Diagnosis Of Germ Cell Tumors Research Articles

Abstract 2291: Incidence of intracranial germ cell tumors by race in the United States, 1992-2009: A potential link with autoimmune encephalitis?.

Abstract Introduction: Pediatric germ cell tumors (GCTs) are rare and heterogeneous tumors that are grouped together due to their presumed common cell of origin, the primordial germ cell (PGC). GCTs typically occur in the testes or ovaries; however, abnormal prenatal PGC migration along with lack of apopotosis can result in tumors in extragonadal locations, including the central nervous system (intracranial and intraspinal GCTs; iGCTs). Little is known about the etiology of iGCTs, although international incidence data suggest that the highest incidence occurs in Asian countries. Autoimmune encephalitis (AE) is a paraneoplastic event characterized by abnormal behavior, seizures, and movement disorders; a number of case reports find AE in conjunction with GCT. We note with interest that a recent registry based study in California reported the highest incidence of AE in Asians. In this analysis, we used 1992-2009 data from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program to determine whether the increased rates of iGCT observed in Asian countries was also seen in Asian/Pacific Islanders living in the United States. Methods: Frequencies and incidence rates were evaluated for the entire cohort and for demographic subgroups based on sex, age category (0-9 and 10-29 years), race (white, black, American Indian/Alaskan Native and Asian/Pacific Islander), and tumor location (pineal gland vs. other) as sample size permitted. Analyses were conducted using SEER*Stat 7.1.0. Results: Two peaks in incidence were observed, the first before age 1 year in both sexes and the second at age 10 years for females and age 18 years for males. We observed a significantly higher incidence rate of iGCT in Asian/Pacific Islanders compared with whites (RR=1.98, 95% CI 1.51-2.56 for males and RR=3.21, 95% CI 1.99-5.05 for females) in the 10-29 year age group. This difference was observed for tumors located both in the pineal gland and for tumors in other locations. Conclusions: The increased rates of iGCT we observed in individuals of Asian descent in the SEER registry are in agreement with data from the International Agency for Research on Cancer, where the highest incidence rates were observed in Japan, Singapore, and the Maori population of New Zealand. The explanation for these rate differences has not been investigated to date; however, the increased incidence in individuals of Asian ancestry in the United States suggests that genetic susceptibility may play a role in etiology. The higher frequency of AE in Asians and the co-occurrence with GCT in case reports is also intriguing. It is possible that AE could be triggered by PGCs abnormally present in the cranio-spatial axis prior to GCT diagnosis, and it will be of interest to determine whether a diagnosis of AE precedes iGCT. These differences in incidence patterns by race and the possible link with AE merit further investigation. Citation Format: Jenny N. Poynter, Rachel Fonstad, Jakub Tolar, Logan G. Spector, Julie A. Ross. Incidence of intracranial germ cell tumors by race in the United States, 1992-2009: A potential link with autoimmune encephalitis?. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2291. doi:10.1158/1538-7445.AM2013-2291

Changes in epidemiologic features of testicular germ cell cancer: Age at diagnosis and relative frequency of seminoma are constantly and significantly increasing

ObjectivesTesticular germ cell tumors (GCTs) have their incidence peak in the third and fourth decades of life. Histologically, GCTs comprise of seminoma and nonseminoma at almost equal proportions with a slight preponderance of nonseminoma in most of the major series. Since decades, there is a shift toward decreasing age at presentation. Recently, there are suggestions of a reversal of the age trend, and also, the histologic subtype ratio appears to shift toward seminoma. We retrospectively looked to our patient populations to verify these recent trends. MethodsA total of 2,482 patients with histologically proven GCT diagnosed between 1976 and 2010 were retrospectively evaluated regarding the year of diagnosis, histology of primary tumor, and age at presentation. Patients were categorized according to the following time periods of treatment: before 1990, 1990 to 1994, 1995 to 1999, 2000 to 2004, and 2005 to 2010. Mean age and relative proportion of seminoma were compared among patient categories by employing the chi-square test and analysis of variance, respectively. ResultsThe mean age significantly increased from 28 to 36 years. The age difference between the 2 histologic subtypes remained constant between 6 and 8 years during the entire observation period. The relative proportion of seminoma continuously increased from 30.9% to 56% (P <0.001). ConclusionThere is evidence of a significant shift toward older age at diagnosis of GCT. In addition, the proportion of seminoma is constantly increasing at the expense of nonseminoma. The reasons for these developments are obscure. However, 2 old theories regarding the pathogenesis of GCT may receive support from our results: first, the theory of divergent pathogenetic pathways of seminoma and nonseminoma and second, the involvement of postnatal environmental factors in the pathogenesis of GCTs.

