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.     

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.     

超声鉴别诊断不同类型的睾丸恶性肿瘤

目的探讨超声鉴别诊断不同类型睾丸恶性肿瘤的价值。方法回顾性分析超声和术后病理证实为睾丸恶性肿瘤患者的资料。结果90例睾丸恶性肿瘤患者中,精原细胞瘤（50例）多表现为患侧睾丸增大,内见不均匀低回声;非精原细胞性生殖细胞肿瘤（胚胎癌5例、卵黄囊瘤2例、畸胎瘤2例、混合型生殖细胞肿瘤8例）多有程度不同液化及粗大钙化;非生殖细胞肿瘤（共9例）呈形态规则、边界清晰的低回声;而淋巴瘤10例、横纹肌肉瘤2例、类癌2例未见明显特征性表现。结论不同类型睾丸恶性肿瘤的超声表现各有特点。结合患者年龄、血清肿瘤学检查对临床判断睾丸恶性肿瘤类型具有一定意义。     

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.     

An immunohistochemical study on neuron specific enolase in testicular germ cell tumors]

Testicular germ cell tumors obtained from 44 patients were immunohistochemically studied using anti-neuron specific enolase (NSE) antibody. The level of NSE in the serum was also measured in 9 patients before and after extirpation of the tumor. As for tumor cells of seminoma, 19 of 20 pure seminomas and all 9 of mixed type were positive for NSE. On the contrary, a spermatocytic seminoma was NSE-negative. As for embryonal carcinomas, some tumor cells were NSE-positive in 13 of 15 of mixed type. In yolk sac tumor, a few tumor cells were also NSE-positive in 8 of 21 of both pure and mixed types. Some NSE-positive cells were found in teratomatous components of 10 of 14 mature and immature teratomas of both pure and mixed types. These were in neural cells, chondrocytes, and glandular epithelial cells. Spermatogonia in 5 normal testes were NSE-positive. NSE level in the serum was elevated before extirpation and decreased after extirpation in 4 of 5 cases of seminoma of pure type and in 1 of 2 of mixed type which included seminomatous elements. All of these cases were either in the advanced stage or had a rather large primary tumors. Immunohistochemical study of testicular germ cell tumors using anti-NSE antibody may facilitate histological diagnosis, and serum NSE level may be useful for monitoring the clinical course as well as for clinical diagnosis of seminoma.     

Expression of human chorionic gonadotropin in testicular germ cell tumors

BackgroundWe have shown that most patients with seminomas have elevated serum concentrations of the free β subunit of human chorionic gonadotropin (hCGβ) and that in nonseminomatous testicular cancer, most of the hCG in the serum is hyperglycosylated (hCG-h). However, the tissue expression of hCG-h or hCGβ in germ cell tumors (GCTs) has not been reported. Our objective was to study the expression and diagnostic value of hCG-h and hCGβ in testicular GCTs.MethodsWe studied the immunohistochemical expression of hCG, hCG-h, hCGβ, and the free α subunit of hCG (hCGα) in GCTs from 154 patients. We compared the tissue expression with serum concentrations and evaluated the correlation between staining intensity, established prognostic variables, and outcome.ResultsThe expression varied between tumor types. All forms of hCG, including hCG-h, were detected in embryonal carcinomas (22%) and mixed GCTs (48%). Polyclonal hCG and monoclonal hCGβ antibodies detected immunoreactivity in some seminomas (7%). No form of hCG was found in spermatocytic seminomas, pure teratomas, or a yolk sac tumor. The serum concentrations correlated with the corresponding tumor expression. The staining intensities of hCG, hCGβ, hCG-h, and hCGα correlated with disease stage but not significantly with relapse, disease-related mortality, or progression-free survival.ConclusionTrophoblastic tissue expresses hCG, hCG-h, and free subunits together whereas seminoma tissue occasionally expresses hCGβ. This difference might aid in differential diagnosis of some difficult-to-classify cases.     

Localization of alpha-fetoprotein and human chorionic gonadotropin to specific histologic types of nonseminomatous testicular cancer

We used an indirect immunoperoxidase technique to localize alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) to specific histologic types of testicular germ cell cancers. Among 20 nonseminomatous tumors studied, yolk sac tumor reacted for AFP in 13 of 15 cases, teratoma in 3 of 11 cases, and embryonal carcinoma in 3 of 14 cases. Syncytiotrophoblasts alone reacted for HCG in 14 of 15 cases, and syncytiotrophoblasts associated with choriocarcinoma reacted for HCG in 2 of 2 cases. There was a close correlation between the tissue demonstration of AFP and HCG and elevated serum levels of AFP and HCG, respectively. We conclude that in nonseminomatous testicular cancer yolk sac tumor is the primary site of synthesis of AFP, and syncytiotrophoblasts are the only site of synthesis of HCG.     

