Aurora A in transitional cell carcinoma of urinary bladder: An immunohistochemical study with clinico-pathological correlation.
Fatma Samy Sayed Hafez;
Abstract
Urinary bladder cancer is the ninth most common cancer in the world, accounting for 3.3% of all malignancies. In Egypt, bladder cancer continues to be the most common cancer among males, constituting approximately 14.5 % of all cancers according to the National Cancer Institute Cancer Pathology Registry.
Transitional cell carcinoma (TCC) is the most common histopathological type of bladder cancers, occuring in approximately 90% of all bladder cancers in Western countries, with a peak incidence in the seventh decade of life. In Egypt, the incidence of TCC increased from 22% in 1980 to 73% of bladder cancers in 2005.
Aurora kinase A (AURKA) is critical for proper formation of mitotic spindle through the recruitment of several proteins important in the spindle formation. Morever, Aurora A has been implicated in human carcinogenesis through the development of aneuploidy and chromosomal instability.
Aurora A overexpression has been correlated with phosphorylation of tumor suppressors such as p53, modulating their activities through regulating cell cycle progression, cell survival, and transformation. Moreover, the upregulated levels of Aurora-A expression have been correlated with motility, angiogenesis, chemoresistance or radioresistance of tumor cells.
The aim of this study is to assess the immunohistochemical expression of Aurora A in cases of transitional cell carcinoma of urinary bladder and to correlate it with various clinical and pathological parameters as a trial to outline the characteristics of patients who may benefit from targeted therapy.
The material of this study included a total of 60 selected cases of TCC of urinary bladder of different grades. The specimens were collected retrospectively from the archival files of the specimens received at the Pathology Department of Al-Demerdash Hospital and Ain-Shams Specialized Hospital during the period from January 2009- December 2013.
All cases were subjected to the following:
1. Registeration of all available clinicopathological data from the files of the patients as patient’s age and sex.
2. Histopathological evaluation of H & E stained sections prepared from paraffin blocks at 5 um thickness to assess the different histopathological parameters.
3. Immunohistochemical staining of paraffin embedded tissue sections for Aurora A using streptavidin biotin technique.
4. Statistical analysis to evaluate immunohistochemical expression of Aurora A in urothelial carcinoma and its relation to clinicopathological characteristics.
According to clinical results, the age of the patients ranged from 36 to 82 years with a mean age of 59.15 years. As regards the sex, fifty one out of 60 cases were males (85 %), the remaining nine cases were females (15 %) with a male to female ratio 5.7:1.
As regards the histological type, 33 out of the 60 cases were previously diagnosed as invasive non-papillary TCC (55%), 20 cases were previously diagnosed as invasive papillary TCC (33.3%), 4 cases were previously diagnosed as non-invasive papillary TCC (6.7%), 2 cases were previously diagnosed as PUNLMP (3.3%) and 1 case was previously diagnosed as CIS (1.7%).
As regards the histologic grade of the 59 cases diagnosed as TCC, 41 cases were high grade representing 69.5%, 16 cases were low grade representing 27.1% and 2 cases were PUNLMP representing 3.4%.
In this study, only 43 out of the 60 cases were radical cystectomy specimens and had available lympho-vascular status. Sixteen out of these cases (37.2%) showed positive lympho-vascular invasion while 27 out of the 43 cases (62.8%) were negative for lympho-vascular invasion.
In the current study, fourteen out of 43 cases of radical cystectomy (32.6%) showed positive perineural invasion and 29 cases (67.4%) were negative for perineural invasion.
As regards the pathological T stage of the 58 cases of TCC (two cases of PUNLMP were excluded as they are not categorized by T stage.), one case was Tis representing (1.7%), 4 cases were Ta representing (6.9%), 12 cases were T1 representing (20.7%), 17 cases were T2 representing (29.3%); 16/58 cases were T3 representing (27.6%) and 8 cases were T4 representing (13.8%).
In the current study lymph node status was assessed for 43 radical cystectomy specimens. Ten out of the 43 cases were Nx representing (23.3 %), 22 cases were N0 representing (51.1%), 7 cases were N1 representing (16.3 %) and 4 case were T2 representing (9.3 %).
