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Comparison of mean concentration of BTA and Survivin among study (SG), control group (CG) and control subgroups

5.7 The concentration of the markers (BTA and Survivin) vis-a- vis stage and grade of bladder carcinoma

5.7.2 Comparison of mean concentration of BTA and Survivin among study (SG), control group (CG) and control subgroups

The mean concentration of the markers was highest in the SG, positive control subgroup (controls with haematuria) and BPH patients but lowest in the healthy volunteers (HV). This difference was statistically significant, p=0.000. The mean concentration of the markers in the various group and subgroups is shown below (Table 10).

Table 10: Comparison of Mean values of Survivin and BTA among SG and CG

Urinary marker Group Mean value ± SD p value

BTA TRAK

Survivin ELISA

SG CG

CG+(Haematuria) BPH

Other Benign diseases CAP

HV SG CG

CG+(Haematuria) BPH

Benign disease CAP

HV

242.03 ± 114.70 179.86 ± 138.69 281.40 ± 80.22 304.35 ± 48.01 209.59 ± 163.92 231.30 ± 150.18 54.14 ± 84.12

243.01 ± 374.5 1187.88 ± 558.71

345.56 ± 810.16 166.40 ± 316.64

4.46± 0.00 280.04 ± 739.51 17.42 ± 14.9

0.000 **

0.000*

0.000**

0.000*

Key:* = Kruskal- Wallis test, **= Friedman’s test, CG+ = positive contro

CHAPTER SIX 6.0 DISCUSSION

The mean age of patients in the study and control groups were 47.17 ±17.00 and 44.10 ± 18.89 respectively, with no statistically significant difference between the two groups (p=0.412). This finding of young age group of 47 years in bladder carcinoma patients in this study is comparable to 46years found in previous studies done in schistosomiasis endemic areas 5,7. The exposure to schistosomiasis occur in childhood and hence development of bladder carcinoma at young age.

In the Western world occupational exposure to aromatic hydrocarbons and smoking occurred in adulthood thus the malignancy occurred in older age group at the 7th decade of life. The Male:

Female ratio of 12: 1 is comparable to the previous study done by Mungadi and Malami 5 where the ratio was 11:1. All the patients in control group were males. The predominance of males is not surprising as they formed the main agricultural and fishing work force in this environment.

This was also suggested by previous study done in this area 5. The predominant occupation of the patients in both study and control groups was farming, this was found in about 60% and 56% of patients respectively. This was similar to the finding of the previous study in this environment where 80% of patients were farmers 5. Bladder carcinoma in African countries was associated with schistosomiasis and described in rural farming communities dwelling in riverine areas 5,7,21. All the patients in the study group presented with haematuria and LUTS which is typical of bladder carcinoma 6. In the present study, 54-70% of patients with bladder carcinoma presented with features of advanced disease which included bladder mass, necroturia, weight loss and anorexia apart from the common denominator of haematuria and LUTS. This was higher than 43% reported by the previous study in this environment but comparable to 67% reported in Tanzania schistosoma endemic areas 7,8. In this study, the finding of CRF in 14% of the patients

at the initial presentation posed great management challenge to us, nephrologists and anesthesiologists because of the need for dialysis and anaesthesia for cystoscopy to establish definitive diagnosis. The CRF might be related to delay in presentation that is common in our environment couple with invasive nature of SCC from the onset, arising mostly around the ureteric orifices 20. The commonest risk factor (85%) of bladder carcinoma in the present study was schistosomiasis as observed by previous study in this area where 73% had childhood hematuria 5. The patients in the present study had childhood haematuria in addition to history of fishing, and farming in water logged areas which was highly suggestive of schistosomiasis which was largely untreated or in some occasions treated with traditional herbs. Four patients also smoked about 25 pack-years in 25 years out of which 2 had also childhood haematuria.

In the present study, the sensitivity of Survivin was high (98.9%), comparable to the 94.0 % and 100.0% observed by Moussa et al 16 and Smith et al 58 respectively but higher than what was observed by Sharaf et al 18, Shariat et al 60, Wangs et al 61and Srivastava et al 72 who observed sensitivities of 84.4%, 64.0%, 80.0%, and 82.1% respectively. While the specificity (4.5%) was lower than these previous reports where the specificities of 95.0%, 100.0%, 91.4%, 93.3%, 100.0% and 81.1% observed by Moussa et al 16, Sharaf et al 18, Smith et al 58, Shariat et 60, Wang et al 61, and Srivastava et al 72 respectively. Urine survivin had PPV and NPV of 80.2% and 50.0% respectively in this study which lower than the values obtained by Wang et al 61 who obtained PPV and NPV of 100.0% and 86.0% respectively. The specificity of 4.5% for Survivin in the present study was lower than that of urine cytology which had specificity of 95.5% as reported by Weikert et al 63 and Srivastava et al 72 where urine cytology had specificity of 97.1%

and 95.9% respectively. The urine cytology had sensitivity and 29.1% in this study which was lower than that Survivin of 98.8%. This was similar to what was observed by the previous

