Bladder Pathology 2004: An Update
Peter A. Humphrey
St. Louis, MO
The field of urinary bladder pathology is advancing at a rapid rate, with generation of significant
new knowledge on molecular pathogenesis and cell and tissue-based diagnosis. The aim of this
presentation is to survey selected, recent advances in this broad field, with specific focus on
histologic typing, grading, staging, molecular classification, and reporting on neoplasia of the urinary
Histologic typing of bladder cancer
In 2003, the most recent World Health Organization (WHO) "Blue Book" on Pathology and
Genetics of Tumours of the Genitourinary System was published . Given in Table 1 is the WHO 2003
classification of tumours of the urinary bladder:
Table 1. WHO 2003 histological classification of tumors of the urinary bladder
|Infiltrating urothelial carcinoma |
with squamous differentiation
with glandular differentiation
with squamous and glandular differentiation
Sarcomatoid (w./w.o heterologous elements)
Giant cell variant
|Non-invasive urothelial neoplasias|
|Hyperplasia (flat and papillary) |
Dysplasia (include normal urothelium and atypia)
Urothelial papilloma, inverted type
Non-invasive papillary urothelial neoplasm of LMP
Non-invasive papillary urothelial carcinoma (low grade)
Non-invasive papillary urothelial carcinoma (high grade)
|Squamous cell carcinoma |
Verrucous squamous cell carcinoma
Squamous cell papilloma
Clear cell adenocarcinoma
In situ adenocarcinoma
|Small cell carcinoma |
|Mesenchymal and miscellaneous tumours|
Malignant fibrous histiocytoma
Granular cell tumour
|Metastatic tumours and secondary extension|
This classification system provides a modern, evidence-based, foundation for clinical management of
patients with these conditions and is recommended for routine use. A comparison of the WHO 2003 system
with the WHO 1999 scheme  reveals several changes.
First, in WHO 2003 the term urothelial is used exclusively to refer to tumors derived from
the epithelial lining of the bladder rather than the WHO 1999 use of urothelial or transitional cell.
This is warranted since this lining, the urothelium, is unique and does not represent any sort of
transition from one cell type to another
Urothelial Carcinoma Variants: Diagnostic Terminology
In the WHO 2003 classification, these are subtle alterations in the diagnostic terminology of variants
of urothelial carcinoma. Urothelial carcinoma with malignant squamous and/or glandular epithelium is
urothelial carcinoma with squamous and/or glandular differentiation (WHO 2003) rather than metaplasia
(WHO 1999). Squamous differentiation overall occurs in 21% of urothelial carcinomas, with increasing
frequency with increasing grade and stage
. The proportion of the squamous component varies
considerably; only if the tumor is comprised of pure malignant squamous cells should squamous cell
carcinoma be diagnosed. Similarly, only pure glandular carcinomas should be denoted as adenocarcinoma of
the urinary bladder. Urothelial carcinoma with glandular differentiation is less common, at 6% of all
urothelial carcinomas, than those with squamous differentiation
. Glandular differentiation here is
reserved for the formation of true luminal spaces, and not intracytoplasmic mucin. A visual inspection
estimate of percentage squamous and/or glandular differentiation should be given. Squamous
differentiation may be associated with a poor response to surgery, radiation, and chemotherapy, while the
clinical significance of glandular areas is uncertain.
Carcinosarcoma and spindle cell carcinoma (WHO 1999) are now sarcomatoid carcinoma, with or without
heterologous elements (WHO 2003). Urothelial carcinoma with ectopic placental glycoprotein production
(WHO 1999) is now urothelial carcinoma with trophoblastic differentiation. Newly-recognized variants in
the WHO 2003 publication include urothelial carcinoma with giant cells and a lymphoma-like variant of
urothelial carcinoma . Both are distinctly uncommon. Urothelial carcinoma with giant cells should be
distinguished from urothelial carcinoma with foreign-body or osteoclast-like giant cells in the stroma
and urothelial carcinoma with trophoblastic differentiation , where the giant cells are
syncytiotrophoblasts. Lymphoma-like and the plasmacytoid variants of urothelial carcinoma can represent
a significant diagnostic pitfall, especially in small biopsy tissue samples. Immunostains for
pan-cytokeratin, CK7, and (sometimes) CK20 should be positive, with negative lymphoid markers.
