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Update on Urinary Bladder Pathology:

Recently described and unusual tumors of the urinary bladder

Hemamali Samaratunga MD

Aquesta Pathology

Brisbane, Queensland, Australia

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Greater than 90% of bladder carcinomas are urothelial carcinomas. These have a great

propensity to divergent differentiation. This occurs typically in high-grade disease

resulting in a number of subtypes. These subtypes are morphologically unique and

have significant diagnostic, prognostic and therapeutic differences. Squamous and

glandular subtypes are the most common. These with a number of other well

characterized morphological subtypes are described in the 2004 WHO classification. 1

Some other subtypes have been described or more fully characterized only in the

relatively recent past. Some of these have been listed in the 2004 WHO classification

while others have not been included. In this article, recently described and selected

unusual variants of urothelial carcinoma with significant new information are

discussed. The following topics will be reviewed: Large nested and nested variants of

urothelial carcinoma, Large cell undifferentiated carcinoma not otherwise specified,

Lymphoepithelioma-like carcinoma , Osteoclast rich undifferentiated carcinoma,

Pleomorphic giant cell carcinoma, urothelial carcinoma with syncitiotrophoblastic

giant cells , Lipid cell variant of urothelial carcinoma, Micropapillary Urothelial

Carcinoma, Urothelial carcinoma with abundant myxoid stroma and plasmacytoid

variant of urothelial carcinoma.

LARGE NESTED VARIANT OF UROTHELIAL CARCINOMA

Epidemiology and Clinical features

An invasive urothelial carcinoma (UC) displaying deceptively bland cytological

features and a large nested architecture, often mimicking low-grade urothelial

carcinoma with an inverted growth pattern was first reported by Cox and Epstein in

2011. 2 Twenty three cases in this series are the only reported of this entity to date.

As with typical UC, these occurred more commonly in males and in an older age

group with an age range of 39-89 years.

Pathological features

Histologically, the invasive component has medium to large-sized nests with rounded

or irregular borders or both. These are typically spaced apart with abundant fibrous or

muscular stroma in between. Rarely the invasive component shows a verruciform

pushing growth front reminiscent of verrucous squamous cell carcinoma and these

typically extend into the muscularis propria. Rarely cysts, necrosis, tubules and gland

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formation are present. A fibro inflammatory stromal reaction may or may not be

present. A surface component of papillary UC is commonly present and this is often

low-grade although rare cases can have associated high grade papillary UC. Invasion

into muscularis propria is commonly present with occasional cases displaying

invasion into perivesical tissues. Conventional invasive UC can also be seen in some

cases although usually this is only a small component. Tumor cells are typically bland

with uniform vesicular nuclei, only occasional hyperchromatic or enlarged nuclei and

often only small or indistinct nucleoli. Mitotic figures are rare with 1.5 per 10 high

power fields reported. Lymphovascular invasion has also been found rarely.

Differential diagnosis

Distinction of these tumors from low-grade papillary urothelial carcinoma with an

inverted growth pattern is clearly difficult given the large nested architecture, bland

cytology, absence of a stromal reaction in some cases and the presence of an

accompanying low-grade exophytic papillary UC in most cases. Presence of large

nests within the muscularis propria and an invasive appearance despite the large

nested pattern are not features of papillary UC with an inverted growth pattern. In

contrast to papillary UC with an inverted growth pattern which has rounded nests

which are fairly uniform and evenly spaced, in large nested carcinoma the nests

within the lamina propria and muscularis propria are variably sized and shaped, some

with irregular borders and unevenly distributed, often separated by broad areas of

fibrous tissue or smooth muscle with little or no back-to-back nests present.

Inverted papilloma which is characterized by fairly uniform trabeculae and cords

extending into the lamina propria and von Brunn nests can be distinguished from the

large nested variant of UC due to the variably sized and shaped haphazardly

infiltrating nests. Rarely, however these may pose a differential diagnostic problem.

In contrast to these lesions, large nested carcinoma has mild cytologic atypia with

mild pleomorphism and scattered hyperchromatic nuclei.

Large nested carcinoma shares with the nested variant of UC, bland cytological

features. However, the typical nested variant is composed of confluent small nests of

varying shapes often lacking intervening stroma.

Prognosis and treatment

The large nested variant of UC appears to be an aggressive variant. Three of 17

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patients with follow-up have developed metastatic disease with 2 patients dying of

disease.

NESTED VARIANT OF UROTHELIAL CARCINOMA

Epidemiology and Clinical features

Nested urothelial carcinoma is an aggressive variant of urothelial carcinoma

resembling von Brunn nests due to its small nested architecture and deceptively bland

cytologic features. This is a rare tumor reported mostly as individual cases or small

series. 3-7

The largest series of this entity, of 30 cases was reported in 2010 8. Patients

are aged between 41-83 years and there is a marked male predominance. Patients

usually present with hematuria or urinary obstructive symptoms.

Pathological features

Most cases occur in the bladder, but cases have been also reported in the renal pelvis

and ureter. In the recently reported series, 8 pure nested carcinoma was seen in 37%

and associated with <50% of conventional urothelial carcinoma in 63%. Most of the

conventional urothelial carcinoma in these cases was high grade and rarely low-grade

papillary. Urothelial carcinoma in situ was seen in some cases. Histologically, there

are small nests resembling von Brunn nests displaying bland cytologic features. Some

of these display variable size and disorderly proliferation with some confluence and

focal cordlike areas. There can be focally prominent tubular growth pattern and areas

resembling cystitis cystica. The deeper portion is invariability ragged and infiltrative.

