Germinoma Cells Research Articles

Abstract 634: Targeting metastatic brain germinoma using PDOX tumor models with sequential metastases

Abstract Introduction. Intracranial germ cell tumor is an Asian-centric tumor, showing great variation in geographical distribution, with an incidence 5-8 fold greater in Asia/East Asia, than Western countries. Germinoma is one histological subtype of intracranial germ cell tumors. Current standard of care for germinoma, is chemoradiotherapy. Metastatic/recurrent germinoma have poor prognosis. There is currently no targeted therapy. Purpose: To create patient-derived orthotopic xenograft (PDOX) models of distant metastases in brain germinoma beyond brain boundaries to recapitulate sequential metastases of original patient tumors. These tumor models will serve as clinically accurate metastatic models for preclinical testing, replicating patient's pattern of tumor progression/metastases. There is a lack of such metastatic brain tumor models in the field. c-KIT is the most common mutation in germinoma. We evaluated preclinical efficacy of a c-KIT inhibitor. Experimental Procedures. Most PDOX brain tumor models are created by implanting patient-derived tumor cells in cerebrum/cerebellum. Germinoma originates from pineal gland/suprasellar region. We implanted germinoma cells nearer location of tumor origin. We were successful and achieved consistent tumor implantation into this location (100% post-surgery survival, 0% surgical mortality, 0% post-surgical neurological deficits). Summary. We successfully established two models with sequential metastases. Model 1 was created from metastatic cells from spinal recurrence (Patient 1) post-chemo-radiotherapy. This model faithfully created skull base metastases in 100% of murine replicas (n=9). Both tumor cells from brain and skull base metastases (n=7) were serially transplantable. Our findings were replicated (n=5) and consistent. Model 2 was created from metastatic cells of cerebrospinal fluid dissemination (Patient 2). Brain surface metastases were formed recapitulating patient tumor. Both models recapitulated a similar path of metastases in craniospinal axis, corresponding to respective patients. c-KIT inhibitor, was effective in significantly prolonging animal survival in Model 2 (p=0.0046) but not in Model 1 (p=0.0541). In Model 2, c-kit inhibition in-vivo was efficacious and resulted in 3-fold effect, (1) Significantly improved animal survival, (2) Macroscopically reduced frequency, severity of brain surface metastases (Controls=50%, Treated=14%, lesser in severity), (3) Microscopically reduced tumor burden to minimal residual disease limited to cerebrospinal fluid outline. Control mice brains were largely replaced by tumor bulk, while treated mice had minimal residual tumor burden. Conclusions. Understanding metastatic patterns in such aggressive models is relevant in biologic targeting for preclinical studies and clinical decision to extend radiotherapy field in recurrent disease. Citation Format: Shiying Huang, Sekar Karthik, Jack M Su, Qi Lin, YuChen Du, Ching C Lau, Adesina Adekunle, Angela Major, Kam-Man Hui, M. Tarek Elghetany, Xiaonan Li, Wan-Yee Teo. Targeting metastatic brain germinoma using PDOX tumor models with sequential metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 634.

Type, Frequency, and Spatial Distribution of Immune Cell Infiltrates in CNS Germinomas: Evidence for Inflammatory and Immunosuppressive Mechanisms.

Central nervous system germinomas are characterized by a massive immune cell infiltrate. We systematically characterized these immune cells in 28 germinomas by immunophenotyping and image analysis. mRNA expression was analyzed by Nanostring technology and in situ RNA hybridization. Tumor infiltrating lymphocytes (TILs) were composed of 61.8% ± 3.1% (mean ± SE) CD3-positive T cells, including 45.2% ± 3.5% of CD4-positive T-helper cells, 23.4% ± 1.5% of CD8-positive cytotoxic T cells, 5.5% ± 0.9% of FoxP3-positive regulatory T cells, and 11.9% ±1.3% PD-1-positive TILs. B cells accounted for 35.8% ± 2.9% of TILs and plasma cells for 9.3% ± 1.6%. Tumor-associated macrophages consisted of clusters of activated PD-L1-positive macrophages and interspersed anti-inflammatory macrophages expressing CD163. Germinoma cells did not express PD-L1. Expression of genes encoding immune cell markers and cytokines was high and comparable to mRNA levels in lymph node tissue. IFNG and IL10 mRNA was detected in subfractions of TILs and in PD-L1-positive macrophages. Taken together, the strong immune reaction observed in germinomas involves inflammatory as well as various suppressive mechanisms. Expression of PD-1 and PD-L1 and infiltration of cytotoxic T cells are biomarkers predictive of response to anti-PD-1/PD-L1 therapies, constituting a rationale for possible novel treatment approaches.

