Intratubular germ cell neoplasia of unclassified type occupying the whole testis accompanied by a small mature teratoma and metastatic choriocarcinoma and Sertoli cell-only tubules in the other testis

A 19-year-old man with mild mental retardation was diagnosed as having metastatic choriocarcinoma and a testicular tumor. Histopathological examination of the resected testis revealed the presence of a small lesion of mature teratoma but no trace of choriocarcinoma. The remaining seminiferous tubules were atrophic and lined by large atypical germ cells, which were diagnosed as intratubular germ cell neoplasia of the unclassified type (IGCNU). A small area with prominent tubules was also observed. Within this lesion, the tubules were dilated and contained several layers of cells with central necrosis. Immunohistological comparison of staining for several biological markers (Ki-67, c-kit and placental alkaline phosphatase) between cells in the atrophic tubules and those in the dilated tubules indicated a progression of the latter cells to cells with a more proliferative ability. In the opposite testis, examined at autopsy after death due to metastatic choriocarcinoma, all seminiferous tubules were lined by Sertoli cells only. It was therefore assumed that the germ cell tumor of the combined histological type had primarily arisen in the background of IGCNU, and that choriocarcinoma had spontaneously regressed. The early onset of these testicular neoplastic lesions strongly indicates their occurrence under the genetic background of gonadal dysplasia, the Sertoli cell-only syndrome. The possible relation of gonadal disease to mental retardation in this patient is also discussed.     

Cytogenetic analysis of the mature and immature teratoma components of a metastatic testicular nonseminomatous germ cell tumor.

A case is described in which the mature and immature teratoma components of metastases of the same testicular nonseminomatous germ cell tumor were karyotyped. The highly similar karyotypes of both components suggest that the phenotypic difference is predominantly epigenetically determined.     

Chromosome changes in germ cell tumors of the testis

Chromosome analysis was performed on short-term cultures established from samples of six tumors of the testis. Histologically, four tumors were embryonal cell carcinomas (three primary, one metastatic) and two of mixed histology with predominance of teratoma. The modal chromosome number was hypotriploid in four tumors, triploid in one, and hypertriploid in another. All tumors contained structurally abnormal chromosomes, ranging in number from 1 to 10 in different cases. A small metacentric marker chromosome, identified as an isochromosome of the short arm of chromosome #12 [i(12p)], was present in all tumors analyzed. Unlike other marker chromosomes, this one was invariably present in at least two copies per metaphase in all cases; all other chromosome markers were present in single copy in all tumors. Together with the previous reports on the presence of i(12p) in seminoma and teratoma of the testis, our findings suggest that this karyotypic abnormality is characteristic for all histologic varieties of germ cell tumors of the testis.     

Bowel loop in an ovarian tumor: Grossly visible, completely developed intestinal loop in mature cystic teratoma of malignant mixed germ cell tumor

Although a gastrointestinal-type epithelium is observed in 7–13% of mature cystic teratoma cases, the occurrence of a grossly visible, organized gastrointestinal loop formation is very rare. Presented here is the case of a 14-year-old girl with malignant mixed germ cell tumor in the ovaries. In her left ovary a grossly visible, intestinal loop, 9 cm long, with hanging mesentery attached to the cystic wall of a mature cystic teratoma associated with a yolk sac tumor was observed, and in her right ovary another mature cystic teratoma was observed. Microscopy of the intestinal loop indicated a well-organized, intact layer of small intestinal wall. The yolk sac tumor predominantly had a polyvitelline pattern. Previously, gastrointestinal wall or epithelium that was identified on microscopy has been reported. To the authors' knowledge this is the first case report of the formation of a grossly visible, completely developed intestinal loop in a malignant mixed germ cell tumor.     

