Clinical characteristics, treatment patterns and relapse in patients with clinical stage IS testicular cancer.

PURPOSE: Clinical stage I (CSI) testicular germ cell tumors (TGCT) represents disease confined to the testis without metastasis and CSIS is defined as persistently elevated tumor markers (TM) after orchiectomy, indicating subclinical metastatic disease. This study aims at assessing clinical characteristics and oncological outcome in CSIS. METHODS: Data from five tertiary referring centers in Germany were screened. We defined correct classification of CSIS according to EAU guidelines. TM levels, treatment and relapse-free survival were assessed and differences between predefined groups (chemotherapy, correct/incorrect CSIS) were analyzed with Fisher's exact and Chi-square test. RESULTS: Out of 2616 TGCT patients, 43 (1.6%) were CSIS. Thereof, 27 were correctly classified (cCSIS, 1.03%) and 16 incorrectly classified (iCSIS). TMs that defined cCSIS were in 12 (44.4%), 10 (37%), 3 (11.1%) and 2 (7.4%) patients AFP, ß-HCG, AFP plus ß-HCG and LDH, respectively. In the cCSIS group, six patients were seminoma and 21 non-seminoma. Treatment consisted of active surveillance, carboplatin-mono AUC7 and BEP (bleomycin, etoposide and cisplatin). No difference between cCSIS and iCSIS with respect to applied chemotherapy was found (p = 0.830). 5-year relapse-free survival was 88.9% and three patients (11%) in the cCSIS group relapsed. All underwent salvage treatment (3xBEP) with no documented death. CONCLUSION: Around 1% of all TGCT were classified as cCSIS patients. Identification of cCSIS is of critical importance to avoid disease progression and relapses by adequate treatment. We report a high heterogeneity of treatment patterns, associated with excellent long-term survival irrespective of the initial treatment approach.

[Knowledge and early detection of testicular germ cell cancer among adolescents and young adults]. / Kenntnisstand und Früherkennung maligner Keimzelltumoren des Hodens unter Jugendlichen und jungen Erwachsenen.

INTRODUCTION: Malignant testicular germ cell tumors are the most common tumor disease in young men, affecting not only the period of his reproductive phase but also creating a complex life situation. Therapy includes the risk of development of second neoplasia and sequelae. However, particularly in this age group, knowledge about this disease and risk factors is sparse, and preventive examinations are not available or are not or insufficiently used. MATERIALS AND METHODS: In order to evaluate the state of knowledge on testicular tumors in adolescents, a knowledge survey was conducted at 6 high schools in Hamburg from January to April 2019 among pupils of grades 11 and 12. This was carried out with a questionnaire comprising 15 items, which was analyzed and also evaluated on a gender-specific basis. Only fully completed questionnaires were considered. RESULTS: The overall proportion of correctly answered questions was 60.04%. Broken down by gender, the proportion was 60.18% for female pupils and 59.14% for male pupils, while the gender ratio was 52.2 and 47.8% for female pupils. Special questions on testicular tumors were answered correctly by 59.71% of the female students and 54.8% of the male students, while general questions on the structure and function of the male sexual organs were answered 4.51% better by the male students with 64.9%. These were statistically significant in both cases. CONCLUSION: The survey shows a gender-specific knowledge deficit on testicular tumors, which is more pronounced among boys. As intensified knowledge transfer on this topic alone is insufficient, a preventive examination should be established especially for boys. This would enable individual, risk-commensurate and needs-adapted monitoring and early detection of testicular tumor disease, but also of other health issues in male adolescents.

Expression of miRNA-371a-3p in seminal plasma and ejaculate is associated with sperm concentration.

