—  SHORT COURSE #07  —

An Approach to the Diagnosis of Bladder Lesions in Biopsy and Transurethral Resection Specimens

Section 6 - Mimics of Urothelial Carcinoma

Mahul B. Amin, MD
Jesse K. McKenney, MD


Case 6

History:
82-year-old man with urinary obstructive symptoms. Cystoscopy revealed a 1.5 cm nodular mass at the bladder base.

Diagnosis:
Prostatic adenocarcinoma

Case 7

History:
68-year-old man with urinary obstructive symptoms. He underwent a TURP and, intraoperatively, a 1.3 cm nodular lesion was identified in the trigone of the bladder.

Diagnosis:
Paraganglioma

Mimics of Urothelial Carcinoma

  1. Pseudotumors
    1. Papillary/Polypoid cystitis

    2. Cystitis cystica spectrum

    3. Nephrogenic adenoma (metaplasia)

    4. Endometriosis/Mullerianosis

    5. Eosinophilic cystitis

    6. Malakoplakia

    7. Treatment related changes
      1. Pseudocarcinomatous hyperplasia

      2. Radiation cystitis
    8. Amyloidosis

    9. Ectopic prostate
  2. Neoplasms
    1. Paraganglioma (Pheochromocytoma)

    2. Prostatic adenocarcinoma

    3. Colonic adenocarcinoma (direct extension)

    4. Melanoma
      1. Primary

      2. Metastatic
    5. Plasmacytoma/Myeloma

    6. Other hematologic malignancies

    7. Metastatic carcinoma

Mimics of Urothelial Carcinoma

There are many urothelial and non-urothelial lesions in the urinary bladder that may closely mimic urothelial carcinoma, both clinically and histologically. The list of mimics outlined in this section is not exhaustive, but covers the most common lesions encountered on transurethral biopsy.

I. Pseudotumors of the Urinary Bladder that Mimic Carcinoma

1) Papillary/Polypoid cystitis [1, 2]
Papillary/polypoid cystitis is a clinically benign pattern of urothelial injury usually secondary to an indwelling catheter or a vesical fistula. The papillary and polypoid patterns may be intermixed, but lesions with relatively slender, non-branching exophytic projections are termed papillary cystitis, while broad-based, bulbous lesions have been termed polypoid cystitis. Characteristically, the exophytic appearance results from edema in the lamina propria, but variable fibrosis, chronic inflammation, and associated dilated blood vessels are also present. These lesions exist along a morphologic continuum with bullous cystitis depending on the degree of edema. Some authors have used the following convention: lesions that are taller than they are wide are termed papillary/polypoid cystitis, and vice versa for bullous cystitis. Older lesions tend to have less edema with more stromal fibrosis.

The main diagnostic consideration is a papillary urothelial neoplasm, particularly urothelial papilloma. Small, superficial biopsies of papillary cystitis that do not include the underlying lamina propria may be histologically indistinguishable from a papilloma because both lesions typically share a urothelial lining of normal thickness and morphology. In some cases, usually with recent catheterization, papillary/polypoid cystitis shows marked reactive epithelial changes with small, prominent nucleoli, urothelial hyperplasia, and mitotic activity. In general, papillomas have more slender papillae. The papillae of papillary cystitis often have a bulbous tip with prominent stromal edema. In additon, urothelial papillomas have a few unique features that may aid in the distinction when present [3, 83]: a very prominent umbrella cell layer with a hobnail pattern or marked cytoplasmic vacuolization, a gland-in-gland pattern within the papillae, a dilated lymphatic space filling the papillae, a more complex papillary pattern with secondary and tertiary branching, and a mixed endophytic (inverted) component.

2) von Brunn nests/Cystitis cystica/Cystitis cystica glandularis [4, 5, 6, 7, 8, 9, 10, 11, 12, 13]
von Brunn nests represent a normal variation of bladder histology (most commonly in the trigone) that may result from a prior inflammatory insult. They are characterized by well-circumscribed, evenly spaced nests of invaginated urothelium in the lamina propria. In the bladder, the nests typically have smooth, rounded contours and are often clustered in groups, but the connection with the overlying urothelium may not be identifiable. They are usually located in the superficial lamina propria, but deeper nests have been described. In the ureter and renal pelvis, the individual nests are smaller and may have a more irregular contour; however, they maintain a linear or lobular architecture and have a sharp, linear border at the deep aspect. [10]

The term cystitis cystica is used when the nests are cystically dilated with an inner luminal surface. When the inner adluminal cells have a columnar or cuboidal appearance with prominent apical cytoplasm (not intestinal type goblet cells), the term cystitis cystica glandularis is used. Finally, the presence of intestinal-type goblet cells within the nests warrants the designation cystitis cystica glandularis with intestinal metaplasia. Although rare case reports have described adenocarcinoma adjacent to cystitis cystica glandularis, cystitis cystica is relatively common and is not currently regarded as a precursor to vesical carcinoma. [13]

The main differential diagnosis is a "deceptively benign" form of urothelial carcinoma such as the nested variant. [10] This distinction is discussed in detail in that section of the syllabus (variants of urothelial carcinoma: "deceptively bland patterns"). Occasionally, urothelial carcinoma in-situ may extend into von Brunn nests and mimic invasion. The relatively smooth, round contour of the nests, the absence of surrounding retraction spaces, the lobular or linear arrangement of the nests with a non-infiltrative base, and the absence of a stromal reaction should aid in that distinction. In some instances, the distinction from inverted papilloma (cystitis cystica-like pattern) may be somewhat arbitrary. Inverted papillomas typically show a more anastomosing pattern of the epithelial nests and retain the peripheral palisading of cells even when central lumina are present.

