E U R O P E A N U R O L O GY 7 3 ( 2 0 18 ) 5 6 0 – 5 6 9

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Editorial by Eva Compérat on pp. 570–571 of this issue

Updates in the Eighth Edition of the Tumor-Node-Metastasis

Staging Classification for Urologic Cancers

Gladell P. Paner a,b,*, Walter M. Stadler c, Donna E. Hansel d, Rodolfo Montironi e, Daniel W. Lin f,
Mahul B. Amin g,h
a
Department of Pathology, University of Chicago, Chicago, IL, USA; b Department of Surgery (Urology), University of Chicago, Chicago, IL, USA; c Department
of Medicine (Hematology/Oncology), University of Chicago, Chicago, IL, USA; d Departments of Pathology and Urology, University of California, San Diego, CA,
e
USA; Department of Pathological Anatomy and Histopathology, School of Medicine, Polytechnic University of the Marche Region, Ancona, Italy;
f
Department of Urology, University of Washington and Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;
g
Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA; h Department of Urology, University
of Tennessee Health Science Center, Memphis, TN, USA

Article info Abstract

Article history: The Tumor-Node-Metastasis (TNM) classification on cancer staging, jointly developed by the
Accepted December 14, 2017 American Joint Commission on Cancer (AJCC) and the Union for International Cancer Control
(UICC), has been updated to its 8th edition with two contemporaneous versions published by
Associate Editor: the AJCC and UICC. While the goal of the AJCC and UICC is to have identical TNM staging
James Catto systems, differences exist between these two publications including in the staging of urologic
cancers. Among several new facets in the AJCC staging manual, a select few of greater import
include an expanded section on imaging, presentation of levels of evidence for significant
Keywords: changes, and endorsement of risk assessment models that pass the AJCC quality criteria such
Bladder as in prostate cancer. The updates for urologic cancers in the AJCC stage categories can be
Genitourinary grouped into: (1) newly defined TNM categories and prognostic stage groupings, (2)
clarifications and refinements of previously defined categories, and (3) more systematic
Kidney and expanded presentation of prognostic factors. Changes are harmonized with the current
Penis reporting and treatment guidelines. Contributions from genitourinary pathology are evident
Prostate in the AJCC classification from many of the International Society of Urological Pathology
Staging (ISUP) consensus conferences on prostate, kidney, testicular, and penile neoplasms that
addressed staging issues and the timely publication of the 4th edition of the World Health
Testis
Organization (WHO) classification of urinary and male genital organ tumors. New grading
TNM approaches for penile (WHO/ISUP grade), prostate (Grade group), and kidney (WHO/ISUP
Ureter nucleolar grade) cancers were adopted in the AJCC system. Many of these updates in the AJCC
Urethra staging manual are also included in the 8th UICC TNM edition. In an effort to achieve the
Urinary optimal staging recommendations for urologic cancers, updates in the 8th TNM edition were
generated through the acquisition of best evidences, tapping interdisciplinary resources
Urologic including consensus recommendations, and enhanced data analysis.
Patient summary: In this report, we explain the seminal changes in the 8th edition of the
Tumor-Node-Metastasis staging system for urologic cancers. Major stage category defi-
nitional changes are in Tumor-Node-Metastasis classifications of testicular, penile, and
prostate cancer which improve patient stratification for prognosis and management.
© 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Department of Pathology, The University of Chicago, 5841 South Maryland
Avenue, Room AMB S626 – MC 6101, Chicago, IL 60637, USA. Tel. +1 773 702 2824; Fax: +1 773 834
7644.
E-mail address: Gladell.Paner@uchospitals.edu (G.P. Paner).
https://doi.org/10.1016/j.eururo.2017.12.018
0302-2838/© 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
 E U R O P E A N U R O L O GY 7 3 ( 2 018 ) 5 6 0 – 5 6 9
1. Introduction
The Tumor-Node-Metastasis (TNM) staging system has
been recognized globally for decades as the benchmark in
staging cancers for: (1) cancer classification, (2) prognosti-
cation, (3) management, (4) data registry, and (5) clinical
trials and research. In late 2016, the American Joint
Committee on Cancer (AJCC) published its 8th edition of
the AJCC Cancer Staging Manual (8E AJCC), with an
implementation date of January 1, 2018 for clinical practice
and cancer registry reporting [1]. Changes in stage
classifications were guided by the principle of building
on its “population-based” approach and refining towards a
more “personalized” paradigm to cancer staging, exempli-
fied by the expansion of nonanatomic factors in its
prognostic stage groups for select cancers. The 8E AJCC
demonstrates transparency behind major changes by
providing levels of evidence, established by its Evidence-
Based Medicine and Statistics Core (Table 1) [2]. Through
the AJCC Precision Medicine Core, select risk assessment
models for individualized prognosis were endorsed
and will be continually updated on the AJCC website
(cancerstaging.org) [3].
