REVIEW URRENT C OPINION
Update on testicular germ cell tumors Anitha Nallu a, Roja Chimakurthi a, Arif Hussain b,c, and Heather D. Mannuel a,b
Purpose of review This overview discusses several important developments in testicular germ cell tumors (TGCTs) over the past year. Recent findings Genomic studies continue to investigate gene expression as possible markers for disease relapse and metastatic potential. Optimal treatment strategies for early-stage seminomas continue to evolve toward surveillance versus chemotherapy, although developing radiation delivery modalities may ultimately provide a safe alternative. The role of retroperitoneal lymph node dissection in postorchiectomy early-stage nonseminoma germ cell tumors remains a topic of debate. Summary Treatment paradigms continue to be refined for TGCTs as research in these areas continues. Keywords chemotherapy, germ cell tumor, molecular genomics, radiation, retroperitoneal lymph node dissection
INTRODUCTION Testicular germ cell tumors (TGCTs) are the most common solid tumors in adolescent and young adult men between 15 and 34 years and account for 5% of urological tumors in general. Because of the success of multidisciplinary management, the prognosis of all stages of TGCT is quite good. The development of complementary therapeutic strategies, including modern cytotoxic chemotherapy (ChT) regimens, appropriate utilization of radiotherapy, and timely surgical resection, has made TGCT the model of a ‘curative’ malignancy.
EPIDEMIOLOGY AND RISK FACTORS Risk of TGCT is consistently associated with a history of cryptorchidism in epidemiologic studies. It has been postulated that other congenital malformations, in particular hypospadias, are also associated with increased risk. Using Swedish populationbased registries, Trabert et al. [1 ] evaluated the relationship between birth defects and risk of TGCT. TGCT cases (n ¼ 6593), diagnosed between 15 and 65 years of age, were identified from the Swedish Cancer Registry between 1964 and 2008. Congenital malformations were identified via linkage with the Hospital Discharge Register. In addition to the expected association between cryptorchidism and TGCT risk [odds ratio (95% confidence interval (CI): 3.18 (2.50–4.04)], hypospadias [2.41 (1.27–4.57)],
inguinal hernia [1.37 (1.11–1.68)], and other genital malformations [2.19 (1.17–4.10)] were associated with an increased risk of TGCT. These data suggest that developmental urogenital abnormalities, specifically cryptorchidism, hypospadias, and inguinal hernia, are associated with an increased risk of TGCT, further supporting the hypothesis that prenatal exposure(s) that affect proper genital development are related to this tumor. Factors modifying the association of cryptorchidism may provide insights regarding the cause of TGCT and suggest a basis for individualized care of cryptorchidism. Juniarto et al. [2] evaluated epidemiologic data, including human studies cited in PubMed or ISI Web of Science indices through December 2011, and identified 35 articles and one unpublished dataset with high-quality data on the cryptorchidism-TGCT association. The metaanalysis showed that history of cryptorchidism is associated with four-fold increased TGCT risk
&
www.co-oncology.com
a
Department of Medicine, University of Maryland School of Medicine, Baltimore Veterans Affairs Medical Center and cDepartment of Medicine, Pathology and Biochemistry, University of Maryland School of Medicine, Baltimore, Maryland, USA b
Correspondence to Dr Heather D. Mannuel, University of Maryland Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201, USA. Tel: +1 410 328 2567; e-mail: [email protected] Curr Opin Oncol 2014, 26:294–298 DOI:10.1097/CCO.0000000000000068 Volume 26 Number 3 May 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Update on testicular germ cell tumors Nallu et al.
KEY POINTS Recent studies suggest that a predisposition to develop TGCT may be associated with specific genetic loci, genetic markers, and c-kit signaling. The optimal treatment for CS1 seminoma continues to evolve, with an increasing emphasis on surveillance as the preferred option. Although current radiation modalities carry known longterm toxicity risks, evolving modalities, such as proton beam therapy, seek to decrease these risks. RPLND remains an important option for men with CS1 nonseminoma and may be a preferred approach in certain patients at higher risk for relapse.
[relative risk ¼ 4.1 (95% CI ¼ 3.6–4.7)]. Subgroup analyses identified five determinants of stronger association: bilateral cryptorchidism, unilateral cryptorchidism ipsilateral to TGCT, delayed cryptorchidism treatment, TGCT diagnosed before 1970, and seminoma histology. On the basis of available data, the authors suggest that cryptorchidism patients and their parents or caregivers should be made aware of elevated TGCT risk following orchidopexy, regardless of age at repair, unilateral versus bilateral nondescent, or position of undescended testes.
