S. Variend

Comprehensive Genetic and Histopathologic Study Reveals Three Types of Neuroblastoma Tumors

PURPOSE To determine the relationship between multiple genetic features, tumor morphology, and prognosis in neuroblastoma. PATIENTS AND METHODS The genetic alterations and morphologic features that underpin three histopathologic risk classifications were analyzed in 108 neuroblastoma patients. Tumors were subdivided into four groups based on the three most frequent and prognostically significant genetic alterations (17q gain, 1p deletion, and MYCN amplification), and all other genetic, morphologic, and clinical data were analyzed with respect to these groups. RESULTS Our analyses identify three nonoverlapping tumor types with distinct genetic and morphologic features, defined here as types 1, 2, and 3. Type 1 tumors show none of the three significant genetic alterations and have good prognosis. Both type 2 (17q gain only or 17q gain and 1p del) and type 3 (17q gain, 1p del, and MYCN amplification) tumors progress. However, these tumor types are distinguished clinically by having significantly different median age at diagnosis and median progression-free survival (PFS). Multivariate analysis indicates that 17q gain is the only independent prognostic factor among all genetic, histopathologic, and clinical factors analyzed. Among histopathologic risk systems, the International Neuroblastoma Pathology Classification was the best predictor of PFS. CONCLUSION Our results indicate that specific combinations of genetic changes in neuroblastoma tumors contribute to distinct morphologic and clinical features. Furthermore, the identification of two genetically and morphologically distinct types of progressing tumors suggests that possibilities for different therapeutic regimens should be investigated.

Defects of metabolism of fatty acids in the sudden infant death syndrome.

Two hundred consecutive cases of the sudden infant death syndrome were reviewed for the presence of fat in the liver; 14 showed diffuse panlobular microvesicular fatty change indistinguishable from that found in Reyes syndrome. Samples of frozen liver were available in five of the 14 cases; histochemical analysis showed well preserved cytochrome oxidase and succinate dehydrogenase activity in all five, uncharacteristic of Reyes syndrome. Fatty acyl-coenzyme A dehydrogenase activity in the liver was assayed biochemically in two of the same five cases with severe hepatic fatty infiltration; both showed a defect in medium chain acyl-coenzyme A dehydrogenase activity using the substrate octanoyl-coenzyme A. Both cases also showed cerebral oedema in association with fatty infiltration of renal tubules, myocardium, and skeletal muscle, characteristic of Reyes syndrome. It is concluded that diffuse panlobular microvesicular fatty change of the liver in victims of the sudden infant death syndrome, although essentially non-specific, indicates that the state of mitochondrial enzymes should be investigated.

Breakpoint position on 17q identifies the most aggressive neuroblastoma tumors

Gain of chromosome arm 17q is a powerful prognostic factor in neuroblastoma, and the distribution of 17q breakpoints suggests that the dosage of one or more genes in 17q22–23 to 17qter is critical for tumor progression. To identify the smallest region of 17q gain, we used eight probes to map translocation breakpoints in 48 primary neuroblastoma tumors. We identified at least five different breakpoints, all localized within the proximal part of 17q (from D17Z1 to MPO). The shortest region of gain identified by these probes extends from MPO (17q23.1) to 17qter. Surprisingly, we found that breakpoints localized proximal to ERBB2 (17q12) were associated with significantly better patient survival than breakpoints localized distal to ERBB2. Breakpoints localized distal to ERBB2 identified patients with a particularly poor prognosis, higher mitotic karyorrhectic index, and stage 4 disease. This implies that breakpoint position on 17q is a discriminative factor within this prognostically poor group of patients. This result also suggests that the biological effect of 17q gain during neuroblastoma progression has a complex basis. We propose that this involves dosage alterations of genes localized on both sides of the 17q breakpoints, with a gene or genes mapping between 17cen and 17q12 acting to suppress progression, and a gene or genes mapping between 17q23.1 and 17qter acting to promote tumor progression.