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.     

The frequency and histology of hepatic tissue in germ cell tumors

The frequency of hepatic tissue and its histological characteristics were examined in 516 germ cell tumors. Hepatic tissue was observed in 48 cases (9.3%). The incidence of hepatic tissue was low in tumors of the ovary (5%), high in both retroperitoneal (27%) and sacro-coccygeal (24%) tumors, and low in both mature (0.3%) and immature teratomas (11%). It was usually encountered in infancy, and the frequency was high in both yolk sac tumors (48%) and mixed germ cell tumors (52%). The hepatic tissue found mainly in mature or immature grade 1 teratomas was similar to adult normal human liver tissue (Ha-type). Tissue in areas consisting of some immature somatic elements of a mixed germ cell tumor was similar to embryonic or fetal liver tissue (Hf-type). Many hepatic nests found in a polyembryoma were of both Ha- and Hf-types. The hepatic tissue found in close relation to yolk sac elements showed predominantly hepatocellular carcinoma-like features (HCLS). Immunohistochemically, the cytoplasm of adult liver-type cells was positive for alpha-1-antitrypsin (AAT), human albumin (ALB), and the third (C3) and fourth (C4) components of the complement system. The cytoplasm of fetal liver-type cells showed the same positivity; in addition, these cells were positive for alpha-fetoprotein (AFP) in 25% of the cases. The cytoplasm of hepatic cells of HCLS was positive for AFP, AAT, ALB, C3, and C4. A weakly positive reaction for CEA and CA19-9 was observed in bile duct-like structure in some Hf-type cases.     

Oncofetal protein glypican-3 distinguishes yolk sac tumor from clear cell carcinoma of the ovary

Clear cell carcinoma (CCC) of the ovary is the surface epithelial neoplasm most often confused with primitive germ cell tumors, particularly yolk sac tumor (YST) and dysgerminoma. OCT3/4 has proven to be a sensitive and relatively specific marker for the latter entity, but existing markers for YST are limited. Recent studies suggest that glypican-3 (GPC3), an oncofetal protein expressed in fetal liver and malignant tumors of hepatocytic lineage, is also expressed in germ cell tumors, particularly YST. To investigate whether GPC3 is useful in distinguishing YST from ovarian CCC, we studied the expression of GPC3 in a large series of ovarian neoplasms and compared it to the expression profiles of CK7 and alpha-fetoprotein. Tissue microarrays containing over 400 benign and malignant ovarian neoplasms, including 34 CCCs were stained with monoclonal GPC3 (clone 1G12, Biomosaics, Burlington, VT). These arrays contained a wide assortment of ovarian surface epithelial neoplasms and sex cord stromal neoplasms, as well as germ cell tumors. Full paraffin tissue sections from 32 YSTs and 10 CCCs were also assessed. All but one YST (97%), including those associated with mixed germ cell tumor were positive for GPC3, whereas all teratomas and embryonal carcinomas were negative. Both cytoplasmic and membrane staining were present in the positive cases, with no background staining. The syncytiotrophoblastic cells in the germ cell tumors and placental villi included in the arrays were also positive for GPC3. Most CCCs (83%) were completely negative for GPC3, as were 99% serous, 94% endometrioid, and 100% mucinous tumors. Five CCCs exhibited focal, moderate to strong GPC3 expression and in 2 the expression was focal and weak. All other tissues, including normal ovary were negative for GPC3. GPC3 seems to be a promising diagnostic marker for differentiating YST from ovarian CCC (P < 0.0001). Because GPC3 may be associated with alpha-fetoprotein expression, further studies are required to determine the utility of GPC3 in differentiating YST from CCC with hepatoid differentiation.     

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.     

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.     

Biology of testicular tumors.

Testicular tumors arise from the germ cell line and therefore exhibit characteristics of both neoplastic and normal growth and differentiation. Experimental model systems of animal and human tumors have been reviewed with emphasis on the biologic characteristics of these tumors. The embryonal carcinoma cell is the totipotential stem cell that resembles normal germ cells in many ways and is capable of differentiating along the somatic pathways to form endoderm, mesoderm and ectoderm cell types (teratoma) or along extraembryonic pathways to form trophoblast (choriocarcinoma) or yolk sac (endodermal sinus tumor). Markers of the extraembryonic cell types have been defined, and the cell surface characteristics of embryonal carcinoma cells are being intensively studied. Clarification of the biology of testicular tumors will provide the basis for future rational therapy.     

