The Classification of Urothelial Tumors… Once Again
Victor E. Reuter
Memorial Sloan-Kettering Cancer Center
New York, NY
Pathologists play an important role in the management of urinary bladder cancer by making a careful
morphologic assessment of the primary tumor and its relation to adjacent structures. Ideally, evaluation
of the primary site will segregate patients into groups with distinct clinical features, biologic
behavior, and response to therapy. Traditionally, pathologists have relied on factors such as histologic
tumor type, grade, depth of invasion, presence of absence of vascular invasion, etc., to accomplish this
goal. Recently, new modalities have been introduced such as flow cytometry, monoclonal antibodies,
assessment of proliferative rate, cytogenetics and molecular genetics in an effort to enhance our ability
to subclassify these patients. Without question we are advancing into an era in which tumors will be
classified based not only on their cytomorphological features but also on their molecular "fingerprint".
Nevertheless, at this time morphology remains the "gold standard" and consequently the best tool to
assess the biologic potential of early bladder cancer.
Unfortunately, there are many problems with the pathologic evaluation of these tumors, mostly due to
the inherent subjectivity of the field and the lack of universal, standardized criteria for the
evaluation of the above-mentioned morphologic parameters. Nowhere is this issue more apparent than in
grading. In many, if not all, sites there is significant interobserver variability when it comes to
grading. We tend to agree better at the extremes, that is to say that we agree with what is benign and
what is high grade. We do less well segregating the degrees of dysplasia, separating "significant
atypia" from low grade carcinoma, low grade from intermediate grade carcinoma, and intermediate grade
from high grade carcinoma. In fact, in any classification scheme, the more options we are given the
poorer the interobserver variability. These statements do not apply solely to bladder cancer but to most
Another issue that compounds the problem is the fact that multiple other factors such as age,
recurrences, status of the adjacent mucosa, and size affect the biologic behavior of a tumor. As such,
it is wise for us to look at our role in the morphological assessment of bladder tumors as but one
component in risk prognostication.
Grading of Urothelial Tumors
Grading is a method by which pathologists evaluate the cytologic and/or growth pattern
characteristics of a tumor in an attempt to predict its biologic potential. To this effect, multiple
grading schemes have been developed and employed throughout the years. In all classifications, those
lesions which cytologically resemble normal urothelium are low grade (well differentiated) while
cytologic anaplasia characterized high grade or poorly differentiated carcinomas. Nevertheless,
classifications differ in their recognition of a benign tumor counterpart and in the number of categories
into which transitional cell carcinoma should be graded.
In October 1997, Dr. F.K. Mostofi assembled a group of pathologists, urologists, urologic
oncologists, and basic scientists with an interest in bladder neoplasia at a meeting in Washington, D.C.
with the purpose of discussing the terminology of bladder lesions and making recommendations to the World
Health Organization (WHO) Committee on Urothelial Tumors. All in attendance agreed that it was
imperative to develop a universally acceptable classification system for bladder neoplasia that could be
used effectively by pathologists, urologists, and oncologists. Following this meeting, a group of
urologic pathologists who had attended the Washington meeting decided to broaden the representation of
the group and arranged a meeting primarily of the members of the International Society of Urologic
Pathologists (ISUP) at the 1998 United States and Canadian Academy of Pathology Meeting held in Boston,
Massachusetts. At this meeting issues regarding terminology of bladder lesions ¾ primarily neoplastic
and putative preneoplastic lesions ¾ were discussed, resulting in a consensus statement. In December
1998, barely 14 months from the beginning of this initiative, we published the WHO/ISUP consensus classification of urothelial (transitional cell) neoplasms of the
CLASSIFICATION OF UROTHELIAL (TRANSITIONAL CELL) NEOPLASMS
the terms "urothelium" and "transitional epithelium" are synonymous and may be used interchangeably.
- Many pathologists overuse the diagnosis of "mild dysplasia". Flat lesions
with minimal cytologic atypia and architectural disorder should be designated as normal rather than as
- Flat Urothelial Hyperplasia
Papillary Urothelial Hyperplasia
- Flat urothelial hyperplasia consists of a markedly thickened mucosa without cytologic atypia.
- This lesion may be seen adjacent to low grade papillary urothelial neoplasms, but there is no data as to its premalignant potential when seen by itself.
