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Bladder

Urothelial carcinoma-invasive

General

 

Reviewer: Rugvedita Parakh, Cedars-Sinai Medical Center, Las Angeles, California

Revised: 9 June 2010, last major update June 2010

Copyright: (c) 2002-2010, PathologyOutlines.com, Inc.

 

See also distinct variants and histologic types of urothelial carcinoma

 

Definition

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

 

Terminology

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● Also called transitional cell carcinoma (older term)

● Microinvasive: invasion to a depth of 2 mm or less

 

Epidemiology

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● 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 developing countries, 75% of bladder cancers are squamous cell carcinoma, usually due to Schistosomiasis (eMedicine)

● In US, there were 64,000 cases and 13,000 deaths in 2006 (all types, National Institutes of Health)

● Note: these statistics include invasive and noninvasive types

 

● Patient characteristics: M > F, cigarette users, urban, age 50+ years (similar to bronchogenic carcinoma)

● Developed countries have 6x higher incidence of bladder carcinoma (all types) than nondeveloped countries

● Twice as common in white men than black men

 

Sites

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● Can arise anywhere in bladder, even diverticula

● Often multifocal

● Multiple tumors may be independent or have common origin (Mod Pathol 1997;10:428)

 

Etiology

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● Cigarette smoking is major risk factor (50-80% of cancers, risk associated with duration and intensity)

● Arylamines (2-naphthylamine) and aniline dyes

● Schistosoma haematobium: ova are deposited in bladder wall and cause chronic inflammatory response, 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

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● 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

 

Endoscopy

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● 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

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● 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 T1, 50% for T2 and 20% for T3

● 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 invasive into lamina propria have poorer prognosis than noninvasive high grade papillary, but prognosis is similar for low grade papillary invasive into lamina propria versus noninvasive low grade papillary (Am J Clin Pathol 2010;133:788)

● In general, high grade tumors have poorer prognosis than low 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 decreased expression of p63 (Clin Cancer Res 2003;9:5501) and E-cadherin (Oncol Rep 2007;17:925) and increased expression of CK20 (Cancer Lett 2007;245:121)

 

Diagnosis

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

 

Case reports

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● 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 (Archives 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)

 

Treatment

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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)

 

Variants: treated similarly to conventional urothelial carcinoma except:

● Lymphoepithelioma-like carcinoma (pure): more responsive to chemotherapy

● Micropapillary carcinoma: treated surgically at low stage (pT1)

● Small cell carcinoma: chemotherapy regimen

● Urothelial carcinoma with squamous differentiation: less responsive to adjuvant therapies

 

Gross description (Macroscopy)

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● Typically large infiltrative mass

● Multifocal, flat to papillary with delicate fronds

 

Gross images

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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 (Histopathology)

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● See also variants and other carcinoma subtypes

● Distinguishing histologic variants may have clinical significance (Mod Pathol 2009;22 Suppl 2: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 Suppl 2: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

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Figure 12 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author      Lamina propria invasion by transitional cell carcinoma of bladder.   Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

 

Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author   Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author   Figure 4 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author   Figure 5 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

pT1 tumors (invasion into lamina propria)

 

 

Figure 9 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author   Figure 13 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author   Muscle invasion by transitional cell carcinoma of bladder.         

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

 

 

  

pT2 (muscular propria invasion)

High grade               With perineural invasion

 

 

Figure 15 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author                                Figure 16 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

pT3 (perivesical invasion)                pT4 (invasion into prostatic stroma)

 

 

Figure 21 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author                                Figure 23 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author      

Infiltrative growth                               Lymphovascular invasion

 

 

               

Grade 3: pleomorphism and                  H&E, p53+                Glandular, micropapillary and

mitotic figures                                                                              plasmacytoid differentiation

 

 

Figure 7 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author                                Figure 7 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author                                               

Stromal responses                            Inflammation may obscure invasion            

 

 

Figure 24 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author                        Figure 17 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author               

Positive margin                                   Nodal metastases

 

 

Fig. 1.                                Fig. 4.

p63 and beta-catenin                        Uroplakin III and p63

 

Other images: poorly differentiated:  #1;  #2;  various: #1;  #2;  #3;  #4;  necrosis;  vascular invasion

 

Cytology description

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● 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

● Invasion cannot be conclusively diagnosed on cytology specimensm but presence of necrosis, lysed blood and degenerated red blood cells is most suggestive

● 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

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Neoplastic cells with high nuclear-cytoplasmic        Central tumor cells and normal cell

ratios and marked nuclear eccentricity,                      at lower left

as well as a characteristic chromatin

pattern and irregular nuclear borders

 

 

Cytologic appearance of transitional cell carcinoma of bladder. The tumor cells, arranged in a tight cluster, show hyperchromatic nuclei and abnormal nucleocytoplasmic ratio.                                                               

Tight cluster of tumor cells                                             Atypical urothelial cells identified with

(a) fluorescent monoclonal antibodies;

(b) H&E

 

Virtual slides

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High grade muscle invasive

 

Positive stains

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● CK7, CK20 (50%), HMW keratin (80%), uroplakin (40-60%, but highly specific), thrombomodulin (Am J Surg Pathol 2003;27:1)

● Also MUC1, CEA, p53, GATA 3, S100P

● CA125 (27%, Int J Biol Markers 1994;9:224), variable HER2 and p63

● 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 (Archives 2001;125:921)

 

Negative stains

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● 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 descriptions

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● Pleomorphic microvilli

● Decrease in specialized junctions

 

Molecular / cytogenetics

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● 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

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● 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 (Archives 1998;122:903)

● Low grade lesions resemble Brunn’s nests or cystitis glandular/cystica

 

End of Bladder > Urothelial carcinoma-invasive > General

 

 

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