SALL4 is a useful marker in the diagnostic work-up of germ cell tumors in extra-testicular locations

We evaluated the impact of SALL4 immunostaining on the diagnosis of non-testicular germ cell tumors in clinical practice. We retrieved cases of six mediastinal, five retroperitoneal, and eight central nervous system tumors that were diagnosed as extra-testicular germ cell tumors (GCT) as well as 20 location-matched non-GCT. Each tumor we stained immunohistochemically for PLAP, OCT3-4, CD117, CD30, FP, -HCG, glycipan-3, SALL 4, AE1-AE3, EMA, CK7, CK20, CD45, TTF1, vimentin, and GFA. The results were assessed independently by two experienced pathologists. In 18 of 19 cases (95 %), SALL4 was strongly expressed, either homogenously (16 cases) or focally (two cases). All other GCT markers (PLAP, OCT3-4, CD117, CD30, FP, -HCG, and glycipan-3) were expressed with a lower frequency (21-69 %). The specificity of SALL4 was 100 % in our series. SALL4 should be part of the first panel of antibodies for the diagnosis of a midline tumor (mediastinal, retroperitoneal, or pineal) in patients under the age of 40 years. We also recommend that SALL4 be used in the diagnostic work-up of undifferentiated tumors in any location and in patients of any age. When a tumor is SALL4 positive, in case of need the diagnosis of germ cell tumor can be further confirmed using additional conventional markers.

Validation of tumor markers in central nervous system germ cell tumors by real-time reverse transcriptase polymerase chain reaction using formalin-fixed paraffin-embedded tissues

The therapeutic protocols for treatment of germinomas and non-germinomatous germ cell tumors (NGGCTs) are completely different, so it is important to distinguish pure germinomas from NGGCTs. As it can be difficult to diagnose by morphology alone, immunohisto-chemistry (IHC) has been widely used as an ancillary test to improve diagnostic accuracy. However, IHC has limitations due to the misinterpretation of results or the aberrant loss of immunoreactivity. However, real-time RT-PCR has certain advantages over IHC, including its quantitative nature. The aim of our study was to evaluate the usefulness of real-time RT-PCR on formalin-fixed paraffin-embedded (FFPE) tissue blocks for the diagnosis of germ cell tumors of the central nervous system. We selected eight markers of germ cell tumors using a literature search, and validated them using real-time RT-PCR. Among them, POU5F1, NANOG and TGFB2 were statistically significant (P=0.05) in multiple comparisons (MANOVA) of three groups (pure germinomas, mature teratomas and malignant germ cell tumors). Two-group (pure germinomas and NGGCTs) discriminant analysis achieved a 70.0% success rate in cross-validation. We concluded that real-time RT-PCR using FFPE tissue has adequate validating power comparable to IHC in the diagnosis of central nervous system germ cell tumors; therefore, when IHC is not available, not conclusive or not informative, RT-PCR is a potential alternative to a repeat biopsy.

Granulomatosis and Testicular Germ Cell Tumors

To determine the cumulative incidence of granulomatous disease among patients with testicular germ cell tumor (GCT) at the University of Pennsylvania and to describe these patients' characteristics and disease outcomes. A computerized search of a large electronic medical database at the University of Pennsylvania was conducted to identify all patients from 1997 to 2012 with a diagnosis of granulomatous disease and GCT. A total of 14 patients were identified. The median age at the diagnosis of GCT was 32.5 years, and the median age at the diagnosis of granulomatous disease was 31 years. Most patients were diagnosed with granulomatous disease either concomitantly or after their diagnosis of GCT. The estimated cumulative incidence of granulomatous disease in patients with GCT at the University of Pennsylvania from 1997 to 2012 was 168.7/100,000. These data suggest a strong association between granulomatous disease and GCTs. The observed incidence of granulomatous disease among patients with GCT represents a 10-fold increase compared with the general population. Additional investigation is needed to elucidate the true nature of this association.

