Bladder: Urothelial carcinomas

2003-10-01   Angela van Tilborg , Bas van Rhijn 

1.Department of Pathology, Josephine Nefkens Institute, Erasmus University, 3000 DR Rotterdam, The Netherlands

Summary

Atlas Image
Bladder cancer : gross pathology : the bladder wall is massively infiltered by an ulcerated and hemorragic tumor. Courtesy Pierre Bedossa

Classification

Classification

Histologic types:
  • urothelial carcinoma of the bladder, herein described
  • squamous cell carcinoma
  • adenocarcinoma (2%), rare
  • poorly differenciated carcinoma/small cell carcinoma, exceptional.
  • Clinics and Pathology

    Epidemiology

    urothelial carcinoma of the transitional epithelium is the most frequent bladder cancer in Europe and in the USA, representing 90-95 % of cases, while sqamous cell carcinoma represents only 5% in these countries, but up to 70-80% of cases in the Middle East; annual incidence: 250/106, 2% of cancers, the fourth cancer in males, the seventh in females, 3M/1F; occurs mainly in the 6th-8th decades of life; risk factors: cigarette smoking and occupational exposure (aniline, benzidine, naphtylamine); 20 to 30 yrs latency after exposure.

    Clinics

    Hematuria, irritation.
    Atlas Image
    staging - Editor

    Pathology

    grading and staging: tumours are:
  • graded by the degree of cellular atypia (G1->G3), and
  • staged:
    - papilloma
    - papillary tumor of low malignant potential (PTLMP)
    - papillary urothelial carcinomas low grade
    - papillary urothelial carcinomas high grade.
  • Treatment

    Resection (more or less extensive: electrofulguration --> cystectomy); chemo and/or radiotherapy, BCG-therapy.

    Evolution

    Recurrence is highly frequent.

    Prognosis

    According to the stage and the grade; pTa is of good prognosis (> 90% are cured); prognosis is uncertain in pT1 and G2 tumours. 20% survival at 1 yr (stable at 3yrs) is found in T4 cases; however, identification of individual patients prognosis is often difficult, although of major concern for treatment decision and for follow up.
    Multiple endpoints may be identified in bladder cancer. Recurrence (does it come back), recurrence rate (how soon/often does it come back), progression and (disease specific) survival are of importance. Patients with superficial bladder cancer (pTa and pTis) are frequently evaluated by cystoscopy to allow early detection of a possible recurrence and to prevent disease progression to invasive, potentially lethal, bladder cancer.
    According to mutational status of FGFR3 and TP53; tumors with an FGFR3 mutation have a lower recurrence rate, tumors with elevated immunohistochemical expression of p53 and MIB-1 have the highest recurrence rate: and the highest propensity for progression and death of disease (see figure below).

    Cytogenetics

    Cytogenetics morphological

    Karyotype
    Urothelial carcinomas exhibit pseudo diploid karyotypes with only a few anomalies in early stages, evolving towards pseudo-tetraploides complexes karyotypes. Partial or complete monosomy 9 (-9) is an early event, found in half cases. Deletion (11p) or -11 is found in 20-50% of cases, more often in high grade and invasive tumours. Del(13q) is found in 25% of cases and correlated with high grade/stage; tumours with Rb alterations are invasive. Del(17p) is a late event, found in 40% of cases; TP53 alterations are correlated with grade and stage, tumour progression, and a worse prognosis. Del(1p), i(5q), +7, and many other rearrangements - more often deletions than duplications - are frequently found. These losses of heterozygocity point to a multistep complex process involving tumor suppressor genes.

    Amplifications

  • Chromosome 1: P73 (1p36) is often over-expressed.
  • Chromosome 8: C-MYC (8q24) is rarely amplified.
  • Chromosome 11: cyclin D1 is often over-expressed.
  • Amplifications 10q13-14, 13q21-31 and 17q22-23 have been noted.

