Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas.

Histopathologic prognostic factors of 295 pretreatment tumors of a total 641 neuroblastomas and ganglioneuroblastomas were studied with the use of the following proposed tumor classification. The tumors were divided into 2 groups: stroma-poor (235 cases) and stroma-rich (60 cases) according to their organizational pattern (stromal development). The stroma-poor group was classified further into 2 subgroups: favorable stroma-poor (84% survival) and unfavorable stroma-poor (4.5% survival) according to the patient's age at diagnosis, degree of maturation, and nuclear pathology [mitosis-karyorrhexis index (MKI)] of the neuroblastic cells. The stroma-rich group was further classified into 3 subgroups: well differentiated (100% survival), intermixed (92% survival), and nodular (18% survival) on the basis of morphology of the immature element in the tumor tissue without regard to patient's age or quantitative maturation. Favorable stroma-poor and well-differentiated and intermixed stroma-rich groups seem to make good prognosis groups (87% survival), which show gradual progression along a maturational sequence according to the age of the patient. Unfavorable stroma-poor and nodular stroma-rich groups form poor prognosis groups (7% survival) and show morphological evidence of malignant or aggressive behavior, such as inappropriate immaturity for age, higher MKI, and gross nodule formation by immature neuroblasts.

Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer.

BACKGROUND: Individuals who had cancer in childhood are at higher risk of developing bone cancer than any other type of second primary cancer. PURPOSE: Using the population-based National Registry of Childhood Tumours in Britain, we investigated the incidence and etiology of second primary bone cancer after childhood cancer in a cohort study and in a case-control study. METHODS: A cohort study of 13,175 3-year survivors of childhood cancer diagnosed in Britain between 1940 and 1983 revealed 55 subsequent bone cancers. A largely nested case-control study comprised 59 case subjects developing second primary bone cancer, and 220 control subjects were selected and matched for sex, type of first cancer, age at first cancer, and interval between diagnosis of first cancer and subsequent bone cancer. Outcome measures were the incidence of bone cancer after childhood cancer, the cumulative dose of radiation received at the site of the second cancer in the case subject and at the corresponding anatomic site in the matched control subjects, and the cumulative dose of alkylating agents and vinca alkaloids received by case and control subjects. RESULTS: The percentage of 3-year survivors developing bone cancer within 20 years did not exceed 0.9%, except following heritable retinoblastoma (7.2%), Ewing's sarcoma (5.4%), and other malignant bone tumors (2.4%). The risk of bone cancer increased substantially with increased cumulative dose of radiation to the bone (P< .001, linear trend). At the highest levels of exposure, however, the risk appeared to decline somewhat (P=.065, nonlinearity). Exposure to less than 10 Gy was at worst, associated with only a small increased relative risk (RR) of bone cancer (RR= 0.7; 95% confidence interval = 0.2-2.2). The risk of bone cancer increased linearly (P= .04, one-tailed test) with increased cumulative dose of alkylating agents. IMPLICATIONS: This population-based study provides grounds for reassurance of the majority of survivors in that their risk of developing bone cancer within 20 years of 3-year survival did not exceed 0.9%. The higher risks found for bone cancer following the other specific rare types of childhood cancer provide a rational basis for surveillance. The RRs reported for bone cancer after specified levels of exposure to radiation should help in making decisions concerning future treatment protocols.

Weibel-Palade bodies in endothelial cells as a marker for angiogenesis in brain tumors.

A transmission electron microscope study was made of eight childhood brain tumors divided up into three zones, center, edge, infiltrating zone, and also of adjacent "normal-looking" brain. In seven of eight tumors, the numbers of Weibel-Palade bodies in endothelial cells were significantly increased in peripheral zones compared with central zones. A similar significant increase was observed after treatment of chick chorioallantoic membranes with tumor angiogenesis factor. It is suggested that large numbers of Weibel-Palade bodies may be a marker for proliferating endothelial cells in vivo.

Results of the United Kingdom Children's Cancer Study Group first Wilms' Tumor Study.