According to immunohistochemistry in the present study, 51 out of the 60 cases (85%) expressed diffuse cytoplasmic staining and 9 cases (15%) expressed cytoplasmic and nuclear staining.
Regarding the combined score of Aurora A staining in this study, 3 out of the 60 cases were score 2 representing (5%), 10 cases were score 3 representing (16.7%), 12 cases were score 4 representing (20%), 20 cases were score 5 representing (33.3%) and 15 cases were score 6 representing (25%). Consequently 25 out of the 60 cases of TCC showed low expression (combined score 2, 3 and 4) representing 41.7% and 35 cases showed high expression (combined score 5 and 6) representing 58.3%.
Regarding the age and sex of the patients, there was no significant difference in combined score among TCC of different age (P value = 0.48 > 0.05), or among males and females (P value = 0.58> 0.05).
Most cases of invasive non-papillary TCC (69.7%) showed high expression of Aurora A, while most of CIS/PUNLMP cases (66.7%) and non-invasive papillary TCC cases (75%) showed low expression of Aurora A. This relation was statistically significant. (P value = 0.04<0.05).
Most cases of high grade TCC (73.2%) showed high expression of Aurora A while most cases of low grade TCC (75%) and the two cases of PUNLMP (100%) showed low expression. This relation was statistically significant (P value = 0.04<0.05).
There was no significant relation between combined score and lympho-vascular invasion of TCC (P value = 0.95>0.05), or perineural invasion of TCC (P value = 0.24>0.05).
All of T4 cases (100%) and most of T3 cases (81.3%) showed high expression of Aurora A while most of T1cases showed low expression (91.7%). This relation was statistically significant (P value <0.001).
As regards lymph node status, there was no significant relation between combined score of Aurora A expression and lymph node status (P value = 0.10>0.05).
Aurora A is closely related to tumor carcinogenesis, progression and aggressiveness of TCC. Furthermore, Aurora A seems to be a highly valuable target for therapy. Immunohistochemical staining could substitute direct measurement of Aurora kinase A activity in vivo to predict tumor response to Aurora A inhibitors, as direct in vivo measurement is difficult.
Transitional cell carcinoma (TCC) is the most common histopathological type of bladder cancers, occuring in approximately 90% of all bladder cancers in Western countries, with a peak incidence in the seventh decade of life. In Egypt, the incidence of TCC increased from 22% in 1980 to 73% of bladder cancers in 2005.
Aurora kinase A (AURKA) is critical for proper formation of mitotic spindle through the recruitment of several proteins important in the spindle formation. Morever, Aurora A has been implicated in human carcinogenesis through the development of aneuploidy and chromosomal instability.
Aurora A overexpression has been correlated with phosphorylation of tumor suppressors such as p53, modulating their activities through regulating cell cycle progression, cell survival, and transformation. Moreover, the upregulated levels of Aurora-A expression have been correlated with motility, angiogenesis, chemoresistance or radioresistance of tumor cells.
The aim of this study is to assess the immunohistochemical expression of Aurora A in cases of transitional cell carcinoma of urinary bladder and to correlate it with various clinical and pathological parameters as a trial to outline the characteristics of patients who may benefit from targeted therapy.
The material of this study included a total of 60 selected cases of TCC of urinary bladder of different grades. The specimens were collected retrospectively from the archival files of the specimens received at the Pathology Department of Al-Demerdash Hospital and Ain-Shams Specialized Hospital during the period from January 2009- December 2013.
All cases were subjected to the following:
1. Registeration of all available clinicopathological data from the files of the patients as patient’s age and sex.
2. Histopathological evaluation of H & E stained sections prepared from paraffin blocks at 5 um thickness to assess the different histopathological parameters.
3. Immunohistochemical staining of paraffin embedded tissue sections for Aurora A using streptavidin biotin technique.
4. Statistical analysis to evaluate immunohistochemical expression of Aurora A in urothelial carcinoma and its relation to clinicopathological characteristics.
According to clinical results, the age of the patients ranged from 36 to 82 years with a mean age of 59.15 years. As regards the sex, fifty one out of 60 cases were males (85 %), the remaining nine cases were females (15 %) with a male to female ratio 5.7:1.