CNS germinomas are characterized by global demethylation, chromosomal instability and mutational activation of the Kit-, Ras/Raf/Erk- and Akt-pathways.

CNS germinomas represent a unique germ cell tumor entity characterized by undifferentiated tumor cells and a high response rate to current treatment protocols. Limited information is available on their underlying genomic, epigenetic and biological alterations. We performed a genome-wide analysis of genomic copy number alterations in 49 CNS germinomas by molecular inversion profiling. In addition, CpG dinucleotide methylation was studied by immunohistochemistry for methylated cytosine residues. Mutational analysis was performed by resequencing of candidate genes including KIT and RAS family members. Ras/Erk and Akt pathway activation was analyzed by immunostaining with antibodies against phospho-Erk, phosho-Akt, phospho-mTOR and phospho-S6. All germinomas coexpressed Oct4 and Kit but showed an extensive global DNA demethylation compared to other tumors and normal tissues. Molecular inversion profiling showed predominant genomic instability in all tumors with a high frequency of regional gains and losses including high level gene amplifications. Activating mutations of KIT exons 11, 13, and 17 as well as a case with genomic KIT amplification and activating mutations or amplifications of RAS gene family members including KRAS, NRAS and RRAS2 indicated mutational activation of crucial signaling pathways. Co-activation of Ras/Erk and Akt pathways was present in 83% of germinomas. These data suggest that CNS germinoma cells display a demethylated nuclear DNA similar to primordial germ cells in early development. This finding has a striking coincidence with extensive genomic instability. In addition, mutational activation of Kit-, Ras/Raf/Erk- and Akt- pathways indicate the biological importance of these pathways and their components as potential targets for therapy.

GC-02 * CNS GERMINOMAS ARE CHARACTERIZED BY GLOBAL DEMETHYLATION, CHROMOSOMAL INSTABILITY AND MUTATIONAL ACTIVATION OF THE KIT-, RAS/RAF/ERK- AND AKT-PATHWAYS

CNS germinomas represent a unique germ cell tumor entity characterized by uniform undifferentiated tumor cells and a high response rate to current treatment protocols. However, only limited information is available on their underlying genomic, epigenetic and biological alterations. In this study we perfomed a genome-wide analysis of genomic copy number alteration and allelic disbalances in 37 cases of CNS germinomas by molecular inversion profiling. In addition, CpG dinucleotide methylation was studied by immunohistochemistry with a specific antibody against methylated cytosine residues. Mutational analysis was performed by resequencing of candidate genes including KIT and RAS family members using FFPE derived DNA. Ras/Erk and Akt pathway activation was analysed by immunostaining with specific antibodies against phospho-Erk and phospho-Akt. All germinomas coexpressed Oct4 and Kit but showed an extensive global demethylation of nuclear DNA compared to other germ cell tumors and normal tissues. Molecular inversion profiling showed predominant genomic instability in 32/37 tumors with a high frequency of regional gains and losses including high level amplifications. Activating mutations of KIT exons 11, 13, 17 as well as a case with genomic KIT amplification and activating mutations or amplifications of RAS gene family members including KRAS, NRAS, RRAS2 and RHOH as well as mutation of BRAF indicated mutational activation of crucial signalling pathways. Activation of both, Ras/Erk and Akt pathways was demonstrated by immunohistochemistry of phospho-Erk and phospho-Akt in germinomas. These data suggest that CNS germinoma cells display a demethylated nuclear DNA similar to primordial germ cells in early development. This finding is associated with extensive genomic instability in the majority of germinomas. In addition, mutational activation of KIT, Ras/Raf/Erk- and Akt- pathways is characteristic indicating the biological importance of these pathways and potential targets for therapy.

