|Ahead of print publication
Expression of CD10 in urothelial carcinoma of the bladder and its correlation with histopathological grade, pathological stage, and survival of patients
Sushil Kumar Shukla1, Smita Chandra1, Neena Chauhan1, Rajeev Sarpal2
1 Department of Pathology, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, Uttarakhand, India
2 Department of Surgery, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, Uttarakhand, India
|Date of Submission||22-Sep-2018|
|Date of Decision||13-Oct-2019|
|Date of Acceptance||23-Oct-2019|
|Date of Web Publication||13-May-2020|
Department of Pathology, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Jolly Grant, Doiwala, Dehradun - 248 140, Uttarakhand
Source of Support: None, Conflict of Interest: None
Background: CD10 plays a role in signal transduction pathway and regulation of cell growth apoptosis, and therefore, it has been evaluated in different malignancies. The present study was conducted to study the immunoexpression of CD10 in urothelial carcinoma and to correlate it with histological grade, pathological stage, and survival of patients.
Materials and Methods: The study included 51 cases of urothelial carcinoma diagnosed on histopathology along with 50 controls having nonneoplastic urothelium. All the cases and controls were subjected to CD10 immunostaining. The CD10 expression was compared between the cases and controls and was also correlated with histological grade, pathological stage, histomorphological features, and 1-year survival.
Results: The study included 78.4% of high-grade urothelial carcinoma (HGUC) and 21.6% of low-grade urothelial carcinoma. The positive score of CD10 expression was observed in 68.6% of cases, while 96% of controls observed negative immunostaining. About 90.9% of low-grade carcinoma observed score 0, while 83.7% of high grade observed positive score of 1 and 2. Although there was statistical significant difference between CD 10 score and stage of tumor, its expression did not correlate with 1-year survival of cases.
Conclusion: CD10 expression increases with the grade of tumor and thus may be helpful in differentiating low grade from HGUC. Its expression also increases with stage and poor prognostic factors suggesting its possible role in pathogenesis and progression of urothelial carcinoma. CD 10 may be further analyzed for molecular targeted therapy against urothelial carcinoma.
Keywords: CD10, grade, prognosis, stage, urothelial carcinoma
|How to cite this URL:|
Shukla SK, Chandra S, Chauhan N, Sarpal R. Expression of CD10 in urothelial carcinoma of the bladder and its correlation with histopathological grade, pathological stage, and survival of patients. J Can Res Ther [Epub ahead of print] [cited 2020 Jun 2]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=284262
| > Introduction|| |
Globally, the incidence of urinary bladder carcinoma is 4.5%, with age-standardized rate of 9/100,000 population and mortality of 2.6%. Majority of the cases (75%–85%) are confined to the bladder mucosa with long course of disease, but few cases may present with advanced muscle infiltrative tumor at the time of the diagnosis., Although depth of the bladder wall invasion and histopathological grade play an important role in the prognostication of bladder carcinoma, various molecular markers are also being explored to study its prognosis., CD10 is a cell surface metalloprotease which is responsible for enzymatic hydrolysis of peptides along with a role in signal transduction pathway leading to the regulation of cell growth apoptosis and tumor progression. It shows variable expression in different malignancies with high CD10 immunoexpression in melanoma, papillary thyroid cancer and decreased expression in prostate carcinoma showing androgen-independent progression and cervical carcinoma.,,, Some studies have also evaluated expression of CD10 in bladder urothelial carcinoma. They have observed variable results with few concluding increased expression with grade of tumor while others predicted favorable outcomes with increased expression.,
The present study was, therefore, conducted to study the immunoexpression of CD10 in urothelial carcinoma. It was also intended to correlate CD10 expression with histological grade, pathological stage, and survival of patients with urothelial carcinoma. This would be thus helpful in evaluating the role of CD10 in the prognosis of urothelial carcinoma.