There are foci of high-grade cytologic atypia with enlarged nuclei and coarse

chromatin, most prominent in the deep part of the tumor. A stromal reaction can be

minimal but can be desmoplastic or myxoid and rarely there can be focal tissue

retraction. Lymphovascular invasion is common.

Immunostaining is identical to that seen in conventional urothelial carcinoma with

CK7, CK20, p63 and 34E12 positivity.

Differential diagnosis

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This entity can cause significant diagnostic problems with benign entities such as von

Brunn nests, cystitis cystica and glandularis, nephrogenic metaplasia, carcinoid and

paraganglioma. This is a particular problem in small biopsy specimens. It can also be

under recognized as conventional urothelial carcinoma. This lesion is distinguished

from benign urothelial lesions by its disorderly growth pattern, irregular jagged

infiltrating deep portion of the tumor, foci of prominent cytologic atypia most

marked in the deep infiltrating portion and in most cases and muscularis propria

invasion which is not seen in benign urothelial perforations.

Nephrogenic metaplasia in contrast to this tumor, typically has a mixed pattern

including, tubular, papillary, vascular-like dilated structures and only rarely has deep

muscle invasion

In contrast to this tumor, inverted papilloma has invaginated cords of cells and lacks a

nested architecture and carcinoid has a monotonous pseudoglandular pattern with

regular uniform nuclei containing stippled chromatin

This tumor can mimic paraganglioma, however, the prominent vascular network of

paraganglioma surrounding nests of cells is usually not present in nested carcinoma

Prognosis and treatment

Most cases (85%) present at an advanced stage( pT2) and have a progressive clinical

course with 70% dying of metastatic cancer 4-40 months after diagnosis despite

therapy. In the recently reported large series, 8 invasion of muscularis propria at

TURBT, pT3 disease at cystectomy and metastatic disease at presentation were found

in 70%, 83% and 67% compared with , 31%, 33 % and 19% with conventional

urothelial carcinoma. There were no significant differences in clinical stage,

pathologic stage or later development of metastases between the pure nested group

and those with partially nested morphology associated with conventional urothelial

carcinoma. For muscle invasive, nonmetastatic disease, radical cystectomy is the

treatment of choice. The use of neoadjuvant or adjuvant chemotherapy might offer a

survival advantage in some patients. 8

LARGE CELL UNDIFFERENTIATED CARCINOMA OF THE URINARY

BLADDER

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Epidemiology and Clinical features

Large cell undifferentiated carcinoma not otherwise specified (LCUC) is

characterized by sheets of large polygonal or round cells with moderate to abundant

cytoplasm and distinct cell borders. This has been previously included with other

tumors such as pleomorphic giant cell carcinoma, osteoclast-rich undifferentiated

carcinoma and lymphoepithelioma like carcinoma as undifferentiated carcinoma. 9, 10

The 2004 WHO classification has a brief section on undifferentiated carcinoma

without describing features of this entity 1. LCUC has been suggested to occur in the

recent literature, 11, 12

however, the only series of these cases to date was published

only in 2010 by Lopez Beltran et al. 13

This is a rare tumor of unknown incidence considering that it is likely to be reported

as high-grade urothelial carcinoma by some pathologists. It occurs mostly in men and

the reported age range was 61-87 years. Presenting features are usually hematuria

sometimes with dysuria and frequency. 13

Pathological features

Histologically there are solid expansile sheets or infiltrating tumor composed of large

polygonal or round cells with moderate to abundant eosinophilic cytoplasm, distinct

cell borders and vesicular nuclei with prominent sometimes multiple nucleoli. A high

mitotic count is typically seen. In the reported cases, a conventional urothelial

carcinoma component was seen in a few cases, although this was small. These tumors

are positive for cytokeratin AE1/AE3, and CK 7, sometimes for CAM 5.2, CK 20,

thrombomodulin and uroplakin 111 and have a high proliferation index on Ki 67

immunohistochemistry. These are negative for neuroendocrine markers, beta-HCG,

alpha-fetoprotein and PSA.

Differential diagnosis

An important differential diagnostic consideration in these cases is metastatic

malignancy. The possibility of metastatic disease has to be ruled out clinically and

radiologically before the diagnosis of LCUC. Immunostaining with positivity for

cytokeratin, thrombomodulin and Uroplakin 111 can be of value. Presence of a

typical urothelial carcinoma component is very useful in the diagnosis. Pattern 5

Prostatic adenocarcinoma typically has smaller, more monotonous cells which can be

at least focally PSA positive. Anaplastic large cell lymphoma is also composed of

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sheets of polygonal cells with a moderate amount of cytoplasm. However these tumor

cells are not cohesive, are negative for cytokeratin and positive for lymphoid markers

LCUC needs also to be differentiated from large cell neuroendocrine carcinoma.

