COMMENTARY Open Access

How much do you know about benign,preneoplastic, non-invasive and invasiveneoplastic lesions of the urinary bladder classifiedaccording to the 2004 WHO scheme?Rodolfo Montironi1*, Liang Cheng2, Marina Scarpelli1, Roberta Mazzucchelli1 and Antonio Lopez-Beltran3

Abstract

The aim of this essay is the self assessment of the level of knowledge of the 2004 WHO classification of bladderneoplasms through a series of MCQs, each associated a short commentary. This paper is directed to all who areinvolved with the application of this classification at the anticancer research, diagnostic, prognostic and therapeuticlevels, in particular to uropathologists, urologists and oncologists.

IntroductionThe 1973 WHO histological grading of bladder cancer isone of most successful grading systems among all organsites and has been validated since its introduction threedecades ago. In 1998, a system of classifying non-inva-sive flat and papillary urothelial neoplasms of the urin-ary bladder was proposed by the International Society ofUrologic Pathology in association with the World HealthOrganization. This became known as the 1998 WHO/ISUP classification system [1]. In 2004, this classificationsystem was adopted in Pathology and Genetics ofTumours of the Urinary System and Male GenitalOrgans, one of a series of WHO “Blue Books” for theclassification of tumours (Additional file 1: Appendix 1).This is known as the 2004 WHO classification [2].This paper is directed to all who are involved with the

application of this classification at the anticancerresearch, diagnostic, prognostic and therapeutic levels,in particular to uropathologists, urologists and oncolo-gists. The aim of this essay is to test the level of knowl-edge of the 2004 classification through a series ofMCQs, each associated a short commentary. Additionalfile 2: Appendix 2 can be used by the readers to recordthe correct answers. The list with the correct answers

will be published in the next journal issue. Those inter-ested to discuss the MCQs with the authors of this con-tribution should contact the corresponding author.

Multiple choice questions and explanatory notesQuestion No 1. Normal urothelium. Which of the followingsitems is wrong?

1. It is the type of epithelium lining the urinary blad-der, ureters, and renal pelvis2. Its thickness varies with the state of distension ofthe bladder3. By immunohistochemistry it shows reactivity forCK20 only in the basal cell layer4. Frequently technical problems such as tangentialcut, thick sections and vagaries of staining and fixa-tion may cause the normal urothelium appear hyper-chromatic and hyperplastic

Explanatory notesUrothelium (Figure 1) is a multilayered epithelium ofthe urinary bladder, ureters, and renal pelvis in whichthe cells mature to form the very large surface “umbrellacells.” The thickness of the normal urothelium varieswith the state of distension of the bladder (2 to 4 celllayers when dilated and 5 to 7 layers when contracted)[3]. The urothelium of the renal pelvis, urethra and thebladder neck is usually composed of slightly larger cells,which have diminished cytoplasmic clearing and hencemay be misinterpreted as dysplasia. Umbrella cells may

* Correspondence: r.montironi@univpm.it1Section of Pathological Anatomy, School of Medicine, Polytechnic Universityof the Marche Region (Ancona), Ancona, ItalyFull list of author information is available at the end of the article

Montironi et al. Diagnostic Pathology 2011, 6:31http://www.diagnosticpathology.org/content/6/1/31

© 2011 Montironi et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.

show some degree of nuclear pleomorphism, whichshould not be misconstrued to be dysplastic. If the sec-tions are thick, the urothelium may appear hyperchro-matic and this artifact compounded with tangentialsectioning may result in changes felt to represent dys-plasia. Vagaries of staining and fixation may also imparthyperchromasia to benign nuclei. Normal urotheliumshows reactivity for CK20 only in the superficialumbrella cell layer, while CD44 staining is limited to thebasal and parabasal urothelial cells. Nuclear staining forp53 is absent in normal urothelium [4].

Question No 2. Flat urothelial hyperplasia. Which of thefollowing items is correct?

