Tumors Of Germ Cell Origin Research Articles

Anterior mediastinal neuroblastoma in an adult: an additional case of a rare tumor in an unusual location with review of the literature

Neuroblastoma is rare in the adult population, especially in thoracic or mediastinal locations, with only 25 previously reported cases. We report an additional example of primary thymic neuroblastoma in a previously asymptomatic 71-year-old man with an anterior mediastinal mass who underwent robotic excision with pericardium and adjacent lung. The tumor was a 5.2 cm partially encapsulated, white-tan and rubbery mass with grossly identifiable areas of necrosis (25%) and hemorrhage. Histologically, the specimen showed a rim of adipose tissue and residual thymic tissue with areas of cystic thymic epithelium and prominent lymphoid tissue containing Hassall’s corpuscles. The tumor was composed of uniform, round cells with scant cytoplasm and small nuclei with inconspicuous nucleoli set within a background of conspicuous neuropil. Mitotic figures were easily found. By immunohistochemistry, the tumor cells expressed synaptophysin, chromogranin, NKX2.2 (diffuse, nuclear), GFAP (patchy), SMI31 (neurofilament) (focal, cytoplasmic), and TdT (diffuse, nuclear), while lacking expression of CD99, TTF-1, CK 20, MCPyV, PHOX2B, Olig2, OCT3/4, CD45, CD3 and PAX5. S100 protein was negative in the neuroblastic cells, with scattered positive cells in a vague sustentacular-like pattern. Fluorescence in situ hybridization for isochromosome 12p and EWSR1 gene rearrangement were negative. As thymic neuroblastoma is extremely rare in adults, a neuroblastic tumor of germ cell origin (either primary or metastatic) or spread from a sinonasal tract tumor should be excluded because of differing treatments and prognoses. The properties of these rare neoplasms appear similar to olfactory neuroblastoma rather than pediatric-type neuroblastoma.

Intratesticular Rhabdomyosarcoma- A Rare Childhood Tumour

Primary malignant of tumours of the testis are rare in children. Tumours of germ cell origin account for 60-77% of primary testicular tumors. Intrascrotal tumours of nongerm cell origin are rare. Rhabdomyosarcomas (RMS) are the commonest tumours among nongerm cell tumours. RMS are more commonly seen in paratesticular region. Pure testicular RMS are rare. A 16 yr boy was evaluated right sided testicular mass. Histopathology and immunohistochemistry confirmed it to be an anaplastic embryonal rhabdomyosarcoma. Here we report this case with a brief review of literature.

A sinonasal yolk sac tumor in an adult.

Yolk sac tumors (YSTs), which are also called endodermal sinus tumors, are malignant tumors of germ cell origin. These tumors usually occur in the gonads, but 20% of cases have been reported at extragonadal sites. The head and neck is a rarely affected region that accounts for just 1% of all malignant tumors of germ cell origin. In addition, YSTs arise mostly in childhood. We present a rare pathologically pure case of primary adult YST in the sinonasal area. A 45-year-old male patient presented with a rapidly growing mass in the nasal cavity, which caused nasal obstruction and bloody post-nasal drip. The histopathologic features indicated pure YST, and immunohistochemical analysis revealed positive reactivity for Sal-like protein 4 and alpha-fetoprotein. Herein, we discuss the clinical, radiologic, and histologic features of this YST and review other cases of sinonasal YST in adults.

Pineal region tumors: A retrospective analysis

Pineal region tumors are rare comprising 0.4% to 0.1% of all primary tumors of the central nervous system1,2 and constitute 3% to 11% of childhood brain tumors.3-5 These tumors are classified into tumors of germ cell origin, which clearly account for the majority of tumors in this region and those originating from pineal parenchymal cells.1 The latter include pineoblastomas, pineocytomas, and tumors of glial origin. These retain the potential for neuronal or glial differentiation.1,6 Approximately three-fourths of tumors in this area are malignant with the propensity for seeding(3,7,8,9,10). Retrospectively we have analyzed 47 cases of pineal region tumors and have discussed the clinical features, histopathology, management and outcome. Keywords: Pineal tumors, Central nervous system, Tumors of glial origin.

