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Urothelial carcinoma-invasive


Reviewers: Rugvedita Parakh, Cedars-Sinai Medical Center; Monika Roychowdhury, M.D., University of Minnesota Medical Center – Fairview (see Reviewers page)
Revised: 3 July 2011, last major update June 2011
Copyright: (c) 2002-2011, PathologyOutlines.com, Inc.

See also distinct variants and histologic types of urothelial carcinoma


● Urothelial carcinoma that has penetrated the basement membrane and invaded into the lamina propria or deeper


● Also called invasive transitional cell carcinoma (older term)
Microinvasive: invasion to a depth of 2 mm or less
● The World Health Organization classifies bladder cancers as low grade (grade 1 and 2) or high grade (grade 3)
● Tumors are also classified by growth patterns as papillary (70%), sessile or mixed (20%) or and nodular (10%)


● In US, 90% of bladder tumors are urothelial carcinoma, <5% are pure squamous cell carcinoma or adenocarcinoma
● #4 most common cancer in US males, #8 in US females
● In US, there were 64,000 cases and 13,000 deaths in 2006 (all types, invasive and noninvasive, National Institutes of Health)
● Patient characteristics resemble bronchogenic carcinoma: M > F, cigarette users, urban, age 50+ years
● Twice as common in white men vs. black men
● Developed countries have 6x higher incidence of bladder carcinoma (all types) than developing countries
● In developing countries, 75% of bladder cancers are squamous cell carcinoma, usually due to endemic Schistosomiasis (eMedicine)


● Can arise anywhere in bladder, even diverticula
● Often multifocal
● Multiple tumors may be independent or have common origin (Mod Pathol 1997;10:428)


● Cigarette smoking is major risk factor (50-80% of cancers, risk associated with duration and intensity)
● Also arylamines (2-naphthylamine) and aniline dyes
● In developing countries, Schistosoma haematobium ova are deposited in bladder wall and cause chronic inflammation, squamous metaplasia, dysplasia; 70% of tumors are squamous cell carcinoma
● HPV may cause condyloma, squamous dysplasia, squamous cell carcinoma sequence
● Phenacetin use (usually long term use in younger women, tumors involve upper collecting system)
● Chronic urinary tract infection and calculi
● Rarely cyclophosphamide with long term use

Clinical features

● Typically age 60+ years
● Initial symptoms are painless hematuria, infection, obstruction if near ureteral orifices
● 60% are single tumors, 70% of tumors are localized to bladder
● Tumors tend to recur (50% of low grade tumors recur vs. 80% of high grade), often at higher grade and at different site
● Tumors in young adults and children are rare, tend to be low grade and indolent (urothelial papilloma and papillary urothelial neoplasm of low malignant potential)
● May spread via mucosa to seminal vesicles (Am J Surg Pathol 1987;11:951)
● Elevation of beta hCG and CEA is occasionally seen
● Leukemoid reaction may be seen after cystectomy
● Rarely diagnosed at prostate needle biopsy (Am J Surg Pathol 2001;25:794)
Superficial (pT1): some progress to pT2 disease and require cystectomy instead of conservative management
Invasion of muscularis propria (pT2): 50% have occult metastases at diagnosis, usually becoming overt within 1 year
Distant metastasis: extremely poor prognosis, and poor response to adjuvant therapy


● Accurate for determining benign/reactive vs. dysplastic/malignant
● Not accurate for determining high grade vs. low grade papillary lesions, or determining microscopic invasion (Hum Pathol 2001;32:630)

Poor prognostic factors

● Stage is most important prognostic factor (see staging, includes depth of invasion, nodal and distant metastases), particularly pTa/pT1 vs. pT2 (i.e. whether or not there is muscularis propria invasion); 5 year survival is 75% if pT1, 50% for pT2 and 20% for pT3
● Predictors of prolonged survival in pTa and pT1 are small tumor size, lack of cyclin D3 expression, low proliferation index (Am J Clin Pathol 2004;122:444)
● For muscle invasive urothelial carcinoma, pathologic T stage and lymph node status are the most powerful predictors of progression; histologic grade (Malmstrom system) of invasive component was not helpful (Am J Surg Pathol 2000;24:980)
● Some histologic variants have poorer prognosis: carcinoma with rhabdoid features, micropapillary carcinoma, plasmacytoid carcinoma, sarcomatoid carcinoma, small cell carcinoma, undifferentiated carcinoma
● High grade tumors that invade into lamina propria have poorer prognosis than noninvasive high grade papillary, but prognosis is similar for low grade papillary that invade into lamina propria versus noninvasive low grade papillary (Am J Clin Pathol 2010;133:788)
● In general, high grade tumors (40% of newly diagnosed bladder cancer) have poorer prognosis than low grade tumors; almost all disease related deaths are due to high grade tumors

