Small cell carcinoma (SmCC) of the urinary bladder is a rare, highly aggressive neoplasm. The diagnosis is usually made on morphologic grounds, with the help of immunohistochemistry to document neuroendocrine differentiation. However, neuroendocrine markers generally have low sensitivity, ranging between 30-70%. Recent studies have reported p16 over-expression in SmCC of the lung, suggesting that p16 immunohistochemistry may be useful in the diagnosis of bladder SmCC. This is the first study to analyze the usefulness of p16 in the distinction of small cell and high grade urothelial cell carcinoma (HG-UCC). Fourteen cases of SmCCs and sixteen cases of HG-UCC of the bladder were stained with p16, p63, cytokeratin 20 (CK20), cytokeratin 7 (CK7), chromogranin (Chr), synaptophysin (Syn), and CD56. P16 expression was significantly higher in SmCCs (92.8%) when compared to HG-UCCs (43.7%). P63 and CK20, on the other hand, were positive in the majority of HG-UCCs (81.3% and 50%, respectively), while only 14.3% of SmCCs showed focal immunoreactivity with CK20. The sensitivity of the traditional neuroendocrine markers was low, ranging between 28.6% (Chr) and 71.4% (CD56) in SmCCs. P16 positivity in the absence of p63 and CK20 is highly characteristic of SmCC, while p63 and CK20 positivity with or without p16 expression is typical of HG-UCC.
Blomjous CE, Vos W., De Voogt HJ, Van der Valk P., Meijer CJSmall cell carcinoma of the urinary bladder. A clinicopathologic, morphometric, immunohistochemical, and ultrastructural study of 18 cases. Cancer. 1989;64:1347-1357.
2.
Holmäng S., Borghede G., Johansson SLPrimary small cell carcinoma of the bladder: a report of 25 cases. J Urol. 1995;153:1820-1822.
3.
Abrahams NA, Moran C., Reyes AO, Siefker-Radtke A., Ayala AGSmall cell carcinoma of the bladder: a contemporary clinicopathological study of 51 cases. Histopathology. 2005;46:57-63.
4.
Eble, JN, ed. WHO Classification of Tumours. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs . Lyon, France: IARC Press; 2004:135-136.
5.
Beasley MB, Lantuejoul S., Abbondanzo S., et al. The p16/ cyclinD1/Rb pathway in neuroendocrine tumors of the lung. Hum Pathol. 2003;34:136-142.
6.
Wang X., MacLennan GT, Lopez-Beltran A., Cheng L.Small cell carcinoma of the urinary bladder-histogenesis, genetics, diagnosis, biomarkers, treatment and prognosis. Appl Immunohistochem Mol Morphol. 2007;15:8-18.
7.
Choong NW, Quevedo JF, Kaur JSSmall cell carcinoma of the urinary bladder. The Mayo Clinic experience. Cancer. 2005;103:1172-1178.
8.
Mills SE, Wolfe JT 3rd, Weiss MA, et al. Small cell undifferentiated carcinoma of the urinary bladder. A light-microscopic, immunocytochemical, and ultrastructural study of 12 cases . Am J Surg Pathol. 1987;11:606-617.
9.
Soriano P., Navarro S., Gil M., Llombart-Bosch A.Small-cell carcinoma of the urinary bladder. A clinico-pathological study of ten cases. Virchows Arch. 2004;445:292-297.
10.
Jones TD, Kernek KM, Yang XJ, et al. Thyroid transcription factor 1 expression in small cell carcinoma of the urinary bladder: an immunohistochemical profile of 44 cases. Hum Pathol. 2005;36:718-723.
11.
Alijo Serrano F., Sánchez-Mora N., Angel Arranz J., Hernández C., Alvarez-Fernández E.Large cell and small cell neuroendocrine bladder carcinoma. Am J Clin Pathol. 2007;128:733-739.
12.
Bassily NH, Vallorosi CJ, Akdas G., Montie JE, Rubin MACoordinate expression of cytokeratins 7 and 20 in prostate adenocarcinoma and bladder urothelial carcinoma. Am J Clin Pathol. 2000;113:383-388.
13.
Iczkowski KA , Shanks JH, Allsbrook WC, et al. Small cell carcinoma of urinary bladder is differentiated from urothelial carcinoma by chromogranin expression, absence of CD44 variant 6 expression, a unique pattern of cytokeratin expression, and more intense γ-enolase expression. Histopathology . 1999;35:150-156.