Diagnostic utility and correlation of tumor markers in the serum and cerebrospinal fluid of children with intracranial germ cell tumors

In order to predict whether tumor markers assist in the histopathologic diagnosis of germ cell tumors (GCTs), we analyzed the correlation of beta human chorionic gonadotropin (βhCG) and alpha-fetoprotein (AFP) in serum and cerebrospinal fluid (CSF) samples at baseline and subsequent follow-up examinations. A retrospective study of patients diagnosed with intracranial GCTs between July 1985 and February 2011 at our institution was conducted to review clinical, surgical, radiological, laboratory, and histopathologic data. Of the 67 patients eligible for the study, 42 had germinomas and 25 non-germinomatous GCTs. At baseline, serum and CSF AFP agreed in 97.9 % of patients (Cohen's Kappa 0.93). Baseline βhCG samples agreed in only 72.5 % of patients (Cohen's Kappa 0.46). In most cases, values were higher in serum for AFP and in CSF for βhCG. ROC curves estimated from logistic regression model indicated that CSF and serum samples had almost equal diagnostic utility, and the DeLong test showed that the difference in area under curves was not statistically significant. During follow-up (185 paired CSF and serum values from 43 patients), 90.3 % of AFP values correlated between CSF and serum (Cohen's Kappa 0.22, showing fair agreement). For βhCG, 96.2 % of values agreed in serum and CSF (Cohen's Kappa 0.61). In some patients, intracranial GCTs can be diagnosed based solely upon positive serum AFP values. In addition, marker values from serum only may be sufficient to predict tumor relapse at interval follow-up examinations.

Cervical metastasis of germ cell tumors: Evaluation, management, complications, and outcomes

Head and neck surgeons can be involved in the management of germ cell tumor (GCT) metastatic to the neck from initial diagnosis through postchemotherapy management of residual neck masses. This article reports on 34 consecutive patients with GCT metastatic to the neck. Retrospective chart review. A single-institution retrospective chart review of 34 consecutive patients with GCT metastatic to the neck who underwent postchemotherapy neck surgery between 1991 and 2009 was performed. Seventy-four percent of patients had a neck mass at initial diagnosis, with 50% of patients having a neck mass as the presenting symptom leading to a diagnosis of GCT. Of the 37 neck procedures, positive nodes were found in 22. No significant relationship between preoperative tumor markers and neck pathology (P = .35) was identified. No patients had neck recurrence. No patients had permanent nerve injury or chyle leak. As a secondary end point, survival analysis related to cervical pathology showed that viable tumor in the neck predicted disease-specific survival (P = .01). Five- and 10-year disease-specific survival was 82.3% (median, 52-month follow-up). Operative management for patients with metastatic GCT to the neck can achieve long-term durable cervical control with limited complications.

Thromboembolic events identified during diagnosis of germ cell tumors in 2 children

We describe 2 cases in which radiographic evidence of thromboembolic events was obtained during germ cell tumor diagnosis. There was no evidence of coagulation factor abnormalities or contributory procedures or drugs in either patient. We used anticoagulation therapy for thrombolysis in one patient, but in the other, the thromboembolism resolved spontaneously.

Associations between variants in KITLG, SPRY4, BAK1, and DMRT1 and pediatric germ cell tumors