Large cell neuroendocrine carcinoma also has large cells with abundant eosinophilic

cytoplasm, however appears different with coarsely granular chromatin, only

occasional prominent nucleoli and a nesting pattern typical of neuroendocrine

differentiation. These tumors are also uniformly reactive for synaptophysin or

chromogranin. Lymphoepithelioma- like carcinoma is another undifferentiated

carcinoma which in contrast to LCUC has a heavy inflammatory infiltrate almost

obscuring the neoplastic cells. Plasmacytoid urothelial carcinoma typically has

dyscohesive cells with small hyperchromatic eccentric nuclei with plasmacytoid

features. Osteoclast-Rich undifferentiated carcinoma in contrast to LCUC has a

biphasic appearance with numerous osteoclast-type giant cells. In contrast to the

monotonous cells in LCUC, pleomorphic giant cell carcinoma has numerous highly

pleomorphic tumor giant cells. Given the presence of focal vacuoles in LCUC, rarely

signet ring cell adenocarcinoma and lipid cell variant of urothelial carcinoma may be

considered in the differential diagnosis. However, in these cases vacuoles containing

mucin or suggesting lipoblasts are numerous.

Prognosis and treatment

Given that there could be associated focal conventional urothelial carcinoma, LCUC

may represent a poorly differentiated urothelial carcinoma. This tumour appears to

have a dismal prognosis although reported number of cases is small. In the reported

series 7 all patients had advanced disease at presentation (≥pT3 ) and 87% had lymph

node metastases. With follow up ranging from 6-26 months 75% of patients died of

disease and 25% were alive with metastases. When compared with conventional

urothelial carcinoma of similar stage, the survival was significantly worse in LCUC.

LYMPHOEPITHELIOMA-LIKE CARCINOMA

Epidemiology and Clinical Features

Lymphoepithelioma-like carcinoma is a rare entity characterised by syncytial masses

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of undifferentiated carcinoma admixed with a prominent often obscuring

inflammatory infiltrate resembling nasopharyngeal undifferentiated carcinoma or

lymphoepithelioma . 14-16

These tumours occur predominantly in the bladder with rare

cases reported in the renal pelvis and the urethra. Males are much more commonly

affected with the reported age range 44-90 years (mean age: 70 years).

Pathological Features

Lymphoepithelioma-like carcinoma can be pure, predominant or focal. Most cases are

pure, while others are seen in association with other patterns of carcinoma, including

invasive urothelial carcinoma, invasive adenocarcinoma and squamous cell

carcinoma. Up to 50% of cases are associated with urothelial carcinoma in situ.

Rarely, there can be surface high grade papillary urothelial carcinoma.

Microscopically, there are nests, sheets cords and individual cells of undifferentiated

carcinoma cells with large pleomorphic nuclei and prominent nucleoli. The

cytoplasmic margins are poorly defined imparting a syncytial appearance. This is

associated with a prominent inflammatory infiltrate which often obscures the

carcinomatous component. Rarely, typical lymphoepithelioma-like carcinoma can

have focal glandular differentiation or focal clear cell change. The inflammatory

infiltrate consists predominantly of lymphocytes or a mixed inflammatory infiltrate

composed of neutrophils, eosinophils, lymphocytes, histiocytes and plasma cells.

None of the cases have demonstrated Epstein Barr Virus infection in the form of

EBV-encoded RNA by in situ hybridization 16

or immunohistochemistry for Epstein

Barr Virus latent membrane prostate 14

. Tumour cells are positive for AE1/AE3,

EMA, 34 beta E12, CK7 and p63 in most cases. CD30 and Thyroid Transcription

Factor-1 are consistently negative. CK20 staining has been found to be negative or

only weakly positive. A recent study has shown frequent chromosomal abnormalities

on FISH similar to those of urothelial carcinoma. 14

In this study, tumours with

concurrent urothelial, squamous, sarcomatoid and glandular components displayed

identical FISH abnormalities present in both areas.

Differential Diagnosis

Due to the presence of a heavy inflammatory infiltrate, Lymphoepithelioma -like

carcinoma can be misdiagnosed as a reactive inflammatory lesion or lymphoma. This

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can be a particular problem in small biopsy samples. Careful examination should

reveal an epithelial component and it is important to perform keratin Immunostaining

in any suspicious cases. A large cell undifferentiated carcinoma can have focal

inflammatory cells, but not the prominent inflammatory infiltrate seen in these cases.

Another differential diagnostic consideration is high grade urothelial carcinoma with

abundant lymphocytes in the stroma. In contrast to these cases, lymphoepithelioma -

like carcinoma has a syncytial arrangement of undifferentiated cells, often obscured

by the inflammatory infiltrate.

Prognosis and treatment

About 70% of the patients present as stage ≥pT2. This tumour has been found to be

responsive to chemotherapy. Some studies have shown that cases which are

predominantly or entirely lymphoepithelioma-like carcinoma have a better prognosis

than those with only a focal lymphoid lymphoepithelioma-like carcinoma component.

14, 17 However, a recent study has shows that lymphoepithelioma-like carcinoma

whether in pure or mixed form had a similar prognosis to conventional urothelial

carcinoma when treated with cystectomy.16

OSTEOCLAST-RICH UNDIFFERENTIATED CARCINOMA OF THE

URINARY TRACT

Epidemiology and Clinical features

Bladder cancers with an undifferentiated histological appearance and giant cells with

features of osteoclasts were designated “osteoclast-Rich undifferentiated carcinoma of

the urinary tract by Baydar et al in 2006. 10

This is a rare tumor with less than 30 cases reported in the literature. This is the

largest series of this entity with 6 cases 10

whereas previous reports had only 1 or 2

cases describing it as osteoclast-like giant-cell tumor of the urothelial tract. 18, 19

These have occurred mostly in males in their seventh decade or older, but one case

was reported in a 39-year-old male. 10

The presenting symptoms are nonspecific and

typical for urothelial tumors in general with gross hematuria as the most common

manifestation. These occur both in the bladder and the renal pelvis. Reported cases

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have been large at presentation, ranging from 5 to 11 cm.