POTENCY OF SECRETING HCG- IN GERMINOMAS. CLINICAL AND BIOLOGICAL ANALYSIS

BACKGROUND: It has long been discussed whether HCG secreting germinomas are more malignant than pure germinomas. The Japanese study group insists of no difference in survival between two kinds of germinomas, whereas the European and American study groups put HCG germinomas into the high risk group. In order to solve the question, we analyzed the treatment results, the titer of a small amount of HCG-β in the cerebrospinal fluid (CSF), and the expression of HCGβ mRNA in germinoma cells. METHODS: (1) We selected 80 germinoma patients with or without HCG secretion for PFS analysis who were treated by proper radiation volume for their tumors developing in/around the third ventricle in the Japanese prospective study. (2) The initial serum and CSF samples were measured for HCG-β with the ultrasensitive technique to detect picogram levels of HCG-β in 36 histologically confirmed germinomas. (3) The expression of HCGβ mRNA was analyzed by qPCR in 76 germ cell tumors. RESULTS: (1) There was no significant difference in 15 year PFS between pure germinomas (93.1%, n = 61) and HCG-germinomas (80.7%, n = 19) in the Japanese prospective study. (2) In 36 germinomas examined, the HCG-β was detectable in both serum and CSF. The serum levels were 3.1–5851 pg/mL (median 44.8), and the CSF levels were 13–13116.3 pg/mL (median 119.5). (3) Most of the germ cell tumors expressed HCG-β mRNA in higher degrees compared with the normal brain tissue (comparative ratio to brain: 0.46 - 7.6 × 107). The expression of HCG-β mRNA in germinomas was highly variable, ranging from 72.6 - 2.1 × 105 to below the brain (0.46 - 1.4 × 103), and the differences of the expression among cases were linear, and not bimodal, suggesting no clear cut-off titer. CONCLUSIONS: These results suggest that all germinomas can produce HCG-β and fall into the same category in terms of HCG-β productivity. Based on this theory, all germinoma patients should be treated with the same protocol. SECONDARY CATEGORY: Pediatrics.

An unusual case of primary central nervous system germinoma with meningeal dissemination

Central nervous system germinomas often extend or disseminate into the ventricular and subarachnoid space. We present a case of primary central nervous system germinoma consisting mainly of meningeal dissemination, which is extremely unusual. A 16-year-old boy presented with pure germinoma, manifesting as anorexia and headache for 10 days. Radiological examinations revealed a large mass lesion in the posterior fossa and a small mass lesion on the pineal lobule with thickening of the tentorium cerebelli and falx. The patient underwent partial removal of the infratentorial tumor via open surgery. Intraoperative findings indicated extension of the dural and supracerebellar mass lesions into the epiarachnoid space. Three chemotherapy courses comprising ifosfamide, etoposide, and cisplatin were administered after the surgery. Craniospinal irradiation was administered subsequently. The adjuvant therapy had a complete response. Central nervous system germinoma cells may have similar compatibility to meningeal components as they do to cerebrospinal fluid or the ventricular system. If there is a possibility of the tumor extending into the subdural space during surgical intervention or other events, a range of postdiagnostic irradiation should be considered to cover a wider range.

Abstract 2491: High-dose acetaminophen with N-acetylcysteine rescue enhances the efficacy of cisplatin chemotherapy

Abstract Acetaminophen (AAP) has been shown to enhance cisplatin (CDDP) cytotoxicity in hepatoblastoma cell lines. Further, one published case report demonstrated clinical efficacy of administering acetaminophen in conjunction with cisplatin and followed 6 hours later with n-acetylcysteine (NAC) rescue. In this study, atypical rhabdoid tumor (ATRT) and germinoma cells were treated with CDDP and AAP with or without NAC rescue. We then evaluated the cells with western blots for cleaved PARP and caspase 3 to demonstrate effects on apoptosis. Further, MTS assays were performed to evaluate cell viability of treated cells. To evaluate the effects of the various treatments on oxidative stress, dihydroethidium (DHE) and 2′,7′-dichlorofluorescin (DCFH) assays were performed to test for superoxide and hydrogen peroxide levels, respectively. It was demonstrated that AAP enhances CDDP cell kill and apoptosis in germinoma and ATRT cell lines. Further, both AAP and CDDP, independently and together, cause increased oxidative stress as measured by DHE and DCFE, but this oxidative stress is only reversed by NAC in the DCFE assay. This makes sense because NAC, a glutathione precursor, detoxifies peroxide but not superoxide. Further, our group has learned of five previously unpublished patients with recurrent liver tumors (hepatocellular carcinoma and hepatoblastoma) treated with AAP and CDDP with delayed NAC rescue. All patients tolerated the treatment well. Two of the five patients responded to the treatment, suggesting the potential of this approach. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2491. doi:1538-7445.AM2012-2491