BACKGROUND: The microRNAs of the miR-371-3 cluster are novel serum markers for testicular germ cell tumors. Sporadic reports suggested the expression of this miRNA in semen. OBJECTIVES: To verify the expression of miR-371a-3p in seminal plasma and unprocessed ejaculate; to compare seminal plasma miRNA levels in germ cell tumors patients with those of controls; to look for an association of miRNA levels with semen quality. MATERIALS AND METHODS: The miR-371a-3p expression was analyzed with qPCR. The study population consisted of 100 participants: seminal plasma samples from 20 germ cell tumors patients and 30 controls, serum samples from 12 healthy men, ejaculate samples from 38 men undergoing fertility testing. RESULTS: The seminal plasma miR-371a-3p levels of germ cell tumors patients were not different from controls. The miRNA expression was very low in serum but much higher in seminal plasma. In ejaculate samples, the miRNA expression significantly correlated with sperm concentration and the total sperm count. DISCUSSION: miR-371-a-3p is present in sperm-containing fluids. Seminal plasma levels cannot be used to distinguish germ cell tumors from controls. The correlation with sperm concentration in ejaculate samples suggests the spermatozoa as possible source of miR-371a-3p production. CONCLUSION: The miR-371a-3p levels in ejaculate could represent a novel biomarker for the non-invasive evaluation of male infertility.

Testicular epidermoid cysts: a reevaluation.

BACKGROUND: Testicular epidermoid cysts (TECs) are rare benign testicular neoplasms. As TECs are rarely associated with germ cell tumours (GCTs), the understanding of biological behaviour and clinical management of TEC is unresolved. METHODS: We retrospectively searched the files of patients treated for testicular neoplasms and germ cell cancer in the time from 2000 to 2017. Those with TEC were subjected to closer review looking to clinical and histological features, and to results from imaging with ultrasonography (US), contrast enhanced sonography (CEUS) and magnetic resonance imaging (MRI). RESULTS: Among 589 patients undergoing surgery for testicular tumour, nine simple TECs were identified (1.5, 95% confidence intervals 0.53-2.50%). Median age was 26 years. Imaging revealed sharply demarcated roundish lesions with avascular central areas. Eight patients underwent testis-sparing excision with no recurrence ensuing. One had orchiectomy because of large size of the mass. Histologically, TECs consisted of cornifying squamous cell epithelium and no accompanying germ cell neoplasia in situ. Two additional cases (0.3% of all) required orchiectomy because these TECs were associated with ipsilateral GCT. CONCLUSIONS: TEC is usually a benign lesion that can safely be diagnosed with US, CEUS and MRI due to its roundish shape and its avascular centre. Histologically, this TEC corresponds to the prepubertal-type teratoma unrelated to germ cell neoplasia in situ of the 2016 WHO classification. The other subtype of TEC that is associated with invasive GCT represents a teratoma of postpubertal-type. From a clinical point of view it could be easier to differentiate between a "simple TEC" which is benign (prepubertal type) and a "complex TEC" which is malignant because of its association with invasive GCT.

Is there still a place for retroperitoneal lymph node dissection in clinical stage 1 nonseminomatous testicular germ-cell tumours? A retrospective clinical study.

BACKGROUND: Primary retroperitoneal lymph node dissection (RPLND) ultimately lost its role as the standard management of clinical stage (CS) 1 nonseminomatous (NS) testicular germ cell tumours (GCTs) in Europe when the European Germ Cell Cancer Consensus Group released their recommendations in 2008. Current guide-lines recommend surgery only for selected patients but reasons for selection remain rather ill-defined. We evaluated the practice patterns of the management of CS1 patients and looked specifically to the role of RPLND among other standard treatment options. METHODS: We retrospectively evaluated the treatment modalities of 75 consecutive patients treated for CS1 NS at one centre during 2008-2017. The patients undergoing RPLND were selected for a closer review. Particular reasons for surgery, clinical features of patients, and therapeutic outcome were analyzed using descriptive statistical methods. RESULTS: Twelve patients (16%) underwent nerve-sparing RPLND, nine surveillance, 54 had various regimens of adjuvant chemotherapy. Particular reasons for surgery involved illnesses precluding chemotherapy (n = 2), patients´ choice (n = 4), and teratomatous histology of the primary associated with equivocal radiologic findings (n = 6). Five patients had lymph node metastases, two received additional chemotherapy. Antegrade ejaculation was preserved in all cases. One patient had a grade 2 complication that was managed conservatively. All RPLND-patients remained disease-free. CONCLUSIONS: Primary RPLND is a useful option in distinct CS1 patients, notably those with concurrent health problems precluding chemotherapy, and those with high proportions of teratoma in the primary associated with equivocal radiological findings. Informed patient's preference represents another acceptable reason for the procedure. RPLND properly suits the needs of well-selected patients with CS1 nonseminoma and deserves consideration upon clinical decision-making.

ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up.

The European Society for Medical Oncology (ESMO) consensus conference on testicular cancer was held on 3-5 November 2016 in Paris, France. The conference included a multidisciplinary panel of 36 leading experts in the diagnosis and treatment of testicular cancer (34 panel members attended the conference; an additional two panel members [CB and K-PD] participated in all preparatory work and subsequent manuscript development). The aim of the conference was to develop detailed recommendations on topics relating to testicular cancer that are not covered in detail in the current ESMO Clinical Practice Guidelines (CPGs) and where the available level of evidence is insufficient. The main topics identified for discussion related to: (1) diagnostic work-up and patient assessment; (2) stage I disease; (3) stage II-III disease; (4) post-chemotherapy surgery, salvage chemotherapy, salvage and desperation surgery and special topics; and (5) survivorship and follow-up schemes. The experts addressed questions relating to one of the five topics within five working groups. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel. A consensus vote was obtained following whole-panel discussions, and the consensus recommendations were then further developed in post-meeting discussions in written form. This manuscript presents the results of the expert panel discussions, including the consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

Can germ cell neoplasia in situ be diagnosed by measuring serum levels of microRNA371a-3p?

PURPOSE: Diagnosing germ cell neoplasia in situ (GCNis) can detect germ cell tumours (GCTs) at the pre-invasive stage. To date, testicular biopsy with the potential of surgical complications is the only way of safely diagnosing GCNis. Recently, microRNAs (miRs) 371-3, and miR 367 were shown to be valuable serum biomarkers of GCTs. We explored the usefulness of these candidate miRs as a marker for GCNis. METHODS: 27 patients with GCNis and no concomitant GCT were enrolled. All patients underwent measuring serum levels of miR-371a-3p and miR-367-3p before treatment, 11 had repeat measurement after treatment, 2 also had testicular vein blood examinations. Serum levels were measured by quantitative PCR. In addition, four orchiectomy specimens of patients with GCT were examined immunohistochemically and by in situ hybridization (ISH) with a probe specific for miR-371a-3p to look for the presence of this miR in GCNis cells. RESULTS: The median serum level of miR-371a-3p was significantly higher in patients with GCNis than in controls, miR-367 levels were not elevated. Overall, 14 patients (51.9%) had elevated serum levels of miR-371a-3p. The highest levels were found in patients with bilateral GCNis. Levels in testicular vein serum were elevated in both of the cases. After treatment, all elevated levels dropped to normal. In two orchiectomy specimens, miR-371a-3p was detected by ISH in GCNis cells. CONCLUSIONS: Measuring miR-371a-3p serum levels can replace control biopsies after treatment of GCNis. In addition, the test can guide clinical decision making regarding the need of testicular biopsy in cases suspicious of GCNis.

[Assessment of physicians? : Results of a sample analysis for the selection of physicians for staff positions]. / Assessment für Mediziner? : Ergebnisse einer Stichprobenanalyse zur Personalauswahl für Ärzte.

As in aviation and other organizations requiring high levels of safety, medical complications and errors can in most cases be traced back to the human factor as a main cause. The correct selection of medical students and physicians is therefore very important, especially in leadership and key positions. This is not only a necessary safety aspect but also the prerequisite for the stipulated efficiency of modern medicine.

Contralateral biopsies in patients with testicular germ cell tumours: patterns of care in Germany and recent data regarding prevalence and treatment of testicular intra-epithelial neoplasia.

