Protocol for the Examination of Specimens From Patients With

Carcinoma of the Urinary Bladder

Version: UrinaryBladder 4.0.1.0 Protocol Posting Date: June 2017
th
Includes pTNM requirements from the 8 Edition, AJCC Staging Manual

For accreditation purposes, this protocol should be used for the following procedures AND tumor types:
Procedure Description
Cystectomy Includes specimens designated partial, total or radical cystectomy,
radical cystoprostatectomy (for bladder cancer), and anterior
exenterations
Tumor Type Description
Carcinomas Includes invasive carcinomas of the urinary tract, including urothelial
carcinoma and its morphological variants (squamous cell carcinoma,
adenocarcinoma, Mϋllerian carcinoma, neuroendocrine carcinoma, and
#
sarcomatoid carcinoma)
# This protocol is recommended for reporting noninvasive urothelial tumors (papillary and flat), but it is not required for
accreditation purposes.

This protocol is NOT required for accreditation purposes for the following:
Procedure
#
Biopsy, transurethral resection of the bladder tumor (TURBT), or enucleations
Primary resection specimen with no residual cancer (eg, following neoadjuvant therapy)
Cytologic specimens
#
Transurethral resection of a bladder tumor is NOT considered to be the definitive resection specimen, even though the entire
cancer may be removed. This protocol is recommended for reporting TURBT specimens for clinical care purposes, but it is not
required for accreditation purposes.

The following tumor types should NOT be reported using this protocol:
Tumor Type
Urachal Carcinoma
Lymphoma (consider the Hodgkin or non-Hodgkin Lymphoma protocols)
Sarcoma (consider the Soft Tissue protocol)

Authors
Ming Zhou, MD, PhD*; John R. Srigley, MD*; Mahul B. Amin, MD; Robert Allan, MD; Brett Delahunt, MD; Bernard
H. Bochner, MD; Jonathan I. Epstein, MD; David J. Grignon, MD; Peter A. Humphrey, MD, PhD; Rodolfo
Montironi, MD; Gladell P. Paner, MD; Jason Pettus, MD; Victor E. Reuter, MD

With guidance from the CAP Cancer and CAP Pathology Electronic Reporting Committees.
* Denotes primary author. All other contributing authors are listed alphabetically.

© 2017 College of American Pathologists (CAP). All rights reserved.

For Terms of Use please visit www.cap.org/cancerprotocols.
 Genitourinary • Urinary Bladder
UrinaryBladder 4.0.1.0

Accreditation Requirements
This protocol can be utilized for a variety of procedures and tumor types for clinical care purposes. For
accreditation purposes, only the definitive primary cancer resection specimen is required to have the core and
conditional data elements reported in a synoptic format.
• Core data elements are required in reports to adequately describe appropriate malignancies. For
accreditation purposes, essential data elements must be reported in all instances, even if the response is
“not applicable” or “cannot be determined.”
• Conditional data elements are only required to be reported if applicable as delineated in the protocol. For
instance, the total number of lymph nodes examined must be reported, but only if nodes are present in the
specimen.
• Optional data elements are identified with “+” and although not required for CAP accreditation purposes,
may be considered for reporting as determined by local practice standards.
The use of this protocol is not required for recurrent tumors or for metastatic tumors that are resected at a
different time than the primary tumor. Use of this protocol is also not required for pathology reviews performed at
a second institution (ie, secondary consultation, second opinion, or review of outside case at second institution).

Synoptic Reporting
All core and conditionally required data elements outlined on the surgical case summary from this cancer protocol
must be displayed in synoptic report format. Synoptic format is defined as:
• Data element: followed by its answer (response), outline format without the paired "Data element:
Response" format is NOT considered synoptic.
• The data element must be represented in the report as it is listed in the case summary. The response for
any data element may be modified from those listed in the case summary, including “Cannot be
determined” if appropriate.
• Each diagnostic parameter pair (Data element: Response) is listed on a separate line or in a tabular format
to achieve visual separation. The following exceptions are allowed to be listed on one line:
o Anatomic site or specimen, laterality, and procedure
o Pathologic Stage Classification (pTNM) elements
o Negative margins, as long as all negative margins are specifically enumerated where applicable
• The synoptic portion of the report can appear in the diagnosis section of the pathology report, at the end of
the report or in a separate section, but all Data element: Responses must be listed together in one location
Organizations and pathologists may choose to list the required elements in any order, use additional methods in
order to enhance or achieve visual separation, or add optional items within the synoptic report. The report may
have required elements in a summary format elsewhere in the report IN ADDITION TO but not as replacement for
the synoptic report i.e. all required elements must be in the synoptic portion of the report in the format defined
above.

CAP Laboratory Accreditation Program Protocol Required Use Date: March 2018*
* Beginning January 1, 2018, the 8th edition AJCC Staging Manual should be used for reporting pTNM.

