Visual complaints in intracranial germinomas.

OBJECTIVE: Patients with brain tumors often report having visual complaints. This may be due to increased intracranial pressure, compression/invasion of the optic pathway or diplopia. We assessed the incidence and the etiology of visual symptoms in patients with intracranial germinoma tumors (ICGTs). METHODS AND MATERIALS: We performed a blinded retrospective review of the clinical charts and the initial magnetic resonance imaging (MRI) of 28 patients with ICGT. Thirteen tumors were pineal, five suprasellar, seven bifocal, and further three involved either the optic nerve, the corpus callosum, or the brainstem. RESULTS: Twelve patients reported visual disturbances, seven of whom mainly experienced a decrease in vision. Two of those were initially managed as "retrobulbar neuritis" when endocrinologic symptoms prompted assessment by MRI. Involvement of the optic pathway was underestimated, and both relapsed. Field deficits were definitive sequelae, whereas visual acuity was sometimes regressive in the absence of optic atrophy. CONCLUSIONS: Compression or invasion of the optic pathway by germinomas is not a rare occurrence, and this possibility should not be overlooked when thickening or contrast enhancement is detected. Radiotherapy fields should be extended accordingly.

Pineal germinoma in a child with interferon-γ receptor 1 deficiency. case report and literature review.

Interferon-γ receptor 1 (IFN-γR1) deficiency is one of the primary immunodeficiencies conferring Mendelian Susceptibility to Mycobacterial Disease (MSMD). Some cases of neoplasms have been recently reported in patients with MSMD, underlying the already known link between immunodeficiency and carcinogenesis. We report the first case of intracranial tumour, i.e. pineal germinoma, in a 11-year-old patient with complete IFN-γR1 deficiency. The first clinical presentation of the genetic immunodeficiency dates back to when the child was aged 2 y and 10 mo, when he presented a multi-focal osteomyelitis caused by Mycobacterium scrofulaceum. The diagnosis of IFN-γR1 deficiency (523delT/523delT in IFNGR1 gene) was subsequently made. The child responded to antibiotic therapy and remained in stable clinical condition until the age of 11 years, when he started complaining of frontal, chronic headache. MRI revealed a solid pineal region mass lesion measuring 20 × 29 × 36 mm. Histological findings revealed a diagnosis of pineal germinoma. The patient received chemotherapy followed by local whole ventricular irradiation with boost on pineal site, experiencing complete remission, and to date he is tumor-free at four years follow-up. Four other cases of tumors have been reported in patients affected by MSMD in our knowledge: a case of Kaposi sarcoma, a case of B-cell lymphoma, a case of cutaneous squamous cell carcinoma and a case of oesophageal squamous cell carcinoma. In conclusion, in patients with MSMD, not only the surveillance of infectious diseases, but also that of tumors is important.

Oct-3/4 is a dose-dependent oncogenic fate determinant.

The Oct-3/4 transcription factor sustains embryonic stem (ES) cell self-renewal and is a dose-dependent cell fate determinant. In the adult male, its expression is restricted to type A spermatogonia. We show that Oct-3/4 is expressed in all human testicular germ cell tumors (GCTs) tested, even in the early premalignant component. We demonstrate that Oct-3/4 dictates ES cells' oncogenic potential in a dose-dependent manner; high levels increase the malignant potential of ES cell-derived tumors while Oct-3/4 inactivation induces regression of the malignant component. Oct-3/4 expression in a heterologous cell system transforms nontumorigenic cells and endows tumorigenicity in nude mice. Our findings suggest that Oct-3/4 is not only a distinctive immunohistochemical marker for GCTs, but also plays a critical role in the genesis of these tumors.

Clinical profile and etiologies of children with central diabetes insipidus: a single-center experience from Turkey.

