Diagnosis and Management of Intratubular Germ Cell Neoplasia In Situ: A Systematic Review
2020; Lippincott Williams & Wilkins; Volume: 204; Issue: 1 Linguagem: Inglês
10.1097/ju.0000000000000758
ISSN1527-3792
AutoresMohit Gupta, Joseph Cheaib, Hiten D. Patel, Ritu Sharma, Allen Zhang, Eric B Bass, Phillip M. Pierorazio,
Tópico(s)Sarcoma Diagnosis and Treatment
ResumoYou have accessJournal of UrologyReview Articles1 Jul 2020Diagnosis and Management of Intratubular Germ Cell Neoplasia In Situ: A Systematic ReviewThis article is commented on by the following:Editorial Comment Mohit Gupta, Joseph G. Cheaib, Hiten D. Patel, Ritu Sharma, Allen Zhang, Eric B. Bass, and Phillip M. Pierorazio Mohit GuptaMohit Gupta Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland , Joseph G. CheaibJoseph G. Cheaib Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland , Hiten D. PatelHiten D. Patel Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland , Ritu SharmaRitu Sharma The Johns Hopkins Evidence-Based Practice Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland , Allen ZhangAllen Zhang The Johns Hopkins Evidence-Based Practice Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland , Eric B. BassEric B. Bass The Johns Hopkins Evidence-Based Practice Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland , and Phillip M. PierorazioPhillip M. Pierorazio *Correspondence: The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, 600 N. Wolfe St./Marburg 150, Baltimore, Maryland 21287 telephone: 410-502-5984; FAX: 410-502-7711; E-mail Address: [email protected] Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland View All Author Informationhttps://doi.org/10.1097/JU.0000000000000758AboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Abstract Purpose: We performed a systematic review of studies assessing the diagnosis and effectiveness of management strategies for germ cell neoplasia in situ. Materials and Methods: Paired investigators independently searched for studies on the diagnosis and management of testicular germ cell neoplasia in situ using PubMed®, Embase® and the Cochrane Central Register of Controlled Trials from January 1, 1980 through August 2018. The reviewers then extracted data and assessed quality. Results: Eighteen studies met inclusion criteria. Among patients with a testicular germ cell tumor the prevalence of contralateral germ cell neoplasia in situ was 4.0% to 8.1%. No significant difference in the risk of metachronous malignancy was identified between unscreened groups vs those with routine contralateral testicular screening (cumulative incidence 1.9% vs 3.1%, p=0.097, respectively). Patients who presented with a history of testicular atrophy, age less than 40 years or cryptorchidism had an elevated risk of germ cell neoplasia in situ. In patients with germ cell neoplasia in situ the use of 18 to 20 Gy radiation therapy demonstrated the lowest rate of disease on followup biopsies (0% to 2.5%), compared to a median of 30% on biopsies in patients treated with cisplatin based chemotherapy. Carboplatin based treatment regimens demonstrated positive disease in 66% to 75% on repeat biopsies. Rates of treatment related hypogonadism were 30.8% to 38.5% and 13% to 20% for patients treated with 18 to 20 Gy and cisplatin based chemotherapy, respectively. Conclusions: In patients with a testicular germ cell tumor the risk of having contralateral germ cell neoplasia in situ is 4% to 8%, with a greater risk in patients with testicular atrophy, cryptorchidism or age less than 40 years. The risk is high enough to support use of contralateral testicular biopsy in patients with these risk factors for germ cell neoplasia in situ. However, routine screening is not advised. Radiation therapy with 18 to 20 Gy was associated with much better eradication of germ cell neoplasia in situ than chemotherapy. Chemotherapy may eradicate germ cell neoplasia in situ in up to two-thirds of patients undergoing chemotherapy as adjuvant treatment for a primary germ cell tumor. Further research and data are needed to strengthen many aspects of the evidence base. Abbreviations and Acronyms AUA American Urological Association GCNIS germ cell neoplasia in situ RT radiation therapy TGCT testicular germ cell tumors Germ cell neoplasia in situ, first described by Skakkebaek in 1972 in a report of 2 infertile patients with atypical intratubular germ cells, is the malignant precursor to testicular