Ultrasonographic findings of testicular microlithiasis associated with intratubular germ cell neoplasia.

Testicular microlithiasis is an uncommon condition in which calcified concretions fill the lumina of seminiferous tubules. We report the case of a twenty-three-year-old white man with a metastatic germ cell tumor and normal findings on testicular physical examination, but abnormal ultrasonography of the right testis. Orchiectomy revealed intratubular germ cell neoplasia with testicular microlithiasis. Multiple circular echogenic foci on ultrasound correlated with the histologic finding of testicular microlithiasis. Further studies are indicated for assessing ultrasonography as an adjunct for screening the population at risk for intratubular germ cell neoplasia.     

睾丸微结石的临床意义及处理

睾丸微结石(TM)是生精小管内的钙盐沉积。随着阴囊B超的广泛应用,临床诊断的TM病例增多。TM可并发于多种疾病,包括隐睾、男性不育、精索静脉曲张、睾丸扭转、克氏综合征、生精小管生殖细胞内瘤(IGCN)和睾丸生殖细胞瘤(TGCT)等。泌尿外科及男科医师关注的问题是TM常并发IGCN、TGCT及男性不育。TM的病因不明,其生物学性能及临床意义未能确定。目前对TM与IGCN、TGCT及男性不育之间的相互关系尚有争议。本文介绍TM的定义、发病率、病因学及组织病理学,并简要概述TM并发IGCN及TGCT,TM并发男性不育及TM的处理。     

Testicular Microlithiasis Associated with Teratocarcinoma and Intratubular Germ Cell Neoplasia: A Case Report

Testicular microlithiasis is a rare condition that has characteristic sonographic and histologic features. It is often associated with premalignant changes and malignant neoplasms of the testes. We report a case of testicular microlithiasis associated with teratocarcinoma and intratubular germ cell neoplasia. Three previously reported cases documented development of malignant germ cell tumor during the clinical follow-up period of patients with testicular microlithiasis. We think that testicular microlithiasis is strongly associated with testicular neoplasms, and that coexistence of intratubular germ cell neoplasia and malignant germ cell tumors with testicular microlithiasis is common.     

Significance of testicular microlithiasis

INTRODUCTION: Testicular microlithiasis is an uncommon condition characterized by calcifications within the seminiferous tubules. The true prevalence in a normal population has not been defined. METHODS: A review of the literature with emphasis on the connection between testicular microlithiasis and testicular malignancy was carried out. RESULTS: Testicular microlithiasis is associated with different testicular pathologies, including testicular cancer. However, a direct causative connection between testicular microlithiasis and testicular pathologies is not supported by the literature. CONCLUSIONS: Patients with testicular microlithiasis should be followed up regularly. Further investigations concerning the etiology of testicular microlithiasis remain to be done.     

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.     

Testicular microlithiasis

Testicular microlithiasis is an uncommon condition that is characterized by calcifications within the lumina of seminiferous tubules. It is usually an incidental finding on high frequency scrotal sonography. Testicular microlithiasis is a benign condition but is associated with testicular malignancies. Recent reports support this association and suggest regular follow-up in these patients.     

Testicular microlithiasis: report of 14 cases

Testicular microlithiasis (TM) is a comparatively rare condition in which calcified congelations fill the lumina of the seminiferous tubules. Using high-frequency linear transducers (10 MHz), TM is easily demonstrated as tiny punctate echogenic foci, which typically do not give an acoustic shadow, and is classified into classic type (CTM) and limited type (LTM) on the basis of the presence of five or more microliths at least on one image of the testes. Fourteen patients were found to have TM, 6 of which were LTM and 8 were CTM. In one patient with CTM, coexisting mixed germ cell tumor (seminoma, embryonal cell carcinoma) was demonstrated. Until further data are available, it seems reasonable to consider patients with TM as having an increased risk of developing a primary testicular tumor.     

Clinicopathological study of the testicular microlithiasis

PURPOSE: Testicular microlithiasis (TM) is a relatively rare condition characterized by calcific concref1p4 within the seminiferous tubules. Little has been reported on the incidence or the clinical implication of TM among Japanese. To address the problem, we evaluated pathologic specimens from biopsies and orchiectomies, of testes with various conditions. MATERIALS AND METHODS: Pathologic specimens of the testes of 200 cases, 56 from orchiectomy and 144 from testicular biopsy, were investigated. RESULTS: The pathological diagnosis of TM was confirmed in seven (3.5%) cases, four of which were associated with germ cell tumors and the other three were obtained from testicular biopsies performed for examination of infertile men. Of the 41 patients with germ cell tumors, four (9.8%) were found to have TM, and another three (2.5%) were identified among 122 patients with infertility. The prevalence of TM is significantly higher in specimen with germ cell tumors than those without germ cell tumors (p < 0.05). CONCLUSIONS: Although TM is rarely encountered, this condition is relatively often accompanied by testicular malignancy. Further investigation would be fundamental to ascertain the relationship between TM and testicular malignancy.     