AIM: The aim of this study is to evaluate the clinical, anthropometric, hormonal, and radiological characteristics of children with central diabetes insipidus (DI). METHODS: Case records of 34 children (22 boys and 12 girls) with documented central DI referred to the Pediatric Endocrinology and Adolescent Clinic of Dokuz Eylul University Faculty of Medicine were reviewed. The mean age at diagnosis was 6.4 +/- 5.6 years (range, 0.08-16 years). All patients underwent anterior pituitary function assessment and magnetic resonance imaging of pituitary at diagnosis. The median duration of follow-up was 7.9 +/- 4.5 years. RESULTS: The etiology of central DI was organic in 22 (64.7%) patients, trauma in 2 (5.9%) patients, and idiopathic in 10 (29.4%) patients. Organic causes consisted of craniopharyngioma in 7 patients, Langerhans cell histiocytosis in 4 patients, germinoma in 4 patients, holoprosencephaly in 3 patients, astrocytoma in 1 patient, cavernous hemangioma in 1 patient, Rathke's cleft cyst in 1 patient, and autoimmune polyendocrinopathy in 1 patient. Anterior pituitary hormone deficiencies were documented in 18 (53%) patients. Organic central DI group had a greater prevalence of anterior pituitary hormone deficiency when compared with the idiopathic group (66% and 10%, respectively; p = 0.007). The final height of patients with organic etiology were significantly lower than the idiopathic group (155 and 178, cm respectively; p = 0.021). CONCLUSIONS: Etiological diagnosis is possible in a significant proportion (70.6%) of children with central DI. Findings of this study suggest that accompanying anterior pituitary hormone deficiencies and short stature may be considered as indicators of organic etiology.

Central diabetes insipidus caused by a pituitary stalk germinoma resembling infundibuloneurohypophysitis.

We report the case of a pituitary stalk germinoma initially misdiagnosed and treated as infundibuloneurohypophysitis (INH). A 27-year-old man presented with a 1-year history of polydipsia, polyuria, nycturia consistent with central diabetes insipidus and a hyperintense pituitary stalk lesion on MRI. A possible INH diagnosis was considered, after excluding other pathologies. Lesion biopsy was discarded at that time on the ground of a small target and the high risk of added morbidity. Oral desmopressin led to initial symptoms resolution but, in the following months, an anterior panhypopituitarism developed, in spite of appropriate treatment and, by that time, the brain MRI also revealed lesion growth, which prompted a biopsy recommendation. The pathology analysis revealed a germinoma. After chemotherapy and radiotherapy, there was complete disappearance of the pituitary lesion, but the panhypopituitarism persisted. In conclusion, this case highlights the importance and difficulty of precise diagnosis in the initial assessment of pituitary stalk lesions and the need for close monitoring of treatment response. Diagnostic reassessment and biopsy in atypical cases is the only path to achieve the correct diagnosis and treatment.

Loss of drug-induced activation of the CD95 apoptotic pathway in a cisplatin-resistant testicular germ cell tumor cell line.

Testicular germ cell tumors (TGCTs) are unusually sensitive to cisplatin. In the present study the role of the CD95 death pathway in cisplatin sensitivity of TGCT cells was studied in Tera and its in vitro acquired cisplatin-resistant subclone Tera-CP. Cisplatin induced an increase in CD95 membrane expression, which preceded the onset of apoptosis. Cisplatin-induced apoptosis was efficiently blocked by caspase-8 inhibitor zIETD-fmk in Tera cells, but only partially in Tera-CP cells. In addition, cisplatin induced FADD and caspase-8 recruitment to the CD95 receptor in Tera cells, which was not noticed in Tera-CP cells. Moreover, overexpression of vFLIP reduced apoptosis induction by cisplatin in Tera cells. CD95L-blocking experiments revealed the involvement of CD95/CD95L interactions in cisplatin-induced apoptosis of Tera cells as well as cisplatin-sensitive 833KE TGCT cells. Tera and 833KE cells, treated with low doses of cisplatin, were sensitive for an apoptosis-inducing anti-CD95 antibody. In contrast, CD95L blocking had no effect on cisplatin-induced apoptosis in Tera-CP or Scha, an intrinsic resistant TGCT cell line, nor did anti-CD95 antibody induce additional apoptosis in cisplatin-treated Tera-CP or Scha cells. Taken together, these results show that (1) cisplatin sensitivity of TGCT cells is dependent on the activation of the CD95 death pathway and (2) loss of cisplatin-induced activation of this CD95 signaling pathway may result in resistance to cisplatin.

Paternity in men with stage I testis tumors on surveillance.

