—  SHORT COURSE #07  —

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

Section 5 - Histologic Heterogeneity in Invasive Carcinoma of the Urinary Bladder: Variants

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


Case 3

History:
53-year-old man who presented with weight loss and microscopic hematuria. Imaging studies revealed an intramural bladder mass. No other intra-abdominal masses were present. Cystoscopy showed a 3.2 cm nodular mass in the left posterolateral wall.

Diagnosis:
Adenocarcinoma, involving the muscularis propria (See Comment)

Comment:
This adenocarcinoma could be accepted as primary at this site (urinary bladder) if a metastasis or direct extension from an adjacent organ can be ruled out clinically.

F/U:
No other intrabdominal tumor was present, and the location in the posterolateral wall was confirmed (excluding a urachal primary). The tumor was, therefore, classified as primary vesical adenocarcinoma.

Case 4

History:
67-year-old woman who presented with right hydronephrosis. Imaging studies revealed a filling defect at the right ureteral orifice. Cystoscopy showed a 1.2 cm nodular lesion at the right ureteral orifice.

Diagnosis:
Invasive urothelial carcinoma, nested type, with invasion of the muscularis propria.

Case 5

History:
54-year-old man who presented with hydronephrosis and hematuria. Cystoscopy revealed multiple raised lesions with hyperemic surfaces at the bladder base.

Diagnosis:
Invasive urothelial carcinoma, micropapillary type, with invasion of the muscularis propria.

Histologic Heterogeneity in Invasive Carcinoma of the Urinary Bladder: Variants

  1. Conventional urothelial carcinoma with alternative differentiation
    1. Squamous differentiation

    2. Glandular differentiation

    3. Trophoblastic differentiation
  2. Urothelial carcinoma with unusual cytologic features
    1. Plasmacytoid features

    2. Rhabdoid features

    3. Glycogen-rich

    4. Lipid-rich
  3. Deceptively bland urothelial carcinoma
    1. Nested

    2. Microcystic

    3. Small tubular
  4. Micropapillary carcinoma

  5. Neuroendocrine tumors
    1. Carcinoid

    2. Small cell carcinoma

    3. Large cell neuroendocrine carcinoma
  6. Poorly differentiated carcinomas
    1. Lymphoepithelioma-like carcinoma

    2. Giant cell carcinoma (Undifferentiated carcinoma)
  7. Urothelial carcinoma with unusual stromal changes
    1. Stromal osteoclast-like giant cells
  8. Adenocarcinoma spectrum
    1. Villous adenoma

    2. Adenocarcinoma in-situ

    3. Invasive adenocarcinoma
      1. Histologic heterogeneity

      2. Anatomic variation
  9. Squamous Neoplasms
    1. Squmaous metaplasia

    2. Squamous papilloma

    3. Condyloma acuminatum

    4. Squmaous dysplasia (carcinoma in-situ)

    5. Carcinoma
      1. Verrucous

      2. Typical (NOS)

Variants of Urothelial Carcinoma

Primary invasive urothelial carcinomas of the urinary bladder have a broad morphologic spectrum. This section of the course will detail each histologic pattern with a discussion of both differential diagnoses and clinical relevance.

I. Alternative Differentiation in Urothelial Carcinoma
Invasive urothelial carcinomas frequently show alternative lines of differentiation; the two most common forms are squamous and glandular patterns with rare cases showing trophoblastic features.

A) Urothelial Carcinoma with Squamous Differentiation [1, 2, 3, 4, 5, 6]
Squamous differentiation is relatively common in invasive urothelial carcinoma (up to 21% in some series). It is defined by the presence of intercellular bridges and/or keratinization. The percentage of squamous differentiation is extremely variable with some cases consisting almost entirely of squamous elements. By definition, the presence of any component of urothelial neoplasia, including cases with only associated urothelial carcinoma in-situ, are classified as "urothelial carcinoma with squamous differentiation". It is difficult to ascertain any independent prognostic significance, because most tumors with squamous differentiation are high grade and muscle invasive at presentation. Some studies, however, have suggested that tumors with squamous differentiation are less responsive to radiation or chemotherapy. [4, 6, 8] It is, therefore, recommended that the percentage of squamous differentiation be estimated and reported.

The distinction from primary vesical squamous cell carcinoma rests on the presence of a recognizable urothelial component or a past history of urothelial carcinoma. Associated keratinizing squamous metaplasia in the flat epithelium and squamous dysplasia are commonly seen in association with pure squamous cell carcinoma and would support that diagnosis. It should be emphasized that in the United States, urothelial carcinoma with squamous differentiation is much more common than primary vesical squamous cell carcinoma.

B) Urothelial Carcinoma with Glandular Differentiation [3, 8]
Glandular differentiation is also occasionally identified in cases of invasive urothelial carcinoma (approximately 6% of urothelial carcinomas), but is less common than squamous differentiation. It is characterized by the presence of true glandular spaces with/or without mucin secretion. "True" glandular differentiation has been defined as a central luminal space typically lined by a single layer of columnar or cuboidal cells. The apical cytoplasm is often more prominent and may be mucinous. Many urothelial carcinomas contain small, round intraepithelial spaces, likely secondary to individual cell necrosis, but that finding is not regarded as true glandular differentiation because the space-lining cells are urothelial. Focal intracytoplasmic mucin in an otherwise typical urothelial carcinoma, under current definitions, is not sufficient for classification as glandular differentiation. Glandular differentiation may show a varied morphology including enteric-type, colloid, or signet-ring cell patterns. The clinical significance of "true" glandular differentiation is uncertain.

Similarly to squamous cell carcinoma, the diagnosis of primary vesical adenocarcinoma is reserved for pure tumors without any evidence of urothelial differentiation. Any admixture of a urothelial neoplasm (including carcinoma in-situ) or history of primary urothelial carcinoma warrants a designation of "urothelial carcinoma with glandular differentiation".

Urothelial carcinomas with tubular or microcystic patterns are described below as "deceptively bland carcinomas". Their distinction from tumors classified as urothelial carcinoma with glandular differentiation, as defined by the authors of several small series, is based on the urothelial appearance of the cells lining the luminal spaces. [22, 23]

C) Urothelial Carcinoma with Trophoblastic Differentiation [10, 11, 12, 13, 14, 15]
The literature on this subject is somewhat confusing because of the heterogeneity of tumors reported as "urothelial carcinomas with trophoblastic differentiation." For purposes of reviewing clinical significance, we have divided this group of neoplasms into three categories: 1) urothelial carcinoma with scattered syncytiotrophoblasts, 2) urothelial carcinoma with choriocarcinomatous differentiation or pure choriocarcinoma, and 3) urothelial carcinoma with immunohistochemical expression of β-HCG, but no recognizable trophoblasts.

Rare, high-grade urothelial carcinomas contain scattered syncytiotrophoblastic giant cells that are immunoreactive for antibodies to β-HCG. The syncytiotrophoblasts may comprise a very minor cell population and can easily be overlooked. Very rarely, foci of choriocarcinoma, defined as sheets of cytotrophoblasts intimately associated with a rim of pleomorphic syncytiotrophoblasts, are seen admixed with urothelial carcinoma. The occurrence of a pure germ cell tumor in the urinary bladder without an associated urothelial carcinoma is exceedingly rare, and most reported cases likely represent urothelial carcinomas masked by extensive overgrowth of a trophoblastic component. One recently reported case, however, was associated with an isochromosome 12p, a specific genetic marker found in germ cell tumors of any histologic type. [16]

The term "trophoblastic" differentiation has been used non-specifically for both scattered syncytiotrophoblasts in an otherwise typical urothelial carcinoma and true choriocarcinomatous foci. Although most reported cases with "trophoblastic" differentiation have followed a rapidly progressive course, the prognostic significance of only scattered syncytiotrophoblasts is unknown, as many of the reported cases have presented with high grade tumors at advanced stage. There has not been a study comparing tumors of similar grade and stage with and without admixed syncytiotrophoblasts to definitively answer this question. It does appear that choriocarcinomatous differentiation has a very high risk of metastatic disease and tumor related death. Because of its rarity, the utility of germ cell therapy for vesical choriocarcinoma has not been fully addressed; initial cases reported a poor response, but there are reports of good clinical responses to germ cell therapy in rare patients with pure choriocarcinomas. [10, 11] Whether or not pure choricarcinomas represent a tumor with better chemosensitivity is unknown. The possibility of a metastatic choriocarcinoma should always be excluded clinically before the diagnosis of a primary vesical choriocarcinoma is accepted.

