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.     

Recent advances in the understanding of the pathology of testicular germ-cell tumors

Summary Most testicular cancers probably arise in intratubular germ cells. This article proposes that tumorigenesis involves two steps: activation of the germ cells, which can result either in simple proliferation (intratubular atypia) or in parthenogenetic development (teratomas), and malignant transformation, either simultaneously (embryonal carcinoma) of later (tumors with restricted developmental potential). The embryonal carcinoma cells then may be able to differentiate into the other types of nonseminomatous tumors according to the traditional schema. This model implies that histologically similar tumors have different origins and destinies. The clinical implications are discussed briefly.     

Fortschritte in der Grundlagenforschung bei testikulären Keimzelltumoren

Human testicular germ cell tumors (GCTs) comprise several types of neoplasias with different pathogenesis and clinical behavior, referred to as types I, II, and III. They represent different cells of origin, explaining their specific characteristics, including expression of markers useful for diagnosis. Here, the most frequent variant of testicular GCTs will be discussed, i.e., the type II GCT, referred to as TGCTs, i.e. seminomas and nonseminomas. Various risk factors have been identified. These tumors originate from a transformed primordial germ cell/gonocyte, known as carcinoma in situ (CIS), that is able to generate all differentiation lineages (omnipotent). The c-KIT-stem cell factor pathway is of relevance for development of this cancer. Retention of embryonic characteristics probably explains the unique treatment responsiveness to DNA-damaging agents. OCT3/4, a marker of pluripotency, is the optimal diagnostic marker for seminoma and embryonal carcinoma, and CIS, the latter also in semen, suitable for non-invasive screening. In addition, distinction between seminoma and embryonal carcinoma can be made using SOX17 and SOX2. Micro-satellite instability as well as BRAF mutations have been identified to be related to treatment resistance, possibly leading to improved clinical management.     

Intermediate trophoblast in germ cell neoplasms

One-hundred-twenty-four germ cell tumors and 11 gestational choriocarcinomas were assessed immunohistochemically for the presence of the following placental markers: human chorionic gonadotrophin, human placental lactogen, and pregnancy-specific beta-1 glycoprotein, and for the expression of cytokeratin. A total of 40 cases contained syncytial trophoblastic cells, large mononuclear cells, or both. These cases included all gestational choriocarcinomas and choriocarcinomatous foci in 11 mixed germ cell tumors, 14 embryonal carcinomas, and four seminomas. Syncytial trophoblastic cells reactive for cytokeratin were identified in all choriocarcinomas, 12 embryonal carcinomas, and two seminomas. Human placental lactogen-reactive syncytial trophoblastic cells were observed in nine gestational choriocarcinomas, 10 choriocarcinomatous foci in mixed germ cell tumors, four embryonal carcinomas, and one seminoma. Pregnancy-specific beta-1 glycoprotein-reactive syncytial trophoblastic cells were seen in 10 gestational choriocarcinomas, all choriocarcinomatous foci in mixed germ cell tumors, 11 embryonal carcinomas, and one seminoma. Cytotrophoblasts, as expected, were identified only in choriocarcinomas. Cytokeratin-reactive cytotrophoblast was seen in all gestational choriocarcinomas and 10 choriocarcinomatous foci in mixed germ cell tumors. Human chorionic gonadotrophin-reactive cytotrophoblast was observed in two gestational choriocarcinomas and three choriocarcinomatous foci in mixed germ cell tumors. Cytotrophoblast was uniformly nonreactive for human placental lactogen and pregnancy-specific beta-1 glycoprotein. Cytokeratin-reactive large mononuclear cells were observed in 10 gestational choriocarcinomas, all choriocarcinomatous foci in mixed germ cell tumors, five embryonal carcinomas, and three seminomas. Human placental lactogen-reactive large mononuclear cells were identified in nine gestational choriocarcinomas, seven choriocarcinomatous foci in mixed germ cell tumors, one embryonal carcinoma, and one seminoma. Pregnancy-specific beta-1 glycoprotein-reactive large mononuclear cells were present in 10 gestational choriocarcinomas, 10 choriocarcinomatous foci in mixed germ cell tumors, two embryonal carcinomas, and two seminomas. Because of morphologic and immunohistochemical similarities of large mononuclear cells with intermediate trophoblast of the normal placenta and gestational trophoblastic neoplasms, we propose that the large mononuclear cells in gonadal and extragonadal germ cell neoplasms are equivalent to the intermediate trophoblast.     

