Long-term follow-up and residual sequelae after treatment for intracerebral germ-cell tumour in children and adolescents.

BACKGROUND: Information on long-term follow-up of children and adolescents treated for intracerebral germ-cell tumour is scant. We report on the results of a small series of patients treated at a single institution. PATIENTS AND METHODS: Hospital records from 15 patients treated between 1980 and 1998 were reviewed. An attempt was made to correlate sequelae to tumour location and treatment modalities. RESULTS: This cohort constitutes 5.5% of all brain tumours diagnosed at our institution. HISTOLOGY: 10 germinomas, 2 benign teratomas, 2 malignant teratomas, and one mixed germ-cell tumour. Overall survival was 87%, with a mean follow-up time of 7 years and 8 months. The majority of patients have long-term sequelae involving one or several organ systems. In 66% endocrine, in 47% ophthalmologic, in 60% neuropsychological defects were observed. Endocrine and ophthalmologic sequelae show a correlation to tumour location. Neuropsychological long-term abnormalities are frequent and are associated with cranial irradiation in particular at young age, but less with tumour location, irradiation dose or surgery. CONCLUSIONS: Our preliminary data suggest that today intracerebral germinomas and mature teratomas have a good prognosis even when a relapse occurs. The outcome for mixed germ-cell tumours and malignant teratomas is less favourable. Although long-term sequelae are present in the majority of patients, there is some evidence that patients treated after 1990 suffer fewer severe long-term defects, thereby indicating that recent treatment protocols may result in a reduction of sequelae.

Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90.

In study NHL-BFM 90, we investigated whether the serum lactate dehydrogenase (LDH) concentration and early response are useful markers for stratification of therapy for childhood B-cell neoplasms in addition to stage, if the outcome of patients with abdominal stage III and LDH >/=500 U/L can be improved by high-dose (HD) methotrexate (MTX) at 5 g/m(2) instead of intermediate-dose (ID) MTX at 500 mg/m(2) in the preceding study 86; whether 2 therapy courses are enough for patients with complete resection; and whether combined systemic and intraventricular chemotherapy is efficacious for central nervous system-positive (CNS(+)) patients. After a cytoreductive prephase, treatment was stratified into 3 risk groups: patients in R1 (completely resected) received 2 5-day courses (ID-MTX, dexamethasone, oxazaphorins, etoposide, cytarabine, doxorubicin, and intrathecal therapy), patients in R2 (extra-abdominal primary only or abdominal tumor and LDH <500 U/L) received 4 courses containing HD-MTX, and patients in R3 (abdominal primary and LDH >/=500 U/L or bone marrow/CNS/multilocal bone disease) received 6 courses. Incomplete responders after 2 courses received an intensification containing HD-cytarabine/etoposide. Patients with no or necrotic tumor thereafter received 3 more courses; 6 patients with viable tumor received autologous bone marrow transplantation. From April 1990 through March 1995, 413 evaluable patients were enrolled (R1, 17%; R2, 40%; and R3, 43%). The 6-year event-free survival (pEFS) was 89% +/- 2% for all and 100%, 96% +/-2%, and 78% +/- 3% in R1, R2, and R3, respectively. The pEFS of patients with abdominal stage III and LDH >/=500 U/L was 81% +/- 4% as compared with 43% +/- 10% in study 86. Of 26 CNS(+) patients, 5 died early, but only 3 relapsed.

[Insufficient understanding of second tumors after childhood neoplasms in Switzerland]. / Ungenügende Erfassung von Zweittumoren nach Neoplasien im Kindesalter in der Schweiz.

Second malignancy after childhood neoplasms is a well-known complication. However, frequency differs considerably according to the types of primary neoplasm and the specifics of therapy. Ten patients with a second malignancy after being cured of the primary tumor are described. There were 2 patients with acute lymphoblastic leukemia, one with non-Hodgkin's lymphoma, and one with breast cancer after Hodgkin's disease. Two patients with heritable retinoblastoma developed osteosarcomas in the irradiation field after a latent period of 7 and 14 years respectively. There was another osteosarcoma in a Wilms' tumor survivor. One patient with acute lymphoblastic leukemia developed a secondary AML 10 years after achieving initial remission, and a meningioma was diagnosed in another patient with cured acute lymphoblastic leukemia. One patient died of peritoneal sarcomatosis of unknown origin 20 years after the diagnosis of acute myeloid leukemia. All patients received radiotherapy for the primary neoplasms. Secondary neoplasms in other patients were probably missed because they occurred in adulthood when the patients were transferred to other medical centres. It is impossible to trace these patients because central registration of patients with neoplasms is lacking. It is therefore important to establish a central cancer registry for the whole of Switzerland. Second malignancy after childhood cancer is not a rare event and requires long-term follow-up of patients with neoplasms.