Recent genome wide association studies have identified susceptibility loci for adult testicular germ cell tumors (GCT) near KITLG, SPRY4, BAK1, and DMRT1. We evaluated variants in these four genes to determine whether these are also susceptibility loci for pediatric GCTs. DNA was isolated from 52 pediatric GCTs (ages 0-21 years) obtained from the Cooperative Human Tissue Network. Control DNA was isolated from de-identified dried blood spots from 141 white newborns. Genotyping was conducted using TaqMan assays (rs4474514) or by PCR and sequencing (rs4324715, rs210138, and rs755383). Associations between variants and GCT were evaluated using logistic regression with adjustment for sex. We also evaluated whether the associations differed by age at GCT diagnosis (0-9 years, 10-21 years), sex, and tumor location (gonadal, non-gonadal). We observed a significant association for rs210138 (BAK1) and pediatric GCT overall (odds ratio (OR) = 1.80, 95% confidence interval (CI) 1.10-2.95, P = 0.02) with non-significant associations similar in magnitude in both the pediatric (P = 0.09) and adolescent (P = 0.06) age groups. The KITLG (rs4474514) and SPRY4 (rs4324715) variants were significantly associated with GCT only in the adolescent age group (rs4474514: OR = 2.28, 95% CI 1.09-4.79, P = 0.03 and rs4324715: OR = 2.40, 95% CI 1.19-4.83, P = 0.01). Associations were mostly similar when stratified by sex. This is the first study to suggest that these loci may also be important in susceptibility to GCTs in the adolescent (KITLG, SPRY4, and BAK1) and pediatric (BAK1) age groups.

Treatment of epidural spinal cord involvement from germ cell tumors with chemotherapy

Germ cell tumors (GCTs) are chemosensitive, and epidural spinal cord compression (ESCC) from GCT may be amenable to treatment with chemotherapy (CT) only. This retrospective study compares the clinical outcome of GCT patients with ESCC treated with CT or radiotherapy (RT) + CT. All patients with a histologic diagnosis of GCT from 1984 to 2009 were included in this study. Patients with ESCC were identified. Age, clinical features, histology, treatment, and outcome were analyzed. The authors identified 1734 patients with GCT, of whom 29 (1.7%) had ESCC. The median age of these 29 patients was 32 years. The ESCC was treated with CT only in 16, RT + CT in 11, and 2 patients received palliative care only. The ESCC was more extensive in the RT + CT than the CT group. Patients who received RT + CT had a higher proportion of failed prior CT regimens, a higher percentage of nonseminomatous GCT, T-spine involvement, multilevel epidural disease, and bony vertebral metastases. Median overall survival after diagnosis of ESCC was not reached for those treated with CT alone versus 15 months for those receiving RT + CT (P = .02). There was also a significant difference in survival in patients receiving first-line therapy (n = 15), where median overall survival was not reached in the CT group (n = 11), compared with 22 months in the RT group (n = 4) (P = .04). GCTs rarely involve the epidural compartment. Patients with ESCC who are likely to have chemosensitive disease can receive CT alone as definitive treatment.

Serum tumor markers in the evaluation of male germ cell tumors

Serum tumor markers play a critical role in the diagnosis, staging, risk stratification, and surveillance of patients with testicular germ cell tumors (GCTs). Production of the oncofetal substances α fetoprotein and human chorionic gonadotropin can aid the diagnosis of testicular GCTs, and specific patterns of marker elevation can be used to determine the type of tumor, particularly as it pertains to nonseminoma. These markers, in addition to lactate dehydrogenase, have been incorporated in the standard TNM staging system for testicular tumors; the S stage category corresponds to serum elevation of these proteins. Furthermore, the degree of serum tumor marker elevation has been incorporated into standardized patient risk groupings, which are used to guide therapeutic management. The rate of tumor marker decay after radical orchiectomy is an important index to monitor, as a slow decline might be indicative of metastatic disease and should prompt a thorough systemic survey. The rate of tumor marker decline is already being utilized in the setting of metastatic GCTs to determine response to chemotherapy, and has been used in some scenarios to individualize the type of chemotherapy patients received. Compared to any other solid organ malignancy, the role of serum tumor markers in GCT is unprecedented; these markers are instrumental in the diagnosis and management of testicular GCT.