PURPOSE: We report long-term paternity in men with stage I testis tumors who were managed initially by surveillance. PATIENTS AND METHODS: One hundred five patients with clinical stage I nonseminomatous germ cell tumors of the testis were entered on a surveillance protocol and followed up for more than 10 years. Actual fertility potential was assessed by pregnancy. RESULTS: Of the 105 patients, 41 (39%) have fathered children, which includes 36 of 78 (46%) patients while on active surveillance and five of 27 (19%) patients after treatment for relapse. Of 63 couples who attempted a pregnancy on surveillance or were presumed capable of impregnation (whether they tried or not), 41 (65%) were successful. CONCLUSION: These results show that the majority of men with stage I testis tumor who are on surveillance after orchiectomy, have a suitable partner, and attempt impregnation achieve a successful pregnancy. Pregnancy rates appear to be less than reported in men who have a nerve-sparing retroperitoneal lymph node dissection (RPLND) because more patients on surveillance require treatment for relapse, which reduces their chances for pregnancy.

Evaluation of reproductive capacity in germ cell tumor patients following treatment with cisplatin, etoposide, and bleomycin.

PURPOSE: To evaluate the infertility rate in patients with germ cell tumors receiving chemotherapy with cisplatin, etoposide (VP-16), and bleomycin (PVP16B). PATIENTS AND METHODS: Thirty patients were evaluated. All patients had undergone chemotherapy with two to four cycles of PVP16B. A single semen analysis was performed 24 to 78 months following initiation of chemotherapy. All 30 patients were continuously disease-free. Eight of these patients had also undergone nerve-sparing retroperitoneal lymph node dissection (RPLND). RESULTS: The median sperm concentration was 33.9 x 10(6), with a median volume of 3.2 mL. The median total sperm count was 86.4 x 10(6). Oligospermia (< 40 x 10(6) total sperm count) was found in 13 patients (43%), including six (20%) who were azoospermic. There was a high incidence of morphologically abnormal sperm, with only one patient having more than 50% normal spermatozoa. Only 13 patients (43%) had sperm motility greater than 50%. Five patients had positive semen antisperm immunoglobulin G (IgG). Eight patients fathered children, including three with document oligospermia. CONCLUSION: Patients with germ cell tumors successfully treated with PVP16B chemotherapy are at substantial risk for persistent semen abnormalities. However, some patients with oligospermia will slowly recover and others are still capable of reproductive capacity despite continued oligospermia.

Regulation of Sertoli cell and germ cell differentation.

Unwanted childlessness affects approximately one in six couples worldwide. According to the World Health Organization, in nearly 40% of cases the cause can be attributed to the female, in 20% to the male, in 25% to both, and in 15% the cause remains unknown. The incidence of male factor infertility in the general population is approximately 7%. The majority of these men experience irreversible idiopathic infertility and cannot father children without some form of medical intervention. Male factor infertility, in addition, may be caused by testicular germ cell cancer, which is known to represent the most common cancer among young men in Western industrialized countries. There is growing evidence that this cancer originates from fetal germ cells exhibiting an aberrant programme of gene expression and that tumour progression may be favoured by an aberrant Sertoli cell-germ cell communication. The present monograph aims to shed more light on the regulation of Sertoli and germ cell differentiation. Involving knockout and transgenic mouse models, the authors focus on (a) male factor infertility that might be related to altered maturation of Sertoli cells, (b) male factor infertility that might be due to incorrect histone-to-protamine exchange in haploid spermatids, and (c) progression of testicular germ cell cancer that might be favoured by an aberrant Sertoli cell-germ cell communication.

Estrogen metabolism and impaired spermatogenesis in germ cell tumors of the testis.