Rare examples of florid cystitis cystica with extensive intestinal metaplasia and mucin extravasation have also been reported. [11, 12] These florid metaplasias may closely mimic invasive adenocarcinoma because they fill the lamina propria and abut the muscularis propria. Adenocarcinomas typically show greater nuclear atypia, more extensive mucin extravasation, and more mitotic activity. In addition, adenocarcinomas usually present with obvious, destructive invasion of the muscularis propria. One series of florid cystitis cystica glandularis with intestinal metaplasia reported two cases with "focal, superficial extension" into the muscularis propria, [12] but this likely represents an irregular muscularis/lamina propria junction and is distinctive from the extensive, irregular invasion of the muscularis propria.

3) Nephrogenic adenoma (metaplasia) [14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24]
Nephrogenic adenoma is a benign proliferative lesion occurring in the bladder (80%), urethra (12%), or ureters (8%) that is thought to arise secondary to urothelial injury. These lesions are usually small (less than 1 cm), but have been reported to reach sizes as large as 7 cm. 19 % of patients with nephrogenic adenoma have multiple lesions. The main importance of recognizing this lesion is its distinction from papillary urothelial bladder neoplasms and prostatic adenocarcinoma. Although a broad histologic spectrum has been reported for nephrogenic adenoma, there are three main growth patterns that are often intermixed, and will be discussed separately: papillary/polypoid, tubular, and diffuse. [21] The individual cells also have a variable morphology; they are typically low cuboidal with scant eosinophilic cytoplasm. They frequently have prominent nucleoli, but, by definition, nephrogenic adenomas do not show marked nuclear atypia (irregular nuclear membranes, irregular chromatin condensation, nuclear pleomorphism) or easily identified mitotic activity. Degenerative type atypia has been described, however, and is characterized by large cells with a hyperchromatic appearance secondary to a smudged, indistinct chromatin pattern (similar to so-called "ancient change" in Schwannomas). Other rare features of nephrogenic adenoma include cytoplasmic clearing or bulbous apical nuclei producing a hobnail pattern.

The tubular pattern is most common and consists of well-delineated tubules lined by a single layer of low columnar to cuboidal epithelium occasionally with prominent nucleoli. Most frequently, the individual tubules are well-spaced with intervening stroma, but the tubules may be very compact (back-to-back), imparting a solid, nested appearance focally. The tubules may also become dilated imparting a cystic appearance. In these cystic patterns, the epithelial lining is frequently flattened and attenuated. There is also variable peritubular hyalinization with a basement membrane-like appearance, and intraluminal eosinophilic and basophilic secretions are relatively common. Small compressed tubules with only a single lining cell apparent at the periphery of the lumen may closely resemble a signet-ring cell, but this is usually present only focally. The degenerative appearing cells described above typically line tubules that are flattened and can resemble blood vessels.

The papillary/polypoid pattern of nephrogenic adenoma is most commonly characterized by large edematous polypoid excrescenses, but a relatively simple, filiform branching pattern is also seen in a minority of cases (approximately 10%). Complex epithelial budding is rare, and usually focal. The polypoid excresences and papillae are lined by a single layer of low cuboidal cells with scant eosinophilic cytoplasm. The cytoplasm is occasionally more prominent with an oncocytic appearance or more cuboidal with pale cytoplasm.

The "diffuse" pattern is rare, and is almost always admixed with other patterns of nephrogenic adenoma. It is characterized by a very compact or solid growth pattern with little to no intervening stroma. A cord-like growth pattern somewhat reminiscent of a carcinoid tumor has also been reported in these diffuse areas.

Nephrogenic adenoma typically has a laminar distribution underlying the urothelium with a sharp line of demarcation within the lamina propria at the base. Although it seems infrequent, there are rare reports of extension into the superficial muscularis propria and into prostatic stroma. We would recommend extreme caution in making the diagnosis of nephrogenic adenoma with muscularis propria involvement; a "deceptively bland" pattern (tubulocystic pattern) of urothelial carcinoma should be carefully considered in that setting. That distinction is discussed in detail in the variants portion of the syllabus (variants of urothelial carcinoma: "deceptively bland patterns").