No clear evidence for an association between GH replacement and relapse of intracranial germ cell tumours: single centre and KIMS experience

GH replacement (GHR) is well established, and has been widely accepted to be safe in patients with a wide spectrum of pituitary pathologies. However, GHR in patients with treated germ cell tumours (GCTs) remains controversial, and its use has been cautioned (1, 2). Anecdotal experience from our centre and elsewhere (1–3) suggests that vigilant monitoring is mandatory in treated GCTs who are GH replaced. There are no published studies of long-term outcome and recurrence rates after GHR in treated GCTs. We have therefore surveyed our long-term experience with GHR in 18 adult patients with previously treated GCTs and a global experience of 142 patients from the KIMS database (Pfizer International Metabolic Database) in this diagnostic category in order to determine whether GHR plays a role in tumour relapse. This is a longitudinal observational study reporting a single centre experience and global experience using the KIMS database. The study groups comprised 18 consecutive patients with GCT treated at St Bartholomew’s Hospital, London (SBH) (median duration of follow-up from diagnosis of GCT 13 years (range 0.5–44)) and 142 patients with GCT enrolled in the KIMS database (median duration of follow-up 14.8 years (0.7–36.4)). The relapse rates pre-GHR and during GHR and relapse-free survival were evaluated. The characteristic and treatments of SBH and KIMS patients are shown in Table 1. In the SBH cohort, there were three relapses prior to GHR. All three patients had a histological diagnosis of non-germinomatous GCT (NGGCT), and had been treated with chemotherapy and/or surgery as primary treatment; radiotherapy was subsequently used after first relapse of disease; none of the patients received radiotherapy or craniospinal irradiation (CSI) as initial treatment. Four patients, two with germinomatous GCT (GGCT) and two with NGGCT, relapsed after GHR. Of the patients demonstrating a first relapse, only one had been treated previously with CSI. One patient relapsed prior to GHR, and was retreated successfully with external beam radiotherapy to the primary site of disease together with chemotherapy, but subsequently also relapsed after GHR. The estimated relapse rates were 240 and 323 per 10-000 patient-years, pre-GHR and during GHR respectively. The relative risk (RR) of relapsing after GHR was 1.34 (95% confidence interval (95% CI): 0.23–7.83; PZ0.73). Five instances of relapse were reported during KIMS follow-up. Of interest, two of these patients had never been treated with GHR (true nao ¨ve) before KIMS entry. The most relevant comparison of relapse rate during versus prior to GHR is for true nao ¨ve patients. This group had a RR of relapse during KIMS of 3.40 (95% CI: 0.26–101.4; PZ0.36). For the semi- and non-nao ¨ve patients (previously treated with GH within 6 months or !6 months before KIMS entry), the RR of relapse during KIMS was statistically similar to the true nao ¨ve group, or 2.62 (95% CI: 0.45–15.3; PZ0.27). RR for nao ¨ve versus semi- or non-nao ¨ve patients (including pre KIMS experience) was 1.36 (95% CI: 0.28–5.46; PZ0.65), indicating similar reported relapse rates between true nao ¨ve and those not true nao ¨ve. For all KIMS patients, the estimated relapse rates were 26.6 and 77.2 per 10-000 patient-years, pre-KIMS and during KIMS entry respectively. The RR of relapse during KIMS for all patients was 2.90 (95% CI: 0.73–12.13; PZ0.13). Our results do not support the hypothesis that GHR increases the recurrence of GCT. In view of the relative rarity of intracranial GCT, we elected to utilise longitudinal follow-up and calculation of relapse frequency expressed per patient years. Despite the variation in treatment modalities, there appeared to be similar relapse rate before and after exposure to GHR in the SBH cohort. Of particular interest, most relapses were NGGCT, which is well known to have a higher risk of relapse. Furthermore, the risk of relapse is also enhanced with the lack of use of radiotherapy as primary treatment. In general patients with NGGCT and those not treated with CSI appeared to have a worse relapsefree survival but no statistical significance was observed. The data from the KIMS do not provide evidence for an association between GHR and relapse. The KIMS relapse rate appears to be lower pre-KIMS than during KIMS, but the difference was not statistically significant. The disparity in recurrence frequency between the SBH and

Testicular seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Testicular seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

A novel SRY missense mutation affecting nuclear import in a 46,XY female patient with bilateral gonadoblastoma

