Case 5 -
Primary Enteric-type Adenocarcinoma of the Prostatic Urethra
University of Alabama School of Medicine
Click on each slide thumbnail image for an enlarged view
A 62-year old gentleman with intermittent urinary retention, previously managed medically, presents to
his urologist with hematuria and increasing retention. Upon performing a transurethral resection of the
prostate, the urologist noted "globs of mucus" in the prostate.
Case 5 - Slide 1
Case 5 - Figure 1
Primary enteric-type adenocarcinoma of the urethra appearing as a polypoid glandular proliferation. Notice the benign-appearing orderly and villous glandular pattern near the top.
Case 5 - Figure 2
The tumor is composed of a complex glandular proliferation in which abundant dirty necrosis is evident. The appearances are clearly identical to what is seen in invasive colonic adenocarcinoma.
Case 5 - Figure 3
Enteric-type adenocarcinoma displaying stratified columnar cells with elongated nuclei. Abundant mitotic activity is present.
Case 5 - Figure 4
A high power magnification shows a malignant gland with dirty necrosis.
Case 5 - Figure 5
Other areas of the tumor showed a prominent cribriform architecture also reminiscent of colonic adenocarcinoma.
Case 5 - Figure 6
In this figure, adenocarcinomatous epithelium is seen within and distorting a von Brunn nest. This could represent adenocarcinoma in-situ, or more likely, extension of adenocarcinoma into von Brunn nests in the manner usually seen with urothelial carcinomas.
Case 5 - Figure 7
The tumor was diffusely positive for CDX2. The tumor was also positive for villin (not shown) and displayed a nuclear staining pattern for beta-catenin (not shown).
Case 5 - Figure 8
The tumor was also positive for cytokeratin 20 but negative for cytokeratin 7 (not shown).
- Primary enteric-type adenocarcinoma
- Metastatic colonic adenocarcinoma
- Prostatic ductal adenocarcinoma
- Invasive urothelial carcinoma with glandular differentiation
Primary enteric-type adenocarcinoma of the prostatic urethra
Primary Enteric-Type Adenocarcinoma of the Prostatic Urethra
Based on the World Health Organization classification, glandular tumors of the urinary tract include
villous adenoma and adenocarcinoma.  The latter is subclassified into enteric, mucinous,
signet-ring cell, clear-cell as well as mixed variants. Primary adenocarcinomas most frequently arise in
the bladder; nevertheless, they are uncommon and represent only about 2% of malignant bladder neoplasms.
These tumors may be of urachal or, more commonly, of non-urachal origin often developing in patients with
a nonfunctional bladder or with exstrophy. Although controversial,  there is
some evidence to suggest that cystitis glandularis with intestinal metaplasia may be a precursor for
non-urachal bladder adenocarcinomas. 
In comparison to the bladder, primary enteric-type adenocarcinomas of the urethra are quite rare, with
only 20 cases reported in men to date.
Most of these have been reported as
"mucin-producing urothelial-type adenocarcinomas of the
to emphasize the presence of abundant extracellular mucin (see below) and
the presumed origin from the urothelial lining of the prostatic urethra or prostatic ducts. Given that a
significant proportion of cases are also associated with adjacent intestinal metaplasia (see below), the
pathogenesis is believed to be similar to that of non-urachal bladder adenocarcinomas.
Patients with enteric-type adenocarcinomas tend to present in the sixth decade of life or later (age
range, 55-93 years). The majority present with urinary obstruction; hematuria and mucosuria have also
been described as other symptoms. Colonoscopy was performed in almost all of the reported cases and was
Similar to their bladder counterparts, enteric-type adenocarcinomas of the urethra are characterized
by infiltrating glandular and cribriform structures composed of columnar cells with psudostratified or
stratified elongated or cigar-shaped nuclei. Intraluminal "dirty" necrosis is often present. In
addition, except for one of the previously reported cases,  mucin production is usually
evident. This is usually manifested both intracellularly and also as pools of extracellular mucin that
dissect the tissue stroma; signet-ring cells may also be seen. In 11 of the 20 reported cases, adjacent
foci of glandular/intestinal metaplasia (urethritis glandularis) with adenomatous change or villous
features were evident. The presence of such foci can be very helpful in establishing the primary nature
of these neoplasms (see below).