Molecular genetic parameters in pathogenesis and prognosis of testicular germ cell tumors

Aim of this review article was to critically analyze the recently described cytogenetic and molecular markers for testicular germ cell tumors with regard to their clinical utility. The isochromosme i(12p) represents the most common and characteristic cytogenetic finding which already appears in testicular carcinoma in situ. A number of proto-oncogenes (cyclin D and PTHLH) as well as putative tumor suppressor genes are localized on 12p; however, their role in pathogenesis and prognosis of testicular germ cell tumors has not been defined yet. Clinical characteristics of patients with familial testicular germ cell tumors indicate a genetic background for the development of testicular tumors. Although a number of chromosomal loci encoding potential testicular tumor susceptibility genes have been identified, the genetic basis of testicular cancer pathogenesis is still unknown. With regard to molecular prognostic risk factors most of the reported data on proliferation markers, tumor suppressor genes, proteases and adhesion molecules have to be confirmed in prospective randomized trials prior to their widespread clinical use. Based on the available data on prospective studies the percentage of embryonal carcinoma and vascular invasion appear to be the most significant prognosticators. Investigation and identification of those factors determining the aggressive biologic behavior of embryonal carcinoma compared to all other histological components appear to be most promising in the research for prgnosticators of metastatic disease. In conclusion, the increasing knowledge of molecular genetic events involved in pathogenesis and prognosis of testicular germ cell tumors will not only help to better understand development and progression of testicular cancer, but it will also define new approaches to classification and management of germ cell tumors     

Primary mediastinal germ cell tumors

The most frequent site of extragonadal germ cell tumors is the mediastinum. The majority (80%) of mediastinal germ cell tumors are benign mature teratomas, which can be easily removed. Malignant germ cell tumors account for approximately 20% of all cases and are clinically classified into seminoma and non-seminomatous germ cell tumors. Seminomas are radiosensitive and have relatively a good prognosis. Patients with non-seminomatous germ cell tumors had a very poor prognosis, however, the introduction of cis-platinum based chemotherapy has improved the prognosis of patients with these tumors. Three hundred twenty nine cases of malignant mediastinal germ cell tumors have been described in the literature and reports up to 1988 in Japan. The types and cases are following: [table: see text] Multi-drug chemotherapy with cis-platinum has improved the prognosis of patients with embryonal carcinoma and yolk sac tumors, although patients with choriocarcinoma have yet a poor response to the combination chemotherapy. Five year survivors have consisted of 19 patients with seminomas and five patients with non-seminomatous germ cell tumors. Most long survival patients have undergone surgical resection of tumors. The results suggested that the improvement for prognosis requires earlier prognosis and complete surgical removal of tumors associated with chemotherapy combining further effective regimens.     

Vasculogenesis and angiogenesis in nonseminomatous testicular germ cell tumors

Testicular germ cell tumors (TGCTs) comprise the vast majority of all testicular malignancies and are the most common type of cancer among young male adults. The nonseminomatous variant of TGCTs is characterized by the presence of embryonic and extraembryonic tissues together with a population of pluripotent cancer stem cells, the so-called embryonal carcinoma. One of the main causes of the resistance of these tumors to therapy is their ability to invade adjacent tissues and metastasize into distant sites of the body. Both of these tumor processes are highly favored by the neovascularization of the malignant tissue. New vessels can be generated by means of angiogenesis or vasculogenesis, and both have been observed to occur during tumor vascularization. Nevertheless, the precise contribution of each process to the neoplastic vascular bed of TGCTs remains unknown. In addition, another process known as tumor-derived vasculogenesis, in which malignant cells give rise to endothelial cells, has also been reported to occur in a number of tumor types, including experimental TGCTs. The participation and cross talk of these 3 processes in tumor vascularization is of particular interest, given the embryonic origin of teratocarcinomas. Thus, in the present review, we discuss the importance of all 3 vascularization processes in the growth, invasion, and metastasis of testicular teratocarcinomas and summarize the current state of knowledge of the TGCT microenvironment and its relationship with vascularization. Finally, we discuss the importance of vascularization as a therapeutic target for this type of malignancy.     