| > Materials and Methods|| |
The prospective study was conducted over a period of 1 year, including 51 consecutive cases of urothelial carcinoma diagnosed in the Department of Pathology of the Institute. The histopathological specimens included both transurethral resection tissue and radical cystectomy specimens. The histopathological diagnosis and grading were done according to the WHO classification of urinary tract tumors. Clinical details, occupation, and smoking habit which is considered relevant in the pathogenesis of urothelial carcinoma were noted along with laboratory and radiological findings. The pathological staging of all the cases was done according to tumor, node, and metastasis classification of urinary bladder carcinoma by Union for Cancer Control (UICC). The study also included 50 controls which had nonneoplastic urothelial mucosa on histopathological examination. Superficial biopsies which did not include deep muscle to comment on its invasion were excluded from the study. All the cases and controls were subjected to immunohistochemical staining for CD10 (BioGenex, CA, USA) on automated immunostainer. The CD10 immunostain was assessed in cytoplasm and cytoplasmic membrane of epithelial cells semiquantitatively based on the percentage of cells showing positivity by counting at least 1000 cells. Score 0 (negative staining) was given when <5% cells were positive; score 1 (positive), 5%–50% cells positive and score 2 when >50% positive cells were present. The CD10 immunostaining was compared between cases of urothelial carcinoma cases and controls along with correlation with histological grade, pathological stage and morphological features, including necrosis, mitosis, lymphovascular, and perineural invasion. Association of CD10 expression with 1-year survival of cases was also studied.
The statistical analysis was performed using the Statistical Package for the Social Science version 22.0 (SPSS Inc., Chicago, IL, USA). Fisher's exact and Student's t-test were used for statistical evaluation. P < 0.05 was considered as statistically significant.
All procedures performed in the current study were approved by the Institutional Review Board in accordance with the 1964 Helsinki declaration and its later amendments. Informed consent was obtained from all individuals participants included in the study.
| > Results|| |
The study included 51 cases of urothelial carcinoma with a male-to-female ratio of 7:1, mean age of 60.40 ± 13.34 years, and range of 21–78 years. The most common occupation of cases was farming (33.3%) and 84.3% of cases were active smokers. Painless hematuria (98%) was the common presenting complaint followed by increased urinary frequency (56.9%) and burning micturation (56.9%). Radiological findings, including ultrasonography, computed tomography and/or magnetic resonance imaging, and cystoscopic examination, revealed that 80.4% cases showed unifocal lesion and most commonly involving the lateral wall of the bladder (45.1%). The tumor size was >4 cm × 4 cm × 4 cm in maximum number of cases (45.10% of total cases). The histopathological examination observed that 40/51 cases (78.4%) showed high-grade urothelial carcinoma (HGUC), while 11/51 cases (21.6%) showed low-grade urothelial carcinoma (LGUC). The deep muscle invasion was present in 28/40 cases (70%) of HGUC, while only 2/11 cases (18.2%) of LGUC observed deep muscle invasion. [Table 1] shows the associated histomorphological features in urothelial carcinoma cases. Lymphovascular and perineural invasion was observed in only 10 (19.6%) and 3 cases (5.9%), respectively. Moderate-to-severe necrosis was observed in 24/51 cases (47.05%), and of these, 95.83% of cases were HGUC. It was observed that only 12.5% HGUC cases (29/40) showed 1 year survival, while 90.9% of LGUC (10/11 cases) survived for 1 year after the diagnosis. The positive score of CD10 expression of 1 and 2 was observed in 35/51 cases (68.6%) of urothelial carcinoma cases, while 48/50 (96%) of controls observed negative score of 0 [Figure 1]. The CD 10 immunoexpression was statistically significantly higher in urothelial carcinoma cases in comparison to controls (P < 0.001). [Table 2] shows the association of CD10 expression with histopathological grade of urothelial carcinoma. It shows that 90.9% (10/11 cases) of LGUC observed score 0 for CD10 staining, while 83.7% (31/37 cases) of HGUC observed positive score of 1 and 2. There was statistically significant difference between the grade of urothelial carcinoma and CD10 scoring (P < 0.001). [Figure 2] shows the CD10 immunostaining in different grades of urothelial carcinoma. [Table 1] shows the association of CD10 with histo-morphological features observed in urothelial carcinoma. It was observed that cases showing necrosis, lymphovascular, and deep muscle invasion showed statistically significant high score of CD10 immunostaining (P < 0.05). [Table 3] shows that urothelial carcinoma cases with stage pT1 showed score 0 in 11/19 (57.8%) of the cases, while none of the case with stage pT4 showed score 0 (0/3) cases. There was statistical significant difference between stage of tumor and CD10 score (P < 0.001). However, CD10 expression observed no statistically significant difference with 1-year survival of urothelial carcinoma cases.