The precursor of testicular germ cell tumours (GCTs), called testicular intra-epithelial neoplasia (TIN/CIS), is safely diagnosed immunohistologically. Testicular biopsy provides a valuable tool for early detection of GCTs in risk groups. Although this knowledge is undisputed, testicular biopsies are utilized poorly. The patterns of care regarding the use of biopsies remain unknown. Uncertainty exists about the prevalence and specific treatment of TIN/CIS. We asked clinical urologists in Germany whether or not they employed contralateral biopsies in GCT patients. We evaluated the prevalence of contralateral TIN/CIS in a retrospective analysis of 780 consecutive GCT patients. All had contralateral double biopsies. Discordance of TIN/CIS findings among biopsy pairs as well as age, histology of the primary tumour and clinical stage was noted. Evaluation of data comprised descriptive statistical methods. To evaluate treatment options for TIN/CIS, we performed a literature search. 52.1% of German urologists always perform the biopsy, 17% do it mostly, 27.3% in select cases, 3.5% never. Curiously, there was a geographic north-south gradient regarding biopsy use. Contralateral TIN/CIS was found in 5%. The median ages of patients with TIN/CIS and those without were 31.8 and 34.9 years respectively (p = 0.02). The discordance rate among biopsy pairs was of 33%. Two-site biopsies provide a 17% gain in diagnostic sensitivity. Local radiotherapy with 20 Gy is the safest treatment of TIN/CIS failing in 2%. Chemotherapy has significantly lower efficacy. Contralateral testicular biopsies in GCT patients are well accepted among German urologists. The prevalence of contralateral TIN/CIS found in this series is in accordance with previous reports. Double biopsies should be the diagnostic standard because of their diagnostic superiority. Local radiotherapy with 20 Gy is the safest way of eradicating TIN/CIS. Failures occur in only 2%, usually many years after irradiation. Cisplatin-based chemotherapy is dose dependent and less effective.

MicroRNA miR-371a-3p in serum of patients with germ cell tumours: evaluations for establishing a serum biomarker.

As only 60% of the patients with germ cell tumour (GCT) express the classical markers, new markers as for example microRNAs (miRNAs) are required. One promising candidate is miR-371a-3p, but data are sparse to date. We measured serum levels of miR-371a-3p in GCT patients, in controls, and in cases with other malignancies. We also assessed the expression in other body fluids and we looked to the decline of serum miR-371a-3p levels after treatment. miR-371a-3p levels were measured by quantitative polymerase chain reaction in serum samples of 25 GCT patients, 6 testicular intraepithelial neoplasia (TIN) patients, 20 healthy males and 24 non-testicular malignancies (NTMs). Testicular vein blood (TVB) was examined in five GCT patients and five controls. Five GCT patients had serial daily measurements after orchiectomy. Five seminal plasma samples, three urine specimens and one pleural effusion fluid were processed likewise. GCT patients had significantly higher miR-371a-3p serum levels than controls and NTMs. Serum levels of controls, TINs and NTMs were not significantly different. TVB samples of GCT patients had 65.4-fold higher serum levels than peripheral blood. Malignant pleural effusion fluid had extremely high levels of miR-371a-3p, seminal plasma had strongly elevated levels by comparison with serum levels of controls. In urine of GCT patients, no miR-371a-3p expression was detected. Daily measurements after orchiectomy in stage 1 patients revealed a decline by 95% within 24 h. Serum levels of miR-371a-3p appear to be a promising specific biomarker of GCTs as is suggested by high serum levels in GCT patients, the rapid return of elevated levels to normal range after treatment, the association of serum levels with tumour bulk, the non-expression in NTMs and the much higher levels of miR-371a-3p in TVB. This potential marker deserves further exploration in a large-scale clinical study.

[Contralateral testicular biopsy in patients with germ cell tumors: practice patterns in Germany 2014]. / Kontralaterale Biopsie beim Hodentumor : Die Praxis in Deutschland 2014.

