Contemporary Issues in Bladder Neoplasia
Section 1 -
Classification and Grading of Urothelial Neoplasms
Wayne State University School of Medicine
The last decade has seen a tremendous upheaval in this very important area that only
recently seems to have settled down to a level of general though still not complete concurrence. For
over 2 decades the WHO classification and grading of urothelial neoplasms [Mostofi, 1973] dominated
although several variations and different schemes were published [Bergkvist, 1965; Malmstrom, 1987;
Lipponen, 1992]. In the early 1990's several factors emerged that resulted in the need to re-evaluate
this approach. First, the controversy of calling grade 1 papillary tumors "carcinoma" arose with several
groups led by William Murphy beginning to call all tumors in the low-grade end papilloma [Jordan, 1987;
Murphy, 1994]. Second, the use of intravesical therapy as a standard practice in the treatment of
high-risk non-invasive papillary tumors demanded that high-risk tumors be identified. Third, the WHO
(1973) was severely criticized for the imprecision of the histologic criteria (see table below), leading
many pathologists to essentially use this 3 grade system to create 5 grade groups (1, 1-2, 2, 2-3, and
3); one result being that only a small percentage of cases were placed in the grade 3 group. The effect
of the latter was confusion among clinicians as to how to treat grade 2 tumors that clearly included many
high-risk patients that should receive intravesical therapy as well as many patients with very low-risk
1973 WHO grading criteria [Mostofi, 1973]
|Grade 1 ||Tumors with the least degree of cellular anaplasia compatible with a diagnosis of malignancy|
|Grade 2 ||Histologic features between grades 1 and 3|
|Grade 3 ||Tumors with the most severe degrees of cellular anaplasia|
Recognizing the many emerging issues, in 1997 Mostofi organized a meeting of a small
group of urologic pathologists, urologists and oncologists to address these concerns. This was followed
by a much larger consensus conference that was held under the auspices of the International Society of
Urologic Pathology (ISUP) in March of 1998. The results of this consensus were subsequently adopted by
the WHO and the results published in 1998 as the WHO/ISUP consensus classification [Epstein, 1998]. Most
controversial was the adoption of the term Papillary Urothelial Neoplasm of Low Malignant Potential
(PUNLMP). PUNLMP represents a compromise term where the papilloma and carcinoma advocates could be
comfortable and bring that controversy to conclusion. Most important was the adoption of the grading
system that had been described by Malmstrom et al . The value of the latter was viewed as two-fold
– first, the morphologic criteria were well defined and second, it appeared to place the majority of
patients with high-risk disease into the high-grade category.
The publication of the 1999 WHO blue book the following year introduced a new variation on
this system with the splitting of the low and high grade categories of the 1998 WHO/ISUP into 3 groups
(grades 1, 2 and 3) while retaining the PUNLMP category [Mostofi, 1999]. This re-ignited the controversy
with some experts urging a return to the 1973 WHO [Cheng, 2000a]. Others criticized the 1998 WHO/ISUP
system as simply representing a renaming of the 1973 WHO [Oyasu, 2000], a clearly incorrect
interpretation [Lopez-Beltran, 2004a]. At a 2001 meeting in Ancona, Italy a modified version of the 1973
WHO was proposed.
This issue became the primary focus of debate at the WHO meetings prior to the release of the 2004 WHO
Classification. Following extensive debate and discussion it was agreed overwhelmingly to essentially
reproduce the 1998 WHO/ISUP classification as the 2004 WHO recommended classification scheme [Eble,
2004]. Similarly the authors of the 4th Series AFIP fascicle covering bladder neoplasia have
followed this system [Murphy, 2004]. With this consistent approach adopted by arguably the 2 most
influential references for tumor classification and grading, work can continue on evaluating the biologic
and clinical relevance and value of this system [Reuter, 2006]. The success of this in addressing the
key issues outlined in the first paragraph has been stressed, in particular the reclassification of
high-risk Grade 2 tumors (WHO 1973) in the high-grade papillary carcinoma category [Samaratunga, 2002;
Lopez-Beltran, 2004a; Yin, 2004]. For example, in the study by Yin et al , 13 of 46 WHO (1973)
grade 2 tumors (28%) were placed in the WHO (2004) high-grade category resulting in 23% of the cases
being considered high-grade in WHO 2004 compared to only 4% being called grade 3 in the 1973 WHO.