The 8E AJCC has divided chapters presented in the
Genitourinary section of the 7th edition into two separate
sections—Male Genital Organs (3 chapters) and Kidney and
Urinary Tract (4 chapters). The updates and emphasis in the
8E AJCC are most evident in the pathological aspects of
staging and other prognostic factors. Besides the actual
revisions in the TNM categories, attention was also devoted
to: (1) clarify stage category definitions by using contem-
porary histoanatomic terminology used by practicing
pathologists, (2) updating tumor histologic classifications,
and (3) presenting prognostic factors in a more systematic
and expanded manner. Since the publication of the 7th
edition, the International Society of Urological Pathology
(ISUP) had conducted consensus conferences on prostate
cancer in 2009, kidney cancer in 2012, and testicular and
Table 1 – American Joint Commission on Cancer levels of evidencea
Level Evidence
I The available evidence includes consistent results from multiple
large, well-designed, and well-conducted national and international
studies in appropriate patient populations, with appropriate
endpoints, and appropriate treatments. Both prospective studies and
retrospective population-based registry studies are acceptable;
studies should be evaluated based on methodology rather than
chronology.
II The available evidence is obtained from at least one large, well-
designed, and well-conducted study in appropriate patient
populations and with appropriate endpoints and with external
validation.
III The available evidence is somewhat problematic due to one or more
factors, such as: number, size, or quality of individual studies,
inconsistency of results across individual studies, appropriateness of
patient population used in one or more study, or appropriateness of
outcomes used in one or more study.
IV The available evidence is insufficient because appropriate studies
have not yet been performed.
a
Reproduced from Amin et al [1].
561
penile cancers in 2015, the proceedings of which have
informed several pathologic staging issues [4–10]. The 4th
edition of the World Health Organization (WHO) classifica-
tion for urologic cancers was published in early 2016 and
was incorporated as the histologic classification system in
the 8E AJCC [11]. Urologic specimen handling strategies
including those provided by ISUP and the College of
American Pathologists are also recommended [4–10,12].
The 8E AJCC is a compendium of all currently available
information on the staging of adult cancers for most
clinically important anatomic sites developed by the AJCC in
cooperation with the UICC. While the two organizations
work closely together at every level to create a staging
schema that is largely identical between the two organiza-
tions; some significant differences exist. The differences
arise as UICC aims to maintain its focus on cancer incidence
and surveillance across the world and hence requires
international applicability across all countries, particularly
those that are severely economically restrained. AJCC's
vision is to build on the anatomic basis of the extent of
disease foundation of the TNM classification developed
robustly over the past seven editions and judiciously
incorporate nonanatomic factors critical in cancer classifi-
cation and prognostication. Thus, AJCC aims to meet both
the cancer surveillance and registry needs while gaining
increased clinical relevance at the individual patient care
level. Contemporaneous to the 1024-page 8E AJCC manual,
the UICC published its more condensed 253-page 8th
edition of the TNM Classification of Malignant Tumours (8E
UICC) [13]. The UICC has retained many of the categories
unchanged from the 7th TNM edition. Some genitourinary
pathology experts have criticized the UICC for publishing its
8th edition TNM version with fewer updates and exclusion
of major ISUP recommendations in urologic cancers
[14]. This review summarizes the changes in the 8th TNM
staging edition for penile, prostate, testicular, kidney,
bladder, and urinary tract cancers (Tables 2–7).
1.1. Penile cancer
Significant changes in skin-derived (nonurethral) penile
cancer have been promulgated over past editions. Ta is now
significantly expanded to noninvasive localized squamous
cell carcinoma (SCC) from the previous noninvasive verru-
cous carcinoma (level of evidence II). The older definition
was confusing to pathologists who may deem it is
applicable to all verrucous carcinomas; most of which have
broad pushing invasion and its extent can be difficult to
assess. The new definition does not permit any overt
destructive invasion in well sampled verrucous carcinoma
and also encompasses other noninvasive SCC types such as
basaloid, warty, papillary, and mixed types [11,15]. Ta is
analogous to noninvasive papillary urothelial carcinoma of
the urinary tract that contrasts the Tis for flat carcinoma in
situ (CIS) or penile intraepithelial neoplasia.
