Case 3 -

Urothelial-Type Adenocarcinoma of the Prostate with Prominent Intraductal Spread James Kench, Royal Prince Alfred Hospital, Sydney, Australia

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Clinical History A 65 year old man presented to his urologist with urgency, poor stream and hematuria. His serum PSA was 1.8ng/mL. Cystourethroscopy showed essentially normal bladder and urethra. A TURP was performed followed by a radical prostatectomy 1 month later. No preoperative gastrointestinal workup was performed but post operative colonoscopy was normal except for sigmoid diverticular disease. The patient had a recurrence at the urethral anastomosis 3 years later. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: Microscopic features The TURP sections showed adenocarcinoma infiltrating the stroma beneath benign urothelium. No urethritis glandularis, intestinal metaplasia, or carcinoma in situ was identified. The radical prostatectomy specimen showed adenocarcinoma infiltrating the periurethral region and transition zone of the prostate. The neoplastic glands closely resembled those of colorectal carcinoma, being lined by columnar epithelium and containing mucin and necrotic debris. Focal extravasation of mucin was seen. Extensive intraductal spread was present with focal extension into the smaller ducts of the peripheral prostate forming satellite nodules of tumour, each <2mm in diameter. The intraductal tumour had a cribriform and papilliform pattern in some areas. No acinar adenocarcinoma or high grade PIN was present. Immunohistochemistry Staining for CEA was diffusely positive in the tumor while cytokeratins 34βE12, 7, and 20 demonstrated patchy positivity. Focal staining for CDX2 was present although most of the carcinoma was negative. AMACR was weakly positive focally. Stains for PSA, PSAP, PSMA, MUC1, MUC2 and thrombomodulin were entirely negative. The tumor displayed membranous staining for β-catenin with negative cytoplasmic and nuclear staining. Case 3 - Figure 1 The TURP section shows invasive adenocarcinoma beneath intact urothelium. Case 3 - Figure 2 Low power view of the radical prostatectomy specimen shows adenocarcinoma involving the periurethral region and transition zone with focal extension into the peripheral zone. Urethra is seen at top right. Case 3 - Figure 3 PASd staining demonstrates abundant mucin in the neoplastic glands. A hyperplastic nodule is present at bottom right. Case 3 - Figure 4 In some areas the tumor consists of glands of varying size infiltrating the prostatic stroma. The tumor has an appearance reminiscent of colorectal carcinoma with necrotic debris and mucin present in the glandular lumens. Case 3 - Figure 5 The neoplastic glands are lined by columnar epithelium with palisaded nuclei and scattered mitotic figures. Case 3 - Figure 6 Small foci of tumor, each <2 mm diameter and centered on involved ducts, are present separated by non-neoplastic peripheral zone tissue. Case 3 - Figure 7 Prominent intraductal spread is present with an abrupt transition between neoplastic epithelium and benign prostatic epithelium. Case 3 - Figure 8 Immunostaining for high molecular weight cytokeratin 34βE12 highlights residual basal cells surrounding cribriform carcinoma within the ducts. Case 3 - Figure 9 Tumor is focally positive for HMW cytokeratin 34βE12. Case 3 - Figure 10 PSA is negative in the neoplastic epithelium and strongly positive in the surrounding prostatic acini and ducts. Case 3 - Figure 11 Diffuse positive staining for CEA. Case 3 - Figure 12 CDX2 is negative in most of the tumor. Case 3 - Figure 13 However, focally there is strong staining for CDX2, including some of the intraductal component. Differential Diagnoses: Direct extension or metastasis from colorectal carcinoma Direct extension or metastasis from adenocarcinoma of the urinary bladder Ductal adenocarcinoma of the prostate Urothelial-type adenocarcinoma of the prostate Final Diagnosis: Urothelial-type adenocarcinoma of the prostate with prominent intraductal spread Discussion Urothelial-type adenocarcinoma of the prostate gland was first described as a distinct entity by Tran and Epstein in 1996 [1] , who described 2 cases of PSA negative adenocarcinoma within the prostate which were characterised by lakes of mucin lined by tall columnar epithelium with varying degrees of cytologic atypia. In the last decade a further 19 cases have been reported indicating an increased awareness of this tumor (see Table 1). Generally, the patients present with urinary obstructive symptoms or hematuria, but interestingly, a significant proportion of cases exhibited mucusuria (4 cases) reflecting extensive mucus extravasation [2, 3] . Most patients have normal serum PSA levels although 4 published cases had