Association of intratubular seminoma and intratubular embryonal carcinoma with invasive testicular germ cell tumors

The classification of intratubular germ cell neoplasia of the testis includes an unclassified type (IGCNU), in addition to various other intratubular lesions that show specific forms of differentiation, such as intratubular seminoma and intratubular embryonal carcinoma. Although IGCNU is recognized as a precursor lesion for testicular germ cell tumors, the relationship between differentiated types of intratubular germ cell neoplasia and invasive germ cell tumors of the testis is not well established. The aim of the present study was to examine the association between invasive testicular germ cell tumors and intratubular neoplastic lesions, with particular emphasis on differentiated types of intratubular germ cell neoplasia. The seminiferous tubules adjacent to 42 testicular germ cell tumors were evaluated for the presence of various forms of intratubular germ cell neoplasia. IGCNU was observed in 37 (88%) of 42 cases, whereas intratubular seminoma and intratubular embryonal carcinoma were seen in 19% and 7% of the cases, respectively. Intratubular seminoma was associated primarily with seminomas or mixed germ cell tumors with a seminomatous component, but was also present in a case of a nonseminomatous germ cell tumor. Intratubular embryonal carcinoma was associated exclusively with nonseminomatous germ cell tumors. All cases of intratubular embryonal carcinoma were identified morphologically and exhibited histologic features corresponding to traditional definitions of this lesion. No examples of intratubular embryonal carcinoma as defined by CD30 expression alone in the absence of an intratubular proliferation were observed. The presence of intratubular seminoma in a nonseminomatous germ cell tumor suggests that it is a true preinvasive lesion rather than a manifestation of intratubular spread of an established invasive seminoma. The low incidence of intratubular embryonal carcinoma supports the theory that most nonseminomatous germ cell tumors evolve initially as seminomas, rather than directly from a differentiated intratubular neoplastic lesion.     

Raman spectroscopic analysis identifies testicular microlithiasis as intratubular hydroxyapatite

PURPOSE: As diagnosed by ultrasonography, testicular microlithiasis is associated with various benign and malignant conditions. The molecular constitution of these microliths is largely unknown. Raman spectroscopy provides detailed in situ information about the molecular composition of tissues and to our knowledge it has not been applied to gonadal microliths. We analyzed the molecular composition of gonadal microlithiasis and its surrounding region using Raman spectroscopy in malignant and benign conditions. MATERIALS AND METHODS: Multiple microliths from 6 independent samples diagnosed with gonadal microlithiasis by ultrasound and histologically confirmed were investigated by Raman spectroscopy. The samples included 4 testicular parenchyma samples adjacent to a germ cell tumor (4 seminomas), a gonadoblastoma of a dysgenetic gonad and testicular biopsy of a subfertile male without malignancy. RESULTS: Raman spectroscopic mapping demonstrated that testicular microliths were located within the seminiferous tubule. Glycogen surrounded all microliths in the samples associated with germ cell neoplasm but not in the benign case. The molecular composition of the 26 microliths in all 6 conditions was pure hydroxyapatite. CONCLUSIONS: Microliths in the testis are located in the seminiferous tubules and composed of hydroxyapatite. In cases of germ cell neoplasm they co-localize with glycogen deposits.     

Early orchiopexy: prepubertal intratubular germ cell neoplasia and fertility outcome

OBJECTIVES: To investigate the prepubertal prevalence of intratubular germ cell neoplasia of the unclassified type (ITGCNU) and its significance as a predictor of testicular cancer and to evaluate the effect of early orchiopexy (at younger than 2 years of age) on subsequent fertility of patients with bilateral cryptorchidism. METHODS: Testicular biopsies (n = 660) from 440 prepubertal patients with cryptorchidism who underwent orchiopexy between January 1, 1970 and December 31, 1979 were evaluated for ITGCNU using placental-like alkaline phosphatase (PLAP) antibody. The clinical outcome in 15 patients with PLAP-positive germ cells was evaluated in 1997. In addition, the effect of age at surgery on the fertility of patients with bilateral cryptorchidism was assessed by clinical follow-up until 1997 and was correlated with the histologic data at orchiopexy. RESULTS: PLAP-positive germ cells morphologically identical with adult ITGCNU were found in the biopsies of 22 patients (5%). After more than two decades, none of the 15 patients with successful follow-up developed testicular cancer. The fertility outcome in the patients with bilateral cryptorchidism correlated with the number of spermatogonia at orchiopexy (P = 0.018), but correlated inversely with age at orchiopexy (P = 0.021). CONCLUSIONS: PLAP-positive germ cells in prepubertal testicular biopsy specimens are not necessarily precursors of testicular cancer after orchiopexy. In addition, our data support the idea that early orchiopexy may be beneficial in preventing infertility.     