Urethral adenocarcinomas have been found to express high molecular weight cytokeratin (34βE12),
albeit often weakly and/or in a focal manner, while expression of cytokeratins 7 and 20 has been
variable, with most cases at least focally expressing both of these markers. Given their urothelial
origin, these tumors have always been negative for prostate specific antigen (PSA) and/or prostate
specific acid phosphatase (PSAP). Most cases have also been negative for CDX2, with diffuse expression
seen in only one 
out of the eleven cases tested in the literature.
the single study evaluating its expression in these tumors, all 10 cases tested were reported to be
negative for beta-catenin. However, if one were to consider the histogenitically and histologically
similar enteric-type adenocarcinomas of the bladder, that, for the most part, have an identical
immunoprofile, [10-13] then expression of CDX2 (and villin) would still be compatible with the
diagnosis, as these were found to be expressed in 47% and 65% of 17 primary bladder adenocarcinomas,
respectively;  other studies with smaller number of cases (3-4) have found that all cases
expressed CDX2 
The single study evaluating beta-catenin
expression in bladder adenocarcinomas did find membranous (with or without cytoplasmic) expression in 15
(88%) of 17 cases evaluated; nuclear expression was not seen. Interestingly, CDX2
and nuclear beta-catenin  expression have both been demonstrated in cystitis
cystica with intestinal metaplasias, suggesting a possible pathogenetic role for these in the development
of enteric metaplasia and their proposed premalignant nature.
Behavior and Outcome:
Primary enteric-type adenocarcinoma in men (urothelial-type adenocarcinomas of the prostate) appears
to behave in an aggressive fashion, regardless of treatment. Of the 19 patients with available follow up
information, 9 died of disease, 4 were alive with disease, and 5 had no evidence of disease after a
median follow up of 27 months (range 2-161 months).
Metastatic colonic adenocarcinomas. This is the main differential
diagnosis. Given the degree of morphological and immunohistochemical overlap between primary
enteric-type adenocarcinoma and metastatic colonic adenocarcinoma,  one cannot distinguish
between the two except when adjacent foci of intestinal metaplasia and/or an adenomatous/villous lesion
are present. These would strongly support a primary lesion. In the absence of such foci, the
distinction can only be made based on clinical, endoscopic or radiographic findings; the history of prior
or concurrent colorectal adenocarcinomas would strongly favor a recurrent/metastatic lesion.
Prostatic adenocarcinoma. Both prostatic mucinous adenocarcinoma
(with its characteristic abundant extracellular mucin production), as well as prostatic ductal
adenocarcinoma (with its papillary or cribriform growth pattern and often stratified and elongated
nuclei), need to be considered in the differential diagnosis. The absence of dirty necrosis and nuclear
uniformity with vesicular nuclei and single prominent nucleoli would be more suggestive of a prostatic
tumor. The presence of PSA and PSAP immunoreactivity (especially strong/diffuse staining) can obviously
be decisive in making the diagnosis of prostatic adenocarcinoma. It should be noted, however, that weak
expression of these markers has rarely been seen in urinary bladder and paraurethral gland
Nuclear beta-catenin  and
have not been detected in prostatic adenocarcinomas, while CDX2 expression has been identified in 6% of
such tumors (as well as in benign prostatic tissue).