1. The diagnosis does not usually requires countingthe number of cell layers in the urothelium2. It consists of a markedly thinned urothelium,lower than seven cells layers thick, with minimalcytological atypia3. When seen by itself, there are data proving that ithas premalignant potential4. It is a reactive process unrelated to bladder cancer

Explanatory notesHistorically the term “hyperplasia” has been equatedwith counting cell layers and specifically considering theepithelium to be hyperplastic if there were more than 7cell layers (Figure 2). It is well recognized that theapparent number of cell layers in the normal urotheliumis variable and dependent on the state of contraction ofthe bladder wall. The 2004 classification recognizeshyperplasia as when there is a “markedly thickenedmucosa without atypia.” Counting cell layers is notrecommended. The relationship between hyperplasiaand neoplasia is unknown [2,5,6].

Question No 3. Reactive atypia. Which of the followings iscorrect?

1. It is a preneoplastic lesion

2. It is a synonymous of flat dysplasia3. It consists of cytological abnormalities occurringin acutely or chronically inflamed urothelium4. It never coexists with dysplasia or in situcarcinoma

Explanatory notesIn the presence of acute and/or chronic inflammation,the urothelium shows a wide range of reactive changes(Figure 3). There is usually a history of instrumentation,infection or treatment with intravesical agents. Somepatterns of atypia are associated with specific aetiologies.In reactive atypia the epithelium may or may not bethickened. Although a thickened epithelium is typicallyassociated with a reactive process, carcinoma in situ canalso produce a thicker than normal epithelium. Nucleiare uniformly enlarged, vesicular, and may have promi-nent usually centrally located nucleoli. Mitoses may befrequent and are in the lower epithelial layers. Inflam-mation is almost always present [2].

Figure 1 Normal urothelium.Figure 2 Flat urothelial hyperplasia.

Figure 3 Reactive atypia.

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Question No 4. Papillary urothelial hyperplasia(Pseudopapillary hyperplasia). Which of the followings iscorrect?

1. Well-developed branching fibrovascular cores arepresent2. Urothelium exhibiting a slight “tenting”, undulat-ing, or papillary growth; often there are one or sev-eral dilated capillaries at the base of the lesion3. It is not a preneoplastic lesion/condition4. This term is also used to describe polypoid cystitis

Explanatory notesIn the 1998 WHO/ISUP classification, papillary hyperpla-sia was included as a category with the group of papillarylesions [1]. In the 2004 WHO classification, this is nolonger included as a specific designation but it is recog-nized that hyperplasias may be flat or pseudopapillary (Fig-ure 4) [2]. In the current classification, hyperplasia with apseudopapillary architecture refers to a slight tenting orundulation of the urothelium lacking a well defined centralfibrovascular core, although small vessels may be presentat the base of the papillae. There is no significant cytologicor architectural atypia. These have most often beendescribed in the setting of known papillary neoplasia.

When identified de novo the significance regarding subse-quent development of neoplasia is unknown.

Question No 5. Urothelial dysplasia Which of thefollowings is correct?

1. There is no evidence that dysplasia may be a pre-cursor of invasive carcinoma2. The natural history of dysplasia in humans ispoorly understood. There is some evidence that dys-plasia may be a precursor of invasive carcinoma3. It consists of a markedly thickened urothelium,greater than seven cells layers thick, with cytologicalatypia4. The thickness of the urothelium and the polarityof the cells are maintained

Explanatory notesHistologically there is some architectural distortion. Thenuclei are irregularly enlarged with some hyperchromasiaand pleomorphism present. Overall the features are thoseof a neoplastic atypia but fall short of the criteria for car-cinoma in situ outlined below (Figure 5). This categoryalso suffers from a significant problem in diagnosticreproducibility. The natural history of lesions with dys-plastic features of a lesser degree than the moderate tosevere categories is unknown. There is however someevidence, largely genetic that it shares some abnormal-ities with CIS and therefore likely represents a precursorlesion. It is most often diagnosed in the context ofknown urothelial neoplasia. One study that applied the1998 WHO/ISUP criteria indicated a 15% risk of devel-oping cancer with a mean follow up of 4.9 years [7].

Question No 6. Carcinoma in situ of the urothelium. Whichof the followings is wrong?

1. The type of atypia often seen in invasive urothelialcarcinoma

Figure 4 Papillary urothelial hyperplasia (pseudopapillaryhyperplasia). Figure 5 Urothelial dysplasia.