We evaluated spermatogenesis in 36 patients with germ cell tumors [11 with seminoma (S) and 25 with nonseminoma (NS)] in terms of sperm concentration and histological score (Johnsen's mean score) of spermatogenesis in the ipsilateral and contralateral testes. We also measured the steroid concentration in the spermatic vein of the tumor-bearing side and performed biochemical and immunohistochemical studies of aromatase activity of the tumor to investigate the mechanism of exocrine and endocrine testicular dysfunction, with particular emphasis on the role of estrogen metabolism. The sperm concentration was significantly lower in patients with S (42.9 +/- 40.7 x 10(8)/mL) and NS (17.6 +/- 20.8 x 10(6)/mL) compared to normal adult men (114.4 +/- 41.2 x 10(6) mL; P < 0.01). The histological score was lower in patients with NS than in patients with S. The histological score was highest in the contralateral testis, followed by the ipsilateral testis far from the tumor and the ipsilateral testis near the tumor in both the S and NS groups. Serum levels of estradiol and hCG were significantly elevated in both the systemic and spermatic veins of patients with NS compared to normal values, but they were within normal limits in patients with S. The histological score count in the contralateral testis was significantly and inversely correlated with the tumor weight and serum levels of hCG and estradiol. Aromatase activity examined in 9 tumors (5 S and 4 NS) and 6 ipsilateral nonneoplastic testis (3 S and 3 NS) was significantly higher in both neoplastic and nonneoplastic testes in NS patients (tumor, 5.343 +/- 4.027; nontumor, 14.647 +/- 7.688 pmol/h.pg protein) compared to S patients (tumor, 0.622 +/- 0.408; nontumor, 1.979 +/- 1.164 pmol/h.pg protein). Aromatase immunoreactivity was observed in Leydig cells of the nonneoplastic testis in both S and NS patients and in interstitial or stromal cells in 16 of 25 of NS patients and none of S patients. Our results suggest that impaired spermatogenesis in patients with testicular germ cell tumor is caused by increased tumor size in both NS and S patients and/or by increased aromatization and in situ estrogen production in Leydig cells of the nonneoplastic testis and in interstitial or stromal cells of the tumor in patients with NS.

Gonadal function in men with testicular cancer.

This article reviews current knowledge on the effect of testicular germ cell cancer (TGCC) on gonadal function and of the cancer treatment on spermatogenesis and Leydig cell function. It seems likely that development of TGCC shares common etiological factors with development other types of testicular dysfunction. This suggestion is supported by the observation that men with various types of gonadal dysfunction such as testicular dysgenesis, androgen insensitivity syndrome, and cryptorchidism have increased risk of testicular cancer. Epidemiological and clinical data indicate common etiology between testicular germ cell cancer and other abnormalities in male reproductive health such as infertility and cryptorchidism. These observations are in agreement with the suggestions of hormonal involvement in the etiology of testicular cancer. It is well documented that testicular cancer is associated with impaired spermatogenic function and some patients have impairment of Leydig's cell function already before orchidectomy. The degree of spermatogenic dysfunction is higher than what can be explained by local tumor effect and by a general cancer effect. These observations are supported by histological investigations, which have shown a high prevalence of abnormalities of spermatogenesis in the contralateral testis in patients with unilateral TGCC. The spermatogenetic function is still severely impaired after orchidectomy and radiotherapy as well as chemotherapy induce further dose-dependent impairment of spermatogenesis. Recovery of spermatogenesis after treatment may be long, in some patients lasting more than 5 years. Sufficient androgen production is seen in the majority of the patients but some patients do suffer from testosterone deficiency. The effect of chemotherapy on Leydig's cell function seems to be dose dependent. Trials on protection of spermatogenetic function against the harmful effects of radiotherapy and chemotherapy by suppression of spermatogenesis has not been successful. The only way to maintain fertility is to limit gonadal exposure to harmful agents. Moreover cryopreservation of semen should be done before treatment. The optimal time for cryopreservation is before orchiectomy at least in some patients. Generally men with TGCC need counselling about their reproductive function, with respect to semen cryopreservation, chance for recovery of spermatogenesis, fertility, and the possibility of need for androgen replacement.

Reproductive function after treatment of malignant germ cell ovarian tumors.

The outcome and reproductive function were examined among patients with malignant ovarian germ cell tumors treated since 1980. Between 1980 and 2001, fertility-sparing surgery was performed in 26 women, 23 of whom received adjuvant chemotherapy. With a median follow-up of 66.6 months, all patients have been alive, with histological types of 6 immature teratomas, 8 dysgerminomas, 6 yolk sac tumors, and 6 mixed types. Clinical stages were involved of 17 early stage and 9 advanced stage patients. After treatment, 20 women out of 26 recovered menstruation within 6 months. During follow-up, two chemotherapy-untreated and one treated patients experienced 4 conceptions in total. A treated patient conceived but selected artificial termination by affection of chemotherapy. Conservative surgery with adjuvant chemotherapy is the standard approach to treat patients with malignant ovarian germ cell tumors. In these 20 years, we experienced no delivery, so that fertility seems to be seriously affected by treatments.