CAP Urinary Bladder Protocol Summary of Changes

Version 4.1.0.0 errata:

Size of Largest Metastatic Deposit
• MODIFIED Unit of measure from millimeters to centimeters

Version 4.0.0.0:
The following data elements were modified:
Pathologic Stage Classification (pTNM, AJCC 8th Edition)

2
CAP Approved Genitourinary • Urinary Bladder
UrinaryBladder 4.0.1.0

Surgical Pathology Cancer Case Summary

Protocol posting date: June 2017

URINARY BLADDER: Biopsy and Transurethral Resection of Bladder Tumor (TURBT)

Note: This case summary is recommended for reporting biopsy and TURBT specimens, but is not
required for accreditation purposes.

Select a single response unless otherwise indicated.

Procedure (Note A)
___ Biopsy
___ TURBT
___ Other (specify): ____________________________
___ Not specified

Tumor Site (select all that apply)

___ Trigone
___ Right lateral wall
___ Left lateral wall
___ Anterior wall
___ Posterior wall
___ Dome
___ Other (specify): ____________________________
___ Not specified

Histologic Type (select all that apply) (Note B)

Urothelial
___ Papillary urothelial carcinoma, noninvasive
___ Papillary urothelial carcinoma, invasive
___ Urothelial carcinoma in situ
___ Urothelial carcinoma, invasive
___ Urothelial carcinoma, nested (including large nested) variant
___ Urothelial carcinoma, microcystic variant
___ Urothelial carcinoma, micropapillary variant
___ Urothelial carcinoma, lymphoepithelioma-like variant
___ Urothelial carcinoma, plasmacytoid / signet ring / diffuse variant
___ Urothelial carcinoma, sarcomatoid variant
___ Urothelial carcinoma, giant cell variant
___ Urothelial carcinoma, poorly differentiated variant
___ Urothelial carcinoma, lipid-rich variant
___ Urothelial carcinoma, clear cell variant
___ Urothelial carcinoma with squamous differentiation
+ Specify percentage of squamous differentiation: _____%
___ Urothelial carcinoma with glandular differentiation
+ Specify percentage of glandular differentiation: _____%
___ Urothelial carcinoma with trophoblastic differentiation
+ Specify percentage of trophoblastic differentiation: _____%
___ Urothelial carcinoma with Mϋllerian differentiation
+ Specify percentage of Mϋllerian differentiation: _____%

+ Data elements preceded by this symbol are not required for accreditation purposes. These optional elements may be 3
clinically important but are not yet validated or regularly used in patient management.
CAP Approved Genitourinary • Urinary Bladder
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Squamous
___ Pure squamous cell carcinoma
___ Verrucous carcinoma
___ Squamous cell carcinoma in situ (no invasive carcinoma identified)

Glandular
___ Adenocarcinoma
___ Adenocarcinoma, enteric
___ Adenocarcinoma, mucinous
___ Adenocarcinoma, mixed
___ Adenocarcinoma in situ (no invasive carcinoma identified)

Tumors of Mϋllerian Type

___ Clear cell carcinoma
___ Endometrioid carcinoma

NeuroendocrineTumors
___ Small cell neuroendocrine carcinoma
+ Specify percentage of small cell neuroendocrine component: _____%
___ Large cell neuroendocrine carcinoma
+ Specify percentage of large cell neuroendocrine component: _____%
___ Well-differentiated neuroendocrine carcinoma
+ Specify percentage of well-differentiated neuroendocrine component: _____%

___ Other histologic type not listed (specify): ____________________________

+ Associated Epithelial Lesions (select all that apply) (Note C)

+ ___ None identified
+ ___ Urothelial papilloma
+ ___ Urothelial papilloma, inverted type
+ ___ Papillary urothelial neoplasm, low malignant potential (PUNLMP)
+ ___ Urothelial dysplasia
+ ___ Urothelial proliferation of uncertain malignant potential
+ ___ Cannot be determined

Histologic Grade (Note C)

For urothelial carcinoma, other variants, or divergent differentiation

___ Low-grade
___ High-grade
___ Other (specify): ____________________________

For squamous cell carcinoma or adenocarcinoma

___ G1: Well-differentiated
___ G2: Moderately differentiated
___ G3: Poorly differentiated
___ GX: Cannot be assessed

___ Other (specify): ____________________________

___ Not applicable
___ Cannot be assessed

+ Data elements preceded by this symbol are not required for accreditation purposes. These optional elements may be 4
clinically important but are not yet validated or regularly used in patient management.
CAP Approved Genitourinary • Urinary Bladder
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+ Tumor Configuration (select all that apply)