Relationship between histopathological features, MYCN amplification, and prognosis: A UKCCSG study

Histological sections from 231 patients with neuroblastoma were reviewed and morphological features and their relationship to age, stage, MYCN amplification (in 128 tumours by Southern analyses), and clinical outcome (based on Shimada risk grouping) determined. Stage 4 disease was associated with poorly differentiated and undifferentiated tumours (P = 0.001), an MKI of >2% (P< 0.001), and Shimada unfavourable histology (UHi) P< 0.0001. In univariate analysis MKI was significant in predicting a poorer relapse-free survival (RFS), low vs. intermediate and high (P< 0.001). Age, MYCN amplification, and Shimada UH also emerged as significant variables. There was a higher proportion of MYCN-amplified tumours with Shimada UH (P = 0.03), and this group had a decreased RFS (P = 0.002). In patients with Shimada FH, MYCN amplification did not significantly predict a poor prognosis. In those with stage 4 disease, Shimada classification was not significant in predicting survival (P = 0.97); the same was true for those over the age of 1 year (P = 0.66). In multivariate analysis, MYCN amplification and Shimada UH both emerged as independent prognostic factors. In conclusion, morphological features assigned some subsets of patients to prognostic risk groups. Most MYCN-amplified tumours have unfavourable histology and a poorer prognosis. However, in patients with stage 4 disease and those over the age of 1 year, other factors that may influence prognosis should be determined.

Acylcoenzyme A dehydrogenase deficiency in heart tissue from infants who died unexpectedly with fatty change in the liver

Heart muscle from infants who died unexpectedly and who showed fatty changes in the liver at necropsy was analysed for long chain and medium chain acylcoenzyme A dehydrogenase activities by using the natural electron acceptor. In two of the seven cases investigated a deficiency in acylcoenzyme A dehydrogenase activity was found. In one case the deficiency was in medium chain acylcoenzyme A dehydrogenase activity and in the other long chain acylcoenzyme A dehydrogenase activity. These findings emphasise the importance of investigating fatty acid oxidation in infants who have died unexpectedly.

p53 is nuclear and functional in both undifferentiated and differentiated neuroblastoma.

Aberrant cytoplasmic sequestration has been reported as an alternative mechanism of p53 inactivation to mutation in neuroblastoma. We hypothesized that p53 localization and function in neuroblastoma is related to differentiation status. Eighty-two untreated and 24 paired pre and post-chemotherapy neuroblastomas were studied by immunocytochemistry for p53, p21WAF1, BAX, Bcl2 and Ki67. Predominantly nuclear p53 was detected in undifferentiated neuroblastoma, and both nuclear and cytoplasmic p53 in differentiating neuroblastoma. The nuclear p53 labeling index (LI) correlated with the Ki67 LI (r = 0.51, p

The weight of the cerebellum in children with myelomeningocele.

The cerebellums were removed and weighed from 100 children who had died with myelomeningocele and from 60 apparently normal control children who had died from other causes. 19 cases with myelomeningocele had received Holter valve decompression treatment for their hydrocephalus. The weight of the cerebellum in the children with myelomeningocele was uniformly diminished in the immediate postnatal period in comparison with the control group. This was in contrast with the weight of the cerebral hemispheres, which have been shown to be increased above the normal range at the time of birth.

Combined hepatoblastoma and yolk sac tumor of the liver.

The authors report a liver tumor that occurred in a 6‐month‐old boy in which areas of yolk sac and hepatoblastoma were identified. To the best knowledge of the authors, this morphologic pattern has not been reported previously. Theories of histogenesis are discussed. Cancer 1992; 69:1323‐1326.

The pathology of the central lobes of the cerebellum in children with myelomeningocele.

A study has been carried out of 100 cerebellums from children with myelomeningocele. Deformities were present in all to varying degrees. There was necrosis and atrophy of the most caudal lobes of the cerebellum, particularly the nodule, and there was evidence that the nodule could completely disappear in some cases.

An animal model for copper-associated cirrhosis in infancy

In Indian childhood cirrhosis (ICC) and related disorders of infancy, hepatic copper overload is associated with cirrhosis. Since copper administration alone has not been shown to induce cirrhosis in animals, synergy between copper and a second hepatotoxin has been suggested. This study investigates the ability of long‐term exposure to copper and a pyrrolizidine alkaloid, retrorsine, to produce a model of copper‐associated cirrhosis in rats. Groups of rat pups suckled on mothers fed 25 mg/kg diet retrorsine were weaned onto a diet containing 0·5 g/kg diet copper and retrorsine in varying dosage for 13 weeks. Histological similarities between the human disease and rats given copper with retrorsine 5 mg/kg diet included parenchymal destruction, fibrosis, nodular regeneration, and copper accumulation. There were significant histological differences from the human disorder, possibly attributable to inter‐species variability or the critical timing or duration of exposure to hepatotoxins in the neonatal period. The hypothesis that ICC results from copper and a second hepatotoxin has not been disproved. Copyright