Improved survival for children with anaplastic Wilms' tumors.

Combined modality treatment has resulted in cure rates of approximately 80% for children with Wilms' tumor. According to the National Wilms' Tumor Studies (NWTS), a group of patients with histologic features of anaplasia or sarcomatous Wilms' tumors (malignant rhabdoid tumors and clear cell sarcomas) were less responsive to vincristine and actinomycin. The survival rate of patients in this group with unfavorable histologic conditions was 54% compared with 90% for those with favorable histologic conditions. We have reviewed 80 consecutive cases of Wilms' tumor treated with a minimum follow-up interval of 5 years. Two pathologists independently reviewed all histologic specimens that were initially classified as having unfavorable histologic conditions and specimens from children with favorable histologic conditions who subsequently relapsed. One of 13 children with favorable histologic conditions had recurrent disease that was found to have unfavorable histologic conditions on rereview. All five patients with sarcomatous Wilms' tumor had a rapidly progressive course. Treatment of eight children with anaplastic Wilms' tumor with vincristine, actinomycin, cyclophosphamide, and abdominal radiation resulted in good disease-free and overall survival rates (5-year survival rate, 87.5%) that were not significantly different from children with tumors having favorable histologic conditions (5-year survival rate, 94%). All children with sarcomatous histologic conditions, however, did not to respond.

Osteosarcoma in young children.

The clinicopathologic features of osteosarcoma in 12 children younger than 16 years of age treated at The Children's Hospital and Dana-Farber Cancer Institute, Boston, during a 70-year time period are presented. Only one of six children treated before 1972 is a long-term survivor. Four of six children (67%) treated after 1972 are disease-free with an average follow-up of 8.8 years. The year 1972 marked the onset of use of effective chemotherapy in osteosarcoma, namely, high-dose methotrexate and leucovorin rescue. It would appear that the pathologic features and behavior of osteosarcoma in young children is similar to that of osteosarcoma in older children and adolescents. A combination of complete (wide) surgical resection or amputation and aggressive chemotherapy offers the best chance of long-term survival.

Bone sarcomas as second malignant neoplasms following childhood cancer.

This study explores the relationship between histologic variants of bone sarcomas and previous therapy in patients in whom an unrelated malignant neoplasm had been diagnosed during childhood. Sarcomas of bone were the most common second malignant neoplasm (SMN) reported to the Late Effects Study Group, a 13-institution consortium consisting of pediatric oncology centers from western Europe, Canada, and the United States. The authors attempted to relate the histologic subtypes of the 91 bone tumors to clinical factors such as previous therapy and genetic predisposition because morphologic variants have been shown to have biologic significance in other tumors and may have etiologic import. The literature concerning the subtypes of bone tumors, clinical and experimental, is also reviewed. The authors also investigated the effect of several factors on the time interval from the first diagnosis to the SMN (i.e., the bone sarcoma). Anthracyclines significantly shortened the interval by about 3 years. The primary diagnosis also significantly affected the interval, with leukemia/lymphomas having the shortest interval and retinoblastoma the longest. The authors could not demonstrate any significant relationship between morphologic characteristics of the osteosarcoma and predisposing conditions. However, lesions diagnosed as chondrosarcoma and malignant fibrous histiocytoma occurred almost exclusively in patients who had received radiation therapy to the site in which the SMN developed.

Flow cytometric evaluation of multicystic dysplastic kidneys.

The most appropriate management of the multicystic dysplastic kidney remains controversial. At issue is the long-term risk of the development of malignancy in the multicystic dysplastic kidney. The association between renal dysplasia and neoplasia has not been confirmed, with only 6 cases of malignancy reported. Nephroblastomatosis, a probable precursor of Wilms tumor, has been found in 5 to 7% of the cases of multicystic dysplastic kidney when specifically sought. In an attempt to determine whether a relationship exists between renal dysplasia and neoplasia in terms of abnormalities of cellular deoxyribonucleic acid content we performed flow cytometric evaluation on 30 formalin fixed, paraffin embedded archival specimens of multicystic dysplastic kidneys. None of the kidneys had evidence of malignancy. Nuclear deoxyribonucleic acid ploidy studies were performed on single dissociated nuclei prepared by the technique of McLemore and associates and stained with propidium iodide. All specimens demonstrated a diploid pattern of deoxyribonucleic acid, including 3 specimens with nephroblastomatosis or extensive papillary growth, and no specimen demonstrated a tetraploid or aneuploid pattern. The mean G0/G1 fraction was 85.94% (standard deviation 4.59) and the mean S/G2/M fraction was 12.54% (standard deviation 4.72). These findings do not support or negate the potential for neoplasm associated with multicystic dysplastic kidney, since a diploid deoxyribonucleic acid pattern does not eliminate the possibility of the future development of malignancy.

myc gene amplification and expression in primary human neuroblastoma.