MOLECULAR AND GENOMIC STUDIES TGCT is notable for its high familial risks; so far, six loci associated with TGCT have been reported. Ruark et al. [3] identified nine new susceptibility loci for testicular cancer. From genome-wide association study (GWAS) analysis of 307 291 single nucleotide polymorphisms (SNPs) in 986 TGCT cases and 4946 controls, 694 SNPs were selected and further genotyped in another cohort of TGCT cases (n ¼ 1064) and controls (n ¼ 10082) from the United Kingdom. SNPs were identified at nine new loci (1q22, 1q24.1, 3p24.3, 4q24, 5q31.1, 8q13.3, 16q12.1, 17q22, and 21q22.3) showing association with TGCT [P < 5 10(–8)], which together account for an additional 4–6% of the familial risk of TGCT. Chung et al. [4] conducted a combined analysis of three GWAS and six new independent sample sets, which revealed that the risk of TGCT was significantly associated with markers at four previously unreported loci: 4q22.2 in HPGDS, 7p22.3 in MAD1L1, and 16q22.3 in RFWD3 and 17q22, a locus that includes TEX14, RAD51C, and PPM1E. Familial testicular germ cell tumors (FTGCTs) are hypothesized to result from the combined
interaction of several low-penetrance genes. Azevedo et al. [5 ] studied 94 patients with FTGCTs and 50 at-risk male relatives from 63 unrelated kindreds in whom the PDE11A gene had been sequenced. They also examined cyclic adenosine monophosphate (cAMP) and c-KIT signaling in testicular tissues and cell lines and extended the studies to two sporadic cases, one with and one without a PDE11A defect. It was found that patients with FTGCT and PDE11A defects also carry KITLG risk alleles more frequently, suggesting that there may be an interaction between cAMP and c-KIT signaling in the predisposition to TGCTs. Protein-tyrosine phosphatase nonreceptor type 23 (PTPN23) is a candidate tumor suppressor involved in the tumorigenesis of various organs. Tanaka et al. [6] investigated the function and regulation of PTPN23 in the formation of TGCT. Quantitative reverse transcription polymerase chain reaction (RT-PCR) data revealed significantly higher expression of miR-142-3p in human seminomas compared with normal testes. A lack of PTPN23 protein expression in human TGCT correlated with a relatively higher miR-142-3p expression. These data suggest that PTPN23 is a tumor suppressor, and that repression of PTPN23 expression by miR-142-3p plays an important role in the pathogenesis of TGCT. Nakamura et al. [7] studied the distribution of pituitary adenylate cyclase-activating polypeptide (PACAP) in the human testis and in TGCTs. PACAP is a neuropeptide expressed in the central nervous system and peripheral organs. Although previous studies revealed the role and distribution of PACAP in the rodent testis, its role in the human testis and in TGCTs is not known. The mRNAs for PACAP and its receptors were detected in human testes. PACAP immunoreactivity was observed in spermatogonia and spermatids from normal testes. In contrast, diffuse PACAP immunopositivity was observed in seminoma tumor cells, whereas only faint immunoreactivity was observed in embryonal carcinoma cells. The data suggested that PACAP may play a role in human spermatogenesis and in TGCT development. Syndecan-4 has been implicated in cancer progression, and its expression in TGCT has been studied by Labropoulou et al. [8]. Immunohistochemical staining in 71 tissue specimens and mRNA analysis revealed significant overexpression of syndecan-4 in TGCT. In seminomas, a high percentage of tumor cells exhibited membranous and/or cytoplasmic staining for syndecan-4 in all cases. Results indicated that syndecan-4 is differentially expressed in seminomas and nonseminoma germ cell tumors (NSGCTs) and might be a useful marker.
1040-8746 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
www.co-oncology.com
295
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Genitourinary system &
Mohamed et al. [9 ] conducted a study to identify genomic markers that are reliable in predicting lymph node metastases in clinical stage I (CS1) NSGCT. Twelve stage 1 mixed germ cell testicular tumors were analyzed, eight from patients who had no evidence of nodal metastasis on retroperitoneal lymph node dissection (RPLND) and four from patients who had nodal metastases on RPLND. Statistically suggestive differences in mean copy number of the Y chromosome were found between metastatic and nonmetastatic cases (P ¼ 0.0142). This finding suggests the presence of chromosome Y deletions to be a potential genetic marker for prediction of mixed germ cell tumor progression.
TREATMENT OF CLINICAL STAGE I SEMINOMA Seminomas represent about 60% of all TGCTs, with stages I and II accounting for 80 and 15% of all seminomas at presentation, respectively [10]. The last three decades have seen a substantial change in the philosophy of management, with surveillance and carboplatin-based ChT identified as successful alternatives to adjuvant radiation, and cisplatinbased ChT recognized as a curative modality either in the first line or salvage setting. Leung et al. [11 ] evaluated 764 patients with stage I seminoma who underwent either surveillance or adjuvant radiation therapy. First relapse on surveillance was managed either with radiation therapy alone, or with combination ChT for more extensive recurrence. In all, 484 patients underwent surveillance, and 280 received adjuvant radiation therapy. The 5 and 10-year overall survival rates were 98.6 and 97.7% for surveillance, and 97.2 and 91.4% for adjuvant radiation therapy [2]. A total of 72 (15%) patients in the surveillance group relapsed; treatment for relapse was radiation therapy (n ¼ 56), ChT (n ¼ 15), and surgery (n ¼ 1). Second relapse occurred in six patients, five of whom had received radiation therapy, and one had received ChT at first relapse; these patients then received ChT as definitive treatment for their second relapse. Of the patients in the adjuvant radiation therapy group, 14 (5%) relapsed: salvage treatment included ChT (n ¼ 10), surgery (n ¼ 1), and further radiation therapy (n ¼ 3). The overall treatment burden represented by number of treatment episodes per patient was 0.16 in the surveillance group and 1.05 in the adjuvant radiation therapy group. The authors conclude that surveillance reduces the overall treatment burden in patients with stage I seminoma and is the preferred management option; the selective use of radiation therapy at first relapse for patients on surveillance leads to a similar &&
296
www.co-oncology.com
requirement for subsequent ChT to that for patients on adjuvant radiation therapy [11 ]. Kobayashi et al. [12] evaluated 118 patients with stage I seminoma, of whom 56 received adjuvant radiation therapy, one received ChT, and 61 were managed with surveillance. During the mean observation period of 104 months, no patient had cause-specific death. One patient (1.7%) receiving radiation therapy and four (6.6%) patients managed with surveillance had disease relapse; the 10-year relapse-free survival (RFS) rate was 93.4% in men managed with surveillance, and their RFS was not different from that in patients receiving adjuvant radiotherapy (log rank P ¼ 0.15) [12]. Of note, men with tunica albuginea involvement showed a poorer RFS than those without, suggesting that these men may constitute a group that should be offered adjuvant therapy to decrease the risk of relapse [12]. &&
RADIATION Micronuclear frequency in mononucluear lymphocytes has been shown to be a relevant biomarker of long-term genome damage. Fucic et al. [13 ] evaluated chromosome aberration and micronuclear assays in 10 patients 7 years after completion of 25 Gy of radiation therapy for stage I seminoma, and compared the results with 10 healthy control individuals matched for age and smoking status. Although mean chromosome aberration frequency did not deviate from control values, significantly increased frequencies of dicentrics, double minutes, and ring chromosomes were detected in the seminoma patients; the average percentage of centromere-positive micronuclear was 62.6% in seminoma patients [13 ]. Although the small study size limits drawing definitive conclusions, the data demonstrate the long-term persistence of unstable chromosome aberration in patients in the post-radiation therapy setting. Hoppe et al. [14] evaluated possible dosimetric advantages of proton therapy compared with threedimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) in the treatment of patients with stage I and II seminoma. For stage I disease, proton therapy reduced the mean dose to the stomach, ipsilateral kidney, pancreas, bowel space, small bowel, and colon compared with 3DCRT and IMRT; in stage II disease, proton therapy provided additional reductions in mean dose to the bladder and rectum [14]. Although recent trends have accepted adjuvant ChT as a preferred alternative to radiation therapy, proton therapy may offer an improvement in toxicity reduction that may translate into lower risks of acute gastrointestinal side-effects, infertility, and secondary malignancies. &
&
Volume 26 Number 3 May 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Update on testicular germ cell tumors Nallu et al.
