Dominik T. Schneider

Germ-cell tumors in childhood and adolescence

Summary In mature and immature teratoma the treatment is surgical. The risk of recurrence can be estimated from the parameters primary site (with the coccygeal tumors being most at risk), histological grade of immaturity and completeness of the primary resection including the adjacent organ of origin (coccyx, ovary, testis etc.). In case of a microscopically complete tumor resection there is no role for adjuvant chemo- or radiotherapy irrespective of the histological grade of immaturity. Malignant germ-cell tumors (GCT) account for 2.9% of all malignant tumors of children younger than 15 years of age. More than half of the tumors occur at extragonadal sites such as the ovaries (26%), the coccygeal region (24%), the testes (18%) and the brain (18%) represent then primary sites. In patients with extensive tumor growth, metastatic disease or secreting intracranial tumors a delayed tumor resection after preoperative chemotherapy is preferable. In these patients malignant non-seminomatous GCT may be diagnosed clinically due to the increased serum or cerebrospinal fluid levels of the tumor markers AFT and/or [J-HCG. Current risk adapted treatment protocols containing cisplatinum allow long-term remissions in about 80% including patients with bulky or metastatic tumors. In the cisplatinum era the prognostic factors like histology, primary site of the tumor and initial tumor stage have partly lost their former impressive significance in infants and children. On the other hand the completeness of the primary tumor resection according to oncological standards has been established as the most powerful prognostic parameter superior to tumor marker levels or primary site of the tumor.

Renal medullary carcinoma: clinical, pathologic, immunohistochemical, and genetic analysis with pathogenetic implications

OBJECTIVES To investigate the pathologic, clinical, and genetic features of renal medullary carcinomas (RMCs) in search of clues to their pathogenesis. METHODS We analyzed 40 RMCs for clinical features, for immunohistochemical expression using a panel of markers, and for genetic changes using comparative genomic hybridization. RESULTS Patients presented at 5 to 32 years of age, and 82% were African American. All patients tested had sickle cell trait or disease. Seven patients presented with suspected renal abscess or urinary track infection without a clinically recognizable mass. Of the 15 tumors able to be analyzed, all were positive for epithelial markers CAM 5.2 and epithelial membrane antigen. All were negative for high-molecular-weight cytokeratin 34betaE12. Cytokeratins 7 and 20 and carcinoembryonic antigen were heterogeneous and variable. Ulex was focally positive in a minority of cases. Eight of 12 tumors showed significant positivity for TP53 protein (greater than 25% nuclear positivity). All tumor tested (n = 8) were strongly positive for vascular endothelial growth factor and hypoxia inducible factor. Of nine tumors analyzed for genetic gains and losses using comparative genomic hybridization, eight showed no changes and one showed loss of chromosome 22. Survival ranged from 2 weeks to 15 months (mean 4 months). CONCLUSIONS These findings suggest that RMC is clinically and pathologically distinct from collecting duct carcinoma. The hypothesis that chronic medullary hypoxia secondary to hemoglobinopathy may be involved in the pathogenesis of RMC is suggested by strong vascular endothelial growth factor and hypoxia inducible factor expression and positivity for TP53.