+ ___ Papillary
+ ___ Solid/nodule
+ ___ Flat
+ ___ Ulcerated
+ ___ Cannot be determined
+ ___ Other (specify): ____________________________

Muscularis Propria Presence (Note D)

___ No muscularis propria (detrusor muscle) identified
___ Muscularis propria (detrusor muscle) present
___ Cannot be determined (explain): _________________________

Lymphovascular Invasion (Note E)

___ Not identified
___ Present
___ Cannot be determined

Tumor Extension (select all that apply) (Note F)

___ Noninvasive papillary carcinoma
___ Flat carcinoma in situ
___ Tumor invades lamina propria (subepithelial connective tissue)
___ Tumor invades muscularis propria
___ Urothelial carcinoma involving prostatic urethra in prostatic chips sampled by TURBT
___ Urothelial carcinoma involving prostatic ducts and acini in prostatic chips sampled by TURBT
___ Urothelial carcinoma invasive into prostatic stroma in prostatic chips sampled by TURBT
___ Cannot be assessed

+ Additional Pathologic Findings (select all that apply)

+ ___ Urothelial carcinoma in situ
+ ___ Urothelial dysplasia, low-grade
+ ___ Inflammation/regenerative changes
+ ___ Therapy-related changes
+ ___ Cautery artifact
+ ___ Cystitis cystica et glandularis
+ ___ Keratinizing squamous metaplasia
+ ___ Intestinal metaplasia
+ ___ Other (specify): ____________________________

+ Comment(s)

+ Data elements preceded by this symbol are not required for accreditation purposes. These optional elements may be 5
clinically important but are not yet validated or regularly used in patient management.
CAP Approved Genitourinary • Urinary Bladder
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Surgical Pathology Cancer Case Summary

Protocol posting date: June 2017

URINARY BLADDER: Cystectomy and Anterior Exenteration

Select a single response unless otherwise indicated.

Procedure (Note G)
___ Partial cystectomy
___ Total cystectomy
___ Radical cystectomy
___ Radical cystoprostatectomy
___ Anterior exenteration
___ Other (specify): ____________________________
___ Cannot be determined

Tumor Site (select all that apply)

___ Trigone
___ Right lateral wall
___ Left lateral wall
___ Anterior wall
___ Posterior wall
___ Dome
___ Other (specify): ____________________________
___ Cannot be determined

Tumor Size
Greatest dimension (centimeters): ___ cm
+ Additional dimensions (centimeters): ___ x ___ cm
___ Cannot be determined (explain): __________________________

Histologic Type (select all that apply) (Note B)

Urothelial
___ Papillary urothelial carcinoma, noninvasive
___ Papillary urothelial carcinoma, invasive
___ Urothelial carcinoma in situ
___ Urothelial carcinoma, invasive
___ Urothelial carcinoma, nested (including large nested) variant
___ Urothelial carcinoma, microcystic variant
___ Urothelial carcinoma, micropapillary variant
___ Urothelial carcinoma, lymphoepithelioma-like variant
___ Urothelial carcinoma, plasmacytoid / signet ring / diffuse variant
___ Urothelial carcinoma, sarcomatoid variant
___ Urothelial carcinoma, giant cell variant
___ Urothelial carcinoma, poorly differentiated variant
___ Urothelial carcinoma, lipid-rich variant
___ Urothelial carcinoma, clear cell variant
___ Urothelial carcinoma with squamous differentiation
+ Specify percentage of squamous differentiation: _____%
___ Urothelial carcinoma with glandular differentiation
+ Specify percentage of glandular differentiation: _____%
___ Urothelial carcinoma with trophoblastic differentiation
+ Specify percentage of trophoblastic differentiation: _____%

+ Data elements preceded by this symbol are not required for accreditation purposes. These optional elements may be 6
clinically important but are not yet validated or regularly used in patient management.
CAP Approved Genitourinary • Urinary Bladder
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___ Urothelial carcinoma with Mϋllerian differentiation

+ Specify percentage of Mϋllerian differentiation: _____%

Squamous
___ Pure squamous cell carcinoma
___ Verrucous carcinoma
___ Squamous cell carcinoma in situ (no invasive carcinoma identified)

Glandular
___ Adenocarcinoma
___ Adenocarcinoma, enteric
___ Adenocarcinoma, mucinous
___ Adenocarcinoma, mixed
___ Adenocarcinoma in situ (no invasive carcinoma identified)

Tumors of Mϋllerian Type

___ Clear cell carcinoma
___ Endometrioid carcinoma

Neuroendocrine Tumors
___ Small cell neuroendocrine carcinoma
+ Specify percentage of small cell neuroendocrine component: _____%
___ Large cell neuroendocrine carcinoma
+ Specify percentage of large cell neuroendocrine component: _____%
___ Well-differentiated neuroendocrine carcinoma
+ Specify percentage of well-differentiated neuroendocrine component: _____%