Flat lesions with atypia:
- This term in the past has been used imprecisely, frequently to describe polypoid cystitis, an inflammatory and reactive condition.
- Characterized by urothelium of variable thickness without atypia and exhibiting a slight "tenting", undulating, or papillary growth. These areas lack fibrovascular cores but often have one or several dilated capillaries at its base.
- The relationship between this lesion and papillary urothelial neoplasia is controversial, although it is frequently associated with either a prior or concurrent history of papillary bladder cancer.
- Reactive atypia
Atypia of unknown significance
- Reactive (inflammatory) atypia consists of nuclear abnormalities occurring in acutely or chronically inflamed urothelium.
- This lesion should not be considered neoplastic.
Dysplasia: Low-grade Intraurothelial Neoplasia
- In some cases it is difficult to differentiate between reactive and neoplastic atypia, due to a greater degree of pleomorphism and/or hyperchromatism out of proportion with the extent of inflammation.
- This designation will allow patients to be followed more closely and re-evaluated once the inflammation subsides.
Carcinoma in situ (High-grade Intraurothelial Neoplasia)
- Dysplastic urothelium (low-grade intraurothelial neoplasia) has appreciable cytologic and architectural abnormalities felt to be neoplastic, yet falling short of the diagnostic threshold for urothelial carcinoma in situ.
- Because of problems with interobserver reproducibility, the lack of a uniform definition, and confusing reports in the literature, the natural history of dysplasia in humans is poorly understood.
- There is some evidence along several lines of investigation that dysplasia may be a precursor of invasive carcinoma.
Papillary Urothelial Neoplasms:
- Carcinoma in situ (CIS) is a flat lesion of the urothelium that is a documented precursor of invasive cancer in many cases.
- Characterized by the presence of cells with large, irregular, hyperchromatic nuclei that may be either present the entire thickness of the epithelium or only part of it.
- Urothelial carcinoma in situ is frequently underdiagnosed and described as moderate dysplasia or atypia.
- CIS cells may be found scattered within the urothelium, have a pagetoid spread, or present as isolated cells in a partially denuded surface; b) high nuclear to cytoplasmic ratio is not necessarily seen in CIS; c) umbrella cells may still be present overlying; and, d) there is a wide spectrum of cytologic features and degree of cytologic atypia, despite the fact that, by definition, all CIS are high grade lesions.
The classification of papillary urothelial neoplasms has been a long-standing source of controversy.
Some experts have applied very restrictive criteria for the diagnosis of urothelial papilloma, in part
based on the number of cell layers, and regarded all other all other papillary neoplasms as carcinomas.
Others have applied a broader definition of "urothelial papilloma" so as not to label all patients with
papillary lesions with minimal cytologic and architectural atypia as having carcinoma.
Another source of controversy lies in the grading of papillary urothelial carcinomas. There are
numerous grading systems, all of which have poor interobserver reproducibility with most cases falling
into the intermediate category. One system, which is a modified version of the scheme proposed by
Malstrom et al., was recently evaluated by a group of the consensus committee and found to be fairly
reproducible. It is described below.
- Urothelial Papilloma
Inverted Urothelial Papilloma
- Discrete, exophytic papillary growth with a central fibrovascular core lined by
urothelium of normal thickness and cytology.
- It is a rare benign
condition typically occurring as a small, isolated growth seen primarily, but not exclusively, in younger
Papillary Urothelial Neoplasm of Low Malignant Potential
- Endophytic lesion which shares several features with exophytic urothelial
- Rarely, hybrid cases exist with portions of the lesion
resembling exophytic urothelial papilloma and others inverted urothelial papilloma.
- Inverted papillomas have a low risk of recurrence when completely excised.
- May be seen in patients with a history of urothelial carcinoma, and rarely,
urothelial carcinoma may arise within inverted urothelial papilloma.
Papillary Urothelial Carcinoma, Low Grade
- This term describes a papillary urothelial neoplasm with an
orderly arrangement of cells within papillae with minimal architectural abnormalities and minimal nuclear
atypia, irrespective of cell thickness.
- Mitoses are infrequent and
usually limited to the basal layer.