 Cytokeratin 7 and 20 immunostains are
not useful in this differential diagnostic setting because of a variable profile in prostatic
Invasive urothelial carcinoma with glandular differentiation. This
may also be associated with abundant extracellular mucin production. In most situations, a conventional
urothelial carcinoma component is evident and will point towards the right diagnosis. Otherwise
immunohistochemistry can be very helpful as urothelial carcinomas characteristically show diffuse
expression of high molecular weight cytokeratins (34βE12 or CK5/6) and/or p63; they are also very
frequently strongly positive for CK7.  Thrombomodulin and uroplakin III expression can also
help point towards the diagnosis of urothelial carcinoma. 
Nuclear beta-catenin, 
have not been found to be expressed in
Other glandular lesions of the urethra. Characteristic
histological findings and the absence of malignant features are usually sufficient to distinguish urethritis glandularis with intestinal metaplasia, villous adenoma, prostatic urethral
(epithelial) polyp and nephrogenic adenoma from enteric-type
adenocarcinomas. Clear cell adenocarcinoma, which is very rare in males,
can be distinguished from enteric-type adenocarcinoma mostly by its characteristic histological features
including sheets and tubules composed of clear cells, often with a hobnail appearance.
Immunohistochemistry can also be useful as clear cell adenocarcinomas are characteristically CK 7 and
CA125 positive and CK20 negative. Paraurethral gland adenocarcinomas, as
noted above, can be positive for PSA and PSAP, and, given their rarity, may only be distinguished based
on clinical grounds. Finally, recurrent/metastatic Mullerian adenocarcinomas from the gynecological tract should also be considered
in the differential diagnosis of urethral adenocarcinomas arising in women, as the urethra is not
infrequently involved by such lesions. The frequent presence of disease elsewhere can usually point to
the correct diagnosis and immunohistochemistry may also be of some utility.
Take home points:
Case 5 - Table 1: Immunohistochemical findings in primary enteric adenocarcinoma
of the urethra and its more common mimickers
- Primary and secondary adenocarcinomas of the urethra can
have very similar histological appearances.
- The degree of overlap in the profiles of different
urethral carcinomas (Table 1) can sometimes limit the utility of immunohistochemistry in making the
- Clinical and radiological findings are integral to
confirm or exclude secondary carcinomas involving the urethra.
|Markers/Immunostain ||Primary enteric adenocarcinoma ||Metastatic colonic adenocarcinoma ||Mucinous or ductal prostatic adenocarcinoma ||Urothelial carcinoma with glandular differentiation|
|CK7 and CK20 || || || |
| CK7 ||Usually positive ||Usually negative ||Variable ||Usually positive|
| CK20 ||Usually positive ||Usually positive ||Variable ||Usually positive|
|"UROTHELIAL" || || || |
| HMWK ||Often focally positive ||Often focally positive ||Can be positive in ducal ||Positive|
| p63 ||Negative ||Presumed negative ||Can be positive in ducal ||Positive|
| Thrombomodulin ||? ||Negative ||Negative ||Often positive|
| Uroplakin III ||? ||Negative ||Negative ||Often positive|
|"PROSTATIC" || || || |
| PSA ||Negative ||Negative ||Positive ||Negative|
| PSAP ||Negative ||Negative ||Positive ||Negative|
| AMACR ||May be positive ||Often positive ||Often positive ||Can be positive|
|"COLONIC" || || || |
| CDX2 ||Variable ||Positive ||Rare ||Negative|
| ?-catenin (nuclear) ||May be positive ||Usually positive ||Negative ||Negative|
| Villin (luminal) ||Positive ||Positive ||Negative ||Negative|
| CEA ||Positive ||Positive ||Positive ||Positive|
- Eble JN, et al. Tumors of the Urinary System and Male Genital Organs. Lyon, France: IARC Press; 2004
- Hameed O. Humphrey PA. The Urinary Bladder. In: The Washington Manual of Surgical Pathology, Humphrey PA, Pfeifer JD, Dehner LP, eds. Philadelphia: Lippincott Williams & Wilkins (in press)
- Bullock PS, Thoni DE, Murphy WM. The significance of colonic mucosa (intestinal metaplasia) involving the urinary tract. Cancer. 1987;59:2086-90.