germ cell tumors.1 GCNIS was originally called carcinoma in situ and later intratubular germ cell neoplasia or testicular intraepithelial neoplasia, but these terms are considered antiquated as GCNIS is a more accurate description of the neoplastic process. Historical series have indicated that GCNIS is present in the contralateral testicle of approximately 5% of all patients with TGCT and, if untreated, will progress to an invasive tumor in nearly 50% of patients within 5 years and in 70% within 7 years.2–6 However, the ideal treatment paradigm for patients with biopsy proven GCNIS is not clearly defined. While there is extensive literature addressing the management of solid germ cell tumors, there is a paucity of prospective data to guide the diagnosis and treatment of patients with GCNIS. Screening protocols for contralateral GCNIS remain controversial, with differing recommendations in available guideline statements.7,8 Current treatment options based largely on seminal studies performed in the 1980s include orchiectomy, testicular radiation therapy or surveillance.7,9 Given the use of cisplatin and carboplatin chemotherapy regimens in patients with solid germ cell tumors, chemotherapy has also been evaluated for the management of GCNIS. While some studies indicate that GCNIS may at least in part respond to chemotherapy, others have found minimal to no impact.2,5,7,10 As a result there is currently no consensus regarding the optimal approach toward patients with GCNIS, and most patients are typically treated according to physician preferences or institutional practice patterns. In this report we present a systematic review of published studies to evaluate the diagnosis and treatment of patients with GCNIS. Materials and Methods Data Sources and Searches The methods for this systematic review followed the Agency for Healthcare Research and Quality Methods Guide for Comparative Effectiveness Reviews.11 Key Questions were defined by the AUA Guidelines Panel for Testicular Cancer. We searched PubMed, Embase and the Cochrane Central Register of Controlled Trials from January 1980 to August 2018 for studies regarding the diagnosis and treatment of GCNIS. Study Selection, Data Extraction and Analysis Study selection was based on predefined eligibility criteria within a PICOTS (population, interventions, comparisons, outcomes, type of study, timing and setting) format (supplementary Appendix, https://www.jurology.com). Two reviewers independently screened titles, abstracts and full text for inclusion. Differences between investigators were resolved through consensus adjudication. We used DistillerSR (Evidence Partners, Ottawa, Ontario, Canada 2010) to manage screening. For this Key Question we further restricted the study publication date to 1990 or later. In contrast to analyses performed for other Key Questions posed by the AUA Guidelines Panel for Testicular Cancer, this systematic review did not exclude patients with advanced stages of TGCT due to the significant heterogeneity in inclusion criteria for most studies and in order to evaluate the effect of chemotherapy on GCNIS. We created standardized forms for data extraction and pilot tested the forms before data extraction. Reviewers extracted information on study characteristics, demographic data, clinical staging, treatment characteristics and pathological data. Outcomes for GCNIS treatment included rates of persistent disease on biopsy following treatments, rates of recurrence, progression to TGCT or metastatic disease, and treatment associated morbidities. One reviewer completed data abstraction and the second reviewer confirmed the first reviewer's data abstraction for completeness and accuracy. A meta-analysis was conducted for oncologic outcomes following treatment for GCNIS using random effects modeling. Freeman-Tukey double arcsine transformation was applied to stabilize variances for binomial data in line with prior studies.12,13 The unadjusted proportion of patients experiencing GCNIS recurrence/persistence after treatment was pooled and compared by a Pearson chi-square test. Analyses were conducted using Stata® version 15.0. Risk of Bias Assessment and Strength of Body of Evidence Two reviewers independently assessed the risk of bias in included studies. The Cochrane Risk of Bias Assessment Tool for Non-Randomized Studies of Interventions (ACROBAT-NRSI) was used for cohort studies. For noncomparative single arm