Histopathology 2019, 74, 112–134. DOI: 10.1111/his.

13734

REVIEW

Staging of bladder cancer

Martin J Magers,1 Antonio Lopez-Beltran,2,3 Rodolfo Montironi,4,5 Sean R Williamson,6,7
Hristos Z Kaimakliotis8 & Liang Cheng1,8
Departments of 1Pathology and Laboratory Medicine, 2Urology, Indiana University School of Medicine, Indianapolis, IN,
USA, 3Department of Pathology, 4Faculty of Medicine, Department of Surgery, Unit of Anatomical Pathology, Cordoba,
Spain, 5Champalimaud Clinical Center, Lisbon, Portugal, 6Institute of Pathological Anatomy and Histopathology, School
of Medicine, Polytechnic University of the Marche Region (Ancona), United Hospitals, Ancona, Italy, 7Department of
Pathology and Laboratory Medicine and Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI, USA,
and 8Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA

Magers M J, Lopez-Beltran A, Montironi R, Williamson S R, Kaimakliotis H Z & Cheng L

(2019) Histopathology 74, 112–134. https://doi.org/10.1111/his.13734
Staging of bladder cancer

Urothelial carcinoma of the urinary bladder is a Several critical changes and clarifications are made
heterogeneous disease with multiple possible treat- by the AJCC 8th edition relative to the 7th edition.
ment modalities and a wide spectrum of clinical Although the most obvious changes in the 8th edi-
outcome. Treatment decisions and prognostic expec- tion are in the N (i.e. perivesical lymph node involve-
tations hinge on accurate and precise staging, and ment now classified as N1) and M (i.e. M1 is
the recently published American Joint Committee on subdivided into M1a and M1b) categories, several
Cancer (AJCC) Staging Manual, 8th edition, should points are clarified in the T category (e.g. substaging
be the basis for staging of urinary bladder tumours. It of pT1 should be attempted). Further optimisation,
is unfortunate that the International Union Against however, is required. No particular method of sub-
Cancer (UICC) 8th edition failed to incorporate new staging pT1 is formally recommended. In this review,
data which is considered in the AJCC 8th edition. these modifications are discussed, as well as points,
Thus, the AJCC 8th edition is the focus of this review. which require further study and optimisation.
Keywords: urinary bladder, urothelial carcinoma/neoplasia, staging classification, prognosis, T1 substaging,
metastasis

Introduction published American Joint Committee on Cancer

(AJCC) Staging Manual 8th edition.2 These parame-
Urothelial carcinoma is the most common cancer of ters guide treatment decisions, and it is important for
the urinary bladder, and is a heterogenous disease surgical pathologists to be aware of current staging
with multiple possible treatment modalities, ranging guidelines for urinary bladder cancer.1,3 Unfortu-
from surveillance to radical cystectomy.1 Patients nately, a point of confusion in regard to accurate
with urinary bladder cancer are stratified by tumour tumour grading and staging may arise due to con-
grade and by tumour stage, according to the recently flicting and confusing recommendations made by the
International Union Against Cancer (UICC) 8th edi-
tion, which was published in 2016.4,5 The UICC 8th
Address for correspondence: Liang Cheng, Department of Pathology
and Laboratory Medicine, Indiana University School of Medicine,
edition failed to incorporate new data which was
350 West 11th Street, IUHPL Room 4010, Indianapolis, IN 46202, taken into consideration in the AJCC 8th edition. For
USA. e-mail: [email protected] example, the UICC retained the old term ‘transitional
© 2018 John Wiley & Sons Ltd.
 Staging of bladder cancer 113

cell carcinoma’, the UICC does not indicate which Thus, this review will discuss current staging recom-
grading system should be used for grading of urothe- mendations made by the AJCC Staging Manual 8th
lial neoplasms and the UICC still recommends differ- edition, with emphasis on problematic decision points
ent stages for in-situ involvement of the prostatic and areas which need further refinement in future
urethra (i.e. Tis pu) and prostatic duct involvement staging systems (Figure 1).
(Tis pd), even though there is no prognostic difference
between these groups.5
Furthermore, the UICC recommendations for pT2
Stage pT0 carcinoma
and pT4 tumours are incomplete and confusing. The Pathological stage pT0 is assigned when there is no
UICC recommendations for pT2 staging are not stated residual urothelial carcinoma (non-invasive or inva-
clearly, as they refer to inner muscle and outer mus- sive) in the cystectomy specimen (Table 1). This
cle invasion, and the inner muscle invasion could be occurs typically following a diagnosis of muscle inva-
confused to mean muscularis mucosa invasion rather sive bladder carcinoma in the biopsy or transurethral
than the inner half of the muscularis propria. Regard- resection (TUR) specimen(s) and completion of neoad-
ing pT4 tumours, the UICC fails to discuss the route juvant chemotherapy (NAC), although some patients
of invasion by urothelial carcinoma into prostatic are stage pT0 at radical cystectomy without undergo-
stroma (i.e. direct invasion from the bladder into pro- ing NAC.6 NAC should be designated in the patholog-
static stroma or invasion from the prostatic urethra). ical stage with the modifier ‘y’ (e.g. ypT0).