More commonly, β-HCG expression can be demonstrated in typical urothelial carcinoma (up to 33% of high-grade tumors) and urothelial carcinoma in-situ in the absence of histologically identified trophoblasts. [14, 99, 100] Immunohistochemical expression of β-HCG clearly increases with higher tumor grade. Reportedly, up to 50% of patients with widely disseminated urothelial carcinoma of typical morphology have an associated elevation in serum β-HCG; [98] however, his finding does not correlate with the presence of syncytiotrophoblasts or other trophoblastic elements. There have been reports that suggest an adverse prognosis in patients with elevated serum β-HCG, [100] but, again, the true clinical significance has been questioned because most reported cases have had high stage disease at the time of diagnosis. There are some reports that suggest conventional urothelial carcinomas with strong β-HCG reactivity may be more radioresistant than non or weakly expressing tumors, however, there is not sufficient evidence to support routine immunostaining for β-HCG in otherwise typical urothelial carcinoma.

In summary, trophoblastic differentiation in urothelial carcinoma spans a spectrum from immunohistochemical expression for β-HCG in otherwise typical urothelial carcinoma, to the presence of syncytiotrophoblasts, to the presence of foci resembling choriocarcinoma, to the very rare predominant or pure choriocarcinoma. It may be more useful to report such cases descriptively as "urothelial carcinoma with focal syncytiotrophoblastic differentiation" or "with choriocarcinomatous differentiation". The term "with trophoblastic differentiation" does not distinguish between these two morphologies that may possibly have different prognostic or treatment significance.

II. Urothelial Carcinoma with Unusual Cytologic Features
This section discusses unusual cytologic features of invasive urothelial carcinoma that may closely mimic other tumors and lead to diagnostic confusion. The clinical/prognostic significance of these morphologic patterns, independent of stage, is not known.

1) Plasmacytoid/Lymphoma-like [17, 21, 103]
Rare invasive urothelial carcinomas have cytologic features closely mimicking plasma cells with round cytoplasmic borders, abundant eosinophilic cytoplasm, and an eccentrically placed, hyperchromatic nucleus. The neoplastic cells are usually discohesive and set in a loose, myxoid stroma. Almost all reported cases have features of conventional invasive urothelial carcinoma at least focally. Small biopsies occasionally show only the plasmacytoid pattern and may closely mimic a plasmacytoma or lymphoma. Immunohistochemistry may be required in this setting, and demonstration of cytokeratin reactivity confirms the diagnosis of carcinoma. Carcinomas may express CD138, so this marker should not be used in isolation as evidence of a plasma cell neoplasm. [102]

Cytokeratin positive tumors may require additional work-up for distinction between primary urothelial and metastatic carcinomas. Metastatic carcinomas (e.g., breast or gastric adenocarcinomas) are not typically plasmacytoid and, in general, have a signet-ring or non-specific appearance. One series of urothelial carcinomas has been reported with discohesive, non-plasmacytoid single cells that may be indistinguishable from a diffuse gastric or lobular breast carcinoma. [103] In that setting, immunoreactivity for CK20 is characteristic of a bladder or gastric primary. In difficult cases or in women with a known breast primary, immunostains for gross cystic disease fluid protein 15 (GCDFP-15), estrogen receptor, and progesterone receptor may help add evidence of a breast primary.

2) Rhabdoid [18]
Urothelial carcinomas may also rarely have focal areas showing rhabdoid features: a population of large, relatively discohesive cells with distinct cell borders, large vesicular nuclei, prominent nucleoli, and eosinophilic cytoplasmic inclusions. Most cases have features of conventional urothelial carcinoma at least focally.

The differential diagnosis is more difficult when the tumor has a homogeneous rhabdoid phenotype. The main distinction is from a true malignant extrarenal rhabdoid tumor. Although there are two case reports of "true" malignant rhabdoid tumors of the bladder in young patients, their existence is controversial. Given that malignant rhabdoid tumors have a characteristic mutation or deletion of the INI1 gene at chromosome 22q11, we suggest that molecular confirmation is mandatory for the diagnosis of malignant rhabdoid tumor in the bladder. Immunohistochemical loss of nuclear INI1 expression has also been reported as an adjunctive test to confirm the diagnosis of malignant extra-renal rhabdoid tumors. [101] From a practical standpoint, tumors with a rhabdoid morphology in adults are almost always poorly differentiated carcinomas.

3) Glycogen-rich [20]
Reports have described urothelial carcinomas with glycogen-rich, clear cytoplasm. These carcinomas are typically high-grade, so the differential diagnosis includes clear cell adenocarcinoma, metastatic renal cell carcinoma, or prostatic carcinoma. Clear cell adenocarcinomas typically have a papillary or tubulocystic architectural arrangement; the papillae are lined by a single epithelial layer with a hyalinized core. In contrast, poorly differentiated urothelial carcinomas have a more sheet-like growth pattern. Metastatic renal cell carcinoma can usually be excluded based on clinical grounds (presence of renal mass). In the one reported series of seven cases, all patients had metastatic renal cell carcinoma in multiple organs; no patient had isolated bladder metastasis. Morphologically,the presence of a well-developed alveolar or nested pattern with intervening septa comprised of small capillaries and admixed mature lymphocytes should greatly raise suspicion of a renal primary. The utility of renal cell carcinoma marker has not been studied in this precise clinical setting. Strong, diffuse immunoreactivity with PSA and/or PSAP would support a prostatic carcinoma. (Immunohistochemical distinction of urothelial carcinoma from prostatic carcinoma, a more common dilemma, is discussed fully in the section on mimics).

4) Lipid-rich [19]
There are even rarer reports of urothelial carcinomas with lipid-filled cytoplasm that may mimic a signet ring adenocarcinoma. The absence of intracellular mucin by special stains may aid in this distinction. The diagnosis of an atypical lipomatous tumor or pleomorphic liposarcoma might also be considered, but the typical features of lipoblasts such as eccentric, scalloped, hyperchromatic nuclei with cytoplasmic septations are not present in these rare lipid-rich carcinomas. The demonstration of cytokeratin reactivity should resolve the diagnosis of carcinoma in most difficult case.

III. Micropapillary Carcinoma [35, 36, 37, 104]
This rare pattern of invasive urothelial carcinoma is morphologically similar to papillary serous carcinoma of the ovary. It comprises 0.6-1% of urothelial carcinomas and shows a definite male predominance (male to female ratio 37:1 in one series) which is higher than in conventional urothelial carcinoma. More than 95% of these tumors are muscle invasive at the time of diagnosis.

Histologically, the micropapillary pattern may be found in the non-invasive component, the invasive component, and in metastases. It is frequently admixed with more typical patterns of urothelial carcinoma and may be focal or extensive. An association with adjacent urothelial carcinoma in-situ is also common. The surface component typically consists of slender, fine papillary processes rarely with a small fibrovascular core (similar to the micropapillary pattern of ovarian serous neoplasia). The invasive component, as well as the metastases, are characterized by small nests of cells and filiform papillae with a surrounding retraction space closely mimicking angiolymphatic invasion. The lacunar architecture is the most striking feature of micropapillary carcinoma; the surrounding spaces may be lined focally by flattened, spindled stromal cells or may lack a lining. Most cases do not show a stromal reaction. Although this growth pattern mimics angiolymphatic invasion, obvious vascular invasion is usually identified at least focally. The neoplastic cells are characteristically high-grade (as defined by 2004 WHO/ISUP classification).