Mixed germ cell tumor of the midbrain

This 14-year-old boy presented with left hemiparesis, gait disturbance, and multiple cranial nerve palsies. Magnetic resonance imaging revealed a multicystic mass with hemorrhagic fluid-fluid levels in the right midbrain, suggesting the presence of a cavernous malformation. Diffusion tensor imaging showed the mass to be close to the right corticospinal tract and ipsilateral medial lemniscus. Subtotal removal of the mass was performed via a right subtemporal approach. The histopathological diagnosis was of a mixed germ cell tumor (GCT) comprising mature teratoma and germinoma cells with syncytiotrophoblastic giant cells. The patient underwent postoperative chemotherapy and radiotherapy, and no tumor progression was found during 1 year of follow-up. Intracranial GCTs arise mainly in the pineal and the suprasellar area. Germ cell tumors in the brainstem are rare, with only 12 reported cases. Among these, 4 were in the midbrain and histologically were pure germinomas. To the authors' knowledge, this is the first reported case of a mixed GCT in the midbrain combining mature teratoma and germinoma cells.

Tumors of the sellar region mimicking pituitary adenomas.

In the sellar region most tumors of our collection (n = 1937) are pituitary adenomas, followed by craniopharyngiomas, chordomas and meningiomas. Difficulties in morphological differential diagnosis by light microscopy may occur in meningiomas, plasmacytomas, chordomas and germinomas. In these cases, immunohistological investigations and sometimes even electron microscopy are helpful in solving the problems. Meningiomas can sometimes resemble pituitary adenomas. Of diagnostic value in these cases is the expression of vimentin and S-100-protein in the meningioma cells. Plasmacytomas may also mimic pituitary adenomas. In these cases, the positive reaction with antibodies against LCA and immunoglobulins or against kappa-light-chains and lambda-light-chains leads to the diagnosis. Chordomas, too, can sometimes be hardly distinguished from pituitary adenomas. In these cases, the expression of S-100-protein, vimentin and CEA by the chordoma cells and the typical electron microscopic features of chordomas are helpful for the differential diagnosis. Germinomas may sometimes be indistinguishable from lymphocytic hypophysitis. Of diagnostic importance are here the expression of HCG and placental alkaline phosphatase by germinoma cells. In the above mentioned cases, it is also important to perform immunohistochemical examinations for pituitary hormones including alpha-subunit. All these tumors do not express these hormones.

Pituitary and systemic autoimmunity in a case of intrasellar germinoma

Germinomas arising in the sella turcica are difficult to differentiate from autoimmune hypophysitis because of similar clinical and pathological features. This differentiation, nevertheless, is critical for patient care due to different treatments of the two diseases. We report the case of an 11-year-old girl who presented with diabetes insipidus and growth retardation, and was found to have an intra- and supra-sellar mass. Initial examination of the pituitary biopsy showed diffuse lymphocytic infiltration of the adenohypophysis and absent placental alkaline phosphatase expression, leading to a diagnosis of hypophysitis and glucocorticoid treatment. Because of the lack of clinical and radiological response, the pituitary specimen was re-examined, revealing this time the presence of scattered c-kit and Oct4 positive germinoma cells. The revised diagnosis prompted the initiation of radiotherapy, which induced disappearance of the pituitary mass. Immunological studies showed that the patient’s serum recognized antigens expressed by the patient’s own germinoma cells, as well as pituitary antigens like growth hormone and systemic antigens like the Sjögren syndrome antigen B and alpha-enolase. The study first reports the presence of pituitary and systemic antibodies in a patient with intrasellar germinoma, and reminds us that diffuse lymphocytic infiltration of the pituitary gland and pituitary antibodies does not always indicate a diagnosis of autoimmune hypophysitis.

Podoplanin expression in primary central nervous system germ cell tumors: a useful histological marker for the diagnosis of germinoma

Podoplanin, a mucin-like transmembrane sialoglycoprotein, promotes platelet aggregation and may be involved in cancer cell migration, invasion, metastasis, and malignant progression. Podoplanin/aggrus is highly expressed in testicular seminoma, suggesting that it may be a sensitive marker for testicular seminomas. Here we investigated the expression of podoplanin in central nervous system (CNS) germ cell tumors (GCTs) by immunohistochemical staining of tumor samples from 62 patients. In 40 of 41 (98%) germinomas (including germinomatous components in mixed GCTs), podoplanin was diffusely expressed on the surface of germinoma cells; lymphocytes, interstitial cells, and syncytiotrophoblastic giant cells were negative for podoplanin. Except for immature teratomas (12/17; 71%), podoplanin expression was absent in non-germinomatous GCTs, including seven teratomas, seven embryonal carcinomas, seven yolk sac tumors, and seven choriocarcinomas. In immature teratomas, focal podoplanin staining was observed in fewer than 10% of immature squamous and columnar epithelial cells. Thus, podoplanin expression may be a sensitive immunohistochemical marker for germinoma in CNS GCTs. As such, it may be useful for diagnosis, for monitoring the efficacy of treatment, and as a potential target for antibody-based therapy.

Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues

Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues

Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues

Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues

Pineal Germinoma With Granulomatous Reaction-Case Report-

A 20-year-old man presented with diplopia. Neurological examination revealed mild skew deviation and upbeat nystagmus. Computed tomography showed a clover-shaped isodense mass in the pineal region with homogeneous enhancement. The lesion was isointense on both T(1)- and T(2)-weighted magnetic resonance (MR) imaging with homogeneous enhancement by gadolinium-diethylenetriaminepenta-acetic acid. Cerebral angiography showed no tumor staining. Serum and cerebrospinal fluid were negative for beta-human chorionic gonadotropin, alpha-fetoprotein, and placental alkaline phosphatase. Open biopsy was performed using a right occipital transtentorial approach. Histological examination revealed a tumor consisting of clusters of germinoma cells, but with prominent infiltration of lymphocytes, plasma cells, and macrophages, and proliferation of small vessels. The histological diagnosis was germinoma with granulomatous reaction. MR imaging showed complete disappearance of the tumor after chemoradiotherapy. Neurosurgeons should be aware of this rare tumor to avoid misdiagnosis as granulomatous inflammation.

Expression and distribution of c-kit receptor and its ligand in human CNS germ cell tumors: A useful histological marker for the diagnosis of germinoma

We previously reported the expression of protooncogene c-kit in CNS germ cell tumors and suggested that the soluble form of c-kit (s-kit) may represent a specific clinical marker for germinoma-containing tumors. Here we investigated the expression of stem cell factor (SCF), a specific ligand of c-kit, in CNS germ cell tumor samples from 16 patients, using immunohistochemical methods to assay the expression of c-kit and SCF protein. The immunostaining patterns of c-kit and SCF were almost identical. In all germinoma-containing tumors, c-kit and SCF were diffusely expressed on the surface of germinoma cells; lymphocytes and interstitial cells were negatively stained. In immature teratomas, only some mature components, e.g., cartilage and gland, were immunoreactive for c-kit and SCF. Syncytiotrophoblastic giant cells (STGCs) were negative for both SCF and c-kit, suggesting that germinoma cells primarily coexpress SCF and c-kit. The coexpression of c-kit and SCF may be an important immunohistochemical marker for the diagnosis of CNS germinoma, and the SCF/c-kit pathway may be an alternative molecular target for the treatment of human CNS germinomas.

Diagnostic significance of soluble c-kit in the cerebrospinal fluid of patients with germ cell tumors.

Overexpression of the protooncogene c-kit has been suggested in a gonadal germ cell tumor (GCT). Recently, the soluble isoform of c-kit (s-kit) has been expressed in a variety of cell types. The goal of this study was to investigate the expression of c-kit and the clinical significance of s-kit in patients with GCTs. The authors first conducted an immunohistochemical investigation of the expression of the c-kit protein in 27 surgical specimens. In all 18 specimens that contained germinomas, c-kit was diffusely expressed on the cell surface of the germinoma cells, but was not found on lymphocytes or interstitial cells. In seven of eight immature teratomas, only some mature components, such as cartilage and glands, were immunoreactive for c-kit. Syncytiotrophoblastic giant cells (STGCs) demonstrated negative findings as well, suggesting that primarily germinoma cells express c-kit. Next, 47 cerebrospinal fluid (CSF) samples collected from 32 patients with GCTs (15 samples from patients with pure germinomas, 16 from patients with STGC germinomas, 14 from patients with teratomas, and two from a patient with a choriocarcinoma) were analyzed using a sandwich enzyme-linked immunosorbent assay. The level of s-kit was significantly higher in CSF collected from patients with germinomas and STGC germinomas than in CSF collected from patients with teratomas or non-germ cell brain tumors, or in CSF collected from controls. The concentration of s-kit in CSF was correlated with the patient's clinical course: it was significantly higher in pretreatment samples obtained before and in samples obtained at the time of tumor recurrence than in samples collected from patients in whom the tumor was in remission. The level of s-kit was remarkably high in CSF collected from patients with subarachnoid tumor dissemination. These results indicate that the concentration of s-kit in CSF may be a useful clinical marker for germinomas, especially for detecting recurrence or subarachnoid dissemination of these lesions.