Figure 1. Overview of staging of tumours arising from the urinary bladder, diverticulum and urachal remnants.

© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.

114 M J Magers et al.

Table 1. The American Joint Committee on Cancer (AJCC) increases a patient’s chance of achieving stage
Staging System (8th edition, 2017) pT0.13–15 Even so, most patients do not achieve a
Primary tumour (T)
stage pT0 following NAC. A possible predictor of like-
lihood of pT0 at cystectomy following NAC is the
TX Primary tumour cannot be assessed presence or absence of variant histology, and this
T0 No evidence of primary tumour should be included in the surgical pathology report.
Demonstrating this, a recent study of 50 patients
Ta Non-invasive papillary carcinoma with and without pT0 at cystectomy found that any
Tis Carcinoma in situ: ‘flat tumour’ variant histology (e.g. squamous or sarcomatoid dif-
ferentiation) in the TUR specimen decreases the likeli-
T1 Tumour invades subepithelial connective tissue
hood of achieving pT0 compared to patients with
T2 Tumour invades muscularis propria pure urothelial carcinoma lacking variant histol-
ogy.16 Achieving pT0 portends a significantly better
pT2a Tumour invades superficial muscularis propria (inner half)
prognosis for the patient, particularly when the
pT2b Tumour invades deep muscularis propria (outer half) patient has a complete pathological response
(pT0N0M0), as these patients had better overall sur-
T3 Tumour invades perivesical tissue
vival and recurrence-free survival than patients with-
pT3a Microscopically out a complete pathological response in the
pT3b Macroscopically (extravesical mass)
aforementioned recent meta-analysis.13
Although prognosis is much improved relative to
T4 Tumour invades any of the following: prostatic stroma, higher stage bladder carcinoma, the clinical outcome
seminal vesicles, uterus, vagina, pelvic wall, abdominal
of patients with stage pT0 bladder carcinoma remains
wall
somewhat variable, as 5-year recurrence-free, cancer-
T4a Tumour invades prostatic stroma, uterus, vagina specific and overall survivals were 84, 88 and 84%,
T4b Tumour invades pelvic wall, abdominal wall
respectively, in a large study of 120 patients, due
probably to extravesical spread prior to cystectomy.9
Regional lymph nodes (N) Thus, identifying and reporting parameters which
NX Lymph nodes cannot be assessed can stratify stage pT0 patients is important. Multi-
variate analysis demonstrated that independent pre-
N0 No lymph node metastasis dictors of outcome include lymphovascular invasion
N1 Single regional lymph node metastasis in the true pelvis (LVI) and carcinoma in situ (CIS) in the TUR speci-
(hypogastric, obturator, external iliac or presacral lymph men(s); the 5-year overall survival for patients with
node) LVI was 70%, while the overall survival for patients
N2 Multiple regional lymph node metastasis in the true without LVI was 89%.9 LVI is clearly an important
pelvis (hypogastric, obturator, external iliac or presacral prognostic factor in some patients, and standardisa-
lymph node metastasis) tion of reporting of LVI with possible formal incorpo-
ration into staging systems may be necessary.17
N3 Lymph node metastasis to the common iliac lymph
nodes Lymph node metastases in patients with stage pT0
bladder carcinoma occur rarely, with 3–7% of
Distant metastasis (M) patients developing nodal metastases and, as dis-
M0 No distant metastasis cussed above, these patients may have a worse
prognosis.8,11
M1 Distant metastasis
In summary, pT0 urinary bladder cancer is
increasing in incidence due to utilisation of NAC and
prognosis is generally very good, particularly in
Historically, the incidence of stage pT0 bladder car- patients with a complete pathological response, but
cinoma was approximately 10%.7–12 With increased death can occur in patients with metastatic disease.
utilisation of NAC, however, the incidence of stage
pT0 bladder carcinoma may be increasing. A recent
meta-analysis found an incidence of pT0 of nearly
Stage pTa carcinoma
30%; another recent meta-analysis found that NAC
achieved higher rates of pT0 than radical cystectomy Papillary urothelial carcinoma which lacks invasion
alone, and a primary benefit of NAC may be that it is assigned stage pTa, according to the AJCC Staging

© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.