Undoubtedly further changes will follow in the years ahead, however at the present time this is the
system of choice. The College of American Pathologists (CAP) utilizes WHO 2004 in its recommendations
for the reporting of urothelial tumors [Amin, 2005]; other authors have recommended reporting both grades
until there is complete resolution of the issue [Lopez-Beltran, 2004b].
Relationship between 1973 and 2004 WHO (from Lopez-Beltran, 2004a)
2004 WHO CLASSIFICATION OF UROTHELIAL NEOPLASMS
- FLAT LESIONS WITH ATYPIA
- Reactive (inflammatory) atypia
- Atypia of unknown significance
- Dysplasia (low grade intra-urothelial neoplasia)
- Carcinoma in situ (high grade intra-urothelial neoplasia)
- PAPILLARY NEOPLASMS
- Inverted papilloma
- Papillary urothelial neoplasm of low malignant potential
- Papillary carcinoma, low grade
- Papillary carcinoma, high grade
- INVASIVE NEOPLASMS
Historically the term "hyperplasia" has been equated with counting cell layers and
specifically considering the epithelium to be hyperplastic if there were more than 7 cell layers. It is
well recognized that the apparent number of cell layers in the normal urothelium is variable and
dependent on the state of contraction of the bladder wall. The current classification recognizes
hyperplasia as when there is a "markedly thickened mucosa without atypia." Counting cell layers is not
recommended. The relationship between hyperplasia and neoplasia is unknown.
In the presence of acute and/or chronic inflammation, the urothelium shows a wide range of
reactive changes. There is usually a history of instrumentation, infection or treatment with
intravesical agents. Some patterns of atypia are associated with specific etiologies. In reactive
atypia the epithelium may or may not be thickened. Although a thickened epithelium is typically
associated with a reactive process, carcinoma in situ can also produce a thicker than normal epithelium.
Nuclei are uniformly enlarged, vesicular, and may have prominent usually centrally located nucleoli.
Mitoses may be frequent and are in the lower epithelial layers. Inflammation is almost always present.
ATYPIA OF UNKNOWN SIGNIFICANCE
One of the major grey zones in any consideration of intraepithelial lesions lies between
reactive atypias and true neoplastic (dysplastic) alterations. Reproducibility studies have clearly
demonstrated the lack of consistency in this particular area. This category was created to include those
instances where a lesion cannot be confidently placed in the reactive vs dysplastic categories.
Histologically there is usually an inflammatory background. The degree of cytologic atypia is judged to
be outside of the accepted range for reactive processes although this possibility cannot be excluded.
Reevaluation after inflammation subsides may resolve the problem, particularly in the follow up of
patients with known urothelial neoplasia who have been treated with intravesical therapy.
DYSPLASIA (LOW GRADE INTRAUROTHELIAL NEOPLASIA)
This category also suffers from a significant problem in diagnostic reproducibility. The
natural history of lesions with dysplastic features of a lesser degree than the moderate to severe
categories is unknown. There is however some evidence, largely genetic that it shares some abnormalities
with CIS and therefore likely represents a precursor lesion. It is most often diagnosed in the context
of known urothelial neoplasia. One study that applied the 1998 WHO/ISUP criteria indicated a 15% risk of
developing cancer with a mean follow up of 4.9 years [Cheng, 1999]. Histologically there is some
architectural distortion. The nuclei are irregularly enlarged with some hyperchromasia and pleomorphism
present. Overall the features are those of a neoplastic atypia but fall short of the criteria for
carcinoma in situ outlined below.
CARCINOMA IN SITU (HIGH GRADE INTRAUROTHELIAL NEOPLASIA)
The classification recognizes the need to expand the category of CIS to include lesions
that had been graded in the moderate to severe dysplasia categories in previous systems. This change
reflects current practice in major institutions treating bladder cancer. It also recognizes the general
trend for under diagnosis of higher grade lesions. There is also recognition that this is the most
reproducible diagnostic category. CIS is accepted as a precursor of invasive carcinoma.