Micropapillary carcinomas typically present at high-stage with invasion into the muscularis propria, obvious vascular invasion, and lymph node metastases. For micropapillary carcinoma of the bladder, cystoscopic re-evaluation with additional biopsy is usually suggested if no muscularis propria invasion is identified at the initial staging. In fact, a recent clinical publication is advocating cystectomy for micropapillary carcinoma of the urinary bladder even in the absence of muscularis propria invasion. [105]

The main differential diagnosis is a metastatic papillary serous carcinoma, especially if the tumor is originally discovered in the peritoneum, abdominal lymph nodes, or mesentery; however, carcinomas with a micropapillary histology have also been reported in the lung, breast, salivary glands, and more recently colon. Clinical/radiographic correlation is usually required, but the possibility of a bladder primary may be suggested if there is no obvious primary tumor at another anatomic site. Identification of an admixed urothelial carcinoma of more typical morphology or adjacent urothelial carcinoma in situ are the most specific evidence of a bladder primary. Of note, psammoma bodies are extremely rare in micropapillary carcinoma of the bladder. Studies have not specifically addressed the immunohistochemical distinction of micropapillary carcinoma of the bladder from ovarian serous carcinoma, or micropapillary carcinoma of the breast, lung, salivary gland, or colon.

IV. "Deceptively Bland" Carcinoma
Reports of cytologically bland urothelial carcinomas showing deep invasion of the bladder wall and lymph node metastases have been described under different names including nested variant, microcystic variant, and "deceptively bland" urothelial carcinoma. [22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34] Individual cases may have mixed features or may be associated with a more typical papillary urothelial neoplasm, but three main histologic patterns closely mimicking a benign process are generally recognized as described below. By definition, these tumors do not show the high-grade nuclear features typical of invasive urothelial carcinoma.

Nested Pattern [25, 26, 27, 28, 29, 30]
The nested pattern is the most frequently reported subtle pattern of urothelial carcinoma. It may closely mimic von Brunn's nests and is characterized by small, well-delineated, confluent nests of urothelial cells infiltrating the lamina propria and/or muscularis propria. It has been reported in association with papillary urothelial tumors and urothelial carcinoma in-situ, but in most cases the nested pattern of carcinoma has no other component. There is often only subtle nuclear enlargement with mild variation in nuclear size and occasional nucleoli. The neoplastic cells do not show the typical high-grade features (marked hyperchromasia, obvious pleomorphism, mitotic activity) of invasive urothelial carcinoma. Despite the bland appearance of this neoplasm, deep muscle invasion, metastases, and tumor related death have all been reported with the nested variant of carcinoma. The main reason for recognizing these tumors is to avoid misinterpretation as a benign mimic because stage-for-stage they appear to behave as aggressively as conventional invasive urothelial carcinoma despite the low-grade appearance. No studies have looked specifically at the potential for different responses to treatment.

The main differential diagnosis is von Brunn's nests. [30] The best distinguishing feature is the extension of von Brunn's nests to a uniform level within the lamina propria creating a sharp, linear border at the base that contrasts with the irregular, infiltrative base of nested carcinoma. Other subtle features of invasion may be seen in nested carcinomas such as small clusters or individual neoplastic cells with surrounding retraction artifact. The overall architectural arrangement of the neoplastic cells may also have a subtle difference when compared to von Brunn's nests, but these features are not as definitive. The presence of small, irregularly sized, unevenly distributed nests creating confluent, branching patterns should serve as a clue to carefully consider the possibility of a nested carcinoma, as von Brunn's nests are often clustered, evenly spaced, and round. In the ureter and renal pelvis, von Brunn's nests may have smaller, more irregular nests, but they still have a lobular or linear arrangement with a sharp border at the base. [30] Invasion of the muscularis propria , despite the bland nuclear features, is diagnostic of carcinoma and is the most definitive distinguishing feature. Unfortunately, the distinction of nested carcinoma from a mimic such as von Brunn's nests may not be possible in superficial biopsies when some of the subtle clues are not present, particularly when complicated by extensive cautery artifact. In difficult cases, correlation with the clinical impression of the urologist may suggest the presence of a more aggressive lesion.

Nephrogenic adenoma may also enter the differential as it sometimes has a more irregular border and deeper location than von Brunn's nests. The admixed tubular and papillary architecture is very characteristic of nephrogenic adenoma. In addition, the tubules and papillae of nephrogenic adenoma are lined by a single cell layer of cuboidal, columnar, or flattened cells, as opposed to the typically stratified urothelial layer or solid nests of nested carcinomas. Rare cases of nephrogenic adenoma are reported with superficial extension into the muscularis propria, but other characteristic histologic features are typically present making this distinction relatively straightforward in most cases.

Finally, inverted papillomas might be considered because of their irregular, anatomosing pattern of growth within the lamina propria. Inverted papillomas, however, generally have a more complex anastomosing or trabecular architecture with little intervening stroma. As with von Brunn's nests, they have a sharp border at the base. In addition, the individual nests have a distinct basal palisading of cells around the periphery and also frequently show spindling of the lesional cells centrally. The subtle low-power architectural differences distinguishing these lesions are summarized in schematic form below.

Small Tubular Pattern [31]
Other examples of deceptively bland carcinoma show the small irregular nests of urothelium typical of nested carcinoma, but with small central lumina. Again, these tumors may be mixed with the nested pattern, and the differentials are the same as discussed above.

Microcystic Pattern [22, 23]
Another reported pattern of deceptively bland invasive urothelial carcinoma has been called "microcystic". As with the nested pattern, the nests of cytologically bland urothelium infiltrate the lamina propria and/or muscularis propria, but they contain prominent cystic change with central lumina. The lumina are lined by urothelial cells or cells with a more cuboidal appearance due to increased eosinophilic cytoplasm at the luminal surface or mucin. The nests show more variation in size than the nested pattern, and the larger cysts may have an attenuated or denuded lining. Calcification has been reported in the walls of the cysts. In the reported cases, the surrounding stroma may have no morphologic changes or, or rarely, a desmoplastic response.

The most important differential diagnostic considerations include benign mimics such as cystitis cystica glandularis and nephrogenic adenoma, but carcinomas such as clear cell carcinoma and urothelial carcinoma with glandular differentiation might also be considered. As discussed above, this pattern of carcinoma has an infiltrative growth with an uneven, irregular border at the base and irregularly spaced nests of variable size, features that aid in distinction from cystitis cystica. Although nephrogenic adenoma may have large dilated cystic structures and an irregular base, they are lined by a single cuboidal layer of epithelium, in contrast to the stratified urothelium of the microcystic carcinoma. Clear cell carcinoma also frequently shows a tubular pattern, but, by definition, those tumors have marked nuclear pleomorphism and hyperchromasia, features absent in the microcystic pattern. Finally, by strict definition, urothelial carcinoma with glandular differentiation refers to tumors with luminal spaces lined entirely by columnar or cuboidal cells with prominent apical cytoplasm. In contrast, microcystic carcinomas have luminal spaces lined by an admixture of stratified urothelial cells and scattered cells with intracytoplasmic mucin.

Deceptively Bland Carcinoma vs. Benign Mimics:
Schematic Architectural Comparison



V. Neuroendocrine Tumors
The spectrum of neuroendocrine tumors arising in the urinary bladder are similar to those occurring in other anatomic sites and include carcinoid tumor (well-diferentiated neuroendocrine carcinoma), small cell carcinoma, and large cell neuroendocrine carcinoma. Well-differentiated tumors are more indolent, but metastases and tumor related deaths have been reported.

Carcinoid (Well-Differentiated Neuroendocrine Carcinoma) [38, 39, 40, 41]
Carcinoid tumors have been described in the bladder and are identical to those described in the lung and the gastrointestinal tract. By definition, these neuroendocrine tumors are well-differentiated with relatively round cells, minimal mitotic activity, and no necrosis. The differential diagnosis mainly includes urothelial carcinoma and paraganglioma. The presence of an insular or trabecular pattern and stippled nuclear chromatin are useful for recognizing a carcinoid tumor, but the demonstration of both cytokeratin and neuroendocrine marker (synaptophysin or chromogranin) reactivity may be needed.

Small Cell Carcinoma [42, 43]
Small cell carcinoma of the urinary bladder is histologically identical to the pulmonary type. They may be homogeneous or admixed with a typical urothelial carcinoma (approximately 50%), squamous cell carcinoma (rare), or adenocarcinoma (rare). The differential diagnosis includes lymphoma or another subtype of poorly differentiated carcinoma. Immunoreactivity for cytokeratins and chromogranin or synaptophysin is confirmatory. The distinction from a metastatic small cell carcinoma (when the tumor does not show evidence of an underlying urothelial carcinoma) is based on clinical/radiographic correlation. TTF-1 may be expressed in small cell carcinomas of any anatomic site, and does not indicate a lung origin. [45] It is important to recognize a component of small cell carcinoma when present because a different chemotherapeutic approach is usually employed. As in the lung, these carcinomas are clinically aggressive.