Patients with disorders of sex development (DSD), especially those with gonadal dysgenesis and hypovirilization, are at risk of developing the so-called type II germ cell tumors (GCTs). Both carcinoma in situ and gonadoblastoma (GB) can be the precursor lesion, resulting in a seminomatous or non-seminomatous invasive cancer. SRY mutations residing in the HMG domain are found in 10-15% of 46,XY gonadal dysgenesis cases. This domain contains two nuclear localization signals (NLSs). In this study, we report a unique case of a phenotypical normal woman, diagnosed as a patient with 46,XY gonadal dysgenesis, with an NLS missense mutation, on the basis of the histological diagnosis of a unilateral GB. The normal role of SRY in gonadal development is the upregulation of SOX9 expression. The premalignant lesion of the initially removed gonad was positive for OCT3/4, TSPY and stem cell factor in germ cells, and for FOXL2 in the stromal component (ie, granulosa cells), but not for SOX9. On the basis of these findings, prophylactical gonadectomy of the other gonad was performed, also showing a GB lesion positive for both FOXL2 (ovary) and SOX9 (testis). The identified W70L mutation in the SRY gene resulted in a 50% reduction in the nuclear accumulation of the mutant protein compared with wild type. This likely explains the diminished SOX9 expression, and therefore the lack of proper Sertoli cell differentiation during development. This case shows the value of the proper diagnosis of human GCTs in identification of patients with DSD, which allows subsequent early diagnosis and prevention of the development of an invasive cancer, likely to be treated by chemotherapy at young age.

Testicular non-seminoma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

Testicular non-seminoma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

Evaluation of PS beta 1G and other tumor markers in germ cell tumors of the testis.

Pregnancy Specific beta 1 Glycoprotein (PS beta 1G), human choriogonadotropin (hCG), alpha foeto protein (AFP) and Carcino Embryonic Antigen (CEA) were assayed in 58 patients with active germ cell tumors and 20 patients in complete clinical and radiological remission. The markers were negative in all the cases in remission as well as in one case of pure teratoma. The positivity rate of the four markers together is 75%, which is better than for any marker alone. All the markers except AFP seem ubiquitous with respect to the histological classification. The highest positivity rate is obtained for hCG in all the histological types. PS beta 1G is related to hCG but its positivity rate is quite lower. AFP is mainly related to embryonal carcinoma but can be associated with any type of tumor except seminoma. CEA is less frequently positive, always associated with other markers and seems therefore useless for the diagnosis of germ cell tumors.

46, XY Pure Gonadal Dysgenesis and Tumoral Risk

Purpose Gonadal dysgenesis corresponds to an impaired development of the gonad. One of its major characteristic is its high propensity to malignancy. This study presented the cases of 46, XY pure gonadal dysgenesis (GD) managed in our center over an 18 years period. Material and Methods The charts of 10 patients treated for 46, XY pure GD (non ambiguous female phenotype) were reviewed. Results The diagnosis circumstances were: Gonadal tumour (2 girls): dysgerminomas. In the first case (7 years old), the diagnosis of GD was made post operatively. For the other case (17 years old), this diagnosis was suspected on the association of tumour with slight pubertal development and low HCG blood level. A preoperative karyotype confirmed the diagnosis. Genetic familial investigations in these 2 families led to diagnose 4 additional cases of affected children. Amenorrhea (2 patients, aged 15 and 23 years) Clitoromegaly (1 patient, neonate) Campomelic dysplasia (1 patient, 4 years) Thus, bilateral gonadectomy was performed for therapeutic reasons in the 2 cases of dysgerminomas. In the remaining 8 patients, gonadectomy was performed for prophylactic reasons (median age 7.25 years, range 0-23) but revealed 5 gonadoblastomas with an associated dysgerminoma in one case (11 years old). Of note, the 23 year-old patient seen for amenorrhea had breast and pubic hair development related to hormonal tumoral secretion. Conclusions A gonadal tumour arising in girl with pubertal delay may be related to the dysgenesis of this gonad. The diagnosis of germ cell tumour in girls with low HCG level is likely to be a dysgerminoma.The diagnosis of dysgerminomas should warrant karyotype study and familial screening if 46, XY pure GD is confirmed and should drive to early removal of the gonads.