The corpora are covered externally by varying tissue
layers at the different regions of the penis (glans, foreskin,
and shaft). The 8E AJCC has revised the definition of T1 or
noncorporal invasive cancers according to penile region-
562 E U R O P E A N U R O L O G Y 7 3 ( 2 0 18 ) 5 6 0 – 5 6 9
Table 2 – Updates in the American Joint Commission on Cancer
staging of penile cancer
Category Details
Histologic Three-tiered WHO/ISUP grading adopted
grade (G1–G3)
Ta Broadened to noninvasive localized squamous cell
carcinoma
T1 Tumor invasion to layers superficial to corporal tissues
specified according to region's histoanatomy (glans,
foreskin, or shaft)
Perineural invasion included to divide T1a and T1b
Sarcomatoid change clarified as one high grade variable
to divide T1a and T1b
T2 Confined to tumor invasion into corpus spongiosum
Tumor invasion of corpus cavernosum excluded
T3 Tumor invasion into corpus cavernosum
Urethral involvement no longer the determinant and can
be T2 or T3
pN1 Increased to up to two unilateral inguinal LN metastases
without extranodal extension
pN2 Increased to >2 unilateral or bilateral inguinal LN
metastases without extranodal extension
Prognostic Includes organ-confined disease with corporal tissue
stage group II invasion or, with LVI, PNI, or high-grade features divided
by presence of corpus cavernosum invasion (IIA or IIB)
Prognostic Includes organ-confined disease divided by number and/
stage group III or laterality of inguinal LN metastasis (IIIA or IIIB)
ISUP = International Society of Urological Pathology; LN = lymph node;
LVI = lymphovascular invasion; PNI = perineural invasion; WHO = World
Health Organization.
specific histoanatomy (level of evidence I). Having precise
definitions by glans, foreskin, or shaft regions allow for
more consistent categorization of T1 disease over the
previous editions which used nonspecific subepithelial
tissue layer as a general definition. T1 is subcategorized
into T1a and T1b which have different risks for lymph node
(LN) metastasis (10.5–18.1% vs 33.3–50%), and is significant
when opting for inguinal LN dissection [16,17]. Perineural
invasion is recognized as a predictor for regional LN
metastasis and is now added as another separation criterion
for T1a and T1b tumors besides LVI and high-grade
histology (level of evidence III) [18]. While previously
grouped with T2, studies have shown that corpus spongio-
sum invasion compared to corpus cavernosum invasion is
associated with lower inguinal LN involvement (33–35.8%
vs 48.6–52.5%) and better survival [16,19]. Thus, T2 is now
restricted to invasion into corpus spongiosum while
invasion into corpus cavernosum is upstaged to T3 (level
of evidence II). Urethral invasion, previously defined as T3
disease, can now be either T2 or T3 depending on the more
important level of corporal invasion. Penile cancer near the
meatus may invade directly into the distal urethra
bypassing the corpora and is not associated with worse
outcome.
The AJCC 7th edition pN1 (single inguinal LN) and pN2
(multiple or bilateral inguinal LNs) categories were shown
in some clinical scenarios to have no significant difference
in risk for death from disease [20]. For example, disease-
specific survival of patients with one or two unilateral
inguinal metastases (with no extranodal extension) was
similar to those with a single positive node. Further,
metastasis involving three or more unilateral or bilateral
inguinal LNs have poorer outcomes compared with
metastasis involving one or two unilateral inguinal LNs
(60.5% vs 90.7% 3-yr cancer-specific survival) [16,20]. Later-
ality of LN metastasis further increases the accuracy to
predict the outcome [21]. Thus, pN1 is now increased to up
to two unilateral inguinal LN metastases, while pN2 is
now modified as more than three unilateral or bilateral
inguinal LN metastases (level of evidence II). The resulting
migration to the lower pN1 may avoid adjuvant chemo-
therapy to some patients with (two positive) LN disease
since this treatment has been recommended to pN2
patients [22]. Prognosis of pN3 is poorer and recent data
suggests that pelvic LN involvement is worse than extra-
nodal inguinal LN involvement (3-yr cancer-specific surviv-
al of 28.6% vs 47.9%) [20,21,23].
Histologic grade in penile SCC is a significant predictor
of regional LN metastasis and has been shown to improve
the ability of the AJCC stage to predict cancer-specific
mortality [18,24]. The three-tiered WHO/ISUP grading
system has now replaced the four-tiered modification
of the Broder's grading system for SCC (level of evidence
III) [11,18,25]. The WHO/ISUP grading for SCC considers any
amount of anaplasia as grade 3 (G3). Poorly-differentiated
histology or anaplasia particularly when >50% is a strong
predictor for LN metastasis. The two grade extremes
(G1 and G3) facilitate prognostic categorization of penile
SCC [26]. In the T1 category, high-grade (G3) histology is
one variable used to separate T1b from T1a cancers (level
of evidence I). Sarcomatoid carcinoma, a known aggressive
histology of SCC, is now stated as a high-grade feature of
T1b cancer [27].
1.2. Prostate cancer
The impact of a more personalized approach to TNM staging
is evident in the prostate cancer stage revisions as based on
nonanatomic factors (grade group [also rarely referred to as
ISUP grade] and serum prostate-specific antigen [PSA])
organ-confined cancer may be designated as AJCC prognos-
tic stage group III (if the tumor is grade group 5 and/or
patient has a serum PSA of >20 ng/ml; level of evidence II).