    Losses

  • Chromosome 8: loss of 8p12-22. The potential target is the FEZ1/LZTS1 gene, which is downregulated in high-grade carcinomas.
  • Chromosome 9: Allelic loss on chromosome 9q is a very frequent event in bladder carcinogenesis. Monosomy 9 or deletions of chromosome 9 are found in about 50% of cases; at times found as the sole anomaly, demonstrating that it is an early event, found equally in pTa stage and in more advanced stages; not associated with a given grade, and not correlated with p53 expression. Efforts have been directed towards identifying the postulated tumour suppressor genes on this chromosome arm by deletion mapping and mutation analysis. However, no convincing candidate genes have been identified. Homozygous deletions of CDKN2A/MTS1/P16 (9p21) have been documented; LOH + mutation on the second allele of CDKN2A are rare, but of significance; CDKN2A is implicated in pTa stage but not in pTIS, where p53 is found mutated; CDKN2B/INK4B/P15 (9p21) is also implicated in a small subset of cases. LOH + mutation on the second allele of TSC1 (9q33-34) has been described. Homozygous deletion and methylational silencing of a candidate gene DBCCR1 (9q32-33) has been reported.
  • Chromosome 10: PTEN (10q23), appears to be implicated in a very few percentage of cases (homozygote deletion has been found); Fas/APO1/CD95 (10q24): loss of one allele and mutation in the second allele has been reported; a hot-spot of mutations has been determined.
  • Chromosome 11: HRAS1 (11p15.5) is mutated in 15% of cases.
  • Chromosome 13: an altered Rb (13q14) is expressed in 30 to 40% of tumours; these are high stage, invasive, and indicate a short survival; 90% of tumours expressing Rb are invasives; disregulation of the normal P16-Rb interactions have been documented, with hyper expression of Rb and loss of function of P16.
  • Chromosome 17: P53 (17p13) alterations are correlated with grade and stage (often PT3), and tumour progression; P53 is mutated in more than 50% of high grade/stage tumours, and in most PTIS; P53 is a prognostic factor: by high grade/stage tumours, those expressing P53 are of a worse prognosis; by low grade/stage, those not expressing P53 are of better outcome; there is usually LOH + mutation on the second allele of P53; ERBB2 (HER2/Neu) (17q21) is expressed in high grade/stages tumours, in metastases, and is associated with relapses; NF1 (17q11) expression may be very low in tumours

    LOH
    LOH analysis in bladder cancer has so far not led to the identification of tumor suppressor genes. LOH appears to be numerous within a given chromosome (e.g. on chromosome 9 five regions, 9p21, 9q22, 9q31-32, 9q33 and 9q34, and on chromosome 5 four regions, 5q13.3-q22, 5q22-q31.1, 5q31.1-q32, and 5q34, and on chromosome 3 frequent LOH has been found in three regions, 3p12-14, 3p21.3-22 and 3p24.2-25), but loci remain to be precised, as reports are controversial. Due to the unique possibility to study multiple recurrent tumors from the same patient, it is now becoming apparent that loss of heterozygosity (LOH) on chromosome 9 is almost never the characteristic first step in tumor development. LOH can be detected in up to 67% of markers tested. The regions of loss are multiple and variable in different tumours from the same patient and expand in subsequent tumours. Moreover, the regions of loss on chromosome 9 vary from patient to patient. To explain the type and extent of genetic damage in combination with the low stage and grade of these tumors, it was hypothesized that in bladder cancer pathogenesis an increased rate of mitotic recombination is acquired early in the tumorigenic process.

  • Cytogenetics molecular

    (Matrix) CGH
    Array-based comparative genomic hybridization detected high-level amplification of 6p22.3 (E2F3), 8p12 (FGFR1), 8q22.2 (CMYC), 11q13 (CCND1, EMS1, INT2), and 19q13.1 (CCNE) and homozygous deletion of 6p22 (TRAF6), 9p21.3 (CDKN2A/p16) and 8p23.1.