___ Other histologic type not listed (specify): ____________________________

+ Associated Epithelial Lesions (select all that apply) (Note C)

+ ___ None identified
+ ___ Urothelial papilloma
+ ___ Urothelial papilloma, inverted type
+ ___ Papillary urothelial neoplasm, low malignant potential (PUNLMP)
+ ___ Urothelial proliferation of uncertain malignant potential
+ ___ Urothelial dysplasia
+ ___ Cannot be determined

Histologic Grade (Note C)

For urothelial carcinoma, other variants, or divergent differentiation

___ Low grade
___ High grade
___ Other (specify): ____________________________

For squamous cell carcinoma or adenocarcinoma

___ G1: Well differentiated
___ G2: Moderately differentiated
___ G3: Poorly differentiated
___ GX: Cannot be assessed

___ Other (specify): ____________________________

___ Not applicable
___ Cannot be assessed

+ Data elements preceded by this symbol are not required for accreditation purposes. These optional elements may be 7
clinically important but are not yet validated or regularly used in patient management.
CAP Approved Genitourinary • Urinary Bladder
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+ Tumor Configuration (select all that apply)

+ ___ Papillary
+ ___ Solid/nodule
+ ___ Flat
+ ___ Ulcerated
+ ___ Cannot be determined
+ ___ Other (specify): ___________________________

Tumor Extension (select all that apply) (Note D)

___ No evidence of primary tumor
___ Noninvasive papillary carcinoma
___ Urothelial carcinoma in situ, “flat tumor”
___ Tumor invades lamina propria (subepithelial connective tissue)
___ Tumor invades muscularis propria
___ Tumor invades superficial muscularis propria (inner half)
___ Tumor invades deep muscularis propria (outer half)
___ Tumor invades perivesical tissue
___ Microscopically
___ Macroscopically (extravesical mass)
#
___ Tumor invades adjacent structures
Male
##
___ Prostate (transmural invasion from the bladder tumor)
___ Seminal vesicles
Female
___ Uterus
___ Vagina
___ Adnexae
Male/Female
___ Pelvis wall
___ Abdominal wall
___ Rectum
___ Other (specify): ______________________________
___ Cannot be assessed
#
Note: Use the Urethral protocol for tumors that involve the urethral mucosa without invasion, tumors that involve the urethral
mucosa with invasion of subepithelial connective tissue/prostate stroma, or tumors that involve prostatic ducts and acini with or
without stromal invasion.
##
See Note D, Figure 1.

Margins (select all that apply) (Note G)

___ Cannot be assessed
___ Uninvolved by invasive carcinoma and carcinoma in situ/ noninvasive urothelial carcinoma
___ Uninvolved by invasive carcinoma
___ Involved by invasive carcinoma
___ Right ureteral margin
___ Left ureteral margin
___ Urethral margin
___ Soft tissue margin
#
___ Other margin(s) (specify) : _______________________
___ Involved by carcinoma in situ/noninvasive high-grade urothelial carcinoma
___ Right ureteral margin
___ Left ureteral margin
___ Urethral margin
___ Soft tissue margin
#
___ Other margin(s) (specify) : _______________________
___ Involved by noninvasive low-grade urothelial carcinoma/urothelial dysplasia

+ Data elements preceded by this symbol are not required for accreditation purposes. These optional elements may be 8
clinically important but are not yet validated or regularly used in patient management.
CAP Approved Genitourinary • Urinary Bladder
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___ Right ureteral margin

___ Left ureteral margin
___ Urethral margin
___ Soft tissue margin
#
___ Other margin(s) (specify) : _______________________
#
Note: For partial cystectomies, if the specimen is received unoriented precluding identification of specific margins, it should
be denoted here.

Lymphovascular Invasion (Note E)

___ Not identified
___ Present
___ Cannot be determined

Regional Lymph Nodes

___ No lymph nodes submitted or found

Lymph Node Examination (required only if lymph nodes are present in the specimen)

Number of Lymph Nodes Involved: _____

___ Number cannot be determined (explain): ____________________

Number of Lymph Nodes Examined: _____

___ Number cannot be determined (explain): ____________________

+ Size of Largest Metastatic Deposit (centimeters): ___ cm

+ Specify Site: _________

+ Size of Largest Lymph Node Involved (centimeters): ___ cm

+ Specify Site: _________

+ Extranodal Extension
+ ___ Not identified
+ ___ Present
+ ___ Cannot be determined
th
Pathologic Stage Classification (pTNM, AJCC 8 Edition) (Note F)
Note: Reporting of pT, pN, and (when applicable) pM categories is based on information available to the pathologist at the time
the report is issued. Only the applicable T, N, or M category is required for reporting; their definitions need not be included in
the report. The categories (with modifiers when applicable) can be listed on 1 line or more than 1 line.