Although N-myc amplification in neuroblastomas correlates with poor prognosis, not all neuroblastomas which fail to respond to therapy have N-myc amplification. To determine whether other modes of myc gene activation underlie progression of some neuroblastomas, 45 were analyzed for amplification of N-myc, c-myc and L-myc and 26 were studied for transcription of these oncogenes. N-myc amplification was found in 6 of 45 tumors; no tumor had amplification of c-myc or L-myc. Transcription of both N-myc and c-myc occurred in 21 of 26 neuroblastomas. No tumor without N-myc amplification had a level of N-myc expression near that of a tumor or cell line with amplification. One tumor with N-myc amplification was the only specimen with N-myc but not c-myc expression. Five samples had c-myc but not N-myc expression; all had histological features of ganglioneuroma. DNA index did not correlate with myc gene amplification or expression. It is concluded that N-myc and c-myc are commonly expressed in primary untreated neuroblastomas, but in the absence of N-myc amplification, expression of these genes does not appear to correlate with disease progression.

Radiologic and pathologic abnormalities of the trachea in older patients with cystic fibrosis.

The possibility of tracheal enlargement in older patients with cystic fibrosis was investigated by examining chest radiographs of 42 living adults (age range, 30-45 years) who had the disease and by performing postmortem studies (anatomic and histologic) on the tracheas of older adolescents and young adults (age range, 15-33 years) who died with the disease. Anteroposterior tracheal diameters were enlarged in 41 of the living adults. The average diameter was 1.3 +/- 0.9 SD standard deviations above the mean for normal subjects. These increases did not correlate with severity of pulmonary disease as judged radiographically. Enlargement seemed to have developed slowly, over many years or decades. A few tracheas were grossly irregular in outline. One patient had a severely increased transverse diameter of 4.7 standard deviations above the normal mean. The average transverse diameter was 0.3 +/- 1.1 SD standard deviations above the normal mean. The tracheas of adults and older adolescents who had died with cystic fibrosis were abnormally flaccid. Some collapsed suddenly during deflation. Microscopic examination showed instances of severe inflammation, focal epithelial metaplasia, hypertrophy and hyperplasia of the mucous glands, degenerative changes in the muscle of the pars membranacea, and death of cartilage cells. The structural changes shown histologically and the many decades of frequent, vigorous coughing may be important in the enlargement of these tracheas and their flaccidity.

Pneumatosis intestinalis in cystic fibrosis.

We retrospectively reviewed the clinical and radiographic findings in patients with pneumatosis intestinalis (PI), who were identified among 441 patients with cystic fibrosis. Since 1944, the age at onset and the incidence of PI have increased. Pneumomediastinum, pneumothorax, or pulmonary interstitial emphysema was found in 95% of patients with PI compared with 62% of patients without PI. The type, distribution, and severity of PI often changed with time. PI is correlated with the development of obstructive pulmonary disease, which facilitates air dissection into interstitial spaces. Dissection of air is often clinically silent and tends to be self-perpetuating.

Nonexpression of cartilage type II collagen in a case of Langer-Saldino achondrogenesis.

A lethal short-limbed dwarfism was diagnosed at autopsy as the Langer-Saldino variant of achondrogenesis by radiological, histological, and gross pathological criteria. Cartilage was obtained for biochemical and ultrastructural analyses from the ends of long bones, from ribs and from a scapula of the newborn infant. At all sites, it had an abnormal gelatinous texture and translucent appearance. Biochemical analyses of the cartilages to identify pepsin-solubilized collagen alpha-chains and collagen-specific CNBr-peptides failed to detect type II collagen at any site where it would normally be the main constituent. Instead, type I was the predominant collagen present. However, three cartilage-specific minor collagen chains identified as 1 alpha, 2 alpha, and 3 alpha chains by their electrophoretic mobility were present at about 10% of the total collagen. Cartilage-specific proteoglycans also appeared to be abundant in the tissue judging by its high hexosamine content and high ratio of galactosamine to glucosamine. The findings indicate that a chondrocyte phenotype had differentiated but without the expression of type II collagen. In addition to the skeletal abnormalities, the severe pulmonary hypoplasia was also felt to be directly related to the underlying pathology in collagen expression. The term chondrogenesis imperfecta rather than achondrogenesis should be considered a more accurate description of this and related conditions.