Epigenetics: A way to understand the origin and biology of testicular germ cell tumors

Testicular germ cell tumors are neoplasms carrying two unique features. First, testicular germ cell tumors have a pluripotential nature and show protean histology ranging from that of germ cells to embryonal and differentiated somatic cells. Therefore, testicular germ cell tumors are interesting resources positioned at a crossroad in developmental and neoplastic processes. The second unique feature of testicular germ cell tumors is their exquisite sensitivity to cisplatin‐based chemotherapy. This review summarizes recent research progress in the epigenetics of testicular germ cell tumors in an attempt to explain the abovementioned biological and clinical characteristics of testicular germ cell tumors.     

Nestin expression in central nervous system germ cell tumors

Central nervous system (CNS) germ cell tumors constitute a unique class of rare tumors that mainly affect children and adolescents. These tumors are believed to originate from displaced primordial germ cells. Recently, results of treatment of germ cell tumors have improved with use of radiotherapy and combination chemotherapy. However, some tumors have proven refractory to intensive treatment with surgery, radiation, and combination chemotherapy. Nestin is an intermediate filament protein expressed in undifferentiated cells during CNS development and in CNS tumors and is used as a marker of immature elements of tumors, including brain tumor stem cells. In this study, we examined for the first time nestin expression in 19 CNS germ cell tumors (nine pure germinomas, five germinomas with syncytiotrophoblastic giant cells, one yolk sac tumor, one choriocarcinoma, one embryonal carcinoma, and two mature teratomas). Nestin was expressed in 14 cases but was not expressed in three pure germinomas and two mature teratomas. Clinically, nestin-negative tumors did not exhibit dissemination, while all tumors that exhibited dissemination also strongly expressed nestin protein. These findings suggest that the detection of nestin expression could be useful in the management of CNS germ cell tumors, as an auxiliary predictor of dissemination and/or progression.     

Mediastinal germ cell tumors in childhood. A clinical and pathological study of 21 cases

Twenty-one patients aged 16 years or less had been treated for a primary mediastinal germ cell tumor at the Children's Hospital, Boston Massachusetts, during the last 54 years. There were 13 boys and eight girls with the average age at diagnosis being 7 years (range 2 weeks to 16 years). Twelve mediastinal germ cell tumors were classified as pure teratoma, five contained embryonal carcinoma admixed with other germ cell components, and four were pure embryonal carcinoma. Of 12 patients with pure teratoma, 10 underwent complete surgical resection and were alive and well 1 to 13 years later; two children left untreated died of complications related to local tumor growth. Complete surgical resection was possible for only two of nine patients with embryonal carcinoma; both received adjuvant therapy and were alive and well 3 and 20 years later. Seven patients received radiation and/or chemotherapy but died of residual or metastatic disease. Successful treatment for children with embryonal carcinoma requires an operation aimed at either debulking or complete resection (if possible) coupled with early and aggressive combination chemotherapy. The role of radiation in primary therapy remains undefined with regard to curative intent.     

Diffuse embryoma of the testis. A distinctive form of mixed germ cell tumor

Two testicular tumors characterized by a diffuse, orderly arrangement of embryonal, yolk sac, and trophoblastic elements are described as examples of a newly recognized form of mixed germ cell neoplasia. In one case, ribbons of embryonal carcinoma and yolk sac tumor wound around one another to create a distinctive necklace pattern. In the second case, differentiation of the yolk sac component was more advanced with the formation of numerous clusters of cells resembling hepatocytes. Tumors with these patterns are appropriately designated diffuse embryomas to distinguish them from polyembryomas and other forms of malignant mixed germ cell tumor.     

Distribution of pituitary adenylate cyclase‐activating polypeptide (PACAP) in the human testis and in testicular germ cell tumors

Pituitary adenylate cyclase‐activating peptide (PACAP) is a neuropeptide expressed in the central nervous system and peripheral organs. Previous studies revealed the role and distribution of PACAP in the rodent testis, however, its presence in the human testis and in testicular germ cell tumors is not known. We used RT‐PCR and immunohistological observations to investigate whether human testicular tissue and testicular germ cell tumors contain PACAP. The mRNAs for PACAP and its receptors were detected in total RNA extracted from human testes. PACAP immunoreactivity was observed in spermatogonia and spermatids from normal testes. In contrast, diffuse PACAP immunopositivity was observed in seminoma tumor cells, while only faint immunoreactivity was observed in embryonal carcinoma cells. Our data suggest that PACAP may play a role in human spermatogenesis and in testicular germ cell tumor development.     