Gonadal function after multimodality treatment in men with testicular germ cell cancer.

We evaluated gonadal function in 63 patients with testicular cancer both within 1 month of unilateral orchiectomy before further treatment (pretreatment) and 3 years after treatment discontinuation (post-treatment). Sixteen patients underwent orchiectomy alone (group 1), nine patients underwent infradiaphragmatic radiotherapy (group 2) and 28 patients received four cycles (group 3) and 10 patients received six cycles (group 4) of cisplatin-based chemotherapy (cisplatin, vinblastine and bleomycin-PVB, or cisplatin, etoposide and bleomycin-PEB). Pretreatment semen analyses showed reduced sperm cell density, motility and impaired morphology of spermatozoa in all four groups (p > 0.05). At the same time elevated estradiol and decreased serum follicle-stimulating hormone (FSH) levels in 28.5% of subjects were correlated with high serum beta human chorionic gonadotropin concentrations. Semen analyses revealed the lowest values for all parameters after infradiaphragmatic radiotherapy. Sperm cell count, motility and morphology were significantly better in patients treated with orchiectomy alone or with a conventional dose of chemotherapy than in the groups that received radiotherapy or high doses of chemotherapy (p < 0.05). We also observed a correlation between serum FSH values and sperm cell density for both pretreatment and post-treatment in every group of patients (p < 0.05). Persistent subclinical Leydig cell dysfunction in groups treated with radiotherapy or high doses of chemotherapy was expressed by increased basal luteinizing hormone levels (78% of patients in group 2 vs 60% of patients in group 4) (p < 0.05) and by normal testosterone serum values (89% of patients in group 2 vs 80% of patients in group 4). Spermatogenesis and Leydig cell function are, therefore, persistently impaired in the majority of testicular cancer patients treated with radiotherapy or with more intensive chemotherapy.

Composite germ cell tumor and B-cell non-Hodgkin's lymphoma arising in the sella turcica.

We report the case of a composite malignant neoplasm consisting of germ cell tumor and B-cell non-Hodgkin's lymphoma occurring in the sella turcica of a young girl who presented with hypopituitarism. Routine hematoxylin and eosin-stained sections of a resected suprasellar tumor demonstrated a neoplasm composed of 2 distinct morphologies. A panel of immunohistochemical markers was used to confirm the morphologic impression of germinoma (cytokeratin AE1/AE3-CAM 5.2, cytokeratin 7, neuron-specific enolase, and focally placental alkaline phosphatase positive) and mature B-cell lymphoma (CD20 positive; pancytokeratin, placental alkaline phosphatase, and terminal deoxynucleotidyl transferase negative). To the best of our knowledge, this is the first reported case of such a composite tumor in the central nervous system.

Germ cell cancer and disorders of spermatogenesis: an environmental connection?

Why is there a small peak of germ cell tumours in the postnatal period and a major peak in young age, starting at puberty? And, paradoxically, small risk in old age, although spermatogenesis is a lifelong process? Why is this type of cancer more common in individuals with maldeveloped gonads, including undescended testis, gonadal dysgenesis and androgen insensitivity syndrome? Why has there, during the past 50 years, been a quite dramatic increase in testicular cancer in many developed countries? These are just a few of many questions concerning testicular cancer. However, the recent progress in research in the early stages of testicular cancer (carcinoma in situ testis (CIS)) allows us to begin to answer some of these questions. There is more and more evidence that the CIS cell is a gonocyte with stem cell potential, which explains why an adult man can develop a non-seminoma, which is a neoplastic caricature of embryonic growth. We consider the possibility that CIS cells may loose their stem cell potential with ageing. Along these lines, a seminoma is regarded a gonocytoma where the single gonocytes have little or no stem cell potential. The Sertoli and Leydig cells, which are activated postnatally and during and after puberty, may play a crucial role for both the development of the CIS gonocyte and progression of the neoplasm to invasiveness. The reported increase in testicular cancer is not the only sign that male reproductive health is at risk. There are reports that undescended testis and hypospadias have become more common. Also semen quality has deteriorated, at least in some countries. The epidemiological evidence suggests that environmental factors may play a role. Are the environmental hormone disrupters (e.g. DDT, PCB, nonylphenol, bisphenol A) to be blamed for the apparently synchronised deterioration in these aspects of male reproductive health?