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2. It is histologically characterized by unequivocalsevere cytological atypia3. A common feature of CIS is the lack of intercellu-lar cohesion resulting in extensive denudation4. Human polyoma virus infection might result inthe development of CIS

Explanatory notesHistologically CIS is characterized by architectural dis-order and nuclear pleomorphism (Figure 6). The cyto-logically atypical cells need not involve the fullthickness of the epithelium and at the minimum singlemalignant cells growing in a pagetoid fashion are suffi-cient for the diagnosis of CIS. Individual cells tend toshow marked cytological atypia but increased N:C ratiois not a prerequisite (not present in the large cell typeof CIS). In some cases only a few isolated cells are pre-sent clinging to the basement membrane (denudingCIS).The classification recognizes the need to expand the

category of CIS to include lesions that had been gradedin the severe dysplasia category in previous systems.This change reflects current practice in major institu-tions treating bladder cancer. There is recognition thatthis is the most reproducible diagnostic category. CIS isaccepted as a direct precursor of invasive carcinoma.The development of invasion is seen in the follow-up in20 to 30% of the cases [2,5,8].

Question No 7. Papillary urothelial neoplasm of lowmalignant potential. Which of the followings is correct?

1. Papillae with minimal architectural abnormalitiesand nuclear atypia, with more cell layers thanpapilloma2. Papillary urothelial neoplasm of low malignantpotential is associated with invasion or metastasis3. Follow-up of the patient is not needed

4. Patients are not at an increased risk of developingrecurrent or new papillary lesions usually of similarhistology

Explanatory notesMorphologically PUNLMP largely, though not comple-tely, corresponds to grade 1 papillary carcinoma in theold WHO system (Figure 7). The tumour consists ofdelicate papillae with little or no fusion. The coveringurothelium shows minimal if any architectural irregular-ity. Nuclei are roughly normal in size, lack significantnuclear hyperchromasia or pleomorphism. The chroma-tin is fine and nucleoli are inconspicuous. Mitoses areinfrequent and basally located. These tumors have a sig-nificantly lower rate of recurrence than either low- orhigh-grade papillary carcinomas and a very low rate ofstage progression [5,9]. In a review of published studies,Lopez-Beltran [5,8] found the mean tumour recurrencerate to be 36% and stage progression rate to be 3.7%.

Question No 8. Low-grade papillary urothelial carcinoma.Which of the followings is correct?

1. This lesion is usually associated with invasion ormetastases at the time of presentation1. Mitotic figures, including atypical forms, are fre-quently seen at all levels2. Low grade papillary urothelial carcinomas have ahigh risk of progression, with figures varying from15% to 40%, and of association with invasive diseaseat the time of diagnosis3. The urothelium lining the papillae is similar toflat urothelial dysplasia

Explanatory notesThis category contains the intermediate group of lesions.In the 1973 WHO system this would include the lower

Figure 6 Carcinoma in situ of the urothelium.Figure 7 Papillary urothelial neoplasm of low malignantpotential.

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1/2 of grade 2 papillary carcinoma. Histologically thepapillae are largely delicate and separate but somefusion may be seen. At low magnification there is a gen-erally ordered appearance to the cells within the epithe-lium (Figure 8). The nuclei tend to be uniformlyenlarged and retain the elongated to oval shape of nor-mal urothelial cells. The chromatin remains fine withsmall and generally inconspicuous nucleoli. Mitoses maybe present but are few and remain basally located. Theurothelium lining the papillae is similar to flat dysplasia.These tumors have a significantly higher recurrence ratethan for PUNLMP and similar to high-grade papillarycarcinomas. They also have a significantly higher rate ofstage progression than PUNLMP but significantly lowerthan for high-grade papillary carcinoma [2,5,9]. A reviewof the literature revealed a mean recurrence rate of 50%and mean stage progression rate of 10% [5,8].

Question No 9. High-grade papillary urothelial carcinomaWhich of the followings is correct?