Cytogenetic abnormalities in Langerhans cell histiocytosis.

We present the cytogenetic investigations of five histiocytic tumour lesions from children. In four cases there was a confirmed diagnosis of Langerhans cell histiocytosis (LCH) and one case of histiocytosis that did not fulfil all the criteria for true LCH. All five cases showed cytogenetic abnormalities, including the first report of an abnormal clone in LCH. The clone showed a t(7;12)(q11.2;p13) translocation and was detected in only a small percentage of cells. This case and a further three also contained non-clonal abnormalities and an increase in chromosome breakage. The fifth case, the only one in which no acquired abnormalities were seen, had a constitutional paracentric inversion of chromosome 13q.

Primary resection of soft-tissue sarcomas: yes and no.

UNLABELLED: The primary tumour site is the most common origin in relapses of soft-tissue sarcomas (75%). Therefore, prevention of a relapse depends mainly on local tumour control in the primary therapeutic regimen. There are three modalities of treating children with sarcomas: surgical removal, radiation therapy and systemic chemotherapy. The aim is to reach a complete removal of the primary tumour and to preserve all vital and functionally useful structures. Under this aspect we evaluated the results of 22 patients, treated for soft-tissue sarcoma at the University Children's Hospital, Zurich, between 1989 and 1995. The age of the patients ranged between 3 and 16 years. The tumours of 11 patients were primarily resected, but in 9 patients the removal was incomplete (7 microscopically, Z macroscopically). Only 2 patients had a complete primary removal of their tumours, both being paratesticular sarcomas. In 11 patients an incisional biopsy was performed. Two of these patients had stage IV initially. Two tumours were removed completely in a second operation. Six patients did not need any further resections because of a very good response to chemotherapy. In 1 patient with unresectable tumour it was possible to remove the tumour almost completely after primary chemotherapy. CONCLUSIONS: Our experience with primary chemotherapy in soft tissue sarcomas showed the following advantages: 1. The low morbidity after biopsy allows a rapid beginning of the treatment. 2. In case of a very good response to chemotherapy it is possible to avoid a second operation. 3. The information of a poor response to chemotherapy makes the decision for an extensive surgery easier. 4. The possibility of a delayed, but complete removal of a primarily unresectable tumour will be more likely after chemotherapy. 5. Only a small group of tumours should be considered for removal during a primary surgical procedure.

Routine karyotyping in Wilms tumor.

We describe the karyotypes of nine Wilms tumors (WT). Four tumors were initially karyotyped from diagnostic needle core biopsies, 3 after postchemotherapy tumor resection and the remainder from xenografts grown in nude mice. The 9 nephroblastomas were composed of 7 with favorable histology (intermediate-grade malignancy) and 2 with unfavorable histology (anaplastic or high-grade malignancy). The 7 tumors with favorable histology had karyotypes typical of WT, with the previously described nonrandom abnormalities +1q, +6, +7, +8, +12, +13, +18 and structural abnormalities of 1p and 16q present in at least 1 case. The most common abnormalities were trisomy 18 (4 cases) and +1q (3 cases). The 2 tumors with unfavorable histology both had complex karyotypes atypical for WT. We suggest that cytogenetics can act as a marker when histologic grade is in doubt. Karyotypic analysis from needle core biopsies was attempted in 6 samples, including 1 from a nephrogenic rest (NR) of the nonaffected kidney and provided a result on 5 occasions. The NR were present in the sole case with a constitutional abnormality, a mosaic partial duplication of 8q. However, both the tumor and the NR were apparently derived from the normal cell line. Here we demonstrate that a cytogenetic result can be routinely obtained from needle core biopsies and will thus facilitate true diagnostic tumor karyotypes in both WT and other tumors.

A childhood fibrolamellar hepatocellular carcinoma with increased aromatase activity and a near triploid karyotype.

We report a 15-year-old boy with hepatocellular carcinoma (HCC) of the fibrolamellar type. He presented with advanced disease and a non-resectable tumor. Clinical features included marked gynecomastia which had been present for 3 years, failure to enter puberty, and failure to thrive. These features might have been due to a high aromatase activity of the tumor. The course of the illness suggested that the tumor had been present for at least 3 years prior to diagnosis. At diagnosis the patient had multiple metastases which included infiltrated ascites. Cytogenetic analysis of the ascites revealed a near triploid karyotype with cell-to-cell variation and an abnormality of chromosome 1 q. This to our knowledge is the first karyotype report of fibrolamellar HCC in a child.

