. The available evidence on the prognostic value of the risk factors, however, is hampered by heterogeneity of the study populations included and variable reporting of the histopathological features. The aim of this study is to identify pathological risk factors for relapse in an unselected large nationwide cohort of patients with stage I disease. METHODS AND ANALYSIS: All incident cases of stage I testicular germ cell cancer diagnosed in Denmark between 2013 and 2018 will be identified using the nationwide prospective Danish Testicular Cancer (DaTeCa) database. Archived microscopic slides from the orchiectomy specimens will be retrieved through linkage to the Danish Pathology Data Bank and reviewed blinded to the clinical outcome. The DaTeCa database includes 960 stage I seminoma patients with expected 185 relapses and 480 patients with stage I non-seminoma with expected 150 relapses. A minimum follow-up period of 3 years of all patients will be ensured. Predefined prognostic variables will be investigated with regard to relapse in univariable and multivariable analysis using the Cox proportional hazards model. ETHICS AND DISSEMINATION: This study protocol has been approved by the Regional Ethics Committee (Region Zealand, Denmark) and the Danish Data Protection Agency. All data will be managed confidentially according to legislation. Study results will be presented at international conferences and published in peer-review journals.

Seminal human papillomavirus originates from the body surface and is not a frequent aetiological factor in azoospermia.

Human papillomavirus (HPV) DNA has been detected in the testis tissue of 6.5% of 185 men with non-obstructive azoospermia (NOA). Others have suggested that seminal HPV originates from contamination from the genital skin and mucosa. One hundred unselected azoospermic men and 43 normal men undergoing vasectomy were recruited. Testicular biopsies for HPV examination were collected from all the men. Additionally, the normal men undergoing vasectomy delivered a semen sample and had a swab for HPV examination taken from the genital skin before vasectomy. A piece of each Vas deferens obtained during the vasectomy was examined for the presence of HPV. Two of the primarily azoospermic men were shown to have cryptozoospermia. It was not possible to detect HPV in the testis tissue of any of the included 98 azoospermic men or the 43 proven fertile men. In the proven fertile men, HPV DNA was detected in the semen of 15 men (35%), on the genital skin of 28 men (65%), and in the Vas deferens in three cases (7%). In 13 (87%) men with HPV-positive semen samples, HPV DNA was also detected in the skin swabs, and in 11 men (73%), identical HPV genotypes were found in the two locations.

Testicular Damage following Testicular Sperm Retrieval: A Ram Model Study.

The aim of this study was to evaluate the possible development of histological abnormalities such as fibrosis and microcalcifications after sperm retrieval in a ram model. Fourteen testicles in nine rams were exposed to open biopsy, multiple TESAs, or TESE, and the remaining four testicles were left unoperated on as controls. Three months after sperm retrieval, the testicles were removed, fixed, and cut into 1/2 cm thick slices and systematically put onto a glass plate exposing macroscopic abnormalities. Tissue from abnormal areas was cut into 3 µm sections and stained for histological evaluation. Pathological abnormalities were observed in testicles exposed to sperm retrieval (≥11 of 14) compared to 0 of 4 control testicles. Testicular damage was found independently of the kind of intervention used. Therefore, cryopreservation of excess sperm should be considered while retrieving sperm.

The Danish Testicular Cancer database.

AIM: The nationwide Danish Testicular Cancer database consists of a retrospective research database (DaTeCa database) and a prospective clinical database (Danish Multidisciplinary Cancer Group [DMCG] DaTeCa database). The aim is to improve the quality of care for patients with testicular cancer (TC) in Denmark, that is, by identifying risk factors for relapse, toxicity related to treatment, and focusing on late effects. STUDY POPULATION: All Danish male patients with a histologically verified germ cell cancer diagnosis in the Danish Pathology Registry are included in the DaTeCa databases. Data collection has been performed from 1984 to 2007 and from 2013 onward, respectively. MAIN VARIABLES AND DESCRIPTIVE DATA: The retrospective DaTeCa database contains detailed information with more than 300 variables related to histology, stage, treatment, relapses, pathology, tumor markers, kidney function, lung function, etc. A questionnaire related to late effects has been conducted, which includes questions regarding social relationships, life situation, general health status, family background, diseases, symptoms, use of medication, marital status, psychosocial issues, fertility, and sexuality. TC survivors alive on October 2014 were invited to fill in this questionnaire including 160 validated questions. Collection of questionnaires is still ongoing. A biobank including blood/sputum samples for future genetic analyses has been established. Both samples related to DaTeCa and DMCG DaTeCa database are included. The prospective DMCG DaTeCa database includes variables regarding histology, stage, prognostic group, and treatment. CONCLUSION: The DMCG DaTeCa database has existed since 2013 and is a young clinical database. It is necessary to extend the data collection in the prospective database in order to answer quality-related questions. Data from the retrospective database will be added to the prospective data. This will result in a large and very comprehensive database for future studies on TC patients.