studies we considered design, consecutive enrollment and objective measurement of outcome. If all 3 items were assessed favorably, the study was high quality. If just 1 item was false or unclear, the study was considered moderate quality. If 2 or 3 items were false or unclear, the study was considered low quality. We graded strength of evidence on outcomes by adapting the AUA scheme of 3 predefined levels of strength of evidence. Results We identified 7,037 unique citations regarding testicular cancer, of which 5,653 were excluded during abstract screening (fig. 1). Through full manuscript screening we excluded an additional 1,071 citations. A total of 18 articles met inclusion criteria for this systematic review. Participant and tumor characteristics are outlined in supplementary table 1 (https://www.jurology.com). Figure 1. Detailed summary of literature search. KQ, Key Question. GCNIS Screening One nationwide, population based, retrospective study assessed the utility of a routine screening protocol in patients with a history of TGCT for GCNIS in the contralateral testicle.14 Use of contralateral biopsy concomitantly with orchiectomy demonstrated no significant difference in the risk of metachronous TGCT between screened and unscreened cohorts with a cumulative incidence of 1.9% vs 3.1% (p=0.097), respectively (HR 1.59 for the unscreened cohort, 95% CI 0.85–2.95, p=0.144). Median followup was 14 (IQR 9–19) vs 26 (IQR 24–27) years for the screened and unscreened cohorts, respectively. The prevalence of GCNIS was 4.4% in the screened cohort. In 7 retrospective studies evaluating patients with a history of TGCT, the prevalence of GCNIS found on contralateral biopsies ranged from 4.0% to 8.1%.15–21 Use of multiple site biopsies yielded higher rates of GCNIS detection compared to single site biopsies (5.0% to 8.1% vs 4.0% to 6.6%, respectively).18–20 Testicular atrophy, age at presentation and history of cryptorchidism were independent predictors of GCNIS.15–18 Testicular atrophy was present in 19.0% to 36.4% of patients with GCNIS15,17,18 and the largest study, which evaluated 2,318 patients with testicular TGCT, reported a RR of 3.78 (95% CI 2.55–5.60) for GCNIS.18 Patients presenting at age 30 years or younger also had an increased prevalence of GCNIS (20.5% to 37.5%), and 1 study reported patients age 30 or younger had a 1.7-fold increased RR of contralateral GCNIS vs patients older than 30 years (95% CI 1.2–2.6).16,17 Similarly, in another prospective study patient age older than 40 years conferred a significantly reduced RR of GCNIS of 0.30 (95% CI 0.17–0.54).18 Cryptorchidism was also noted to be a risk factor for GCNIS. In 1 study a history of cryptorchidism was reported in 16.7% of patients with GCNIS vs 8.3% of those without (p=0.008, RR 2.1, 95% CI 1.2–3.6).17 The strength of evidence in studies of screening for GCNIS is grade B. Oncologic Outcomes by Treatment Type Eleven studies evaluated management options for GCNIS, including surveillance, chemotherapy and RT, and provided oncologic data including rates of biopsy proven GCNIS recurrence stratified by treatment type (supplementary table 2, https://www.jurology.com).9,15,17,22–29 Two studies were prospective, multicenter trials evaluating the use of low dose RT for GCNIS.24,26 The remaining studies were retrospective cohorts that provided comparative data analyzing RT, chemotherapy and surveillance. Notably, patients in these studies had a history of TGCT of varying histologies, stages and treatments before undergoing the studied intervention for GCNIS in the contralateral testicle. It remains unclear if differences in the treatment of the initial primary tumor affected treatment outcomes for GCNIS in the contralateral tumor and, consequently, contributed to variability among studies. For RT a total dose of 18 to 20 Gy (daily doses of 2 Gy, 5 fractions per week) demonstrated the lowest rates of GCNIS on subsequent biopsy at least 3 to 6 months after RT (fig. 2).15,17,22,24,25,27 Rates of GCNIS on biopsy after administration of 18 to 20 Gy RT were 0% to 2.5%. Three studies evaluated the effectiveness of RT with doses less than 18 to 20 Gy, which appeared to result in lower rates of complete eradication of GCNIS.24–26 One study that retrospectively evaluated 48 patients receiving doses between 14 and 20 Gy over a median 68-month followup (range 25 to 188) reported a case of relapse (1, 7.1%) on biopsy at 20 months after