    Genes Involved and Proteins

    Gene name

    FGFR3 (Fibroblast Growth Factor Receptor 3)

    Location

    4p16.3

    Note

    The expression of a constitutively activated FGFR3 in a large proportion of bladder cancers is the first evidence of an oncogenic role for FGFR3 in these carcinomas. FGFR3 currently appears to be the most frequently mutated oncogene in bladder cancer: it is mutated in more than 30% of cases. FGFR3 seems to mediate opposite signals, acting as a negative regulator of growth in bone and as an oncogene in several tumour types. Complete elucidation of the role of FGFR3 in normal and malignant tissues requires further investigation. Missense mutations were observed identical to those in thanatophoric dysplasia (R248C, S249C, G372C, and K652E), achondroplasia and SADDAN (G380/382R and K650/652M, respectively) and Crouzon Syndrome with Acanthosis Nigricans (A393E). Furthermore, a K650/652T mutation was found not previously identified in carcinomas or thanatophoric dysplasia. In urothelial papilloma, generally considered a benign lesion, 9/12 (75%) mutations were found. Another novel finding was the occurrence of two simultaneous FGFR3 mutations in four tumours.

    Gene name

    TP53 (Tumour protein p53 (Li-Fraumeni syndrome))

    Location

    17p13.1

    Note

    The TP53 gene in bladder cancer is mainly an indicator of progression and recurrence rate. Interestingly, mutations in FGFR3 and TP53 are mutually exclusive in bladder cancer.

    Gene name

    HRAS (Harvey rat sarcoma viral oncogene homolog)

    Location

    11p15.5

    Note

    HRAS mutations are found in approximately 15% of cases.

