Int J Clin Exp Pathol 2013;6(8):1665-1670 www.ijcep.com /ISSN:1936-2625/IJCEP1306007

Case Report Urethral adenocarcinoma associated with intestinal-type , case report and literature review

Christopher S Hale1, Hongying Huang1, Jonathan Melamed1, Ruliang Xu1, Larry Roberts2, Rosemary Wieczorek1, Zhiheng Pei1, Peng Lee1

1Department of , New York Harbor Healthcare System, New York University School of Medicine, New York, NY, USA; 2Sound Shore Medical Center, New Rochelle, NY, USA Received June 6, 2013; Accepted July 8, 2013; Epub July 15, 2013; Published August 1, 2013

Abstract: The presence of glandular epithelium in urinary tract biopsies poses a diagnostic challenge. Intestinal metaplasia of the urethra may be seen in many congenital, iatrogenic, and reactive conditions, as well as in as- sociation with malignant conditions such as urethral adenocarcinoma. We present a case of a 61 year-old woman presenting with microscopic hematuria. Successive biopsies showed glandular epithelium with focal atypia in close association with , but no overt malignancy. Only on surgical resection was the associated high grade adenocarcinoma revealed. When intestinal-type mucosa is present within a urinary tract biopsy, associated malig- nancy may be present only focally. Thorough sampling and consideration of the differential diagnosis is imperative.

Keywords: Urethral adenocarcinoma, intestinal metaplasia

Introduction from this area were sent for histopathologic examination. After an unremarkable CT scan of Development of intestinal-type mucosa as a the pelvis, a repeat biopsy was performed with metaplastic response is a well-described phe- similar findings. Transurethral resection six nomenon in sites such as the . months later showed high grade urethral Rarely, metaplastic intestinal-type mucosa may adenocarcinoma. also be seen in the urinary tract. This is particu- larly true in the bladder, where glandular muco- sa may be seen in the benign reactive condition cystitis glandularis [1]. Glandular cells may also The first biopsy Figure( 1) was received in two represent a primary or metastatic malignancy, parts. Hematoxylin and eosin stained, formalin- and merit careful inspection for atypical fea- fixed, paraffin embedded sections of showed tures. This diagnostic dilemma is even greater acute inflammatory exudate with mucin and when intestinal-type epithelium is seen in less rare clusters of benign glandular cells. The sec- common locations, such as the urethra. We ond part showed acutely inflamed benign uro- report the case of a urethral biopsy containing thelium with squamous and glandular metapla- areas of intestinal-type glandular tissue, which sia. Trichrome and smooth muscle actin stains on resection proved to be associated with high- demonstrated expected submucosal composi- grade urethral adenocarcinoma. tion of fibro connective tissue without desmo- plasia. An immunostain for PIN-4 (p63, 34βe12 Clinical presentation and AMACR) demonstrated positivity for p63 and 34βe12 in an area of squamous metapla- A 61 year-old woman was found to have micro- sia, as well as within a periurethral glandular scopic hematuria on routine medical examina- remnant. The adjacent area of glandular meta- tion. Cystoscopic work-up revealed a ragged, plasia lacked PIN-4 immunoreactivity. An area red lesion on the anterior mid-urethra. Biopsies of and an area of residu- Urethral adenocarcinoma and intestinal-type metaplasia

Figure 1. A: H&E shows predominately benign glandular cells; B: a periurethral Skene’s gland and an area of squa- mous metaplasia are highlighted by p63 and 34βe12, but not AMACR (PIN-4 cocktail). Adjacent glandular metapla- sia lacks immunoreactivity.