MORPHOLOGIC PATTERNS OF CIS
- Small cell CIS
- Large cell CIS
- Denuding CIS "denuding cystitis"
- Underming (lepedic) growth
- Pagetoid CIS
Histologically CIS is characterized by architectural disorder and nuclear pleomorphism. The
cytologically atypical cells need not involve the full thickness of the epithelium and at the minimum
single malignant cells growing in a pagetoid fashion are sufficient for the diagnosis of CIS. Individual
cells tend to show marked cytologic atypia but increased N:C ratio is not a prerequisite (not present in
the large cell type of CIS). In some cases only a few isolated cells are present clinging to the
basement membrane (denuding CIS).
HISTOLOGIC FEATURES OF VALUE IN EVALUATING FLAT LESIONS
- Thickness of urothelium
- Nuclear size
- Nuclear crowding
- Nuclear borders including notches
- Nuclear chromatin distribution
- Accompanying inflammation
- Neovascularity at base
In the majority of cases the diagnosis of a lesion as being "papillary" in the urinary
bladder is straight forward and the questions are more related to proper classification (grading) and
evaluation of stage related issues. Occasionally there can be problems in differential diagnosis with
lesions that can mimic a papillary process (polypoid or papillary cystitis, fragmented or tangentially
cut flat lesions) or papillary lesions that are not strictly speaking urothelial (nephrogenic adenoma,
More problematic is the entire concept of papillary hyperplasia and particularly in the
setting of know papillary neoplasia when to call a small lesion a true papillary neoplasm. I personally
rarely use the term papillary hyperplasia as a diagnosis – if a true papillary stalk is evident then the
lesion is graded and classified into the categories of papilloma, PUNLMP, etc. A papillary stalk is
defined by the presence of a central fibrovascular core in an exophytic lesion. In the presence of known
neoplasia I am quite aggressive in diagnosing a lesion as a papillary tumor.
For cases with an undulating or tenting of the urothelium where no fibrovascular core
is evident, the term papillary hyperplasia has been suggested [Taylor, 1966]. These are more
"pseudopapillary" than truly papillary and diagnosis is dependent on evaluating the surface urothelium as
a "flat" lesion. In this setting if unequivocal dysplasia or CIS is present the diagnosis is dysplasia
or CIS. The term "atypical papillary hyperplasia" has been applied by one group but this is not widely
utilized [Swierczynski, 2002]. If the latter term is used, the report must explicitly indicate the
nature of the surface change. In the report by Swierczynski , the surface epithelium showed frank
CIS in 8 of 15 cases and in 13 of 15 cases there was a concurrent urothelial neoplasm (high grade
papillary carcinoma with or without invasion , carcinoma in situ , invasive urothelial carcinoma
 and papilloma . In one of the 2 lesions without concurrent pathology, a high-grade papillary
carcinoma subsequently developed and in the other no follow up was available. This whole issue revolves
around the concept of what appears first – changes in the flat epithelium followed by development of the
papillary architecture or development of a papillary architecture followed by transformation of the
epithelium or a combination of both.
In the 1998 WHO/ISUP classification, papillary hyperplasia was included as a category with
the group of papillary lesions. In the 2004 WHO classification, this is no longer included as a specific
designation but it is recognized that hyperplasias may be flat or pseudopapillary [Eble, 2004]. In the
current classification, hyperplasia with a pseudopapillary architecture refers to a slight tenting or
undulation of the urothelium lacking a well defined central fibrovascular core, although small vessels
may be present at the base of the papillae. There is no significant cytologic or architectural atypia.
These have most often been described in the setting of known papillary neoplasia. When identified de
novo the significance regarding subsequent development of neoplasia is unknown.
There has been a long standing controversy regarding the nature of papillary lesions
with minimal cytologic atypia. The application of this term by some experts to up to 1/3 of all
papillary lesions, was a major stimulant to the reevaluation of these lesions that began in 1997. The
current classification retains the very restrictive traditional WHO criteria. Histologically, papilloma
is characterized by a few fine papillary fronds without fusion or complexity. Individual fronds are
covered by an essentially normal urothelium without architectural or cytologic atypia. The number of
cell layers is not a criteria for diagnosis.