TNM Descriptors (required only if applicable) (select all that apply)

___ m (multiple primary tumors)
___ r (recurrent)
___ y (posttreatment)

Primary Tumor (pT)

___ pTX: Primary tumor cannot be assessed
___ pT0: No evidence of primary tumor
___ pTa: Noninvasive papillary carcinoma
___ pTis: Urothelial carcinoma in situ: “flat tumor”
___ pT1: Tumor invades lamina propria (subepithelial connective tissue)
___ pT2: Tumor invades muscularis propria
___ pT2a: Tumor invades superficial muscularis propria (inner half)
___ pT2b: Tumor invades deep muscularis propria (outer half)
___ pT3: Tumor invades perivesical soft tissue
+ Data elements preceded by this symbol are not required for accreditation purposes. These optional elements may be 9
clinically important but are not yet validated or regularly used in patient management.
CAP Approved Genitourinary • Urinary Bladder
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___ pT3a: Tumor invades perivesical soft tissue microscopically

___ pT3b: Tumor invades perivesical soft tissue macroscopically (extravesical mass)
___ pT4: Extravesical tumor directly invades any of the following: prostatic stroma, seminal vesicles, uterus,
vagina, pelvic wall, abdominal wall
___ pT4a: Extravesical tumor invades directly into prostatic stroma, seminal vesicles, uterus, or vagina
___ pT4b: Extravesical tumor invades pelvic wall, abdominal wall

Regional Lymph Nodes (pN)

___ pNX: Lymph nodes cannot be assessed
___ pN0: No lymph node metastasis
___ pN1: Single regional lymph node metastasis in the true pelvis (perivesical, obturator, internal and external
iliac or sacral lymph node)
___ pN2: Multiple regional lymph node metastasis in the true pelvis (perivesical, obturator, internal and external
iliac or sacral lymph node metastasis)
___ pN3: Lymph node metastasis to the common iliac lymph nodes

Distant Metastasis (pM) (required only if confirmed pathologically in this case)

___ pM1: Distant metastasis
___ pM1a: Distant metastasis limited to lymph nodes beyond the common iliacs
___ pM1b: Non-lymph node distant metastases

Specify site(s), if known: ____________________________

+ Additional Pathologic Findings (select all that apply)

+ ___ Urothelial carcinoma in situ
+ ___ Urothelial dysplasia, low-grade
+ ___ Adenocarcinoma of prostate (use protocol for carcinoma of prostate)
+ ___ Inflammation/regenerative changes
+ ___ Therapy-related changes (specify): _________________
+ ___ Cystitis cystica et glandularis
+ ___ Keratinizing squamous metaplasia
+ ___ Intestinal metaplasia
+ ___ Other (specify): ____________________________

+ Comment(s)

+ Data elements preceded by this symbol are not required for accreditation purposes. These optional elements may be 10
clinically important but are not yet validated or regularly used in patient management.
Background Documentation Genitourinary • Urinary Bladder
UrinaryBladder 4.0.1.0

Explanatory Notes

A. History
1-4
A relevant history is important for interpretation of all bladder specimens. Cystoscopic visualization findings hold
useful information on the nature and extent of bladder lesions in biopsy and TURBT specimens. A history of renal
stones, recent urinary tract procedures, infections, or obstruction may influence the interpretation of random
biopsies obtained on patients with hematuria. Any neoplasms previously diagnosed should be specified, including
the histologic type, primary site, and histologic grade. If prior therapy has been given, it should be described
(systemic or intravesical chemotherapy, immunotherapy, radiation, etc). The method of collection and date also
should be specified in urine cytology specimens.

B. Histologic Type
The vast majority (more than 95%) of carcinomas of the urinary bladder, renal pelvis, and ureter are urothelial cell
in origin. The most recent 2016 World Health Organization (WHO) classification of tumors of the urothelial tract,
including urethra, urinary bladder, ureter, and renal pelvis, is provided in this note. Benign tumors are included in
this classification because, within the same patient, a spectrum of differentiation from benign to malignant tumors
may be seen in the bladder, either at the same time or over the clinical course of the disease. Also, clinicians
5-13
stage most tumors irrespective of histologic grade. The distinction between a urothelial carcinoma with
divergent squamous, glandular, or Müllerian differentiation and a pure squamous cell carcinoma, adenocarcinoma
or Müllerian is rather arbitrary. Most authorities, including the 2016 WHO classification, require a pure histology of
squamous cell carcinoma, adenocarcinoma or Müllerian to designate a tumor as such, all others with
recognizable papillary, invasive, or flat carcinoma in situ (CIS) urothelial component being considered as
urothelial carcinoma with divergent differentiation. A malignant neoplasm with small cell neuroendocrine
carcinoma component arising in the urinary tract is designated as small cell carcinoma.