Origin of a second malignancy harboring isochromosome 12p [i(12p)] in patients with history of testicular germ cell tumor (TGCT).

412 Background: The cumulative incidence of subsequent solid malignant neoplasm (SMN) after treatment of TGCT is about 10% over a 25-year period. i(12p) has been used to define tumor of germ cell origin. We evaluated the prevalence of i(12p) on various subsequent SMN in patients with a history of TGCT. Methods: From the Tumor Registry database at MD Anderson, we identified 655 TGCT patients who developed a second (third or fourth) malignancy between January 1990 and September 2018. Of those 114 SMN from the GI tract, GU system, chest, brain, sarcomas or melanomas between 2011 and 2017, 43 had tumor tissue available at our institution and of sufficient quality for fluorescence in situ hybridization (FISH) of i(12p). Results: Our cohort comprised 43 patients, excluding 2 cases (#6 and 7) whose SMN tested positive and their non-tumor controls negative for i(12p). Diagnosis of primary TGCT and SMN: age, mean 41 yrs (range 20-68 yrs) and 59 yrs (range 34-86 yrs), respectively, and interval of 18 yrs (range 0-57 yrs). Of those 43 cases (5 did not hybridize), 5 (11%) harbored i(12p), while 16 (37%) had additional copies of chromosome 12 without apparent gain of 12p. Conclusions: Prevalence of i(12p) on subsequent SMN in our patient cohort with a history of TGCT was 11%. Detection of i(12p) in those patients with TGCT in general and with nonseminomas in particular suggests somatic transformation, emphasizes importance of a complete surgical resection of residual teratomatous tumor after chemotherapy, and implicates a stem-cell origin and nature (e.g., plasticity, heterogeneity, dormancy) of cancer. *deceased; Rx – initial treatments; S – seminoma; NS – nonseminoma; BEP – bleomycin, etoposide, cisplatin; CEB – carboplatin, etoposide, bleomycin; XRT – radiation therapy. Groot HJ, Lubberts S, de Wit R, et al. Risk of solid cancer after treatment of testicular germ cell cancer in the platinum era. J Clin Oncol 2018;36:2504-13.

Non-epithelial Ovarian Cancer: Elucidating Uncommon Gynaecological Malignancies.

Non-epithelial ovarian cancers (NEOC) are a group of fascinating but uncommon malignancies which can be extremely challenging to treat. Collectively, these tumours only represent 10-15% of all ovarian cancers and occur in all age groups from childhood to old age. This broad term includes diverse tumours of germ cell origin, sex cord-stromal cell origin, as well as extremely rare types of ovarian cancer, such as small-cell carcinomas and sarcomas, each of which require specialist management. It is imperative that these rare tumours are managed with accurate diagnosis, staging and treatment in order to optimize patient outcomes. The aetiology and molecular origins of each sub-group of NEOC remain poorly understood and international cooperation to facilitate high quality translational research is needed. This review summarizes the published literature on the incidence, clinical presentation, pathology, therapeutic interventions, survival and prognostic factors of each sub-type of NEOC.

Clinicopathological characteristics of ovarian tumours according to menarchal status in Korean girls