Pathological Features

Morphologically, these tumors closely resemble giant cell tumor of bone with a

biphasic appearance. There is a background of sheets and nodules of mononuclear

cells and scattered evenly spaced osteoclast-like giant cells. Mononuclear cells are

plump ovoid or elongated with abundant cytoplasm. Mononuclear cells can display

variable atypia with mild to moderate pleomorphism but not severe pleomorphism.

Mitotic figures are often frequent and atypical mitoses can be seen. Giant cells are

cytologically bland and uniformly distributed through the tumor. These are identical

to osteoclastic giant cells with up to 50 nuclei with bi- or trinucleated variants.

Prominent vascularity, large hemorrhagic areas, blood-filled cysts, red cell

extravasation and deposition of hemosiderin are also features in common with giant

cell tumor. Large areas of necrosis, widespread invasion into surrounding tissues,

tumor thrombi in large veins and atypical mitoses also common in these tumours are

in keeping with their aggressive behavior. In most cases reported, there is an

associated high grade papillary or in situ urothelial carcinoma. However, a merging of

the undifferentiated component with invasive high-grade urothelial carcinoma has not

been demonstrated.

The multinucleated cells have morphological and immunohistochemical

properties of osteoclasts, positive for markers of monocytic/ macrophage lineage,

CD68, LCA , CD 51 and CD 54 and negative for cytokeratins and EMA.

Ultrastructural similarities to osteoclasts have also been shown. The mononuclear

component has variable expression of smooth muscle actin, desmin, S100, LCA and

CD 68 similar to those in skeletal osteoclastic giant cell tumors. However,

mononuclear cells can also be positive for epithelial markers, cytokeratin AE1/ AE3,

CAM 5.2, CK 7 and EMA unlike these tumours. P53 can be positive in the

mononuclear cells and in these cases parallels the staining of the accompanying

urothelial carcinoma whereas the osteoclastic cells are always negative. Ki 67 stains

mononuclear tumor cells but not the osteoclast -like giant cells.

Differential Diagnosis

Other tumors of the bladder with giant cells including pleomorphic giant cell

carcinoma, carcinosarcoma with malignant spindled giant cells, invasive high-grade

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urothelial carcinoma with syncytiotrophoblastic giant cells or reactive stromal giant

cells and tumors of classical morphology of osteoclastic giant cell tumors are

morphologically distinct from osteoclast-rich undifferentiated carcinoma of the

bladder.

Prognosis and treatment

The histogenesis of this tumor has been debated. However, given the immunoprofile

with focal epithelial marker positivity in the undifferentiated component and the

association with high-grade urothelial carcinoma in most cases, this is likely to be a

variant of urothelial carcinoma. The osteoclastic-like giant cells appear to be a

reactive component. The behavior of these tumors is unlike like that of giant cell

tumor of bone with most cases presenting at an advanced stage. In the largest series of

these tumors, 4 of 5 patients with follow-up died of disease within 15 months of

diagnosis. Of 8 previously reported cases with follow up 60% died of disease 10, 18, 19

PLEOMORPHIC GIANT CELL CARCINOMA

Epidemiology and Clinical features

Although mentioned in the 2004 WHO classification 1

as a type of urothelial

carcinoma with giant cells, characteristics of pleomorphic giant cell carcinoma were

described in the literature only in 2009 when Lopez Beltran et al. reported a series of

8 cases 20

. This is a rare aggressive variant of urothelial carcinoma characterized by

the presence of highly pleomorphic bizarre tumor giant cells similar to giant cell

carcinoma of the lung. It occurs more commonly in males with ages ranging from 55-

88 years. Patients present with hematuria with dysuria or frequency.

Pathological features

The pleomorphic giant cell component in the reported series varied from 20% to

100% of the tumor. There are variably cohesive expansile masses or infiltrating nests

or single cells of pleomorphic epithelioid tumor with bizarre anaplastic

multinucleated and mononucleated tumor giant cells. Extensive necrosis is common.

Tumor cells have abundant cytoplasm, and have frequent typical or atypical mitotic

figures. A hypocellular desmoplastic stromal response, intracytoplasmic vacuoles or

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hyaline droplets are seen in some cases. A chronic inflammatory cell infiltrate can be

present but is not prominent. Occasionally, osteoclastic-like giant cells can be present

but these are in the minority compared with the number of pleomorphic giant cells.

A concurrent conventional invasive urothelial carcinoma is present in most cases and

sometimes there are other variants such as micropapillary urothelial carcinoma.

Immunohistochemically, both the pleomorphic giant cell carcinoma and associated

conventional urothelial carcinoma are positive for CK7, CAM 5.2, AE1/AE3 and

EMA. Some cases are positive for P63, thrombomodulin and Uroplakin111. CK 20,

Melan-A, HMB-45, beta-HCG, PSA, vimentin, synaptophysin, MyoD1 and desmin

are negative. Ki 67 labeling index is high (up to 90%, mean 71%) and P53 staining

ranges from 50-90%. 20

Differential diagnosis

In contrast to sarcomatoid carcinoma, this tumor does not have a malignant spindle

cell component. If there is a component of malignant spindle cells associated with

pleomorphic giant cell carcinoma, then it has to be considered a mixed pleomorphic

giant cell carcinoma and sarcomatoid carcinoma.