2016 WHO Classification of Tumors of the Urothelial Tract

Urothelial tumors
Infiltrating urothelial carcinoma
Nested, including large nested
Microcystic
Micropapillary
Lymphoepithelioma-like
Plasmacytoid/signet ring cell/diffuse
Sarcomatoid
Giant cell
Poorly differentiated
Noninvasive urothelial lesions
Urothelial carcinoma in situ
Noninvasive papillary urothelial carcinoma, low grade
Noninvasive papillary urothelial carcinoma, high grade
Papillary urothelial neoplasm of low malignant potential
Urothelial papilloma
Inverted urothelial papilloma
Urothelial proliferation of uncertain malignant potential
Urothelial dysplasia

Squamous cell neoplasms

Pure squamous cell carcinoma
Verrucous carcinoma
Squamous cell papilloma

Glandular neoplasms
Adenocarcinoma, NOS
Enteric

11
Background Documentation Genitourinary • Urinary Bladder
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Mucinous
Mixed
Villous adenoma

Urachal carcinoma

Tumors of Mullerian type

Clear cell carcinoma
Endometrioid carcinoma

Neuroendocrine tumors
Small cell neuroendocrine carcinoma
Large cell neuroendocrine carcinoma
Well-differentiated neuroendocrine tumor
Paraganglioma

C. Histologic Grade
10-17
Flat intraepithelial lesions and papillary and invasive lesions are graded separately. There has been significant
controversy in the classification of these lesions. Flat lesions were graded as mild, moderate, and severe
dysplasia and carcinoma in situ; or atypical hyperplasia and carcinoma in situ; or dysplasia and carcinoma in
5,7
situ. Papillary lesions were classified as papillomas (grade 0) and transitional cell carcinomas, grades I, II and
13-15
III; or as papillomas, low-grade and high-grade transitional cell carcinomas. Due to variable classification
systems and the need for a universally acceptable system, the World Health Organization/International Society of
13
Urological Pathology (WHO/ISUP) consensus classification was proposed. This system is adopted in the WHO
10 12
2004 classification and 2004 Armed Forces Institute of Pathology (AFIP) fascicle, and has been validated by
many studies to be prognostically significant. The 2016 WHO system used essentially the same classification with
11
minor modification. Other systems (that were being used previously) may still be used according to institutional
13 10
preference. Tumor grade according to both the WHO/ISUP (1998) / WHO (2004) system and the older WHO
15
(1973) system may be concurrently used.

2004 WHO / ISUP Consensus Classification for Urothelial Lesions

Normal
#
Normal
Hyperplasia
Flat hyperplasia
Papillary hyperplasia
Flat Lesions with Atypia
Reactive (inflammatory) atypia
Atypia of unknown significance
#
Dysplasia (low-grade intraurothelial neoplasia)
##
Carcinoma in situ (high-grade intraurothelial neoplasia)
Papillary Neoplasms
Papilloma
Inverted papilloma
Papillary neoplasm of low malignant potential
Papillary carcinoma, low-grade
###
Papillary carcinoma, high-grade
Invasive Neoplasms
Lamina propria invasion
Muscularis propria (detrusor muscle) invasion
#
May include cases formerly diagnosed as “mild dysplasia.”
##
Includes cases with “severe dysplasia.”
###
Option exists to add comment as to the presence of marked anaplasia.

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Flat and papillary urothelial hyperplasia has been renamed as “urothelial proliferation of uncertain malignant
potential” in the 2016 WHO classification.

Squamous carcinomas and adenocarcinomas may be graded as well-differentiated, moderately differentiated,

and poorly differentiated.

D. Extent of Invasion
A critical role of the surgical pathologist is to diagnose the depth and extent of invasion into the subepithelial
18-20
connective tissue/lamina propria/submucosa (pT1), muscularis propria (pT2), or beyond (pT3 or pT4). In
papillary tumors, invasion occurs most often at the base of the tumor and very infrequently in the stalk. In the
urinary bladder, a tumor infiltrating the lamina propria (pT1) is sometimes overdiagnosed as vascular invasion;
hence, caution should be exercised when diagnosing this feature, which in some cases may be supported by
21
performing immunohistochemical studies for endothelial markers. Depth of invasion is a critical prognostic
determinant in invasive urothelial carcinoma. In T1 disease, several substaging methods have been proposed but
10,13
have been difficult to adopt due in part to the inherent lack of orientation of the specimen. Pathologists are,
however, encouraged to provide some assessment as to the extent of lamina propria invasion (ie, maximum
dimension of invasive focus, or depth in millimeters, or by level – above, at, or below muscularis mucosae).
Designation of a tumor as merely muscle invasive is inappropriate, but the type of muscle invasion, ie, muscularis
22,23
mucosae (pT1 tumors) versus muscularis propria (pT2 tumors) invasion, needs to be clearly stated.
Descriptive terminology, such as “urothelial carcinoma with muscle invasion, indeterminate for type of muscle
invasion,” may be used when it is not possible to be certain whether the type of muscle invaded by the tumor is
hypertrophic muscularis mucosae or muscularis propria. A comment on thermocoagulation effect may be made,
24
especially if its presence impedes diagnostic evaluation. In TURBT specimens invasive into muscularis propria,
no attempt should be made to substage the depth of muscularis propria invasion. Since fat may be present in the
lamina propria and muscularis propria, the presence of tumor in adipose tissue is not necessarily diagnostic of
23,25
extravesical spread; this determination is reserved for cystectomy specimens.