To evaluate our experience with ovarian tumours in young girls and to identify specific characteristics in relation to their menarchal status that might assist in the early diagnosis and prompt management. Girls younger than 18 years of age who had an adnexal tumour confirmed at surgery from 1985 to 2008 were identified from the pathology database of Hanyang University Medical Centre. Clinicopathological characteristics such as patient's age, age at menarche, presenting symptoms, operative findings and final histological diagnosis were analysed. Twenty-four of the 90 patients operated on for an ovarian tumour were pre-menarchal and 66 were post-menarchal. Most tumours were of germ cell origin: 83% of tumours in pre-menarchal and 53% in post-menarchal girls. Most of the patients complained of abdominal pain (∼70%), although a palpable mass was identified in only 17% of pre-menarchal and 30% of post-menarchal patients. Vomiting was a major complaint in pre-menarchal patients (30%) but was uncommon in post-menarchal patients (<5%). The frequency of torsion was significantly higher in pre-menarchal (50%) than in post-menarchal (17%) patients, and more than 90% of the torsion in pre-menarchal patients occurred in tumours of germ cell origin. The incidence of ovarian tumour and torsion is rare, especially in pre-menarchal girls. However, we found a higher prevalence of torsion in pre-menarchal girls with an ovarian tumour. A high level of suspicion for torsion should be considered when treating pre-menarchal girls with an ovarian tumour, irrespective of the tumour size to preserve adnexal tissue.

Re-evaluation of the significance of cerebrospinal fluid human chorionic gonadotropin in detecting intracranial ectopic germinomas

This study was conducted to establish a reference value for cerebrospinal fluid (CSF) human chorionic gonadotropin (hCG) levels. We also evaluated the sensitivity of CSF hCG as a biomarker to detect intracranial ectopic germinomas that arise in rare sites other than the pineal and suprasellar regions. CSF hCG was measured in 201 male patients who had various types of neurological disease (not tumours of germ cell origin or other malignant tumours). A reference value of 1.009 U/L was established, and the CSF hCG level among different age groups was not significantly different. CSF and serum hCG were measured before and after radiotherapy in 14 consecutive patients with intracranial ectopic germinomas. The CSF hCG levels were all above 1.009 U/L before radiotherapy. In male patients, a CSF hCG value above 1.009 U/L suggests abnormal intrathecal hCG secretion. These results demonstrate that the CSF hCG assay is a sensitive method for diagnosing intracranial ectopic germinoma.

Oral Metastasis of the Mediastinal Germ Cell Tumor (Yolk Sac)

A yolk sac tumor is a rare malignant tumor of germ cell origin. It most commonly arises from the testes and ovaries in young adults, but extragonadal sites of origin are reported in 10% to 15% of the cases. Yolk sac tumors are malignant, tend to recur locally, and may present with widespread metastases at the time of diagnosis. Involvement of the head and neck is uncommon. In this study, we present the case of a 23-year-old man presenting with mandibular and adjacent gingival metastasis of a mediasatinal yolk sac tumor. Thus, the patient has already undergone chemotherapy; no additional treatment was provided. In this case report, clinical and histopathologic features of the oral metastases of a yolk sac tumor were briefly discussed.

Tatsuya Kobayashi, Dade Lunsford (Eds), Progress in Neurosurgery Series-Vol. 23 Pineal Region Tumors, Diagnosis and Treatment Options

The introduction is a presentation of the statistical analysis of pineal tumors based on the data of the brain tumor registry of Japan. The frequency of pineal tumors in Japan is five times as high as in western countries. The first section deals with Tumors of Pineal Cell Origin. The first chapter deals with the pathology of pineal parenchymal tumors including immunohistology and electron microscopy. It ends with a brief account of genetic alterations. The second chapter of this section describes the occipital transtentorial approach and combined treatments of pineal parenchymal tumors. It also includes a brief description of histopathological findings. The third chapter addresses the role of streotactic radiosurgery in the management of pineal parenchymal tumors. The second section deals with Tumors of Germ Cell Origin. The first chapter of this section describes the pathology of these tumors including their histogenesis and classification as well as a brief account of genetic alterations; then, follows a chapter on the general management of these tumors and another one on the strategy of combined treatment of germ cell tumors with a classification according to prognosis. The next chapter is on radiation therapy and includes a review of prospective studies with chemotherapy and radiation, followed by a chapter on stereotactic radiosurgery for pineal and related tumors (germ cell as well as pineal parenchymal tumors). The next chapter is a proposal for a modern strategy with radiation and chemotherapy. The last chapter deals with the quality of life of extremely long-time germinoma survivors mainly treated with radiotherapy. This book provides a good picture of the state of the art in the management of pineal tumors. From the purely technical neurosurgical point of view, I missed the description of the infratentorial supracerebellar approach. The volume has the drawback of a multi-author book with some repetitions from one chapter to another. It can be of interest for neurosurgeons, radiotherapists, and medical oncologists.