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.     

Expression of SpanX proteins in normal testes and in testicular germ cell tumours

We investigated the expression of the SpanX protein family in cells of normal testes and in testicular germ cell tumours, mainly seminomas and embryonal carcinomas, using an immunohistochemical approach. Most of the normal germ cells, belonging to spermatogonial and primary spermatocytic classes, showed a strong nuclear positivity. In contrast, post-meiotic germ cells showed diffused cytoplasmic and sometimes also perinuclear localization of the signal. The vast majority of cells were also positive in eight seminomas, six embryonal cell carcinomas and one teratocarcinoma. In all seminomas, nuclei were either exclusively or preferentially labelled; whereas, the nuclear signal intensity decreased in parallel with the appearance of some cytoplasmic staining in embryonal carcinomas. In conclusion, these data suggest that the SpanX protein family is not exclusively expressed post-meiotically and that seminomas and embryonal carcinomas may originate from SpanX-positive carcinoma-in-situ cell.     

Yolk sac differentiation in germ cell tumors. A morphologic study of 50 cases with emphasis on hepatic, enteric, and parietal yolk sac features

We assessed 50 germ cell tumors with areas of yolk sac tumor (YST) for a variety of features including histologic patterns; hyaline droplets; syncytiotrophoblastic elements; hepatic, enteric, and parietal yolk sac differentiation; and granulomatous reaction. Of prime interest was the fact that many YSTs formed hepatic-like foci (22%), enteric-like glands (34%), and parietal yolk sac structures (92%). Hepatoid areas were characterized by nests and cords of polygonal, acidophilic cells with prominent nucleoli and intense cytoplasmic staining for alpha-fetoprotein. Enteric differentiation occurred as well-defined glands with a sharp, striated border and relatively bland nuclear features. Ultrastructurally these glands had apical microvilli with associated glycocalyx and long anchoring rootlets. The apical cytoplasm and luminal contents stained for carcinoembryonic antigen. Parietal yolk sac differentiation was characterized by the intercellular accumulation of basement membrane substance as generally thick and longitudinally arranged bands of eosinophilic material. Such material, by electron microscopy, was both intra- and extracellular, and had irregular outlines and inhomogeneous electron density. It contrasted with the strictly intracellular, round, homogeneous, hyaline globules that, we believe, represent visceral yolk sac differentiation. This intercellular material stained positively for laminin, a basement membrane component. Assessment of 22 embryonal carcinomas and 24 germinomas failed to show hepatic, enteric, and parietal yolk sac features, with one possible exception. We believe these features, especially parietal yolk sac differentiation, are helpful in differentiating YSTs from embryonal carcinomas and germinomas.     

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.     

Prepubertal testicular and paratesticular tumors in China: a single-center experience over a 10-year period

ObjectivePrepubertal testicular tumors are rare and fundamentally distinct from adult testicular tumors. We reviewed our 11-year experience in a single medical center of China.Material and MethodsThis study reports the clinical characteristics, histopathologic diagnosis, treatment methods, and outcome in a series of 63 prepubertal boys who were treated between 1997 and 2008.ResultsA total of 63 primary prepubertal testicular and paratesticular tumors were identified. The median age at presentation was 11 months. Of these tumors, 27 (42.9%) were mature teratomas, 5 (7.9%) were immature teratomas, 21 (33.3%) were yolk sac tumors, 4 (6.3%) were epidermoid cyst, 2 (3.2%) were Leydig cell tumors, 1 (1.6%) was a mixed malignant germ cell tumor, and 3 (4.8%) were paratesticular tumors. The most common clinical presentation (95.2%) was a painless scrotal mass or swelling. Forty-eight tumors were treated with radical inguinal orchiectomy, and 15, with a testis-sparing procedure. Follow-up was available in 59 cases, range from 4 to 128 months (median, 50 months). One patient with yolk sac tumor had recurrence and progression to metastasis at the end of 4 months after surgery. Other patients were disease free at last follow-up.ConclusionsMost of the prepubertal testicular lesions were benign, and the most common histologic subtype was teratoma. Our experience with testis-sparing procedures supports the current trends that less invasive treatment should be performed for benign lesions. This study confirms the excellent cure rates obtained in children with prepubertal testicular tumors.