Large Cell Neuroendocrine Carcinoma [44]
Large cell neuroendocrine carcinomas have also been reported in the urinary bladder and, again, are identical to those occurring in the lung. They differ from small cell carcinoma because of more prominent eosinophilic cytoplasm and recognizable nucleoli. They may have a homogeneous morphology or be mixed with other more typical types of urothelial carcinoma. The reported cases have presented at high stage with poor response to therapy.

VI. Poorly Differentiated Carcinoma

Lymphoepithelioma-like Carcinoma [46, 47, 48, 49]
Several series have reported carcinomas with a morphologic pattern very similar to nasopharyngeal (lymphoepithelial) carcinomas. They are characterized by nests and sheets of poorly differentiated tumor cells with poorly defined cell borders (syncytial growth) that are intimately admixed with a chronic inflammatory infiltrate rich in mature lymphocytes. Other patterns may be intermixed including typical urothelial carcinoma, squamous cell carcinoma, or adenocarcinoma. The inflammatory infiltrate may mask the underlying carcinoma, but cytokeratin immunostains will resolve most cases.

No evidence of an association with Epstein-Barr virus has been demonstrated in these bladder tumors. There is evidence to suggest that pure lymphoepithelial-like carcinomas are more responsive to chemotherapy and have a better outcome, stage-for-stage, than other bladder carcinomas. [46, 47, 48] This relatively more favorable prognosis has not been found in tumors showing a mixture of both lymphoepithelial-like and typical urothelial carcinoma.

Giant Cell Carcinoma (Undifferentiated Carcinoma) [49]
Giant cell carcinoma of the urinary bladder is histologically identical to the so-called giant cell carcinoma of the lung. They are characterized by sheets of large anaplastic cells with bizarre shaped nuclei and prominent eosinophilic or ampholphilic cytoplasm. Multiple nuclei and/or macronucleoli are common. This pattern likely represents a form of poorly differentiated/undifferentiated urothelial carcinoma and many authors prefer the term "undifferentiated carcinoma". There is no known difference in prognosis or response to therapy from other forms of high-grade urothelial carcinoma, but no studies have addressed this issue to date.

The differential diagnosis includes other poorly differentiated malignant neoplasms including lymphoma and melanoma. Immunostains for epithelial, lymphoid, and melanocytic markers should help resolve most cases. Because of the name "giant cell", these tumors are also commonly confused with urothelial carcinomas containing admixed osteoclast type giant cells. Those tumors, discussed below, have giant cells with enumerable, relatively bland round nuclei identical to those seen in giant cell tumor of bone, and lack the anaplastic features of giant cell carcinoma.

VII. Urothelial Carcinoma with Unusual Stromal Changes

Urothelial Carcinoma with Pseudosarcomatous Stroma
This exuberant stromal response to carcinoma is discussed in the section on spindle cell lesions.

Urothelial Carcinoma with Osteoclast-like Giant Cells [50, 51, 106]
Some rare tumors of the urinary bladder have a prominent osteoclast-like giant cell component. Osteoclast type giant cells are large, round, multinucleated cells with enumerable small, round nuclei (may contain 50 nuclei or more) and prominent eosinophilic cytoplasm. Some tumors have typical invasive urothelial carcinoma admixed with the giant cells, while others are composed of giant cells and a proliferation of relatively uniform, cytologically bland round to spindle cells histologically similar to giant cell tumor of bone or true giant cell tumor of soft tissue. Recent studies have suggested that most, if not all, osteoclast-like giant cell rich tumors are undifferentiated carcinomas with a reactive histiocytic (giant cell) component. [106]

VIII. Primary Glandular Neoplasms of the Urinary Bladder
The spectrum of glandular neoplasia in the urinary bladder is analogous to that occurring in the gastrointestinal tract, ranging from villous adenoma to carcinoma in-situ to invasive adenocarcinoma.

Villous Adenoma [52, 53]
Villous adenomas, identical to those occurring in the colon, have been reported in the urinary bladder. They may occur in the urachus, or may arise from metaplastic urothelium, usually in the trigone. Histologically, they are characterized by exophytic villi with large fibrovascular cores lined by a columnar layer of pseudostratified, enteric-type epithelium. Associated carcinoma in-situ and/or invasive carcinoma have also been reported. Pure adenomas (with or without carcinoma in-situ) have an excellent prognosis if completely resected. Incompletely resected tumors, especially those with carcinoma in-situ, have a risk for progression to invasive adenocarcinoma. All villous adenomas should be completely sampled and all of the biopsy tissue should be examined histologically to ensure that an occult invasive component is not present.

Adenocarcinoma In-situ [54]
A series of in-situ adenocarcinomas of the bladder unaccompanied by villous adenoma or infiltrating adenocarcinoma was recently reported. Adenocarcinoma in-situ is defined as a noninvasive, glandular lesion lined by atypical columnar epithelium, often with apical cytoplasm. The distinction of in-situ and invasive carcinoma is based on criteria similar to that applied in the gastrointestinal tract; irregular or angulated glands extending into the lamina propria with an associated stromal reaction are classified as invasive. Urothelial carcinoma in-situ occasionally has round, intraepithelial spaces, sometimes with intraluminal mucin, but they are distinguished by an absence of lining columnar cells.

Adenocarcinoma in-situ is frequently associated with urothelial carcinoma in-situ and non-invasive papillary urothelial neoplasms. They also have a high incidence of association with invasive small cell carcinoma or invasive micropapillary carcinoma on concurrent or follow-up biopsy. [34]

Invasive Adenocarcinoma
Invasive adenocarcinoma involving the urinary bladder may be seen in different anatomic regions of the bladder and in different clinical settings. As in other organs, primary adenocarcinomas of the urinary bladder may have a variety of morphologic patterns including enteric, mucinous, signet-ring, clear cell, and hepatoid. For most patterns, the main differential diagnosis is secondary extension or metastasis from another primary site (exceptions are noted in the discussion below). If any portion of the tumor has a typical urothelial appearance or associated urothelial carcinoma in-situ, then, by definition, the tumor is classified as "urothelial carcinoma with glandular differentiation". Because of its rarity and its morphologic overlap with other adenocarcinomas, primary vesical adenocarcinoma is always a diagnosis of exclusion. We recommend adding a comment to the pathology report such as "this adenocarcinoma could be accepted as primary at this site if a metastasis or direct extension from an adjacent organ can be ruled out clinically." In this setting, it would be very easy to make a misdiagnosis because of inadequate clinical information. Most adenocarcinomas are deeply invasive at diagnosis, but stage for stage, they have a behavior similar to urothelial carcinoma.

Histologic Variation in Adenocarcinoma

Typical intestinal type (Enteric) [56, 57, 58, 59, 60, 61, 62, 63, 64]
Enteric type adenocarcinomas are characterized by irregular anatomosing or cribriform glands with a pseudostratified columnar lining. This pattern of carcinoma may be morphologically indistinguishable from a neoplasm with direct extension from the colon, rectum, appendix, or prostate. Although prostatic adenocarcinomas are generally more monomorphic with round nuclei and round, "punched-out" cribriform spaces, ductal-type prostatic adenocarcinomas may be histologically indistinguishable. Immunohistochemical stains for PSA and PSAP will aid in the distinction from prostatic adenocarcinoma, but, it should be noted, that some vesical adenocarcinomas may show cross-reactive staining with antibodies to PSAP. The PSAP staining is usually focal, in contrast to the diffuse pattern typical in prostatic carcinomas. [68]

In the distinction of primary vesical adenocarcinoma from colorectal adenocarcinoma clinical findings are paramount, but a few morphologic clues may help further distinguish between primary and secondary adenocarcinoma. The presence of extensive cystitis cystica glandularis with intestinal metaplasia is strong evidence for a primary adenocarcinoma. In addition, the presence of any component of urothelial carcinoma or urothelial carcinoma in-situ, usually warrants the diagnosis of urothelial carcinoma with glandular differentiation and would generally obviate the need for immunohistochemistry. Nonetheless, immunohistochemical studies often aid in classification and may be crucial.