- But in exceptional cases, a
papillary urothelial neoplasm of low malignant potential is not associated with invasion or
- It is a clinically important lesion because patients are at
an increased risk of developing recurrent or new papillary lesions.
- Patients with papillary urothelial neoplasms of low malignant potential are at
risk of developing new bladder tumors ("recurrence"), usually of similar histology. However,
occasionally these subsequent lesions manifest as urothelial carcinoma, such that follow-up of the
patient is warranted.
Papillary Urothelial Carcinoma, High Grade
- Exhibit an overall orderly appearance but have variability in architecture
and/or cytologic features which are easily recognizable at scanning magnification.
- Variability in polarity, nuclear size, shape, and chromatin texture are minimal
but comprise the hallmarks of the cytologic atypia seen in low grade papillary urothelial carcinoma.
- Mitotic figures are infrequent. Although mitoses may be seen at any level
of the urothelium, they are usually limited to the lower half.
to see fusion of adjacent papillae, a feature that may lead to overgrading due to an appearance of
- Frequently recur, may invade the bladder wall, and have a low
(<5%) risk of progression.
It is important to remember that a single papillary urothelial neoplasm may contain a spectrum of
cytologic and architectural abnormalities. In tumors with variable histology, the tumor should be graded
according to the highest grade, although current practice is to ignore minuscule areas of higher grade
tumor. Studies are needed to determine how significant a minor component must be in order to have an
impact on prognosis.
- Characterized by a disorderly appearance due to marked architectural and
cytologic abnormalities, recognizable at low magnification.
pleomorphism ranges from moderate to marked.
- Mitotic figures, including
atypical forms, are frequently seen at all levels of the urothelium.
- Pathologists are free to comment on the presence of "anaplasia".
- Progression rate varies from 15% to 40%, much higher than low grade
- Commonly associated with invasive disease at the time of
initial presentation and the adjacent mucosa may show evidence of CIS.
What has happened since the publication of this "consensus" classification has not been pretty.
Suffice it to say that it has not been universally accepted with pockets of resistance within the
pathology as well as urology communities. In fact some of the members of the panel that participated in
the original paper went on to discredit it. One of the major sources of criticism was the fact that the
classification was not based on hard data but rather the "experience" of seasoned pathologists. Several
papers, including well-designed studies from the Malström group in fact validated the classification,
whereas others questioned several aspects, particularly lumping a variety of tumors into a high grade
category. The 1999 edition of the World Health Organization International Classification of Tumors
subclassified tumors into LMP, grades 1, 2, and 3 disease.
There was a meeting held in Ancona, Italy in 2001 which was promulgated as a "consensus meeting"
regarding grading, which suggested reverting to 1973 WHO classification but, quite frankly, all sides of
the debate were not represented so it is difficult to give their conclusions much significance. Luckily,
relief may be on the horizon. Late last year and under the auspices of the WHO, a group of urologic
pathologists met in Lyon to discuss and finalize the new "Blue Book" on the pathology and genetics of
tumors of the urinary system. I understand that the 1998 WHO/ISUP classification was accepted with few
changes and few dissenting votes. It is imperative that we move on to more important issues if we are to
move ahead as a field. Rather than arguing about classification, we should be participating in
multidiciplinary studies evaluating multiple risk factors, including molecular markers, to stratify
patients into prognostic groups better.
Invasive Urothelial Neoplasms:
Staging of Bladder Cancer:
In invasive disease, the most powerful prognostic factor is stage. Both the Jewett-Marshall and the
AJCC classifications are able to stratify patients based on the depth of invasion; superficial disease
(Ta,T1) has an excellent prognosis while survival greatly decreases in deeply invasive tumors
(T2-T3b). Pathologic staging takes on greater importance since we know that
clinical over- or understaging may occur in up to 40% of cases. Unfortunately, pathologic staging also
has its problems. Pathologists do not agree as to what constitutes lamina propria invasion. There are
many cases of T1 disease which are unequivocal but there are an equal number in which invasion
is minimal or not existent. Pathologists' interpretations in the latter group are inconsistent and not
reproducible. This lack of consistency is responsible, in great part, for the clinicians' lumping of TA
and T1 tumors together into one prognostic group ("superficial disease"). Obviously, better
parameters are needed to make this distinction and furthermore, should be adhered to by all
pathologists. Studies evaluating the biologic differences between pTa and clear-cut pT1
lesions would be interesting and very informative.