Testicular microlithiasis in 2 children with bilateral cryptorchidism.

Testicular microlithiasis, associated with bilateral cryptorchidism, is studied in 2, 6-year-old children. In case 1 autopsy revealed that 60 per cent of the seminiferous tubules contained completely calcified microliths. Similar mineralized concretions also were found in different areas of the cerebrum and cerebellum. In the testicular biopsy obtained from case 2, 30 per cent of the seminiferous tubules contained microliths showing different degrees of calcification. The study of such calcifications supports the hypothesis that the mineralization process occurs according to the following stages: 1) accumulation of cellular debris in the tubular lumen, 2) deposit of concentric rings of glycoprotein material surrounding the central core and 3) calcification of the glycoprotein lamellar material. The presence of similar concretion in the nervous system as well as the lung in other reported cases suggests that microlithiasis could be a systemic disease.     

How worrisome is testicular microlithiasis?

PURPOSE OF REVIEW: Anecdotal reports of men developing testicular cancer after previous identification of microcalcifications on ultrasound generated significant concern in the literature about the relationship of testicular microlithiasis and testis cancer. Until 2001 little prospective data were available on the prevalence or natural history of testicular microlithiasis in the healthy male population. RECENT FINDINGS: Testicular microlithiasis is present in 5.6% of the male population between 17 and 35 years of age (14.1% in African Americans), far more common than testicular cancer (7:100,000). The majority of men with testicular microlithiasis will not develop testicular cancer. Previously recommended surveillance regimens using ultrasound, tumor markers or testicular biopsy are too costly and do not offer an improved outcome over testicular self-examination. SUMMARY: Testicular microlithiasis is common and while microcalcifications do exist in roughly 50% of germ cell tumors the majority of men with testicular microlithiasis will not develop testicular cancer. Increased emphasis on testicular examination is the recommended follow up for men identified with testicular microlithiasis.     

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.     

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.     

胎儿睾丸组织异种移植后生精细胞发育初探

目的 :以人胎儿睾丸组织为供体 ,免疫缺陷小鼠为受体 ,研究人类睾丸生精细胞异种移植后的继续发育情况。　方法 :将 2 6周胎儿的睾丸组织植入去势裸鼠背部 ,于移植后 1 35d取出移植物 ,进行组织形态学观察 ,分析原始生精细胞在异种异位的发育情况。　结果 :移植 1 35d后取出的移植物显示 ,其生长幅度已由移植前直径约 1mm和湿重约 5mg ,分别增加到移植后大于 3mm和 2 0mg。组织形态学观察发现 ,移植前的睾丸主要是由直径为(6 0± 1 5 ) μm的精曲小管索构成 ,其中包含的细胞主要是原始Sertoli细胞和少量原始生精细胞 ,细胞排列呈弥散无规则状态 ;而移植后 1 35d的精曲小管索已发育成具有管腔的精曲小管 ,出现由Sertoli细胞和生精细胞组成的完整生精上皮 ,直径增大到 (80± 2 5 ) μm。原本呈不规则分布的原始Sertoli细胞和生精细胞大部分已迁移到基膜处 ,其中有少数生精细胞发育成为精原细胞。　结论 :人胎儿睾丸组织移植到去势裸鼠背部后 ,可以继续存活并进一步生长发育。     

Current management strategies for testicular microlithiasis

The association of testicular microlithiasis with testicular tumor and the management of incidentally detected testicular microlithiasis have generated a great deal of interest. We review the current literature on testicular microlithiasis with regard to its association with testicular tumor. This association seems complex. The available data suggest that men with incidental findings of testicular microlithiasis but who have otherwise normal testes are at low risk of developing testicular cancer. The only follow-up recommended is regular testicular self-examination. Testicular microlithiasis is, however, associated with a high risk of developing testicular malignancy in men with subfertility, history of contralateral testicular tumor or history of cryptorchidism. Regular testicular self-examination is recommended for follow-up of high-risk patients, but the role of surveillance with serial ultrasonography and measurement of tumor markers is still not clear.     

Testicular microlithiasis: a review and its association with testicular cancer

Testicular microlithiasis (TM) is an entity of unknown etiology that results in the formation of intratubular calcifications. It is of concern to the urologist because of its possible association with intratubular germ cell neoplasia and testicular germ cell cancer. Although commonly present in patients with germ cell tumors, there appears to be no definitive association with TM and cancer. Therefore, follow-up at this time should be dictated based on risk factors for developing testis cancer more than on the presence of TM.     