Figure 2. A: H&E shows an area of bland appearing intestinal-type metaplasia; B: Ki-67 immunostain shows focally increased proliferation. al Skene’s gland tissue both showed strong atypical glandular cells. Trichrome and smooth nuclear reactivity for p63. The metaplastic muscle actin stains demonstrated expected glandular cells lacked p63 immunoreactivity. submucosal composition without desmoplasia Nuclear Ki-67 reactivity in the areas of squa- or invasion. mous metaplasia showed 10% reactivity in a basal pattern, whereas Ki-67 positivity in the Six months after the repeat biopsy, transure- glandular areas was 5%. thral resection was performed. During the pro- cedure, bimanual examination showed a fusi- After an unremarkable CT scan of the pelvis, a form mass surrounding the entire urethra and repeat biopsy was performed. The repeat biop- bladder neck. Cystoendoscopy showed a fusi- sy (Figure 2) was processed as described form papillary-nodular tumor involving the blad- above and showed glandular intestinal-type der neck, proximal, mid and distal urethra, but epithelium with clusters of highly atypical cells not the urethral meatus. The tumor was resect- within the superficial lamina propria, as well as ed and submitted in multiple specimens for his- fragments of benign squamous epithelium. tology (Figure 3). Tissue from the bladder neck Significant chronic inflammation was present in showed intestinal metaplasia with severe atyp- most of the biopsy parts. An immunostain for ia, similar to the earlier biopsies; however, tis- Ki-67 showed 85% nuclear positivity in the sue from the anterior urethra demonstrated

1666 Int J Clin Exp Pathol 2013;6(8):1665-1670 Urethral adenocarcinoma and intestinal-type metaplasia

Figure 3. Sections from the initial transurethral re- section show (A) extensive intestinal metaplasia with atypia and (B) invasive adenocarcinoma with (C) lam- ina propria involvement.

high grade invasive adenocarcinoma associat- Significant atypia was present on each biopsy, ed with extensive intestinal metaplasia with but chronic inflammation and associated atypia. The tumor invaded the lamina propria, benign glandular tissue prevented an unequiv- but did not involve the muscularis propria. ocal diagnosis of adenocarcinoma. Only on Prominent proliferative cystitis was also resection was the patient’s high grade adeno- present. carcinoma definitively shown in association with the severely atypical glandular epithelium. Following systemic chemotherapy (Ifex, Taxol, This highlights the importance of adequate and Carboplatin), residual tumor remained on sampling in diagnosis of glandular urethral MRI. Examination under anesthesia showed lesions. abarely palpable mass extending from the prox- imal urethra to the meatus. Repeat transure- The origin of female primary urethral adenocar- thral resection was performed and submitted cinomais not fully understood. Prostate-specific in several specimens for histology. Histology antigen (PSA) expression inprimary urethral showed adenomatous changes with focal high adenocarcinoma supports an origin from grade /focal carcinoma in situ, with female periurethral (Skene’s) glands [2, 3]. no invasive carcinoma. More recently, PSA non-reactive, mAbDas1- reactive cases of primary urethral adenocarci- Discussion noma have been reported in association with The differential diagnosis for glandular lesions intestinal metaplasia, leading to speculation in the female urethra is challenging and that some cases of female primary urethral includes developmental heterotopia, intestinal- adenocarcinoma may arise from malignant type metaplasia, and adenocarcinoma. In this transformation of urethritis glandularis, a con- case, the etiology of the glandular epithelium dition histologically characterized by intestinal was unclear despite two sets of biopsies. metaplasia [3, 4]. In this case, the lack of PSA