    Bibliography

    Pubmed IDLast YearTitleAuthors
    100792531999Urinary bladder transitional cell carcinogenesis is associated with down-regulation of NF1 tumor suppressor gene in vivo and in vitro.Aaltonen V et al
    103682521999The expression of PAX5 in human transitional cell carcinoma of the bladder: relationship with de-differentiation.Adshead JM et al
    103606731999Somatic mutation of PTEN in bladder carcinoma.Aveyard JS et al
    109294272000Aberration of chromosomes 8 and 11 in bladder cancer as detected by fluorescence in situ hybridization.Awata S et al
    96491321998Is chromosome 9 loss a marker of disease recurrence in transitional cell carcinoma of the urinary bladder?Bartlett JM et al
    100246751999p16 involvement in primary bladder tumors: analysis of deletions and mutations.Baud E et al
    100221251999Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer.Benedict WF et al
    107544992000Loss of heterozygosity analysis on chromosome 5p defines 5p13-12 as the critical region involved in tumor progression of bladder carcinomas.Böhm M et al
    113953712001Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors.Billerey C et al
    107382592000Cigarette smoking and bladder cancer in men: a pooled analysis of 11 case-control studies.Brennan P et al
    97390201998Chromosomal changes during progression of transitional cell carcinoma of the bladder and delineation of the amplified interval on chromosome arm 8q.Bruch J et al
    96714021998Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers.Cairns P et al
    104714911999Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas.Cappellen D et al
    76144561995Novel suppressor loci on chromosome 14q in primary bladder cancer.Chang WY et al
    91608861997Superimposed histologic and genetic mapping of chromosome 17 alterations in human urinary bladder neoplasia.Chaturvedi V et al
    103831321999Elevated and biallelic expression of p73 is associated withprogression of human bladder cancer.Chi SG et al
    107972622000Loss of heterozygosity at chromosome segments 8p22 and 8p11.2-21.1 in transitional-cell carcinoma of the urinary bladder.Choi C et al
    107193702000Genetic modeling of human urinary bladder carcinogenesis.Czerniak B et al
    76091031995New efforts to stage bladder cancer.Droller MJ et al
    124691232003Identifying distinct classes of bladder carcinoma using microarrays.Dyrskjøt L et al
    79707021994Deletion of two regions on chromosome 4 in bladder carcinoma: definition of a critical 750kB region at 4p16.3.Elder PA et al
    101007581998Microsatellite alterations at chromosomes 9p, 13q, and 17p in nonmuscle-invasive transitional cell carcinomas of the urinary bladder.Erbersdobler A et al
    91404601997Cytogenetics of bladder cancer.Gibas Z et al
    91757391997A novel candidate tumour suppressor locus at 9q32-33 in bladder cancer: localization of the candidate region within a single 840 kb YAC.Habuchi T et al
    80150801994Uncertainty, stage and outcome of invasive bladder cancer.Herr HW et al
    100373581999Can p53 help select patients with invasive bladder cancer for bladder preservation?Herr HW et al
    127278422003Genome-wide genetic characterization of bladder cancer: a comparison of high-density single-nucleotide polymorphism arrays and PCR-based microsatellite analysis.Hoque MO et al
    103536101999Mutation of the 9q34 gene TSC1 in sporadic bladder cancer.Hornigold N et al
    97218601998Genetic alterations in primary bladder cancers and their metastases.Hovey RM et al
    99175071999Interphase cytogenetic diagnosis of bladder cancer on cells from urine and bladder washing.Junker K et al
    75364611995Identification of gains and losses of DNA sequences in primary bladder cancer by comparative genomic hybridization.Kallioniemi A et al
    94771041998Detecting human bladder carcinoma cells in voided urine samples by assaying for the presence of telomerase activity.Kavaler E et al
    102143551999Detection of genetic alterations in bladder tumors by comparative genomic hybridization and cytogenetic analysis.Koo SH et al
    117204382001p15(INK4b) in bladder carcinomas: decreased expression in superficial tumours.Le Frère-Belda MA et al
    103972461999Alterations of Fas (APO-1/CD95) gene in transitional cell carcinomas of urinary bladder.Lee SH et al
    108996592000Initiation-development modelling of allelic losses on chromosome 9 in multifocal bladder cancer.Louhelainen J et al
    102265181999Comparison of comparative genomic hybridization, fluorescence in situ hybridization and flow cytometry in urinary bladder cancer.Mahdy E et al
    85711311996Molecular detection of primary bladder cancer by microsatellite analysis.Mao L et al
    125443412003Fibroblast growth factors and their receptors in transitional cell carcinoma.Munro NP et al
    109081542000High density deletion mapping of bladder cancer localizes the putative tumor suppressor gene between loci D8S504 and D8S264 at chromosome 8p23.3.Muscheck M et al
    77882581995Numerical chromosome aberrations in bladder cancer detected by in situ hybridization.Nemoto R et al
    99239321999Polysomies but not Y chromosome losses have prognostic significance in pTa/pT1 urinary bladder cancer.Neuhaus M et al
    124742262003Frequent genetic alterations in flat urothelial hyperplasias and concomitant papillary bladder cancer as detected by CGH, LOH, and FISH analyses.Obermann EC et al