1. Mitotic figures are infrequent and usually seen inthe lower half of the urothelium2. Tumour recurrence, stage progression andtumour-related mortality occur in approximately35%, 4% and 2% of patients, respectively3. Tumour recurrence, stage progression andtumour-related mortality are approximately 50%,10% and 5%, respectively4. High grade papillary urothelial carcinomas have ahigh risk of progression, with figures varying from15% to 40%, and of association with invasive diseaseat the time of diagnosis

Explanatory notesTumors that in many cases would have been included inthe 1973 WHO grade 2 category (upper 1/2) have a sig-nificant frequency of invasion and biologically havemore in common with the grade 3 tumors.

Histologically, the papillae are frequently fused formingapparent solid masses. The overall impression is one ofdisordered growth. The epithelium is of variable thick-ness and is similar to flat CIS (Figure 9). Individual cellsare haphazardly arranged within the epithelium andhave a generally discohesive nature. Nuclei are hyper-chromatic and pleomorphic. The chromatin is dense,irregularly distributed and often clumped. Nucleoli maybe single or multiple and are often prominent. Mitosesare generally frequent and may be seen at any level ofthe epithelium. These tumours not only have a risk ofinvasion but have a significant risk of recurrence andprogression. For this reason the consensus was thatthese were better included in a high-grade category withthe traditional WHO grade 3 neoplasms. The overallprogression rate (to invasive carcinoma) ranges from15% to 40%. These tumours, when noninvasive (pTa)likely all require additional intravesical therapy. Hetero-geneity of grade is recognized in papillary lesions[2,8,10] and the consensus was that tumours should begraded on their worst part although this needs furtherstudy.

Question No 10. Inverted urothelial papilloma. Which ofthe following statements is wrong?

1. Endophytic lesion which shares several featureswith exophytic urothelial papilloma2. Rarely, hybrid cases exist with portions of thelesion resembling exophytic papilloma and othersinverted urothelial papilloma3. Urothelial carcinoma may arise within invertedurothelial papilloma4. Urothelial nests, clusters, or single cells invadingthe lamina propria

Explanatory notesInverted papilloma is a distinct clinical pathologic entitytypically arising in the trigone region in a younger

Figure 8 Low-grade papillary urothelial carcinoma. Figure 9 High-grade papillary urothelial carcinoma.

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patient population than papillary neoplasms. Grosslyinverted papilloma typically shows an exophytic poly-poid growth pattern. Histologically it consists of anasto-mosing trabeculae of urothelium covered by a normal orattenuated urothelium (Figure 10). There is no signifi-cant nuclear pleomorphism and few mitoses can beseen. Squamous or glandular differentiation may be pre-sent. In TUR material the fragmentation of the lesionmay result in apparent true papillary structures makingdiagnosis difficult. Distinction from papillary carcinomawith an inverted growth pattern can be problematic (Seebelow). Cases of synchronous inverted papilloma andpapillary carcinoma are well described. It is associatedwith a low risk of recurrence (< 5%) [11]. Recent geneticdata supports the idea that inverted papilloma is notrelated to papillary urothelial neoplasms [12].

Question No 11. Urothelial carcinoma with endophyticgrowth patterns is

1. A variant of invasive urothelial carcinoma2. A non-invasive urothelial carcinoma exhibiting aprominent endophytic growth pattern resulting inconsiderable difficulty in assessing invasion3. Any invasive urothelial carcinoma4. Does not occur in the bladder

Explanatory notesSome papillary urothelial carcinomas exhibit a promi-nent endophytic growth pattern resulting in consider-able difficulty in assessing invasion [13]. Endophyticgrowth is evident either as inter-anastomosing cordsand columns of urothelium, often with a striking resem-blance to inverted papilloma (inverted papilloma-likepattern), or as broad, pushing bulbous invaginationsinto the lamina propria (broad-front pattern) (Figure11). Distinction from inverted papilloma requires

attention to architectural and cytological features. Adiagnosis of invasion requires the unquestionable pre-sence within the lamina propria of irregularly shapednests or single cells that may have evoked a desmoplas-tic or inflammatory response. A stromal response maybe absent. In such instances, irregularity of the contoursof the invasive nests, architectural complexity, andrecognition of single-cell invasion are helpful. Occasion-ally, the cells in the invading nests appear morphologi-cally different from the cells at the base of the tumour,and they may appear as smaller aggregates presentwithin empty spaces. These spaces may mimic vascularinvasion closely, but they are believed to be retractionartifacts.