Papillomas meeting these restricted criteria occur at a younger age than other urothelial
bladder tumors and often present with only one or a few papillary processes. They have a low recurrence
rate with a low risk for the subsequent development of higher grade tumors [Cheng, 1999; Eble,
Inverted papilloma is a distinct clinical pathologic entity typically arising in the
trigone region in a younger patient population than papillary neoplasia. It is associated with a low
risk of recurrence (< 5%), distinctly different from papillary urothelial neoplasms [Cameron, 1976;
Cheng, 2005]. Recent genetic data supports the idea that these are not related to papillary urothelial
neoplasms [Sung, 2006]. Cases of synchronous inverted papilloma and papillary carcinoma are well
described although distinction from papillary carcinoma with an inverted growth pattern can be
problematic. Grossly these lesions typically have an exophytic polypoid growth pattern. Histologically
inverted papilloma consists of anastomosing trabeculae of urothelium covered by a normal or attenuated
urothelium. There is no significant nuclear pleomorphism and few mitoses. Squamous or glandular
differentiation may be present. In TUR material the fragmentation of the lesion may result in apparent
true papillary structures making diagnosis difficult.
PAPILLARY UROTHELIAL NEOPLASM OF LOW MALIGNANT POTENTIAL
The creation of this category represented a compromise between the "papilloma" camp and
those insisting on the use of "carcinoma" for all papillary lesions. The 1998 consensus statement
acknowledged that the lower grade papillary neoplasms were not intrinsically malignant but were
associated with a significant risk for the development of new papillary tumors (recurrence). These
lesions at the lower end of the spectrum were acknowledged to be clinically significant with close
clinical follow up necessary but further intravesical therapy not indicated. Morphologically this
category largely though not completely corresponds to grade 1 papillary carcinoma in the old WHO system.
The tumor consists of delicate papillae with little or no fusion. The covering urothelium shows minimal
if any architectural irregularity. Nuclei are roughly normal in size, lack significant nuclear
hyperchromasia or pleomorphism. The chromatin is fine and nucleoli are inconspicuous. Mitoses are
infrequent and basally located.
These tumors have a significantly lower rate of recurrence than either low- or high-grade
papillary carcinomas and a very low rate of stage progression [Malmstrom, 1987; Cheng, 1999; Holmang,
2001; Alvarez Kindalan, 2001; Oosterhuis, 2002; Campbell. 2005; Yin, 2004]. In a review of published
studies, Lopez-Beltran [2004a] found the mean tumor recurrence rate to be 36% and stage progression rate
to be 3.7%.
PAPILLARY UROTHELIAL CARCINOMA, LOW GRADE
This category contains the intermediate group of lesions. In the 1973 WHO system this
would include the lower ½ of grade 2 papillary carcinoma. These tumors have a low but definite risk of
invasion. Additionally they are associated with a high risk of "recurrence" and may progress to higher
grade lesions and require close clinical follow up but may not need additional intravesical therapy. The
latter needs to be studied in clinical trials. Histologically the papillae are largely delicate and
separate but some fusion may be seen. At low magnification there is a generally ordered appearance to
the cells within the epithelium. The nuclei tend to be uniformly enlarged and retain the elognated to
oval shape of normal urothelial cells. The chromatin remains fine with small and generally inconspicuous
nucleoli. Mitoses may be present but are few and remain basally located.
These tumors have a significantly higher recurrence rate than for PUNLMP and similar to
high-grade papillary carcinomas. They also have a significantly higher rate of stage progression than
PUNLMP but significantly lower than for high-grade papillary carcinoma [Malmstrom, 1987; Alvarez
Kindalan, 2001; Oosterhuis, 2002; Yin, 2004]. A review of the literature revealed a mean recurrence rate
of 50% and mean stage progression rate of 10% [Lopez-Beltran, 2004a]
PAPILLARY UROTHELIAL CARCINOMA, HIGH GRADE
Tumors that in many cases would have been included in the 1973 WHO grade 2 category (upper
½) have a significant frequency of invasion and biologically have more in common with the grade 3 tumors.