|Table 1: CD10 expression with histomorphological features in urothelial carcinoma|
Click here to view
|Figure 1: (a) Histopathological section showing nonneoplastic urothelium (H and E, ×20). (b) Histopathological section showing negative CD10 immunostain of score 0 in nonneoplastic urothelium (CD10 immunostain, ×40). (c) Histopathological section showing urothelial carcinoma (H and E, ×40). (d) Histopathological section showing positive CD10 immunostain of score 2 in case of urothelial carcinoma (CD10 immunostain, ×40)|
Click here to view
|Figure 2: (a) Histopathological section showing low-grade urothelial carcinoma (H and E, ×20). (b) Section showing positive CD10 Score 1 in low-grade urothelial carcinoma (×20). (c) Section showing high-grade urothelial carcinoma (H and E, ×40). (d) Section showing positive CD10 Score 2 in high-grade urothelial carcinoma (×40). (e) Section showing high-grade urothelial carcinoma with deep muscle invasion (H and E, ×20). (f) Section showing positive CD10 Score 2 in high-grade urothelial carcinoma with deep muscle invasion (×20)|
Click here to view
|Table 3: CD10 score with pathological stage and survival in urothelial carcinoma|
Click here to view
| > Discussion|| |
Urothelial carcinoma is the seventh most carcinoma worldwide and is associated with risk factors including cigarette smoking, occupational exposure to aromatic amines, chronic infections, and arsenic. Our study also observed that 84.3% cases of urothelial carcinoma were active smokers. Painless hematuria, dysuria, and urgency were the most common complaints in this study. Saltsman et al. have also concluded in their single-center study that hematuria is the most common sign of bladder neoplasia in children and young adults and should be investigated by cystoscopy. Recently, it has been concluded that advanced age or sex are independent and have no impact of immune pathways and checkpoints in invasive urothelial carcinoma. The grade and stage of the tumor are important factors in determining the prognosis of urothelial carcinoma and it has been observed that there is significant difference in survival of patients which are showing noninvasive carcinoma to patients with infiltration in lamina or muscularis propria. The present study also observed larger number of cases (90.9%) of LGUC showing 1-year survival in comparison to HGUC (12.5%).
Various immunohistochemical markers are being studied recently to correlate with tumor grade and stage of urothelial carcinoma and determine its prognosis. Li et al. concluded that expression of epidermal growth factor receptor (EGFR) and human EGFR 2 correlate with pathological grade, clinical stage, and tumor recurrence of bladder transitional cell carcinoma. CD10 which is single chain zinc-dependent metalloprotease plays an important role in cell growth, apoptosis and by altering cellular microenvironment may also affect invasion and metastasis of tumor cells. It is considered to be dual-edge sword which on one hand may be driving force for cancer progression and on the other hand may be associated with a good prognosis and treatment response. Thus, it shows variable expression in different malignancies and its role is being explored in cancer detection, prognosis, and molecular targeted therapy.,, Recently, CD10 is also being evaluated in urothelial carcinoma to study its association, if any, with pathological grade, stage, and the prognosis of tumor. The present study observed that 68.6% of urothelial carcinoma cases observed positive CD10 immunostaining in comparison to only 4% of cases showing positive staining in nonneoplastic urothelium with statistical significant difference. Although few previous studies have also observed decreased or negative CD10 immunostaining in nonneoplastic urothelium, in contrast, occasional studies have demonstrated positive CD10 immunostaining in nonneoplastic urothelium., These variable observations may be either related to difference in molecular profile or micro-environment of nonneoplastic urothelium or may be due to difference in affinity of normal urothelium to CD10 in comparison to neoplastic mucosa., It is also suggested that CD10 may result in down-regulation of anti-apoptotic and growth-promoting signals by degradation of delivery molecules and thus preventing carcinogenesis in normal urothelium. It was also observed in the present study that with the increase in grade and stage of urothelial carcinoma the CD10 immunostaining score also increased with 90.9% of LGUC showing score 0 or negative immunostaining. In addition, urothelial carcinoma with poor morphological prognostic factors, including necrosis, lymphovascular invasion, and deep muscle invasion, showed significant high score of CD10 immunostaining (P < 0.05). Similarly, few recent studies have also observed increased CD10 expression with high-grade carcinoma., However, in contrast, occasional studies have shown no significant association between pathologic stage and CD10 score in urothelial carcinoma., Our study suggests that CD10 may play an important role in progression and pathogenesis of urothelial carcinoma This may be attributed to different molecular properties of CD10 which have been discussed previously in literature pertaining to various other malignancies and have been responsible for the regulation of apoptosis or change in tumor milieu and microenvironment., Murali and Delprado have concluded in their study that accumulation of nonfunctional mutated CD10 may be responsible for increased CD10 expression with grade and stage of urothelial carcinoma. It was also observed in the present study that there was significant correlation of CD10 expression with lymphovascular invasion. This may be associated with regulation of endothelin levels by CD10 which may facilitate angiogenesis and vascular invasion.