Intratubular germ cell neoplasia of the testis: testicular intraepithelial neoplasia

The observations of Skakkebaek and the evolution of the concept of intratubular germ cell neoplasia (or testicular intraepithelial neoplasia (TIN)) indicate that most, but not all, germ cell tumors of the testis evolve from a common neoplastic precursor lesion: intratubular germ cell neoplasia, unclassified type (IGCNU). It is defined as the presence of malignant germ cells within the seminiferous tubules. At 5 years about 50% of patients with a testicular biopsy positive for IGCNU have developed invasive germ cell tumors, and only a small fraction remain free of invasive tumors by 7 years. Orchiectomy is the treatment of choice in patients with unilateral IGCNU, and low-dose radiation is efficacious in patients with bilateral IGCNU (although sterility is certain). So far, there is only one published report of occurrence of two cases of germ cell cancer despite previous local radiotherapy to the testis. A recent study demonstrated an estimated risk of recurrent IGCNU following chemotherapy of 21% and 42% at 5 and 10 years, respectively.     

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.     

Testicular microlithiasis and concomitant testicular intraepithelial neoplasia

We report a case of testicular microlithiasis developing during cancer follow-up in a previously normal testicle. Biopsy revealed testicular intraepithelial neoplasia which was treated with radiotherapy. We believe that especially in cancer follow-up newly developing microlithiasis must lead to biopsy to rule out otherwise undetectable germ cell neoplasia precursor.     

Testicular embryonal carcinoma with contralateral synchronous intratubular germ cell neoplasia: analysis of a case

We report the case of a 20-year old male with a right testicular tumor. Bilateral orchidectomy was practised considering the synchronous clinical, ultrasonographical and histological (intraoperative biopsy) findings of the left testis. The definitive pathological report showed a right embryonal carcinoma with wide intratubular germ cell neoplasia (IGCN) of the contralateral testis. IGCN (formerly carcinoma in situ) is present in about 5% of cases in the contralateral gonad of those patients with a testicular neoplasm. More than 50% will develop cancer in that testis. Clinical and physical examination findings are usually unspecific. The diagnosis of IGCN is based on biopsy, although ultrasonography could give some data too, as some authors report. We analyze the therapy options for IGCN: (orchidectomy, chemotherapy, radiotherapy, or "wait and see"). In our case, the first one was made. Chemotherapy was used due to existence of retroperitoneal lymph node metastases, with an excellent follow-up afterwards.     

Bilateral testicular microlithiasis predicts the presence of the precursor of testicular germ cell tumors in subfertile men

PURPOSE: A high prevalence of testicular microlithiasis has been described in adolescent and adult clinical cases of invasive testicular germ cell tumor (TGCT), that is seminomas and nonseminomas. However, to our knowledge it remains to be established whether testicular microlithiasis also indicates the presence of the pre-invasive lesion of this cancer, known as carcinoma in situ (CIS). We determined the predictive value of unilateral and bilateral testicular microlithiasis for CIS in subfertile men, a known risk population for TGCTs (approximately 1%). MATERIALS AND METHODS: In a retrospective cross-sectional study the association between testicular microlithiasis and CIS was studied in a group of 263 men referred for subfertility. Testicular microlithiasis and CIS were diagnosed in all men by scrotal ultrasound and in testicular histology specimens as part of the routine evaluation of all patients. RESULTS: Of the 263 subfertile men 53 (20%) had testicular microlithiasis. No CIS or TGCT was identified in the 23 men with unilateral testicular microlithiasis. In contrast, 6 of the 30 men (20%) with bilateral testicular microlithiasis were diagnosed with CIS. Therefore, the prevalence of CIS in subfertile men with bilateral testicular microlithiasis is significantly higher than in patients without testicular microlithiasis (1 of 210, 0.5%) and with unilateral testicular microlithiasis (0 of 23, 0%) (p <0.0001). CONCLUSIONS: Bilateral testicular microlithiasis is indicative for CIS in subfertile men. Since these men are at particular risk for invasive TGCT, an assessment of testicular microlithiasis is a valuable tool for the early diagnosis of this disease.     