CHEMOTHERAPY IN THE SALVAGE SETTING Since the introduction of cisplatin, the therapeutic outcome of men with TGCT has markedly improved; however, approximately 20–30% of patients with advanced disease are not cured by initial therapy and require subsequent salvage treatment. Yamada et al. [15] evaluated the outcomes of 11 men with disease that was refractory or relapsed after cisplatinbased therapy who were treated with a salvage regimen of docetaxel, ifosfamide, and nedaplatin. Ten (91%) of the 11 patients achieved favorable responses, including complete response in one case and partial response in nine cases; the nine (81%) patients with partial response have continued to show no evidence of disease after salvage ChT followed by subsequent surgical resection, with a median follow-up period of 52 months [15]. Ten (91%) patients developed Grade 4 leukopenia, which was managed using standard granulocyte colonystimulating factors; no patients developed sensory neuropathy or renal dysfunction [15]. The authors suggest that the docetaxel, ifosfamide, and nedaplatin regimen is an efficacious and well tolerated alternative for salvage ChT in men with advanced cisplatin-refractory or cisplatin-relapsed TGCT.
ROLE OF RETROPERITONEAL LYMPH NODE DISSECTION The optimal treatment for postorchiectomy CS1 NSGCTs remains highly debated, with established options including observation, adjuvant ChT, and RPLND. Basiri et al. [16] performed a retrospective review of 55 men with CS1 NSGCT who underwent modified RPLND according to the Sloan-Kettering modified RPLND template between April 2002 and April 2012. Clinicopathologic parameters, retroperitoneal relapse, and rate of anterograde ejaculation were evaluated at a mean follow-up duration of 56 months (range 6–120 months). No tumor recurrences were identified in any of the individuals at the end of the follow-up period. Overall perioperative and postoperative complication rate was 18% (seven patients). Out of 38 patients, 23 (61%) experienced anterograde ejaculation at the end of the study [16]. The authors suggest that modified template RPLND is a well tolerated, effective, and sufficient treatment for patients with no retroperitoneal micrometastases; furthermore, this strategy may obviate the need for the costly and potentially harmful alternative of adjuvant ChT in this population. With the progressive advancement of laparoscopic vascular surgical techniques, laparoscopic
RPLND (L-RPLND) has become a feasible alternative for some patients with NSGCT. Aufderklamm et al. [17] identified 18 patients with NSGCT in whom bilateral L-RPLND was performed to address residual disease post-ChT. Infiltration of the great vessels was confirmed intraoperatively. There were no significant perioperative complications in the group and no conversions to open surgery; mean intraoperative blood loss was 310 ml (range 50–1000 ml). At a mean follow-up of 18 months, no patient had developed distant or in-field recurrence. The authors conclude that L-RPLND may be a safe and promising alternative to the open procedure in men with residual NSGCT and vascular infiltration.
PROGNOSTIC FEATURES Verhoeven et al. [18] utilized data from 12 European cancer registries and the US Surveillance, Epidemiology, and End Results database to report survival trends for patients diagnosed with testicular seminomas and nonseminomas between 1993–1997 and 2003–2007. Additionally, a model-based analysis was used to compare survival trends and relative excess risk (RER) of death between Europe and the USA, adjusting for differences in age and histology. In 2003–2007, the 5-year relative survival of patients with seminoma was at least 98% among those aged less than 50 years, whereas survival of patients with nonseminoma remained 3–6% lower. Despite improvements in the relative survival of nonseminoma patients aged at least 50 years by 13–18%, survival remained lower than the survival of seminoma patients of the same age. Model-based analyses showed increased RERs for nonseminomas, older, and European patients. Although there remains little room for survival improvement among testicular seminoma patients, especially for those aged less than 50 years, older patients remain at increased risk of death, which seems mainly attributable to the lower survival among the nonseminoma patients.
CONCLUSION Although TGCT remains a highly treatable and generally curable disease, controversy persists as to the optimum modality of management of earlystage disease, even within existing standard-of-care models. Additionally, men in poorer prognosis groups remain resistant to conventional treatments and constitute groups that require further study. The pace of ongoing clinical and preclinical studies remains robust, and further insights are expected into the optimal management of patients from initial diagnosis to long-term follow-up.