A urothelial carcinoma variant included in the WHO 1999 book but not the WHO 2003 text is
the osteoclastic variant . The WHO 2003 approach does not separate stromal responses as variants, but
it is important to be aware that unusual stromal responses include the aforementioned osteoclast giant
cells, pseudosarcomatous stroma, a prominent lymphoid infiltrate, and stromal osseous metaplasia .
Deceptively Benign - Appearing Variants of Urothelial Carcinoma
| Inverted pattern|
| Small tubular pattern|
| Microcystic pattern|
| Nested pattern|
The WHO 2003 classification does not formally include inverted or small tubular patterns
as variants, but does list and describe the microcystic and nested variants.
Whereas most papillary urothelial carcinomas exhibit an exophytic architectural
arrangement of finger-like papillae, endophytic urothelial neoplasms display either a broad front
verrucous carcinoma-like growth or inverted papilloma-like growth. Diagnostic challenges arise due to
difficulty in the differential diagnosis with benign inverted papilloma and in assessment of invasion
. Features useful for diagnosis of urothelial carcinomas with inverted papilloma-like growth
include cords and trabeculae with irregularity of width and with transition into solid areas, minimal to
absent maturation, spindling or palisading, and cytologic atypia
Small tubular pattern urothelial carcinoma could be mistaken for nephrogenic adenoma
. It is briefly mentioned within the nested variant section in the 2003 WHO book, where it is
noted that some urothelial carcinoma nests have small tubular lumens
. It is potentially
confounding that the nuclear atypia of the tubular lining cells is minimal. Here, the diagnosis of
carcinoma is rendered upon recognition of the haphazard disposition of the tubules, variation of tubular
shape, and frequent muscle wall invasion . The clinical significance of this pattern is not clear,
since these are so few cases, and many are admixed with a nested pattern, which imparts a worse
Microcystic urothelial carcinoma demonstrates variable-sized cysts ranging up to 1 to 2 mm
. The cysts are round to oval and may contain necrotic material or pink
secretions . The lining cells layer may be flattened or denuded . The differential diagnosis
includes cystitis cystica, cystitis glandularis, and nephrogenic adenoma . The correct diagnosis is
achieved by detection of association with usual urothelial carcinoma , haphazard and infiltrative
growth, and cyst size and shape variability .
The nested variant of urothelial carcinoma is a rare, aggressive neoplasm with an
appearance that can simulate von Brunn nests, cystitis cystica and glandularis, inverted papilloma, and
. Clues that are of aid in establishing the diagnosis are the
high-density, nearly confluent nests that can anastomose and invade muscularis propria (wall). Nuclear
atypia may be only focally present, and is often found in the deeper aspects of the proliferation.
Although the nested variant of urothelial carcinoma has a higher proliferation index than florid von
Brunn nests by MIB-1 immunostaining (8.8% vs. 2.8%), and a higher p53 immunopositivity (4.2% vs. 1.5%),
the degree of overlap precludes use of these markers as diagnostic tools .
Typing of Poorly-differentiated/undifferentiated Urothelial Carcinoma:
Substantiation of urothelial differentiation in the differential diagnosis with other
neoplasms can be accomplished by an immunophenotypic marker panel:
|Marker ||Positivity in|
Urothelial Carcinoma 
|High molecular weight cytokeratin|
|Uroplakin III ||57%|
Note that of these markers, only uroplakin III is specific for urothelial differentiation (21).
Grading of Non-invasive Urothelial Tumors
Histological grading is of prime importance for non-invasive urothelial tumors, is of
probable importance in pT1 tumors, and is of questionable significance in pT2 and higher stage tumors
since these are mainly high-grade . The diagnostic classification and grading of papillary urothelial
neoplasms has been controversial
The WHO 2003 recommended nomenclature for non-invasive urothelial tumors  is identical
to the WHO-ISUP 1998 classification . The chief difference compared to the WHO 1999 scheme is that
rather than three grades of papillary urothelial carcinoma, there are two - low grade and high-grade - in
the WHO 2003 classification (Table 1). However, it is specifically stated in the text that for the
high-grade tumors pathologists have the option of recording the presence or absence of diffuse anaplasia
in a comment. This seems to leave open the possibility that high-grade carcinomas should be divided
into two grades. Arguments against this  include the finding that only a small percentage (4 to 5%)
of high-grade non-invasive papillary cancers harbor marked anaplasia
and the potential confusion
that may arise when using the G1 to G3 systems of WHO 1973 and WHO 1999, which differ in definitions.