Intratubular germ cell neoplasia in an infantile testis with immature teratoma

A case of intratubular germ cell neoplasia adjacent to an immature teratoma is described in an 8-month-old boy with normally descended testes. The pattern of intratubular germ cell neoplasia in the infantile testis appeared different from that in the adult, but the abnormal germ cells were morphologically and immunohistochemically similar. In the few previous reports, which have investigated infantile testicular tissue for the presence of intratubular germ cell neoplasia adjacent to germ cell tumours, intratubular germ cell neoplasia in conjunction with a yolk sac tumour and mature teratoma have not been found, and cases with immature teratoma have not been reported. The presence of intratubular germ cell neoplasia in conjunction with immature teratoma and its apparent absence in conjunction with the mature form and with yolk sac tumour may indicate difference in tumour development. Whether there is a true difference in the occurrence of intratubular germ cell neoplasia in the infantile testis according to the various types of germ cell tumours remains, however, to be proven by investigations of more cases.     

Teratoma with somatic-type malignant components in germ cell tumors of the testis: a clinicopathologic analysis of 40 cases with outcome correlation

Teratoma with a malignant somatic component (MSC) is a rare phenomenon recognized when a somatic type malignancy occurs in the context of a germ cell tumor (GCT). The authors present their 29-year experience with 40 patients treated from 1981 to 2009 in their institution. The average age was 31 years. All patients underwent radical orchiectomy, which demonstrated a GCT in 19 with an MSC. The MSC was observed in the other 21 cases in metastatic sites, including lung (13), liver (3), pleura (1), mediastinum (7), supraclavicular lymph nodes (1), and retroperitoneal lymph nodes (9). The most common histologic types were rhabdomyosarcoma (n = 11) and primitive neuroectodermal tumors (n = 10), followed by adenocarcinoma (n = 9), sarcoma, not otherwise specified (n = 5), well-differentiated liposarcoma (n = 2), leiomyosarcoma (n = 2), chondrosarcoma (n = 2), nephroblastoma (Wilms's tumor), carcinoid, malignant peripheral nerve sheath tumor, and a gemistiocytic astrocytoma with choroid plexus tumor (each n = 1). Clinical data were collected through a dedicated database and are available for all 40 cases. After a median follow-up of 37 months, 29/40 (72.5%) were alive and disease-free. Stage-specific survival was 100% for stage I, 87.5% for stage II, and 53% for stage III patients suggesting that patients with MSC confined to the testis have a good prognosis. A lower sensitivity to chemotherapy for a MSC when compared with typical GCT is reported. Surgical excision of the MSC is therefore an essential part of the management.     

N-cadherin expression in malignant germ cell tumours of the testis

Background

Testicular germ cell tumours (TGCTs) are the most common malignancy in young men aged 18–35 years. They are clinically and histologically subdivided into seminomas and non-seminomas. Cadherins are calcium-dependent transmembrane proteins of the group of adhesion proteins. They play a role in the stabilization of cell-cell contacts, the embryonic morphogenesis, in the maintenance of cell polarity and signal transduction. N-cadherin (CDH2), the neuronal cadherin, stimulates cell-cell contacts during migration and invasion of cells and is able to suppress tumour cell growth.

Methods

Tumour tissues were acquired from 113 male patients and investigated by immunohistochemistry, as were the three TGCT cell lines NCCIT, NTERA-2 and Tcam2. A monoclonal antibody against N-cadherin was used.

Results

Tumour-free testis and intratubular germ cell neoplasias (unclassified) (IGCNU) strongly expressed N-cadherin within the cytoplasm. In all seminomas investigated, N-cadherin expression displayed a membrane-bound location. In addition, the teratomas and yolk sac tumours investigated also differentially expressed N-cadherin. In contrast, no N-cadherin could be detected in any of the embryonal carcinomas and chorionic carcinomas examined. This expression pattern was also seen in the investigated mixed tumours consisting of seminomas, teratomas, and embryonal carcinoma.

Conclusions

N-cadherin expression can be used to differentiate embryonal carcinomas and chorionic carcinomas from other histological subtypes of TGCT.