1667 Int J Clin Exp Pathol 2013;6(8):1665-1670 Urethral adenocarcinoma and intestinal-type metaplasia expression in the glandular tissue and lack of Intestinal-type metaplasia has also been atypia in the adjacent periurethral glands point reported in association with posterior urethral towards a non-periurethral gland origin (Figure polyps or “caruncles”. In addition to intestinal- 1). type epithelium, metaplasia of urethral polyps may also exhibit squamous or rarely even gas- The role of intestinal metaplasia in genitouri- tric-type differentiation [12]. Paneth cell meta- nary tract carcinogenesis is not known. One ret- plasia was an unusual finding in another case rospective study of 19 patients with intestinal [13]. Metaplastic change in urethral polyps metaplasia of the bladder did not find evidence could arise as the result of mechanical irrita- that intestinal metaplasia represents a precur- tion, or as a reaction to the inflammation that sor to bladder adenocarcinoma [5]. Intestinal gave rise to the polyp. Analogy has been made metaplasia could still be a precursor lesion to between this process, solitary rectal ulcer syn- adenocarcinoma more distally in the urinary drome, and inflammatory cloacogenic polyps tract. A case report of a woman with an exter- [7]. Stricture of the prostatic urethra in men nal urethral meatus tumor found mucinous has also been reported in association with adenocarcinoma in close association with both intestinal metaplasia with dysplasia [14]. intestinal metaplasia and urethritis cystica, Similar mechanical obstruction or stricture in suggesting a connection [3]. In this case, a con- the female urethra could also lead to metaplas- tinuum of dysplastic changes is present: benign tic response. Another study of over 300 pros- glandular mucosa, glandular mucosa with tatic urethra specimens has suggested that severe atypia, and high grade adenocarcinoma. glandular metaplasia in the prostatic urethra The intimate association of these changes in may be a normal histologic finding [15]. our view points towards a connection. Exposure of the urothelium to irritants such Although extremely rare, intestinal-type epithe- bacterial colonization and retained urine, as lium has been found near the urethral meatus occurs in urethral diverticula, may be associat- in females ranging from 2 to 78 years of age ed with development of intestinal-type meta- [6]. In younger patients, these rare cases of plasia, villous adenoma, or even adenocarcino- intestinal-type epithelium have been attributed ma [13, 16]. Metaplastic diverticular epithelium to benign developmental malformation result- can undergo malignant transformation, with up ing from abnormal differentiation of the cloacal to 6% of diverticula in one case series contain- ing invasive adenocarcinoma [16]. Other pre- epithelium [6, 7]. In utero, the female urinary malignant glandular lesions were also reported system is formed by division of the cloaca by in the same case series, including high grade the urorectal septum between 6 to 9 weeks of dysplasia and villous adenoma [16]. Diverticula gestation [8]. If this division is perturbed, het- can also occur in children, usually as a compli- erotopic rests of intestinal-type tissue could cation of surgical correction of anorectal mal- persist in the urinary tract. formations. Intestinal-type metaplasia in pedi- atric urethral diverticula has not been reported, In older women, intestinal-type metaplasiais although a case of mucinous adenocarcinoma believed to represent a metaplastic response has been reported [17]. Conversely, removal of to chronic injury [6, 9, 10]. This injury may be the urothelium from the normal flow of urine due to inflammation, as well as to mechanical may also be associated with glandular urothe- or chemical irritation. In the bladder urotheli- lial lesions. A case of mucinous adenocarcino- um, it has been reported that intestinal meta- ma, not known to be associated with intestinal plasiais accompanied by acquisition of CDX-2 metaplasia, was reported in a patient with uri- immunopositivity, whereas cystitis cystica nary diversion without cystectomy [18]. retains the CDX-2 negative immunophenotype of normal urothelium [11]. On the basis of these Evaluation of urethral adenocarcinomas should results, it has been suggested that intestinal also include exclusion of metastatic origin. metaplasia in the bladder may represent an Local extension or metastasis of gastrointesti- alternative pathway of response to urothelial nal or prostatic malignancies can be difficult to injury [11]. Whether this could be the case distinguish from primary urethral adenocarci- more distally in the urethral urothelium has not noma. Colonic adenocarcinoma metastatic to been explored. the urethra presents a particular diagnostic