The main differential diagnostic consideration for the tubular pattern is prostatic adenocarcinoma. The well-spaced architectural arrangement of the tubules, the peritubular hyalinization, epithelial flattening with cystic change, and mixed papillary/polypoid patterns should aid in the diagnosis of nephrogenic adenoma. Immunohistochemistry may be misleading in this setting because weak cytoplasmic immunoreactivity with PSA or PSAP is reported in nephrogenic adenoma. In addition, P504S (alpha-methylacyl-CoA racemase) immunoreactivity has also recently been documented in nephrogenic adenoma and should, therefore, not be used as a distinguishing marker for prostatic adenocarcinoma in this setting. [22, 23]

The main differential diagnosis for papillary/polypoid nephrogenic adenoma is a low-grade papillary urothelial neoplasm (papilloma, PUNLMP, or low grade carcinoma). In general, papillary urothelial neoplasms have a stratified lining consisting of multiple cell layers. In addition, the individual neoplastic cells of urothelial tumors have more elongated cells, often with nuclear grooves. Higher-grade urothelial carcinomas have nuclear pleomorphism, nuclear hyperchromasia, and increased mitotic activity, making their distinction somewhat more straightforward. Identification of a mixed tubular pattern in a nephrogenic adenoma may also be helpful in this differential diagnostic setting.

The diagnosis of clear cell adenocarcinoma of the bladder is often considered in this setting because of the mixed papillary/ tubulo-cystic pattern. Clear cell carcinomas, however, typically have marked nuclear pleomorphism, obviously increased mitotic activity, more cellular stratification, and more prominent cytoplasmic clearing. Some authors have suggested the utility of p53 stains in this differential setting (nuclear reactivity in adenocarcinoma), [24]but most authors use the morphologic features discussed above.

A recent study has reported the potential utility of immunohistochemistry for PAX2 in this differential diagnostic setting. Nuclear reactivity for PAX2 in nephrogenic adenoma may aid in the distinction from prostatic adenocarcinoma. [84 ]Its utility in the distinction from other lesions such as clear cell carcinoma requires further study.

4) Endometriosis/Endocervicosis/Müllerianosis [25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36]
Endometriosis may involve the bladder and is morphologically identical to that seen in other, more common anatomic locations. [25, 26, 27, 28, 29, 30, 31] The diagnosis rests on the identification of cytologically bland endometrial-type glands surrounded by a cuff of endometrial stroma that is characterized by small, cytologically bland round to fusiform cells with little cytoplasm. Curiously, there are case reports of vesical endometriosis occurring in men, possibly related to anti-androgen therapy. [27, 31]

The presence of endocervical, tubal, and endometrial type glands (without associated stroma) within the wall of the bladder has also been described. [33, 34, 35, 36] They are usually present within the muscularis propria, but may extend to the perivesical soft tissue or the lamina propria. The glands are typically haphazardly arranged within the smooth muscle of the posterior wall or posterior dome, and are commonly lined by columnar, endocervical type epithelium with no significant cytologic atypia (no pleomorphism, hyperchromasia, or increased mitotic activity). The individual glands may be rounded or irregularly shaped, and cystic dilation is common. The reported series describe adjacent stroma with no response or a surrounding fibrous stroma that is focally loose and edematous with admixed acute and chronic inflammatory cells. Mucin extravasation secondary to gland rupture is common in these lesions and typically elicits a reactive fibroblastic or histiocytic response. The diagnostic term endocervicosis has been used when the glands are composed of purely endocervical type epithelium [32, 34] with the term müllerianosis reserved for mixed types. [33, 35, 36] The differential diagnosis with primary vesical adenocarcinoma and urachal carcinoma is discussed in those sections of the syllabus (variants of urothelial carcinoma: adenocarcinoma spectrum).

6) Eosinophilic cystitis [37, 38, 39, 40, 41, 42, 43]
" Eosinophilic cystitis" is a descriptive term that has been applied to mixed inflammatory infiltrates of the lamina propria rich in eosinophils. It is best regarded as a pattern of inflammation associated with a variety of causes and not a single diagnostic entity. Clinically, it often has a polypoid appearance mimicking polypoid cystitis or urothelial carcinoma in adults, and rhabdomyosarcoma in children. In children, bladder eosinophilia has been reported in association with allergic gastroenteritis, asthma, or other allergic disorders. [38, 39, 41] In adults, it is more frequently associated with prostatic hyperplasia, bladder carcinoma, or prior biopsy. Rarely, it may be secondary to a parasitic infection. [40]

7) Malakoplakia [45, 46]
Malakoplakia is an inflammatory lesion that is caused by impaired intraphagosomal digestion resulting in histiocytic accumulation. [46] It occurs in a variety of anatomic locations, but is most common in the urinary bladder and typically associated with a coliform bacterial infection (often E. coli). Morphologically, it consists of sheets of histiocytes with granular eosinophilic cytoplasm (von Hansemann cells) with small basophilic intracytoplasmic inclusions (Michaelis-Gutmann bodies). The histiocytes are typically in the lamina propria with an intact, overlying urothelium. The inclusions are spherical, concentrically laminated (imparting a "bull's eye" appearance), and typically range from 5-8 microns in size. The inclusions contain calcium, so they are highlighted by von Kossa stain.

The main differential diagnostic consideration is urothelial carcinoma with a sheet-like growth pattern. The small bland nuclei of the histiocytes and identification of the Michaelis-Gutman bodies are usually sufficient for this distinction. In more difficult cases, an absence of cytokeratin immunoreactivity may be helpful.