The giant cells in these cases are highly pleomorphic tumor giant cells

morphologically distinct from those in osteoclast-rich undifferentiated carcinoma in

which giant cells resemble osteoclasts and urothelial carcinoma with

syncytiotrophoblastic giant cells. In contrast to osteoclasts which stain positively with

CD68 and syncytiotrophoblastic giant cells positive for beta-HCG these giant cells are

positive for epithelial markers

Presence of an associated invasive conventional urothelial carcinoma

component is helpful in differentiating primary pleomorphic giant cell carcinoma

from metastatic carcinoma or melanoma. In other cases, clinicopathological

correlation and immunostaining need to be performed.

Pleomorphic giant cell carcinoma arising in the prostate can spread to the

bladder and can be PSA negative or only focally positive. 21

Presence of conventional

urothelial carcinoma and other variants of urothelial carcinoma versus presence of

other patterns of prostate cancer can help in the differentiation. In other cases a panel

of immunostains including 34 ß E12, P63, PSA, PSAP and uroplakin should be

performed.

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Prognosis and treatment

This tumor has a very poor prognosis . Patients have advanced stage cancer at

presentation ( ≥pT3) and often have lymph node metastases. In the reported series, 2

90% died of disease or were alive with metastases up to 19 months later. Only 10%

had no evidence of disease at 74 months.

UROTHELIAL CARCINOMA WITH SYNCYTIOTROPHOBLASTIC GIANT

CELLS

Epidemiology and Clinical features

Trophoblastic differentiation is a very rare form of divergent differentiation in urothelial

carcinoma. It may take the form of HCG production in an otherwise typical urothelial

carcinoma, syncytiotrophoblastic giant cells within a urothelial carcinoma and exceptionally

rarely, choriocarcinoma in association with urothelial carcinoma .22-24

Patients usually

present with macroscopic haematuria, a tumor mass on cystoscopy, elevation of serum and

urinary HCG or Gynecomastia due to the HCG elevation

Pathological features

Microscopically, there is invasive high-grade urothelial carcinoma with scattered

syncytiotrophoblastic giant cells. These have deeply eosinophilic cytoplasm and multiple

large irregularly shaped hyperchromatic and often smudged appearing nuclei. These often

have cytoplasmic lacunae. Invasive high-grade urothelial carcinoma with associated

choriocarcinoma has an admixture of syncitiotrophoblastic, cytotrophoblastic and

intermediate trophoblastic tissue in a haemorrhagic background. This tumor is highly

vascular with prominent necrosis and frequent mitoses including atypical mitoses.

Syncytiotrophoblastic cells are positive for Human chorionic gonadotrophin (HCG),

placental alkaline phosphatase, human placental lactogen, alpha inhibin, epithelial membrane

antigen and cytokeratin

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Differential diagnosis

This tumor is morphologically distinct due to the presence of characteristic

syncytiotrophoblastic cells with deeply eosinophilic cytoplasm and multiple irregularly

shaped often smudged appearing nuclei, in a background of conventional high grade

urothelial carcinoma in contrast to pleomorphic giant cell carcinoma in which the giant cells

are bizarre anaplastic mononuclear or multinuclear tumor giant cells in a highly pleomorphic

undifferentiated background and undifferentiated carcinoma with osteoclast-like giant cells in

which the giant cells have features of osteoclasts.

Choriocarcinoma from a primary arising in the genital tract can spread to the bladder.

Clinicopathological correlation is helpful in this diagnosis.

Prognosis and Treatment

Prognosis of urothelial carcinoma with syncytiotrophoblastic giant cells and choriocarcinoma

appears to be much worse than that of typical high grade urothelial carcinoma, including

those displaying HCG positivity. 22-25

In most cases, survival has been less than 1 year. 24

Treatment includes cystectomy and combination chemotherapy

LIPID CELL VARIANT OF UROTHELIAL CARCINOMA

Epidemiology and Clinical features

Lipid cell variant of urothelial carcinoma characterized by numerous lipoblast-like

vacuoles was first described by Mostofi et al. in 1999. 26

since then, there have been a

few case reports and a small series of 5 cases. 27

Most recently, in 2010 Lopez Beltran

et al. reported a series of 27 cases. 28

This is a rare tumor occurring far more

frequently in males than females. Age range reported has been 42-94 years with a

mean age of 70 years. Patients usually present with hematuria with obstructive urinary

symptoms, fever, anemia and urinary retention, occurring less commonly.

Pathological features

Histologically, there are solid expansile nests or infiltrating nests of large epithelioid

cells containing abundant vacuolated cytoplasm indenting the nuclei imparting a

lipoblast- like or signet ring cell like appearance to the cells. Nuclei can be

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moderately to highly pleomorphic and sometimes nucleoli are prominent. High-grade

conventional urothelial carcinoma is present in all cases (lipid cell component varying

from 10-50%) and carcinoma in situ in some cases. Squamous or glandular

differentiation or associated micropapillary or plasmacytoid urothelial carcinoma are

present rarely.