Question No 12. Urothelial carcinoma with lamina propriainvasion. Which of the following statements is wrong?

1. Urothelial nests, clusters, or single cells invadingthe lamina propria.2. Often associated with a desmoplastic or inflamma-tory stromal response3. Nests of invasive tumour within the lamina pro-pria may exhibit prominent retraction artifact whichis frequently overdiagnosed as vascular invasion.4. Urothelial nests invading adipose tissue is alwayspT3 stage

Explanatory notesThe invasive front of the tumour may be seen as singlecells or nests or finger-like extensions (Figure 12) [9].The infiltrating component often shows higher degreeof nuclear pleomorphism and has abundant eosinophiliccytoplasm. Stroma may show a desmoplastic or heavyinflammatory response. Retraction artifacts, mimickingvascular-lymphatic invasion, are particularly frequent intumours superficially invading into the lamina propria

Figure 10 Inverted urothelial papilloma.

Figure 11 Urothelial carcinoma with endophytic growthpattern.

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and should not be overdiagnosed as vascular invasion.Vascular invasion in cases with lamina propria invasionis uncommon and should be diagnosed only in unequi-vocal cases or after immunohistochemistry [14]. In theabsence of stromal response the diagnosis of invasionrely on the characteristics of the infiltrating epithelium.Recently-emphasized pitfalls in the diagnosis of lamina

propria invasive urothelial carcinoma include tangentialsectioning, thermal artifact, obscuring inflammation, CISinvolving von Brunn nests, deceptively bland tumourssuch as microcystic and nested urothelial carcinoma var-iants, invasion into indeterminate type of muscle, andinvasion into adipose tissue within lamina propria[14,15]. Determination of the type of muscle (muscularismucosae vs. muscularis propria) invaded by carcinomacan be particularly difficult due to different problemsincluding: small sample size, tissue distortion, cauteryartifact, poor orientation, fibrosis and inflammation eli-cited by destructive growth of invasive tumour, evenhypertrophy of the normally thin and discontinuousmuscularis mucosae. In those cases the designation of“muscle type indeterminate” is a viable description [16].Only in the last few years has the presence of adiposetissue in all layers of the bladder including lamina pro-pria and muscularis propria been well-documented [17].Thus the presence of carcinoma in fat does not necessa-rily indicate extra-vesical extension. Invasive tumourshould be graded as low-or high-grade analogous to thescheme used for grading non-invasive lesions.

Question No 13. Urothelial carcinoma with muscularispropria invasion. Which of the statements is wrong

1. Tumour cells infiltrate thick muscle bundles2. Urothelial nests, clusters, or single cells within thesubepithelial connective tissue3. Is much more aggressive than low-gradecarcinoma

4. In a TUR specimen there should be no attempt tosubstage the depth of muscularis propria invasion

Explanatory notes(See also comments related to MCQ 12) The level ofinvasion of the lamina propria is related to patient out-come, with a worse prognosis for tumours that invadebeyond the muscularis mucosae (pT1b) [14] or deeplyinto the subepithelial connective tissue, as quantitatedusing an ocular micrometer. The WHO 2004 grouprecommended that some estimate of extent of laminapropria invasion (for example: pT1a - above or intomuscularis mucosae vs. pT1b - tumours below) (Figure13) [2] be provided but this is currently not a formalpart of the 2002 TNM system, and it is not universallyreported, since there is no established method that isconsistently applicable and reproducible. In fact it isoften difficult to identify the depth of lamina propriainvasion due to the lack of orientation in the transure-thral resection (TUR) chips or because of the absence ofmuscularis mucosae and thick-walled vessels. Neverthe-less, pathologists are encouraged to provide someassessment as to the extent of lamina propria invasion.If the tumour invades muscularis mucosae, it should bementioned in the report unambiguously so that theurologist does not confuse muscularis mucosae withmuscularis propria. The presence or absence of

Figure 12 Urothelial carcinoma with lamina propria invasion.