studies where Weikert et al 63 and Srivastava et al 72 reported urine cytology sensitivities of 31.4% and 66.7% respectively. The differences observed between Survivin and urine cytology in this study were not statistically significant (p=0.053). This might be accounted for by lower sample size of our study when compared with the previous studies. In the present study using ROC curve Survivin is more effective than urine cytology. The AUC of Survivin was 0.609 while that of urine cytology was 0.355 (p= 0.015). The optimal cut off value for the present study of Survivin using ROC curve was 18.8pg/ ml. This will yield sensitivity and specificity of 100%

and 100% respectively. This cut off value of 18.8 pg/ ml was comparable to the value suggested by Srivastava et al 72 of 17.7pg/ ml, which gave sensitivity and specificity of 82.9% and 81.1%

respectively in their study.

The commonest histopathological type of bladder carcinoma in this study was SCC which was found in about 60% of the patients. This is comparable to the previous finding of SCC of 65.1%

in this environment 5. Adenocarcinoma was found in 2.4% of patients which was lower than 4.7% found in the previous report in our environment but comparable to 2.0% reported worldwide 5,6. But the finding of TCC of 38.1% was higher than the 27.9% reported by the previous study in our environment, which might be attributable to more awareness and campaigns about schistosomiasis in which population at risk were treated with Praziquantel in mass chemotherapy. This tends to lead to progressive increase in the rate of TCC which may reverse the ratio of SCC and TCC with time as it was seen in Egypt 4. In this study schistosoma ova was found in biopsy specimens of 47% of the patients with bladder carcinoma, this is comparable to 50% and 46% reported in our environment and Tanzania schistosoma endemic areas 5,7. The finding of schistosoma ova in biopsy tissues of the bladder carcinoma patients in this study was not restricted to SCC but also TCC and adenocarcinoma, which is in keeping with

was reported in the literature, that schistosomiasis can predispose to other histopathological types of bladder carcinoma in pure or mixed forms 6. In the previous study done in this area 50.0% of SCC is G1 while 42.9% are G2 contrary to 16.0% and 80% respectively in this study. Out of the 25 patients with SCC, 20 patients (80%) had moderately differentiated tumour while out of the 16 patients with TCC, 6 patients each (37.5%) had low-grade and high-grade tumours. The only patient with adenocarcinoma had moderately differentiated tumour. The finding of predominant moderately differentiated tumours in SCC and adenocarcinoma is contrary to the previous studies where these tumours were reported to be invasive and high grade at the time of presentation 6,7. This may be due to inter observer differences among pathologists in assigning G2 (WHO 1973, grading) as it may include some G3 tumours, confounded by inadequate sample size more especially in the TCC and adenocarcinoma groups. The WHO 1973 grading {G1 (low-grade), G2 (moderate-grade) and G3 (high-grade)} was replaced by WHO in 2004 with another grading (high or low-grade) which correlates with progression and aggressiveness 6. The classification removed gray zone (G2) for both GI and G3 tumours. But the former classification is simpler, more familiar to urologists and used by previous studies.

In the current study, urine survivin assay (ELISA) was 100% false positive (FP) in patients with haematuria from other conditions and BPH, 33% FP for cancer of the prostate, 50.0% FP for other benign diseases (stone, stricture) and 75.0% FP in HVs. This is contrary to the findings of Smith et al 58 where the Survivin was not detected in HVs and patients with other genitourinary malignancies but detected in only 3 patients (10%) with benign diseases. The finding of high concentration of Survivin in patients with bladder carcinoma compared with HVs and patients with benign urologic diseases was similar to was observed by Srivastava et al but in contrary the concentration of Survivin was high similar to the bladder carcinoma patients in patients with

cancer of the prostate. Similarly the Survivin concentration was equally low in both HVs and patients with stricture and stone as previously reported but in contrary the concentration of Survivin was very high in patients with BPH as compared to the other benign diseases 5. This might be explained by the Survivin cut off value of 12pg/ ml used in this study, which might not be appropriate for our community. This is because of the finding of statistically significant differences in mean Survivin concentrations between the HV and other groups, with the lowest values in HVs, patients with urethral stricture and stone diseases (p= 0.00). When cut off value of 17.4 ng/ ml is used, all the HVs, stricture and stone disease patients in the current study will be negative for Survivin. This value is even slightly lower than value of 17.7 pg/ ml suggested by one Srivastava et al 72 where all HVs tested negative for Survivin. This underscores the importance of establishing reference value for the marker in various patients groups and HVs.

The Survivin concentration in this study correlated significantly with grade of bladder carcinoma (p=0.00). This finding was similar to previous studies 17,18. One of these studies was by Sharaf et al 18 in Egypt. But the concentration of the Survivin in this study correlated negatively with the stage of the bladder carcinoma which was contrary to what was observed by the previous studies

17,72. This may be explained by small sample size of the current study.