These tumors not only have a risk of invasion but have a significant risk of recurrence and progression.
For this reason the consensus was that these were better included in a high-grade category with the
traditional WHO grade 3 neoplasms. The overall progression rate (to invasive carcinoma) ranges from 15%
to 40%. These tumors, when noninvasive (pTa) likely all require additional intravesical therapy.
Heterogeneity of grade is recognized in papillary lesions [Cheng, 2000] and the consensus was that tumors
should be graded on their worst part although this needs further study.
In high grade tumors the papillae are frequently fused forming apparent solid masses. The
overall impression is one of disordered growth. The epithelium is of variable thickness and may resemble
"denuding CIS" in some instances. Individual cells are haphazardly arranged within the epithelium and
have a generally discohesive nature. Nuclei are hyperchromatic and pleomorphic. The chromatin is dense,
irregularly distributed and often clumped. Nucleoli may be single or multiple and are often prominent.
Mitoses are generally frequent and may be seen at any level of the epithelium.
PAPILLARY UROTHELIAL NEOPLASMS
|ARCHITECTURAL FEATURES ||LMP ||LOW GRADE ||HIGH GRADE|
|PAPILLAE ||Delicate ||Delicate ||Delicate|
|Rarely fused ||Occasionally fused ||Fused and branching|
|ORGANIZATION ||Polarity normal ||Predominantly ordered with minimal crowding and loss of polarity ||Predominantly disordered with crowding, overlapping cells and loss of polarity|
|Any thickness ||Any thickness ||Any thickness - may be single cells (denuding)|
|Cohesive cells ||Cohesive cells ||Often discohesive|
PAPILLARY UROTHELIAL NEOPLASMS
|NUCLEAR FEATURES ||LMP ||LOW GRADE ||HIGH GRADE|
|Elongated - oval -round|
|CHROMATIN ||Fine ||Fine with some variation ||Frequently coarse with marked variation|
|NUCLEOLI ||Absent to inconspicuous ||Usually inconspicuous ||Prominent|
Single to multiple
Basal if present
Basal if present
Several studies have looked at a variety of biologic markers in papillary tumors at their
relationship to the 3 groups; for the most part these have demonstrated significant differences of the
respective marker in the different categories [Cina, 2001; Pich, 2001; Yin, 2004].
DIAGNOSIS OF INVASION
Having made a diagnosis of either a papillary neoplasm or carcinoma in situ, the next
decision that must be reached is whether there is or is not invasion of the underlying tissue. In most
cases this is straightforward however it is not uncommon to face cases where this can be quite
problematic. Several reports have documented significant differences in the diagnosis of the presence or
absence of invasion and in the presence or absence of muscularis propria invasion when cases are reviewed
[Abel, 1998; True, 1996; Tosoni, 2000; van der Meijden, 2000]. In two large series, 35% and 53% of cases
reported to be pT1 were considered to be noninvasive on review [Tosoni, 2000; van der Meijden, 2000;
Witjes, 2006]. Any case of high-grade papillary carcinoma or CIS should be studied with the mindset that
invasion is common and must be excluded. For papillary lesions invasion can occur at the tumor base or
within the fibrovascular cores so both areas must be evaluated. The literature contains many series that
include Grade 1 tumors reported to be invasive (pT1); the occurrence of such cases has been challenged
[Jordan, 1987; Mikulowski, 2005]. In my experience all tumors reported as grade 1, pT1 tumors have not
demonstrated convincing invasion and I have downstaged them to pTa (or upgraded them).