8) Pseudocarcinomatous hyperplasia associated with radiation or chemotherapy [47, 48]
Rarely, patients with radiation or chemotherapy cystitis present with an unusual, benign epithelial proliferation on biopsy that can closely mimic invasive urothelial carcinoma. [47, 48]H istologically, these epithelial proliferations are within the lamina propria (they do not involve muscularis propria) and consist of small nests of urothelium with variable rounded to irregular, jagged contours creating an infiltrative appearance. The individual urothelial cells may have a "squamoid" appearance and show some nuclear enlargement with slight variation in nuclear size, but the nuclear chromatin is bland and they do not show the degree of atypia (marked pleomorphism and hyperchromasia) required for a diagnosis of carcinoma in situ or high grade urothelial carcinoma. The most helpful and unique feature of these lesions is that the epithelial nests wrap around blood vessels with associated fibrin and congestion. The fibrin is found both within the wall of the vessels and within the lamina propria. Associated hemorrhage, fibrosis, acute and chronic inflammation, and ulceration are also common, as well as other, radiation-induced changes such as ectatic vessels with intimal proliferation.

The main differential diagnostic consideration is an invasive urothelial carcinoma. In the pseudocarcinomatous proliferations, the lack of significant nuclear atypia, the presence of other radiation-induced changes, and, most importantly, the intimate association of the epithelium with blood vessels and fibrin generally allow this distinction.

9) Radiation cystitis [49, 50]
Radiation cystitis typically mimics urothelial carcinoma in-situ, both clinically and histologically. It is, therefore, discussed in that section of the syllabus.

10) Amyloidosis [51, 52, 53]
The bladder can be involved by systemic amyloidosis or, rarely, by primary amyloidosis. The morphologic appearance is identical to that seen in other anatomic sites: deposits of an eosinophilic, amorphous material. The amyloid is typically present in the lamina propria with extension into deeper connective tissue. Perivascular amyloid deposits are, reportedly, less common. As in other locations, Congo red stains are typically used for confirmation.

11) Ectopic prostate tissue [54]
Ectopic prostate tissue presenting as a polypoid mass lesion in the bladder (usually the trigone) has been reported. The morphologic appearance is identical to that described for benign prostatic urethral polyps. The submucosal component consists of admixed stroma and histologically benign prostate glands. The overlying surface is often papillary with a lining consisting of prostatic epithelium, urothelium, or an admixture of both. Identification of the prostatic epithelial component usually allows distinction from a papillary urothelial neoplasm.

Neoplasms Involving/or Primary to the Urinary Bladder that Mimic Urothelial Carcinoma

1) Paraganglioma (Pheochromocytoma) [55, 56, 57, 85]
Paragangliomas (pheochromocytoma) may occur in the bladder and closely mimic urothelial carcinoma. Clinically, patients are usually somewhat younger (median- 44 years) than those with urothelial carcinoma. Presentation with symptoms related to hormone release (urinary urgency, headache, anxiety, and sweating) have been reported, but in the most recently reported series these symptoms only present in 19% of cases.

Histologically, as in carotid body tumors, paragangliomas characteristically grow in a nested or "zellballen" pattern with an associated delicate fibrovascular stroma. In some cases, the nests of neoplastic cells are less tightly clustered because of marked stromal fibrosis making the zellballen pattern less recognizable, a pattern similar to paragangliomas of the middle ear. A minority of cases show a diffuse sheet-like growth pattern, but a nested pattern can usually be identified focally. The neoplastic cells usually have abundant amphophilic or eosinophilic cytoplasm, sometimes with a slightly granular appearance. The nuclei typically are round with smooth contours, even chromatin, small nucleoli, and occasional nuclear inclusions. Scattered pleomorphic cells with smudged, hyperchromatic nuclei are occasionally found as seen in other endocrine tumors (i.e. "endocrine anaplasia"), and rare cases show nuclear clearing. Paragangliomas may be present anywhere within the bladder wall (including the muscularis propria), but no surrounding stromal reaction is present. Although many reported cases of paraganglioma in the urinary bladder have followed a benign clinical course, late metastases are known to occur. As in other anatomic sites, it has been difficult to establish histologic criteria to definitively predict behavior, and long-term follow-up care is warranted.

The main differential is an invasive urothelial carcinoma, however, the characteristic nested pattern with fibrovascular septa, the usually bland cytology, the absence of a stromal reaction, and the absence of appreciable mitotic activity should suggest the diagnosis of paraganglioma. Immunohistochemistry is usually confirmatory, as paragangliomas are reactive for neuroendocrine markers (chromogranin and synaptophysin) and non-reactive for cytokeratin, while the opposite is true of carcinomas.

The possibility of a carcinoid tumor may also be considered, but the absence of even focal cytokeratin expression should exclude that possibility. Melanoma might show some morphologic overlap, but paragangliomas have a distinctive s-100 protein reactivity pattern (expression in sustentacular cells surrounding the nests) and are non-reactive for other, more specific melanoma markers (HMB-45 and Melan-A).