 Staging of bladder cancer 115

Figure 3. Urothelial carcinoma in situ (pTis).

Figure 2. Whole mount view of non-invasive papillary urothelial

carcinoma (pTa). invasive urothelial carcinoma or high-grade papillary
urothelial carcinoma, but it can also be present alone.
Cystectomy specimens possessing urothelial CIS with-
Manual 8th edition (Figure 2).2 Histological grade out an invasive component are assigned pathological
should be designated in the surgical pathology report stage pTis, according to the AJCC Staging Manual
and is an important prognostic factor for pTa bladder 8th edition.2 Urothelial CIS is present without con-
tumours.18 Any invasion removes a tumour from the comitant invasive urothelial carcinoma (i.e. pTis) in
category of pTa. Conversely, if a flat urothelial lesion approximately 10% of radical cystectomy speci-
(i.e. urothelial CIS) is truly present, it should also be mens.19
reported, as this can have important prognostic impli- Urothelial CIS may be resistant to chemotherapy
cations. Caution should be taken when diagnosing and can progress to invasion,20–22 and CIS is often
CIS in the presence of high-grade papillary urothelial present in the cystectomy specimen following NAC,
carcinoma, however, as the ‘shoulder’ or base of the either alone or in association with residual invasive
papillary lesion may appear flat. While no consensus urothelial carcinoma. Urothelial CIS is not only criti-
guidelines for this situation exist, the authors of this cal to identify when it is the ‘worst’ pathological find-
review recommend that (1) the CIS be located remo- ing (i.e. pTis), but it is also an important prognostic
tely from the papillary tumour or present in an indicator in patients with an invasive tumour (i.e.
entirely different tissue fragment; (2) if present in the pT1-2) with associated CIS.
same tissue fragment, a strip of normal (i.e. non-neo- The presence of urothelial CIS in association with
plastic) urothelium is present between the CIS and stage pT0–pT2 bladder carcinoma is associated with
the papillary tumour; or (3) the CIS looks histologi- worse cancer-specific mortality compared to patients
cally distinct from the papillary tumour. If both a with stage pT0–pT2 bladder carcinoma lacking
papillary tumour and CIS are present, the AJCC Stag- urothelial CIS.23 Cancer-specific mortality of patients
ing Manual 8th edition is not entirely clear regarding with stage pT3–pT4 bladder carcinoma, however, is
what is the correct stage assignment.2 One approach, unaffected by the presence of urothelial CIS.23
which is recommended by the authors, is to assign
both pTa and pTis (i.e. pTa/pTis).
Stage pT1 carcinoma
Invasion of lamina propria by urothelial carcinoma
Stage pTis carcinoma without extension into muscularis propria is assigned
Urothelial carcinoma in situ is a flat urothelial lesion stage pT1 (Figure 4).2 Additionally, the AJCC Staging
composed of atypical, enlarged urothelial cells with Manual 8th edition strongly recommends substaging
hyperchromasia, nuclear pleomorphism, high nuclear pT1 tumours to stratify patients and separate a small
to cytoplasm ratio and frequent mitotic figures which focus of invasion from extensive invasion, but it does
lack invasion (Figure 3). It is often associated with not fully endorse any method for doing so. Thus,
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.
116 M J Magers et al.