Two cases of intracranial germinoma showing a cell arrangement mimicking carcinoma

Tumors of germ cell origin uncommonly arise in extragonadal sites. We report two cases of intracranial germinoma, in which it was necessary to distinguish between intracranial germinoma and metastatic carcinoma in cytological specimens. Cytologically, not only single tumor cells or loosely connective tumor cells but also closely packed clusters of cells and pair cells were recognized. Immunocytochemically, almost all tumor cells were immunoreactive for M2A, placental alkaline phosphatase, and c-kit. Closely packed clusters were also immunoreactive for pan-cytokeratin. Therefore, Cytopathologists should be aware that tumor cell clusters, mimicking carcinoma might appear in cytological specimens of intracranial germinomas. Although immunocytochemical analysis assists in correct diagnosis, some cell clusters showing cytokeratin immunoreactivity does not become the basis for the diagnosis of metastatic carcinoma. A panel of antibodies including D2-40, PLAP, and c-kit should be used.

Monoclonal antibodies to early pregnancy factor perturb tumour cell growth

The pregnancy-associated substance early pregnancy factor (EPF) has previously been reported as a product of tumours of germ cell origin. More recently EPF (or an EPF-related substance, tEPF) has also been detected in the serum of patients bearing tumours of non-germ cell origin. We report here the production of tEPF by a variety of cultured transformed and tumour cell lines, of both germ and non-germ cell origin. Antibodies specific for EPF remove all tEPF activity from tumour cell conditioned medium. tEPF production is found to be associated with cell division; tEPF is no longer detected after growth arrest or differentiation. Co-culture of tumour cells with increasing doses of anti-EPF monoclonal antibodies resulted in a significant, dose-dependent decrease in rate of cell growth and viability. Similar anti-EPF concentrations had no effect on the concanavalin A induced proliferation of mouse spleen cells. These studies suggest, therefore, that tEPF is a growth-regulated product of cultured tumour and transformed cells. These cells are also dependent upon tEPF for continued growth, i.e. tEPF is acting in the autocrine mode.

Yolk sac tumor in the nasal cavity

Yolk sac carcinoma (YST) is rare malignant tumor of germ cell origin. It most commonly arises from the gonads but extragonadal sites of origin are reported in 20% of the cases. Head and neck germ cell tumors are uncommon and only a small number are malignant. We present the case of a 48 years old man presenting with a YST of the sinonasal tract and the arterior skull base. The patient underwent an anterior craniofacial resection and postoperative radiotherapy and continues showing no evidence of disease seven years after treatment. We discuss radiological and histological features of this tumor and provide a review of three other cases of YST arising in children.

TSPY Expression Is Variably Altered in Transgenic Mice with Testicular Feminization1

TSPY (testis-specific protein, Y-encoded) genes are expressed in premeiotic germ cells and round spermatids. The topology and timing of TSPY expression, and also its homology to members of the TTSN-family, suggest that TSPY is a proliferation factor for germ cells. There is also evidence for a role of TSPY in the aetiology of testis cancer. TSPY is a candidate for GBY, the elusive gonadoblastoma locus on the human Y chromosome, which is thought to predispose dysgenetic gonads of 46, XY sex-reversed females to develop gonadoblastoma. We have previously generated a TSPY transgenic mouse line (Tg(TSPY)9Jshm) that carries approximately 50 copies of the human TSPY gene on the mouse Y chromosome. In order to elucidate TSPY expression under complete androgen insensitivity and to investigate a possible role of TSPY in gonadal tumorigenesis, we have now generated sex-reversed TSPY transgenic Ar(Tfm) mice hemizygous for the X-linked testicular feminization mutation (Ar(Tfm)). We can show that the TSPY transcript is aberrantly spliced in the testes of TSPY-Ar(Tfm) mice, and that TSPY expression is upregulated by androgen insensitivity in some but not all animals. TSPY transgenic mice showed significantly increased testes weights. In one TSPY transgenic Ar(Tfm) animal, spermatogenesis proceeded beyond meiotic prophase. No tumors of germ cell origin were found in the testes of TSPY-Ar(Tfm) mice. Five out of 46 TSPY transgenic Ar(Tfm) mice, and 3 out of 31 age-related NMRI-Ar(Tfm) controls developed Leydig cell tumors, whereas none of the age-matched Ar(Tfm) mice (n=44) on a wild type background were affected by Leydig cell tumorigenesis.