Fertility in men with testicular germ cell tumors.

OBJECTIVE: To assess the prevalence of fertility or infertility in men before and after treatment for unilateral testicular cancer. The results were compared with the lifetime prevalence of infertility in the general population (20%-28%). DESIGN: Survey. SETTINGS: University referral center for testicular cancer. PATIENT(S): Two hundred twenty-six patients treated for testicular cancer. INTERVENTION(S): Questionnaire on fertility and fertility-related factors before and after treatment of disease. MAIN OUTCOME MEASURE(S): Prevalence of fertility before and after treatment for testicular cancer. RESULT(S): Before the cancer was diagnosed, 79 (66%) of 120 couples who attempted to conceive succeeded within 1 year. After treatment, 38 (43%) of 88 couples conceived within 1 year. Seven couples used cryopreserved sperm to conceive a child after treatment. The different treatment modalities did not significantly influence the outcome of patients' wish for children. Congenital malformations were recorded in approximately 4% of the children born before or after treatment. CONCLUSION(S): Although the majority of the patients with testicular cancer have a fulfilled wish with regard to children, it seems to be more difficult to father a child after treatment compared with the case in the general population. Because it is not possible to predict which patient will have fertility problems after treatment, cryopreservation should be offered to every testicular cancer patient. An increased risk for congenital malformations was not observed.

Fertility after chemotherapy for testicular germ cell cancer.

OBJECTIVE: To investigate the impact of cytostatic chemotherapy on long-term fertility in patients with testicular germ cell cancer. BACKGROUND: Many patients with testicular germ cell cancer show impaired spermatogenesis before undergoing cytotoxic chemotherapy. The known infertility before treatment and the reversibility of the fertility problems observed in some of them after successful anticancer treatment so far have prevented an assessment of the true impact of chemotherapy on long-term fertility. The introduction of a wait-and-see strategy (surveillance) for patients with testicular cancer and recent prospective trials comparing patients with and without cytotoxic chemotherapy now have provided the means for estimating the extent to which chemotherapy itself affects long-term fertility. RESULT(S): Whether spermatogenesis is impaired irreversibly by chemotherapy is determined by the cumulative dose of cisplatin. At cumulative doses > 400 mg/m2, irreversible impairment of gonadal function should be expected. CONCLUSION(S): At cumulative cisplatin doses < 400 mg (equivalent to 4 courses of state-of-the-art treatment), chemotherapy is unlikely to cause irreversible damage to fertility.

Facilitation of ipsilateral motor pathways during recovery from hemiplegia in two adolescent patients.

In two hemiplegic patients with acquired cerebral lesions, transcranial magnetic stimulation (TMS) was carried out to examine the contribution of the ipsilateral motor pathways to recovery from hemiplegia. A 13-year-old girl (patient 1) had acute hemiplegia due to a rupture of an arteriovenous malformation, and a 13-year-old boy (patient 2) had subacute hemiplegia due to a brain tumour. They showed complete upper limb palsy but recovered after therapy; patient 1 had slightly disabled motor function of the arm, and patient 2 recovered completely. Motor evoked potentials (MEPs) were recorded from the biceps brachii muscles on both sides. The MEPs of the paretic biceps were only elicited by TMS of the intact hemisphere at the beginning of recovery from hemiplegia, but not by TMS of the affected hemisphere. The MEP amplitudes increased and cortical representation areas for the paretic biceps by TMS were enlarged temporarily during recovery. They regressed in patient 1 and MEPs were not evoked at all in patient 2 after recovery. Conversely, MEPs were obtained by TMS of the affected hemisphere after recovery in both patients. These data indicate that ipsilateral motor pathways play a role in recovery from hemiplegia, especially at the beginning, and become inactivated when the contralateral motor pathways recover.