In the absence of incorporation of these nonanatomic
Table 3 – Updates in the American Joint Committee on Cancer
(AJCC) staging of prostate cancer
Category Details
Histologic grade Grade group to be reported in addition to
Gleason score
Gleason score to be based on ISUP 2014 criteria
pT2 Pathologically organ-confined tumors no longer
subcategorized based on bilaterality and extent
of involvement
Prognostic stage Includes select organ-confined disease tumors
group III based on PSA and Gleason/grade group status
Statistical prediction Prognostic models that met all AJCC quality
models criteria added
ISUP = International Society of Urological Pathology; PSA = prostate-
specific antigen.
 E U R O P E A N U R O L O GY 7 3 ( 2 018 ) 5 6 0 – 5 6 9
factors into stage grouping, the exercise of staging had little
clinical relevance for organ-confined cancers.
The assignment of Gleason score (GS) in clinical practice
is now based on the 2014 ISUP consensus criteria
[28,29]. The 2014 ISUP consensus on Gleason grading
addressed key areas including definitions of grading
patterns of usual and variant morphologies of prostate
adenocarcinoma, grading of intraductal carcinoma, and the
support for the novel grade groups. Among the specific
important modifications adopted in the consensus confer-
ence publication are grading of all cribriform and glomer-
uloid architectures as Gleason pattern 4, grading of
mucinous carcinoma based on its underlying growth, and
the exclusion of intraductal carcinoma from grading. The 8E
AJCC now requires reporting of grade group together with
the GS (level of evidence II). The grade group, first described
in 2013, equates the GS with the following prognostic
groups: grade group 1 (GS 6), grade group 2 (GS 3+4 = 7),
grade group 3 (GS 4+3 = 7), grade group 4 (GS 8), and grade
group 5 (GS 9–10). The key contributions of the grade
groups are: (1) it designates grade group 1 as the lowest
score in contrast to 6 in GS, which is at the middle of the
scale (GS 2–10)—a recurring problem when counseling
patients, in particular, for active surveillance, (2) GS 7 is not
considered as a homogenous cancer and splitting into grade
groups 2 and 3 accounts for the differences in prognosis, and
management approach in clinical trials and in routine
practice, and (3) GS 8–10, often considered as one group of
high-grade disease, can be separated prognostically and
stratify patients for different treatment strategies in grade
group 4 and 5 [28,29]. The accurate prognostic stratification
of grade groups has been validated in a large multi-
institutional cohort of radical prostatectomies and prostate
biopsies [30]. The grade group has been adopted by the
2016 WHO tumor classification, 2017 College of American
Pathologists prostate cancer protocols, and recent clinical
guidelines [11,12,31,32]. Grade group is anticipated to be
used in combination with GS for the foreseeable future with
its value analyzed over time.
The primary clinical T (cT) stage assessment includes
information from the digital rectal examination (DRE) of
the prostate. It should be noted that neither imaging nor
tumor laterality information from the prostate biopsy
should be used for cT categorization. Although imaging
may eventually improve cT staging accuracy, there are
several issues that hamper its adoption and incorporation
into the current AJCC edition, including interobserver
reproducibility, issues with patient selection, and contra-
dictory results [33]. Thus, at this point, imaging alone does
not replace the DRE as the clinical staging standard. cT1
tumors are still nonpalpable by DRE, and there is no
pathologic T1 (pT1) staging category.
In the 8E AJCC T2 category, the pathologically organ-
confined tumors are no longer subclassified based on
bilaterality and extent of involvement (ie, pT2a, pT2b and
pT2c) because of the prognostic evidence (level of evidence
III) [7,34–36]. Further, there is peculiarity in the previous
pathologic T2 subcategory that pT2b was extremely rare
and small multifocal tumors could be assigned a higher
563
subcategory of pT2 [7,37]. Furthermore, there are no reports
that definitively allow correlation between the previous pT2
stage subgroupings with survival in localized prostate
cancer, likely due to the indolent and prolonged clinical
course of the disease. There are emerging data that unlike
the pT2 subdivisions, tumor volume measurement may be
more prognostically informative [38]. Conversely, the three-
tiered T2 subclassification, however, is retained in the cT
categories, the laterality being determined only by DRE
findings, as these cT subgroupings remain important in risk
stratification and management of localized disease. There is
a minor clarification that bilateral (vs unilateral) extrapro-
static extension and seminal vesicle invasion are still in T3a
and T3b, respectively.