    102213331999Localization of tumor suppressor gene associated with distant metastasis of urinary bladder cancer to a 1-Mb interval on 8p22.Ohgaki K et al
    75631861995Deletion of the p16 and p15 genes in human bladder tumors.Orlow I et al
    98865951999Multifocality of transitional cell carcinoma results from genetic instability of entire transitional epithelium.Pycha A et al
    92301901997Marked genetic differences between stage pTa and stage pT1 papillary bladder cancer detected by comparative genomic hybridization.Richter J et al
    105826851999Chromosomal imbalances are associated with a high risk of progression in early invasive (pT1) urinary bladder cancer.Richter J et al
    108111262000Progressive increases in de novo methylation of CpG islands in bladder cancer.Salem C et al
    128759712003Gene discovery in bladder cancer progression using cDNA microarrays.Sanchez-Carbayo M et al
    79059301994Review of chromosome studies in urological tumors. II. Cytogenetics and molecular genetics of bladder cancer.Sandberg AA et al
    88728571996Genetics of bladder cancer.Saran KK et al
    77518831995Prognostic value of p53 nuclear overexpression in patients with invasive bladder cancer treated with neoadjuvant MVAC.Sarkis AS et al
    77478071995c-myc copy number gains in bladder cancer detected by fluorescence in situ hybridization.Sauter G et al
    76642481995Y chromosome loss detected by FISH in bladder cancer.Sauter G et al
    87497811995Origins and clinical implications of aneuploidy in early bladder cancer.Shackney SE et al
    98288321998Chromosomal aberrations associated with invasion in papillary superficial bladder cancer.Simon R et al
    88957611996Evidence for two tumor suppressor loci associated with proximal chromosome 9p to q and distal chromosome 9q in bladder cancer and the initial screening for GAS1 and PTC mutations.Simoneau AR et al
    99269301999Four tumor suppressor loci on chromosome 9q in bladder cancer: evidence for two novel candidate regions at 9q22.3 and 9q31.Simoneau M et al
    83063421994Two molecular pathways to transitional cell carcinoma of the bladder.Spruck CH 3rd et al
    103984321999Arylamine N-acetyltransferase type 2 (NAT2), chromosome 8 aneuploidy, and identification of a novel NAT1 cosmid clone: an investigation in bladder cancer by interphase FISH.Stacey M et al
    88733831996The 9p21 region in bladder cancer cell lines: large homozygous deletion inactivate the CDKN2, CDKN2B and MTAP genes.Stadler WM et al
    86498001996Deletion mapping implicates two tumor suppressor genes on chromosome 8p in the development of bladder cancer.Takle LA et al
    76144521995Gelsolin: a candidate for suppressor of human bladder cancer.Tanaka M et al
    102086361999Genes for human arylamine N-acetyltransferases in relation to loss of the short arm of chromosome 8 in bladder cancer.Thygesen P et al
    98817041998Early acquisition of homozygous deletions of p16/p19 during squamous cell carcinogenesis and genetic mosaicism in bladder cancer.Tsutsumi M et al
    94266831998Loss of heterozygosity on chromosome 9 and loss of chromosome 9 copy number are separate events in the pathogenesis of transitional cell carcinoma of the bladder.Van Tilborg AA et al
    127825932003Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors.Veltman JA et al
    77786741995Detection of chromosomal imbalances in transitional cell carcinoma of the bladder by comparative genomic hybridization.Voorter C et al
    85758481996Loss of chromosome 11 and 11 p/q imbalances in bladder cancer detected by fluorescence in situ hybridization.Voorter CE et al
    92848241997Chromosome 8p deletions are associated with invasive tumor growth in urinary bladder cancer.Wagner U et al
    81740801994Nonrandom changes of chromosome 10 in bladder cancer. Detection by FISH to interphase nuclei.Wang MR et al
    119212862002Molecular genetic analysis of chromosome 9 candidate tumor-suppressor loci in bladder cancer cell lines.Williams SV et al
    101026331999Overexpression of the wild type p73 gene in human bladder cancer.Yokomizo A et al
    104935211999Chromosomal imbalances in noninvasive papillary bladder neoplasms (pTa).Zhao J et al
    120961392002Genome-wide study of gene copy numbers, transcripts, and protein levels in pairs of non-invasive and invasive human transitional cell carcinomas.Ørntoft TF et al
    124616892002Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders.van Rhijn BW et al
    123752682002The random development of LOH on chromosome 9q in superficial bladder cancers.van Tilborg AA et al

    External Links

    Citation

    Angela van Tilborg ; Bas van Rhijn

    Bladder: Urothelial carcinomas

    Atlas Genet Cytogenet Oncol Haematol. 2003-10-01

    Online version: http://atlasgeneticsoncology.org/solid-tumor/5001/bladder-urothelial-carcinomas

    Historical Card

    2000-10-01 Bladder: Urothelial carcinomas by  Jean-Loup Huret,Claude Léonard 

    Department of Pathology, Josephine Nefkens Institute, Erasmus University, 3000 DR Rotterdam, The Netherlands

    1999-10-01 Bladder: Urothelial carcinomas by  Jean-Loup Huret,Claude Léonard 

    Department of Pathology, Josephine Nefkens Institute, Erasmus University, 3000 DR Rotterdam, The Netherlands

    1997-08-01 Bladder: Urothelial carcinomas by  Jean-Loup Huret,Claude Léonard 

    Department of Pathology, Josephine Nefkens Institute, Erasmus University, 3000 DR Rotterdam, The Netherlands