The two-tiered WHO 2003 grading of carcinoma was deemed a "work in progress" . The authors of the
WHO 2003 system cite genetic studies that suggest there are "two major subtypes of urothelial neoplasms
which might have a distinctly different clinical course" - genetically stable tumors which include most
non-invasive low-grade carcinomas and genetically unstable non-invasive high-grade carcinomas and
invasive carcinomas . Currently, these genetic differences and specific molecular markers, such as
cytokeratin 20, p53, p63, CD44, FGFR3, and Ki-67
hold promise for the future, but are not in
routine use in grading of urothelial proliferations. Prospective evaluation of the WHO 2003 grading
system and of molecular aids in grading are desirable goals for the future.
Staging of Urothelial Carcinoma
Currently, pathologic staging of bladder cancer should be
performed according to the 2002 AJCC/UICC TNM staging guidelines 
Table 2. 2002 AJCC/UICC TNM Staging of Bladder Carcinoma
From reference . See that reference for stage groupings.
|Primary Tumor (T)|
|TX ||Primary tumor cannot be assessed|
|T0|| No evidence of primary tumor|
|Ta|| Non-invasive papillary carcinoma|
|Tis|| Carcinoma in situ : "flat tumor"|
|T1|| Tumor invades subepithelial connective tissue|
|T2|| Tumor invades muscle|
|pT2a|| Tumor invades superficial muscle (inner half)|
|pT2b ||Tumor invades deep muscle (outer half)|
|T3 ||Tumor invades perivesical tissue|
|pT3b ||macroscopically (extravesical mass)|
|T4 ||Tumor invades any of the following : prostate, uterus, vagina, pelvic wall, abdominal wall|
|T4a ||Tumor invades prostate, uterus, vagina|
|T4b ||Tumor invades pelvic wall, abdominal wall|
|Regional Lymph Nodes (N)|
Regional lymph nodes are those within the true pelvis;
all others are distant lymph nodes
|NX ||Regional lymph nodes cannot be assessed|
|N0 ||No regional lymph node metastasis|
|N1 ||Metastasis in a single lymph node, 2 cm or less in greatest dimension|
|N2 ||Metastasis in a single lymph node, more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, none more than 5 cm in greatest dimension|
|N3 ||Metastasis in a lymph node, greater than 5 cm in greatest dimension|
|Distant Metastasis (M)|
|MX ||Distant metastasis cannot be assessed|
|M0 ||No distant metastasis|
|M1 ||Distant metastasis|
staging method does not differ from the 1997 TNM system. Accurate pathologic staging of bladder cancer
remains a critical task that allows for appropriate prognostic and therapeutic stratification of
patients. Recognition of invasion and anatomic depth of invasion by carcinoma is vital. Most invasive
bladder cases are high-grade
although a minority of pT1 cancers are low-grade , especially the
deceptively-benign variants discussed above. Diagnostic patterns of lamina propria invasion as recently
presented  can facilitate pT1 stage assignment:
Table 3. Histologic Patterns of Lamina Propria Invasion
|Invading epithelium:|| irregularly shaped nests |
irregular or absent basement membrane
tentacular finger-like processes
invasive component with higher nuclear grade or more cytoplasm
|Stromal response: || desmoplasia |
absent stromal response Reference 8, p. 83.
Recently-emphasized pitfalls in the diagnosis of lamina propria invasive urothelial carcinoma include
tangential sectioning, thermal artifact, obscuring inflammation, CIS involving von Brunn nests,
deceptively bland urothelial carcinoma, invasion into indeterminate type of muscle, and invasion into
adipose tissue within lamina propria . Determination of the type of muscle (muscularis mucosae vs.
muscularis propria) invaded by carcinoma can occasionally be difficult due to small tissue sample size,
tissue distortion, cautery artifact, poor orientation, fibrosis and inflammation elicited by destructive
growth of invasive tumor and even hypertrophy of the normally thin, wispy, and discontinuous muscularis
mucosae. This designation of "muscle type indeterminate" is a viable description. As always, the
presence or absence of muscularis propria in biopsy and transurethral resection of bladder tumor (TURBT)
samples, and presence or absence of carcinoma in identified muscularis propria, should be specified.
Only in the last few years has the presence of adipose tissue in all layers of the bladder including
lamina propria and muscularis propria (muscle wall or detrusor), been well-documented . So, the
presence of carcinoma in fat does not indicate extra-vesical extension.