Childhood NHL in Switzerland: incidence and survival of 120 study and 42 non-study patients.

Based on the Swiss Pediatric Oncology Group (SPOG) cancer registry data during 1981-1991, a high average incidence of 8 new NHL per million children younger than 15 years per year was found. Of 162 children with NHL registered in 1976-1991, 120 were study patients, i.e., officially registered and treated according to SPOG or Pediatric Oncology Group (POG) protocols, while 42 were non-study patients, i.e., patients not officially enrolled on protocols. Overall, 91 of 120 (76%) study patients remained alive. Seventy-nine study patients were treated according to older SPOG protocols, and 53 (67%) of these survived, while 38 of 41 (93%) study patients treated according to newer POG protocols remained alive (P = 0.0068). Only 22 (52%) of the 42 non-study patients survived (P = 0.0001). There was no improvement if the survival of non-study patients before and since 1986 was compared. Population-based treatment results in Switzerland were similar to those in the United Kingdom. They provided an important base for the development of future treatment strategies.

Non-Hodgkin's lymphoma in four children infected with the human immunodeficiency virus. Association with Epstein-Barr Virus and treatment.

BACKGROUND: Reports on lymphoid malignancy and its treatment in children infected with human immunodeficiency virus (HIV) are limited. METHODS: Antibodies to Epstein-Barr virus (EBV) were detected by indirect immunofluorescence. DNA was extracted from peripheral blood lymphocytes or biopsy specimens. Polymerase chain reaction was run using primers for EBV. Reaction products underwent Southern blot analysis to confirm EBV specificity. Tumor clonality was assessed by immunohistochemistry and by Southern blot analysis of immunoglobulin heavy-chain and T-cell receptor beta-gene rearrangement. RESULTS: Within 1 year, non-Hodgkin's lymphoma (NHL) was diagnosed in four children infected with HIV. All four were EBV-seropositive and had detectable EBV DNA in peripheral blood lymphocytes. The EBV-linked disorders lymphoid interstitial pneumonia and recurrent parotid enlargement preceded NHL in three and two of the children, respectively. In all four patients, NHL involved at one time the central nervous system (CNS). All three tested NHL tissues were positive for EBV DNA: A 12-week course of chemotherapy given to two children resulted in rapid tumor regression. One of these children experienced meningeal relapse and died 16 months after diagnosis. The other child, who in addition received local irradiation of the affected eye and who underwent surgical removal of the involved ovaries, has been in continuous remission for 20 months. CONCLUSIONS: EBV-associated NHL may be seen more frequently in pediatric patients with HIV. Treatment protocols taking into account NHL propensity for the CNS in this age group need to be developed.

Thymic rebound following successful chemotherapy of B-lymphoma in an adolescent boy.

Four months after termination of successful chemotherapy for epipharyngeal B-non-Hodgkin lymphoma, an enlarging anterior mediastinal mass was discovered in a 15-year-old boy. There was no other suspicion of tumour recurrence. A simple thymic rebound was likely and a conservative management was chosen. Follow up for more than 12 months was uneventful. The frequency of thymic hyperplasia after termination of chemotherapy is discussed. It is a benign immunological rebound phenomenon and does not require operative intervention.

[Treatment of neuroblastoma. Results of therapy at the Zurich University Pediatric Clinic, 1967-1987]. / Neuroblastombehandlung. Therapieresultate der Universitäts-Kinderklinik Zürich, 1967-1987.

Between 1967 and 1987 58 children with the diagnosis of neuroblastoma or ganglioneuroblastoma, all under 10 years of age, were admitted to the University Children's Hospital of Zurich for treatment. According to Evan's classification, 8 (14%) patients had stage I disease, 5 (9%) stage II, 6 (10%) stage III, 26 (45%) stage IV, and 13 (22%) stage IV-S. The 2-year survival rate of 46 patients with adequate follow-up was 6/6 (100%) for stage I, 4/4 (100%) for stage II, 5/6 (83%) for stage III, 6/23 (26%) for stage IV, and 7/7 (100%) for stage IV-S. The excellent results in stage IV-S patients confirm the active but cautious treatment policy. Analysis of catecholamine metabolites in 24-hour urine collections proved to be a reliable method to evaluate the further course: all 21 children who showed complete normalization of metabolite levels during therapy, survived.

Prognostic factor analysis in acute lymphocytic leukemia of childhood.

