Doctoral Degrees (Anatomical Pathology)
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Item An immunohistochemical and microsatellite analysis of nephroblastomas.(2008) Govender, Dhirendra.; Chetty, Runjun.The aims of this study were: (i) to determine the association between p53, bcl-2, pRb, p21, cyclin A and p-glycoprotein immunoexpression and prognosis, and (ii) to determine the frequency of loss of heterozygosity and microsatellite instability at 11 p, 16q and mismatch repair gene loci and their association with prognosis, in nephroblastomas in South African children. There were 138 cases (111 of whom received preoperative chemotherapy) in the immunohistochemical study and, 70 cases (48 with preoperative chemotherapy) in the microsatellite study. The following monoclonal antibodies were used after heat induced epitope retrieval; p53, bcl-2, pRb, p21, cyclin A and p-glycoprotein. Six polymorphic microsatellite markers were selected from the 11p region, 5 from the 16q region and 6 from the loci of known mismatch repair genes. Automated fluorescent DNA technology was used in the analysis. The results of the immunohistochemical and microsatellite studies were correlated with patient age, gender, preoperative chemotherapy, SlOP histological classification, SlOP histological risk group, clinicopathological stage, patient outcome and survival using X2 , Fisher's exact test, Cox regression model and Kaplan-Meier estimates. The majority of patients presented with advanced disease. Anaplastic tumours and high-risk histology were associated with high disease stage. Mortality was directly related to increasing stage and histological risk group. Multivariate analysis showed that clinicopathological stage was the only factor significantly associated with survival (p<0.001) (hr=5.6, 95%CI: 2.1-14.9). High expression of p53 was more frequent in anaplastic tumours suggesting that p53 mutations are common events in this tumour type (p<0.001). Despite the strong association with tumour histology, there was no association with stage. Although p53 expression was found to be a predictor of survival in the univariate analysis this was not retained in the multivariate analysis. Tumours treated with preoperative chemotherapy showed higher bcl-2 immunoreactivity (p=0.027 but lower levels of pRb (p=0.040) and cyclin A expression (p<0.001). All anaplastic tumours showed high expression of pRb compared to the other histological types (p=0.003). Expression of xxii pRb was significantly associated with survival in the univariate analysis but not in the multivariate analysis. High cyclin A expression was associated with high risk histology (p<0.001). Cyclin A expression was found to be a significant predictor of survival in both the univariate (hr=1.7; 95%CI 1.2-2.4; p=0.002) and multivariate analyses (hr=1.7; 95%CI1.1-2.7; p=0.032). Although tumours with high risk histology were more likely to express high levels of p-glycoprotein, this did not reach significance. LOH at 11 p was seen in 64.7% of 68 informative cases. LOH at 11 p13 was more frequent than LOH at 11p15. LOH for both 11p13 and 11p15 was found in 39.7% of all tumours. MSI at 11 p was seen in 22.1 % of informative cases. The majority showed MSI for one marker only. LOH 16q was seen in 66.7% of 66 informative cases. MSI at 16q was seen in 16.7% of cases. LOH for 016S496 and 016S520 appear to be related to tumour histology and risk group. The most frequent locus for LOH was 16q21-22, which is known to harbour important genes, such as, E2F4 and E-cadherin. LOH for MMR markers was seen in 43.5% of 69 informative cases. MSI was seen in 11.6% of tumours. In the multivariate analysis there was no significant correlation between LOH at any of the loci studied and survival. There were no tumours with high frequency MSI. Low frequency MSI was of no clinicopathological significance. The following conclusions are made: (i) p53 mutations determined by high p53 expression is a frequent finding in anaplastic tumours, (ii) Bcl-2 may play a role in the chemoresistance of nephroblastomas, (iii) Rb gene alterations are not important in the development of nephroblastoma and anaplasia, (iv) Cyclin A expression is an independent predictor of survival, (v) p-glycoprotein may be responsible for the chemoresistance in a proportion of nephroblastomas, (vi) MSI is a rare occurrence in nephroblastoma and does not play a role in the development of nephroblastoma, (vii) LOH at 11 p and 16q are frequent findings in nephroblastomas, (viii) LOH for the specific 16q markers (016S496 and 016S520) may have an important prognostic role in nephroblastoma.Item The pathological aspects of heart failure in the Natal African.