Other poor prognostic factors:
● Lymphovascular invasion, coexisting urothelial carcinoma in situ (associated with recurrence), short time interval to first recurrence, large tumor size, multicentricity
● Also possibly decreased expression of p63 (Clin Cancer Res 2003;15:5501), loss of E-cadherin expression (Oncol Rep 2007;17:925) and increased CK20 expression (Cancer Lett 2007;245:121)


● Cystoscopy, biopsy (should include muscularis propria and benign appearing areas), cytology (see below), flow cytometry of sediment (to detect aneuploidy)

Case reports

● 14 year old boy without risk factors with a high grade invasive tumor (Am J Surg Pathol 1989;13:1057)
● 67 year old man with urothelial and prostatic carcinoma metastasizing to same lymph node (Arch Pathol Lab Med 2001;125:1354)
● 83 year old man with high grade carcinoma with acinar/tubular pattern resembling Gleason grade 3 prostatic adenocarcinoma (Hum Pathol 2004;35:769)
● Post-menopausal woman whose tumor had a choriocarcinomatous component (Hum Pathol 1984;15:793)


Low-grade carcinoma and papillary urothelial neoplasm of low malignant potential:
● Surveillance, urine cytology screening, adjunctive molecular screening

"Superficial" bladder cancer (carcinoma in situ, pTa-noninvasive papillary, pT1-invasive into lamina propria):
● Intravesical therapy, like bacillus Calmette-Guérin (bcg)
● Cystectomy for tumors refractory to conservative management

Urothelial carcinoma invasive into muscularis propria:
● Radical cystectomy (Urology 2007;69:3) or possibly partial cystectomy (J Urol 2006;175:2058)
● Neoadjuvant / adjuvant therapy (varies between institutions)

Tumors with distant metastases:
● Have extremely poor prognosis, with poor response to adjuvant therapy

Variants: treat similar to conventional urothelial carcinoma except:
Lymphoepithelioma-like carcinoma (pure): more responsive to chemotherapy
Micropapillary carcinoma: treated surgically even at low stage (pT1)
Small cell carcinoma: chemotherapy regimen
Urothelial carcinoma with squamous differentiation: less responsive to adjuvant therapies

Gross description

● Typically large infiltrative mass
● Multifocal, flat to papillary with delicate fronds

Gross images

Large nodular hemorrhagic tumor

Large ulcerative lesion near ureteral orifice

Exophytic and papillary tumor

High grade invasive urothelial carcinoma

Other images: #1; #2; #3; #4; #5

Invasion of cervix: #1; #2

Micro description

● See also variants and other carcinoma subtypes
● Distinguishing histologic variants may have clinical significance (Mod Pathol 2009;22:S96)
● High grade lesions often have foci of squamous differentiation with focal or extensive keratinization and intracellular bridges; also scattered syncytiotrophoblasts / bizarre nuclear pleomorphism associated with hCG
● Focal clear cells or choriocarcinomatous areas may be present (rare)
● May have spindle cells, osteoclasts, glandular or benign stromal elements, plasmacytoid cells, lipid cells
● May have focal pseudosarcomatous stroma
● Stromal retraction often present (Am J Clin Pathol 2005;123:851)
● No consensus grading scheme (Mod Pathol 2009;22:S70); grade of invasive component appears to have no prognostic value (Am J Surg Pathol 2000;24:980)

● Cases diagnosed on prostatic needle biopsy often have only in-situ involvement of prostatic ducts and acini by urothelial carcinoma; compared to prostatic adenocarcinoma, have greater nuclear pleomorphism, increased mitoses and necrosis; are PSA/PAP negative, CK7+, CK20+, 34betaE12+
● Most die of disease (mean survival 23 months), even if only in-situ involvement present
● Cure possible with aggressive chemotherapy and adjuvant chemoradiotherapy (Am J Surg Pathol 2001;25:794)

● Variant morphologic patterns may suggest nonbladder primary, although most urothelial carcinoma variants maintain urothelial immunophenotype (CK7+, CK20+, high molecular weight cytokeratin/34ßE12+, p63+)
● Variant histology type and percentage should be listed in report as it has diagnostic, prognostic or therapeutic implication
● Variant histology may be seen at metastatic sites or metastatic carcinoma, and carcinoma secondarily involving bladder may be mistaken for a variant

● For cases in bladder, important to indicate depth of invasion, which requires understanding microscopic anatomy:

Lamina propria
● Connective tissue between urothelium and detrusor muscle (muscularis propria)
● Made of loose stroma, variably sized blood vessels and thin muscle bands of muscularis mucosae, which may occasionally appear hyperplastic (Am J Surg Pathol 2007;31:1420)

Muscularis propria
● Thick aggregated bundles of detrusor muscle
● Smoothelin, a marker of terminally differentiated smooth muscle cells, is relatively specific for muscular propria compared to muscularis mucosa, and may be useful in confirming muscularis propria invasion (Am J Surg Pathol 2010;34:792, Am J Surg Pathol 2009;33:91)