It has also been suggested that the lack of common standardized immunohistochemical CD10 staining and scoring system may also be responsible for discrepancy in observation of CD10 positivity. The authors, therefore, suggest universal common staining pattern including cytoplasmic and/or cytoplasmic membrane for evaluating CD10 in grading and staging of urothelial carcinoma. In addition, the subjective error due to lack of deeper muscle in the biopsy may also be responsible for erroneous correlation of CD10 with stage of urothelial carcinoma. However, this confounding factor was eliminated in the present study by excluding the cases, in which deeper muscle was not included in the histopathological specimens. Some studies have also assessed the CD10 expression in fibroblastic stromal cells and have observed increased CD10 expression in stromal and epithelial cells, especially in bilharziasis associated urothelial carcinoma. It has also been reported that tumorous CD10 is more strongly related to progression of UC than stromal CD10 and is an independent factor for UC prognosis. However, the present study evaluated only the tumorous epithelial CD10 and not stromal CD10. Similarly, other markers have also been evaluated in stromal and epithelial cells and it has been observed that miR-21 in both forms leads to progression of urothelial carcinoma.
Another interesting finding that was observed in the present study was low CD10 expression in cases which survived for 12 months and more in cases which died within 1 year. However, no statistically significant difference was observed between CD10 score and 1-year survival in our study. This may be attributed to an important limitation of the present study that it included lesser number of cases with study of shorter period of survival. The authors, therefore, suggest that further larger studies with extended follow-up may be done to know the exact role of CD10 in the pathogenesis and prognosis of urothelial carcinoma. This may, in turn, be also helpful in designing molecular targeted therapy against CD10 in urothelial carcinoma.
| > Conclusion|| |
CD10 expression is positive in urothelial carcinoma, while nonneoplastic urothelium shows negative expression. CD10 expression increases with the grade of tumor and thus may be helpful in differentiating low grade from HGUC. In addition, its expression also increases with the stage of the carcinoma along with poor prognostic factors including necrosis, lymphovascular, and deep muscle invasion. This suggests the possible role of CD10 in the pathogenesis and progression of urothelial carcinoma which may be further analyzed for molecular targeted therapy against this carcinoma. Further larger studies with extended follow-up are recommended to evaluate the definite role of CD10 as prognostic marker in urothelial carcinoma.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al
. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide. IARC Cancer Base No 11. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan
. [Last accessed on 2018 Feb 08].
Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Böhle A, Palou-Redorta J, et al.
EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol 2011;59:997-1008.
Matalka I, Bani-Hani K, Shotar A, Bani Hani O, Bani-Hani I. Transitional cell carcinoma of the urinary bladder: A clinicopathological study. Singapore Med J 2008;49:790-4.
Ho ME, Quek SI, True LD, Seiler R, Fleischmann A, Bagryanova L, et al.
Bladder cancer cells secrete while normal bladder cells express but do not secrete AGR2. Oncotarget 2016;7:15747-56.
Omran OM. CD10 and E-cad expression in urinary bladder urothelial and squamous cell carcinoma. J Environ Pathol Toxicol Oncol 2012;31:203-12.
Mishra D, Singh S, Narayan G. Role of B cell development marker CD10 in cancer progression and prognosis. Mol Biol Int 2016;2016:4328697.
Bilalovic N, Sandstad B, Golouh R, Nesland JM, Selak I, Torlakovic EE. CD10 protein expression in tumor and stromal cells of malignant melanoma is associated with tumor progression. Mod Pathol 2004;17:1251-8.
Mokhtari M, Ameri F. Diagnostic value of CD-10 marker in differentiating of papillary thyroid carcinoma from benign thyroid lesions. Adv Biomed Res 2014;3:206.
Freedland SJ, Seligson DB, Liu AY, Pantuck AJ, Paik SH, Horvath S, et al.