raised PSA [2, 3, 4, 5] , presumably produced by concomitant but separate conventional acinar adenocarcinoma (identified in 5 cases). In the radical prostatectomy and cystoprostatectomy specimens, the tumors have varied in gross appearance from cystic lesions containing abundant mucin [1, 6] to large pale tan firm and focally necrotic masses [5] . In some cases the tumour was centered on the prostatic urethra [7] while in others it replaced almost an entire lobe or much of the prostate [1, 5] . Microscopically, the tumours consisted of varying sized glands, some with a cribriform or micropapillary architecture, infiltrating the prostatic parenchyma. The neoplastic glands were lined by columnar epithelium with nuclear stratification, resembling those seen in colorectal carcinomas. Cytologic atypia varied from mild to severe. In most, but not all, cases there were large mucin pools with prominent dissection of the stroma, leading several authors to label these tumours as mucin-producing urothelial type adenocarcinoma, analogous to the mucinous subtype of bladder adenocarcinoma [1, 2, 4, 6, 7, 8] . Many cases exhibited foci of "dirty" necrosis [1, 2, 5, 7] while goblet cells or signet ring cells were identified in a minority of cases [2, 4, 6] . In two cases prominent intraductal spread was observed with formation of small satellite nodules in the peripheral zone, as in the case presented [6, 7] . Indeed, in the case described by Sakamoto et al the tumour exhibited mainly intraductal growth with marked dilatation of the prostatic ducts at the interface between the transition and peripheral zones [6] . In almost half of the cases reported, urethritis glandularis, intestinal metaplasia, intraurothelial neoplasia or adenocarcinoma in situ were identified in the adjacent prostatic urethra, suggesting that these tumours may arise through a progression model involving intestinal metaplasia then intraepithelial neoplasia and carcinoma in situ, analogous to that proposed for adenocarcinoma of the bladder [2, 4] . Presumably, in the other cases the precursor lesions were either destroyed by the expanding tumour mass or not sampled. In some cases with normal urethral urothelium [6, 7] , the precursor lesion could have been located in the prostatic ducts as the urothelium that lines the prostatic urethra may extend into the proximal prostatic ducts, or can develop in the more distal ducts and acini (through urothelial metaplasia). Urothelial-type adenocarcinomas of the prostate demonstrate positive immunohistochemical staining for CEA, in a membranous or cytoplasmic pattern, usually either patchy or diffuse staining for cytokeratins 7 and 20, and focal positivity for 34 β E12 [4, 5, 6, 7] . Immunostaining for PSA, PSAP, PSMA and thrombomodulin is negative [2, 6, 7] . Stains for CDX2 and β -catenin were positive in some reported cases [3, 5] but negative in most [2] . Interestingly, CDX2 may occasionally be positive in acinar, ductal and mucinous prostate cancers, raising the potential for misdiagnosis as secondary colorectal carcinoma [9, 10] . AMACR was reported as negative in the two cases where it was assessed [3, 5] , however, the weak positive staining in the case presented is not surprising given the tumor's enteric differentiation and that AMACR is positive in a high proportion (65%) of primary bladder adenocarcinomas [11] . Urothelial-type adenocarcinoma appears to have a poor prognosis. In the largest series reported, adverse pathological features were found in all 8 cases that had a radical resection: extraprostatic extension was present in 8, seminal vesicle invasion in 4 and positive surgical margins in 4 [2] . There were only two patients alive without metastasis at last follow up (38 and 71 months), although prolonged survival was noted in two cases who eventually died of disease (at 130 and 161 months). Other reports also detail aggressive behaviour with liver, lung and bone metastases [5, 7] and it is important to recognize urothelial-type adenocarcinoma given that these tumors do not respond to hormonal therapy [4] . Table 1 # of cases Specimen Glandular metaplasia Intraductal spread Separate acinar carcinoma Behaviour Tran 1996 [1] 2 TURP, prostatectomy See Osunkoya Not mentioned See Osunkoya See Osunkoya Ortiz-Rey 2004 [4] 1 TURP 1/1 case Not mentioned Nil DOD 40 mth Curtis 2005 [7] 2 Needle biopsy, prostatectomy 0/2 cases 1/2 cases 1/2 DOD 9 mth, Well 16 mth Sakamoto 2005 [6] 1 TURP, prostatectomy 0/1 case 1/1 case 1/1 Well 2 yr Adley 2006 [5] 1 Needle biopsy, prostatectomy 0/1 case Not mentioned 1/1 Local recurrence & mets <4 mth Osunkoya 2007 [2] 15* TURP, prostatectomy +/- bladder, exenteration 8/15* cases Not mentioned 2/15 8/15 DOD at average of 49 mth Chen 2011 [3] 1 TURP 0/1 case Not