(1967) Kallichurum, Soromini.; Wainwright, J.The aims and objects of this work, as outlined in the introduction, were to a s s e s s the necropsy incidence of deaths due to heart failure in the African in Durban, to a s s e s s the necropsy incidence of the various aetiological types of heart failure with particular reference to right ventricular hypertrophy and failure, and to compare and contrast the incidence, complications, morbidity and mortality of heart disease in the Natal African with the same in other African and racial groups, both in South African and elsewhere. Many of the points emerging from this work merely confirm what has long been known, but others refute previous concepts. The all-age average necropsy incidence of deaths from heart failure in the African in Durban is of the order of 8%. This percentage does not, unfortunately, lend itself to straight comparison with most other series because of the high infant mortality shown in the present study. However, in considering deaths due to heart failure in the 10-plus age groups, the African still shows a lower mortality from heart disease in comparison with figures obtained for Indians or those reported for the Coloured and White races in South Africa. There are six major causes of heart disease in the African, which in order of frequency are, rheumatic heart disease, hypertensive heart disease, cardiomyopathy, cor pulmonale, pericarditis, and syphilitic heart disease. While little difference is apparent in the incidence of rheumatic and hypertensive heart disease, and possibly cor pulmonale, among the various races, cardiomyopathy, pericarditis and syphilitic heart disease are far more important causes of heart failure in the African by contrast with the other racial groups in South Africa. Although coronary a r t e r y disease is by comparison very uncommon in the African, cardiomyopathy, pericarditis, and syphilitic heart disease together claim as many deaths from heart failure in these people as does coronary heart disease among the Indian and White races in the Republic. Except for minor variations in the incidence of certain aetiological types, and the geographical distribution of endomyocardial fibrosis and cardiomyopathy/. . cardiomyopathy, the g e n e r a l p a t t e r n of h e a r t d i s e a s e among the Africans in Natal a p p e a r s to be s i m i l a r to that r e p o r t e d from other P r o v i n c e s in South Africa and most other c o u n t r i e s on the continent. Rheumatic h e a r t d i s e a s e is r e s p o n s i b l e for 21. 5% of all deaths from congestive h e a r t failure in the African in Durban. The immediate and the l a t e c a r d i a c complications of r h e u m a t i c fever in the Durban African a r e , on the whole, found to be no different from those r e p o r t e d in W e s t e r n communities. The findings in t h i s study t h e r e f o r e refute the view that r h e u m a t i c h e a r t d i s e a se i s infrequent in the African after the age of 40 y e a r s , and failed to support the suggestion that the d i s e a s e affects them m o r e s e v e r e l y or that death from r h e u m a t i c heart d i s e a s e o c c u r s at an e a r l i e r age in t h i s r a c e . While it is a g r e e d that s e v e r e valvular deformity in young African subjects (under 15 y e a rs of age) o c c u r s c o m p a r a t i v e l y m o r e frequently, it must be stated that this is in no way p e c u l i a r to the African, similar lesions being o b s e r v e d in Indian s u b j e c t s of c o r r e s p o n d i n g age. Hypertensive h e a r t d i s e a s e is common among the African in Durban, accounting among t h em for 18. 9% of all deaths from congestive h e a r t f a i l u r e. While both e s s e n t i a l and secondary forms of h y p e r t e n s i o n occur in the local indigenous population, the former appears to be m o r e common, with a peak incidence in the seventh decade of life. Secondary hypertension, mostly r e n a l in origin, is an i m p o r t a n t cause of h y p e r t e n s i v e congestive c a r d i ac f a i l u r e in the fourth decade. The wide v a r i a t i o n s in the type of h y p e r t e n s i on r e p o r t e d from the different regions in Africa, and the doubt e x i s t i n g as r e g a r ds the significance of focal lesions in the kidneys, point towards the need for g e n e r a l l y accepted c r i t e r i a in the diagnosis of r e n a l hypertension, p a r t i c u l a r ly with r e g a r d to chronic phylonephritis. Cardiomyopathy c l a i m s 15. 8% of all deaths from congestive heart f a i l u r e in the local African population. While many of the pathological changes o c c u r r i n g in the h e a r t in t h i s d i s e a s e were found to be s i m i l a r to those of other i n v e s t i g a t o r s , c e r t a i n f e a t u r e s , relating to c a r d i a c hypertrophy and s t r u c t u r a l a l t e r a t i o n s in the pulmonary v e s s e l s , have been e s p e c i a l ly i n v e s t i g a t e d / . . . investigated and results obtained in this series of cases show that whereas pure right ventricular hypertrophy is uncommon in cardiomyopathy biventricular hypertrophy with predominance of the right ventricle is the most frequent form of cardiac enlargement in such cases. Equal hypertrophy of the ventricles is the next common form of enlargement; left ventricular predominance is by far the least frequent, and no case of exclusive left ventricular hypertrophy was encountered. Although structural alterations in the pulmonary a r t e r i e s , indicating pulmonary a r t e r i a l hypertension, were observed in a large number of cases investigated, such changes were in no way specific to cardiomyopathy, since similar changes were observed in cor pulmonale due to emphysema and also in some cases of hypertensive congestive heart failure. Structural alterations in the small muscular pulmonary a r t e r i e s and arterioles were also identical with those found in emphysema. Whereas fresh pulmonary emboli and infarcts were frequently encountered and were often of such degree as to be the immediate cause of death, chronic pulmonary thrombo-embolism of an extent sufficient to have been the cause of right ventricular predominance was seldom found. It is suggested that