Spermatogenese

Spermatogenesis takes place within the testicular seminiferous tubules which consist of the peritubular lamina propria and the seminiferous epithelium. The latter is composed of germ cells and somatic Sertoli cells. Sertoli cells trigger germ cell development by mediating follicle-stimulating hormone and androgen hormonal stimuli. Spermatogenesis comprises proliferation of spermatogonia, meiosis of spermatocytes, and differentiation of spermatids into spermatozoa (spermiogenesis). There are six distinct and specific germ cell associations (I–VI). These “stages of spermatogenesis” occur sequentially along the length of a tubule. Different defects in spermatogenesis occur in adjacent seminiferous tubules (mixed atrophy) and are associated with deficits in differentiation of Sertoli cells. Biopsy specimens should be fixed in Bouin’s solution. Diagnosis of preinvasive carcinoma in situ is based on the immunohistochemical demonstration of placental-like alkaline phosphatase (PLAP), which is expressed exclusively in carcinoma in situ cells. Histological evaluation should be performed using a score count system, and the use of histological techniques for protein and mRNA expression. Testicular biopsy should only be performed in accordance with strict indication criteria, and histological evaluation should be carried out in specialist centres, i.e. as recommended by the European Academy of Andrology (EAA).     

Spermatogenesis--physiology and pathophysiology

Spermatogenesis takes place within the testicular seminiferous tubules which consist of the peritubular lamina propria and the seminiferous epithelium. The latter is composed of germ cells and somatic Sertoli cells. Sertoli cells trigger germ cell development by mediating follicle-stimulating hormone and androgen hormonal stimuli.Spermatogenesis comprises proliferation of spermatogonia, meiosis of spermatocytes, and differentiation of spermatids into spermatozoa (spermiogenesis). There are six distinct and specific germ cell associations (I-VI). These "stages of spermatogenesis" occur sequentially along the length of a tubule. Different defects in spermatogenesis occur in adjacent seminiferous tubules (mixed atrophy) and are associated with deficits in differentiation of Sertoli cells. Biopsy specimens should be fixed in Bouin's solution. Diagnosis of preinvasive carcinoma in situ is based on the immunohistochemical demonstration of placental-like alkaline phosphatase (PLAP), which is expressed exclusively in carcinoma in situ cells. Histological evaluation should be performed using a score count system, and the use of histological techniques for protein and mRNA expression. Testicular biopsy should only be performed in accordance with strict indication criteria, and histological evaluation should be carried out in specialist centres, i.e. as recommended by the European Academy of Andrology (EAA).     

The rat testis produces large amounts of an interleukin-1-like factor

Homogenates of whole testis, isolated seminiferous tubules, testicular cytosol, conditioned media from seminiferous tubules obtained from intact or cryptorchid rats, as well as seminiferous tubules devoid of peritubular cells, showed high concentrations of interleukin-1 (IL-1). Cytosol from spleen showed low IL-1 activity, while no activity was found in cytosol from heart, kidney, prostate, ovary or liver. Interleukin-1 activity was not detected in spent medium from cultures of immature Sertoli cells (10-day-old rats) or from peritubular cells or in homogenates of interstitial cells from adult rats. Ultrogel AcA 44 gel chromatography and HPLC size exclusion chromatography exhibited a single peak of IL-1 activity corresponding to a relative molecular mass of 17,000-20,000 (Mr = 17-20 K). Similarly, chromatofocusing revealed only one peak of activity with an apparent isoelectric point of 5-6. It is concluded that the rat testis contains large amounts of an IL-1 alpha-like factor. The adult Sertoli cell or possibly germ cells are suggested as its primary source. Testicular IL-1-like activity is of particular interest in view of the intense cell proliferation during spermatogenesis, and the tendency to testicular relapse of acute lymphoblastic leukaemia.     

Exploration for testicular remnants: implications of residual seminiferous tubules and crossed testicular ectopia

PURPOSE: Testicular remnants identified during exploration for cryptorchidism contain vascularized fibrous nodules at the termination of the vas deferens, hemosiderin, calcification, a pampiniform plexus or occasionally residual seminiferous tubules that may contain germ cells. An absent testis lacks the features of testicular remnants. To our knowledge testicular remnants have not been described in a crossed ectopic location. We reviewed orchiectomy specimens obtained at exploration for a nonpalpable testis to characterize the features of testicular remnants, including the frequency of seminiferous tubules, germ cells and crossed ectopia, as well as to clarify the diagnostic criteria for testicular remnants. MATERIALS AND METHODS: From 1990 to mid 2000 medical records and histological slides from 101 boys with nonpalpable testes who had undergone inguinal exploration and orchiectomy were reviewed. RESULTS: Of the 71 testicular remnants identified 7 (9.8%) contained residual tubules, of which 4 (5.6%) contained germ cells. In 4 boys the testis was deemed absent but 3 did not undergo laparoscopic exploration. There were 2 ectopic remnants (2.8%) on the contralateral side-the pelvis or in the scrotum. Both crossed remnants demonstrated dissociation of the testis from the vas/epididymis which remained on the correct side associated with a pampiniform plexus. No müllerian remnants were encountered. CONCLUSIONS: Adequate exploration for nonpalpable testis requires laparoscopy with visualization of the contralateral pelvic region because an ectopic remnant may be dissociated from the vas/epididymis and vessels. Identification of a pampiniform plexus, vas and spermatic vessels may not be a reliable indicator of a testicular remnant. Continued removal of testicular remnants is warranted because at least 9.8% contain residual viable tubules.