1040-8746 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-oncology.com
297
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Genitourinary system
Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Trabert B, Zugna D, Richiardi L, et al. Congenital malformations and testicular & germ cell tumors. Int J Cancer 2013; 133:1900–1904. The authors used Swedish population-based registries to evaluate the relationship between birth defects and TGCT. In addition to the expected association between cryptorchidism and TGCT risk, hypospadias, inguinal hernia, and other genital malformations were associated with an increased risk of TGCT. The other (nongenital) malformations evaluated were not associated with TGCT. 2. Juniarto AZ, Setyawati BA, Miranti IP, et al. Gonadal malignancy in 13 consecutive collected patients with disorders of sex development (DSD) from Semarang (Indonesia). J Clin Pathol 2013; 66:198–204. 3. Ruark E, Seal S, McDonald H, et al., UK Testicular Cancer Collaboration (UKTCC). Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14. Nat Genet 2013; 45:686– 689. 4. Chung CC, Kanetsky PA, Wang Z, et al. Meta-analysis identifies four new loci associated with testicular germ cell tumor. Nat Genet 2013; 45:680– 685. 5. Azevedo MF, Horvath A, Bornstein ER, et al. Cyclic AMP and c-KIT signaling in & familial testicular germ cell tumor predisposition. J Clin Endocrinol Metab 2013; 98:E1393–E1400. The authors studied 94 patients with FTGCTs and 50 at-risk male relatives from 63 unrelated kindreds. It was found that patients with FTGCT and PDE11A defects also carry KITLG risk alleles more frequently, suggesting that there may be an interaction between cAMP and c-KIT signaling in predisposition to TGCTs. 6. Tanaka K, Kondo K, Kitajima K, et al. Tumor-suppressive function of proteintyrosine phosphatase nonreceptor type 23 in testicular germ cell tumors is lost upon overexpression of miR142-3p microRNA. J Biol Chem 2013; 288:23990–23999. 7. Nakamura K, Nakamachi T, Endo K, et al. Distribution of pituitary adenylate cyclase-activating polypeptide (PACAP) in the human testis and in testicular germ cell tumors. Andrologia 2013. doi: 10.1111/and.12102. 8. Labropoulou VT, Skandalis SS, Ravazoula P, et al. Expression of syndecan-4 and correlation with metastatic potential in testicular germ cell tumours. Biomed Res Int 2013; 2013:214864.
298
www.co-oncology.com
9. Mohamed GH, Gelfond JA, Nicolas MM, et al. Genomic characterization of & testis cancer: association of alterations with outcome of clinical stage 1 mixed germ cell nonseminomatous germ cell tumor of the testis. Urology 2012; 80:485.e1-5. The authors analyzed 12 stage I testicular tumors obtained from eight patients who were RPLND negative and four patients who were RPLND positive. Statistically significant differences in mean copy number of the Y chromosome were found between metastatic and nonmetastatic cases (P ¼ 0.0142), suggesting the presence of chromosome Y deletions to be a potential genetic marker for prediction of mixed germ cell tumor progression. 10. Chung P, Warde P. Contemporary management of stage I and II seminoma. Curr Urol Rep 2013; 14:525–533. 11. Leung E, Warde P, Jewett M, et al. Treatment burden in stage I seminoma: a && comparison of surveillance and adjuvant radiation therapy. BJU Int 2013. doi: 10.1111/bju.12330. [Epub ahead of print] The authors evaluated 764 patients with stage I seminoma who underwent either surveillance or adjuvant radiation therapy, with first relapse on surveillance managed either with radiation therapy or combination ChT. Five and 10-year overall survival rates were 98.6 and 97.7% for surveillance, and 97.2 and 91.4% for adjuvant radiation therapy. Fifteen percent of patients in the surveillance group and 5% in the radiation therapy group relapsed, and went on to receive salvage treatments. The overall treatment burden represented by number of treatment episodes per patient was 0.16 in the surveillance group and 1.05 in the adjuvant radiation therapy group. Thus, surveillance reduces the overall treatment burden in patients with stage I seminoma, suggesting that it is the preferred management option. 12. Kobayashi K, Saito T, Kitamura Y, et al. Oncological outcomes in patients with stage I testicular seminoma and nonseminoma: pathological risk factors for relapse and feasibility of surveillance after orchiectomy. Diagn Pathol 2013; 8:57. 13. Fucic A, Gamulin M, Katic J, et al. Genome damage in testicular seminoma & patients seven years after radiotherapy. Int J Radiat Biol 2013. [Epub ahead of print] The authors evaluated chromosome aberration and micronuclear assays in 10 patients 7 years after completion of 25 Gy of radiation therapy for stage I seminoma, and compared the results with 10 healthy control individuals matched for age and smoking status. Increased frequencies of dicentrics, double minutes, and ring chromosomes were detected in the seminoma patients, demonstrating the long-term effects of radiation therapy on chromosomes 14. Hoppe BS, Mamalui-Hunter M, Mendenhall NP, et al. Improving the therapeutic ratio by using proton therapy in patients with stage I or II seminoma. Am J Clin Oncol 2013; 36:31–37. 15. Yamada S, Saito H, Ohara S, et al. Salvage chemotherapy with docetaxel, ifosfamide and nedaplatin (DIN) for patients with advanced germ cell tumors: a preliminary report. Jpn J Clin Oncol 2013; 43:734–739. 16. Basiri A, Ghaed MA, Simforoosh N, et al. Is modified retroperitoneal lymph node dissection alive for clinical stage I nonseminomatous germ cell testicular tumor? Urol J 2013; 10:873–877. 17. Aufderklamm S, Todenhofer T, Hennenlotter J, et al. Postchemotherapy laparoscopic retroperitoneal lymph node dissection for nonseminomatous germ cell tumors infiltrating the great vessels. J Endourol 2014. [Epub ahead of print] 18. Verhoeven RH, Gondos A, Janssen-Heijnen ML, et al., EUNICE Survival Working Group. Testicular cancer in Europe and the USA: survival still rising among older patients. Ann Oncol 2013; 24:508–513.