2) Prostatic adenocarcinoma [58, 59, 60]
Prostatic adenocarcinoma may present clinically as a bladder mass at cystoscopy. Characteristic features of prostatic adenocarcinoma that aid in the distinction from urothelial carcinoma include the usual monotonous appearance of the nuclei, sometimes prominent nucleoli, and focal acinar differentiation. Recent reports highlight rare prostatic adenocarcinomas with nuclear anaplasia that may closely mimic urothelial carcinoma. [89, 90] Cases with a sheet-like growth pattern or more nuclear pleomorphism may require immunohistochemical studies. Prostatic adenocarcinoma is typically immunoreactive for PSA and PSAP, but negative for high molecular weight cytokeratin, and the opposite immunophenotype is typical of urothelial carcinoma. One large study has recommended PSA, PSAP, and cytokeratin 34BE12 as an initial panel with Leu7, cytokeratin 7, and p53 as a secondary panel. [60] The utility of uroplakin III and thrombomodulin as markers of urothelial differentiation has also been proposed, [59] and one study has demonstrated their utility in this diagnostic setting. [86] Lastly, p63 expression is reported in most urothelial carcinomas and is less frequently expressed in prostatic carcinoma. [88]

The reported immunoprofiles are summarized below.

Prostatic vs. Urothelial Carcinoma: Immunoprofiles

Prostate Urothelial
PSA 68-94% 0%
PSAP 78-95% 0%
HMWCK (34ßE12) 6-10% 65-100%
Uroplakin III 0% 57-60%
Thrombomodulin 0% 49-69%
p63 0-18% 70-75%
CD57 (Leu 7) 94% 17%

PSA: Prostate-specific antigen; PSAP: Prostate-specific acid phosphatase; HWWCK: High-molecular weight cytokeratin

3) Colonic adenocarcinoma (direct extension) [61, 62, 63]
Colonic adenocarcinoma may involve the bladder by direct extension and present as an intravesical mass for biopsy. The morphology is typical of colonic adenocarcinoma, but may be morphologically indistinguishable from a primary bladder adenocarcinoma. This differential diagnosis is discussed fully in the section on primary adenocarcinoma of the bladder (See Variants of Urothelial Carcinoma).

4) Melanoma [64, 65]
Primary malignant melanoma of the genitourinary tract is most common in the urethra, but has been reported in the bladder as well. These neoplasms have similar morphologies to those occurring in the skin with a broad morphologic spectrum. Immunostains for s-100 protein, HMB-45, and Melan A are useful for confirmation. As with all diagnoses of melanoma, the possibility of metastasis from a cutaneous primary must be excluded clinically before the tumor is accepted as vesical primary.

5) Plasmacytoma/Multiple myeloma [66]
Rare plasma cell neoplasms may involve the bladder as primary tumors or, more commonly, as secondary involvement in patients with myeloma. These neoplasms may closely mimic the plasmacytoid variant of urothelial carcinoma, but immunostains for cytokeratin are usually sufficient for this distinction. One should be cautious in the use of the CD138 antibody for plasma cells, because reactivity in carcinomas is well documented. [71]

6) Other hematologic malignancies [67, 68, 69, 70]
An in depth discussion of lymphoma is beyond the scope of this course, but almost all types of hematologic malignancy have been reported to involve the bladder secondarily. The most common primary vesical lymphoma is extranodal marginal zone lymphoma (MALT-type lymphoma). [67]

Most diagnostic difficulties arise in the setting of a high-grade undifferentiated neoplasm with cellular discohesion in which both carcinoma and high-grade lymphoma such as diffuse large B-cell lymphoma are considered. Immunostains for both epithelial and lymphoid markers usually allow distinction in this setting.

7) Metastatic carcinoma [72, 73, 74, 75, 76, 77, 78, 79, 80]
There are case reports of metastatic carcinomas involving the bladder from many different anatomic sites. The most common tumors that involve the urinary bladder secondarily (local extension or metastasis) have been discussed elsewhere in relevant sections of the course where their morphologies overlap considerably with primary bladder tumors.

Selected References for Mimics of Urothelial Carcinoma

Papillary/Polypoid Cystitis
  1. Young RH. Papillary and polypoid cystitis: a report of 8 cases. Am J Surg Pathol 1988;12:542-546.

  2. Buck EG. Polypoid cystitis mimicking transitional cell carcinoma. J Urol 1984;131:963.

  3. McKenney JK, Amin MB, Young RH. Urothelial (transitional cell) papilloma of the urinary bladder: a clinicopathologic study of 26 cases. Mod Pathol 2003;16:623- 629.
  1. Magi-Galluzzi C, Epstein JI. Urothelial papilloma of the bladder: a review of 34 de novo cases. Am J Surg Pathol 2004;28:1615-1620.

von Brunn's Nests/Cystitis Cystica Spectrum
  1. Mostofi FK. Potentialities of bladder epithelium. J Urol 1954; 71:705-714.

  2. Morse HD. The etiology and pathology of pyelitis cystica, ureteritis cystica, and cystitis cystica. Am J Pathol 1928;4:33-50.

  3. Goldstein AMB, Fauer RB, Chinn M, et al. New concepts on formation of Brunn's nests and cysts in the urinary tract mucosa. Urol 1978;11:513-17.

  4. Wiener DP, Koss LG, Sablay B, et al. The prevalence and significance of Brunn's nests, cystitis cystica, and squamous metaplasias in normal bladders. J Urol 1979;122:317-321.