1668 Int J Clin Exp Pathol 2013;6(8):1665-1670 Urethral adenocarcinoma and intestinal-type metaplasia dilemma [19]. Normal urothelium lacks immu- chemical evidence of more than 1 tissue of noreactivity for CDX-2, but CDX-2 reactivity has origin. J Urol 1999; 161: 1881-1884. been reported in urethral intestinal metaplasia [5] Smith AK, Hansel DE and Jones JS. Role of cys- and in urethral adenocarcinoma [20]. Absence titis cystica et glandularis and intestinal meta- CK7 immunoreactivity and the presence of vil- plasia in development of bladder carcinoma. Urology 2008; 71: 915-918. lin immunoreactivity may be useful in distin- [6] Jarvi OH, Marin S and de Boer WG. Further guishing colonic from urothelial origin. In the studies of intestinal heterotopia in urethral male urethra, both CDX-2 and CK-20 immuno- caruncle. Acta Pathol Microbiol Immunol reactivity may also be seen in mucinous pros- Scand A 1984; 92: 469-474. tatic adenocarcinomas [21]. In exceptional [7] Willett GD and Lack EE. Periurethral colonic- cases, prostatic adenocarcinoma may spread type polyp simulating urethral caruncle. A case to involve the urethra [22]. At least some cases report. J Reprod Med 1990; 35: 1017-1018. of mucinous prostatic adenocarcinoma appear [8] Acien P. Embryological observations on the fe- to arise from PSA-immunonegative, CEA immu- male genital tract. Hum Reprod 1992; 7: 437- nopositive intestinal metaplasia of the prostat- 445. ic urethra [23]. [9] Jarvi OH and Marin S. Intestinal mucosal het- erotopia of an urethral caruncle. Acta Pathol Acknowledgements Microbiol Immunol Scand A 1982; 90: 213- 219. This material is based upon work supported in [10] Urakami S, Igawa M, Shiina H and Ishibe T. part by the Department of Veterans Affairs, Urethral caruncle with coexistence of intestinal Veterans Health Administration, Office of heterotopia. A case report. Int Urol Nephrol Research and Development (Biomedical 1997; 29: 341-344. Laboratory Research and Development) and by [11] Sung MT, Lopez-Beltran A, Eble JN, MacLen- grant UH3CA140233 from Human Microbiome nan GT, Tan PH, Montironi R, Jones TD, Ulbright Project of the NIH Roadmap Initiative and TM, Blair JE and Cheng L. Divergent pathway of intestinal metaplasia and cystitis glandularis National Cancer Institute. of the urinary bladder. Mod Pathol 2006; 19: Disclosure of conflict of interest 1395-1401. [12] Jaidane M, Hidoussi A, Slama A, Hmida W, Ben No conflict of interest to declare. Sorba N and Mosbah F. Gastric metaplasia of posterior urethral polyp: a case report. Cases J Address correspondence to: Dr. Peng Lee, 2009; 2: 9119. Departments of Pathology and Urology, New York [13] Niemiec TR, Mercer LJ, Stephens JK and Hajj Harbor Healthcare System, New York University SN. Unusual urethral diverticulum lined by co- lonic epithelium with Paneth cell metaplasia. School of Medicine, 423 E. 23rd Street, Room Am J Obstet Gynecol 1989; 160: 186-188. 6139N, New York, NY, USA. E-mail: peng.lee@ [14] Maung R, Kelly JK and Grace DA. Intestinal nyumc.org metaplasia and dysplasia of prostatic urethra References secondary to stricture. Urology 1988; 32: 361- 363. [1] Young RH and Bostwick DG. Florid cystitis glan- [15] Kiernan M and Gaffney EF. Brunn’s nests and dularis of intestinal type with mucin extravasa- glandular metaplasia: normal urothelial vari- tion: a mimic of adenocarcinoma. Am J Surg ants in the supramontanal prostatic urethra. J Pathol 1996; 20: 1462-1468. Urol 1987; 137: 877-879. [2] Kato H, Kobayashi S, Islam AM and Nishizawa [16] Thomas AA, Rackley RR, Lee U, Goldman HB, O. Female para-urethral adenocarcinoma: his- Vasavada SP and Hansel DE. Urethral divertic- tological and immunohistochemical study. Int J ula in 90 female patients: a study with empha- Urol 2005; 12: 117-119. sis on neoplastic alterations. J Urol 2008; 180: [3] Chan YM, Ka-Leung Cheng D, Nga-Yin Cheung 2463-2467. A, Yuen-Sheung Ngan H, Wong LC. Female ure- [17] Alam S, Lawal TA, Pena A, Sheldon C and Levitt thral adenocarcinoma arising from urethritis MA. Acquired posterior urethral diverticulum glandularis. Gynecol Oncol 2000; 79: 511- following surgery for anorectal malformations. 514. J Pediatr Surg 2011; 46: 1231-1235. [4] Murphy DP, Pantuck AJ, Amenta PS, Das KM, [18] Taneous M, Ramalingam P, Mode DG, Heiner Cummings KB, Keeney GL and Weiss RE. Fe- JG, Terris MK and Lee JR. Primary mucinous male urethral adenocarcinoma: immunohisto- adenocarcinoma in a defunctionalized urinary

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