Volume 26 Number 3 May 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Update on testicular germ cell tumors Anitha Nallu a, Roja Chimakurthi a, Arif Hussain b,c, and Heather D. Mannuel a,b
Purpose of review This overview discusses several important developments in testicular germ cell tumors (TGCTs) over the past year. Recent findings Genomic studies continue to investigate gene expression as possible markers for disease relapse and metastatic potential. Optimal treatment strategies for early-stage seminomas continue to evolve toward surveillance versus chemotherapy, although developing radiation delivery modalities may ultimately provide a safe alternative. The role of retroperitoneal lymph node dissection in postorchiectomy early-stage nonseminoma germ cell tumors remains a topic of debate. Summary Treatment paradigms continue to be refined for TGCTs as research in these areas continues. Keywords chemotherapy, germ cell tumor, molecular genomics, radiation, retroperitoneal lymph node dissection
INTRODUCTION Testicular germ cell tumors (TGCTs) are the most common solid tumors in adolescent and young adult men between 15 and 34 years and account for 5% of urological tumors in general. Because of the success of multidisciplinary management, the prognosis of all stages of TGCT is quite good. The development of complementary therapeutic strategies, including modern cytotoxic chemotherapy (ChT) regimens, appropriate utilization of radiotherapy, and timely surgical resection, has made TGCT the model of a ‘curative’ malignancy.
EPIDEMIOLOGY AND RISK FACTORS Risk of TGCT is consistently associated with a history of cryptorchidism in epidemiologic studies. It has been postulated that other congenital malformations, in particular hypospadias, are also associated with increased risk. Using Swedish populationbased registries, Trabert et al. [1 ] evaluated the relationship between birth defects and risk of TGCT. TGCT cases (n ¼ 6593), diagnosed between 15 and 65 years of age, were identified from the Swedish Cancer Registry between 1964 and 2008. Congenital malformations were identified via linkage with the Hospital Discharge Register. In addition to the expected association between cryptorchidism and TGCT risk [odds ratio (95% confidence interval (CI): 3.18 (2.50–4.04)], hypospadias [2.41 (1.27–4.57)],
inguinal hernia [1.37 (1.11–1.68)], and other genital malformations [2.19 (1.17–4.10)] were associated with an increased risk of TGCT. These data suggest that developmental urogenital abnormalities, specifically cryptorchidism, hypospadias, and inguinal hernia, are associated with an increased risk of TGCT, further supporting the hypothesis that prenatal exposure(s) that affect proper genital development are related to this tumor. Factors modifying the association of cryptorchidism may provide insights regarding the cause of TGCT and suggest a basis for individualized care of cryptorchidism. Juniarto et al. [2] evaluated epidemiologic data, including human studies cited in PubMed or ISI Web of Science indices through December 2011, and identified 35 articles and one unpublished dataset with high-quality data on the cryptorchidism-TGCT association. The metaanalysis showed that history of cryptorchidism is associated with four-fold increased TGCT risk
&
www.co-oncology.com
a
Department of Medicine, University of Maryland School of Medicine, Baltimore Veterans Affairs Medical Center and cDepartment of Medicine, Pathology and Biochemistry, University of Maryland School of Medicine, Baltimore, Maryland, USA b
Correspondence to Dr Heather D. Mannuel, University of Maryland Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201, USA. Tel: +1 410 328 2567; e-mail: [email protected] Curr Opin Oncol 2014, 26:294–298 DOI:10.1097/CCO.0000000000000068 Volume 26 Number 3 May 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Update on testicular germ cell tumors Nallu et al.
KEY POINTS Recent studies suggest that a predisposition to develop TGCT may be associated with specific genetic loci, genetic markers, and c-kit signaling. The optimal treatment for CS1 seminoma continues to evolve, with an increasing emphasis on surveillance as the preferred option. Although current radiation modalities carry known longterm toxicity risks, evolving modalities, such as proton beam therapy, seek to decrease these risks. RPLND remains an important option for men with CS1 nonseminoma and may be a preferred approach in certain patients at higher risk for relapse.
[relative risk ¼ 4.1 (95% CI ¼ 3.6–4.7)]. Subgroup analyses identified five determinants of stronger association: bilateral cryptorchidism, unilateral cryptorchidism ipsilateral to TGCT, delayed cryptorchidism treatment, TGCT diagnosed before 1970, and seminoma histology. On the basis of available data, the authors suggest that cryptorchidism patients and their parents or caregivers should be made aware of elevated TGCT risk following orchidopexy, regardless of age at repair, unilateral versus bilateral nondescent, or position of undescended testes.
MOLECULAR AND GENOMIC STUDIES TGCT is notable for its high familial risks; so far, six loci associated with TGCT have been reported. Ruark et al. [3] identified nine new susceptibility loci for testicular cancer. From genome-wide association study (GWAS) analysis of 307 291 single nucleotide polymorphisms (SNPs) in 986 TGCT cases and 4946 controls, 694 SNPs were selected and further genotyped in another cohort of TGCT cases (n ¼ 1064) and controls (n ¼ 10082) from the United Kingdom. SNPs were identified at nine new loci (1q22, 1q24.1, 3p24.3, 4q24, 5q31.1, 8q13.3, 16q12.1, 17q22, and 21q22.3) showing association with TGCT [P < 5 10(–8)], which together account for an additional 4–6% of the familial risk of TGCT. Chung et al. [4] conducted a combined analysis of three GWAS and six new independent sample sets, which revealed that the risk of TGCT was significantly associated with markers at four previously unreported loci: 4q22.2 in HPGDS, 7p22.3 in MAD1L1, and 16q22.3 in RFWD3 and 17q22, a locus that includes TEX14, RAD51C, and PPM1E. Familial testicular germ cell tumors (FTGCTs) are hypothesized to result from the combined
interaction of several low-penetrance genes. Azevedo et al. [5 ] studied 94 patients with FTGCTs and 50 at-risk male relatives from 63 unrelated kindreds in whom the PDE11A gene had been sequenced. They also examined cyclic adenosine monophosphate (cAMP) and c-KIT signaling in testicular tissues and cell lines and extended the studies to two sporadic cases, one with and one without a PDE11A defect. It was found that patients with FTGCT and PDE11A defects also carry KITLG risk alleles more frequently, suggesting that there may be an interaction between cAMP and c-KIT signaling in the predisposition to TGCTs. Protein-tyrosine phosphatase nonreceptor type 23 (PTPN23) is a candidate tumor suppressor involved in the tumorigenesis of various organs. Tanaka et al. [6] investigated the function and regulation of PTPN23 in the formation of TGCT. Quantitative reverse transcription polymerase chain reaction (RT-PCR) data revealed significantly higher expression of miR-142-3p in human seminomas compared with normal testes. A lack of PTPN23 protein expression in human TGCT correlated with a relatively higher miR-142-3p expression. These data suggest that PTPN23 is a tumor suppressor, and that repression of PTPN23 expression by miR-142-3p plays an important role in the pathogenesis of TGCT. Nakamura et al. [7] studied the distribution of pituitary adenylate cyclase-activating polypeptide (PACAP) in the human testis and in TGCTs. PACAP is a neuropeptide expressed in the central nervous system and peripheral organs. Although previous studies revealed the role and distribution of PACAP in the rodent testis, its role in the human testis and in TGCTs is not known. The mRNAs for PACAP and its receptors were detected in human testes. PACAP immunoreactivity was observed in spermatogonia and spermatids from normal testes. In contrast, diffuse PACAP immunopositivity was observed in seminoma tumor cells, whereas only faint immunoreactivity was observed in embryonal carcinoma cells. The data suggested that PACAP may play a role in human spermatogenesis and in TGCT development. Syndecan-4 has been implicated in cancer progression, and its expression in TGCT has been studied by Labropoulou et al. [8]. Immunohistochemical staining in 71 tissue specimens and mRNA analysis revealed significant overexpression of syndecan-4 in TGCT. In seminomas, a high percentage of tumor cells exhibited membranous and/or cytoplasmic staining for syndecan-4 in all cases. Results indicated that syndecan-4 is differentially expressed in seminomas and nonseminoma germ cell tumors (NSGCTs) and might be a useful marker.
1040-8746 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
www.co-oncology.com
295
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Genitourinary system &
Mohamed et al. [9 ] conducted a study to identify genomic markers that are reliable in predicting lymph node metastases in clinical stage I (CS1) NSGCT. Twelve stage 1 mixed germ cell testicular tumors were analyzed, eight from patients who had no evidence of nodal metastasis on retroperitoneal lymph node dissection (RPLND) and four from patients who had nodal metastases on RPLND. Statistically suggestive differences in mean copy number of the Y chromosome were found between metastatic and nonmetastatic cases (P ¼ 0.0142). This finding suggests the presence of chromosome Y deletions to be a potential genetic marker for prediction of mixed germ cell tumor progression.
TREATMENT OF CLINICAL STAGE I SEMINOMA Seminomas represent about 60% of all TGCTs, with stages I and II accounting for 80 and 15% of all seminomas at presentation, respectively [10]. The last three decades have seen a substantial change in the philosophy of management, with surveillance and carboplatin-based ChT identified as successful alternatives to adjuvant radiation, and cisplatinbased ChT recognized as a curative modality either in the first line or salvage setting. Leung et al. [11 ] evaluated 764 patients with stage I seminoma who underwent either surveillance or adjuvant radiation therapy. First relapse on surveillance was managed either with radiation therapy alone, or with combination ChT for more extensive recurrence. In all, 484 patients underwent surveillance, and 280 received adjuvant radiation therapy. The 5 and 10-year overall survival rates were 98.6 and 97.7% for surveillance, and 97.2 and 91.4% for adjuvant radiation therapy [2]. A total of 72 (15%) patients in the surveillance group relapsed; treatment for relapse was radiation therapy (n ¼ 56), ChT (n ¼ 15), and surgery (n ¼ 1). Second relapse occurred in six patients, five of whom had received radiation therapy, and one had received ChT at first relapse; these patients then received ChT as definitive treatment for their second relapse. Of the patients in the adjuvant radiation therapy group, 14 (5%) relapsed: salvage treatment included ChT (n ¼ 10), surgery (n ¼ 1), and further radiation therapy (n ¼ 3). The overall treatment burden represented by number of treatment episodes per patient was 0.16 in the surveillance group and 1.05 in the adjuvant radiation therapy group. The authors conclude that surveillance reduces the overall treatment burden in patients with stage I seminoma and is the preferred management option; the selective use of radiation therapy at first relapse for patients on surveillance leads to a similar &&
296
www.co-oncology.com
requirement for subsequent ChT to that for patients on adjuvant radiation therapy [11 ]. Kobayashi et al. [12] evaluated 118 patients with stage I seminoma, of whom 56 received adjuvant radiation therapy, one received ChT, and 61 were managed with surveillance. During the mean observation period of 104 months, no patient had cause-specific death. One patient (1.7%) receiving radiation therapy and four (6.6%) patients managed with surveillance had disease relapse; the 10-year relapse-free survival (RFS) rate was 93.4% in men managed with surveillance, and their RFS was not different from that in patients receiving adjuvant radiotherapy (log rank P ¼ 0.15) [12]. Of note, men with tunica albuginea involvement showed a poorer RFS than those without, suggesting that these men may constitute a group that should be offered adjuvant therapy to decrease the risk of relapse [12]. &&
RADIATION Micronuclear frequency in mononucluear lymphocytes has been shown to be a relevant biomarker of long-term genome damage. Fucic et al. [13 ] evaluated chromosome aberration and micronuclear assays in 10 patients 7 years after completion of 25 Gy of radiation therapy for stage I seminoma, and compared the results with 10 healthy control individuals matched for age and smoking status. Although mean chromosome aberration frequency did not deviate from control values, significantly increased frequencies of dicentrics, double minutes, and ring chromosomes were detected in the seminoma patients; the average percentage of centromere-positive micronuclear was 62.6% in seminoma patients [13 ]. Although the small study size limits drawing definitive conclusions, the data demonstrate the long-term persistence of unstable chromosome aberration in patients in the post-radiation therapy setting. Hoppe et al. [14] evaluated possible dosimetric advantages of proton therapy compared with threedimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) in the treatment of patients with stage I and II seminoma. For stage I disease, proton therapy reduced the mean dose to the stomach, ipsilateral kidney, pancreas, bowel space, small bowel, and colon compared with 3DCRT and IMRT; in stage II disease, proton therapy provided additional reductions in mean dose to the bladder and rectum [14]. Although recent trends have accepted adjuvant ChT as a preferred alternative to radiation therapy, proton therapy may offer an improvement in toxicity reduction that may translate into lower risks of acute gastrointestinal side-effects, infertility, and secondary malignancies. &
&
Volume 26 Number 3 May 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Update on testicular germ cell tumors Nallu et al.