Loss of CD10 (neutral endopeptidase) is a frequent and early event in human prostate cancer. Prostate 2003;55:71-80.
Terauchi M, Kajiyama H, Shibata K, Ino K, Mizutani S, Kikkawa F. Anti-progressive effect of neutral endopeptidase 24.11 (NEP/CD10) on cervical carcinomain vitro
and in vivo
. Oncology 2005;69:52-62.
Bahadir B, Behzatoglu K, Bektas S, Bozkurt ER, Ozdamar SO. CD10 expression in urothelial carcinoma of the bladder. Diagn Pathol 2009;4:38.
Seiler R, von Gunten M, Thalmann GN, Fleischmann A. High CD10 expression predicts favorable outcome in surgically treated lymph node-positive bladder cancer patients. Hum Pathol 2012;43:269-75.
Eble JN, Sauter G, Epstein JI, Sesterhenn IA, editors. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. World Health Organization Calssification of Tumours. Lyon, France: IARC Press; 2004.
Saltsman JA, Malek MM, Reuter VE, Hammond WJ, Danzer E, Herr HW, et al.
Urothelial neoplasms in pediatric and young adult patients: A large single-center series. J Pediatr Surg 2018;53:306-9.
Holland BC, Sood A, Delfino K, Dynda DI, Ran S, Freed N, et al.
Age and sex have no impact on expression levels of markers of immune cell infiltration and immune checkpoint pathways in patients with muscle-invasive urothelial carcinoma of the bladder treated with radical cystectomy. Cancer Immunol Immunother 2019;68:991-7.
Breau RH, Karnes RJ, Farmer SA, Thapa P, Cagiannos I, Morash C, et al.
Progression to detrusor muscle invasion during urothelial carcinoma surveillance is associated with poor prognosis. BJU Int 2014;113:900-6.
Li W, Wang Y, Tan S, Rao Q, Zhu T, Huang G, et al.
Overexpression of epidermal growth factor receptor (EGFR) and HER-2 in bladder carcinoma and its association with patients' clinical features. Med Sci Monit 2018;24:7178-85.
Bircan S, Candir O, Kapucuoglu N, Serel TA, Ciris M, Karahan N. CD10 expression in urothelial bladder carcinomas: A pilot study. Urol Int 2006;77:107-13.
Murali R, Delprado W. CD10 immunohistochemical staining in urothelial neoplasms. Am J Clin Pathol 2005;124:371-9.
Jang TJ. CD10 is again expressed at a certain stage during the neoplastic process of bladder transitional cell carcinomas. Cancer Res Treat 2012;44:262-6.
Popov H, Ghenev P. Expression of CD10 as a prognostic and predictive factor in urothelial carcinoma. Trakia J Sci 2015;13:144-6.
Atique M, Abbasi MS, Jamal S, Khadim MT, Akhtar F, Jamal N, et al.
CD 10 expression intensity in various grades and stages of urothelial carcinoma of urinary bladder. J Coll Physicians Surg Pak 2014;24:351-5.
Kandemir NO, Bahadir B, Gun BD, Yurdakan G, Karadayi N, Ozdamar SO. CD10 expression in urinary bladder carcinomas: Staining patterns and relationship with pathologic parameters. Turk J Med Sci 2010;40:177-84.
Mohammed AS, Ali HH, Qasim BJ, Chaloob MK. CD10 and CA19.9 immunohistochemical expression in transitional cell carcinoma of the urinary bladder. Urol Ann 2013;5:81-5.
] [Full text]
Iwaya K, Ogawa H, Izumi M, Kuroda M, Mukai K. Stromal expression of CD10 in invasive breast carcinoma: A new predictor of clinical outcome. Virchows Arch 2002;440:589-93.
Bostrom PJ, Van Rhijn B, Fleshner N, Finelli A, Jewett M, John T, et al
. Staging and staging errors in bladder cancer. Eur Urol Suppl 2010;9:2-9.
Kumagai-Togashi A, Uozaki H, Kikuchi Y, Watabe S, Numakura S, Watanabe M. Tumorous CD10 is more strongly related to the progression of urothelial carcinoma than stromal CD10. Anticancer Res 2019;39:635-40.
Ohno R, Uozaki H, Kikuchi Y, Kumagai A, Aso T, Watanabe M, et al.
Both cancerous miR-21 and stromal miR-21 in urothelial carcinoma are related to tumour progression. Histopathology 2016;69:993-9.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]