Involvement of the prostate gland may occur in several different patterns. Tumors (flat carcinoma in situ, papillary
or invasive carcinoma) can first spread along the prostatic urethral mucosa and prostate glands and subsequently
invade prostatic stroma (transurethral mucosal route) (Figure 1, B). Tumors may also invade through the bladder
26
wall and the base of the prostate directly into the prostate gland (Figure 1, A, straight arrow). Tumors can also
invade into extravesical fat and then extend back into the prostate gland (Figure 1, B, curved arrow). The latter
two routes are considered direct transmural invasion. The American Joint Committee on Cancer (AJCC) 8th
edition staging manual defines direct extension of urinary bladder cancer into the prostate gland as T4 disease
and excludes transurethral mucosal prostatic stroma invasion from the pT4a staging status. However, there is
limited data on the best methodology to stage urothelial carcinoma that concurrently involves the urinary bladder
and the prostatic urethra. In patients who have a large urinary bladder carcinoma that has invaded through the full
thickness of the bladder wall and thereby secondarily involves the prostatic stroma, a T4 stage should be
assigned per urinary bladder staging. In other circumstances in which involvement by urothelial carcinoma is seen
in both sites, separate urinary bladder and prostatic urethral staging should be assigned.

13
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Figure 1. Prostatic invasion from urinary bladder cancer via direct transmural and extravesical route (A) and transurethral
invasion (B). From: Patel AR, Cohn JA, El Latif AA, et al. Validation of new AJCC exclusion criteria for subepithelial prostatic
stroma invasion from pT4a bladder urothelial carcinoma. J Urol. 2013;189:53-58. Reproduced with permission.

E. Lymphovascular Invasion
Urothelial carcinoma may invade blood vessels or lymphatic channels. Lymphovascular invasion has been shown
27
to be an independent predictor of recurrence and decreased overall survival. Presence of lymph-vascular
28
invasion in TURBT specimens is associated with higher nodal metastasis. In suspicious cases, blood vessels
can be highlighted by immunohistochemical staining for factor VIII-related antigen, CD31 or CD34. Staining will
not resolve the problem of differentiating lymphatic versus artifactual space entrapment by tumor cells, and as
mentioned, this is frequently seen in urothelial tumors invading the lamina propria. Retraction artifact is also
7
prominent in the “micropapillary variant” of urothelial carcinoma.

F. TNM and Stage Groupings

18
The TNM Staging System for carcinomas of the urinary bladder of the AJCC is recommended. A
cystoprostatectomy specimen may contain three separate primaries: carcinoma of the urinary bladder, carcinoma
of the prostate and carcinoma of the urethra. Depending on the pathology in a given case, the number of
protocols to be used in a cystoprostatectomy specimen will vary.

By AJCC convention, the designation “T” refers to a primary tumor that has not been previously treated. The
symbol “p” refers to the pathologic classification of the TNM, as opposed to the clinical classification, and is based
on gross and microscopic examination. pT entails a resection of the primary tumor or biopsy adequate to evaluate
the highest pT category, pN entails removal of nodes adequate to validate lymph node metastasis, and pM
implies microscopic examination of distant lesions. Clinical classification (cTNM) is usually carried out by the
referring physician before treatment during initial evaluation of the patient or when pathologic classification is not
possible.

Pathologic staging is usually performed after surgical resection of the primary tumor. Pathologic staging depends
on pathologic documentation of the anatomic extent of disease, whether or not the primary tumor has been
completely removed. If a biopsied tumor is not resected for any reason (eg, when technically unfeasible) and if the
highest T and N categories or the M1 category of the tumor can be confirmed microscopically, the criteria for
pathologic classification and staging have been satisfied without total removal of the primary cancer.

Primary Tumor (T) (Figure 2)

The suffix “m” should be added to the appropriate T category to indicate multiple tumors. The suffix “is” may be
added to any T to indicate the presence of associated carcinoma in situ.

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Figure 2. Extent of Tis, Ta, T1, and T3. From: Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th
ed. New York, NY: Springer; 2017. Reproduced with permission.