eosinophilic cytoplasm and appear less pleomorphic

than overlying in-situ neoplastic cells) (Figure 5C).
Retraction artefact is helpful as a clue in identifying
invasive carcinoma (Figure 5D), but it can also be
problematic when assessing for lymphovascular inva-
sion (LVI). Immunohistochemistry for endothelial
markers (e.g. CD31 and CD34) may be helpful in sep-
arating retraction artefact (i.e. negative for endothe-
lial markers) from true LVI (i.e. positive for
endothelial markers). This is increasingly important,
as LVI has been identified as an important prognostic
feature.26
Additionally, a stromal reaction may also aid in
identifying invasive carcinoma (Figure 6), but this is
not always present.27 When a stromal response is
Figure 4. Whole mount view of pT1 papillary urothelial carci- present, it may be hypocellular with a myxoid back-
noma. ground; cellular with spindle-shaped fibroblasts and
variable collagenisation; pseudosarcomatous; desmo-
plastic; or inflammatory. Immunohistochemistry
there are currently no officially recognised categories using a pan-keratin cocktail may be helpful in identi-
for pT1 substaging. fying invasive carcinoma.28 This, however, should be
performed with caution, as aberrant keratin expres-
sion may be seen in reactive myofibroblastic cells,
CHALLENGES OF DIAGNOSING LAMINA PROPRIA
and not everything that is keratin-positive in the lam-
INVASION
ina propria is carcinoma.29 The spindled morphology
Identification of lamina propria invasion may be chal- with myofibroblastic features and lack of frankly
lenging in some situations, particularly in cases malignant features (e.g. cytological atypia or atypical
which are superficially or focally invasive. Factors mitotic figures) can help to avoid misinterpretation of
which add to this difficulty are problems with embed- immunohistochemical results.
ding the tissue (e.g. tangential sectioning or poorly
orientated tissue fragments), procedural artefact (e.g.
INTEROBSERVER VARIABILITY OF DIAGNOSING
thermal injury or cautery artefact) and tumour-
LAMINA PROPRIA INVASION
induced changes (e.g. severe inflammation at the
interface of the tumour and non-neoplastic tissue).1,24 Underscoring the difficulty of assessing lamina propria
Additionally, some variants of invasive urothelial car- invasion is substantial interobserver variability. While
cinoma are deceptively bland (e.g. nested variant of the majority of changes in staging from pT1 occurs
urothelial carcinoma), and proliferative von Brunn in downstaging (15–56% of pT1 cases), a substantial
nests may mimic invasion.25 Neoplastic cells may number of cases are also upstaged (3–13% of pT1
also involve von Brunn nests via either pagetoid cases).30–34 Change of stage by experienced or expert
spread or direct extension from adjacent tumour, and genitourinary pathologists appears prognostically
this can be confused with lamina propria invasion. In important, as confirmed pT1 tumours have a greater
this situation, the basement membrane typically likelihood for progression or recurrence than those
remains smooth with a regular contour, and a paral- tumours which are downstaged.30,31,34 Further
lel array of thin-walled vessels often lines the base- demonstrating this variability, Comp
erat et al. found
ment membrane (Figure 5A). Morphological features that when eight expert genitourinary pathologists
which may aid in identification of lamina propria annotated invasive areas on virtual slides from cases
invasion include identifying infiltrative single cells or diagnosed initially, as pT1 cancer full agreement was
irregularly shaped nests, jagged basement membrane present in only 47% of cases (j = 0.47).34
contour without a linear array of thin-walled vessels, Interobserver variability in diagnosing pT1 cancer
tentacular or finger-like extensions arising from the clearly has important clinical consequences, and
base of papillary tumours (Figure 5B), retraction arte- striving for higher reproducibility in assessing staging
fact surrounding irregular nests and paradoxical mat- categories, particularly pT1, is important. Bol et al.
uration of invasive cells (i.e. invasive cells gain found that while complete interobserver agreement
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.
 Staging of bladder cancer 117

A B

C D

Figure 5. Histopathological evaluation of lamina propria invasion. A, Urothelial carcinoma involving the von Brunn nests. Note parallel
arrays of thin-walled vessels surrounding von Brunn nests. B, pT1 urothelial carcinoma with ragged irregular borders. C, pT1 urothelial
carcinoma with paradoxical differentiation (arrows). D, pT1 urothelial carcinoma with retraction artefact.