Accurate pathologic staging requires knowledge of the basic histology of the organ in question. In
the urinary bladder, transitional epithelium (urothelium) overlies a basement membrane and lamina propria
composed of connective tissue, vascular and neural structures. The lamina propria in turn is enveloped
by a muscularis propria with its thick but poorly oriented muscle bundles. In transurethral biopsy
material the tissue chips are frequently poorly oriented (not cut perpendicular to the bladder wall).
This fact by itself may make it difficult to establish depth of invasion. Also, it is evident that the
urinary bladder wall thickness is not uniform. In fact, even in the undistended bladder, the lamina
propria is much attenuated (and consequently the muscularis propria is closer to the epithelial surface)
in the area of the trigone, bladder neck and adjacent to the ureteral orifices.
The lamina propria is a connective tissue layer that lies directly under the urothelium, which
commonly contains interrupted fascicles of smooth muscle known as muscularis mucosae. The larger smooth
muscle bundles beneath the lamina propria are referred to as either the muscularis propria or detrusor
muscle. The term "superficial bladder cancer" should not be used as it lumps together three
morphologically and biologically distinct lesions: CIS, noninvasive papillary neoplasia, and carcinoma
with lamina propria invasion. The terms "superficial muscle invasion" and "deep muscle invasion" should
not be used since these terms are employed by some to indicate the extent of muscularis propria invasion
and by others to denote muscularis mucosae and muscularis propria invasion, respectively. Invasive
tumors should be graded as low or high, analogous to the scheme used for grading noninvasive papillary
a) Lamina Propria Invasion
- Characterized by the presence of urothelial nests,
clusters, or single cells within the lamina propria.
- Tumor cells may have abundant eosinophilic cytoplasm at
the advancing edge of the infiltrating nests (so-called "paradoxical differentiation").
- Often associated with a desmoplastic or inflammatory
stromal response that is not always conspicuous.
- Nests of invasive tumor within the lamina propria may
exhibit prominent retraction artefact which is frequently overdiagnosed as vascular invasion. Vascular
invasion in cases with lamina propria invasion is uncommon and the diagnosis should be reserved for
unequivocal cases or those confirmed by immunohistochemistry.
In slightly over 50% of transurethral resection specimens it is possible to identify the mid level of
the lamina propria characterized by the presence of muscularis mucosae and/or medium caliber thick-walled
vessels. While some investigators have shown that it is possible to substage tumor invading the lamina
propria based on these anatomic landmarks, pathologists should not universally adopt this practice. It
is often difficult to identify the depth of lamina propria invasion due to the lack of orientation in the
TUR chips or because of the absence of muscularis mucosae and thick-walled vessels. Nevertheless,
pathologists are encouraged to provide some assessment as to the extent of lamina propria invasion. If
the tumor invades muscularis mucosae, this fact may (but need not) be mentioned in the report. If it is
mentioned, the wording should be unambiguous so that the urologist does not confuse muscularis mucosae
with muscularis propria. The presence or absence of muscularis propria in the specimen should always be
mentioned, even in cases of noninvasive disease, with the purpose of giving feedback to the urologist as
to the depth of their biopsy.
b) Muscularis propria (Detrusor Muscle) Invasion
In interpreting pathologic reports, urologists and oncologists have equated the presence of "muscle
invasion" with T2. Thanks in great part to the work by Ro et al. we now know that up to 94%
of cystectomy specimens contain variable amounts of smooth muscle within the lamina propria. These
muscle bundles may be continuous or discontinuous. The importance of this finding cannot be
overemphasized. Pathologists should make every effort to distinguish this superficial muscle (muscularis
mucosae) from muscularis propria. Moreover, clinicians should not accept a diagnosis of "TCC invading
muscle" without demanding further clarification (if possible) from the pathologist.
- Characterized by tumor cells which infiltrate thick
- In cases where there is uncertainty as to the depth of
invasion, this fact should be conveyed to the urologist so that a restaging TUR be performed.
- In a TUR specimen there should be no attempt to substage
the depth of muscularis propria invasion.
- The presence of tumor in fat is not diagnostic of
extra-vesicle disease, as adipose tissue may be seen within the lamina propria.
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