     

Peripheral lung carcinomas associated with central fibrosis and mixed small cell and other histologic components

Three cases of peripheral small cell lung carcinoma (SCLC) with central fibrosis are presented. Central fibrosis is usually present in adenocarcinomas. Cases 1 and 2 are combined SCLCs with components of papillary adenocar-cinoma, and case 3 is a mixed SCLC with a large cell component. Small cell Components showed intermediate cell type in ail cases. In cases 1 and 2, there was a gradual transition between small cell carcinoma and papillary ade-nocarcinoma. Small cell components showed Grimelius argyrophilia, but other neuroendocrine markers such as neuronspecific enorase, chromogranin A, Leu-7 and syn-aptophysln were negative. The chest X-ray examination of case 1 demonstrated rapid enlargement of a tumor shadow, which was present two years before, for a recent year. Central fibrosis, coexistence of small cell carcinoma and papillary adenocarcinoma, and a change of growth rate in the chest x-ray may suggest that some SCLC derive from papillary adenocarcinomas.     

Pathology and pathomorphologic diagnosis of germ cell tumors of the testis

Testicular germ cell tumors are rare and comprise about 90% of all testis tumors. Genetic factors may play a role in the pathogenesis as can be deduced by a higher family-linked incidence and the p53 gene seems to be important in the development of these tumors which derive from a malignant transformed germ cell. Testicular intraepithelial neoplasia (TIN) may differentiate in two directions, namely into seminomas which comprise nearly 50% of all testicular germ cell tumors and non-seminomas. Since the term "differentiated teratoma" may be misleading, we propose the use of the term "teratoma" only. A preoperative diagnosis by biopsy is not indicated. An exact postoperative diagnosis including all necessary classifications, particularly the WHO and the TNM classifications, requires a very careful preparation of the resected specimen. The histological diagnosis should list all the different types of the WHO classification and the percentage of the tumor should be indicated, at least for embryonal carcinomas. For T categorisation in the TNM classification, the presence of invasion of veins or lymph vessels is important. Documentation, preferably in the form of a standard checklist, is strongly recommended.     

Comparative genomic and in situ hybridization of germ cell tumors of the infantile testis

Chromosomal information on germ cell tumors of the infantile testis, ie, teratomas and yolk sac tumors, is limited and controversial. We studied two teratomas and four yolk sac tumors using comparative genomic hybridization (CGH) and in situ hybridization. No chromosomal anomalies were found in the teratomas by any of the methods, not even after CGH on microdissected tumor cells. All yolk sac tumors showed aneuploidy, loss of parts of 4q and 6q, and gain of parts of 20q. Underrepresentation of parts of 8q and overrepresentation of parts of 3p, 9q, 12p, 17, 19q, and 22 were detected in most cases. In addition, one recurrent yolk sac tumor after a sacral teratoma was studied, showing a highly similar pattern of imbalances. While CGH demonstrated loss of 1p36 in one testicular yolk sac tumor, in situ hybridization revealed loss of this region in all yolk sac tumors. High-level amplification of the 12q13-q14 region was found in one yolk sac tumor. MDM2, of which the encoding gene maps to this chromosomal region, was found in all cases using immunohistochemistry, whereas no p53 could be detected. Accordingly, no mutations within exons 5 to 8 of the p53 gene were observed. These data prove the absence of gross chromosomal aberrations in teratomas of the infantile testis and show a characteristic pattern of gains and losses in the yolk sac tumors. Besides confirmation of previously found anomalies, recurrent losses of 1p21-31 and 4q23-33 and gains of 9q34 and 12p12-13 have not been reported before. While genetic inactivation of p53 seems unimportant in the pathogenesis of these tumors, biochemical inactivation by MDM2 might be involved. These data support the existence of three entities of germ cell tumors of the human testis: teratomas and yolk sac tumors of infants, seminomas and nonseminomas of adolescents and young adults, and spermatocytic seminomas of the elderly, each with its own specific pathogenesis.     

Immunohistochemical staining of germ cell tumors and intratubular malignant germ cells of the testis using antibody to placental alkaline phosphatase and a monoclonal anti-seminoma antibody.