Cisplatin and Etoposide in Childhood Germ Cell Tumor: Brazilian Pediatric Oncology Society Protocol GCT-91

In 1988, we formed a consortium of Brazilian institutions to develop uniform standards for the diagnostic assessment and multidisciplinary treatment of children and adolescents with germ cell tumors. We also implemented the first childhood Brazilian germ cell tumor protocol, GCT-91, evaluating two-agent chemotherapy with cisplatin and etoposide (PE). We now report on the clinical characteristics and survival of children and adolescents with germ cell tumors treated on this protocol. From May 1991 to April 2000, 115 patients (106 assessable patients) were enrolled onto the Brazilian protocol with a diagnosis of germ cell tumor. Patients were treated with surgery only (n = 35) and chemotherapy (n = 71). Important prognostic factors included stage (P = .025), surgical procedure at diagnosis according to resectability (P < .032), and abnormal lactate dehydrogenase value at diagnosis (P < .001). The improvement in survival by the introduction of a standard protocol is an important achievement. This is of particular importance for smaller institutions with previous limited experience in the treatment of childhood germ cell tumors. In addition, the results of a two-agent regimen with PE were favorable (5-year overall survival rate is 83.3% for patients in the high-risk group [n = 36] who received PE v 58.8% for patients in the high-risk patients group who received PE plus ifosfamide, vinblastine, and bleomycin [n = 17; P = .017]). Thus for selected patients, complex three-agent regimens may not be necessary to achieve long-term survival, even for some patients with advanced disease.

Cytologic features of extragonadal germ cell tumors

The objective of the current study was to evaluate and describe the cytologic features of extragonadal germ cell tumors (GCTs), both primary and metastasis from gonadal sites, in fine-needle aspiration cytology. Aspirates from 88 extragonadal GCTs were retrieved with their clinical features and cytologic smears. The smears were assessed for cellularity, cell patterns, and cytologic features, which were summarized. Histopathology was available in 47 cases, and cytohistologic correlation was done in all such cases. Of 88 cases, 57 with adequate cytologic material were analyzed. Each type of GCT, except for embryonal carcinoma, had characteristic morphologic features. Seminomas had dyscohesive tumor cells with well defined, vacuolated cytoplasm; prominent nucleolus; and background lymphocytes. 'Tigroid' background was noted in only a minority of cases. Yolk sac tumors revealed papillary fragments of tumor cells with metachromatic basement membrane-like material in the fragments. Mixed germ cell tumors were difficult to diagnose except for cases in which more than 1 type of GCT was observed on cytologic smears. In 37% of cases with mixed GCT, only 1 component was observed on cytology. Fine-needle aspiration cytology can reliably offer a diagnosis of GCT at extragonadal sites, even in rare locations and in patients in whom metastatic tumor may be the first clinical presentation. Immature teratoma and mixed GCTs pose a significant problem in cytology because of sampling error on needle aspiration. At extragonadal sites, the list of differential diagnoses is wider than that for gonadal GCTs.

Method Validation for Cerebral Spinal Fluid Human Chorionic Gonadotropin Measurement with the Advia Centaur®2

Intracranial germ cell tumors account for 0.4%–3.4% of all brain tumors (1). These tumors can be divided into 2 groups, germinomas and nongerminomatous germ cell tumors. Germinomas, which are fairly treatable, arise from primordial germ cells that fail to migrate correctly in embryogenesis. Nongerminomatous germ cell tumors (including choriocarcinomas), which are more refractory to treatment, are differentiated tumors. Measurement of human chorionic gonadotropin (hCG)1 is an important adjunct method in the diagnosis of germ cell tumors. At high concentrations hCG can be detected in serum, but measurement of hCG concentrations in cerebral spinal fluid (CSF) is a more sensitive and reliable indicator of tumor presence (1). Pure germinomas are associated with very low concentrations of hCG in both serum and CSF. A subset of nongerminomatous germ cell tumors contains syncytiotrophoblastic giant cells. These tumors are associated with moderately increased concentrations of hCG (<1000 IU/L) in the serum, CSF, or both, and the survival rate in patients suffering these tumors is poorer than that for patients with pure germinomas …