Teratoma of the penis in a child

Teratomas are tumors of germ-cell origin, composed of tissues derived from all three germinal layers: ectoderm, endoderm, and mesoderm. Most teratomas have been reported to arise at sites that are midline or paraxial, with the penis being an unusual location for this tumor. The treatment for most pure teratomas is surgical resection. We report a case of primary teratoma of the penis in a 3-month-old child. This is the second reported case of a primary teratoma of the penis and the first in a child.

The pluripotency homeobox gene NANOG is expressed in human germ cell tumors

The NANOG gene, a member of the homeobox family of DNA binding transcription factors, was recently identified in a screen for pluripotency-promoting genes. NANOG overexpression in murine embryonic stem cells is sufficient to maintain self-renewal and to block differentiation. The NANOG gene is located on human chromosome 12p13, a region frequently duplicated in human tumors of germ cell origin and in cultured human embryonic stem cells. Here we investigate the expression and gene copy number of NANOG in human germ cells and tumors of germ cell origin. Immunohistochemistry and quantitative polymerase chain reaction (QPCR) were used to examine the expression and gene copy number of the human NANOG gene in germ cell tumors. NANOG protein was detected in germline stem cells (gonocytes) within the developing testis. Immunohistochemistry and quantitative real-time PCR analysis were used to demonstrate that NANOG is highly and specifically expressed in carcinoma in situ (CIS), embryonal carcinomas, and seminomas, but not in teratomas and yolk sac tumors. NANOG expression in germline stem cells (gonocytes), CIS, embryonal carcinoma, and seminoma reveals a molecular and developmental link between germ cell tumors and the embryonic cells from which they arise. Identification of NANOG as a molecular marker of undifferentiated germ cell tumors provides a novel tool for identifying and classifying tumors of germ cell origin.

Spontaneous ovarian tumors in twelve baboons: a review of ovarian neoplasms in non-human primates.

Twelve spontaneous ovarian tumors were found in the Southwest Foundation for Biomedical Research baboon colony. These included four granulosa cell tumors, three teratomas, two endometrioid carcinomas, one seromucinous cystadenofibroma, a cystic papillary adenocarcinoma, and an ovarian carcinoma. Age was a pre-disposing factor. With one exception, the tumors of surface epithelial- and sex cordstromal origin occurred in baboons over 17 years of age. The exceptional animal was 7 years of age when a malignant granulosa cell tumor with Sertoli cell differentiation was identified. The two endometrioid tumors, which were found in 17- and 30-year-old animals, were both associated with endometriosis. In contrast, the teratomas, which are tumors of germ cell origin, were found in younger animals, i.e. 17 years of age or younger. One case of an ovarian carcinoma with metastases was observed in a 6-month-old infant. Cases of spontaneous ovarian tumors from the literature are reviewed.