A variety of histologic features are associated with the development of invasion into the
underlying submucosa including disruption of the smooth outline of the basement membrane, the presence of
single cells or clusters of cells apparently disconnected from the surface urothelium, irregularly shaped
nests or finger-like projections from the surface [Amin, 1997; Grignon, 1997; Epstein, 2004]. With even
early invasion the individual cells often have different morphological features than the in situ tumor
including more abundant eosinophilic cytoplasm or higher nuclear grade. There is often an associated
stromal response including desmoplasia, edema (myxoid), fibrosis and inflammation. Retraction artifact
around small clusters of cells suggests that they are invasive. In some cases however there is no
apparent stromal reaction. The type of stromal reaction has not been found to have prognostic
significance in pT1 tumors [Samaratunga, 2005]. If there is a marked inflammatory infiltrate care must
be taken to look for obscured tumor cells or nests of cells and occasionally a cytokeratin stain is
needed to clarify the nature of suspicious cells. Certain variants of urothelial carcinoma can mimic
lymphoid lesions including so-called lymphoma-like patterns [Zukerberg, 1991], the plasmacytoid variant
[Sahin, 1991] and lymphoepithelioma-like carcinoma [Amin, 1994].
Criteria for Diagnosis of Invasion into Lamina Propria by Urothelial
- Invasion seen much more frequently, although not exclusively, in high grade (1998 WHO/ISUP classification) lesions.
- Irregularly shaped nests
- Single cell infiltration
- Irregular or absent basement membrane
- Tentacular finger-like projections
- Invasive component with higher nuclear grade and/or more cytoplasm (or morphologically different) than overlying non-invasive component
- Desmoplasia or sclerosis
- Retraction artifact
- Myxoid stroma
- Pseudosarcomatous stroma
- Absent stromal response
DEPTH OF INVASION
Having determined that invasion is present, the next most critical feature is assessing
the specimen for muscularis propria invasion. This is often viewed as the most critical parameter in
treatment algorithms with pT1 tumors managed primarily by TURBT and intravesical therapy (most often BCG)
and pT2 tumors by cystectomy or cystoprostatectomy. Muscularis propria must be distinguished from
muscularis mucosae (MM) [Ro, 1987]. The former is characterized by thick, compact bundles of smooth
muscle cells forming a "solid" tissue. In contrast, MM is characterized by wispy collections of smooth
muscle cells that only rarely form a "solid" layer. The MM layer is typically associated with a layer of
large vascular channels. The trigone region is problematic in that the muscularis propria has a pattern
of interweaving smooth muscle bundles with a thin submucosa. In this region the muscularis mucosae is
for practical purposes impossible to define. Over diagnosis of MP invasion has been documented to occur
in a significant number of cases [Abel 1988; True 1996; van der Meijden, 2004].Thermal artifact related
to cautery can also result in the submucosa having a dense eosinophilic appearance mimicking the MP – on
occasion I have resorted to doing a trichrome or desmin stain to try to elucidate the nature of
If no muscle invasion is present, the concept of substaging pT1 tumors has been advocated
by many. Two approaches have been taken. In 1982 Farrow introduced the idea of microinvasion based on
measuring the depth of invasion with invasion less than 5 mm considered microinvasive. More recently,
Cheng  applied this approach in a study of TURBT specimens and found 4 mm to be the best cut off
for predicting the likelihood of extravesical extension in the subsequent cystectomy specimen. In a
similar study van der Aa  found 5 mm to be a significant cutpoint. McKenney  suggested using
2 mm to define microinvasion but presented no data in support of this measurement.
The possibility of using the muscularis mucosae as a layer to substage pT1 tumors was first proposed
by Younes  who demonstrated that tumors invading to the level of the MM or deeper behaved more like
pT2 tumors than those with invasion superficial to this layer. Many studies have subsequently repeated
this with most having similar findings [Orsola, 2005]. Angulo  reported that in many cases it is
not possible to accurately apply this method of substaging although in a recent report by Orsola 
they were able to substage 87% of cases. In current urologic practice, many urologists are interested in
identifying patients with pT1 disease at high risk for progression and offering them more aggressive
treatment (radical surgery) without demonstrable pT2 disease. In this regard it is appropriate to give
the clinician some at least descriptive information regarding the depth or volume of invasive disease.
In my practice if I see MM invasion I report it, if there is minimal invasion I use terms such as
superficial invasion with a clarifier such as < 1 mm or superficial to the MM, etc.
Finally the diagnosis of pT3 disease in biopsy or TURBT material is complicated by the fact that fat
can be present throughout the bladder wall, including the submucosa [Philip 2000] and so is largely
restricted to cystectomy specimens.
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