PURPOSE: The first United Kingdom Children's Cancer Study Group (UKCCSG) Wilms' Tumor Trial (UKW1) applied treatment regimens stratified by stage and histology in accordance with National Wilms' Tumor Study (NWTS) criteria, seeking to reduce treatment of low-stage, favorable-histology (FH) tumors without impairing survival and to improve prognosis of stage III and IV (FH) and unfavorable-histology (UH) tumors with more intensive chemotherapy. PATIENTS AND METHODS: Three hundred eighty-four consecutively diagnosed patients with Wilms' tumor were recruited from the 20 UKCCSG centers and Oslo, Norway, between January 1980 and June 1986. The regimen for stage I patients was vincristine (Vcr) only, while stage II patients received Vcr and dactinomycin (Act-D). Stage III patients received three-drug therapy and stage IV and UH patients four-drug regimens. Act-D was given as pulsed doses of 1.5 mg/m2 every 3 or every 6 weeks. No lung irradiation was used in stage IV patients. No randomized comparisons were attempted. End points were survival and event-free survival (EFS). RESULTS: Survival at 6 years in FH patients was 96% for stage I, 93% for stage II, 83% for stage III, 65% for stage IV, and 50% for UH patients of all stages. CONCLUSION: Vcr alone is as effective for stage I FH tumors as the two-drug regimen used in the NWTS and International Society of Pediatric Oncology (SIOP) studies. Fractionation of Act-D is unnecessary. The poorer results for stage IV FH and UH patients compared with the NWTS may be due to treatment differences, such as the use of lung irradiation for stage IV FH patients in NWTS3, and/or to case selection bias.

Bone metastases in children presenting with renal tumours.

A survey of bone metastases in 132 children presenting with renal tumours has been carried out using material from the Manchester (England) Children's Tumour Registry during the period 1954 to 1976. Seven such cases were found. Only one of the 117 Wilms' tumours developed bone metastases. The remainder included carcinoma (1/4), 'bone metastasising renal tumour of childhood' (2/3), atypical tumours (2/2), and lymphosarcoma (1/1). Bone metastases from true nephroblastoma seem to be an exceptional finding.

New look at mesoblastic nephroma.

Thirty eight mesoblastic nephromas were studied. The age range of the patients was between the neonatal period and 18 months. The presence of cartilage is consistent with a mesoblastic origin, but squamous epithelium was a feature in three tumours. Particular attention was given to the adjacent renal tissue in which various histological features were noted: vacuolated and dysplastic tubules; cysts; and subcapsular epithelial tumourlets. The findings had aspects in common with both dysplastic kidneys and nephroblastoma. Classification of the tumours as normocellular and hypercellular was attempted, but there was considerable overlap. The behaviour of the tumour was good in all cases, although follow up was relatively short on some patients, and deaths from non-neoplastic causes occurred.

Wilm's tumour and renal dysplasia: an hypothesis.

The incidence of renal dysplasia in a series of Wilms' tumours is presented. The distribution of such lesions is discussed, together with their course of development and regression. The kidney is regarded as a particularly suitable organ for studying the relation between dysplasia and neoplasia. A schema is suggested for this association with regard to Wilms' tumour.

Gonadal infiltration in children with leukaemia and lymphoma.

In a postmortem survey of children with leukaemia and lymphoma, the overall incidence of testicular infiltration was 65% and of ovarian infiltration 66%. In acute lymphoblastic leukaemia, testicular infiltration was found in 25 of 39 cases and ovarian infiltration in 6 of 12 cases. The majority of boys with acute lymphoblastic leukaemia and testicular infiltration also had infiltration in other organs; furthermore, in most cases without testicular infiltration leukaemic infiltration was found in other organs. The findings of this survey support the view that testicular infiltration is indicative of widespread disease.

Isolation of Bacteroides corrodens from infections in children.

Six cases of infections in children with Bacteroides corrodens are reported. In five the infection was mixed but in one fatal extradural and subdural empyema the organism was found in pure culture. The bacteriological findings are presented. It is suggested that Bacteroides corrodens may assume a pathogenic role and the rarity of its isolation may be due to delay in the appearance of the colony.

Germ cell tumours of childhood: a review of 137 cases.