As mentioned above, with the incorporation of PSA and
grade group into the AJCC prognostic stage groups, organ-
confined prostate cancer (T1–T2) may be staged as
prognostic stage group IIIA (of IV) [39]. This is in distinction
to node-negative, nonorgan-confined prostate cancer (T3–
T4), grade group 1-4 is prognostic stage group IIIB, for which
some would recommend consideration for adjuvant radia-
tion. Adjustments in stage groupings were made to be
consistent with the clinical risk categories in the treatment
guidelines, so as to have similar treatment options for T3 or
T4 and T1–T2 but with grade group 5 and PSA of >20 ng/ml
[32]. Stage group IIC was also added and stage groups III and
IV were both subdivided into A and B. The 8E AJCC modified
staging and prognostic stage grouping for prostate cancer
has been validated recently in a large radical prostatecto-
mies cohort [40].
A new undertaking in the 8E AJCC manual for prostate
cancer is the evaluation of statistical prediction models for
endorsement. These are multivariable models where the
risk factors are used to predict future clinical outcome [3].
A set of stringent inclusionary and exclusionary criteria
were established by the AJCC Precision Medicine Core. From
the 15 prostate cancer prognostic models initially identified
in public domains, only two met all the AJCC quality criteria
[41,42]. The two AJCC endorsed prognostic models however
are only for metastatic castration-resistant prostate cancer
patients primarily for various methodologic issues, for
example, lack of calibration plots, external validation, and
use of outcomes other than overall survival. There are no
AJCC approved models for localized or locally aggressive
prostate cancers where staging and risk assessment is more
important.
The 8E UICC also adopted the grade groups for grading
prostate cancer. Unlike the 8E AJCC, the UICC retained the
pT2 subdivisions into pT2a, pT2b, and pT2c. The UICC also
has an additional designation of pNmi (mi for microme-
tastasis) for regional LN metastasis no larger than 0.2 cm in
greatest dimension, although the clinical relevance of this
subcategory in prostate cancer remains to be validated and
will be evaluated in the next edition of the AJCC manual
pending available data to support the category. The 8E UICC
has published only an anatomic stage grouping and has only
commented on, but not included the prognostic stage
groups (ie, with PSA and grade group incorporated) of the
8E AJCC.
564 E U R O P E A N U R O L O G Y 7 3 ( 2 0 18 ) 5 6 0 – 5 6 9
1.3. Testicular cancer
The putative precursor of postpubertal germ cell tumors
(GCTs) was renamed as germ cell neoplasia in situ (GCNIS) in
the 2016 WHO classification which is adopted by the 8E
AJCC manual for definition of Tis lesion [10,11,43]. GCNIS
was referred previously as intratubular germ cell neoplasia
in-situ unclassified type, and the new term intermixes
intratubular germ cell neoplasia with CIS. GCNIS makes a
clearer distinction from intratubular spread of GCT such as
intratubular seminoma or embryonal carcinoma. Sperma-
tocytic seminoma has also been renamed in the 2016 WHO
classification as spermatocytic tumor, to make the distinc-
tion from the usual seminoma, and because of its almost
uniformly favorable outcome; it is emphasized that it
should not be staged [10,43]. This avoids unnecessary
adjuvant radiotherapy or chemotherapy for this tumor type.
In the 8E AJCC T1 category, pure seminoma is now
subclassified into T1a and T1b by a size cut-off of 3 cm (level
of evidence I). Several studies have shown that tumor size in
stage I seminoma is an independent predictor of relapse and
is one factor that may be considered in risk-adapted
adjuvant management [44–47] Although the size cut-off
used in the literature varies (including 4 cm), it was agreed
by the AJCC male genital tract expert panel that the
conservative smaller cut-off of 3 cm should be used.
Some studies showed that invasion into the rete testis by
GCT is an independent predictor for relapse [45,46,48],
but this is contradicted by other studies [44,49]. Invasion of
rete testis may precede hilar soft tissue invasion, as the
latter may be identified in more than half of rete testis
invasion [50]. Due to conflicting evidence, compounded by
the lack of distinction between pagetoid spread and true
invasion in the rete testis in prior studies and by some
pathologists, rete testis invasion is not considered for
staging in the 8E AJCC manual and remains within the
organ-confined (pT1 or pT2 with lymphovascular invasion
[LVI]) category [10,51]. Hilar soft tissue invasion, however, is
upstaged to pT2 (level of evidence II). Hilar soft tissue is
adipose and connective tissue beyond the rete testis at the
same plane of section as the testis parenchyma. Most (about
80%) invasion into the testis hilum occurs via the rete testis,
and a recent study showed that hilar and rete testis
invasions are strongly associated with metastasis at
Table 4 – Updates in the American Joint Committee on Cancer
staging of testicular cancer
Category Details
Tis New terminology germ cell neoplasia
in situ adopted
pT1a and pT1b Pure seminoma subcategorized using
3-cm tumor size cut-off
pT2 Epidydimal invasion upstaged from T1
Hilar soft tissue invasion added
LVI only in spermatic cord without
parenchymal invasion
M1 Discontinuous involvement of
spermatic cord by LVI added
LVI = lymphovascular invasion.
presentation [50]. Invasion into the epididymis, an infre-
quent finding, is also now upstaged to pT2 (from pT1; level
of evidence II). Invasion beyond the angle of epididymis and
spermatic cord is considered as pT3. Direct invasion of
spermatic cord remains as pT3, but it is specified that
discontinuous involvement of spermatic cord and soft
tissues via LVI should be considered a metastatic deposit
(pM1; level of evidence III). LVI only in the spermatic cord
without its parenchymal invasion is considered as pT2.