irradiation with 14 Gy.25 Figure 2. Lowest rates of GCNIS on subsequent biopsy at least 3 to 6 months following RT. ES, effect size. Seven studies evaluated the use of chemotherapy for GCNIS eradication.9,15,17,22,23,28,29 Patients receiving cisplatin based regimens had higher rates of GCNIS found on followup biopsies compared to treatment with RT, with a median rate of 30% (range 18.2% to 100%) during a median overall followup of 48 months.15,17,22,23 On average, cisplatin based regimens had lower rates of GCNIS on subsequent biopsies than carboplatin based regimens, the latter of which demonstrated positive disease in 66% to 75% of repeat biopsies.22,23 Two studies compared 2 vs 3 cycles of cisplatin based therapy, with lower rates of GCNIS present in patients receiving 3 cycles (25% to 50% vs 23.5% to 33.3%, respectively).22,23 Results of a meta-analysis of GCNIS rates following the use of chemotherapy are shown in figure 3. Figure 3. Use of chemotherapy for eradication of GCNIS. ES, effect size. Three studies directly evaluated the comparative efficiency of 18 to 20 Gy RT to cisplatin based chemotherapy and demonstrated lower rates of GCNIS on followup biopsies (0% to 2.5% vs 23.5 to 100%, respectively).15,17,22 A study of 228 patients with biopsy proven GCNIS found lower rates of GCNIS and occurrence of a second testicular germ cell tumor on followup biopsies over a median 48-month followup (range 1.2 to 157.2) for patients treated with 18 to 20 Gy RT vs chemotherapy and surveillance.22 Rates of positive biopsy were reported for RT (in 3 of 122, 2.5%), cisplatin based chemotherapy in 2 cycles (15 of 30, 50%), cisplatin based chemotherapy in 3 cycles (12 of 51, 23.5%), carboplatin chemotherapy (10 of 15, 66%) and surveillance (5 of 10, 50%). Rates of positive biopsy following treatment were significantly different among the groups (log rank test p <0.0001). An exploratory post hoc pairwise comparison of treatment arms showed that RT demonstrated significantly longer event-free survival than cisplatin based chemotherapy with 2 or fewer cycles (p <0.0001), 3 or more cycles cisplatin based chemotherapy (p <0.0001), carboplatin chemotherapy (p <0.0001) and surveillance (p=0.0002). Three studies also evaluated the effectiveness of platinum based chemotherapy regimens in a heterogeneous group of patients with disseminated or extragonadal disease with biopsy proven GCNIS.9,28,29 In a study of 33 patients with disseminated TGCT and biopsy proven GCNIS in 1 or both testicles without invasive tumors, GCNIS was found in 6 patients (18.2%) on biopsy at a median of 12 months following 3 to 6 cycles of platinum based chemotherapy.28 The estimated cumulative risk of GCNIS 5 and 10 years after chemotherapy was 21% and 42%, respectively. Another study, which evaluated 61 patients with a history of testicular TGCT or extragonadal germ cell tumors, of which 26 received abdominal RT to para-aortic nodes, compared patients receiving 1 to 3 cycles of any form of chemotherapy, 4 or more cycles of chemotherapy and no chemotherapy.9 In the group of patients treated with 1 to 3 cycles or no chemotherapy, the probability of subsequent TGCT was significantly increased compared to those exposed to 4 or more cycles (p=0.03, 5-year probability of 42%, 95% CI 27–62 and 22%, 95% CI 8–54, respectively). The strength of evidence in studies regarding treatment for GCNIS is grade C for low quality of evidence due to small sample sizes across studies with heterogeneous inclusion criteria, study design and followup. Hypogonadism Five studies evaluating GCNIS provided treatment related outcomes regarding hypogonadism (supplementary table 3, https://www.jurology.com).17,22,25,26,30 Two studies directly compared rates of hypogonadism between patients receiving 20 Gy RT and those receiving lower doses of RT.25,30 One found that radiation doses less than 20 Gy resulted in lower frequencies of hypogonadism and the other found no difference in rates of low testosterone regardless of radiation dose used. In a study comparing testosterone production in men receiving 16 vs 20 Gy, Bang et al found that men treated with 16 Gy had stable testosterone levels (–1.1% per year, p=0.4) following therapy, whereas men treated with 20 Gy had an annual decrease of 2.4% (p=0.008).30 For the latter group the testosterone decrease was most pronounced in the first 5 years and stabilized during the subsequent 5 years. Androgen substitution