Ovarian Sex Cord–Stromal Tumors in Children and Adolescents

PURPOSE To develop diagnostic standards and a risk-adapted therapeutic strategy for ovarian sex cord-stromal tumors (OSCST). PATIENTS AND METHODS Fifty-four patients were prospectively enrolled as follow-up patients onto the German Maligne Keimzelltumoren protocols. Surgical protocols and histopathology were reviewed centrally (53 patients with complete data). Surgery included ovariectomy in 18 patients, salpingo-ovariectomy in 34 patients, and hysterectomy in one patient. Patients with stage IA tumors were followed-up at regular intervals, whereas nine patients with stage IC and six patients with stage II to III tumors were treated with cisplatin-based chemotherapy. RESULTS International Federation of Gynecology and Obstetrics stage was IA in 27 patients, IC in 21 patients, II in three patients, and III in three patients. After a median follow-up of 59 months (range, 6 to 193 months), event-free survival +/- SD was 0.86 +/- 0.05 (47 of 54 patients) and overall survival was 0.89 +/- 0.05 (49 of 54 patients). Prognosis correlated with stage (event-free survival +/- SD: IA, 1.0 [27 of 27 patients]; IC, 0.76 +/- 0.09 [16 of 21 patients]; and II/III, 0.67 +/- 0.19 [four of six patients]; P =.02). Ten of 15 patients treated with chemotherapy, including four of six stage II to III patients, are alive after a median follow-up of 33 months. CONCLUSION On the basis of a standardized clinical and histopathologic assessment, risk-adapted therapeutic strategies for OSCST can be evaluated. Considering our experience, we would recommend that stage IA tumors be followed up at regular intervals, whereas we would recommend cisplatin-based chemotherapy in stage IC tumors with preoperative rupture or malignant ascites, especially those with high mitotic activity. Finally, cisplatin-based chemotherapy also seems to be effective in advanced-stage tumors.

Mesenchymal Chondrosarcoma of Soft Tissues and Bone in Children, Adolescents, and Young Adults : Experiences of the CWS and COSS Study Groups

Mesenchymal chondrosarcoma (MCS) is a rare tumor with a strong tendency toward late recurrences leading to reported 10‐year survival rates below 50%. The recommended treatment is resection with wide margins; the effectiveness of chemo‐ and radiotherapy remain poorly defined. As reports about MCS in young patients are scarce, treatment and outcomes of children/adolescents/young adults in the CWS and COSS studies were investigated.

Microarray analysis of Ewing's sarcoma family of tumours reveals characteristic gene expression signatures associated with metastasis and resistance to chemotherapy

In Ewings sarcoma family of tumours (ESFT), the clinically most adverse prognostic parameters are the presence of tumour metastasis at time of diagnosis and poor response to neoadjuvant chemotherapy. To identify genes differentially regulated between metastatic and localised tumours, we analysed 27 ESFT specimens using Affymetrix microarrays. Functional annotation of differentially regulated genes revealed 29 over-represented pathways including PDGF, TP53, NOTCH, and WNT1-signalling. Regression of primary tumours (n=20) induced by polychemotherapy was found to be correlated with the expression of genes involved in angiogenesis, apoptosis, ubiquitin proteasome pathway, and PI3 kinase and p53 pathways. These findings could be confirmed by in vitro cytotoxicity assays. A set of 46 marker genes correctly classifies these 20 tumours as responding versus non-responding. We conclude that expression signatures of initial tumour biopsies can help to identify ESFT patients at high risk to develop tumour metastasis or to suffer from a therapy refractory cancer.

DIAGNOSTIC VALUE OF ALPHA1-FETOPROTEIN AND BETA-HUMAN CHORIONIC GONADOTROPIN IN INFANCY AND CHILDHOOD

This article provides a comprehensive review of the current literature and summarizes the experience of the German cooperative protocols for nontesticular germ cell tumors (MAKEI) on the use of alpha1

Primary Mediastinal Germ Cell Tumors in Children and Adolescents: Results of the German Cooperative Protocols MAKEI 83/86, 89, and 96