Tumor adjacent to or surrounding the vas deferens is
identified as spermatic cord invasion (pT3). The evidence
for staging hilar soft tissue, epididymis, and patterns of
spermatic cord involvement are still limited and the
changes were mainly to improve reproducibility as there
was lack of clarity in the previous definitions for tumors
invading outside of the testis [10,51]. The UICC left the 7th
TNM staging system for testis unchanged for the 8th
edition. The UICC, however, noted the new AJCC division for
T1 by the 3-cm size cut-off, thereby, acknowledging the
importance of tumor in the risk-adapted treatment of stage I
(including T1) seminoma, but without incorporating this
variable in the 8E UICC staging.
1.4. Kidney cancer
Changes in kidney cancer staging were minimal compared
with other sites of the male genital and urinary tract as
major changes had been made in the 7th edition and data on
this basis is still accruing. In the 8E AJCC T3 category,
clarifications were made in T3a disease classification
involving renal vein and its tributaries. T3a criteria in the
7th edition had over-reliance on the prosector's gross
inspection of the hilar vessels. However, it is not uncommon
that tumor involvement of renal vessels can be missed
grossly, including in partial nephrectomy specimens. The
thickness of renal vein and its branches is considered a poor
gauge for its identification as it varies and some may be thin
with minimal muscular wall [52]. Histologic examination of
tumor nodules and cords within the renal sinus mostly
reveals intravascular tumor [52]. Thus, the word “grossly” to
describe invasion of renal vein and its segmental branch for
T3a is now removed (level of evidence II). Invasion of the
pelvicalyceal system is also added in T3a, as this part of the
collecting system is within the hilum (level of evidence II).
The renal sinus is being recognized as a principal route for
extrarenal extension, and chances of sinus invasion
Table 5 – Updates in the American Joint Committee on Cancer
staging of kidney cancer
Category Details
Histologic grade (G1–G4) WHO/ISUP nucleolar grading adopted
T3a “Grossly” to describe renal vein and
segmental branch invasion removed
“Muscle containing” changed to
“segmental vein”
Invasion of pelvicaliceal system added
ISUP = International Society of Urological Pathology; WHO = World Health
Organization.
 E U R O P E A N U R O L O GY 7 3 ( 2 018 ) 5 6 0 – 5 6 9
increases with larger tumor size particular for tumors
>4 cm [9,53]. Sampling the renal hilum by pathologists for
microscopic examination of vessel involvement, as recom-
mended by ISUP, is emphasized in the AJCC manual
[9]. Modifications in T3a may have impact on clinical trials
for adjuvant chemotherapy when defining locally-invasive
disease. The UICC virtually left the 7th TNM staging system
for kidney cancer unchanged for its 8th edition. Invasion of
the pelvicalyceal system in particular is not incorporated in
the 8E UICC definition of T3a.
The new four-tiered WHO/ISUP nucleolar grade is
adopted, replacing the traditional Fuhrman nuclear grade
(FNG; level of evidence II) [11,54]. In contrast to FNG, which
assesses a combination of nuclear and nucleolar features,
the WHO/ISUP grading for its first three grades relies
exclusively on the degree of nucleolar prominence provid-
ing better objectivity in the pathologist's interpretation.
Aggressive histologies such as sarcomatoid and rhabdoid
differentiation are incorporated into WHO/ISUP grade
4. Studies have shown that WHO/ISUP grade provides
better grade separation, particularly with grades 2 and 3 (a
problem with FNG) and has stronger association with
patient outcome [55]. The WHO/ISUP grade is best
applicable for clear cell and papillary renal cell carcinoma
(RCC) subtypes, but not for the chromophobe RCC subtype.