One hundred and thirty-seven germ cell tumours occurring in 134 children included in the Manchester University Children's Tumour Registry over a 25-year period have been studied. The incidence and sites of these tumours as seen in a comprehensive population-based registry are presented and the relation between the primary site and histological type is assessed. There were 48 deaths in this series of which 34 were directly due to the tumour. The cause of death in the other 14 cases is given. The behaviour of the germ cell tumours was closely related to the presence of yolk sac elements.

Study of childhood renal tumours using a monoclonal antibody to Tamm-Horsfall protein.

A monoclonal antibody to Tamm-Horsfall glycoprotein was used for the immuno-localization of Tamm-Horsfall protein in formalin fixed, paraffin embedded tissue sections of childhood renal tumours, normal children's kidneys, and human fetal kidneys. The procedure was a dinitrophenyl hapten sandwich staining method. The antibody, diluted 1/100,000, gave a very strong and specific staining of the loop of Henle and distal tubules of normal and fetal kidneys. No staining was seen in Wilms' tumour, mesoblastic nephroma, and bone metastasizing renal tumour of childhood. In contrast, two of seven renal carcinomas and three of four rhabdoid renal tumours were positive for Tamm-Horsfall protein.

Mesoblastic nephroma contains fibronectin but lacks laminin.

Non-metastatic mesoblastic nephromas from four young children were shown to contain fibronectin but not laminin using an immunoperoxidase staining procedure. In contrast, one metastasising spindle celled sarcomatous tumour from a neonate was laminin positive. During embryogenesis primitive nephrogenic mesenchyme contains only fibronectin and no laminin; metanephric blastema (permanent kidney) is positive for laminin. The staining for fibronectin and laminin may help to ascertain the histogenesis of different types of renal tumour.

Study of childhood renal tumours using antisera to fibronectin, laminin, and epithelial membrane antigen.

Using a peroxidase-antiperoxidase staining procedure, formalin fixed paraffin embedded sections of fetal and normal kidney; benign (mesoblastic nephroma); and malignant tumours (Wilms' tumour, clear cell renal carcinoma, rhabdoid renal tumour, and bone metastasising renal tumour of childhood (BMRTC] were examined for their reactivity with antisera to fibronectin, laminin, and epithelial membrane antigen. Mesoblastic nephroma contained fibronectin but no laminin. Most Wilms' tumours lacked both fibronectin and laminin; 50% of rhabdoid renal tumours were positive for fibronectin and laminin--rhabdoid tumours as recognised morphologically may, in fact, be two separate entities. BMRTC and clear cell renal carcinoma lacked both fibronectin and laminin. Epithelial membrane antigen was present in most of the tubular Wilms' tumour but absent in blastemal Wilms' tumours. The presence of epithelial membrane antigen in rhabdoid tumours was surprising, as histologically, this type of tumour shows no sign of epithelial differentiation. Epithelial membrane antigen antiserum stained clear cell renal carcinomas: epithelial membrane antigen is found in the distal and not the proximal tubules of fetal and normal kidneys. Thus an obvious interpretation is that clear cell renal carcinomas originate from distal rather than from proximal tubules, as has always been thought. On the basis of these results and data from other published findings some possible histogenetic origins of childhood renal tumours were proposed.

Study of childhood renal tumours using peroxidase conjugated lectins.

Six peroxidase conjugated lectins were used to compare their ability to bind to formalin fixed paraffin embedded tissue sections of childhood renal tumours (Wilms' tumour, mesoblastic nephroma, renal carcinoma, rhabdoid renal tumour, and bone metastasising renal tumour of childhood (BMRTC) with fetal and normal children's kidney. Lectins were found to be helpful in the differential diagnosis of renal tumours. Another important finding was that the mesenchyme of renal tumours showed differences in its reactivity among various types of kidney tumours. The results of lectin binding were not helpful in establishing the origin of kidney tumours.

Bone marrow fibrosis in acute lymphoblastic leukaemia of childhood.