The level of invasion of carcinoma in pT1 disease is related to patient outcome, with a
worse prognosis for tumors that invade beyond the muscularis mucosae (pT1b)
or deeply into the
subepithelial connective tissue, as quantitated using an ocular micrometer . The WHO 2003 group
recommended that some estimate of extent of lamina propria invasion (for example: pT1a - above or into
muscularis mucosae vs. pT1b - tumors below)
be provided but this is currently not a formal part of
the 2002 TNM system, and it is not universally reported, since there is no established method that is
consistently applicable and reproducible .
Invasion by bladder carcinoma into muscularis propria (muscle wall, detrusor) is an
ominous finding where the patient becomes a candidate for aggressive surgical therapy (radical
cystectomy) or radiation therapy with or without adjuvant chemotherapy. Current staging issues here have
historically been problematic. As discussed above, definitive identification of the thick, compact
smooth muscle bundles of the muscularis propria can be difficult in some cases. Substaging of pT2 (pT2a
- invasion of "superficial" muscle = inner half vs. pT2b - invasion of "deep" muscle = outerhalf) and
distinction of pT2 vs. pT3 can only been done on radical cystectomy specimens, and notTURBT samples.
Even in cystectomy specimens it can be a challenge at times to determine extravesical (pT3) spread since
the boundary between muscularis propria and its fat is not well-demarcated from perivesical fat.
Moreover, this boundary can be distorted, obscured, or obliterated by fibrosis and inflammation
associated with infiltrating tumor.
One portion of the 2002 TNM staging system for bladder cancer that requires future
clarification is bladder cancer involvement of the prostate. Such involvement is currently staged as
pT4a disease, without qualification as to the nature of the involvement. Yet, prognosis for patients
with bladder cancer extending into the prostate is highly dependent on bladder stage and prostatic depth
. Patient survival is strongly linked to prostate stromal invasion , and
prostatic stromal invasion is associated with a better prognosis when the bladder stage is organ-confined
. Prostatic stromal invasion via intraurethral spread confers a better survival than extravesical
tumor extension into the prostate. It has been recommended that bladder and prostate tumors be staged
separately , with specification of prostate with non-invasive urothelial carcinoma, prostatic
stromal-invasive urothelial carcinoma arising from intraurethral spread, or prostatic stromal-invasive
urothelial carcinoma via extravesical spread.
Molecular Classification of Urinary Bladder Neoplasia
Molecular markers hold great promise for the future in classification of urinary bladder
neoplasia, but currently there is no molecular parameter that is sufficiently validated and has
sufficient prognostic power to have accepted clinical value .
Large-scale gene expression profiling of bladder cancer has been reported recently
. Objective prediction of classes of bladder tumors using a limited set of genes identified in
these studies could have potential clinical utility. In particular, molecular markers would be of
substantial value if they could predict which patients with noninvasive (pTa or pTis) bladder cancer
would progress to invasive disease and which patients with muscle-invasive tumors will develop metastatic
disease after radical cystectomy . General categories of genes that harbor potential capacity for
classification include, for example, altered oncogenes, tumor suppressor genes, growth factors, growth
factor receptors, and cell cycle-related genes. Specific molecules with abnormalities in expression
and/or structure in bladder neoplasia include Her2/neu, epidermal growth factor receptor, H-ras, MDM2,
p53, PTEN, RB1, cyclin D1, p15, p16, p21 and p27, to name a few . p53 nuclear protein accumulation
and proliferation (MIB-1) index, as assessed by immunohistochemical staining, are two of the more
, but standardization of methodology and quantitation remain as barriers for
routine use. However, WHO 2003 concluded that "p53 alterations do not sufficiently well discriminate
good and poor prognosis groups in properly staged bladder cancers to have clinical utility" .
Reporting of Bladder Neoplasia
In 2003 checklists for reporting on urinary bladder biopsy and
cystectomy samples were published by the College of American Pathologists as "Surgical Pathology Cancer
Case Summary" protocols . The major categories are summarized here:
Urinary Bladder Biopsy/Transurethral Resection
|Tumor configuration (papillary, solid/nodule, flat, ulcerated)|
|Muscularis propria (present absent, or indeterminate)|
|Additional pathologic findings (carcinoma-in-situ, dysplasia, inflammation, therapy changes)|
|Pathologic stage (pT and pN)|
|Tumor configuration (papillary, solid/nodule, flat, ulcerated)|
|Venous/lymphatic vessel invasion|
|Direct extension (prostate without stromal invasion, prostate with stromal invasion, adjacent viscera)|
|Additional pathologic findings (carcinoma-in-situ, dysplasia, inflammation, metaplasia, therapy-related changes)|
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