Rhabdoid differentiation, characterized by tumor cells
resembling rhabdomyoblasts, is emphasized in the 8E AJCC
manual as a poor prognostic factor for RCC (level of evidence
II) [56,57]. Rhabdoid differentiation, similar to sarcomatoid
differentiation, may occur across any of the RCC subtypes,
predicts poor outcome independent of histology, grade, and
stage, and has a metastatic rate of up to 70% and cancer-
specific mortality of 40–50% [54,56–59]. Microscopic LVI
has been shown in some studies to predict cancer-specific
survival and metastasis-free survival in renal cancer, and
has now been added as a prognostic factor in the 8E AJCC
(level of evidence II) [54]. There are differences in the
histologic prognostic factors enumerated in the 8E AJCC and
the 8E UICC. UICC 8E has retained the use of FNG for clear
cell RCC but has not adopted the WHO/ISUP nucleolar grade
adopted 8E AJCC. Further, rhabdoid differentiation and LVI
are not included as prognostic factors in the 8E UICC.
1.5. Urinary bladder cancer
Although actual changes are only in the N and M categories
and corresponding stage groups, some clarifications and
recommendations were made in the T categories [60]. AJCC
recognized the importance of subdividing T1 in trans-
urethral resection and recommends using some of the
proposed approaches for T1 subcategorization, but at the
same time acknowledges the need for its optimization.
Upstaging of T1 in radical cystectomies is substantial with
up to 50% of tumors upstaged to T2 or higher and 33%
upstaged to nonorgan confined stage [61,62]. T1 subcate-
gorization may help stratify this heterogeneous group of T1
cancers in transurethral resection besides the other known
risk factors such as grade, tumor size, CIS, multiplicity, and
recurrence [63]. Several strategies in T1 subcategorization
565
Table 6 – Updates in the American Joint Committee on Cancer
staging of urinary bladder cancer
Category Details
T1 Attempt for subcategorization in TUR
recommended
T2 Staging of diverticular cancers has no T2
T4 Prostatic stromal invasion clarified that must be
transmural from bladder; subepithelial stromal
invasion staged as T2 (urethral)
N1 Perivesical LN added
M1 Divided into nonregional LN only (M1a) and non-
LN distant metastases (M1b)
Prognostic stage Divided into IIIA and IIIB based on number of
group III regional LN and involvement of common iliac LNs
Prognostic stage Divided into IVA and IVB corresponding to the M1a
group IV and M1b division
LN = lymph node; TUR = transurethral resection.
have been proposed in the literature, including use of
anatomic landmarks in the bladder wall, measurements,
and estimations of volume, among others [60]. One
micrometric approach for T1 subcategorization is using
the 0.5 mm or 1 mm high power field cut-off [64,65]. One
recent study has evaluated all possible methodologies and
identified the optimal approach to be the addition of the
greatest dimension of all invasive cancer in the specimen
and suggests that a cut-off of 2.3 mm in aggregate length is
significantly associated with risk of progression to muscle
invasion [66].
Several studies have shown that bladder cancer with
intraurethral prostatic stromal invasion has a better outcome
than those with transmural prostatic stromal invasion [67–
69]. In the 7th TNM edition, intraurethral spread to the
prostate was excluded from pT4a, which in men only
includes transmural prostatic stromal invasion. This change
was subsequently validated in several studies [70,71]. How-
ever, staging of intraurethral prostatic stromal invasion was
not addressed in the 7th TNM edition. Because of prevailing
ambiguity, the 8E AJCC clarified that intraurethral prostatic
stromal invasion should be categorized as T2 (per urethral
staging and not bladder staging) and the bladder proper
tumor be given a separate T category (per bladder staging). It
remains unclear how a concurrent urethral T2 will impact a
>T2 bladder proper cancer; emphasis in reporting should be
given to the higher stage between the two.
The vast majority of bladder diverticula are acquired and
do not contain a muscularis propria layer [72]. Thus,
diverticular invasive cancer has no T2 category, as the tumor
directly invades from the lamina propria into the perive-
sicular soft tissue. 8E AJCC now recognizes the approach of
skipping T2 in staging diverticular cancer. Studies on
diverticular tumor T categories are limited and thus far
suggest comparable outcome to corresponding bladder
proper T categories [73–75].
Perivesical LNs are involved in the bladder's primary
lymphatic drainage and may be identified in 16–47% of
cystectomies. These LNs are usually not excised separately
by the surgeons and identification relies on the patholo-
gists. Perivesical LN may be positive in 7-10% of cystec-
tomies and is shown to be an independent predictor of
566 E U R O P E A N U R O L O G Y 7 3 ( 2 0 18 ) 5 6 0 – 5 6 9
survival [76]. Further, perivesical LN involvement showed
no significant difference is survival when compared with
nonperivesical regional LN involvement [77]. Thus, the 8E
AJCC now includes perivesical LN among regional LNs under
the N category (level of evidence II).