Tumor cells are strongly positive for AE1/AE3 and CK7 and variably weakly

staining for CK 20, CAM 5.2, EMA, thrombomodulin and 34 beta E12 and negative

for vimentin and S100 protein. Mucin stains are negative in the vacuoles.

Electromicroscopy supports the presence of lipid within tumor cells. Loss of

heterozygosity (LOH) analysis using 4 polymorphic microsatellite markers (D9S171,

D9S177, IFNA and TP53) revealed LOH for at least one marker in most cases with

similar results in the lipid cell variant and conventional urothelial carcinoma. 28

Differential diagnosis

Diagnosis can be difficult particularly in small biopsy samples. Given the presence of

lipoblast-like cells, liposarcoma needs to be considered in the differential diagnosis.

However, primary liposarcoma as a component of carcinosarcoma or secondary

liposarcoma of the bladder is rare. Recognizing that the lipoblast-like cells are present

within cohesive groups of epithelial cells and not within a liposarcomatous

component is crucial in avoiding a misdiagnosis. Keratin staining and absence of

S100 staining can help with the diagnosis.

Primary, signet ring cell adenocarcinoma can cause a diagnostic problem.

Presence of many lipoblast-like cells and not single vacuoles and absence of

cytoplasmic mucin can help in this differentiation. Metastatic signet ring cell

carcinoma from other locations such as breast and stomach are also easily

distinguished due to absence of single mucin containing vacuoles. Presence of an

obvious urothelial carcinoma component in these cases can also help with the correct

diagnosis

Prognosis and treatment

These tumors have a poor prognosis with most cases advanced at presentation. In the

series by Lopez Beltran et al.,28

45% had lymph node metastases at presentation, 60%

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died of disease at 16-58 months and another 30% were alive with disease.

MICROPAPILLARY UROTHELIAL CARCINOMA

Epidemiology and Clinical features

Micropapillary Urothelial Carcinoma (MUC) is characterised by surface tumour of

delicate papillary and filiform processes and invasive tumour of tight clusters of cells

typically within tissue retraction spaces reminiscent of ovarian papillary serous

carcinoma. MUC has morphological similarities to micropapillary carcinoma in other

organs such as breast, lung and pancreas. This tumour was first described by Amin et

al in 1994 .29

Since then, there have been several case series reported 30- 37

with an

incidence varying from 1-6%. Males are more commonly affected . The age range is

45-82 with a mean age of 66 years. Patients usually present with gross or

microscopic haematuria but dysuria, recurrent UTI and urinary obstruction have been

less common presenting symptoms.

Pathological features

MUC can occur anywhere in the urinary tract but most commonly involves the

bladder. Grossly, tumours can be sessile, polypoid, ulcerative or infiltrative.

Histologically, MUC is almost always associated with conventional Urothelial

Carcinoma (UC). MUC has 2 distinct components. Surface MUC consists of small

papillary tufts and delicate filiform processes, with or without central fibrovascular

cores. Invasive MUC is characterised by small tight nests of cells, often seen within

tissue retraction spaces. This pattern is often retained in metastatic sites. Cells often

have a high nuclear cytoplasmic ratio and have small irregular nuclei with coarse

uneven chromatin and prominent nucleoli. In some cases, there is more abundant

clear or eosinophilic cytoplasm. Mitoses can be few to numerous and lymphovascular

invasion is common. These are invariably high-grade given the coarse uneven

chromatin, prominent nucleoli and often frequent mitoses, even though prominent

pleomorphism may be difficult to appreciate due to a cell size smaller than that of

conventional UC. 29- 33

In about 60% of cases there is associated urothelial CIS. 29-33

Psammoma bodies are usually not found. MUC can rarely be associated with foci of

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gland forming adenocarcinoma and even small cell carcinoma. 32, 35

A rare case with

trophoblastic differentiation has been reported. 38

Recently MUC has been reported in

association with pleomorphic giant cell carcinoma 39

and plasmacytoid UC 40

indicating divergent differentiation. Metastases have been reported in lymph nodes,

bone, peritoneum, lung, pleura, skin and the liver.

Immunohistochemical findings

Almost all cases are positive for epithelial membrane antigen (EMA), CK 7, CK 20

and Leu- M1, and many cases for carcinoembryonic antigen (CEA), 34beta E12 ,

PTEN, p53, Ki-67, Her2Neu, uroplakin , 29

CA125, p16 and MUC1 and 2. A

smaller number of cases show immunostaining for B72.3, BerEp4, placental alkaline

phosphatase and S-100 protein. 33, 35, 41, 42

E-cadherin has also been shown to be

diffusely positive in these tumors. 43

Differential diagnosis

MUC of the urinary tract needs to be differentiated from metastatic carcinoma with

micropapillary histology from ovary, endometrium, lung, breast, GIT and salivary

glands. Presence of urothelial carcinoma in situ, papillary or invasive conventional

UC points to a urothelial primary cancer. In other cases, clinicopathological

correlation is necessary demonstrating absence of a primary tumor elsewhere.

Immunohistochemical staining can be helpful, particularly with Uroplakin 111 and

thrombomodulin, which are present in many MUC but not in ovarian, breast, lung or

colonic tumours. 42, 44

. 34 beta E12 present in most MUC, are only rarely present in

other tumours. 33, 44.

CK 7+/CK 20+ immunophenotype strongly suggests a urothelial

primary, whereas MPC from lung, breast and ovary are most likely CK 7+/CK 20 –.