  5. Parker C. Cystitis cystica and glandularis: a study of 40 cases. Proc R Soc Med 1970;63:239-42.

  6. Davies G, Castro JE. Cystitis glandularis. Urology 1977; 10:128-129.

  7. Volmar KE, Chan TY, de Marzo AM, et al. Florid von Brunn's nests mimicking urothelial carcinoma: a morphologic and immunohistochemical comparison to the nested variant of urothelial carcinoma. Am J Surg Pathol 2003;27:1243-1252.

  8. Young RH, Bostwick DG. Florid cystitis glandularis of intestinal type with mucin extravasation: A mimic of adenocarcinoma. Am J Surg Pathol 1996; 20:1462-1468.

  9. Jacobs LB, Brooks JD, Epstein JI. Differentiation of colonic metaplasia from adenocarcinoma of urinary bladder. Hum Pathol 1997; 28:1152-1157.

  10. Corica FA, Husmann DA, Churchill BM, et al: Intestinal metaplasia is not a strong risk factor for bladder cancer: Study of 53 cases with long-term follow up. Urology 1997;50:427-31.

Nephrogenic Adenoma
  1. Baghavan BS, Tiamson EM, Wenk RE, et al. Nephrogenic adenoma of the urinary bladder and urethra. Hum Pathol 1981;12:907-916.

  2. Allen CH, Epstein JI. Nephrogenic adenoma of the prostatic urethra: a mimicker of prosate adenocarcinoma. Am J Surg Pathol 2001;25:802-808.

  3. Stilment MM, Sivoky MB. Nephrogenic adenoma associated with intravesical bacillus Calmette-Guerin treatment: a report of two cases. J Urol 1986; 135:359-361.

  4. Navarre RJ, Loening SA, Narayana A. Nephrogenic adenoma: a report of nine cases and review of the literature. J Urol 1982; 127:775-779.

  5. Molland EA, Trott PA, Paris MI, et al. Nephrogenic adenoma: a form of Adenomatous metaplasia of the bladder. A clinical and electron microscopical study. Br J Urol 1976;48:453-462.

  6. Ford TF, Watson GM, Cameron KM. Adenomatous metaplasia (nephrogenic adenoma) of urothelium: an analysis of 70 cases. Br J Urol 1985; 57:427-433.

  7. Mazal PR, Schaufler R, Altenhuber-Muller R, et al. N Engl J Med 2002; 347:684- 686.

  8. Oliva E, Young RH. Nephrogenic adenoma of the urinary tract: a review of the microscopic appearance of 80 cases with emphasis on unusual features. Mod Pathol 1995;8:722-30.

  9. Skinnider BF, Oliva E, Young RH, Amin MB. Expression of alpha-methylacyl-CoA racemase (P504S) in nephrogenic adenoma: a significant immunohistochemical pitfall compounding the differential diagnosis with prostatic adenocarcinoma. Am J Surg Pathol 2004;28:701-5.

  10. Gupta A, Wang HL, Policarpio-Nicolas ML, et al. Expression of alpha-methylacyl- coenzyme A racemase in nephrogenic adenoma. Am J Surg Pathol 2004;28:1224-9.

  11. Gilcrease MZ, Delgado R, Vuitch F, Albores-Saavedra J. Clear cell adenocarcinoma and nephrogenic adenoma of the urethra and urinary bladder: a histopathologic and immunohistochemical comparison. Hum Pathol 1998;29:1451-6.
  1. Tong G, Melamed J, Mansukhani et al. PAX2:a reliable marker for nephrogenic adenoma. Mod Pathol advance online publication 6 January 2006.

Endometriosis
  1. Nixon WCW. Endometriosis of the bladder. Lancet 1940;1:405-406.

  2. Lichtenfeld FR, McCauley RT, Staples PP. Endometriosis involving the urinary tract. A collective review. Obstet Gynecol 1961;17:762-768.

  3. Pinkert TC, Catlow CE, Straus R. Endometriosis of the urinary bladder in a man with prostate carcinoma. Cancer 1979;43:1562-1567.

  4. Fein RL, Horton BF. Vesical endometriosis: A case report and review of the literature. J Urol 1966; 95:45-50.

  5. Lenaine WO, Admundsen CL, McGuire EJ. Bladder endometriosis: Conservative management. J Urol 2000; 163: 1814-1817.

  6. Comiter CV. Endometriosis of the urinary tract. Urol Clin No Am 2002;29: 625-635.

  7. Randolph Schrodt G, Alcorn MO, Ibanez J. Endometriosis of the male urinary system: a case report. J Urol 1980;124:722-723.

Müllerianosis
  1. Clement PB, Young RH. Endocervicosis of the urinary bladder. A report of six cases of a benign C lesion that may mimic adenocarcinoma. Am J Surg Pathol 1992;16:533-542.

  2. Young RH, Clement PB. Müllerianosis of the urinary bladder. Mod Pathol 1996;9:731-737.

  3. Julié C, Boyé K, Desgrippes A, et al. Endocervicosis of the urinary bladder. Immunohistochemical comparative study between a new case and normal uterine endocervices. Pathol Res Pract 2002; 198: 115-198.

  4. Kim HJ, Lee TJ, Kim MK, et al. Müllerianosis of the urinary bladder, endocervicosis type: A case report. J Korean Med Sci 2001; 16:123-126.

  5. Donné C, Vidal M, Buttin X, et al. Müllerianosis of the urinary bladder: Clinical and immunohistochemical findings. Histopathol 1998; 33:284-285.