Significance of DNA quantification in testicular germ cell tumors

A cytophotometric quantification of DNA in tumor cells was performed in histological sections of orchidectomy specimens from 36 men with testicular germ cell tumors (TGCT), 7 of them showing more than one tumor type. Among the variants of seminoma (classic and spermatocytic) the lowest DNA content were in spermatocytic seminoma. With respect to non-seminomatous tumors (yolk sac tumor, embryonal carcinoma, teratoma, and choriocarcinoma), choriocarcinomas showed the highest DNA content, and the lowest value was found in teratomas. No significant differences were found between the average DNA content of seminomas (all types) and non-seminomatous tumors (all types). Both embryonal carcinoma and yolk sac tumor showed similar DNA content when they were the sole tumor and when they were found associated with other tumors. In this study, except for the 4 cases of teratoma and the case of spermatocytic seminoma, all TGCT examined did not show modal values of DNA content in the diploid range. Such an elevated frequency of aneuploidism in these tumors may be helpful for their diagnosis.     

Sonographically-Detected Impalpable Testicular Cancer with Retroperitoneal Bulky Metastases: A Case Report

We report a case of a sonographically-detected impalpable embryonal cell carcinoma with bulky retroperitoneal metastases. A 34-year-old man, who presented with left flank pain, was presumed to have an extragonadal retroperitoneal germ cell tumor. Scrotal sonography revealed a hypoechoic lesion, 7 mm in diameter, which was histologically diagnosed as a primary embryonal cell carcinoma. Evidence suggested that the primary tumor had grown slowly, as the tumor was well encapsulated. This case suggests that some extragonadal germ cell tumors arise from a primary testicular cancers, and that successful treatment of these tumors should include consideration that they may have arisen as a primary testicular mass.     

Histology in mixed germ cell tumors. Is there a favorite pairing?

PURPOSE: Mixed germ cell tumors account for approximately 30% to 50% of testicular tumors. To our knowledge a systematic review with statistical analysis of the associations of histological subtypes in mixed germ cell tumors has not been done previously. It was our impression that such associations exist. Delineating concordant histological types may provide insight into the ontogeny of testicular tumors and also have important clinical implications. MATERIALS AND METHODS: We retrospectively reviewed the testis cancer data base at our institution. The primary tumor of orchiectomy specimens was examined in 2589 patients. Of these patients mixed histology was noted in 1765 (68.2%). ORs were calculated for all possible combinations of teratoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma and seminoma. In addition, we evaluated the association of various histological types with teratoma at post-chemotherapy retroperitoneal lymph node dissection. RESULTS: Of 10 possible combinations of histological types in the primary tumor, positive correlations were noted in 4. The strongest correlation was found between teratoma and yolk sac tumor (OR 2.58, p <0.001). Teratoma or yolk sac tumor in the testis was associated with teratoma in the pathology specimen at post-chemotherapy retroperitoneal lymph node dissection. CONCLUSIONS: The strongest associations of histological subtypes in mixed germ cell tumors were seen between yolk sac tumor and teratoma. Similar associations are seen in late relapse and in some cases of prepubertal tumors. Further study of these associations may prove valuable in understanding the biology and clinical behavior of germ cell tumors.     

Observation policy for residual masses after chemotherapy for gonadal and extra-gonadal germ cell tumors

Twenty-five patients with germ cell tumors who had marker-free residual masses after undergoing chemotherapy were followed for up to 10 years (median, 21 months). The primary tumor sites were the gonads in 20 patients (6 seminomas [SGCTs] and 14 non-seminomatous germ cell tumors [NSGCTs]) and extra-gonadal regions in 5 patients (5 NSGCTs). All residual masses were observed in patients with SGCT. Residual masses that were 2 cm or less in size were left unresected, while masses that were 5 cm or more in size were resected in patients with NSGCT lesions. The management of other residual masses was decided based on the size, shrinkage, and pathological findings of the tumors. Residual masses were resected in six of the patients with gonadal NSGCTs. Recurrence occurred in one of the six patients with gonadal SGCTs (chemotherapy shrinkage; 11 cm to 3.5 cm) and three of the four cases with extra-gonadal NSGCTs (embryonal cell carcinoma: 3 cm to 1 cm, embryonal cell carcinoma+york sac tumor: 5 cm to 4 cm, embryonal cell carcinoma+chorio carcinoma; 4 cm to 1.2 cm). None of the patients with gonadal NSGCTs experienced a recurrence. Considering the pathologic diagnosis, shrinkage, and international germ cell consensus classification, unnecessary resections of residual masses that were less than 5 cm in size after chemotherapy for gonadal NSGCT should be avoided. However, residual masses in extra-gonadal NSGCTs should be resected.     