33, 44 A recent study

45 found that uroplakin and CK 20 were most useful in identifying

MUC whereas p63, high molecular weight cytokeratin, and thrombomodulin were

less sensitive and specific. In this study, lung MPC was uniformly TTF-1 positive,

breast MPC, ER and mammaglobin positive, and PAX8/WT-1 negative, while

ovarian MPC was ER positive, mammaglobin negative, and PAX8/WT-1 positive.

When dealing with metastatic MPC of unknown primary, MUC should be considered

a possibility. It is important to differentiate MUC from other MPC as treatment

options are different. Clinicopathological findings and immunohistochemistry are

again helpful in this setting.

18

Genetics

In 5 cases studied, MUC showed non-diploid indices with three cases displaying a

higher DNA index than conventional non-invasive papillary UC. 29

In another study

of five cases, with sequencing used to identify point mutations in exons 5 to 9 of p53

and exons 1 and 2 of H-ras no significant abnormalities were found. 34

Prognosis and treatment

The overall prognosis for micropapillary urothelial carcinoma is poor with patients

often presenting at an advanced stage and about 20% with metastases. 29-37

The

proportion of MUC appears to impact on the stage at presentation and survival .32, 33,

36, 37. However, micropapillary morphology appears to worsen the outlook for UC

irrespective of whether it is focal or diffuse. 30

and therefore any amount of MUC

should be reported. Recent studies suggest that early treatment with cystectomy could

improve outcome, as these tumors are unlikely to respond to chemotherapy when used

as a secondary treatment option 30, 46

Given the immunoreactivity of these tumors to

Her2Neu and PTEN, 41

targeted therapy maybe a useful treatment option to be

developed.

UROTHELIAL CARCINOMA WITH ABUNDANT MYXOID STROMA

Epidemiology and Clinical features

Although briefly mentioned in text books, urothelial carcinoma with abundant myxoid

stroma was first described in detail only in 2009 when Tavora and Epstein 47

reported

a series of 13 cases involving the bladder. Shortly thereafter Cox et el 48

reported a

series of 12 similar cases which were labeled invasive urothelial carcinoma with

chordoid features, given the distinct cord like arrangement of tumour cells, at least

focally resulting in patterns resembling myxoid chondrosarcoma, chordoma and yolk

sac tumor. These tumours are striking due to the presence of abundant extracellular

virtually acellular pools of mucin resembling mucinous adenocarcinoma, but in the

absence of any glandular differentiation. These tumours were not listed in the 2004

WHO classification as a separate entity, although mentioned in the section of

19

infiltrating urothelial carcinoma with glandular differentiation. This is a rare tumour,

although in the series by Cox et al 48

at least 5% of extra cellular myxoid stroma was

found in about 7% of invasive urothelial carcinoma cases. The histogenesis of this

tumor is controversial with some suggestion that the extracellular mucin is secreted

by the urothelial carcinoma. These occur more commonly in males than females with

a mean age of 66 (range 45-85years).

Pathological features

In all cases, acellular myxoid stroma is seen in association with invasive urothelial

carcinoma. The percentage of the tumour with myxoid stroma ranges from 5-95%.

Tumour cells have sparse to moderate amounts of cytoplasm and are arranged in

cords, small to medium sized nests, filigree patterns and microcysts with single cells

and sheets of cells found rarely. Nuclear features are those of high grade carcinoma in

most cases but lack prominent pleomorphism and the mitotic count is typically low. A

few can have receptively bland cytologic features similar to the nested variant of UC.

Some cases are associated with a papillary urothelial carcinoma which can be high

grade or low grade. There can be associated other variants and urothelial carcinoma in

situ. These tumours do not show gland formation, intra-cytoplasmic mucin or

sarcomatoid differentiation.

The myxoid stroma stains positively with Alcian blue with and without

hyaluronidase, PAS, colloidal iron and mucicarmine. Tumor cells are positive for

CK7, 34 E12, p63 and variably positive for CK20, MUC2, MUC5 and polyclonal

CEA. Tumor cells are negative for CDX2, calponin and GFAP.

Differential diagnosis

These tumors can be confused with adenocarcinoma either primary in the bladder or

metastatic, particularly from the prostate or intestine. Mucinous prostatic

adenocarcinoma can mimic these tumors given that there are pools of mucin and

relatively bland cytology. In contrast to nests and cords of cells in these tumors,

mucinous prostatic adenocarcinoma, typically has individual or cribriform glands

floating in mucin. In bladder adenocarcinoma (including mixed urothelial carcinoma

and adenocarcinoma) and intestinal adenocarcinoma, mucinous pools are lined by

neoplastic epithelium displaying varying degrees of atypia.

20

In contrast to this tumor, micropapillary urothelial carcinoma shows

prominent retraction artifact surrounding small tight nests of tumor cells reminiscent

of papillary serous carcinoma.

Sarcomatoid carcinoma can mimic this tumor given the presence of myxoid

stroma. In sarcomatoid carcinoma, there are malignant spindle cells embedded in

myxoid stroma in contrast to these tumors in which hypocellular myxoid stroma

surround urothelial carcinoma. Similarly, in urothelial carcinoma with

pseudosarcomatous stroma, there are atypical spindled cells in the stroma.