Twenty-four hour rhythm of melatonin in patients with a history of pineal and/or hypothalamo-neurohypophyseal germinoma.

Melatonin deficiency after a pinealectomy has been investigated in animals; however, in humans, this status can be assessed solely by investigating patients with a tumor originating in the pineal gland. This study analyzes secretion of melatonin and pituitary hormones in 14 patients with germinoma originating in the pineal or the hypothalamic-neurohypophyseal region. Thirteen patients had been successfully treated prior to this study. One patient was included in this study before the initiation of treatments. Plasma sampling was performed every 2 hr for 24 hr and melatonin concentrations were measured by radioimmunoassay. Melatonin secretion was nearly absent in the patients with pineal germinoma regardless of treatment option, even in the patient who had been untreated. In contrast, melatonin secretion and its circadian rhythms were not affected in patients with a hypothalamo-neurohypophyseal germinoma. The circadian rhythms of growth hormone and adrenocorticotropic hormone were not dysregulated in patients with the melatonin deficiency. We conclude that germinoma cells originating the pineal gland impair the production of melatonin by pineocytes and consequently induce a permanent melatonin deficiency in those patients. Since melatonin exerts multiple physiological functions, once a clinical concept of "melatonin deficiency syndrome" is established, melatonin replacement therapy could be investigated in patients who have a pineal germinoma or who have undergone a neurosurgical pinealectomy.

Cerebral germinoma with marked granulomatous inflammation: Granulomatous germinoma

Cerebral germinomas with granulomatous inflammation are rare lesions that can present diagnostic difficulties. Four cases (two male and two female) of germinomas with pronounced inflammatory reaction are presented. The age ranged from 14 to 21 years (mean 18). Three patients with vision defects had masses around the sellar region, and a long duration of symptoms (2, 4 and 5 years). The fourth patient had a mass in the temporal lobe; she had convulsions and the duration of her symptoms was short (3 weeks). All lesions consisted of inflammatory changes with scattered neoplastic germinoma cells that expressed placental alkaline phosphatase. The inflammation area occupied more than two‐thirds of the mass, and consisted of macrophages and their syncytial forms of mutinucleated giant cells, T‐cells, B‐cells, plasma cells, fibroblasts, and histiocytes or glial cells. Sarcoid granulomata were frequently seen, and multinucleated giant cells with Schaumann's bodies were also visible. The term ‘cerebral granulomatous germinoma’ is proposed for these unusual tumors. Moreover, it is likely that the study of cerebral granulomatous germinoma may provide some important clues towards the understanding of granulomatous inflammation in organs in general.

Aromatase expression in human germinomas with possible biological effects.

Gonadal aromatase expression has been demonstrated in human Leydig, granulosa, and thecal cells, but never in human germ cells. In an attempt to explain the unique occurrence of isosexual precocious puberty in a young girl with a hCG-secreting suprasellar germinoma, we demonstrated the presence of aromatase expression in the germ cell component of this tumor. Immunohistochemical staining for P450-aromatase and hCG using a peroxidase-labeled streptaviden-biotin technique was performed on tumor specimens from the above patient and from four other subjects with central nervous system germinoma. Cytoplasmic aromatase staining was present in the germinoma cells of four of five cases of central nervous system germinoma studied. Staining was absent in the lymphocytic element within the tumor and in negative control tissues. The demonstration of aromatase activity in the malignant element of human germinomas indicates that aromatase expression can occur in human germ cells after malignant transformation. This parallels the finding that the transformation of Sertoli cells to sex cord tumor with annular tubules in Peutz Jeghers syndrome is associated with the induction of marked aromatase expression and systemic estrogen effect. We propose that tumor aromatase played a similar role in the unique occurrence of isosexual precocity in a girl with a suprasellar germinoma.

Subarachnoid Dissemination of Pineal Germinoma 9 Years After Radiation Therapy without Local Relapse

A 22-year-old female developed intracranial and spinal subarachnoid metastases 9 years after radiation therapy for a pineal germinoma. Computed tomographic scans showed no evidence of local recurrence. Cerebrospinal axis irradiation achieved total remission. Delayed subarachnoid dissemination may be caused by germinoma cells remaining dormant in the subarachnoid space, outside the radiation field.