Incidental finding of multiple well-differentiated papillary mesotheliomas in peritoneum.

We present a case of multiple well-differentiated papillary mesotheliomas (WDPM) in the peritoneum found incidentally in a 63-year-old man with urothelial carcinoma of the bladder. When multiple tumors are seen, malignant mesothelioma should be excluded by histopathological examination as this may have a similar focal appearance to WDPM. True stromal invasion is by far the most reliable criterion of mesothelial malignancy. In doubtful cases, a conservative diagnostic approach has been recommended. Compared to malignant mesotheliomas, WDPMs are rare and have a relatively indolent clinical course with a good prognosis. Great care is needed when diagnosing mesothelial proliferations, given the crucial nature of a benign vs malignant diagnosis. No standardized treatment has yet been established.

Testicular Sperm Sampling by Subcapsular Orchiectomy in Klinefelter Patients: A New Simplified Treatment Approach.

OBJECTIVE: To evaluate subcapsular orchiectomy as a method to retrieve spermatozoa from minute testicular foci in men with Klinefelter syndrome (KS). METHODS: Fourteen men with KS were consecutively recruited to unilateral subcapsular orchiectomy. Testicular tissue was dissected mechanically and enzymatically to identify possible sperm. Previous testosterone replacement therapy was interrupted for 10 months (range: 9-12 months) to minimize a possible effect on the spermatogenesis. Two men with high estrogen/testosterone ratios were treated with aromatase inhibitor (letrozol, 2.5 mg/d for 3 months) before operation. RESULTS: Testicular sperm were detected in 5 of 14 KS men giving an overall success rate of 36%. The success rate was 50% (5 of 10 men) after exclusion of the 4 men previous treated with androgen substitution. So far, 3 (21%) clinical pregnancies and 2 live births or ongoing pregnancies (14%) have been obtained. Testicular sperm could not be detected in the 2 men treated with aromatase inhibitor before operation. The maximum operative time was 20 minutes, and none had surgical complications such as pain, fever, or hematomas. The mean testosterone level, measured 1-4 months after orchiectomy, decreased to 72% (7.9 ± 2.4 nmol/L) of the preoperative level. CONCLUSION: Subcapsular orchiectomy appears to be easy and quick compared with conventional microtesticular sperm extraction. However, in this pilot study, it has not been possible to demonstrate pregnancy and live birth rates as high as that reported with microtesticular sperm extraction, and further studies are needed before the procedure should be used routinely for sperm retrieval in patients with KS.

[Metastasis in testis from prostate cancer].

We present a case of an 89-year-old male diagnosed with a prostatic adenocarcinoma. He developed a metastasis to his left testis and was treated with bilateral orchiectomy. Histology showed a ductal adenocarcinoma with positive immunohistochemical markers for PSA and p501. Testicular metastases from prostate cancer are rare and are assumed to be associated with progressed disease and poor prognosis. Ductal adenocarcinomas may be associated with a higher risk of dissemination to the testis.

Histological step sectioning of pelvic lymph nodes increases the number of identified lymph node metastases.

Pathological examinations of lymph nodes (LN) in prostate cancer patients are handled differently at various institutions. The objective of this study is to provide means to improve the guidelines by examining the impact of step sectioning on LN status in patients with intermediate and high-risk prostate cancer. Two hundred ten patients who awaited curative indented therapy were included. We first performed a standard pathological examination of the LN, followed by an extended pathological examination of the patients who were LN negative in the standard examination. The extended pathological examination included a 100-µm-deep haematoxylin and eosin (HE) section followed by a slide stained with cytokeratin AE1/AE3 and then by four HE sections at 0.5-mm intervals.The standard pathological examination detected 41 patients with LN metastasis. The remaining 169 patients had 1,185 HE sections made at the standard examination, whereas the extended examination gave additional 7,110 slides and detected 5 additional patients with LN metastasis. In all, 1,158 LN were removed. The additional LN metastases were smaller than the LN metastases found at the standard examination, mean 1.2 mm vs. 7.8 mm.Our results indicate that an extended pathological examination of LN will improve the staging of intermediate- and high-risk prostate cancer patients; however, we acknowledge that it is both costly and time consuming. We do not recommend the use of cytokeratin staining in routine staining because the immunohistochemistry did not reveal new or further information. A detailed guideline on how to handle the LN specimens at the pathological department is needed.

Ulcerating and stenosing enteropathy treated with misoprostol: a case report with analysis of prostaglandin metabolism.