Secondary (AA) amyloidosis in cystic fibrosis. A report of three cases.

The authors report the pathologic features of three cases of amyloidosis associated with cystic fibrosis. Renal biopsy led to the diagnosis (case 1) or suspicion (case 2) of amyloidosis in patients who were 23 and 21 years old, respectively. The third patient died at age 22 years, and amyloidosis was not discovered until autopsy. Immunohistochemical staining and potassium-permanganate pretreatment of histologic sections in all three cases provided evidence that the amyloid seen in these patients is of the secondary (AA) type. Congo red staining in each case and electron microscopy in case 1 confirmed the initial diagnosis of amyloidosis. A markedly elevated serum amyloid A protein (160 micrograms/mL; normal less than 1 microgram/mL) in case 1 indicated the presence of large quantities of the precursor protein from which the AA fibrils of secondary amyloid are derived. The kidneys, spleen, and liver contained amyloid deposits in autopsy material from all three cases. Involvement of other organs by amyloid was variable. Review of autopsy material in Boston from 23 additional cystic fibrosis patients with long-term survival did not reveal any evidence of amyloidosis. It appears that secondary amyloidosis is emerging as a significant, although rare, complication of cystic fibrosis as greater numbers of these patients survive into adulthood.

Phosphoenolpyruvate carboxykinase activity in human liver.

The activity of phosphoenolpyruvate carboxykinase (EC 4.1.1.32) (PEPCK), a rate-limiting gluconeogenic enzyme, was found decreased by others in genetically determined disorders and in Sudden Infant Death Syndrome (SIDS). To understand these findings, we made a systematic study of normal human hepatic PEPCK activities in specimens obtained under various conditions from patients not suspected of having SIDS. PEPCK was assayed by the method of Ballard and Hanson [J. Biol. Chem., 244 (1969) 5625] and activity reported as units (1 mumol/min) per gram protein. Intra-assay precision was 4.1% (n = 1094); inter-assay precision using the same homogenate was 10.4% (n = 51); and inter-assay precision using different homogenates of the same tissue specimen was 16.3% (n = 17). The assay was linear with time and enzyme concentration for at least 60 min up to 1.3 mU/assay and for at least 5 min up to 20 mU/assay. Biopsy specimens had significantly (P = 0.015) higher PEPCK activity, 12.60 +/- 3.01 U/g (range 3.5-10.4, n = 9) compared to specimens obtained at autopsy, 3.20 +/- 0.45 U/g (range 0-8.6, n = 33). Specific activity was not significantly correlated with the patient's age, fresh vs. frozen tissue, postmortem intervals up to 68 h, or length of storage at -70 degrees C up to 21 years. One patient had activity at autopsy (tissue obtained less than 2 h postmortem) 26% less than was observed in his biopsy specimen. Autopsy samples separated by differential centrifugation into mitochondrial and cytosolic fractions and checked with marker enzymes ornithine transcarbamylase (mitochondrial) and arginase (cytosolic) had considerable cross-contamination between the two fractions in fresh and frozen specimens.

Tracheal bronchus: association with respiratory morbidity in childhood.

An aberrant right upper lobe (RUL) bronchus arising from the trachea (tracheal bronchus) can be responsible for recurrent pneumonia. In this hospital, 2% of children requiring bronchoscopy for respiratory symptoms are found to have a tracheal bronchus, which is frequently thought to be an incidental finding. We reviewed findings in 18 patients to determine when a tracheal bronchus is of clinical significance. The age at presentation ranged from 1 day to 54 months (mean 17 months). The children had recurrent pneumonia (nine), stridor (six), respiratory distress (two) and a thoracic mass (one). Other congenital abnormalities were present in 14, including Down syndrome (two), tracheoesophageal fistula (two), and fused or hypoplastic first and second ribs (four). Recurrent RUL pneumonia was present in five. Bronchiectasis or bronchial stenosis was shown by bronchography in four of five; in all five the right upper lobe was surgically resected, with resolution of the recurrent pneumonias. The presence of a clinically significant tracheal bronchus should be considered in every child with recurrent RUL pneumonia, especially in children with Down syndrome or rib abnormalities; if bronchiectasis or bronchial stenosis is found, surgical resection should be performed.

Adamantinoma of the tibia. An ultrastructural and immunohistochemical study.