Perivesical soft tissue
● Adipose tissue deep to muscularis propria
● Note that adipose is also present in lamina propria and muscularis propria, and does not signify an extravesical location

Micro images


pT1 tumors (invasion into lamina propria)

pT1 (muscular mucosae invasion) and pT2 (muscular propria invasion)

pT2 (muscular propria invasion) – left - high grade; right - perineural invasion

pT3 (perivesical invasion)

pT4 (invasion into prostatic stroma)

Histologic features

Infiltrative growth

Lymphovascular invasion

Grade 3: pleomorphism and mitotic figures

Glandular, micropapillary and plasmacytoid differentiation

Stromal responses

Inflammation may obscure invasion

Positive margin

Nodal metastases

H&E, p53+

p63 and beta-catenin

Uroplakin III and p63

Other images, poorly differentiated: #1; #2

Various images: #1; #2; #3; #4; necrosis; vascular invasion

Cytology description

● Spindle, pyramidal and racquet-shapes
● Increased numbers of irregular, three dimensional cell groups
● Intracytoplasmic vacuoles
● Marked pleomorphism with enlarged hyperchromatic nuclei, coarse chromatin, increased N/C ratio, and prominent nucleoli
● Presence of necrosis, lysed blood and degenerated red blood cells is most suggestive of invasion, but invasion cannot be conclusively diagnosed on cytology specimens
● Variants may show divergent morphology corresponding to histology
● p16(INK4a) expression is associated with urothelial carcinoma (Am J Clin Pathol 2009;132:776)

Cytology images

Neoplastic cells with high nuclear-cytoplasmic ratio and marked nuclear eccentricity, as well as a characteristic chromatin pattern and irregular nuclear borders

Central tumor cells and normal cell at lower left

Tight cluster of tumor cells

Atypical urothelial cells identified with (a) fluorescent monoclonal antibodies; (b) H&E

Virtual slides

High grade muscle invasive urothelial carcinoma

Positive stains

● CK7, CK20 (50%), HMW keratin (80%), uroplakin (40-60%, but highly specific), thrombomodulin (Am J Surg Pathol 2003;27:1), variable p63
● Also MUC1, CEA, p53, GATA3, S100
● Variable CA125 (Int J Biol Markers 1994;9:224), variable HER2
● CD31, CD34, and podoplanin (D2-40) are useful to distinguish true lymphatic invasion from retraction artifact, particularly in micropapillary variant
● Note: keratin may stain non-tumor cells in repeat biopsy cases (Am J Surg Pathol 2007;31:390)
● Note: CK20 staining pattern in primary tumor is replicated in metastases (Arch Pathol Lab Med 2001;125:921)

Negative stains

● Prostatic markers PSA, P501S, PSMA, NKX3.1 and pPSA (Am J Surg Pathol 2007;31:1246)
● WT1, MUC2, MUC5AC (Am J Clin Pathol 2004;122:61), HPV, Leu7/CD57

Electron microscopy description

● Pleomorphic microvilli
● Decrease in specialized junctions

Molecular / cytogenetics

● Monosomy 9, 9p- (p16 INK4 / MTS1), 9q- (gene unknown), 13q- (retinoblastoma gene), 14q-, 17p- (p53)
● Low grade tumors may begin with 9p-/9q-, some acquire p53 and become invasive; high grade tumors may begin with p53 alterations
● In pTa tumors, polysomy 1 and 17 are linked to higher risk of recurrences
● Polysomies 1 and 17 are more frequent in pT1 than pTa tumors
● Polysomy 17 is associated with increased risk of progression (Hum Pathol 1999;30:81)

Differential diagnosis

Pseudocarcinomatous epithelial proliferations: Am J Surg Pathol 2008;32:92
Prostatic adenocarcinoma, high grade / poorly differentiated: foamy and pale cytoplasm, oval nuclei with smooth borders, fine, powdery, evenly distributed nuclear chromatin, large prominent nucleolus when present, lack of significant pleomorphism, no/rare mitotic figures, no/rare necrosis, no intraductal growth; positive for PSA or PAP, CD57/Leu7; negative for CK7, CK20, 34betaE12, uroplakin III, thrombomodulin, p53 (high grade urothelial carcinoma is opposite, Mod Pathol 2000;13:1186, Am J Clin Pathol 2000;113:383, Hum Pathol 2002;33:1136, Am J Surg Pathol 2003;27:1)
Vasculitis: particularly with HIV or hepatitis B infection, may present as recurring mass lesion (Arch Pathol Lab Med 1998 Oct;122:903)
● Low grade lesions resemble Brunn’s nests or cystitis glandular/cystica

End of Bladder > Urothelial carcinoma-invasive > General

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