The immunophenotypes of primary vesical enteric-type adenocarcinoma and colonic adenocarcinoma have a significant degree of overlap with traditional markers such as CK7, CK20, villin, and CDX-2. [107] It is true that, overall, the CK7-/CK20+ phenotype is more typical of colonic adenocarcinoma; however, in an individual case, this profile is not specific. In one reported series, colorectal adenocarcinomas expressed CK7 in approximately 8% of cases (each positive case co-expressing CK 20). [108] It has been suggested that, in this diagnostic setting, thrombomodulin expression as a marker of primary vesical adenocarcinoma adds to the specificity of the CK7/CK20 profile. [107] Some evidence also suggests that nuclear β-catenin expression is specific for adenocarcinoma of colonic origin. Wang et al. reported that none of the seventeen primary vesical adenocarcinomas examined showed nuclear reactivity with β-catenin, while 81% of the examined colonic adenocarcinomas had nuclear immunoreactivity. [107] Our limited personal experience with metastatic colorectal adenocarcinoma to the bladder suggests that β-catenin is expressed in approximately 70% of cases and not in primary bladder adenocarcinoma. [109]

Mullerianosis, described in detail in the mimics section, may mimic adenocarcinoma because of the presence of glands deep in muscle wall. In contrast to adenocarcinoma, the cells lining the glands in mullerianosis are cytologically bland and may have the appearance of endocervical or tubal type epithelium. Endometriosis may also be considered, but the surrounding endometrial type stroma makes that distinction straightforward in most cases.

Mucinous [55]
Mucinous, or colloid, carcinomas are histologically identical to those described in other anatomic sites (e.g. colon). They are characterized by small aggregates of tumor cells floating in pools of mucin. Colonic adenocarcinomas involving the bladder can easily mimic this pattern. In addition, rare prostatic adenocarcinomas may have a mucinous morphology, but those carcinomas typically have a monomorphic nuclear appearance, in contrast to the pleomorphism common in invasive urothelial carcinoma. [66, 67]I n addition, pure mucinous prostatic adenocarcinomas are extremely rare; foci with a more typical morphology are usually admixed with the mucinous component.

Signet-ring cell [76, 77, 78, 79]
Signet ring morphology is rarely present in primary adenocarcinomas of the bladder, and is indistinguishable from lobular carcinoma of the breast or a gastrointestinal signet-ring cell adenocarcinoma. As in other sites, they have two morphologies: cells with intraluminal mucin and an eccentric nucleus or a histiocyte-like cells with more central nuclei. These adenocarcinomas are typically discohesive with a single cell infiltrative pattern and usually present at high stage. Unless a component of more typical urothelial carcinoma is identified, this diagnosis requires clinical/radiographic exclusion of a primary tumor in another anatomic site. [65]

Clear cell [80, 81, 82, 83, 84]
Clear cell adenocarcinomas histologically similar to those occurring in the gynecologic tract may arise in the urinary bladder.Morphologically, these neoplasms have one or more of the three typical architectural patterns seen in clear cell carcinomas of the female genital tract, including tubulocystic, papillary and diffuse patterns.Tubules and papillae are generally lined by flat, cuboidal or, rarely, columnar cells, but lining hobnail cells are present at least focally in most tumors. Cells with clear cytoplasm are abundant in most tumors, although virtually all tumors also have an admixture of cells with abundant eosinophilic cytoplasm.Mitotic activity is present, but may be quite variable, and necrosis may be evident.Marked nuclear pleomorphism and hyperchromasia are usually readily apparent.

These tumors initially were thought to arise from mesonephric rests in the trigone area, but it is now believed that they may arise through a process of metaplasia of the surface urothelium or from müllerian rests. In a series of 13 cases, Oliva et al. concluded that 4 were likely of müllerian origin because of associated endometriosis or other müllerian-like rests, while the remaining 9 could have arisen from the urothelium. The latter cases had either admixed morphologic patterns of urothelial carcinoma(n=4) or focal pseudostratified areas histologically reminiscent of urothelium (n=5). [84] Their series included 11 females and 2 males.This strong female predominance is rare for urothelial tumors and suggests that müllerian origin may account for an even larger percent of these cases.Different immunohistochemical profiles were not demonstrated between these two groups of cases.Clear cell carcinomas are typically high-grade, high-stage tumors, and follow an aggressive course. Whether or not they have a different response to typical bladder carcinoma protocols is not known.

The differential diagnosis includes secondary involvement of the bladder by a carcinoma from the female genital tract and nephrogenic adenoma. The distinction from secondary involvement is based on clinical and radiographic correlation as they would be morphologically indistinguishable in most cases. The distinction is, of course, easier if the tumor is admixed with a component of typical urothelial carcinoma. Nephrogenic adenomas are typically superficial and do not show the degree of nuclear atypia (i.e., pleomorphism and hyperchromasia) or mitotic activity typical of clear cell carcinoma. Some authors have suggested the utility of strong immunoreactivity for p53 and a high Mib-1 proliferative index in clear cell adenocarcinomas, but not in nephrogenic adenomas. [110] Although most authors rely on the morphologic features discussed above, a recent study has suggested the utility of PAX-2 in the diagnosis of nephrogenic adenoma. [111]

Hepatoid [85, 86, 87, 88]
The rarest pattern of primary vesical adenocarcinoma is hepatoid morphology. This pattern is identical to tumors that mimic hepatocellualar carcinoma in other anatomic sites such as the stomach. This hepatoid morphology may be homogeneous or admixed with other patterns of urothelial carcinoma. Histologically, the neoplastic cells form sheet-like or anastomosing, trabecular architecture with abundant eosinophilic cytoplasm. Hyaline globules and bile production have been reported, and the tumors characteristically stain for alpha-fetoprotein. Because only case reports have appeared in the literature, the clinical significance of this rare tumor is not known. The differential diagnostic considerations should include secondary involvement by heptocellular carcinoma or yolk sac tumor, diagnoses that should be excluded by clinical/radiographic correlation.

Mixture of above types
The varying patterns of adenocarinoma are frequently intermixed.

Anatomic Variation in Adenocarcinoma

Bladder mucosa
Most cases arise from the lining epithelium, predominantly in the trigone or posterior wall. Adenocarcinoma in situ and/or intestinal metaplasia is commonly seen in the adjacent surface bladder epithelium.

Urachal [69, 70, 71, 72, 73, 74, 75]
Some carcinomas arise in the dome of the bladder from remnants of the urachus. Carcinomas of the urachus are generally adenocarcinomas with enteric, mucinous, or rarely signet ring morphologies. The distinction of urachal carcinoma from a primary vesical carcinoma depends on location in the dome of the bladder in relation to the median umbilical ligament without associated adenocarcinoma in-situ or intestinal metaplasia in the bladder lining. The overlying urothelium may be ulcerated or have prior biopsy site changes making assessment of the overlying urothelium difficult in biopsy specimens. Rarely, urachal remnants, characterized by variably sized cystic structures lined by urothelium or benign glandular epithelium, are identified in association with the tumor.

Other subtypes of carcinoma have been reported to arise in the urachus including squamous cell, urothelial, and anaplastic carcinomas. In addition, rare cases of urachal villous adenomas are reported.

The distinction from non-urachal carcinomas (either bladder primary or secondary involvement from another anatomic site) is important. Urachal carcinoma may be amenable to partial cystectomy with resection of the entire length of the median umbilical ligament, including the umbilicus. Primary vesical adenocarcinoma (non-urachal) is usually associated with a large intraluminal mass of the bladder, in-situ adenocarcinoma, or extensive intestinal metaplasia. In uncertain cases where these features are not identified, the treating clinician should make the distinction based clinical/radiographic data. We generally add a comment such as "this adenocarcinoma could be accepted as primary at this site, including the possibility of urachal origin, if a metastasis or direct extension from an adjacent organ has been ruled out clinically." Because urachal and primary vesical adenocarcinomas may be indistinguishable, errors in this setting may easily occur due to assumptions based on incorrect clinical information.

With extrophy
Patients with bladder extrophy seem to be at higher risk for the development of primary vesical adenocarcinoma.

From endometriosis [84]
Very rarely, endometrioid or clear cell adenocarcinomas arise in endometriosis. This diagnosis would require the identification of an associated endometrial stromal component or adjacent, typical endometriosis. These tumors, like endometriosis, may occur anywhere within the wall of the bladder, including perivesical adipose tissue.