therapy was initiated in 11 of 14 (78.6%) patients treated with 20 Gy RT compared to 18 of the 37 (48.7%) treated with 16 Gy therapy (p=0.03). Conversely, in a study by Petersen et al comparing the effect of RT doses between 14 and 20 Gy on hypogonadism, testosterone showed a stable decrease (3.6% per year) without statistically significant dependence on dose (difference between 20 vs 14 Gy, p=0.33).25 The decrease in testosterone levels continued at the same rate for more than 5 years without any differences between various dose levels. Overall 10 of 18 (55.6%) patients in the 20 Gy group, 2 of 3 (66.7%) in the 18 Gy group, 3 of 9 (33.3%) in the 16 Gy group and 5 of 13 (38.5%) in the 1 Gy group received androgen replacement therapy. Other studies evaluating rates of hypogonadism between different treatment modalities reported similar rates of hypogonadism, which ranged between 30.8% and 38.5% for patients undergoing 18 to 20 Gy RT.17,22 Cisplatin based chemotherapy resulted in 13% to 20% rates of hypogonadism. Dieckmann et al found that rates of hypogonadism in patients receiving chemotherapy (2 or 3 cycles of cisplatin based chemotherapy, or carboplatin) were significantly lower than in patients receiving 18 to 20 Gy RT (16.2% vs 30.8%, respectively, p=0.028).22 The strength of evidence in studies regarding treatment related hypogonadism is grade C for low quality of evidence due to small sample sizes across studies with heterogeneous inclusion criteria, study design and followup. Risk of Bias The risk of bias was high in 10 studies9,15,20,21,23,26–30 and moderate in 8 studies.14,16–19,22,24,25 Most of the studies did not clearly describe the consecutive enrollment. Discussion Although the risk of GCNIS developing into invasive TGCT was recognized in the 1970s, optimal management strategies for GCNIS remain to be clearly defined.3 We present a systematic review regarding contemporary screening and treatment protocols for patients with GCNIS. The findings of this review should be considered in the context of the available evidence, which at times is limited by short followup, heterogeneous inclusion criteria and lack of uniform treatment practices. It should also be noted that most studies evaluated GCNIS in the setting of patients with prior gonadal and extragonadal TGCT who underwent varying treatments for different tumor histologies and clinical stages, and it is unclear if those treatments affected the oncologic outcomes of their GCNIS. Screening for GCNIS remains controversial, and routine screening for GCNIS in the contralateral testicle of patients with TGCT has not been adopted worldwide but is practiced nationwide in Denmark and in many centers in Austria and Germany.14,16 While the use of contralateral biopsies was first reported in 1979 by the Copenhagen group,31 screening for contralateral GCNIS was officially introduced in 1984 in eastern Denmark in unselected patients with unilateral TGCT and was extended nationwide in 1992. In the only study evaluating GCNIS screening in our review, Kier et al investigated the effect of the national population based screening program in Denmark in 5,409 patients and did not find a significant difference in the risk of metachronous TGCT between screened (4,130, 1984 to 2007) and unscreened (462, 1984 to 1988) cohorts (HR 1.59, 95% CI 0.85–2.95, p=0.144) using a contralateral single site biopsy concomitantly with orchiectomy.14 The 20-year cumulative incidence of metachronous TGCT was 1.9% (95% CI 1.4–2.5) in the screened population and 3.1% (95% CI 1.5–4.6) in the unscreened cohort (p=0.097). To prevent 1 case of metachronous TGCT the number of patients needed to screen measured at 20 years was 83 (although insignificant). It is important to consider the limitations of this study when interpreting its findings. The control (unscreened) group was too small to allow for meaningful conclusions and many of the biopsy specimens had not been examined with immunohistological methods. Moreover, the biopsies analyzed in the study were only single site biopsies and not 2-site which, as noted, is the recommended approach. Thus, routine contralateral testicular biopsy is not advised based on available evidence. However, retrospective studies have identified that patients who present with a history of testicular atrophy, age less than 40 years or cryptorchidism are at increased risk for GCNIS.15–18 For example, Dieckmann and Loy found that