14.
Compérat E., Camparo P., Haus R., et al. Immunohistochemical expression of p63, p53 and MIB-1 in urinary bladder carcinoma. A tissue microarray study of 158 cases. Virchows Arch. 2006;448:319-324.
15.
Urist MJ, Di Como CJ, Lu ML, et al. Loss of p63 expression is associated with tumor progression in bladder cancer. Am J Pathol. 2002;161:1199-1206.
16.
Doorbar J.Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci (Lond). 2006;110: 525-541.
17.
McCluggage WGImmunohistochemistry as a diagnostic aid in cervical pathology. Pathology. 2007;39:97-111.
18.
O’Neill CJ, McCluggage WGP16 expression in the female genital tract and its value in diagnosis. Adv Anat Pathol. 2006;13:8-15.
19.
Wikenheiser-Brokamp KARetinoblastoma regulatory pathway in lung cancerCurr Mol Med. 2006;6:783-793.
20.
Zhang H., Liu J., Cagle PT, Allen TC, Laga AC, Zander DSDistinction of pulmonary small cell carcinoma from poorly differentiated squamous cell carcinoma: an immunohistochemical approach. Mod Pathol . 2005;18:111-118.
21.
Wang HL, Lu DWDetection of human papillomavirus DNA and expression of p16, Rb, and p53 proteins in small cell carcinomas of the uterine cervix. Am J Surg Pathol. 2004;28:901-908.
22.
Benedict WF, Lerner SP, Zhou J., Shen X., Tokunaga H., Czerniak B.Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer. Oncogene. 1999;18:1197-1203.
23.
Tzai TS, Tsai YS, Chow NHThe prevalence and clinicopathologic correlate of p16INK4a, retinoblastoma and p53 immunoreactivity in locally advanced urinary bladder cancer. Urol Oncol. 2004;22:112-118.
24.
Xu HJ, Cairns P., Hu SX, Knowles MA, Benedict WFLoss of Rb protein expression in primary bladder cancer correlates with loss of heterozygosity at the Rb locus and tumor progression. Int J Cancer. 1993;53:781-784.
25.
Shariat SF, Tokunaga H., Zhou J., et al. P53, p21, pRb, and p16 expression predict clinical outcome in cystectomy with bladder cancer. J Clin Oncol. 2004;22:1014-1024.
26.
Williamson MP, Elder PA, Shaw ME, Devlin J., Knowles MAP16 (CDKN2) is a major deletion target at 9p21 in bladder cancer. Hum Mol Genet. 1995 ;4:1569-1577.
27.
Hitchings AW , Kumar M., Jordan S., Nargund V., Martin J., Berney DMPrediction of progression in pTa and pT1 bladder carcinomas with p53, p16 and pRb. Br J Cancer. 2004;91:552-557.
28.
Yurakh AO, Ramos D., Calabuig-Fariñas S., et al. Molecular and immunohistochemical analysis of the prognostic value of cell-cycle regulators in urothelial neoplasms of the bladder. Eur Urol. 2006;50:506-515.
29.
Yang CC, Chu KC, Chen HY, Chen WCExpression of p16 and cyclin D1 in bladder cancer and correlation in cancer progression. Urol Int. 2002;69:190-194.
30.
Cordon-Cardo C., Wartinger D., Petrylak D., et al. Altered expression of the retinoblastoma gene product: prognostic indicator in bladder cancer. J Natl Cancer Inst. 1992;84:1251-1256.
31.
Cote RJ, Dunn MD, Chatterjee SJ, et al. Elevated and absent pRb expression is associated with bladder cancer progression and has cooperative effects with p53. Cancer Res. 1998;58: 1090-1094.
32.
Korkolopoulou P., Christodoulou P., Konstantinidou AE, Thomas-Tsagli E., Kapralos P., Davaris P.Cell cycle regulators in bladder cancer: a multivariate survival study with emphasis on p27Kip1 . Hum Pathol. 2000;31:751-760.
33.
Litlekalsoy J., Vatne V., Hostmark JG, Laerum ODImmunohistochemical markers in urinary bladder carcinomas from paraffin-embedded archival tissue after storage for 5-70 years . BJU Int. 2007;99:1013-1019.