Primary testicular lesions are associated with testicular germ cell tumors of adult men

The present study aims to establish the nature and frequency of testicular lesions in the parenchyma adjacent to testicular germ cell tumors (TGCT) to improve understanding of the factors involved in the development of testicular cancer. Fifty-three cases of TGCT that were fixed in both neutral-buffered formalin and Bouin solution, allowing for the nuclear characterization of Sertoli cells (SCs), were included in this study. In each case, at least 3 sections of different areas of preserved parenchyma surrounding the TGCT were studied. We found Leydig cell hyperplasia, microlithiasis, angiopathy, adenomatous hyperplasia of the rete testis, SC nodules, SC dysgenesis and involution, SC-only tubules, tubular atrophy, adluminal compartment lesions, hypospermatogenesis associated with spermatocyte sloughing, spermatogonial maturation arrest, and hypertrophic and multinucleated spermatogonia. These lesions were found in regions both adjacent and far away from the tumoral mass, and abnormal seminiferous tubules were found intermingled with those showing complete spermatogenesis, suggesting that these lesions are primary and existed before the development of the tumor. Our study suggests that SCs might play a more important role in the development of testicular tumors than previously thought. Our data supports the hypothesis that there is an abnormal differentiation of SCs, caused either by genetic anomalies or by environmental agents during fetal life. This abnormal SC differentiation may cause not only primary spermatogenesis failure and spermatogenesis arrest at different levels, but may also contribute to the poor differentiation of gonocytes into spermatogonia. The abnormal gonocyte differentiation might favor the development of dysplastic germ cells that may later transform into intratubular germ cell neoplasia, unclassified type.     

儿童常见睾丸生殖细胞肿瘤的超声表现和临床特征

目的:探讨儿童常见睾丸生殖细胞肿瘤(TGCT)的超声表现和临床特征。方法:回顾性分析2013年3月至2019年1月92例儿童TGCT的实验室检查、超声检查和临床资料,并采用受试者工作曲线(ROC)分析血清AFP值和肿瘤最大直径对肿瘤良恶性的诊断效能。结果:畸胎瘤是儿童最常见的睾丸肿瘤,超声提示畸胎瘤多为囊实混合性(25/40,62.5%)或实性肿块(12/40,32.5%);表皮样囊肿可见典型的"洋葱圈"征(6/18,33.3%)和包膜钙化征(4/18,22.2%);卵黄囊瘤(YST)多表现为等回声(11/26,42.3%)或低回声(8/26,30.9%)实性肿块,肿瘤均不伴钙化,部分YST(7/26,26.9%)肿瘤内部见囊性无回声。彩色多普勒血流显像大部分YST血流信号丰富(25/26,96.2%),所有表皮样囊肿和皮样囊肿内部均未见血流信号。采用ROC曲线分析显示,血清AFP值ROC曲线下面积为0.985,最佳截断值为124.2 ng/ml,AFP诊断良恶性肿瘤的敏感性、特异性分别为92.9%、93.7%;肿瘤最大直径ROC曲线下面积为0.796,最佳截断值为2.7 cm,肿瘤最大直径诊断良恶性肿瘤的敏感性、特异性分别为57.1%、93.7%。结论:不同病理类型儿童TGCT超声声像图有一定的特征性表现,儿童TGCT预后良好,当血清AFP≥124.2 ng/ml、肿瘤最大直径≥2.7 cm时应考虑根治性睾丸切除术。     

Bilateral testicular intratubular germ-cell neoplasia, unclassified in an azoospermic patient

We report the case of a 29-year-old man, who was examined in our hospital for infertility. After complete evaluation, the patient was found to be azoospermic with normal follicle-stimulating hormone levels, whereas his testes were slightly smaller than normal. Thus, there was an indication for testicular biopsy, which showed bilateral testicular intratubular germ-cell neoplasia, unclassified. The patient was informed about his status, and when the staging was completed and the possibility of distant or lymphatic metastases was excluded, the therapeutic choices were discussed. In this case, bilateral orchiectomy was recommended and carried out, followed by hormone replacement therapy.