The light microscopic, ultrastructural, and immunohistochemical characteristics of two tibial adamantinomas are presented. The immunohistochemical studies utilized specific antibodies against Factor VIII-related antigen and keratin protein, considered as markers for endothelial and epithelial cells, respectively. These revealed positive staining for keratin in the tumor cells of both cases, whereas Factor VIII was not found in either. Ultrastructurally, both tumors had tonofilaments, desmosomes, gap junctions, microvillous-like projections, and basement membranes. Patient 1 had disease that was histologically of the classic spindle cell type; the disease of Patient 2 was atypical and closely resembled an epithelioid angiosarcoma. Immunohistochemical and ultrastructural findings in each case indicate an epithelial component in tibial adamantinoma.

Improved survival in neuroblastoma using multimodality therapy.

One hundred and thirty-six patients with neuroblastoma have been treated at our center from 1970 to 1982, using various combinations of surgery, radiation therapy, and chemotherapy. Choice of therapy was individualized but depended primarily on age and stage. The overall disease-free survival was 60% (minimum follow-up of one year). Patients with stage I disease and younger patients with stage II disease usually received less intensive therapy and fared extremely well (100% survival). Patients with stage III disease and older patients with stage II disease also did extremely well (survival of 85% and 90%, respectively). These patients may have benefited from intensive treatment with all three modalities. Patients under one year of age with stage IV neuroblastoma were treated with surgery and multiagent chemotherapy, and 92% (11/12) survived free of disease. Patients over one year old with stage IV disease represented the only group for which therapy was unsuccessful (10% survival). With combination approaches and with more effective multiagent chemotherapeutic regimens, a real impact on the survival of older stage II patients, stage III patients, and younger stage IV patients appears to have been made. However, older stage IV patients are rarely cured with conventional therapy, and better approaches will be needed for this group.

Mesothelioma following Wilms' tumor in childhood.

A high percentage of children with Wilms' tumor are cured with multimodal treatment. A small percentage of these children will develop second tumors, perhaps related to a genetic predisposition to neoplasia or possibly secondary to the treatment utilized for Wilms' tumor. Malignant mesothelioma has been associated with contact with asbestos but has also been reported after radiation exposure. Two patients are reported who developed malignant mesothelioma of the pleura after treatment for Wilms' tumor in childhood. Both received orthovoltage radiation; one patient also received triethylenemelamine (TEM), an alkylating agent closely related to nitrogen mustard, for 5 years. Factors in the development of second tumors are discussed.

Bronchopulmonary dysplasia: a morphometric study with emphasis on the pulmonary vasculature.

Using morphometry, the pulmonary vasculature in lungs obtained at autopsy from 8 patients with bronchopulmonary dysplasia (BPD) was studied. In these specimens the axial arterial pathway was similar in length to those of equivalently aged fetuses and increased with lengthening survival. The internal diameter of axial arteries was variable--excessively wide in 2 patients and diffusely narrow in 3. Microscopically, the percent medial thickness of muscular pulmonary arteries was reduced compared to fetal values and tended to be less in older patients. Compared to normal fetuses, there were more muscularized intraacinar arteries, suggesting peripheral extension of smooth muscle. Arterial concentrations were elevated in 2 long-term survivors. The weight of the cardiac right ventricle was reduced in 4 patients. These findings indicate that in patients with BPD there is a complex dual process of pathological remodeling and an attempt at normal anatomic adaptation of the pulmonary vasculature to extrauterine life.

Hepatocellular carcinoma. Review of 32 cases in childhood and adolescence.

The clinical and pathologic features of 32 children and adolescents with hepatocellular carcinoma (HCC) are reviewed. Their average age at diagnosis was 9.7 years (range, 5 months to 21 years) and there was a slight predilection for males in a ratio of 1.7 to one. Of eight patients with associated or underlying abnormalities, five had cirrhosis, two had an antecedent (or coexisting) tumor fulfilling pathologic criteria for hepatic adenoma, and one developed HCC ten years after nephrectomy and radiation therapy for a Wilms' tumor. Our data reaffirm the high mortality associated with HCC (91%). Three of five tumors classified as fibrolamellar type were amenable to surgical resection while only 15% of the remaining HCC were operable. The average duration of disease for patients with conventional HCC was 4.2 months, while those with the fibrolamellar variant had a more lingering course (average, 28.5 months). Available data indicate that the fibrolamellar variant should be distinguished from HCC with more conventional histology because of greater resectability and improved overall survival.