The recently described myxoid cystitis with “chordoid” lymphocytes can

mimic this tumor due to the abundant myxoid stroma and cords of epithelioid cells

with scanty cytoplasm and round nuclei. 49

in this case the epithelioid cells are B

lymphocytes, have bland nuclei and are admixed with other inflammatory cells.

Immunostaining can sometimes be necessary to confirm the B-cell nature of these

cells.

Another possible mimic is the fibromyxoid variant of nephrogenic adenoma

which can have a corded pattern of growth. 50

Nephrogenic adenoma often has other

patterns typical of nephrogenic adenoma and hyaline basement membrane material

around epithelium. This also expressed nuclear PAX-2 and PAX-8 which is not

usually seen in urothelial carcinoma

Prognosis and treatment

It is difficult to ascertain how the prognosis of this tumor compares with that of

conventional urothelial carcinoma. In one study, 47

69% presented with invasion of

only lamina propria and only 31% had invasion of muscularis propria. 22% of

patients in this series developed metastases and died of disease while a subset,

although only with limited followup, had no evidence recurrence or metastases after

TURB with or without BCG. In the other series, 48

most cases were high stage at

presentation (92% PT 2 or greater) and 6 of 9 patients with 1- 10 months followup

died of disease or were alive with metastases.

PLASMACYTOID UROTHELIAL CARCINOMA

Epidemiology and Clinical features

21

Plasmacytoid urothelial carcinoma is a unique variant of urothelial carcinoma in

which tumor cells bear a strong resemblance to plasma cells. Since its first description

in 1991 51

there have been several case reports and series published. 52- 54

with the

largest series of 32 cases reported in 2011 by Kech et al. 55

Plasmacytoid

differentiation has been reported in 2.7% of muscle invasive urothelial cancers 55, 56

These tumors occurs most commonly in males at an age range of 48- 87. The median

age of patients with muscle invasive plasmacytoid carcinoma was 56.9 years in one

study 55

which was significantly lower than that of conventional urothelial

carcinoma. Patients usually present with hematuria, dysuria, frequency or nocturia.

Pathological features

In reported cases the plasmacytoid component has varied from 10-100% of the tumor

with the majority of cases displaying >50%. Histologically, tumour cells are present

singly and in solid expansile non-cohesive nests. Sometimes there are alveolar

patterns and strands of cells. The growth pattern is reminiscent of lobular carcinoma

of the breast. Tumor cells are small to medium-sized, have eccentrically placed

nuclei, abundant eosinophilic cytoplasm and sometimes an eosinophilic paranuclear

hof reminiscent of plasma cells. Nuclei have mild to moderate pleomorphism.

Nucleoli are indistinct. Intracytoplasmic vacuoles can be present. A large proportion

of cases are associated with conventional invasive high-grade urothelial carcinoma.

Rarely there can be urothelial carcinoma in situ or associated variants such as nested

or micropapillary urothelial carcinoma

Immunostaining reveals positivity for, cytokeratins 7, 20, AE1/AE3 ,

epithelial membrane antigen, GATA-3 (endothelial transcription factor), CD15, p53

and p16. CD138 is strongly positive in some cases. Tumor cells stain negatively for

Leukocyte common antigen, vimentin, multiple myeloma 1/interferon regulatory

factor 4, and κ and λ light chains. 53- 55

The vast majority of cases display negative or

strongly reduced membranous staining for E-cadherin. Multitarget fluorescence in

situ hybridization has shown that these are highly aneuploid and polysomic with

deletions on chromosome 9p 21 appearing to play an important role whereas FGFR3

and PIK3CA mutations are not found. TP53 mutations are found in about one third

of cases. Ki-67 labeling index ranges form 20% to 60% (mean, 35.5%). 55-57

22

Differential diagnosis

Diagnosis can be difficult particularly on small biopsy. Plasmacytoid urothelial

carcinoma can be mistaken for chronic cystitis with a predominant plasma cell

infiltrate or plasmacytoma/ multiple myeloma. CD138 positivity in some cases can

further cause problems given its positivity in plasma cells. Diagnosis may not be

problematic if there is an associated conventional urothelial carcinoma component

which is present in nearly 90% of cases of plasmacytoid urothelial carcinoma. In

other cases, a panel of immunostains including epithelial markers are necessary to

make this distinction

Presence of vacuolated cells can raise the possibility of signet ring cell

adenocarcinoma . Primary signet ring cell carcinoma of the bladder is rare. In contrast

to these cases in which signet ring cells are the predominant component, these are rare

and focal in the plasmacytoid urothelial carcinoma.

Metastatic carcinoma from other primary sites especially breast, stomach and

colon need to be always considered in the differential diagnosis. Again, presence of a

conventional urothelial carcinoma component is very helpful in identifying

plasmacytoid urothelial carcinoma. In other cases, clinicopathological correlation and

immunostaining are necessary to make this distinction

Carcinoma with rhabdoid morphology also should be considered in the

differential diagnosis with plasmacytoid urothelial carcinoma. Unlike plasmacytoid

carcinoma these tumors have dense eosinophilic cytoplasmic inclusions, large

vesicular nuclei, prominent nucleoli and display vimentin immunostaining

Prognosis and treatment

These tumors are often advanced at presentation. In the largest series of these cases

64% presented at pT3 and 23% at pT4 and 60% had metastases. The average

survival of patients treated with radical cystectomy and adjuvant chemotherapy was

also found to be lower than that for comparable conventional urothelial carcinomas. 55

23

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