By Rodney T. Miller, M.D., Director of Immunohistochemistry
On many occasions, the distinction of prostate adenocarcinoma from urothelial carcinoma (transitional cell carcinoma) of bladder origin is readily made on standard H&E examination. However, when prostate or bladder tumors are poorly differentiated, it may be difficult to confidently distinguish between these two tumors, particularly in small needle biopsy specimens or in tissue fragments that show thermal artifact. In these situations, knowledge of the expected immunophenotype of poorly differentiated urothelial carcinoma and poorly differentiated prostate adenocarcinoma can be very useful in determining the definitive primary site of origin, a task that may have significant therapeutic implications.
Prostate Specific Antigen (PSA) and Prostatic Acid Phosphatase (PSAP) are well-known to all surgical pathologists, and expression of these markers in the appropriate clinical context provides strong support for a prostatic primary origin. Non-prostatic tissues or tumors that may express PSA include breast carcinoma, anal glands in males, urethral glands, cystitis cystica/glandularis, some salivary gland tumors (particularly mixed tumor and salivary duct carcinoma), and a minority of nephrogenic adenomas of the prostatic urethra. Non-prostatic tissues or tumors that have been reported to show reactivity with PSAP include the list above, as well as rectal carcinoids, some bladder adenocarcinomas, sweat glands, rare renal cell carcinomas, and islet cell tumors. It is estimated that about 5% of high-grade prostate carcinomas may be negative with both PSA and PSAP, and expression of these markers may be focal in nature. Therefore, the absence of these markers does not completely exclude a prostatic origin. At the recent United States and Canadian Academy of Pathology International Society of Urological Pathology companion meeting in Atlanta, Dr. Mark Wick also described the use of a new prostate marker called Prostate-Specific Membrane Antigen (PSMA), that is expressed in >85% of prostate carcinomas. Unlike PSA and PSAP, this marker has not been reported in salivary or breast carcinomas. Dr. Wick noted that endothelial cells within tumors may express PSMA, so it is important to not misinterpret that finding as a reflection of true prostatic origin.
Use of Cytokeratin antibodies
High Molecular Weight Cytokeratin (Cytokeratin HMW) (34bE12) is only rarely expressed in prostate adenocarcinoma, yet is expressed very frequently in urothelial carcinoma, even when the tumors are poorly differentiated. Therefore, identification of strong reactivity with this reagent supports a urothelial origin. The same can be said for Cytokeratin 7, which is frequently expressed in urothelial carcinoma, but only rarely expressed in prostate adenocarcinoma. Cytokeratin 20 is expressed in roughly 50% of urothelial carcinomas, but a minority of prostatic adenocarcinomas are also reported to show reactivity with cytokeratin 20, so according to some authors, cytokeratin 20 is useful in this situation only when it is coexpressed with cytokeratin 7 (which favors a urothelial origin). Some authors have also advocated the use of Cytokeratin 17, and report that a very high percentage of urothelial carcinomas are positive with cytokeratin 17, but only 6% of prostate carcinomas express this marker.
Thrombomodulin is expressed in a significant percentage of urothelial carcinomas. Some authors report that up to 91% of transitional cell carcinomas express this marker, although in our laboratory I would estimate that perhaps 50% of urothelial carcinomas are positive for thrombomodulin. This marker is not expressed in prostatic adenocarcinoma, so it can be of utility in distinguishing prostate adenocarcinoma from urothelial carcinoma. Strong expression of monoclonal CEA also favors urothelial carcinoma, although focal expression may be observed in a proportion of prostate adenocarcinomas. CD57 (Leu 7) is expressed in a high percentage of prostate adenocarcinomas, even when they are poorly differentiated. This marker is expressed uncommonly in urothelial carcinoma, although we have observed scattered positive tumor cells in a number of cases of poorly differentiated urothelial carcinoma. Prostate carcinomas often expressed Androgen Receptors, although at this point there have been insufficient numbers of cases of urothelial carcinoma studied to know whether or not androgen receptors would be a useful antibody in this differential diagnosis
The information is provided in tabular form below:
Approach to an individual case
The above information is certainly not meant to imply that all of the above antibodies need to be applied in a particular case. My usual “first-line” panel antibodies includes PSA, PSAP, cytokeratin HMW, and sometimes cytokeratin 7 or CD57. Often, a definitive diagnosis can be rendered with these initial antibodies, but if needed, additional markers as suggested above can then be used.
1. Lindeman N, Weidner N: Immunohistochemical Profile of Prostatic and Urothelial Carcinoma. Impact of Heat-Induced Epitope Retrieval and Presentation of Tumors with Intermediate Features. Applied Immunohistochemistry 4 (4): 264-275, 1996.
2. May EE, Perentes E: Anti-Leu 7 Immunoreactivity with Human Tumours: Its Value in the Diagnosis of Prostatic Adenocarcinoma. Histopathology 11: 295-304, 1987.
3. Miettinen M et al: Keratin 17. Immunohistochemical Mapping of Its Distribution in Human Epithelial Tumors and Its Potential Applications. Applied Immunohistochemistry 5 (3): 152-159, 1997.
4. Wick MR Diagnostic Immunohistology in the Differential Diagnosis of Urological Neoplasms. United States and Canadian Academy of Pathology Annual Meeting, March 3rd, 2001, International Society of Urological Pathology Companion Meeting.
Date of last revision: March 2001.