BACKGROUND: Contralateral testicular biopsy is a tool for early diagnosis of contralateral tumors in patients with testicular germ cell tumor (GCT). Though based on a high level of evidence, international guidelines do not unanimously recommend biopsies. We enquired the acceptance of contralateral biopsies among clinical urologists in Germany. METHODS: A total of 326 urologic departments were asked by a questionnaire whether they perform contralateral biopsy in all cases with GCT, in most, in select cases, or never. In addition we enquired for type and size of the department as well as the annual volume of GCT patients. To specify the hospital geographically, we noted the ZIP code. The data were analyzed with descriptive statistical methods. RESULTS: The response rate was 86.5%. Of the departments, 52.1, 17, 27.3, and 3.5% do the biopsy in all cases, in most of them, in select patients, and never, respectively. University departments have significantly lower acceptance of the procedure than general hospitals (50% versus 72.6%), even after adjusting for other hospital characteristics by multivariate analysis. There was no association of acceptance rate with hospital size and annual GCT volume. The biopsy is highly used in the northern parts of Germany and considerably under-used in southern regions. CONCLUSION: Contralateral testicular biopsy is well-established and widely accepted among clinical urologists in Germany. In other countries, biopsies remain controversial. Only in Denmark is it routinely employed. In Sweden, Austria, and Switzerland biopsies are done in selected patients. In view of the multination treatment consensus of GCT, explanations for the dissimilar biopsy rates in various countries remain elusive. Peculiar findings are the inferior acceptance rates in university departments and the north-south gradient within Germany.

Contrast-enhanced ultrasound and real-time elastography for the diagnosis of benign Leydig cell tumors of the testis - a single center report on 13 cases.

PURPOSE: To describe sonomorphological features in testicular Leydig cell tumors (LCTs) with a special focus on contrast-enhanced ultrasonography (CEUS) and real-time elastography (RTE). PATIENTS AND METHODS: In a series of 186 patients with testicular surgery for neoplastic disease, 13 benign LCTs (in 12 patients) were histopathologically diagnosed. Preoperatively, all patients had been examined with a standardized protocol (high-resolution grayscale and color-coded ultrasonography, CEUS). 5 patients underwent RTE. In CEUS, the filling time of the lesion was compared to that of 14 size-matched germ cell tumors (GCT). RESULTS: 10/13 LCTs had a size of < 10 mm, and a sharply demarcated hypoechoic appearance was typical (10/13). Color-coded ultrasonography detected signals in 8 lesions, while CEUS showed clear hypervascularization in all. LCTs had a significantly shorter filling time than GCTs (p < 0.0005), with 9/13 LCTs being completely filled within 4 s. In RTE, all 5 examined lesions were clearly "harder" than the surrounding testicular tissue. CONCLUSION: Contrary to some earlier reports, we could demonstrate marked hypervascularization in LCTs. This feature clearly allows for the differentiation of a small LCT from focal scars. However, it may only be visible on CEUS. In CEUS, LCT is suggested by the findings of a short filling time or by a circumferential vessel with a rapid centripetal filling, combined with a "harder" appearance in RTE. These features along with the findings of a small and peripherally situated hypoechoic tumor would justify an operative strategy with frozen section examination and possibly organ sparing surgery instead of orchiectomy.

[Complications associated with inguinal orchiectomy and scrotal orchiectomy]. / Komplikationen bei inguinaler Ablatio testis und skrotaler Orchiektomie.

Inguinal excision of testis is technically an elementary surgical procedure. According to the indication (e.g., malignant tumors, infarction, inflammation), an inguinal or alternatively a transcrotal approach is possible. Despite its straightforwardness, surgery of the scrotum includes remarkable risks and complications such as postoperative hemorrhage, hematoma formation, infections, and disturbances of wound healing followed by insufficient unfavorable cosmetic results. Nerve injury may be accompanied by temporary or persistent paresthesias which have been documented in our patients undergoing orchiectomy.

Treatment of testicular intraepithelial neoplasia (intratubular germ cell neoplasia unspecified) with local radiotherapy or with platinum-based chemotherapy: a survey of the German Testicular Cancer Study Group.