A case of a 40-year-old man with chronic anaemia because of nonspecific ulcerating and stenosing enteropathy is presented. The diagnosis was made on the basis of capsule endoscopy, histology of resected ileum and no use of NSAIDs. He showed a clinical response to treatment with misoprostol, and therefore, he was investigated for a possible impairment in eicosanoid biosynthesis compared with healthy controls. No deficient synthesis of prostacyclin, prostaglandin E2 and thromboxane was found on examination of metabolites in blood and urine. This suggests a normal release of arachidonic acid from phospholipids. Ex-vivo cyclooxygenase (COX) assays showed normal COX-1 and COX-2 activities. The clinical response to treatment with the prostaglandin E1 analogue misoprostol suggests a defective prostaglandin E synthesis in the intestinal mucosa.

Effects of the change in cutoff values for human epidermal growth factor receptor 2 status by immunohistochemistry and fluorescence in situ hybridization: a study comparing conventional brightfield microscopy, image analysis-assisted microscopy, and interobserver variation.

CONTEXT: New guidelines for HER2 testing have been introduced. OBJECTIVES: To evaluate the difference in HER2 assessment after introduction of new cutoff levels for both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) and to compare interobserver agreement and time to score between image analysis and conventional microscopy. DESIGN: Samples from 150 patients with breast cancer were scored by 7 pathologists using conventional microscopy, with a cutoff of both 10% and 30% IHC-stained cells, and using automated microscopy with image analysis. The IHC results were compared individually and to HER2 status as determined by FISH, using both the approved cutoff of 2.0 and the recently introduced cutoff of 2.2. RESULTS: High concordance was found in IHC scoring among the 7 pathologists. The 30% cutoff led to slightly fewer positive IHC observations. Introduction of a FISH equivocal zone affected 4% of the FISH scores. If cutoff for FISH is kept at 2.0, no difference in patient selection is found between the 10% and the 30% IHC cutoff. Among the 150 breast cancer samples, the new 30% IHC and 2.2 FISH cutoff levels resulted in one case without a firm diagnosis because both IHC and FISH were equivocal. Automated microscopy and image analysis-assisted IHC led to significantly better interobserver agreement among the 7 pathologists, with an increase in mean scoring time of only about 30 seconds per slide. CONCLUSIONS: The change in cutoff levels led to a higher concordance between IHC and FISH, but fewer samples were classified as HER2 positive.

Vacuum sealing and cooling as methods to preserve surgical specimens.

Recently, vacuum-based preservation of surgical specimens has been proposed as a safe alternative to formalin fixation at the surgical theater. The method seems feasible from a practical point of view, but no systematic study has examined the effect of vacuum sealing alone with respect to tissue preservation. In this study, we therefore subjected tissue samples from 5 different organs to treatments with and without vacuum sealing and cooling at 4°C to study the effect of vacuum sealing of surgical specimens with respect to tissue preservation and compare it with the effect of cooling. No preserving effect of vacuum sealing was observed with respect to cellular morphology, detection of immunohistochemical epitopes, or RNA integrity. In contrast, storage at 4°C was shown to preserve tissue to a higher degree than storage at room temperature for all included endpoints, independently of whether the tissue was subjected to vacuum sealing or not. We, therefore, conclude that vacuum sealing is not an alternative to cooling on ice.

[Fine needle aspiration cytology of mammography screening]. / Finnålsaspirationscytologi ved mammografiscreening.

INTRODUCTION: In the year 2000 a quality assurance programme for the preoperative breast diagnostics was introduced in Denmark. The programme was based on the "European guidelines for quality assurance in breast cancer screening and diagnosis" where - among other measures - five cytological diagnostic classes were introduced. The aim of this study was to evaluate the quality assurance programme in a screening population to determine whether fine needle aspiration cytology (FNAC) as first choice remains a useful tool in the preoperative diagnostics, or if needle core biopsy should be the first-choice treatment. MATERIAL AND METHODS: 767 women had FNAC performed from a total of 783 lesions at the Mammography Clinic, University Hospital Odense. All FNACs were compared with the final histology diagnosis. Nine statistical parameters were calculated according to the European guidelines. RESULTS: A total of 66% of the 783 FNACs had a malignant cytology diagnosis, which in 99% of the cases turned out to be the correct diagnosis. Four lesions were false positives all of which represented benign proliferative breast diseases. The surgical procedures in these cases were either excisional biopsy or lumpectomy. The values of eight of the nine mutually dependent statistical parameters of quality scored within the recommended threshold values. Specificity was the only parameter that fell outside the recommended threshold values. CONCLUSION: Although specificity in our study is lower than recommended, we find that the use of FNAC as first-choice in triple diagnostics is a useful tool.