on stage pT1 stage cases among reviewers was only carcinoma into three tiers: grades 1, 2 and 3.
80%, after a second review this increased to 87.7%.30 Tumours that are now considered high-grade urothe-
Thus, consensus review and agreement on criteria for lial carcinoma would previously have been considered
invasion may at least partially ameliorate interob- grades 2 or 3 urothelial carcinoma.35 The previous
server disagreement of stage pT1 cases. Furthermore, system acknowledges the morphological spectrum of
substaging of pT1 is probably valuable in separating tumour grade, and Pellucchi et al. demonstrated that
cases which are superficially invasive and borderline application of the 1973 grading system can stratify
non-invasive from cases which are clearly invasive patients with lamina propria invasion.36 Recurrence-
and borderline muscularis propria-invasive. free and progression-free survival were significantly
worse in the grade 3 group compared to the grade 2
group. These data suggest that application of the
TUMOUR GRADE
1973 grading system may be useful for substaging
Current recommendations for grading urothelial car- pT1 cancers.20,35,37
cinoma are to assign either low- or high-grade as
part of a two-tier grading scheme, and invasive
MICROINVASIVE CARCINOMA
urothelial carcinoma is almost invariably considered
high-grade. Prior to adoption of this system, the One subset of pT1 cancers which merit discussion is
1973 WHO grading classification stratified urothelial so-called ‘microinvasive carcinoma’. Beginning in
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.
118 M J Magers et al.

A B

C D

Figure 6. Different patterns of stromal response. A, Desmoplastic. B, Inflammatory. C, Myxoid. D, Mucinous/pseudosarcomatous.

1976 with the study by Farrow et al., several criteria Alternatively, Lopez-Beltran et al. proposed the cut-off
for microinvasion have been proposed.38–44 Farrow to be 20 infiltrating tumour cells within the lamina
et al. initially defined microinvasion as tumour propria rather than a linear measurement.41 Specifi-
extending up to 5 mm from the basement mem- cally, with regard to papillary urothelial carcinoma,
brane.38,39,44 With this definition in mind, Farrow Lawless et al. compared tumours with stalk-only
examined cystectomy specimens that were entirely invasion and focal tumour base invasion to tumours
embedded and identified cases which possessed exten- with extensive tumour base invasion, and found sig-
sive urothelial CIS involving at least 25% of the blad- nificantly worse outcomes in patients with extensive
der. Of these 70 cases, 24 cases (34%) possessed invasion.51
microinvasion, and 5.8% of patients with microinva- Further investigation and clinical validation is nec-
sion had a lymph node metastasis and died of their essary to confirm the presence of microinvasion as a
disease.44 distinct substage of pT1 cancer and to determine the
Amin et al. and McKenney et al. subsequently pro- optimum cut-off.
posed a 2-mm cut-off and, more recently, a 0.5-mm
cut-off, which is pragmatically equivalent to one
HISTO-ANATOMICAL SUBSTAGING OF PT1
high-power field, was proposed by van der Aa
et al.40,42,43 The 0.5-mm/one high-power field cut-off Microinvasive tumours excluded, pT1 remains a
has been shown to be widely feasible and, in the heterogeneous group with highly variable recurrence
majority of studies, correlated with outcome.42,45–50 and progression rates.25,52–56 Thus, reproducible and
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.
 Staging of bladder cancer 119

accurate substaging of pT1 tumours with more than A

microinvasion is necessary to stratify pT1 patients
into prognostically and clinically distinct groups.
The two main strategies which have been attempted
toward this goal are substaging based on anatomical
relationships (e.g. invasion relative to muscularis
mucosae) and substaging based on linear depth of
invasion (e.g. utilising a cut-off of 3 mm), both of
which have some merits as well as difficulties.
Muscularis mucosae is composed of thin, wavy fas-
cicles of smooth muscle which are frequently associ-
ated with large, thin-walled blood vessels
(Figure 7A). It is present in the mid to upper lamina
propria in the majority of radical cystectomy speci-
mens, but a minority of radical cystectomy specimens
do not have discernable muscularis mucosae (approx- B
imately 6%).57 In biopsy specimens, muscularis
mucosae is variably present (15–83%).25,53,54,57–66
In cases which lack muscularis mucosae, a vascular
plexus typically associated with the muscularis muco-
sae has been proposed as a substitute landmark.25,58–
62,67,68
However, some cases are still unable to be
staged using this criterion, as Angulo et al. was
unable to identify muscularis mucosae or the associ-
ated vascular plexus in 35% of their cases.69 Further-
more, the location of the vascular plexus can vary
greatly either above or below the muscularis muco-
sae, particularly in the trigone, making the use of the
vascular plexus questionable.69 Nonetheless, begin-
ning in 1990 with Younes et al.,62 many studies C
have investigated pT1 substaging relative to the mus-
cularis mucosae and/or vascular plexus with mixed,
but generally positive, results.26,45–49,54,58–60,67–86
Some of these studies substaged pT1 into three cat-
egories (i.e. above, into or below the muscularis
mucosae/vascular plexus), while others utilised only
two substages (i.e. above or below the muscularis
mucosae/vascular plexus) (Figure 7B). Overall, sub-
staging was usually possible (median = 93%;
range = 43–100%), and the majority of the studies
found pT1 substaging to be predictive of outcome
(68% of the studies; 48% by multivariate analysis
and 19% by univariate analysis).87 Not all studies,
however, found utility in substaging based on muscu-
laris mucosae/vascular plexus. For example, Platz Figure 7. Histopathological evaluation of muscularis mucosae inva-
et al. found muscularis mucosae in only 33% of cases, sion. A, normal muscularis mucosae of the urinary bladder. B, pT1
and they identified no significant prognostic value in urothelial carcinoma with muscularis mucosae invasion. C, Exten-
sively invasive urothelial carcinoma. It would be difficult to distin-
utilising the muscularis mucosae/vascular plexus cut-
guish between muscularis mucosae and muscularis propria.
off.69 Similarly, Kondylis et al. found no significant
difference in recurrence and progression in their
study, with a median follow-up of 71 months.73 Con- of 35 months, Roupr^et et al. identified significantly
versely, in the largest of these studies, involving 587 worse recurrence-free survival, progression-free sur-
pT1 patients from six hospitals and median follow-up vival and cancer-specific survival in patients with
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.
120 M J Magers et al.