CHEMOTHERAPY IN THE SALVAGE SETTING Since the introduction of cisplatin, the therapeutic outcome of men with TGCT has markedly improved; however, approximately 20–30% of patients with advanced disease are not cured by initial therapy and require subsequent salvage treatment. Yamada et al. [15] evaluated the outcomes of 11 men with disease that was refractory or relapsed after cisplatinbased therapy who were treated with a salvage regimen of docetaxel, ifosfamide, and nedaplatin. Ten (91%) of the 11 patients achieved favorable responses, including complete response in one case and partial response in nine cases; the nine (81%) patients with partial response have continued to show no evidence of disease after salvage ChT followed by subsequent surgical resection, with a median follow-up period of 52 months [15]. Ten (91%) patients developed Grade 4 leukopenia, which was managed using standard granulocyte colonystimulating factors; no patients developed sensory neuropathy or renal dysfunction [15]. The authors suggest that the docetaxel, ifosfamide, and nedaplatin regimen is an efficacious and well tolerated alternative for salvage ChT in men with advanced cisplatin-refractory or cisplatin-relapsed TGCT.
ROLE OF RETROPERITONEAL LYMPH NODE DISSECTION The optimal treatment for postorchiectomy CS1 NSGCTs remains highly debated, with established options including observation, adjuvant ChT, and RPLND. Basiri et al. [16] performed a retrospective review of 55 men with CS1 NSGCT who underwent modified RPLND according to the Sloan-Kettering modified RPLND template between April 2002 and April 2012. Clinicopathologic parameters, retroperitoneal relapse, and rate of anterograde ejaculation were evaluated at a mean follow-up duration of 56 months (range 6–120 months). No tumor recurrences were identified in any of the individuals at the end of the follow-up period. Overall perioperative and postoperative complication rate was 18% (seven patients). Out of 38 patients, 23 (61%) experienced anterograde ejaculation at the end of the study [16]. The authors suggest that modified template RPLND is a well tolerated, effective, and sufficient treatment for patients with no retroperitoneal micrometastases; furthermore, this strategy may obviate the need for the costly and potentially harmful alternative of adjuvant ChT in this population. With the progressive advancement of laparoscopic vascular surgical techniques, laparoscopic
RPLND (L-RPLND) has become a feasible alternative for some patients with NSGCT. Aufderklamm et al. [17] identified 18 patients with NSGCT in whom bilateral L-RPLND was performed to address residual disease post-ChT. Infiltration of the great vessels was confirmed intraoperatively. There were no significant perioperative complications in the group and no conversions to open surgery; mean intraoperative blood loss was 310 ml (range 50–1000 ml). At a mean follow-up of 18 months, no patient had developed distant or in-field recurrence. The authors conclude that L-RPLND may be a safe and promising alternative to the open procedure in men with residual NSGCT and vascular infiltration.
PROGNOSTIC FEATURES Verhoeven et al. [18] utilized data from 12 European cancer registries and the US Surveillance, Epidemiology, and End Results database to report survival trends for patients diagnosed with testicular seminomas and nonseminomas between 1993–1997 and 2003–2007. Additionally, a model-based analysis was used to compare survival trends and relative excess risk (RER) of death between Europe and the USA, adjusting for differences in age and histology. In 2003–2007, the 5-year relative survival of patients with seminoma was at least 98% among those aged less than 50 years, whereas survival of patients with nonseminoma remained 3–6% lower. Despite improvements in the relative survival of nonseminoma patients aged at least 50 years by 13–18%, survival remained lower than the survival of seminoma patients of the same age. Model-based analyses showed increased RERs for nonseminomas, older, and European patients. Although there remains little room for survival improvement among testicular seminoma patients, especially for those aged less than 50 years, older patients remain at increased risk of death, which seems mainly attributable to the lower survival among the nonseminoma patients.
CONCLUSION Although TGCT remains a highly treatable and generally curable disease, controversy persists as to the optimum modality of management of earlystage disease, even within existing standard-of-care models. Additionally, men in poorer prognosis groups remain resistant to conventional treatments and constitute groups that require further study. The pace of ongoing clinical and preclinical studies remains robust, and further insights are expected into the optimal management of patients from initial diagnosis to long-term follow-up.