Eosinophilic cystitis
  1. Hellstrom HR, Davis BK, Shonnard JW. Eosinophilic cystitis: a study of 16 cases. Am J Clin Pathol 1979;72:777-784.

  2. Rubin I, Pincus MB. Eosinophilic cystitis: the relationship to allergy in the urinary tract to eosinophilic cystitis and the pathophysiology of eosinophilia. J Urol 1974;112:457-460.

  3. Gregg JA, Utz DC. Eosinophilic cystitis associated with eosinophilic gastroenteritis. Mayo Clin Proc 1974;49:185-187.

  4. Oh SJ, Chi JG, Lee SE. Eosinophilic cystitis caused by vesical spargangiosis: a case report. J Urol 1993;149:581-583.

  5. Verhagen PCMS, Nikkels PGJ, de Jong TPVM. Eosinophilic cystitis. Arch Dis Child 2001;84:344-346.

  6. Redman JF, Parham DM. Extensive inflammatory eosinophilic bladder tumors in children: experience with three cases. South Med J. 2002;95:1050-2.

  7. Thjissen A, Gerriidzen RG. Eosinophilic cystitis presenting as invasive bladder cancer: comments on pathogenesis and management. J Urol 1990;144:977-979.

Malakoplakia
  1. Smith BH. Malakoplakia of the urinary tract. A study of 24 cases. Am J Clin Pathol 1965;43:409-417.

  2. McClure J. Malakoplakia. J Pathol 1983;140:275-330.

  3. Abdou NI, NaPombejara C, Sagawa A et al. Malakoplakia: evidence for monocyte lysosomal abnormality correctable by cholinergic agonist in vitro and in vivo. N Engl J Med 1977;287:1413-1419.

Pseudocarcinomatous hyperplasia associated with radiation therapy
  1. Chan TY, Epstein JI. Radiation or chemotherapy cystitis with "pseudocarcinomatous" features. Am J Surg Pathol 2004;28:909-13.

  2. Baker PM, Young RH. Radiation-induced pseudocarcinomatous proliferations of the urinary bladder: a report of 4 cases. Hum Pathol. 2000;31:678–683.

Radiation cystitis
  1. Warren S. Effects of radiation on normal tissues. Effects of radiation on the urinary system. Arch Pathol 1942;34:1079-1084.

  2. Fajardo LF, Berthrong M. Radiation injury in surgical pathology. Part 1. Am J Surg Pathol 1978;2:159-195.

Amyloidosis
  1. Malek RS, Greene LF, Farrow GM. Amyloidosis of the urinary bladder. Br J Urol 1971;43:189-200.

  2. Farah RN, benson DO, Fine G, et al. Primary localized amyloidosis of bladder. Urol 1979;13:200-202.

  3. Akhtar M, Valencia M, Thomas AM. Solitary primary amyloidosis of urinary bladder. Urol 1978;12:721-724.


Ectopic prostate tissue
  1. Remick DG, Kumar NB. Benign polyps with prostatic-type epithelium of urethra and the urinary bladder. Am J Surg Pathol 1984;8:833-839.

Paraganglioma (Pheochromocytoma)
  1. Ostrowski ML, Wheeler TM. Paraganglioma of the prostate: location, frequency, and differentiation from prostatic adenocarcinoma. Am J Surg Pathol 1994;18:412-420.

  2. Cheng L, Leibovich BC, Cheville JC, et al. Paraganglioma of the urinary bladder: can biologic potential be predicted? Cancer 2000;88:844-852.

  3. Zhou M, Epstein JI, Young RH. Paraganglioma of the urinary bladder. A lesion that may be misdiagnosed as a urothelial carcinoma in transurethral resection specimens. Am J Surg Pathol 2004;28:94-100.
  1. Kato H, Suzuki M, Mukai M, Aizawa S. Clinicopathological study of pheochromocytoma of the urinary bladder: immunohistochemical, flow cytometric, and ultrastructural findings with review of the literature. Pathol Int 1999;49:1093-1099.

Prostatic adenocarcinoma
  1. Varma M, Morgan M, Amin MB, Wozniak S, Jasani B. High molecular weight cytokeratin antibody (clone 34betaE12): a sensitive marker for differentiation of high-grade invasive urothelial carcinoma from prostate cancer. Histopathol 42: 167-172, 2003.

  2. Parker DC, Folpe AL, Bell J, Oliva E, Young RH, Cohen C, Amin MB. Potential utility of uroplakin III, thrombomodulin, high molecular weight cytokeratin, and cytokeratin 20 in noninvasive, invasive, and metastatic urothelial (transitional cell) carcinomas. Am J Surg Pathol 2003;27:1-10.
  1. Langner C, Ratschek M, Tsybrovsskyy O, schips L, Zigeuner R. P63 immunoreactivity distinguishes upper urinary tract transition-cell carcinoma and renal-cell carcinoma even in poorly differentiated tumors. J Histochem Cytochem 2003;51:1097-9.