CLINICAL STAGE I TESTIS CANCER: LONG-TERM OUTCOME OF PATIENTS ON SURVEILLANCE

Purpose

The long-term outcome results of a prospective surveillance trial for clinical stage I nonseminomatous germ cell tumors of the testis (NSGCT) are reported in an effort to define the natural history of clinical stage I testis cancer treated with orchiectomy alone, and to determine if a subset of patients exists that may be suitable for surveillance.

Materials and Methods

Between September 1979 and December 1987, 105 patients were entered into the study. Patients with persistent elevation of serum tumor markers (AFP, BHCG, and LDH) following orchiectomy, stage T2-T4 primary tumors, any evidence of metastases and pure choriocarcinoma or pure seminoma on histology were excluded from study. Enrolled patients underwent periodic physical examination, serological testing and radiological imaging according to an established protocol.

Results

Median followup was 11.3 years. Of the patients 78 (74.3%) have remained disease-free and 27 (25.7%) have experienced relapse. Of the patients with relapse 24 are currently disease-free after treatment for relapse for a median duration of 10.8 years and 3 (2.8%) died of disease. All relapses occurred within 24 months of orchiectomy (median 5 months). Significant predictors of relapse during surveillance were a predominant embryonal carcinoma histology (p = 0.016) and vascular invasion (p = 0.0005). In patients with neither embryonal carcinoma nor vascular invasion the relapse rate was 12%, and no patients died of disease.

Conclusions

With extended followup 74% of men with clinical stage I (T1) nonseminomatous germ cell tumor of the testis were cured by orchiectomy alone, and cure rates approached 90% when patients with predominant embryonal carcinoma histology or vascular invasion were excluded from surveillance. These findings support management by surveillance alone in a highly select cohort of men who have clinical stage I (T1) nonseminomatous germ cell tumor of the testis, normal serum markers following orchiectomy and neither predominant embryonal carcinoma or vascular invasion on histology.     

Malignant germ cell tumors of the mediastinum

A review of 56 cases of primary malignant germ cell tumors of the mediastinum revealed that, as with benign teratomas, the tumors occurred in young adults (mean age 29 years) but that the sex distribution differed (86% male and 14% female). A single germ cell element was found in 37 (66%) of the tumors, and various combinations were present in the remaining 19 (34%). The tumors were classified among five recognized types of germ cell tissues. There were 24 seminomas (22 pure and two with mature teratomas), 17 embryonal carcinomas (nine pure and eight with mixtures), five teratomas, seven choriocarcinomas (three pure and four with mixtures), and three pure yolk sac tumors. Most (86%) of the patients were symptomatic at the initial examination, with chest pain, cough, and loss of weight being the most frequent presenting symptoms. The standard posteroanterior and lateral roentgenograms were the most helpful diagnostic tool, showing evidence of an anterior mediastinal mass in 53 patients. The diagnosis was established by surgical exploration of the mediastinum or by biopsy of a lymph node in 55 patients. Of the 55, 24 (43.6%) had complete resection of the tumor and 31 (56.4%) had incomplete resection or biopsy alone. The overall prognosis for mediastinal germ cell tumors is poor, partly because the tumors are far advanced at the time of diagnosis but also because some of the tumors that contain embryonal cell carcinoma, choriocarcinoma, and yolk sac elements are very aggressive. Factors that were prognostic in patients with seminoma--such as age, presence of the superior vena caval syndrome, lymphadenopathy, evidence of hilar disease on the chest roentgenogram, and resectability--were not predictive in patients with other types of malignant germ cell tumors. Although aggressive combination chemotherapy may represent a significant treatment modality for nonseminomatous mediastinal tumors, the present study spanned many years in which no chemotherapy was available. Patients in the later years of the study received combination chemotherapy with various treatment regimens. No conclusions concerning specific chemotherapy, therefore, can be derived from this study.