As regards the histological type, 33 out of the 60 cases were previously diagnosed as invasive non-papillary TCC (55%), 20 cases were previously diagnosed as invasive papillary TCC (33.3%), 4 cases were previously diagnosed as non-invasive papillary TCC (6.7%), 2 cases were previously diagnosed as PUNLMP (3.3%) and 1 case was previously diagnosed as CIS (1.7%).
As regards the histologic grade of the 59 cases diagnosed as TCC, 41 cases were high grade representing 69.5%, 16 cases were low grade representing 27.1% and 2 cases were PUNLMP representing 3.4%.
In this study, only 43 out of the 60 cases were radical cystectomy specimens and had available lympho-vascular status. Sixteen out of these cases (37.2%) showed positive lympho-vascular invasion while 27 out of the 43 cases (62.8%) were negative for lympho-vascular invasion.
In the current study, fourteen out of 43 cases of radical cystectomy (32.6%) showed positive perineural invasion and 29 cases (67.4%) were negative for perineural invasion.
As regards the pathological T stage of the 58 cases of TCC (two cases of PUNLMP were excluded as they are not categorized by T stage.), one case was Tis representing (1.7%), 4 cases were Ta representing (6.9%), 12 cases were T1 representing (20.7%), 17 cases were T2 representing (29.3%); 16/58 cases were T3 representing (27.6%) and 8 cases were T4 representing (13.8%).
In the current study lymph node status was assessed for 43 radical cystectomy specimens. Ten out of the 43 cases were Nx representing (23.3 %), 22 cases were N0 representing (51.1%), 7 cases were N1 representing (16.3 %) and 4 case were T2 representing (9.3 %).
According to immunohistochemistry in the present study, 51 out of the 60 cases (85%) expressed diffuse cytoplasmic staining and 9 cases (15%) expressed cytoplasmic and nuclear staining.
Regarding the combined score of Aurora A staining in this study, 3 out of the 60 cases were score 2 representing (5%), 10 cases were score 3 representing (16.7%), 12 cases were score 4 representing (20%), 20 cases were score 5 representing (33.3%) and 15 cases were score 6 representing (25%). Consequently 25 out of the 60 cases of TCC showed low expression (combined score 2, 3 and 4) representing 41.7% and 35 cases showed high expression (combined score 5 and 6) representing 58.3%.
Regarding the age and sex of the patients, there was no significant difference in combined score among TCC of different age (P value = 0.48 > 0.05), or among males and females (P value = 0.58> 0.05).
Most cases of invasive non-papillary TCC (69.7%) showed high expression of Aurora A, while most of CIS/PUNLMP cases (66.7%) and non-invasive papillary TCC cases (75%) showed low expression of Aurora A. This relation was statistically significant. (P value = 0.04<0.05).
Most cases of high grade TCC (73.2%) showed high expression of Aurora A while most cases of low grade TCC (75%) and the two cases of PUNLMP (100%) showed low expression. This relation was statistically significant (P value = 0.04<0.05).
There was no significant relation between combined score and lympho-vascular invasion of TCC (P value = 0.95>0.05), or perineural invasion of TCC (P value = 0.24>0.05).
All of T4 cases (100%) and most of T3 cases (81.3%) showed high expression of Aurora A while most of T1cases showed low expression (91.7%). This relation was statistically significant (P value <0.001).
As regards lymph node status, there was no significant relation between combined score of Aurora A expression and lymph node status (P value = 0.10>0.05).
Aurora A is closely related to tumor carcinogenesis, progression and aggressiveness of TCC. Furthermore, Aurora A seems to be a highly valuable target for therapy. Immunohistochemical staining could substitute direct measurement of Aurora kinase A activity in vivo to predict tumor response to Aurora A inhibitors, as direct in vivo measurement is difficult.
Other data
| Title | Aurora A in transitional cell carcinoma of urinary bladder: An immunohistochemical study with clinico-pathological correlation. | Other Titles | أرورا-أ فى سرطان الخلايا الانتقاليه فى المثانه: دراسهمناعيه وعلاقتها بالعوامل الاكلينيكيه والباثولوجيه. | Authors | Fatma Samy Sayed Hafez | Issue Date | 2015 |
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