TNM Stage Groupings

#
Stage 0a Ta N0 M0
Stage 0is Tis N0 M0
Stage I T1 N0 M0
Stage II T2a N0 M0
T2b N0 M0
Stage IIIA T3a, 3b, 4a N0 M0
Stage IIIA T1-4a N1 M0
Stage IIIB T1-4a N2, 3 M0
Stage IVA T4b N0 M0
Stage IVA Any T Any N M1a
Stage IVB Any T Any N M1b
#
M0 is defined as no distant metastasis.

TNM Descriptors
For identification of special cases of TNM or pTNM classifications, the “m” suffix and “y” and “r” prefixes are used.
Although they do not affect the stage grouping, they indicate cases needing separate analysis.

The “m” suffix indicates the presence of multiple primary tumors in a single site and is recorded in parentheses:
pT(m)NM.

The “y” prefix indicates those cases in which classification is performed during or following initial multimodality
therapy (ie, neoadjuvant chemotherapy, radiation therapy, or both chemotherapy and radiation therapy). The
cTNM or pTNM category is identified by a “y” prefix. The ycTNM or ypTNM categorizes the extent of tumor
actually present at the time of that examination. The “y” categorization is not an estimate of tumor prior to
multimodality therapy (ie, before initiation of neoadjuvant therapy).

The “r” prefix indicates a recurrent tumor when staged after a documented disease-free interval, and is identified
by the “r” prefix: rTNM.

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Additional Descriptors
Residual Tumor (R)
Tumor remaining in a patient after therapy with curative intent (eg, surgical resection for cure) is categorized by a
system known as R classification, shown below.

RX Presence of residual tumor cannot be assessed

R0 No residual tumor
R1 Microscopic residual tumor
R2 Macroscopic residual tumor

For the surgeon, the R classification may be useful to indicate the known or assumed status of the completeness
of a surgical excision. For the pathologist, the R classification is relevant to the status of the margins of a surgical
resection specimen. That is, tumor involving the resection margin on pathologic examination may be assumed to
correspond to residual tumor in the patient and may be classified as macroscopic or microscopic according to the
findings at the specimen margin(s).

G. Sections for Microscopic Evaluation

Bladder
Sections of bladder for microscopic evaluation are as follows. In TURBT specimens, submit one section per
centimeter of tumor diameter (up to 10 cassettes). If the tumor is noninvasive by the initial sampling, additional
submission of tissue (including possibly submitting all tissue) is necessary to diagnose or rule out the presence of
invasion. If tumor is invasive into lamina propria in the initial sampling, additional sections (including possibly
submitting the entire specimen) may be necessary to diagnose or rule out the possibility of muscularis propria
invasion. In cystectomy specimens, several representative sections of the tumor, including the macroscopically
deepest penetration, should be sampled. Submit several sections of the mucosa remote from the carcinoma,
especially if abnormal, including the lateral wall(s), dome, and trigone. Submit one section of ureteral margin,
unless submitted separately as frozen section specimens, and 1 section of urethral margin. If a long segment of
the ureter(s) is present, then additional sections from the mid-portion may be necessary, as urothelial cancer
often is multifocal.

Prostate and Prostatic Urethra

Prostatic urethral involvement should be carefully investigated in cystectomy specimens. Sections should include
the prostatic urethra, including at the margin and with the surrounding prostatic parenchyma. Representative
sections of the peripheral zone, central zone, and seminal vesicles should be included. Close gross examination
may help target sampling of selective abnormal-appearing areas.

Lymph Nodes
Submit one section from each grossly positive lymph node. All other lymph nodes should be entirely submitted, as
presence of nodal disease may be used as an indication for adjuvant therapy. Lymph nodes may be grossly or
microscopically detected in the perivesical fat.

Other Tissues
Submit one or more sections of uterus (as indicated) and one or more sections of vagina, seminal vesicles, and
other organs (as indicated). If the tumor grossly appears to invade the prostate, uterus, or vagina, sections should
be targeted, such that the relationship of the infiltrating tumor in the bladder wall and the adjacent viscus is clearly
demonstrable.

H. Margins
Resection margins, including those mentioned in Note G, should be carefully specified. Statements about deep
soft tissue margins should specify whether peritoneal surfaces are involved by tumor. In cases of urachal
adenocarcinoma in which partial cystectomy with excision of the urachal tract and umbilicus is performed, the
margins of the urachal tract, ie, the soft tissue surrounding the urachus and the skin around the umbilical margin,
should be specified. In renal pelvis, ureter, and nephroureterectomy specimens, the margins may include radial
hilar soft tissue margin; bladder cuff; and ureteral, renal parenchymal, and Gerota’s fascia margins, depending on
the type of surgical specimen.

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