mentioned Nil Persistent mucusuria at 12 mth * includes 2 cases from Tran 1996 DOD = died of disease Differential diagnosis Distinguishing primary urothelial-type adenocarcinoma of the prostate from urinary bladder adenocarcinoma extending into the prostate gland is the most challenging diagnostic problem since bladder adenocarcinomas with mucinous (colloid) or enteric (colonic) patterns of growth are histologically and immunohistochemically indistinguishable from urothelial-type adenocarcinomas. Signet ring cells may also be seen in both tumors [1, 2, 4, 6] . Essentially, either cystoscopy, or examination of the bladder in a cystoprostatectomy specimen, is required for definitive diagnosis. Colorectal carcinoma (CRC) may involve the prostate either through direct extension or metastasis and cases with prominent intraductal spread have also been reported [12, 13] . CRC has closely overlapping morphologic and immunohistochemical features with prostatic urothelial-type adenocarcinoma as both entities display enteric or mucinous differentiation, although immunohistochemical positivity for cytokeratin 34 β E12, diffuse expression of CK 7, or lack of staining for CDX2 tend to favour urothelial-type adenocarcinoma over colorectal adenocarcinoma [7] . However, exclusion of primary rectal tumours by colonoscopy is vital for unequivocal diagnosis. Prostatic ductal adenocarcinoma should also be considered in the differential diagnosis, especially with respect to examples of urothelial-type carcinoma that lack large mucin pools or have cribriform/papillary areas. In addition, some ductal adenocarcinomas have areas of single non-cribriform glands, mimicking colorectal or urothelial-type carcinoma, but rarely contain either extracellular or intracellular mucin [14, 15, 16] . Furthermore, intraductal tumour with residual basal cells detectable by high molecular weight cytokeratin or p63 may be seen in both ductal and urothelial-type adenocarcinoma of the prostate [6, 7, 17] . Immunohistochemistry greatly aids in differentiating these entities: in contrast to urothelial-type adenocarcinoma, ductal carcinoma is almost uniformly positive for PSA and PSAP, generally negative for CEA, and negative for 34β E12 except in residual basal cells [1, 2, 3, 4, 5, 6, 7, 14, 17, 18, 19] . Likewise, high grade prostatic intraepithelial neoplasia can be differentiated from the rare urothelial-like adenocarcinoma with a prominent intraductal component by a similar immunohistochemical panel. Table 2 Differential diagnosis: Prostatic ductal adenocarcinoma versus Urothelial-type adenocarcinoma PSA PSAP CEA CK7 CK20 34βE12 Ductal adenocarcinoma ++ ++ -/+ -/+ -/+ - (non-basal cells) Urothelial-type adenocarcinoma - - ++ + + + On low power examination, the more mucinous examples of urothelial-type adenocarcinoma may be confused with mucinous adenocarcinoma of the prostate, which typically has cribriform glands and cords of epithelium floating in pools of mucin. At higher power the epithelium of prostatic mucinous adenocarcinoma has an appearance characteristic of acinar adenocarcinoma with oval-to-round nuclei and PAS negative, alcian blue negative, clear or eosinophilic cytoplasm [20] , rather than the columnar mucinous epithelium of urothelial-type adenocarcinoma. Mucinous adenocarcinoma is also generally admixed with conventional acinar adenocarcinoma, rarely contains mucin positive signet ring cells, and is positive for PSA, PSAP on immunohistochemistry [20] . Immunoreactivity for CEA, CK 20 and 34β E12 is typically negative in prostatic mucinous carcinoma in contrast to urothelial-type adenocarcinoma [2, 3, 4, 5, 7, 10, 12] . Interestingly, immunochemistry for the glycoprotein MUC2, has been shown to be positive in 100% of prostatic mucinous adenocarcinomas [21] while in the presented case it was negative, raising the possibility that this may also be a useful marker that warrants further study. Table 3 Differential diagnosis: Prostatic mucinous adenocarcinoma versus Urothelial-type adenocarcinoma PSA PSAP CEA CK7 CK20 34βE12 MUC2 Mucinous adenocarcinoma ++ ++ - -/+ - - ++ Urothelial-type adenocarcinoma - - ++ + + + -* *only presented case examined Conclusion(s): Urothelial-type adenocarcinoma of the prostate is an uncommon tumor which closely mimics both adenocarcinoma of the bladder and colorectal adenocarcinoma. Close correlation with the clinical findings is essential in ensuring correct diagnosis and avoiding inappropriate hormonal therapy. References: 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 Osunkoya AO, Epstein JI. Primary mucin-producing urothelial-type adenocarcinoma of prostate: report of 15 cases. Am J Surg Pathol 2007; 31: 1323-9 Chen Y-L, Chian J-H, Hsiao P-J. 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