The analysis of clinical and hematological data for prognostic relevance in 200 children with acute lymphocytic leukemia (ALL), diagnosed between January 1964 and December 1980, showed that the importance of single risk factors has changed due to improvements in therapy. Morphology and cytochemistry lost their prognostic value they had in those patients treated before October 1971. In the children treated in the seventies, the WBC became the most important prognostic factor, followed by infiltrate size and age. (Age was less important than infiltrates for remission duration, but more for survival.) Immunological markers were evaluated in 56 children, since 1974. Because of the small number, no significance as risk factor was found. Those 25% with E+ blasts tended to have only a slightly worse course than "non-T-non-B"-ALL. Treatment became a highly significant risk factor, because of the improvement in results between those patients treated with CALGB protocol 6801 and those on protocol 7111. Two steps were responsible for this: better treatment strategies, and, most important, CNS-prophylaxis (or "sanctuary"-treatment) in all patients. Even in the sixties, where IT methotrexate alone was given sporadically, omitting the CNS-prophylaxis represented an important risk factor. Since 1971, most patients received cranial irradiation or intermediate dose methotrexate as second mode of CNS-prophylaxis. This resulted in a significant decrease in the incidence of CNS relapse. CNS-prophylaxis mode therefore represented a significant prognostic factor, although age, WBC and infiltrates had become more important. Evaluation of the clinical and hematological data gave the following limits for an increased or lesser risk: WBC over 30.G/l: high risk, under 10.G/l: favourable. Age: below 1 year and over 10 years: high risk, 1-2 years: probably moderately increased risk. Infiltrates: no palpable hepatosplenomegaly and no lymph nodes: favourable, all palpable infiltrates: "standard" or increased risk. Platelets (under 30.G/l) represented a minor good risk factor. The common ALL antigen (CALLA) was not yet examined in this series, calling it a favourable factor is based on recent experience from other centers. T-markers are probably not a risk factor by themselves, but other poor prognostic signs are usually associated and of primary importance. If treatment will be based on risk classification, it is important to keep in mind that treatment improvements might change the significance of any prognostic factor completely.

[Hypereosinophilic syndrome in acute lymphatic leukemia]. / Das Hypereosinophiliesyndrom bei akuter lymphatischer Leukämie.

Acute lymphatic leukemia (common-ALL-Ag positive) was found to be the underlying disease in a 4-year-old boy with arthropathy, generalized rash and marked eosinophilia. ALL may be overlooked in the early stages. Cytochemical, chromosomal and immunological markers are needed to distinguish it from other leukemias. As shown by the data of 25 patients from the literature, hypereosinophilic syndrome (HES) influences morbidity and lethality. Hydroxyurea rapidly lowers the eosinophil counts and may therefore prevent the cardiac involvement typical of HES.

Increased prevalence of minor anomalies in childhood malignancy.

Body measurements were taken and the prevalence of major malformations and of 57 minor anomalies was determined in 106 children with malignant disease, in 81 of their sibs, and in 106 control subjects matched to the patients according to sex, age and ethnic origin. Leukaemic children had a significantly smaller head circumference than the corresponding control children, but no significant differences in height, weight, anthropometric and syndromologic indices were found. No differences were observed in the frequency of associated major malformations including renal malformations detectable by sonography. The prevalence of minor anomalies was significantly higher in the patients with malignant disease and their sibs than in the control children: 69.2% of the patients, 63.0% of the sibs and 34.6% of the control subjects had at least one minor anomaly. When two and more minor anomalies were considered, the prevalence figures were 36.5%, 29.6% and 12.5%, respectively. Among the single minor anomalies only the Sydney line was significantly more frequent in patients with solid tumours. No specific association of an individual dysplasia or a pattern of minor anomalies with a given tumour could be established.

[What have morphology and cytochemistry contributed to the diagnosis and treatment of acute lymphatic leukemia of childhood?]. / Was haben Morphologie und Zytochemie zur Diagnostik und Behandlung der akuten lymphatischen Leukämie im Kindesalter beigetragen?

Correlations between morphological and cytochemical classification and treatment results in 200 children with ALL (diagnosed from 1964 to 1980) resulted in small, insignificant differences: FAB-L2 morphology, and undifferentiated cytochemistry resulted in slightly worse remission or survival duration. A significant difference emerged between the best group (FAB-L2 and PAS-positivity) and the worst (FAB-L2 and undifferentiated cytochemistry). All immunologically examined blasts with strong acid phosphatase positivity showed T-cell markers, but not all those with T-cell markers were phosphatase positive. On the whole, the morphologic/cytochemical classification used here is not satisfactory and has declined significantly in importance due to the much improved treatment results since 1970.