PURPOSE To evaluate children and adolescents with primary mediastinal teratoma and malignant germ cell tumors (GCTs). PATIENTS AND METHODS Forty-seven patients from the German nontesticular GCT studies were analyzed (median age, 2.5 years; range, neonate to 17 years). Teratoma (n = 21) were resected, and no adjuvant treatment was given. Malignant GCTs (n = 26) were treated with cisplatin-based chemotherapy and resection. Three of 26 patients underwent radiotherapy. RESULTS In all patients with teratoma, tumor markers were normal. Surgery of teratoma was complete in 17 of 21 patients and microscopically incomplete in four of 21 patients, and we observed no relapse after a median follow-up of 29 months. In 23 of 26 patients with malignant GCTs, alpha-fetoprotein and/or beta-human chorionic gonadotropin were elevated. Twelve of 26 patients received adjuvant chemotherapy after initial resection, which was complete in six of 12 patients, whereas delayed resection after preoperative chemotherapy was complete in 10 of 11 patients (P =.03). Four of six patients underwent second-look thoracotomy after incomplete primary surgery. Three of 26 patients did not undergo tumor resection. The final completeness of resection was the strongest prognostic indicator (event-free survival ¿EFS, 0.94 +/- 0.06 v 0.42 +/- 0.33; P <.002). Local stage and distant metastases were not prognostically significant at the.05 level. For all malignant GCTs, the 5-year survival rate was 0.87 +/- 0.05 (median follow-up, 51 months), with an EFS of 0.83 +/- 0.05. CONCLUSION The prognosis of mediastinal teratoma is excellent after complete or microscopically incomplete resection. In children with malignant GCT, the prognosis is favorable with a therapeutic strategy of delayed resection after preoperative chemotherapy. In most children, the diagnosis can be based on elevated tumor markers and imaging. Biopsy is indicated in nonsecreting GCT.

Genetic analysis of mediastinal nonseminomatous germ cell tumors in children and adolescents

Primary mediastinal germ cell tumors (M‐GCTs) represent a heterogeneous group of tumors that varies with regard to age at presentation, histologic differentiation, and outcome. We retrospectively analyzed archival tissue samples of mediastinal mature and immature teratomas (n = 15) and malignant nonseminomatous M‐GCTs (n = 20) with comparative genomic hybridization (CGH). The aim of this study was to define distinct genetic subgroups of M‐GCT among the pediatric cohort that may differ in their clinical behavior and prognosis. All pure teratomas showed normal CGH profiles. Malignant M‐GCTs in infants and children < 8 years old most frequently showed a gain of 1q, 3, and 20q and a loss of 1p, 4q, and 6q. Gain of 12p and sex chromosomal abnormalities were not observed in this age group. In contrast, the gain of 12p was the most common aberration in M‐GCTs that arose in children ≥ 8 years old. Additional recurrent changes included the loss of chromosome 13 and the gain of chromosome 21. All ten adolescents with malignant M‐GCT were male, and five showed a gain of the X chromosome. In two of these five patients, Klinefelter syndrome was confirmed by cytogenetic analysis or by fluorescence in situ hybridization (FISH). In conclusion, CGH analysis of M‐GCTs defines distinct genetic subgroups. Mediastinal teratomas show no genetic gains or losses. Malignant M‐GCTs in children < 8 years old show the same pattern of gains and losses identified in sacrococcygeal and testicular GCTs at this age, and they lack sex‐chromosomal abnormalities. Malignant M‐GCTs in children ≥ 8 years old show the same genetic profile previously reported in gonadal GCTs at this age. In addition, approximately 50% demonstrate a gain of the X chromosome, consistent with Klinefelter syndrome. Cooperative group studies reveal a significantly better prognosis of malignant M‐GCT arising in infants compared to that in adolescents, suggesting that these genetic differences are associated with differences in clinical behavior.

Multimodal Treatment of Malignant Sacrococcygeal Germ Cell Tumors: A Prospective Analysis of 66 Patients of the German Cooperative Protocols MAKEI 83/86 and 89