No previous study has compared the performance of Survivin among the various histopathological types of bladder cancer, even though some of the studies were done in schistosoma endemic areas. In the present study, there is significant correlation between the mean Survivin concentration and histological type. There was significantly higher mean Survivin concentration in patients with SCC than TCC (p=0.00). Adenocarcinoma had the highest concentration of Survivin in the single patient, but inadequate sample population in this group might affect the accuracy of comparison with the other histological types. The urinary markers

had the same sensitivity and specificity in bladder carcinoma detection across all the histopathological types. A previous study reported Survivin to detect bladder carcinoma early before the histological evidence of the malignancy 17. A follow-up of patients with squamous metaplasia and papilloma in this study is necessary to confirm this report.

The high sensitivity of BTA TRAK (98.9%) in this study was comparable to the findings by Abdel -El -Gawad 19 (100.0%) and Lorne et al 52 (51.0- 100.0%) but higher than what was reported by Konety et al 51 (66.0%) and Kristen et al 9 (66.0- 72.0%). The specificity of BTA TRAK in this study (13.6%) was much lower than 92.5%, 74.0%, 48.0- 75.0% and 73.0- 92.5%

reported by Abdel-El-Gawad et al 19, Konety et al 51 , Kristen et al 9 and Lorne et al 52 respectively. As reported by the previous studies, BTA TRAK has higher sensitivity (98.9%) but lower specificity (13.6%) than urine cytology. The sensitivity and specificity of urine cytology in the present study were 29.1% and 95.5% respectively. Urine cytology sensitivities of 54.3%, 20.0- 53.0% while specificities of 100.0%, 83.0- 99.0% were reported by Abdel - El- Gawad et al 19 and Kristen et al 9 respectively. The lower specificity of BTA TRAK recorded in this study, may be related to the fact that the commonest predisposition to development of bladder carcinoma in this study was chronic schistosomiasis which itself as an inflammatory process can lead to false positive results in the absence of bladder carcinoma. Using ROC curve, BTA TRAK performed better than urine cytology with higher AUC of 0.751 as compared to the AUC of cytology of 0.355 and the difference was statistically significant (p =0.015). In the current study, there is comparable sensitivity and specificity of 97.4% and 90.0% at ROC curve cut off value of 13.7 u/ ml when compared with the sensitivity and specificity of 100.0% and 92.0% reported by Abd EL Gawad et al 19 in Egypt at a higher cut off value of 78 u/ ml. The authors also proposed the use of combination of markers (BTA TRAK and cytology) to increase both sensitivity and

specificity, more than using a single marker alone. This study is in keeping with their finding as combination of BTA TRAK and urine cytology will produce sensitivity and specificity of 98.8%

and 95.5% respectively, better that recorded by the individual markers, taking advantages of the high sensitivity and specificity of BTA TRAK and urine cytology respectively recorded by this study.

The finding of high false-positive (100%) in patients with haematuria from other urologic conditions and in patients with benign urologic conditions was similar to the previous studies

14,19. The 81% false positive in HVs recorded in this study is contrary to what was reported by the previous studies, in which HVs tested negative for BTA. This might be explained by the reference cut off value of 14 u/ ml for BTA used in the current study as compared to the cut off value of 78 u/ ml used by Abd EL Gawad et al19. Subgroup analysis of BTA concentration among various groups, HVs had significantly lowest BTA mean concentration of 54 u/ ml (p=0.00). Therefore the establishment of reference values in our population for various disease groups and subgroups such as HVs is necessary.

Similar to the previous studies, there was positive correlation between the BTA concentration and the stage of bladder carcinoma. But there was inverse relationship between BTA concentration and the grade of bladder carcinoma. This might be accounted for by the type of grading system used in this study (WHO 1973). This because the commonest grade was G2 which is a gray zone for G3 tumours, which could be taking care of by use of WHO 2004 grading system, which is binary, the tumour is classified as low-grade or high-grade only. This may also be compounded by fewer number of patients in grade 3 (7 patients) compared to grade 1 (10 patients) and 2 (25 patients). No previous study assess detection rate of BTA by histopathological types of bladder carcinoma. In the current study, the highest BTA

concentrations were found in patients with adenocarcinoma and SCC while the lowest concentrations was found in patients with TCC and this difference was statistically significant p=0.00. This finding might be explained by the de novo invasive and aggressive nature of adenocarcinoma and SCC of the bladder.

CHAPTER SEVEN 7.0 CONCLUSION AND RECOMMENDATIONS 7.1 CONCLUSION

Urinary markers, BTA and Survivin, have sensitivity and specificity of 98.9%, 98.9% and 13.6%, 4.5% respectively while their positive and negative predictive values (PPV and NPV) were 81.7%, 80.2% and 75.0%, 50.0% respectively. They are therefore effective in the diagnosis of bladder carcinoma. Survivin and BTA correlated with grade and stage of bladder carcinoma respectively. There were high false positive results (100%) in patients with haematuria from other urologic conditions and patients with benign prostatic hyperplasia.

The commonest histopathological type of bladder carcinoma in the present study was squamous cell type which was found in 59.5% of patients. Other histopathological types were transitional cell carcinoma and adenocarcinoma in 38.1% and 2.4% of patients respectively.