BACKGROUND: The treatment of testicular intraepithelial neoplasia (TIN), the progenitor of testicular germ cell tumours (GCTs), is based on little data. PATIENTS AND METHODS: Two hundred and twenty-eight GCT patients with contralateral TIN were retrospectively enrolled. Ten had surveillance, 122 radiotherapy to testis with 18-20 Gy, 30 cisplatin-based chemotherapy (two cycles), 51 chemotherapy (three cycles), and 15 carboplatin. The study end point was a malignant event (ME), defined as detection of TIN upon control biopsy or occurrence of a second GCT. The Secondary end point was hypogonadism during follow-up. RESULTS: Numbers, proportions of ME, and median event-free survival (EFS) times were: radiotherapy N = 3, 2.5%, 11.08 years; chemotherapy (two cycles) N = 15, 50%, 3.0 years; chemotherapy (three cycles) N = 12, 23.5%, 9.83 years; carboplatin N = 10, 66%, 0.9 years; surveillance N = 5, 50%, 7.08 years. EFS is significantly different among the groups. Hypogonadism rates were in radiotherapy patients 30.8%, chemotherapy (two cycles) 13%, chemotherapy (three cycles) 17.8%, carboplatin 40%, surveillance 40%. CONCLUSIONS: Local radiotherapy is highly efficacious in curing TIN. Chemotherapy is significantly less effective and the cure rates are dose-dependent. Though hypogonadism occurs in one-third of patients, radiotherapy with 20 Gy remains the standard management of TIN.

Maintaining success, reducing treatment burden, focusing on survivorship: highlights from the third European consensus conference on diagnosis and treatment of germ-cell cancer.

In November 2011, the Third European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer (GCC) was held in Berlin, Germany. This third conference followed similar meetings in 2003 (Essen, Germany) and 2006 (Amsterdam, The Netherlands) [Schmoll H-J, Souchon R, Krege S et al. European consensus on diagnosis and treatment of germ-cell cancer: a report of the European Germ-Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377-1399; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 2008; 53: 478-496; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part II. Eur Urol 2008; 53: 497-513]. A panel of 56 of 60 invited GCC experts from all across Europe discussed all aspects on diagnosis and treatment of GCC, with a particular focus on acute and late toxic effects as well as on survivorship issues. The panel consisted of oncologists, urologic surgeons, radiooncologists, pathologists and basic scientists, who are all actively involved in care of GCC patients. Panelists were chosen based on the publication activity in recent years. Before the meeting, panelists were asked to review the literature published since 2006 in 20 major areas concerning all aspects of diagnosis, treatment and follow-up of GCC patients, and to prepare an updated version of the previous recommendations to be discussed at the conference. In addition, ∼50 E-vote questions were drafted and presented at the conference to address the most controversial areas for a poll of expert opinions. Here, we present the main recommendations and controversies of this meeting. The votes of the panelists are added as online supplements.

MicroRNAs miR-371-3 in serum as diagnostic tools in the management of testicular germ cell tumours.

BACKGROUND: miRNAs are small noncoding RNA molecules that can be released into body fluids. Germ cell tumours (GCTs) overexpress miRNAs of the miR-371-3 cluster. Thus, serum levels of these miRNAs may correlate with tumour load. METHODS: miRNAs of the miR-371-3 cluster were quantified in cubital vein blood samples of 20 GCT patients with clinical stage 1, and of 4 patients with advanced stages before and after treatment. In six patients testicular vein blood (TVB) was examined additionally. Seventeen healthy males served as controls. Likewise, expression of miRNAs in 15 matching tumour specimens was measured. RESULTS: In all patients, serum levels of miRNAs 371-3 were much higher than in controls. In stage 1, levels decreased postoperatively 336.7-fold, 7.4-fold, and 7.7-fold for miRNAs 371a-3p, 372, and 373-3p, respectively (P<0.01). Also, in those cases with advanced disease levels dropped to the normal range after completion of treatment. miR-371-3 levels in TVB exceeded those in peripheral blood in all cases. Expression of miR-371a-3p was also documented in tumour tissue. However, no correlation was found regarding the extent of miRNA expression in tissue and the values measured in matching serum. CONCLUSION: Thus, miR-371a-3p serum level appears to be a useful biomarker in GCTs.