A prospective study of bone marrow fibrosis was made in a group of 40 children with acute lymphoblastic leukaemia to see whether it affected the prognosis or course of the disease. Secondary myelofibrosis (SMF) was present at diagnosis in 57% of the cases. It was not statistically significantly related to the prognosis or course of the disease. Thus, although trephine biopsy occasionally provided useful information in different diagnosis and when aspiration was difficult, it provided little information of use for management.

Congenital mesoblastic nephroma: possible prognostic and management value of assessing DNA content.

The case records and pathology of all children with kidney tumours treated in the West Midlands Health Authority Region (WMHAR) from 1957 to 1986 were reviewed. The histology was reviewed by a panel of three paediatric pathologists. Thirteen (6%) out of 211 cases were considered to have congenital mesoblastic nephroma (CMN). Nine were of the conventional type, three of the atypical cellular type, and one mixed. DNA ploidy was investigated and showed two of the tumours to be aneuploid and nine diploid (tissue was not available in the two other cases). The two aneuploid tumours were of atypical cellular and mixed histology, respectively; the diploid tumours were of the conventional type in eight cases and atypical cellular in one. The atypical cellular type has been reported to behave more aggressively, but the benefit of additional treatment after surgery to prevent recurrence remains unclear. Measurement of DNA content by flow cytometry, together with histological subclassification, may be useful in selecting patients who will benefit from further treatment after surgery.

Are germ cell tumors part of the Li-Fraumeni cancer family syndrome?

The occurrence of six cases of germ cell tumors, five testicular and one ovarian, in relatives of children with bone or soft tissue sarcomas is described. It is proposed that germ cell tumors may be an uncommon manifestation of the genetic predisposition to cancer that exists in the Li-Fraumeni cancer family syndrome.

An unusual presentation of non-Hodgkin's lymphoma (NHL) in a child.

A rare case of a primary early T-cell non-Hodgkin's lymphoma (NHL) in the bronchus of a 10 year old boy is presented. Although histological examination of the biopsied material was compatible with the diagnosis of NHL or carcinoma, the use of monoclonal antibodies showed it to be an early T-cell NHL and not carcinoma. Accordingly the child was treated using a chemotherapy protocol of the UKCCG for NHL. The patient responded so well to his treatment regime that within 2 weeks of the initiation of chemotherapy there was re-expansion of the collapsed lobe. Six weeks later bronchoscopy was entirely normal with no evidence of residual tumour and now 15 months after the time of diagnosis he remains very well with normal chest X-ray.

Prognostic relevance of DNA ploidy in rhabdomyosarcomas and other sarcomas of childhood.

A study of DNA content by flow cytometry revealed a significant difference between rhabdomyosarcomas, which were mainly non-diploid, and other sarcomas of children which were mainly diploid (p = 0.01). There was no association between DNA ploidy and survival or aggressive behaviour of the tumour as indicated for example by advanced clinical stage or unfavourable histology. While DNA ploidy correlated with age, it did not correlate with any other clinical characteristic. The apparent lack of prognostic value of DNA content may have been masked by some high CV values and overridden by the effect of chemotherapy which was the most significant variable in determining a patient's survival (p = 0.00005).

A monoclonal antibody which discriminates between sub-types of astrocytoma.

A monoclonal antibody, M2, was produced by somatic cell hybridisation of splenocytes, from mice immunised with human fetal brain, with the murine myeloma cell line NS-1. Indirect immuno-peroxidase staining of formalin-fixed, paraffin embedded tissue sections showed that, whilst the monoclonal antibody gave a positive reaction with 32/39 astrocytomas from adult patients and 33/36 of children's astrocytomas of the adult histological type, only 17/39 of juvenile astrocytomas were stained. A Chi-squared test showed that the difference in staining between the two groups (adult versus juvenile) was highly significant (p less than 0.0001). In contrast, using a polyclonal antiserum to GFAP, a significantly larger proportion of juvenile astrocytomas than adult astrocytomas stained positively (p less than 0.05). Thus, whereas the distribution of GFAP accorded with the general finding that the degree of malignancy of a tumour correlates with the loss of cell type specific markers, the distribution of M2 reactivity was similar to that of some oncogene products which increase with malignancy. From the flow cytometry data it is apparent that the antigen recognised by M2 is not cell cycle dependent.