IX. Primary Squamous Lesions of the Urinary Bladder

Squamous Metaplasia [89, 90]
Non-keratinizing squamous metaplasia is relatively common in the trigone of the bladder in women and is generally considered a variation of normal histology. Keratinizing squamous metaplasia, however, should be mentioned as a pathologic process, because it has been suggested that it represents a risk factor for the development of squamous cell carcinoma or other complications such as bladder contracture or obstruction. [90]

Squamous Papilloma [94]
Squamous papillomas of the bladder have been recently described and appear to be extremely rare. They occur predominantly in elderly women and are characterized by fibrovascular cores lined by normal appearing benign squamous epithelium. By definition, no viral cytopathic effect is present. In the only reported series, the lesions were also negative for HPV by in-situ hybridization studies. No relationship to carcinoma has been reported, but, there is only one reported series of these proliferations in the literature, so data is limited.

Condyloma accuminata [91, 92, 93]
Condyloma accuminata is morphologically identical to lesions occurring on the external gentitalia, anus, and perineum. They are characterized by a squamous epithelial lined papillary/polypoid growth with koilocytotic atypia (perinuclear halos, large hyperchromatic nuclei, frequent binucleation). Within the genitourinary tract, they typically involve the urethra, but have rarely been reported in the bladder or even in the ureters. As in other sites, these lesions may progress to carcinoma.

Squamous Dysplasia
Intraepithelial squamous dysplasia is rarely biopsied de novo because it does not produce clinical symptoms. It is, however, common to find dysplasia adjacent to invasive squamous cell carcinoma. Squamois dysplasia of the bladder is identical to that seen in other, more common, anatomic sites such as the squamous mucosa of the oropharynx.

Verrucous Carcinoma [93, 95]
Verrucous carcinoma has also been rarely reported in the urinary bladder, and is identical to tumors reported as verrucous carcinoma in the oral cavity. The diagnostic features include a well-differentiated, sqaumous proliferation with superficial hyperkeratosis forming "church spires" extending upward from the surface (so-called verrucoid appearance) and a broad-front, pushing deep border that extends into the lamina propria with an associated chronic inflammatory infiltrate. By definition, no significant nuclear atypia (pleomorphism and hyperchromasia) is present. Verrucous carcinomas have been described in association with schistosomiasis or condyloma acuminatum. These tumors are typically clinically indolent. It may be difficult to definitively diagnose verrucous carcinoma in a superficial or poorly oriented, tangential biopsy if the deep border with the lamina propria is not present. It these difficult settings, we use the terminology "atypical squamous proliferation with verrucous features" and explain the diagnostic problems in a comment.

Typical Squamous Cell Carcinoma, NOS [96, 97]
Squamous cell carcinomas are relatively rare (less than 5% of bladder carcinomas), except in regions of the Middle East where schistosomiasis is endemic and it represents the most common form of bladder carcinoma. As discussed in the section on alternative differentiation in urothelial carcinoma, the diagnosis of primary squamous cell carcinoma is reserved for tumors comprised entirely of keratinizing epithelium with keratin-pearl formation, dyskeratotic cells, and intercellular bridges. They may be associated with squamous dysplasia or keratinizing metaplasia in the adjacent flat epithelium.

Squamous cell carcinomas of the urinary bladder vary from well to poorly differentiated tumors and they are frequently high-stage at diagnosis. Histologic subtyping, with the exception of verrucous carcinoma, adds little prognostic information. The primary treatment modality is surgical, as the tumors respond poorly to chemotherapy and radiation.

Selected References for Variants of Urothelial Carcinoma

Conventional urothelial carcinoma with alternative differentiation
  1. Sakamoto N, Tsuneyoshi M, Enjoji M. Urinary bladder carcinoma with a neoplastic squamous component: a mapping study of 31 cases. Histopathol 21:135-141.

  2. Bessette PL, Abell MR, Herwig KR. A clinicopathologic study of squamous cell carcinoma of the bladder. J Urol 1974;112:66-67.

  3. Lopez-Beltran A, Martin J, Garcia J, Toro M. Squamous and glandular differentiation in urothelial bladder carcinomas. Histol Histopathol 1988;3:63-68.

  4. Reuter VE. Bladder. Risk and prognostic factors- a pathologist's perspective. Urol Clin North Am 1999; 26:481-492.

  5. Budia Alba A, Quiepo Zaragoza JA, Perez Ebri ML, et al. [Comparative study of pure epidermoid carcinoma of the bladder and transitional cell carcinoma with squamous or mixed differentiated foci.] Actas Urol Esp 1999;23:111-118.

  6. Martin JE, Jenkins BJ, Zuk RJ, et al. Clinical importance of squamous metaplasia in invasive transitional cell carcinoma of the bladder. J Clin Pathol 1989;42:250- 253.

  7. Grace DA, Winter CC. Mixed differentiation of primary carcinoma of the urinary bladder. Cancer 1968;21:1239-1243.

  8. Logothetis CJ, Dexeus FH, Chong C, Sella A, Ayala AG, Ro JY, Pilat S. Cisplatin, cyclophasmamide, and doxorubicin chemotherapy for unresectable urothelial tumors: the MD Anderson experience. J Urol 1989;141:33-37.

  9. Donhuijsen K, Schmidt U, Richter HJ, Leder LD. Mucoid cytoplasmic inclusions in urothelial carcinomas. Hum Pathol 1992;23:860-864.

  10. Hanna N, Ulbright TM, Einhorn LH. Primary choriocarcinoma of the bladder with the detection of isochromosome 12p. J of Urol 2002;167:1781.

  11. Sievert K, Weber EA, Herwig R, Schmid H, Roos S, Eickenberg H. Pure primary choriocarcinoma of the urinary bladder with long-term survival. Urol 2000; 56:865vii-856ix.

  12. Dirnhofer S, Koessler P, Ensinger C, et al. Production of trophoblastic hormones by transitional cell carcinoma of the bladder: association to tumor stage and grade. Hum Pathol 1998; 29:377-382.

  13. Iles RK, Chard T. Human chorionic gonadotropin expression by bladder cancers: biology and clinical potential. J Urol 1991;145:453-458.

  14. Campo E, Algaba F, Palacin A, et al. Placental proteins in high-grade urothelial neoplasms. An immunohistochemical study of human chorionic gonadotropin, human placental lactogen, and pregnancy-specific beta-1-glycoprotein. Cancer 1989;63;2497-2504.

  15. Jacobsen A-B, Nesland JM, Fosa SD, et al. Human chorionic gonadotropin, neuron specific enolase and deoxyribonucleic acid flow cytometry in patients with high grade bladder carcinoma. J Urol 1990;143:706-707.

  16. Rodriguez E, Mathew S, Reuter V, et al. Cytogentic analysis of 124 prospectively ascertained male germ cell tumors. Cancer Res 1992;52:2285.
  1. Iles RK, Jenkins BJ, Oliver RTD, et al. Beta human HCG in serum and urine. A marker for metastatic urothelial cancer. Br J Urol 1989;64:241-244.

  2. Yamase HT, Wurzel RS, Nieh PT, et al. Immunohistochemical demonstration of human chorionic gonadotropin in tumors of the urinary bladder. Ann Clin Lab Sci 1985;15:414-417.

  3. Oliver RTD, Stephenson C, Collino CE, et al. Clinicopathological significance of immunoreactive beta-HCG production by bladder cancer. Mol Biother 1988;1:43-45.

Urothelial carcinoma with unusual cytologic features
  1. Zuckerberg LR, Harris NL, Young RH. Carcinomas of the urinary bladders simulating malignant lymphoma. Am J Surg Pathol 1991; 15:569-576.

  2. Harris M, Eyden BP, Joglekar VM. Rhabdoid tumor of the bladder: a histological, ultrastructural, and immunohistochemical study. Histopathol 1987;11:1083-1092.

  3. Mostofi FK, Davis CJ, Sesterhenn IA. WHO International Histological Classification of Tumours. Histological Typing of Baldder Tumors. 2nd ed. 1999; Springer- Verlag: Berlin.