  2. Mhawech P, Uchida T, Pelte MF. Immunohistochemical profile of high-grade urothelial bladder carcinoma and prostate adenocarcinoma. Hum Pathol 2002;33:1136-40.
  1. Genega EM, Hutchinson B, Reuter VE, Gaudin PB. Immunophenotype of high- grade prostatic adenocarcinoma and urothelial carcinoma. Mod Pathol 2000;13:1186-91.
  1. Clingan WJ, Gokden N, McKenney JK. Distinguishing poorly differentiated prostatic adenocarcinoma from invasive urothelial carcinoma in transurethral biopsy/resection specimens: utility of p63. Mod Pathol 2006;19, Supplement 1;133A(Abstract 610).

  2. Parwani AV, Herawi M, Epstein JI. Pleomorphic and giant cell adenocarcinoma of the prostate. Report of 6 cases. Am J Surg Pathol 2006;30:1254-1259.

  3. Lopez-Beltran A, Eble JN, Bostwick DG. Pleomorphic giant cell carcinoma of the prostate. Arch Pathol Lab Medicine 2005;129:683-5.

Colonic adenocarcinoma (direct extension)
  1. Silver SA, Epstein JI. Adenocarcinoma of the colon simulating primary urinary bladder neoplasia. A report of nine cases. Am J Surg Pathol 17:171-178, 1993.

  2. Tamboli P, Mohsin SK, Hailemariam S, Amin MB. 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 126:1057-1063, 2002.

  3. Wang HL, Lu DW, Yerian LM, Alsikafi N, Steinberg G, Hart J, Yang XJ. Immunohistochemical distinction between primary adenocarcinoma of the bladder and secondary colorectal adenocarcinoma. Am J Surg Pathol 25: 1380-1387, 2001.

Melanoma
  1. Ainsworth AM, Clark WH Jr, Mastrangelo M et al. Primary malignant melanoma of the urinary bladder. Cancer 1976;37:1928-1936.

  2. Stein DS, Kendall AR. Malignant melanoma of the genitourinary tract. J Urol 1984;132:859-868.

Hematologic malignancies
  1. Ho DS, Patterson AL, Orozco RE, et al. Extramedullary plasmacytoma of the bladder: a case report and review of the literature. J Urol 1993;150:473-474.

  2. Kempton CL, Kurtin PJ, Inwards DJ, et al. Malignant lymphoma of the bladder: evidence from 36 cases that low-grade lymphoma of the MALT-type is the most common primary bladder lymphoma. Am J Surg Pathol 1997;21:1324-1333.

  3. Oshawa M, Aozasa K, Horiuchi K, et al. Malignant lymphoma of the bladder: report of three cases and review of the literature. Cancer 1993;72:1969-1974.

  4. Givler RL. Involvement of the bladder in leukemia and lymphoma. J Urol 1971;105:667-670.

  5. Sufrin G, Keogh B, Moore RH, et al. Secondary involvement of the bladder in malignant lymphoma. J Urol 1977;118:251-253.

  6. Chu PG, Arber DA, Weiss LM. Expression of T/NK-cell and plasma cell antigens in nonhematopoietic epithelioid neoplasms. An immunohistochemical study of 447 cases. Am J Clin Pathol 2003 Jul;120(1):64-70.

Metastatic carcinoma
  1. Melicow MM. Tumors of the urinary bladder: A clinicopathological analysis of over 2500 specimens and biopsies. J Urol 74: 498-521, 1955.

  2. Young RH, Johnston WH. Serous adenocarcinoma of the uterus metastatic to the urinary bladder mimicking primary bladder neoplasia: a report of a case. Am J Surg Pathol 14: 877-880, 1990.

  3. Sim SJ, Ro JY, Ordonez NG, Park YW, Kee KH, Ayala AG. Metastatic renal cell carcinoma to the bladder: a clinicopathologic and immunohistochemical study. Mod Pathol 12: 351-355, 1999.

  4. Oliva E, Amin MB, Jimenez R, Young RH. Clear cell carcinoma of the urinary bladder: a report and comparison of four tumors of mullerian origin and nine of probable urothelial origin with discussion of histogenesis and diagnostic problems. Am J Surg Pathol 26: 190-197, 2002.

  5. Matsuo M, Koga S, Nishikido M, Noguchi M, Sakaguchi M, Nomata K, Maruta N, Hayashi T, Kanetake H. Renal cell carcinoma with solitary metachronous metastasis to the urinary bladder. Urol 60: 911-912, 2002.

  6. Coltart RS, Stewart S, Brown CH. Small cell carcinoma of the bronchus: a rare cause of haematuria from a metastasis in the urinary bladder. J Roy Soc Med 78:1053- 1054, 1985.

  7. Klinger ME. Secondary tumors of the genito-urinary tract. J Urol 65:144-153, 1951.

  8. Henry R, Bracken RB, Ayala A. Appendiceal carcinoma mimicking primary bladder cancer. J Urol 123:590-591, 1980.

  9. Van Driel MF, Ypma AFGVM, Van Gelder B. Gastric carcinoma metastatic to the bladder. Brit J Urol 59:193-194, 1987.

  10. Silverstein LI, Plaine L, Davis JE, Kabakow B. Breast carcinoma metastatic to bladder. Urol 29:544-547, 1987.

  11. Chalbaud RA, Johnson DE. Adenocarcinoma of tongue metastatic to bladder. Urol 4:454-455, 1974.