Antibody to placental alkaline phosphatase (PLAP) has been previously used in immunoperoxidase (IMP) staining studies of germ cell tumors and intratubular malignant germ cells (ITMGC) of the testis, the latter believed to be the precursor of these tumors. In this study, we compared staining by IMP using monoclonal antibody (mAb) and polyclonal antibody to PLAP with that seen using a mAb, M2A, which was previously shown to react with testicular seminomas and ITMGC. Antibody to PLAP and M2A reacted with different cellular components, as assessed by IMP staining of placenta and prepubertal testis and by Western blotting of seminoma lysates. Antibody to PLAP stained pure seminomas (seven of seven), pure embryonal carcinomas (four of four), and the seminoma (three of three) and embryonal carcinoma (six of six) components of mixed testicular germ cell tumors. M2A stained pure seminomas (26 of 26) and the seminoma component (three of three) of the mixed tumors, but failed to stain pure embryonal carcinomas (zero of four) or the embryonal carcinoma component (zero of five) of the mixed tumors. Both antibody to PLAP and M2A stained ITMGC of the testis. Since M2A stained seminomas and ITMGC but not embryonal carcinomas, seminomas would appear to be more closely related to ITMGC than embryonal carcinomas. This result has led us to speculate on the histogenesis of testicular germ cell tumors.     

Immunohistochemical localization of lactate dehydrogenase isoenzyme 1 in germ cell tumors of the testis

In this study, antiserum to lactate dehydrogenase isoenzyme 1 (LD 1) was used to determine immunohistochemical patterns of localization in a variety of germ cell neoplasms of the testis. All 29 seminomas and teratocarcinomas and four of seven embryonal carcinomas were positive for LD 1. These results suggest that elevated serum LD 1 levels noted in patients with germ cell neoplasms may be derived directly from neoplastic tissue and explain the relationship between serum LD 1 levels and tumor burden. A variety of neoplasms from other organs also were evaluated in order to determine the specificity of LD 1 staining for testicular tumors.     

Ploidy of primary germ cell tumors of the testis. Pathogenetic and clinical relevance

The ploidy of testicular germ cell tumors (GCT), a heterogeneous group of neoplasms, was studied by DNA flow cytometry. The DNA index for infantile yolk sac tumor (N = 10), seminomas (N = 20), and nonseminomas (N = 36), was: 1.91, 1.66, and 1.43, respectively. These values differed significantly one from another (p less than 0.01). The seminoma and nonseminoma components of combined tumors (N = 16) had a significantly different median DNA index of 1.61 and 1.40, respectively. Three of the 10 infantile yolk sac tumors, but only one of the 72 testicular GCT of adults were diploid. The consistent aneuploidy of testicular GCTs of adults might be helpful in the differential diagnosis of primary nongerm cell tumors of the testis, and in differentiating between metastases of testicular GCTs and primary extragonadal malignant GCTs. These data fit into a model of pathogenesis of testicular GCTs of adults in which all tumors, with the possible exception of spermatocytic seminoma, pass through a seminoma stage. Tumor evolution seems to result from net loss of chromosomes from a (near)tetraploid carcinoma in situ cell. The pathogenesis of infantile yolk sac tumor might be different from that of testicular GCTs of adults.     

Karyotyping and DNA flow cytometry of mature residual teratoma after intensive chemotherapy of disseminated nonseminomatous germ cell tumor of the testis: a report of two cases

Karyotyping and DNA flow cytometry was performed on mature residual teratoma cells following intensive chemotherapy of disseminated nonseminomatous germ cell tumor of the testis to study its biology. We report herein a successful method for short-term tissue culture and karyotyping of retroperitoneal residual mature teratoma in two cases. In vitro morphology confirmed that the cultured cells were nonembryonal carcinoma cells. Both mature residual teratomas were highly aneuploid and possessed the i(12p) marker characteristic of testicular germ cell tumors. A clone in the retroperitoneal residual lesion of one of the patients showed a DNA-index different from the primary tumor and might represent a clone unmasked by chemotherapy. In view of these data, which are in agreement with recent reports on secondary non-germ cell malignancies arising in mature residual teratoma, aggressive surgery of mature residual lesions seems justified.