  4. Kotliar SN, Wood CA, Schaeffer AJ, Oyasu R. Transitional cell carcinoma exhibiting clear cell features: a differential diagnosis for clear cell adenocarcinoma of the urinary tract. Arch Pathol Lab Med 1995; 119:79-81.

  5. Sahin AS, Myhre, M., Ro JY, et al. Plasmacytoid transitional cell carcinoma. Report of a case with initial presentation mimicking multiple myeloma. Acta Cytologica 1991; 35:277-280.
  1. Hoot AC, Russo P, Judkins AR, Perlman EJ, Biegel JA. Immunohistochemical analysis of hSNF5/INI1 distinguishes renal and extra-renal malignant rhabdoid tumors from other pediatric soft tissue tumors. Am J Surg Pathol 2004; 28:1148-91.

  2. 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;120:64-70.

  3. Baldwin L, Lee AH, Al-Talib RK, Theaker JM: Transitional cell carcinoma of the bladder mimicking lobular carcinoma of the breast: a discohesive variant of urothelial carcinoma. Histopathol 2005;46:50-56.

Deceptively bland urothelial carcinoma
  1. Young RH, Zukerberg LR. Microcystic transitional cell carcinomas of the urinary bladder: a report of four cases. Am J Clin Pathol 1991; 96:635-639.

  2. Paz a, Rath-Wolfson L, Lask D, et al. The clinical and histologic features of transitional cell carcinoma of the bladder with microcysts: analysis of 12 cases. Br J Urol 1997;79:722-725.

  3. Talbert WM, Young RH. Carcinomas of the urinary bladder with deceptively benign appearing foci - a report of three cases. Am J Surg Pathol 1989; 13:374.

  4. Murphy WM, Deana DG. The nested variant of transitional cell carcinoma: a neoplasm resembling proliferation of von Brunn's nests. Mod Pathol 1992; 5:240-243.

  5. Holmang S, Johansson SL. The nested variant of transitional cell carcinoma- a rare neoplasm with poor prognosis. Scand J Urol Nephrol 2001;35:102-105.

  6. Cardillo M, Reuter VE, Lin O. Cytologic features of the nested variant of urothelial carcinoma: a study of seven cases. Cancer 2003;99:23-27.

  7. Drew PA, Furman J, Civantos F, et al. The nested variant of transitional cell carcinoma: an aggressive neoplasm with innocuous histology. Mod Pathol 1996;9:989-994.

  8. Lin O, Cardillo M, Dalbagni G, Linkov I, Hutchinson, Reuter VE. Nested variant of urothelial carcinoma: a clinicopathologic and immunohistochemical study of 12 cases. Mod Pathol 2003;16:1289-1298.

  9. 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.

  10. Young RH, Eble JN. Unusual forms of carcinoma of the urinary bladder. Hum Pathol 1991; 22:948-965.

  11. Young RH, Oliva E. Transitional carcinomas of the urinary bladder that may be underdiagnosed: a report of four cases exemplifying the homology between neoplastic and non-neoplastic transitional cell lesions. Am J Surg Pathol 1996; 20:1148-1454.

  12. Ro JY, Lapham R, Amin MB. Deceptively bland transitional cell carcinoma of the urinary bladder- further characterization of subtle and diagnostically treacherous patterns of invasion in urothelial neoplasia. Adv Anat Pathol 1997;4:244-251.

  13. Oliva E, Young RH. Nephrogenic adenoma of the urinary tract. A review of microscopic appearances of 80 cases with emphasis on unusual features. Mod Pathol 1995; 8:722-730.

Micropapillary carcinoma
  1. Amin MB , Ro JY, El-Sharkawy T, Lee KM, Troncoso P, Silva EG, Ordonez NG, Ayala AG. Micropapillary variant of transitional cell carcinoma of the urinary bladder. A histologic pattern resembling ovarian papillary serous carcinoma. Am J Surg Pathol 1994; 18:1224-1232.

  2. Lopez JI, Elorriaga K, Imaz I, Bilbao FJ. Micropapillary transitional cell carcinoma of the urinary bladder. Histopathology 1999; 34:561-562 (letter).

  3. Johansson SL, Borghede G, Holmang S. Micropapillary bladder carcinoma: a clinicopathological study of 20 cases. J of Urol 1999; 161:1798-1802.
  1. Alvarado-Cabrero I, Sierra-Santisteban FI, Mantilla-Morales A, Hernadez- Hernandez DM. Micropapillary carcinoma of teh urothelial tract: a clinicopathologic study of 38 cases. Annals of Diag Pathol 2005;9:1-5.

  2. Kamat, AM, Gee JR, Dinney CPN, et al. The case for early cystectomy in the treatment of nonmuscle invasive micropapillary bladder carcinoma. J Urol 2006; 175:881-5.

Neuroendocrine tumors
  1. Martingnoni G, Eble JN. Carcinoid tumors of the urinary bladder: Immunohistochemical atudy of 2 cases and review of the literature. Arch Pathol Lab Med 2003;127:e22-24.

  2. Sugihara A, Kajio K, Yoshimotot T, et al. Primary carcinoid tumor of the urinary bladder. Int Urol Nephrol 2002;13:238-242.

  3. Walker BF, Someren A, Kennedy JC, Nicholas EM. Primary carcinoid tumor of the urinary bladder. Arch Pathol Lab Med 1992;116:1217-1220.

  4. Burgess NA, Lewis DC, Matthews PN. Primary carcinoid of the bladder. Br J Urol 1992;69:213-214.

  5. Mills SE, Wolfe JT, Weiss MA, et al. Small cell undifferentiated carcinoma of urinary bladders: a light microscopic, immunohistochemical and ultrastructural study of 12 cases. Am J Surg Pathol 1987; 11:606-617.

  6. Weiss MA. Small cell carcinomas of the urinary tract. Arch Pathol Lab Med 1993; 117:237-238.

  7. Hailemariam S, Gaspert A, Komminoth P, Tamboli P, Amin M. Primary, pure, large-cell neuroendocrine carcinoma of the urinary bladder. Modern Pathol 1998; 11:1016-1020.

  8. Agoff SN, Lamps LW, Philip AT, Amin MB, Schmidt RA, True LD, Folpe AL. Thyroid transcription factor-1 is expressed in extrapulmonary small cell carcinomas but not in other extrapulmonary neuroendocrine tumors. Mod Pathol 2000;13;238-242.

Poorly differentiated carcinoma
  1. Amin MB, Ro JY, Lee KM, Ordonez NG, Dinney CP, Gulley ML, Ayala AG. Lymphoepithelioma-like carcinoma of urinary bladder. Am J Surg Pathol 1994; 18:466-473.

  2. Young RH, Eble JN. Lymphoepithelioma-like carcinoma of urinary bladder. J Urol Pathol 1993; 1:63-67.

  3. Holmang S, Borghede G, Johansson SL. Bladder carcinoma with lympho- epithelioma-like differentiation: a report of 9 cases. J of Urol 1998; 159:779- 782.

  4. Young RH, Eble JN. Unusual forms of carcinoma of the urinary bladder. Hum Pathol 1991;22:948-965.

Urothelial Carcinoma with Unusual Stromal Reaction
  1. Amir G, Rosenmann E. Osteoclast-like giant cell tumour of the urinary bladder. Histopathol 1990;17:413-418.

  2. Zuckerberg LR, Armin AR, Pisharodi L, et al. Transitional cell carcinoma of the urinary bladder with osteoclast-like giant cells: a report of two cases and review of the literature. Histopathol 1990;17:407-411.
  1. Baydar D, Amin MB, Epstein JI. Osteoclast-rich undifferentiated carcinomas of the urinary tract. Mod Pathol advance online publication, 25 November 2005.

Adenocarcinoma
  1. Liang C, Montironi R, Bostwick DG. Villous adenoma of the urinary tract: A report of 23 cases, including 8 with coexistent adenocarcinoma. Am J Surg Pathol 1999; 23: 764-771.

  2. Seibel J, Prasad S, Weiss RE, et al. Villous adenoma of the urinary tract: a lesion frequently associated with malignancy. Hum Pathol 2002;33:236-241.