invasion beyond the muscularis mucosae.82 Further- pT1 tumours. The optimal cut-off point and whether
more, in the only prospective study of the group, linear measurement should be used instead of the
Orsola et al. studied 200 patients with median follow- muscularis mucosae/vascular plexus are, however,
up of 71 months and found invasion beyond the debatable. This is the reason for the current recom-
muscularis mucosae to be an independent risk for mendation by the AJCC Staging Manual 8th edition
progression.86 Thus, although the data are somewhat to attempt some strategy of pT1 substaging without
mixed, there is substantial evidence that suggests sub- specifying which method and cut-off should be used.2
staging based on the muscularis mucosae/vascular Future staging systems will need to bring clarity to
plexus has clinical utility, although it is not always this hotly debated issue.
possible to do so due to histo-anatomical variance. In
cases of extensively invasive urothelial carcinoma, it
may be difficult or impossible to distinguish between
Stage pT2 carcinoma
muscularis mucosae and muscularis propria (Fig-
ure 7C). Stage pT2 urinary bladder cancer is defined as
tumour invasion into the muscularis propria (Fig-
ure 8A). This is subdivided further into tumour
LINEAR DEPTH SUBSTAGING OF PT1
invading the superficial (i.e. inner half) muscularis
An alternative to substaging with muscularis muco- propria (pT2a) and tumour invading the deep (i.e.
sae is to substage pT1 tumours by measuring outer half) muscularis propria (pT2b). The clinical
the depth of invasion using an ocular microme- utility of this subdivision is still questionable.1
ter.47,49,53,54,63,70,88 Measurement of depth of inva- In 1952, Jewett found that patients with what is
sion from the mucosal basement membrane now considered stage pT2b disease had worse sur-
correlates with the final pathological stage at cystec- vival (n = 13, 8% survival) than patients with what
tomy.63,89 This is a similar approach to that dis- is now considered pT2a disease (n = 5, 80%).91 Many
cussed above for microinvasion (i.e. 0.5 mm cut-off), subsequent, larger studies have failed to support these
but the cut-off is greater. Some investigators have initial findings.7,92–103 Cheng et al. found no survival
evaluated a 1-mm cut-off with varied success. Two difference between stage pT2a and pT2b tumours in
studies identified significantly worse clinical out- 64 patients, with a median follow-up of 8.3 years.97
comes in the tumours with > 1 mm compared to Although depth of muscularis propria invasion
tumours with ≤ 1 mm invasion, while a third study demonstrated no difference in outcome, tumour size
showed no difference in the two groups.47,49,63 The (i.e. largest tumour dimension) was predictive of out-
study which failed to show a difference using the 1- come in pT2 patients.97 Patients with a pT2 tumour
mm cut-off demonstrated prognostic significance <3 cm had better 10-year cancer-specific survival
using a cut-off of 1.5 mm, as 95% of patients with compared to patients with a pT2 tumour ≥3 cm (94
invasion ≥ 1.5 mm in TUR had advanced stage versus 73%, respectively).97 Additionally, