Management of the contralateral testis in patients with testicular germ cell cancer

Patients with testicular germ cell tumours (TGCT) are at increased risk of developing a tumour in the contralateral testis. Such a tumour may be preceded by carcinoma in situ (CIS), which is more common in patients with infertility, atrophic testis or a history of cryptorchism. Of 1219 patients with TGCT seen at the Royal Marsden Hospital between 1962 and 1984 in whom the contralateral testis was managed by surveillance, 38 (3.1%) developed a second tumour and 8 died of germ cell tumours. Seventeen of 26 assessable patients (65%) exhibited at least one of the known aetiological risk factors for carcinoma in situ. Diagnosis of carcinoma in situ may lead to more appropriate management of the contralateral testis.     

Screening for intratubular germ cell neoplasia of the testis using OCT4 immunohistochemistry

Specific populations of patients are at high risk for the development of germ cell neoplasia. OCT4 has been shown to be a sensitive and specific marker for intratubular germ cell neoplasia of the testis. Whether or not OCT4 immunohistochemistry is a clinically useful screening tool in patients at risk for developing malignant germ cell tumors is not currently known. We undertook immunohistochemical staining for OCT4 in a large series of patients who underwent testicular biopsy or orchiectomy for reasons other than for management of a testicular mass suspicious for malignancy (infertility, cryptorchidism, atrophic testicle, etc.). OCT4 nuclear staining was identified in germ cells in 6 of 157 patients, all of whom had clinical risk factors for the development of testicular germ cell tumors. Two of the 6 patients were under 1.5 years of age, making the significance of OCT4 positivity less certain in these cases. The remaining patients with OCT4-positive germ cells consisted of 3 adults and 1 7-year-old child. Intratubular germ cell neoplasia was identified by light microscopy in only 1 of the 6 OCT4-positive cases. OCT4 immunostaining was negative in all patients who presented with infertility and who had no additional germ cell tumor risk factors. OCT4 immunohistochemistry may be useful in identifying early forms of preinvasive germ cell neoplasia in patients with risk factors for the development of malignant testicular germ cell tumors. The low incidence of OCT4 positivity in the adult infertility patients argues against the routine use of OCT4 immunostains in testicular biopsies for infertility unless additional risk factors are present.     

Retroperitoneal germ cell tumor with testicular calcification indicating tiny testicular origin: consideration of the origin of retroperitoneal germ cell tumors: report of two cases

Two cases of germ cell neoplasm retrospectively considered to have been of testicular origin are reported. Case 1. A 19-year-old male with brain, liver and retroperitoneal tumors was diagnosed with yolk sac tumor by retroperitoneal tumor biopsy. After multidisciplinary treatment, a region of calcification was detected in the left testis on scrotal sonography and left high inguinal orchiectomy was performed. Case 2. A 57-year-old male with neck, lung and retroperitoneal tumors was diagnosed with yolk sac tumor by supraclavicular biopsy. From initial examination, scrotal sonography revealed a small calcified lesion in the right testis. After chemotherapy, high inguinal orchiectomy and retroperitoneal lymphadenectomy were simultaneously performed. Pathologic evaluation of these testicular specimens revealed calcification and a fibrous scar in correspondence with the clinical diagnosis. These changes were considered as scars of the primary testicular tumor due to burned-out tumor or the result of reaction to chemotherapy. Since a primary tumor of testicular origin may exist in the extragonadal germ cell tumor, it is important to examine the intrascrotal contents in detail in the case of so-called extragonadal germ cell tumors with palpably normal testes. In such cases, there are two possible conditions, an occult testicular tumor and a burned-out testicular tumor. We briefly reviewed 42 such cases in the Japanese literature. It appears that there are very few true extragonadal germ cell tumors, and that the possibility of primary testicular origin metastasizing from viable occult testicular tumor or burned-out testicular tumor with spontaneous regression is high in retroperitoneal germ cell tumors.     

Sonographic testicular microlithiasis as an indicator of premalignant conditions in normal and infertile men.

Sonographic detection of multiple, small hyperechogenic lesions in the testis (testicular microlithiasis; TM) can indicate germ cell tumors. However, it has not been well established whether this finding signifies a risk factor for development of testicular neoplasm in all cases or whether it indicates premalignant changes only in those men with additional risk factors for germ cell cancer, such as infertility, a history of testicular maldescent, or the presence of an atrophic testis. In a retrospective analysis of 1701 consecutively performed scrotal sonographies of patients with (n = 1399) and without (n = 219) infertility or with contralateral testicular tumors (n = 83), the prevalence of TM was compared with that in 198 healthy men who volunteered for different clinical trials. TM was equally frequent in all groups (2.3% [32/1399] of infertile patients, 2.3% [5/219] of other patients without infertility, and 1.5% [3/198] of healthy men). Results of testicular biopsies were available for a subgroup of infertile men. Carcinoma in situ (CIS) was present only in cases with TM (2/11). In addition, sonographic follow-up examinations were performed in another 14 men with TM. Testicular tumors had developed in 2 patients, one whom was infertile and one in the control group. None of these patients had a history of testicular maldescent but all testes affected either by CIS or tumors were reduced in volume. We conclude that diagnosis of TM, especially if it is present in an atrophic testis, demands a diagnostic biopsy or at least sonographic follow-up examinations.     

ORGAN SPARING SURGERY FOR MALIGNANT GERM CELL TUMOR OF THE TESTIS

PURPOSE: We evaluate the indication, technique and long-term outcome of organ preserving tumor resection rather than standard orchiectomy in 73 patients with bilateral testicular germ cell tumors or tumors of a solitary testicle. MATERIALS AND METHODS: Tumor resection was performed in 73 patients with 52 and 17 metachronous and synchronous bilateral testicular germ cell tumors, respectively, and 4 testicular germ cell tumors of a solitary testicle. Histology of the enucleated germ cell tumor revealed seminoma in 42 (57.5%) patients, embryonal carcinoma in 14 (19.2%), mature teratoma in 11 (15.1%), and mixed and combined germ cell tumors in 6 (8.2%). Mean tumor diameter was 15 mm. (range 5 to 30). Associated testicular intraepithelial neoplasia was diagnosed in 82% of patients who underwent local radiation with 18 Gy. RESULTS: After a median followup of 91 months (range 3 to 191) 72 (98.6%) patients had no evidence of disease and 1 died of systemic tumor progression. No local relapse occurred in 46 patients with associated testicular intraepithelial neoplasia treated with local radiation. However, local recurrence did develop in 4 patients after 3, 6, 12 and 165 months without radiation but all survived after undergoing inguinal orchiectomy. Testosterone levels were normal in 62 (84.9%) patients, hypogonadism developed in 7 (9.6%) and preoperative levels remained low in 4 (5.5%). Of the 10 patients who postponed local radiation for paternity reasons 5 had successfully fathered a child after organ sparing surgery. CONCLUSIONS: After a long-term followup of greater than 7 years organ sparing surgery represents a viable therapeutic approach to bilateral testicular germ cell tumor with an excellent postoperative outcome. Tumor enucleation might be considered a standard approach if the guidelines are respected, including cold ischemia, organ confined tumor less than 20 mm., multiple biopsies of the tumor bed, adjuvant local irradiation postoperatively to avoid local recurrence, close followup and high compliance.     

Testicular cancer trends as 'whistle blowers' of testicular developmental problems in populations

Recently a worldwide rise in the incidence of testicular germ cell cancer (TGCC) has been repeatedly reported. The changing disease pattern may signal that other testicular problems may also be increasing. We have reviewed recent research progress, in particular evidence gathered in the Nordic countries, which shows strong associations between testicular cancer, undescended testis, hypospadias, poor testicular development and function, and male infertility. These studies have led us to suggest the existence of a testicular dysgenesis syndrome (TDS), of which TGCC, undescended testis, hypospadias/disorders of sex differentiation and male fertility problems may be symptoms with varying penetration. In spite of their fetal origin, most of the TDS symptoms, including TGCC and poor semen quality, can only be diagnosed in adulthood. Data from a Danish-Finnish research collaboration strongly suggest that trends in TGCC rates of a population may be 'whistle blowers' of other reproductive health problems. As cancer registries are often of excellent quality - in contrast to registries for congenital abnormalities - health authorities should consider an increase in TGCC as a warning that other reproductive health problems may also be rising.     

A case of simultaneous bilateral germ cell tumors arising from cryptorchid testes

We report a rare case of simultaneous bilateral testicular germ cell tumors arising from uncorrected cryptorchid testes. Each side had a different histological type, which consisted of pure high grade seminoma on the left side, and teratocarcinoma with choriocarcinoma and yolk sac tumor elements in addition to seminoma on the right side. Patients with cryptorchidism are known to have a higher risk of germ cell tumors. Genetic factors also may have a role in the oncogenesis in our patient, since his older brother had had a seminoma in the left cryptorchid testis previously. Both patients had the HLA-Aw24 antigen. The characteristics of familial testicular tumors are discussed.     

What is new in cryptorchidism and hypospadias--a critical review on the testicular dysgenesis hypothesis

It has been hypothesized that poor semen quality, testis cancer, undescended testis, and hypospadias are symptoms of one underlying entity—the testicular dysgenesis syndrome—leading to increasing male fertility impairment. Though testicular cancer has increased in many Western countries during the past 40 years, hypospadias rates have not changed with certainty over the same period. Also, recent studies demonstrate that sperm output may have declined in certain areas of Europe but is probably not declining across the globe as indicated by American studies. However, at the same time, there is increasing recognition of male infertility related to obesity and smoking. There is no certain evidence that the rates of undescended testes have been increasing with time during the last 50 years. In more than 95% of the cases, hypospadias is not associated with cryptorchidism, suggesting major differences in pathogenesis. Placental abnormality may occasionally cause both cryptorchidism and hypospadias, as it is also the case in many other congenital malformations. The findings of early orchidopexy lowering the risk of both infertility and testicular cancer suggest that the abnormal location exposes the cryptorchid testis to infertility and malignant transformation, rather than there being a primary abnormality. Statistically, 5% of testicular cancers only are caused by cryptorchidism. These data point to the complexity of pathogenic and epidemiologic features of each component and the difficulties in ascribing them to a single unifying process, such as testicular dysgenesis syndrome, particularly when so little is known of the actual mechanisms of disease.     

Conservative management of small testicular tumors relative to carcinoma in situ prevalence

PURPOSE: We evaluated the prevalence of carcinoma in situ (CIS) in orchiectomy specimens performed for germ cell tumors smaller than 40 mm in diameter to propose an appropriate conservative approach to bilateral tumors or tumor of a solitary testis. MATERIALS AND METHODS: Of 127 patients treated with orchiectomy between 1990 and 2002, 41 who presented with a tumor of less than 40 mm in diameter were selected for histological analysis of testicular parenchyma. The morphological items assessed were CIS, spermatogenesis and Leydig cell hyperplasia. RESULTS: CIS was observed in 39 of the 41 patients (95%). CIS was evenly distributed throughout the testicular parenchyma (ie around and beyond the tumor) in all 39 cases. Spermatogenesis was observed in 12 of 41 specimens (29%), spermatogenesis without spermatozoa was noted in 14 (34%) and absent germ cells were found in 15 (37%). Leydig cell hyperplasia was observed in 24 cases (58%). CONCLUSIONS: Histological analysis of whole orchiectomy specimens showed that CIS is almost always present in testicular parenchyma adjacent to germ cell tumor. In bilateral testis cancer or cancer occurring in a solitary testis tumorectomy plus radiotherapy appears to be the appropriate treatment in patients with a small tumor and no other risk factors. In patients who wish to father a child and have preserved spermatogenesis the natural history of CIS allows the postponement of testicular radiotherapy after orchiectomy, giving the double advantage of preserving testicular endocrine function and maintaining the possibility of natural fatherhood.     

Genetic abnormalities in men with germ cell tumors

We retrospectively reviewed the genetic abnormalities detected clinically in 455 men with advanced germ cell tumors referred for chemotherapy. Of the patients 49 had extragonadal and 406 had testicular germ cell tumors. Of 19 patients with mediastinal germ cell tumors 4 (21 per cent, 3 with teratocarcinoma and 1 with endodermal sinus tumor) had Klinefelter's syndrome. Three of these patients had a 47XXY and 1 had a 48XXYY karyotype. No Klinefelter's syndrome was observed among 30 consecutive patients with retroperitoneal germ cell tumors or among the 406 with testicular tumors. Karyotypes of 35 consecutive patients with testis cancer without evident congenital abnormalities showed normal chromosomal patterns. We found 2 patients with Down's syndrome and testicular tumor, for an incidence of 0.5 per cent (probably significant). We also describe 2 cases of nonseminomatous testicular cancer and Marfan's syndrome (0.5 per cent incidence versus a 5 of 100,000 incidence of Marfan's syndrome in the general population). Apparently, genetic abnormalities are increased in men with germ cell tumors and we discuss the significance of this association.     

Acute scrotum due to arterial bleeding mimicking non-seminomatous germ cell tumor

Men with testicular tumors usually present with painless increase in testis size incidentally noticed by the patient. We report a case of a young patient presenting as an emergency with acute onset of massive right-sided testicular pain without previous injury. After physical examination testicular torsion could not be excluded. Ultrasound examination of the tesds was suspicious for tesdcular tumor. Surgical exploration of the right testis by inguinal approach was performed revealing subcapsular arterial bleeding due to a small nonseminomatous germ cell tumor non-palpable on clinical examination. (Asian J Andro12004 Dec;6:379-381)     

A rare diagnosis： testicular dysgenesis with carcinoma in situ detected in a patient with ultrasonic microlithiasis

A rare case is presented where a dysgenetic testis with microinvasive carcinoma in situ （CIS, also known as intratubular germ cell neoplasm of unclassified type [IGCNU] and testicular intraepithelial neoplasia [TIN]） with microinvasion to rete testis and the interstitial tissue was found in a 32-year-old man presenting with mild scrotal pain and ultrasonic testicular microlithiasis. Knowledge of the association of ultrasound and CIS is important to diagnose patients at the stage prior to development of an overt germ cell tumor. The patient had three of four disorders considered symptoms of the testicular dysgenesis syndrome （TDS）： a dysgenetic left testicle with CIS, a mild left-sided cryptorchidism （high positioned scrotal hypotrophic testis） and a slightly reduced semen quality. Therefore, it should be kept in mind that a patient with one TDS symptom may harbour the other, even CIS or testicular cancer. Accordingly, patients with one TDS symptom ought to be examined for the presence of the others, and if more that one is present, extra concern is warranted.     

Bilateral testicular tumors of germ cell origin.

Four cases of primary testicular tumor of germ cell origin are reported. Three cases were bilateral, while the remaining case involved a unilateral tumor in a non-twin brother of 1 patient with bilateral tumors. Because of the increased likelihood of a second primary tumor developing in a patient who has had a malignant germinal cell tumor and because the changes may be subtle, localized to the testis and occur after a tumor-free interval of many years, careful examination of the contralateral testis and long-term followup are indicated even when systemic chemotherapy for malignancy has been used. This is the seventh time familial occurrence of testis tumors in non-twin brothers has been reported but the first time that one of the brothers had bilateral tumors.     

Bilateral testicular tumors recurring 31 years after the initial treatment: a case report and the literature review

We herein report a case of bilateral testicular germ cell tumor recurring 31 years after right high inguinal orchiectomy. In 2003, a 62-year-old man presented with a mass in the left testis. Ultrasonography demonstrated three hypoechoic mass and microlithiasis of the left testis. Abdominal and breast computed tomography revealed no lymph adenopathy and any metastasis. The preoperative diagnosis was stage I testicular tumor and subsequently left high orchiectomy was performed. Histological examination revealed typical seminoma. At present, the patient is free from recurrence after the surgery. To our knowledge, 166 cases were reported in Japan. Approximately fifty percent of metachronal bilateral testicular tumors previously reported have been recurred after five years and more from the initial surgery. In the testicular cancer, long-term follow-up and self examination of the scrotum are of great importance. We review the metachronal bilateral testicular germ cell tumors previously reported in Japan.     

External genital abnormalities associated with Wilms tumor

The records of 170 patients with unilateral and 18 patients with bilateral Wilms tumor and 6 patients with congenital mesoblastic nephroma were reviewed for abnormalities of the external genitalia. There were 4 patients with cryptorchism, 1 with hypospadias, 1 with mixed gonadal dysgenesis, and 3 with male pseudohermaphroditism. Of the group, these 9 patients had earlier symptoms; 6 of them were under two years old. Five patients (27.7%) with bilateral Wilms tumors had external genital anomalies in contrast to only 4 (2.3%) of those with unilateral tumors. One of the 9 children with genital anomalies had unilateral congenital mesoblastic nephroma; the others had Wilms tumor. In all cases the histologic subtypes were unusual. These observations substantiate the previously reported association between external genital abnormalities and Wilms tumor and also represent a somewhat higher than expected incidence. The children with this association are remarkable for the high frequency of a particular histologic type of tumor and for the high incidence of bilaterality. The high incidence of Wilms tumors in the male pseudohermaphrodite population presented suggests that such patients should be monitored for development of renal tumors.     

Spermatogenesis in the contralateral testis of patients with testicular germ cell cancer: histological evaluation of testicular biopsies and a comparison with healthy males

OBJECTIVE: To assess histologically signs of testicular dysgenesis (TD) in the contralateral testes of patients with testicular germ cell tumours (GCTs) and to compare these findings with the spermatogenetic quality in healthy men, as the contralateral testis is considered to be involved with dysgenetic features such as poor sperm production, and accordingly, GCTs are hypothesized to be part of the 'TD syndrome' (TDS). One testicular biopsy is thought to represent spermatogenesis in the entire testis. We evaluated this view by using testicular two-site biopsies. PATIENTS AND METHODS: 2318 patients with testicular GCT had a contralateral testicular two-site biopsy. Testicular biopsies taken on forensic autopsy from 1388 presumably healthy men served as controls. Spermatogenesis was rated histologically according to a modified Johnsen score. Clinical factors were recorded to explore associations with reduced spermatogenesis. Differences in spermatogenesis scoring results among two-site biopsies were noted. Statistical analysis involved Wilcoxon-Mann-Whitney and Jonckheere-Terpstra tests for comparing patients and controls, and for studying associations with clinical factors. Classification and regression-tree analysis was used to explore multivariate associations. RESULTS: Histologically, patients had significantly poorer spermatogenesis than healthy men. Clinically, hypospermatogenesis was significantly associated with testicular atrophy, undescended testes, male infertility, and advanced clinical stage; 5.4% of cases (95% confidence interval 4.43-6.27) had discordant findings of >2 points on double biopsy and 9.8% had differences of 1 point. Discordance was significantly associated with poor spermatogenesis and testicular atrophy. CONCLUSIONS: We confirmed histologically that there is markedly reduced spermatogenesis in the contralateral testes of patients with GCT. This result lends credence to the view that GCT is part of the so-called TDS. But as hypospermatogenesis is associated with advanced clinical stage, impairment of sperm production might at least partly be acquired secondary to the endocrine activity of GCT. There were clinically relevant discordant results on double biopsy in 5.4%, predominantly in infertile patients and in atrophic testes. Thus the histological evaluation of male infertility is best done by multiple biopsies.     

Accuracy of frozen section examination of testicular tumors of uncertain origin

INTRODUCTION: A total of 80-90% of all testicular masses are malignant germ cell tumors. Benign testicular lesions are recognized in approximately 10-20% enabling a testis-preserving surgery on the findings of frozen section examination (FSE). However, there are only sparse information with regard to the reliability of FSE in testicular tumors of uncertain dignity. Therefore, we retrospectively reviewed our experience concerning the reliability of FSE in primary testicular tumors by comparing each FSE result to the final diagnosis. PATIENTS AND METHODS: From 1974 to 2000, 354 patients were operated on a testicular tumor. During inguinal exploration and after clamping of the spermatic cord and appropriate dressing, a representative biopsy of the tumor was taken and sent for FSE. In case of malignancy radical orchiectomy was performed, in case of benign findings or in case of a germ cell tumor in a solitary testicle, the tumor was enucleated. Slides of FSE and the permanent sections were reviewed and compared with regard to the histological diagnosis and presence/absence of malignancy. RESULTS: Based on FSE, 317 tumors (89.5%) were found to be malignant ((100 seminomas (38.5%), 217 nonseminomas (61.5%)) and 37 tumors (10.5%) were benign (17 epidermoid cysts, 14 Leydig cell tumors, two cystadenomas, two simple cysts, two hemangiomas). Comparing FSE and definitive diagnosis, FSE correctly identified all malignant and benign lesions. There was a failure rate of 10 and 8% to differentiate seminomatous from nonseminomatous tumors and vice versa based on FSE, which, however, was irrelevant for the surgical management. Complications of the enucleations (n = 37) were: testicular atrophy in three cases, testicular hematoma in three cases, orchitis/epididymitis in one case. Not a single case disclosed a local relapse after a mean follow-up of 105 (12-240) months. CONCLUSIONS: Intraoperative FSE correctly identified all malignant and benign testicular masses including radical orchiectomy or organ-preserving surgery. Surgical management of testicular tumors based on FSE results is clinically practicable.     