atrophy of the contralateral testis was present in 36.4% of cases of GCNIS as opposed to 10.6% of cases without (p <0.00001, RR 4.3, 95% CI 2.8–6.4).17 This evidence can be used to guide discussions about performing contralateral biopsy in patients who present with 1 or more of these risk factors due to their increased risks of GCNIS and, consequently, metachronous TGCT. Recent mapping studies of patients with TGCT have also reported a focal, rather than dispersed, distribution of GCNIS within a testicle.32–34 As a result of this heterogeneity recent studies have raised concerns for a risk of a false-negative result using a single site biopsy. Three studies evaluated the use of multiple site biopsies and found that use of 2-site biopsies can increase the diagnostic yield of a biopsy for GCNIS by 8% to 18%.18–20 Therefore, in patients undergoing testicular biopsy for GCNIS use of at least a 2-site biopsy is advised. For treatment of patients with GCNIS studies in our systematic review evaluated the use of RT, chemotherapy and surveillance. Early experience beginning in the 1980s found that RT with a 20 Gy dose proved to be an effective regimen for eradicating GCNIS.2,5,26 While the rationale underlying local RT was based on differences in radiosensitivity between GCNIS and Leydig cells, concerns were raised regarding dose dependent impairment of endogenous androgen production and, thus, contemporary studies have focused on whether the use of lower doses of RT can help preserve testicular function while maintaining oncologic efficiency.35 Our review found that administration of 18 to 20 Gy RT demonstrated the lowest rate of GCNIS on followup biopsies (0% to 2.5%).15,17,25,27 However, doses less than 18 to 20 Gy appeared to result in slightly higher rates of GCNIS on followup biopsy (0% to 7.1%).24–26 Thus, for patients who wish to preserve Leydig cell function, RT with doses less than 18 to 20 Gy may be attempted. However, evidence supporting the potential benefit of this strategy remains limited and patients should be counseled that lower doses of RT may result in lower frequencies of complete GCNIS eradication. While early experience in the 1980s found that chemotherapy led to eradication of GCNIS,5,36 contemporary data have demonstrated the persistence of GCNIS after chemotherapy in more than 30% of cases.17,23,29 In addition, the 10-year recurrence rate of GCNIS has been reported to be as high as 42% in patients treated with platinum based chemotherapy.28 In patients with disseminated disease first managed with chemotherapy, GCNIS has also been found on delayed orchiectomy specimens in 35% to 42% of cases.29,37 While 3 cycles of cisplatin based chemotherapy appear to confer higher rates of eradication compared to 2 cycles, there are inadequate data to substantiate a potential dose-dependent response to chemotherapy.22,23 However, cisplatin based therapy does appear to result in lower rates of persistent GCNIS compared to carboplatin therapy.22,23 The underlying reasons for the inefficacy of chemotherapy in eradicating GCNIS remain unclear.22,23,28 It is hypothesized that the blood-testis barrier, which may potentially modulate intratubular concentrations of cytostatic compounds, as well as a putative primary resistance of GCNIS cells to chemotherapy, may be responsible. While chemotherapy may eradicate GCNIS in up to two-thirds of patients receiving chemotherapy as adjuvant treatment following orchiectomy or in the setting of disseminated disease, providers should be aware of the potential persistent presence of GCNIS. In fact, it is not known whether chemotherapy does really eradicate GCNIS or if it only suppresses it temporarily, thus delaying the outbreak of a second testicular germ cell tumor or dissemination of GCNIS within the testis. As a result, chemotherapy should not be used as a primary treatment for GCNIS due to the risk of persistent disease and, consequently, malignant progression, following chemotherapy. A limited number of studies have evaluated rates of treatment associated hypogonadism. Two studies investigated if lower doses of RT resulted in preserved testosterone levels. While 1 study demonstrated lower rates of hypogonadism with use of lower RT doses,30 the other did not show any dose-dependency on hormone levels after treatment.25 Chemotherapy appeared to result in lower rates of hypogonadism compared to RT. Nevertheless, it should be noted that the