VASA is a specific marker for both normal and malignant human germ cells. zeeman a.m., stoop h., boter m., et al.: Laboratory investigation (2002) 82(2):159–166

SUMMARY: VASA is so far the only known gene in mammals whose expression is specific for the germ cell lineage. We investigated the presence of VASA mRNA and protein in a series of germ cell tumors of different histologic subtypes and anatomic location, as well as in non-germ cell tumors such as testicular lymphomas and Leydig cell tumors. We detected VASA mRNA (by quantitative RT-PCR) and protein (by immunohistochemical staining) in normal spermatogenesis, seminoma (both classic and spermatocytic), carcinoma in situ (the precursor of classic seminoma and non seminoma), dysgerminoma, and gonadoblastoma. VASA immunostaining was relatively weak in seminomas and dysgerminomas compared with spermatocytic seminomas, despite similar mRNA levels, suggesting that VASA is regulated in part by posttranscriptional mechanisms. A higher staining intensity compared with the invasive counterparts was observed in the precursor lesions (ie, carcinoma in situ and gonadoblastoma). No VASA mRNA or protein was detectable in nonseminomatous germ cell tumors (such as embryonal carcinoma, teratoma, and yolk sac tumor) and derived cell lines, or non-germ cell tumors such as lymphoma or Leydig cell tumor. These results provide direct evidence that some germ cell tumors retain germ cell characteristics, whereas other tumors of germ cell origin result from differentiation and loss of germ cell identify. Furthermore, these findings suggest that VASA is likely to serve as a useful and highly specific biomarker for germ cell tumors, particularly classic and spermatocytic seminoma/dysgerminoma, including their precursor stages.

VASA Is a Specific Marker for Both Normal and Malignant Human Germ Cells

VASA is so far the only known gene in mammals whose expression is specific for the germ cell lineage. We investigated the presence of VASA mRNA and protein in a series of germ cell tumors of different histologic subtypes and anatomic location, as well as in nongerm cell tumors such as testicular lymphomas and Leydig cell tumors. We detected VASA mRNA (by quantitative RT-PCR) and protein (by immunohistochemical staining) in normal spermatogenesis, seminoma (both classic and spermatocytic), carcinoma in situ (the precursor of classic seminoma and nonseminoma), dysgerminoma, and gonadoblastoma. VASA immunostaining was relatively weak in seminomas and dysgerminomas compared with spermatocytic seminomas, despite similar mRNA levels, suggesting that VASA is regulated in part by post-transcriptional mechanisms. A higher staining intensity compared with the invasive counterparts was observed in the precursor lesions (ie, carcinoma in situ and gonadoblastoma). No VASA mRNA or protein was detectable in nonseminomatous germ cell tumors (such as embryonal carcinoma, teratoma, and yolk sac tumor) and derived cell lines, or nongerm cell tumors such as lymphoma or Leydig cell tumor. These results provide direct evidence that some germ cell tumors retain germ cell characteristics, whereas other tumors of germ cell origin result from differentiation and loss of germ cell identity. Furthermore, these findings suggest that VASA is likely to serve as a useful and highly specific biomarker for germ cell tumors, particularly classic and spermatocytic seminoma/dysgerminoma, including their precursor stages.

Combination of a Teratoma and Embryonal Carcinoma of the Testis in SD IGS Rats: A Report of Two Cases

Testicular tumors of germ cell origin are extremely rare in rats. We encountered 2 cases of teratoma and embryonal carcinoma in the testes of 8- and 10-week-old Sprague-Dawley IGS rats. A unilateral tumor mass with bilateral testicular atrophy was observed macroscopically in both cases. Microscopic examination revealed that the tumor mass had characteristic features of a teratoma and was composed of several types of differentiated cells and tissues at various stages of maturation. Embryonal carcinoma tissue, composed of undifferentiated cells with an embryonic and anaplastic appearance, was observed within the tumor mass. In addition, foci of intratubular teratomas and embryonal carcinomas were observed in the testis on the side without any obvious mass. No obvious germ cells were observed in the seminiferous tubules in the remnant nontumorous area. Furthermore, intratubular transition of cells was observed from the embryonal carcinoma tissue to the squamous epithelium. This finding indicates that an embryonal carcinoma differentiates toward a teratoma even at a very early stage of development of the germ cell tumor.