睾丸混合性生殖细胞肿瘤临床病理分析

目的:探讨原发性睾丸混合性生殖细胞肿瘤(MGCT)的临床病理特征。方法:对我院13例原发性睾丸MGCT患者的临床病理资料进行回顾性分析,并结合相关文献进行讨论。结果:睾丸MGCT占我院同期睾丸生殖细胞肿瘤的24.1%(13/54),患者年龄2~53岁,平均28.3岁。全部病例均发生于单侧睾丸,左侧6例,右侧7例,左右侧比为0.86∶1。睾丸MGCT病理形态多样,肿瘤成分包括胚胎性癌(11例,84.6%)、精原细胞瘤(8例,61.5%)、畸胎瘤(6例,46.2%)、绒毛膜癌及卵黄囊瘤(均为4例,23.1%)。其中9例(69.2%)包含2种不同的生殖细胞肿瘤成分,3例(30.8%)包含3种不同的肿瘤成分,1例(7.7%)包含5种不同的肿瘤成分。结论:睾丸MGCT非常少见,好发于青壮年男性,不同的肿瘤成分其生物学行为、临床治疗和预后不同,因此准确的病理诊断非常必要,免疫组化标记对病理诊断与鉴别诊断具有重要作用。     

Incidence and clinical pattern of contralateral synchronous and metachronous germ cell testicular cancer

BackgroundIncidence of a second testicular tumor is higher in patients diagnosed with testicular cancer than in the general population. As incidence of unilateral germ cell cancer is increasing worldwide and most of these patients are cured, a growing number of patients at risk of developing a contralateral testis cancer is expected.ObjectiveTo analyze clinical and histological characteristics, as well as the absolute and cumulative incidence of a second testicular cancer in a cohort of 3,834 patients diagnosed with germ cell testicular cancer between I/1994 and I/2018 in 18 referral hospitals of the Spanish Germ Cell Cancer Group.MethodsPatients were treated according to stage and year of diagnoses. Contralateral testis biopsy was not routinely performed, according to European Association of Urology rules. Follow-up of the contra lateral testis consists of a physical exam only and an annual optional testicular ultrasound for 10 years.ResultsMedian age of the patients included was 32 years (18–82). With a median follow-up of 61 months (0–240), 67/3,834 patients (1.74%) were diagnosed with a second testicular tumor. The second testicular tumor was synchronic (diagnosed within 6 months of the first orchiectomy) in 19 patients, and metachronous in 48. Pathology of the second tumor was reported as a seminomatous testis tumor in 47 patients and a nonseminomatous cancer in 20. Cumulative incidence of contralateral testicular cancer was 2% at 5 years, and 4% (IC 95% 3%–5%) at 14 years. Younger age was a risk factor for developing a second testicular tumor (P = 0.006), whereas chemotherapy reduced the risk for a metachronous testicular cancer (P = 0.046). Within our cohort, 6 families with testicular cancer aggregation (more than 2 tumors in the same family) were identified.ConclusionsIncidence of second testicular neoplasm in this cohort of 3,834 patients was similar to that which has been reported in other countries. Metachronous tumors and seminomas are more common. Follow-up of the contralateral testis is mandatory, as well as adequate information for patients to prevent a second neoplasm if feasible, and to detect and treat it as soon as possible.