PURPOSE To evaluate a multimodal approach including surgery and cisplatinum chemotherapy for treatment of children with malignant sacrococcygeal germ cell tumors (GCT) and to compare adjuvant and neoadjuvant strategies in advanced tumors. PATIENTS AND METHODS Between 1983 and 1995, 71 patients with malignant sacrococcygeal GCT were prospectively enrolled onto the German protocols for nontesticular GCT Maligne Keimzelltumoren 83/86 and 89. Five patients who received no chemotherapy (n = 2) or nonplatinum chemotherapy (n = 2) or who did not undergo tumor resection (n = 1) were excluded from this analysis. Among the 66 patients analyzed were 14 boys and 52 girls. The median age was 17.4 months (range, 7 months to 119 months). Median follow-up was 79 months (range, 4 months to 145 months). RESULTS Fifty-two patients presented with locally advanced stage T2 tumors, and 30 patients had distant metastases at diagnosis. Patients received a median of eight cycles (range, four to nine cycles) of cisplatinum-based chemotherapy. Thirty-five patients underwent tumor resection at diagnosis and received adjuvant cisplatinum-based chemotherapy (group A). Thirty-one patients received up-front chemotherapy followed by delayed tumor resection (group B). Group B included more metastatic tumors than group A (group B, 19 of 31 patients; group A, 11 of 35 patients, P =.01). Preoperative chemotherapy facilitated complete tumor resections (group B, 20 of 31 patients; group A, five of 35 patients, P <.001) and avoided second-look surgery. Metastases at diagnosis and completeness of the first attempt of tumor resection were significant prognostic predictors; however, metastases were not predictive for patients treated with up-front chemotherapy. At 5 years follow-up, event-free survival was 0.76 +/- 0.05 (50 of 66 patients), and overall survival was 0.81 +/- 0.05 (54 of 66 patients). Four patients died as a result of therapy-related complications, and eight patients died of their tumors. Patients with locally advanced and metastatic tumors (T2b M1) fared better with neoadjuvant treatment [overall survival: 0.83 +/- 0.09 (16 of 19 patients) versus 0.45 +/- 0.15 (five of 11 patients), P =.01]. CONCLUSION Even locally advanced and metastatic sacrococcygeal GCT can be successfully treated with up-front cisplatinum-based chemotherapy followed by delayed but complete tumor resection.

Introduction of the oncological pediatric risk of mortality score (O-PRISM) for ICU support following stem cell transplantation in children

Prognostic scoring systems based on physiological parameters have been established in order to predict the outcome of ICU patients. It has been demonstrated that the predictive value of these scores is limited in patients following hematopoietic stem cell transplantation (HSCT). Therefore, we evaluated patients from the Düsseldorf pediatric stem cell transplantation center with regard to predisposing factors and prognostic variables for ICU treatment and outcome. Between January 1989 and December 1998, 180 HSCT have been performed. The clinical, laboratory and HSCT-related parameters such as conditioning treatment, engraftment, GVHD, infections and HSCT toxicity were prospectively recorded and retrospectively analyzed. Established pediatric scoring systems (PRISM, TISS, P-TISS) were applied. Twenty-eight patients required intensive care (16 male, 12 female, median age: 10.9 years (range: 0.4 to 18.9 years), five autologous, 13 allogeneic-related and 10 unrelated transplanted patients). Ventilator-dependent respiratory failure was the most frequent cause of admission to the ICU (n = 23). Fourteen of 28 patients were discharged from ICU, and six of 28 patients achieved a long-term survival (110 to 396 weeks). At admission to the ICU, impaired cardiovascular status, high CRP levels and presence of macroscopic bleeding were each associated with fatal outcome (P < 0.05). the pediatric risk of mortality (prism) score was not prognostically significant at the 0.05 level. long-term survival after discharge from the icu correlated with hsct-related parameters such as the type of transplant and severity of gvhd (P = 0.002). by introduction of hsct related parameters such as severity of gvhd (grade 2: 2 points; grade >2: 4 points), crp-level (>10 mg/dl: 4 points), and presence of macroscopic bleeding (4 points) into the PRISM score a new oncological PRISM (‘O-PRISM’) score was established. This score significantly correlated with the risk of mortality in the ICU (P = 0.01). In conclusion, the new O-PRISM score accurately characterizes the clinical situation of children requiring ICU treatment following HSCT. It distinguishes more appropriately between success and failure of ICU treatment following HSCT than the standard prognostic scores. It needs to be evaluated in future prospective studies of critically ill children after HSCT. Bone Marrow Transplantation (2000) 25, 1079–1086.