  3. Chan TY, Epstein JI. In situ adenocarcinoma of the bladder. Am J Surg Pathol 2001; 25: 892-899.

  4. Mostofi FK, Thomson RV, Dean AL. Mucous adenocarcinoma of the urinary bladder. Cancer 1955; 8:741-758.

  5. Nocks BN, Heney NM, Daly JJ. Primary adenocarcinoma of urinary bladder. Urol 1983; 21:26-29.

  6. Anderstrom C, Johansson SL, von Schultz L. Primary adenocarcinoma of the urinary bladder: A clinicopathologic and prognostic study. Cancer 1983; 52:1273-1282.

  7. Grignon DJ, Ro JY, Ayala AG, et al. Primary adenocarcinoma of the urinary bladder: A clinicopathologic analysis of 72 cases. Cancer 1991;67:2165-2172.

  8. Jones WA, Gibbons RP, Correa RJ, et al. Primary adenocarcinoma of the bladder. Urol 1980; 15:119-122.

  9. Malek RS, Rosen JS, O'Dea MJ. Adenocarcinoma of the bladder. Urol 1983; 20:357-359.

  10. Shaaban AA, Elbaz MA, Tribukait. Primary nonurachal adenocarcinoma in the bilharzial urinary bladder: Deoxyribonucleic acid flow cytometric and morphologic characterization in 93 cases. Urol 1998; 51: 469-476.

  11. El-Mekresh MM, El-Baz MA, Abol-Enein H, et al. Primary adenocarcinoma of the urinary bladder: A report of 185 cases. Br J Urol 1998; 82: 206-212.

  12. Dean AL, Mostofi FK, Thompson RV. A restudy of the first fourteen hundred tumors in the bladder tumor registry. J Urol 1954; 71:571-590.

  13. Melicow MM. Tumors of the urinary bladder. A clinicopathological analysis of over 2,500 specimens and autopsies. J Urol 1955; 74:498-521.

  14. Pontes JE, Oldford JR. Metastatic breast carcinoma to the bladder. J Urol 1970; 104:839-842.

  15. Epstein JI, Lieberman PH: Mucinous adenocarcinoma of the prostate gland. Am J Surg Pathol 1985; 9:299-308.

  16. Ro JY, Grignon DJ, Ayala AG, et.al.: Mucinous adenocarcinoma of the prostate: Histochemical and immunohistochemical studies. Hum Pathol 1990; 21:593-600.

  17. Epstein JI, Kuhajda FP, Lieberman PH: Prostate-specific acid phosphatase immunoreactivity in adenocarcinomas of the urinary bladder. Hum Pathol 1986; 17:939-942. Urachal Carcinoma
  1. 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 2001;25:1380-7.

  2. Chu PG, Weiss LM: Keratin expression in human tissues and neoplasms. Histopathol 40:403-439, 2002

  3. Choi WWL, Amin MB, Tamboli P, Eble JN, Young RH: Glandular neoplasms of the urachus: clinicopathologic and immunohistochemical analysis of 43 cases with special emphasis on low-grade mucinous cystic tumors. Mod Pathol 18:134A, 2005

Urachal Carcinoma
  1. Schubert GE, Paukovic MB, Bethke-Bedurftig BA. Tubular urachal remnants in adult bladders. J Urol 1982; 127:40-42.

  2. Johnson DE, Hodge GB, Abdul-Karim FW, et al. Urachal carcinoma. Urol 1985; 26:218-221.

  3. Jakse G, Schneider HM, Jacobi GH. Urachal signet-ring cell carcinoma, a rare variant of vesical adenocarcinoma: incidence and pathological criteria. J Urol 1978; 120:764-766.

  4. Alonso-Gorrea M, Mompo-Sanchis JA, Jorda-Cuevas M, et al. Signet ring cell adenocarcinoma of the urachus. Eur Urol 1985; 11:282-284.

  5. Ghazizadeh M, Yamamoto S, Kurokwak. Clinical features of urachal carcinoma in Japan : review of 157 patients. Urol Res 1983; 11:235-238.

  6. Eble JN, Hull MT, Rowland RG, et al. Villous adenoma of the urachus with mucosuria: a light and electron microscopic study. J Urol 1986; 135:1240-1244.

  7. Hayman J. Carcinoma of the urachus. Pathol 1984; 16:167-171.

Signet Ring Cell Carcinoma
  1. Poore TE, Egbert B, Jahnke R, et al. Signet ring cell adenocarcinoma of the bladder: linitis plastica variant. Arch Pathol Lab Med 1981; 105:203-204.

  2. Choi H, Lamb S, Pintar K, et al. Primary signet-ring cell carcinoma of the urinary bladder. Cancer 1984; 53:1985-1990.

  3. Bernstein SA, Reuter VE, Carroll PR, et al. Primary signet ring cell carcinoma of the urinary bladder. Urol 1988;31:432-6.

  4. Grignon DJ, Ro JY, Ayala AG, et al. Primary signet ring cell carcinoma of the urinary bladder. Am J Clin Pathol 1991;95:13-20.

Clear Cell Carcinoma
  1. Skor AB, Warren MM. Mesonephric adenocarcinoma of the bladder. Urol 1977; 10:64-65.

  2. Schultz RE, Block MJ, Tomaszewski JE, et al. Mesonephric adenocarcinoma of the bladder. J Urol 1984; 132:263-265.

  3. Young RH, Scully RE. Nephrogenic adenoma. A report of 15 cases, review of the literature, and comparison with clear cell carcinoma of the urinary tract. Am J Surg Pathol 1986;10:268-75.

  4. Young RH, Scully RE. Clear cell adenocarcinoma of the bladder and urethra: a report of three cases and review of the literature. Am J Surg Pathol 1985; 9:816-826.

  5. Oliva E, Amin MB, Jimenez R, et al. Clear cell carcinoma of the urinary bladder. A report and comparison of four tumors of Müllerian origin and nine of probable urothelial origin with discussion of histogenesis and diagnostic problems. Am J Surg Pathol 2002; 26: 190-197.
  1. 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.

  2. Tong G, Melamed J, Mansukhani et al. PAX2: a reliable marker for nephrogenic adenoma. Mod Pathol advance online publication 6 January 2006.

Hepatoid Carcinoma
  1. Lopez-Beltran A, Luque RJ, Quintero A, Requena MJ, Montironi R. Hepatoid adenocarcinoma of the urinary bladder. Virchows Arch 2003;442:381-7.

  2. Burgues O, Ferrer J, Navarro S, Ramos D, Botella E, Liombart-Bosch A. Hepatoid adenocarcinoma of the urinary bladder. An unusuyal neoplasm. Virchows Arch 1999;435:71-75.

  3. Sinard J, Macleary L, Melamed J. Hepatoid adenocarcinoma in the urinary bladder. Unusual localization of a newly recognized tumor type. Cancer 1994;1:73:1919-1925.

  4. Lertprasertsuke N, Tsutsumi Y. Alpha-fetoprotein producing urachal adenocarcinoma. Acta Pathol Jpn 1991;41:318-326.

Squamous Neoplasms
  1. Tannenbaun M. Inflammatory proliferative lesion of the urinary bladder: squamous metaplasia. Urology 1976;7:428-9.

  2. Khan MS, Thornhill JA, Gaffney E, et al. Keratinizing squamous metaplasia of the bladder: natural history and rationalization of management based on review of 54 years' experience. Eur Urol 2002;42:469-74.

  3. Keating MA, Young RH, Carr CP, et al. Condyloma acuminatum of the bladder andureter: case report and review of the literature. J Urol 1985;133:465-467.

  4. Walther M, O'Brien D, Birch HW. Condyloma acuminate and verrucous carcinoma of the bladder: case report and literature review. J Urol 1986;135:362-365.

  5. Botella E, Burgues O, Navarro S et al. Warty carcinoma arising in condyloma acuminatum of urinary bladder. A case report. Int J Surg Pathol 2000;8:253-259.

  6. Cheng L, Leibovich BC, Cheville JC, et al. Squamous cell papilloma of the urinary bladder is unrelated to condyloma acuminate. Cancer 2000;88:1679-1686.

  7. Holck S, Jorgensen L. Verrucous carcinoma of the urinary bladder. Urology 1983;21:435-437.

  8. Faysal MH. Squamous cell carcinoma of the bladder. J Urol 1981;126:598-599.

  9. Newman DM, Brown JR, Jay AC, et al. Squamous cell carcinoma of the bladder. J Urol 1968;112:66-67.