- Tran KP, Epstein JI. Mucinous adenocarcinoma of urinary bladder type arising from the prostatic urethra. Distinction from mucinous adenocarcinoma of the prostate. Am J Surg Pathol.1996;20:1346-50.
- Ortiz-Rey JA, Dos Santos JE, Rodríguez-Castilla M, et al. Mucinous urothelial-type adenocarcinoma of the prostate. Scand J Urol Nephrol. 2004;38:256-7.
- Curtis MW, Evans AJ, Srigley JR. Mucin-producing urothelial-type adenocarcinoma of prostate: report of two cases of a rare and diagnostically challenging entity. Mod Pathol. 2005;18:585-90.
- Sakamoto N, Ohtsubo S, Iguchi A, et al. Intestinal-type mucinous adenocarcinoma arising from the prostatic duct. Int J Urol. 2005;12:509-12.
- Adley BP, Maxwell K, Dalton DP, et al. Urothelial-type adenocarcinoma of the prostate mimicking metastatic colorectal adenocarcinoma. Int Braz J Urol. 2006;32:681-7.
- Osunkoya AO, Epstein JI. Primary mucin-producing urothelial-type adenocarcinoma of prostate: report of 15 cases. Am J Surg Pathol. 2007;31:1323-9.
- Wang HL, Lu DW, Yerian LM, et al. Immunohistochemical distinction between primary adenocarcinoma of the bladder and secondary colorectal adenocarcinoma. Am J Surg Pathol. 2001;25:1380-7.
- Tamboli P, Mohsin SK, Hailemariam S, et al. Colonic adenocarcinoma metastatic to the urinary tract versus primary tumors of the urinary tract with glandular differentiation: a report of 7 cases and investigation using a limited immunohistochemical panel. Arch Pathol Lab Med. 2002;126:1057-63.
- Suh N, Yang XJ, Tretiakova MS, et al. Value of CDX2, villin, and alpha-methylacyl coenzyme A racemase immunostains in the distinction between primary adenocarcinoma of the bladder and secondary colorectal adenocarcinoma. Mod Pathol. 2005;18:1217-22.
- Raspollini MR, Nesi G, Baroni G, et al. Immunohistochemistry in the differential diagnosis between primary and secondary intestinal adenocarcinoma of the urinary bladder. Appl Immunohistochem Mol Morphol. 2005;13:358-62.
- Werling RW, Yaziji H, Bacchi CE, et al.CDX2, a highly sensitive and specific marker of adenocarcinomas of intestinal origin: an immunohistochemical survey of 476 primary and metastatic carcinomas. Am J Surg Pathol. 2003;27:303-10.
- Sung MT, Lopez-Beltran A, Eble JN, et al. Divergent pathway of intestinal metaplasia and cystitis glandularis of the urinary bladder. Mod Pathol. 2006;19:1395-401.
- Bryan RT, Nicholls JH, Harrison RF, et al. The role of beta-catenin signaling in the malignant potential of cystitis glandularis. J Urol. 2003;170:1892-6.
- Osunkoya AO, Netto GJ, Epstein JI. Colorectal adenocarcinoma involving the prostate: report of 9 cases. Hum Pathol. 2007;38:1836-41.
- Hameed O, Humphrey PA. Immunohistochemistry in diagnostic surgical pathology of the prostate. Semin Diagn Pathol. 2005;22:88-104.
- Bismar TA, Humphrey PA, Grignon DJ, et al.Expression of beta-catenin in prostatic adenocarcinomas: a comparison with colorectal adenocarcinomas. Am J Clin Pathol. 2004;121:557-63.
- Herawi M, De Marzo AM, Kristiansen G, et al. Expression of CDX2 in benign tissue and adenocarcinoma of the prostate. Hum Pathol. 2007;38:72-8.