Figure 13 Urothelial carcinoma with muscolaris propriainvasion.

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muscularis propria in the specimen should always bementioned, even in cases of noninvasive disease, withthe purpose of giving feedback to the urologist as to thedepth of the biopsy [14].

Question No 14. Urothelial carcinoma with muscularispropria invasion. Which of the statements are correct

1. Substaging of pT2 (pT2a, invasion of “superficial”muscle or inner half, vs. pT2b, invasion of deepmuscle or outer half) can only been done on radicalcystectomy specimens2. Muscularis mucosae invasion is synonymous tomuscularis propria invasion3. The presence or absence of muscularis propria inbiopsy and transurethral resection of bladder tumoursamples, and presence or absence of carcinoma inidentified muscularis propria, should not be specified4. Clinicians should accept a diagnosis of “Urothelialcarcinoma invading muscle” without demandingfurther clarification from the pathologist

Explanatory notesInvasion by bladder carcinoma into muscularis propria(muscle wall, detrusor) is an ominous finding where thepatient becomes a candidate for radical cystectomy orradiation therapy with or without adjuvant chemother-apy. Special studies, such as a Masson stain or immuno-histochemistry with antibodies to actin, help identify allsmooth muscle tissue. The highlighting of numerousmuscle fibres distributed throughout an extensivetumour may lead to a diagnosis of muscularis propriainvasion [14]. Situations where there is uncertainty as tothe presence muscularis propria invasion should be con-veyed to the urologist. Clinicians should not accept adiagnosis of “TCC invading muscle” without demandingfurther clarification (if possible) from the pathologist.The presence or absence of muscularis propria in

biopsy and transurethral resection of bladder tumour(TURBT) samples, and presence or absence of carci-noma in identified muscularis propria, should bespecified.Substaging of pT2 (pT2a - invasion of “superficial”

muscle = inner half vs. pT2b - invasion of “deep” mus-cle = outer half) and distinction of pT2 vs. pT3 canonly been done on radical cystectomy specimens, andnot TURBT samples (Figure 1I, insert) [14]. Even incystectomy specimens it can be a challenge at times todetermine extra-vesical (pT3) spread since the bound-ary between muscularis propria and its fat is not well-demarcated from peri-vesical fat. Moreover, thisboundary can be distorted, obscured, or obliterated byfibrosis and inflammation associated with infiltratingtumour.

Question No 15. Which of the following statements iswrong

1. The WHO 2004 classification is the most currentversion in bladder tumour classification.2. The WHO 1973 classification is still considered bymany urologists and oncologists as the internationalstandard in patient’s management.3. The TNM system should be preferred to theWHO 2004 classification4. Lesions called WHO 1973 grade 3 are by defini-tion high-grade carcinoma in the WHO 2004 system

Explanatory notesA major misconception is that there is a one to onetranslation between the 1973 and 2004 WHO classifica-tion systems. Only at the extremes of grades in the 1973WHO classification, does this correlation hold true.Lesions called papilloma in the WHO classification sys-tem would also be called papilloma in the 2004 WHOsystem. At the other end of the grading extreme, lesionscalled WHO grade 3 are by definition high-grade carci-noma in the 2004 WHO system. However, for WHOgrades 1 and 2, there is no direct translation to theWHO/ISUP system [5].

Additional material

Additional file 1: APPENDIX 1. 2004 WHO classification of the urothelialneoplasms

Additional file 2: Appendix 2. Recording form.

Author details1Section of Pathological Anatomy, School of Medicine, Polytechnic Universityof the Marche Region (Ancona), Ancona, Italy. 2Department of Pathologyand Laboratory Medicine, Indiana University School of Medicine, Indianapolis,IN, USA. 3Unit of Anatomic Pathology, Cordoba University Medical School,Cordoba, Spain.

Received: 8 March 2011 Accepted: 7 April 2011 Published: 7 April 2011

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doi:10.1186/1746-1596-6-31Cite this article as: Montironi et al.: How much do you know aboutbenign, preneoplastic, non-invasive and invasive neoplastic lesions ofthe urinary bladder classified according to the 2004 WHO scheme?Diagnostic Pathology 2011 6:31.

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