majority of studies did not provide preexisting rates of hypogonadism before treatment or rates of hypogonadism in cases managed with surveillance only. In patients with early stage TGCT with no contralateral GCNIS, treatment associated hypogonadism has similarly been reported.38 However, the risk of testosterone deficiency was higher with chemotherapy than with RT. This systematic review identified a number of shortcomings in the published data of GCNIS management and we offer several recommendations for future research on this topic. A major limitation inherent to studies on GCNIS is the heterogeneous inclusion criteria in predominantly retrospective studies. Patients were included with various germ cell histologies, clinical stages, treatment modalities for their primary TGCT and posttreatment followup protocols. Whenever possible, prospective studies using objective selection criteria regarding patient and tumor characteristics are recommended. Most studies also reported very small sample sizes among treatment arms to draw effective conclusions, which is likely in part due to the low prevalence of GCNIS. Finally, most studies were unable to capture data regarding endocrine outcomes such as rates of hypogonadism in many of their patients. Information on paternity rates was not available in studies focused on GCNIS treatment. Future research may better objectify the selection of a given management strategy and address issues of cost-effectiveness and long-term sequelae of treatment. Conclusions Our systematic review of contemporary studies regarding the diagnosis and management of GCNIS demonstrated the limited benefit of routine screening biopsies of the contralateral testicle in patients with TGCT, while also establishing that the risk of GCNIS is elevated in those with a history of testicular atrophy, age at presentation less than 40 years or those with cryptorchidism. For those diagnosed with GCNIS, primary treatment with 18 to 20 Gy RT is associated with more effective eradication compared to chemotherapy. Chemotherapy has limited efficacy in the primary treatment of GCNIS but it may help treat GCNIS in up to two-thirds of patients undergoing chemotherapy as adjuvant treatment or for extragonadal disease. Further research and data are needed to strengthen many aspects of the evidence base. References 1. : Possible carcinoma-in-situ of the testis. Lancet 1972; 2: 516. Google Scholar 2. : Management of carcinoma-in-situ of the testis. 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No direct or indirect commercial, personal, academic, political, religious or ethical incentive is associated with publishing this article. © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsRelated articlesJournal of Urology8 Apr 2020Editorial Comment Volume 204Issue 1July 2020Page: 33-41Supplementary Materials Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.Keywordsdiagnosisradiotherapyneoplasmsgerm cell and embryonalcarcinoma in situtesticular neoplasmsMetricsAuthor Information Mohit Gupta Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland More articles by this author Joseph G. Cheaib Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland More articles by this author Hiten D. Patel Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland More articles by this author Ritu Sharma The Johns Hopkins Evidence-Based Practice Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland More articles by this author Allen Zhang The Johns Hopkins Evidence-Based Practice Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland More articles by this author Eric B. Bass The Johns Hopkins Evidence-Based Practice Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland More articles by this author Phillip M. Pierorazio Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland *Correspondence: The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, 600 N. Wolfe St./Marburg 150, Baltimore, Maryland 21287 telephone: 410-502-5984; FAX: 410-502-7711; E-mail Address: [email protected] Financial interest and/or other relationship with the American Urological Association. More articles by this author Expand All Supported by the American Urological Association. No direct or indirect commercial, personal, academic, political, religious or ethical incentive is associated with publishing this article. Advertisement Advertisement PDF downloadLoading ...
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