the cause of the pulmonary hypertension and certain pathological changes in the heart in cardiomyopathy may lie in some form of exogenous toxin, possibly related to the practice of herbal medication among the African people, which acts as an a r t e r i a l vasoconstrictor in both the pulmonary and systemic circulations. This would suggest that the a r t e r i a l changes observed in the lungs are probably the result and not the cause of pulmonary hypertension. The incidence of cor pulmonale as a cause of congestive heart failure among the African in Durban is of the order of 12%. It has been shown that almost one quarter of all cases of right ventricular failure remains undiagnosed, as regards aetiology, at routine necropsy. The latter finding pointed towards the need for an investigation of the causes of right ventricular failure in the African. Such a study was undertaken and special methods of investigation w e r e / . . . were used as aids towards a more conclusive diagnosis. This study showed fibrosing lung disease, due particularly to the late complications of pulmonary tuberculosis, to be the most important cause in the production of chronic cor pulmonale in the African in Durban. The development of cor pulmonale in such cases depends not only on the presence of pulmonary parenchymal damage by fibrosis, but also on the associated pleural thickening, adhesions between chest cage and diaphragm, emphysema, and the curtailment of the pulmonary a r t e r i a l bed. In this series, all cases of fibrosing lung disease with cor pulmonale investigated for cardiac hypertrophy by means of separate weighing of the ventricles, showed evidence of pure right ventricular enlargement, indicating no significant chronic burden on the left ventricle of a diastolic overload through bronchial shunting. Thrombo-embolic cor pulmonale, hitherto believed to be r a r e in the African, emerges as the most important cause of acute cor pulmonale and the second most common cause of the more chronic varieties of the disease. The usual pathological type of pulmonary thrombo-embolic disease observed in this study is one in which fairly large pulmonary a r t e r i e s , as opposed to those of microscopic size, were involved and in consequence infarction was frequent. The lack of completely organised lesions, and the relatively small increase in total heart weights (majority below 400 Gms) suggest a rapid course in these cases, measured in months rather than in years. The usual source for pulmonary emboli was found to be the veins draining the lower limbs, particularly the deep calf veins. Whereas a predisposing factor for the development of venous thrombosis was found in just over half the number of cases investigated, in 44% of all cases of thrombo-embolic cor pulmonale in this study no cause was found at necropsy for the peripheral venous thrombosis. Of the predisposing causes encountered a posteriorly placed amoebic liver abscess emerges as an interesting aetiologic factor in the development of thrombo-embolic cor pulmonale because of its ability to produce hepatic vein and inferior vena caval thrombosis. Emphysema, usually in association with chronic bronchitis, was found to be the third most common cause of chronic cor pulmonale among Africans/ . . . Africans in Durban, and was encountered mainly in its mixed form (centrilobular and panlobular). Although structural alterations in the pulmonary a r t e r i es were noted in a significant number these were sometimes of insufficient degree to be the cause of pulmonary hypertension, thereby suggesting some other factor in the production of a raised pulmonary a r t e r i a l p r e s s u r e . Results of separate ventricular weighing in these cases show exclusive right ventricular hypertrophy, again indicating strain solely on the right ventricle. Bilharzial cor pulmonale, although one of the r a r e r causes of cor pulmonale in the African in this series, is suspected to be probably more frequent than hitherto believed. The lack of obvious macroscopic changes in the lungs of such cases is stressed, and while this may account for omissions in diagnosis, a sudden recent increase in the incidence of bilharzial cor pulmonale might also suggest that the disease is becoming more severe. Primary pulmonary hypertension as a cause of cor pulmonale in the African is r a r e , being suspected in only one case in this series. In keeping with the generally high incidence of infective diseases in the African, pericarditis as a complication of tuberculosis and hepatic amoebiasis, and the cardiac complications of syphilitic aortitis still occupy major positions among the causes of congestive heart failure in this population; together accounting for 12.4% of all deaths from congestive heart failure. Tuberculosis and amoebiasis are important not only in the production of p e r i c a r d i t i s , but, as mentioned, also play an important part in the development of cor pulmonale. Syphilitic heart disease, besides being a significant factor in the production of congestive heart failure, is the most important cause of a sudden cardiac death in the African. In conclusion it may be said that while little can be achieved with regard to the control of diseases for which no cause has as yet been found, the elimination of infective conditions such as tuberculosis, amoebiasis and syphilis will result in a significant drop in the incidence of death and disability from heart failure in the African in Natal.