Presence of visceral metastasis has been shown to
independently predict poorer outcome in patients with
metastatic or unresectable bladder cancers including those
treated with systemic chemotherapy (gemcitabine or
combination mitomycin, vincristine, adriamycin, and
cisplatin) [78–82]. Patients with metastasis limited to
nonregional LNs have significantly better outcome than
patients with visceral or bone metastasis [82]. A small
subset of these patients experience complete radiologic
response after systemic chemotherapy and become long-
term survivors with or without additional primary tumor
therapy. In patients with locally advanced or metastatic
bladder cancer prospectively treated with gemcitabine or
mitomycin, vincristine, adriamycin, and cisplatin, the 5-yr
survival rates for patients without and with visceral
metastasis to bone, liver, or lung were 20.9% and 6.8%,
respectively [79]. Thus, 8E AJCC now classifies LN positivity
beyond the common iliac as M1a and all other non-LN
metastasis as M1b. Prognostic stage groups III and IV are
also subdivided into A and B according to the number of
regional LN involvement and M1 subcategories, respective-
ly (level of evidence II).
The 8E UICC made a similar modification in the M
category for bladder cancer, dividing into M1a and M1b
based on nonregional LN involvement and non-LN metas-
tasis, respectively. Similar changes were also made in the
anatomic stage groups, subdividing into IIIA and IIIB, and
IVA and IVB.
1.6. Renal pelvis and ureter cancer
Since there are no data to substantiate the three N
categories in the 7th AJCC edition, the previous category
of N3 metastasis in a LN greater than 5 cm is now collapsed
with N2 in 8E AJCC (level of evidence III). Similar revision in
the N category is made in the 8E UICC.
1.7. Urethral cancer
In urothelial carcinoma of the prostate, CIS in prostatic
urethra (previous Tis pu) and ducts (previous Tis pd) are
now collapsed into a single Tis category (level of evidence
III). This is because of the confusing definitions and lack of
strong data to support the separation of Tis pu from Tis pd.
Prostatic acinar involvement is also added under Tis to
emphasize that CIS can spread within acini that are often
histologically indistinguishable from prostatic ducts. A
minor clarification is made in prostate T1 urothelial
carcinoma that this category involves the prostatic urethral
subepithelial connective tissue beneath the urothelium.
This is to avoid understaging invasion into prostatic ducts or
acini subepithelium, which represents prostatic stromal
invasion categorized as T2. It emphasized that urethral
cancer invading into the bladder is categorized as T4, to
Table 7 – Updates in the American Joint Committee on Cancer
staging of urethral cancer
Category Details
Tis CIS in prostatic urethra (previous Tis pu) and ducts (previous
Tis pd) collapsed into a single Tis category
Prostatic acini involvement without stromal invasion added
T2 Clarified for urothelial carcinoma of the prostate as involving
the prostatic urethral subepithelial connective tissue
T4 Clarified that direct bladder extension is included
N1 Perivesical LN added
N1 and N2 Divided only by number of LN involved (single versus
multiple); previous division based on 2 cm LN metastasis
size cut-off removed
CIS = carcinoma in situ; LN = lymph node.
maintain consistency with bladder cancer transmurally
invading into the prostate, which is categorized as T4.
As in urinary bladder cancer, perivesical LN involvement
is also now added in the 8E AJCC N category. This category is
now divided into N1 and N2 only by number of LN
involvement (single versus multiple) and the previous
division based on 2-cm metastasis size cut-off is removed
(level of evidence III).
The 8E UICC made a similar change of dividing N into N1
and N2 based on the number of involved LNs. However, the
T categories are unchanged.
2. Conclusions
We believe that the revised, updated, and expanded Eighth
edition of the AJCC Cancer Staging Manual, in its offerings of
the seven chapters pertaining to urologic malignancies, is a
powerful resource for those involved in the discipline as
they advance the management of these cancers. Down-
stream proactive incorporation into standardized cancer
reporting protocols, clinical decision-making guidelines,
and electronic health records will be beneficial. The steps
taken by the AJCC to remain clinically efficacious and
applicable for the management of individual patients at the
point of care are laudable. In doing so, these steps provide
a conceptual framework and foundation for the future
of cancer staging as further strides occur in the era of
precision/personalized molecular oncology.
Author contributions: Gladell P. Paner had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Paner, Montironi, Amin.
Acquisition of data: Paner, Amin.
Analysis and interpretation of data: Paner, Stadler, Hansel, Montironi, Lin,
Amin.
Drafting of the manuscript: Paner.
Critical revision of the manuscript for important intellectual content: Paner,
Stadler, Hansel, Montironi, Lin, Amin.
Statistical analysis: None.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: None.
Other: None.
 E U R O P E A N U R O L O GY 7 3 ( 2 018 ) 5 6 0 – 5 6 9
Financial disclosures: Gladell P. Paner certifies that all conflicts of
interest, including specific financial interests and relationships and
affiliations relevant to the subject matter or materials discussed in the
manuscript (eg, employment/affiliation, grants or funding, consultan-
cies, honoraria, stock ownership or options, expert testimony, royalties,
or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
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