Primary Enteric-type Adenocarcinoma of the Prostatic Urethra Omar Hameed University of Alabama School of Medicine Birmingham, AL

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Clinical Summary: 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. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer 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. 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. Figure 3 Enteric-type adenocarcinoma displaying stratified columnar cells with elongated nuclei. Abundant mitotic activity is present. Figure 4 A high power magnification shows a malignant gland with dirty necrosis. Figure 5 Other areas of the tumor showed a prominent cribriform architecture also reminiscent of colonic adenocarcinoma. 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. 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). Figure 8 The tumor was also positive for cytokeratin 20 but negative for cytokeratin 7 (not shown). Differential Diagnosis: Primary enteric-type adenocarcinoma Metastatic colonic adenocarcinoma Prostatic ductal adenocarcinoma Invasive urothelial carcinoma with glandular differentiation Final Diagnosis: 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. [1] 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. [2]Although controversial, [1] there is some evidence to suggest that cystitis glandularis with intestinal metaplasia may be a precursor for non-urachal bladder adenocarcinomas. [3] In comparison to the bladder, primary enteric-type adenocarcinomas of the urethra are quite rare, with only 20 cases reported in men to date. [4, 5, 6, 7, 8, 9] Most of these have been reported as "mucin-producing urothelial-type adenocarcinomas of the prostate" [6, 9] 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. Clinical Presentation: 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 always negative. Histological Findings: 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, [8] 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). Immunohistochemical Features: 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 [8] out of the eleven cases tested in the literature. [8, 9] Also, in 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; [12] other studies with smaller number of cases (3-4) have found that all cases expressed CDX2 [14] and villin. [11, 14] 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; [10]nuclear expression was not seen. Interestingly, CDX2 [15] and nuclear beta-catenin [16] 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). Differential Diagnosis: 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, [17] 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 adenocarcinomas. [18] Nuclear beta-catenin [19] and villin expression [14, 19] 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). [20] Cytokeratin 7 and 20 immunostains are not useful in this differential diagnostic setting because of a variable profile in prostatic adenocarcinoma. [18] 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. [18] Thrombomodulin and uroplakin III expression can also help point towards the diagnosis of urothelial carcinoma. [18] Nuclear beta-catenin, [10] CDX2 [12, 14] and villin [12, 14] have not been found to be expressed in urothelial carcinomas. 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: 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 diagnosis. Clinical and radiological findings are integral to confirm or exclude secondary carcinomas involving the urethra. Case 5 - Table 1: Immunohistochemical findings in primary enteric adenocarcinoma of the urethra and its more common mimickers 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 References 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. 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