1040-8746 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-oncology.com
297
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Genitourinary system
Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Trabert B, Zugna D, Richiardi L, et al. Congenital malformations and testicular & germ cell tumors. Int J Cancer 2013; 133:1900–1904. The authors used Swedish population-based registries to evaluate the relationship between birth defects and TGCT. In addition to the expected association between cryptorchidism and TGCT risk, hypospadias, inguinal hernia, and other genital malformations were associated with an increased risk of TGCT. The other (nongenital) malformations evaluated were not associated with TGCT. 2. Juniarto AZ, Setyawati BA, Miranti IP, et al. Gonadal malignancy in 13 consecutive collected patients with disorders of sex development (DSD) from Semarang (Indonesia). J Clin Pathol 2013; 66:198–204. 3. Ruark E, Seal S, McDonald H, et al., UK Testicular Cancer Collaboration (UKTCC). Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14. Nat Genet 2013; 45:686– 689. 4. Chung CC, Kanetsky PA, Wang Z, et al. Meta-analysis identifies four new loci associated with testicular germ cell tumor. Nat Genet 2013; 45:680– 685. 5. Azevedo MF, Horvath A, Bornstein ER, et al. Cyclic AMP and c-KIT signaling in & familial testicular germ cell tumor predisposition. J Clin Endocrinol Metab 2013; 98:E1393–E1400. The authors studied 94 patients with FTGCTs and 50 at-risk male relatives from 63 unrelated kindreds. It was found that patients with FTGCT and PDE11A defects also carry KITLG risk alleles more frequently, suggesting that there may be an interaction between cAMP and c-KIT signaling in predisposition to TGCTs. 6. Tanaka K, Kondo K, Kitajima K, et al. Tumor-suppressive function of proteintyrosine phosphatase nonreceptor type 23 in testicular germ cell tumors is lost upon overexpression of miR142-3p microRNA. J Biol Chem 2013; 288:23990–23999. 7. Nakamura K, Nakamachi T, Endo K, et al. Distribution of pituitary adenylate cyclase-activating polypeptide (PACAP) in the human testis and in testicular germ cell tumors. Andrologia 2013. doi: 10.1111/and.12102. 8. Labropoulou VT, Skandalis SS, Ravazoula P, et al. Expression of syndecan-4 and correlation with metastatic potential in testicular germ cell tumours. Biomed Res Int 2013; 2013:214864.
298
www.co-oncology.com
9. Mohamed GH, Gelfond JA, Nicolas MM, et al. Genomic characterization of & testis cancer: association of alterations with outcome of clinical stage 1 mixed germ cell nonseminomatous germ cell tumor of the testis. Urology 2012; 80:485.e1-5. The authors analyzed 12 stage I testicular tumors obtained from eight patients who were RPLND negative and four patients who were RPLND positive. Statistically significant differences in mean copy number of the Y chromosome were found between metastatic and nonmetastatic cases (P ¼ 0.0142), suggesting the presence of chromosome Y deletions to be a potential genetic marker for prediction of mixed germ cell tumor progression. 10. Chung P, Warde P. Contemporary management of stage I and II seminoma. Curr Urol Rep 2013; 14:525–533. 11. Leung E, Warde P, Jewett M, et al. Treatment burden in stage I seminoma: a && comparison of surveillance and adjuvant radiation therapy. BJU Int 2013. doi: 10.1111/bju.12330. [Epub ahead of print] The authors evaluated 764 patients with stage I seminoma who underwent either surveillance or adjuvant radiation therapy, with first relapse on surveillance managed either with radiation therapy or combination ChT. Five and 10-year overall survival rates were 98.6 and 97.7% for surveillance, and 97.2 and 91.4% for adjuvant radiation therapy. Fifteen percent of patients in the surveillance group and 5% in the radiation therapy group relapsed, and went on to receive salvage treatments. The overall treatment burden represented by number of treatment episodes per patient was 0.16 in the surveillance group and 1.05 in the adjuvant radiation therapy group. Thus, surveillance reduces the overall treatment burden in patients with stage I seminoma, suggesting that it is the preferred management option. 12. Kobayashi K, Saito T, Kitamura Y, et al. Oncological outcomes in patients with stage I testicular seminoma and nonseminoma: pathological risk factors for relapse and feasibility of surveillance after orchiectomy. Diagn Pathol 2013; 8:57. 13. Fucic A, Gamulin M, Katic J, et al. Genome damage in testicular seminoma & patients seven years after radiotherapy. Int J Radiat Biol 2013. [Epub ahead of print] The authors evaluated chromosome aberration and micronuclear assays in 10 patients 7 years after completion of 25 Gy of radiation therapy for stage I seminoma, and compared the results with 10 healthy control individuals matched for age and smoking status. Increased frequencies of dicentrics, double minutes, and ring chromosomes were detected in the seminoma patients, demonstrating the long-term effects of radiation therapy on chromosomes 14. Hoppe BS, Mamalui-Hunter M, Mendenhall NP, et al. Improving the therapeutic ratio by using proton therapy in patients with stage I or II seminoma. Am J Clin Oncol 2013; 36:31–37. 15. Yamada S, Saito H, Ohara S, et al. Salvage chemotherapy with docetaxel, ifosfamide and nedaplatin (DIN) for patients with advanced germ cell tumors: a preliminary report. Jpn J Clin Oncol 2013; 43:734–739. 16. Basiri A, Ghaed MA, Simforoosh N, et al. Is modified retroperitoneal lymph node dissection alive for clinical stage I nonseminomatous germ cell testicular tumor? Urol J 2013; 10:873–877. 17. Aufderklamm S, Todenhofer T, Hennenlotter J, et al. Postchemotherapy laparoscopic retroperitoneal lymph node dissection for nonseminomatous germ cell tumors infiltrating the great vessels. J Endourol 2014. [Epub ahead of print] 18. Verhoeven RH, Gondos A, Janssen-Heijnen ML, et al., EUNICE Survival Working Group. Testicular cancer in Europe and the USA: survival still rising among older patients. Ann Oncol 2013; 24:508–513.
Volume 26 Number 3 May 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