[Chance of a second remission in acute juvenile lymphoblastic leukemia with favorable prognosis]. / Chance einer Zweitremission bei prognostisch günstiger kindlicher akuter lyjmphoblastischer Leukämie.

24 children with low risk acute lymphoblastic leukemia (ALL) in first relapse were re-treated with an aggressive protocol. Therapy of the first episode had adopted two different but equivalent approaches (SAKK-ALL "low risk" 76 and CALGB protocol 7611). With one exception, relapse occurred in all children before discontinuation of therapy. complete remission was achieved in 20 of the 24 children (83%). Five of 11 children in whom the length of the second remission could be evaluated had, at the time of the cutoff, been in continuous remission for 18 to 40 months. The therapy displayed considerable toxicity. From this study it is concluded that remission is achieved in the majority of children with first relapse of ALL, but that the remission can be maintained beyond 18 months only in a few children.

[Prognostic value of T-cell markers in juvenile acute lymphatic leukemia]. / Prognostische Bedeutung der T-Zell-Marker bei der akuten lymphatischen Leukämie im Kindesalter.

Of 58 children with acute lymphatic leukemia who had undergone marker studies of blasts, only 6 (10%) had greater than 30 E+ blasts. Of these, 5 had a high WBC and organomegaly, but only 2 suffered a fatal course. Two more have been in CCR for over 5 years despite other risk factors. Patients with less than 30% E+ cells did not differ from common ALL patients clinically or in their response to treatment. However, 3 older children with Hp-positive but E negative blasts had a very high WBC and died without having remission. Only standardized marker studies, treatment and follow-up of a large series of ALL patients will show the importance to be attached to these and other T-cell markers compared with the better-known clinical and hematologic risk factors.

Adjuvant chemotherapy with procarbazine, vincristine and prednisone for medulloblastomas. A preliminary report.

The survival of 20 children with medulloblastoma who received adjuvant chemotherapy with procarbazine, vincristine and prednisone after resection and craniospinal irradiation is compared with the preliminary results of the Children's Cancer Study Group (CCSG) and the international Society of Pediatric Oncology (SIOP) medulloblastoma studies. Survival with the chemotherapy used in the SPOG study ws not superior to the survival of children who received craniospinal irradiation only.

[Acute myelocytic leukemia in childhood: results of treatment from 1964 to 1979]. / Die akuten myeloischen Leukämien im Kindesalter: Behandlungsresultate 1964--1979.

From 1964 to 1979, 57 children with acute myelocytic leukemia have been treated at the University Children's Hospital, Zürich. The overall remission rate was 0.60, with a median remission duration of 2 months and survival of 6.4 months. Patients with FAB type M 1 responded best, but longtime survivors were observed from all FAB types. Whereas in the 1960s only 4/19 achieved (short) remission, now, since the introduction of cytosine arabinoside, remissions are observed on 79% but median survival (10 months) is still short compared with acute lymphocytic leukemia. However, 11/38 children treated since 1971 survived for more than 2 years. Four of these relapsed (after less than 23 months of complete remission), while of the remaining seven, 5 have been off treatment for 5 to 77 months. This group includes children of both sexes, all ages, low and high WBS's, with organ infiltrates (excluding CNS and skin), and in whom the time taken to achieve M 1 marrow played no role. These results show that, with combination chemotherapy including cytosin arabinoside, remission can almost always be attained, but prolonged remission can be maintained only in about 1/5 of these children. The problems of maintenance treatment and CNS-prophylaxis need more attention in the future.

[Prognostic changes in juvenile abdominal non-Hodgkin's lympomas (NHL)]. / Prognostischer Wandel bei den abdominalen Nicht-Hodgkin-Lymphomen (NHL) im Kindesalter.

From 1964-1978 primary non-Hodgkin's lymphoma was diagnosed and treated in 15 children (13 boys and 2 girls). In the 10 patients treated up to 1974, median survival was only 4 months (the longest being 16 months). Since 1974 all such patients have been put on high-dose combined chemotherapy as early as possible. Of 5 children thus treated, 3 have survived for 60, 26 and 11 months respectively and are still alive disease-free. The other two died after 4 1/2 and 5 1/2 months respectively: both had very widespread disease at diagnosis and chemotherapy was delayed by postoperative complications. The 4 most recent tumors have been classified immunologically: 3 were of the B-cell type and exhibited the classic "Burkitt-type" morphology. Two of these patients are alive and well. Although so small a patient material allows no firm conclusions, the authors feel that early intensive chemotherapy may be curative even in this poor-prognosis group of intraabdominal non-Hodgkin's lymphoma.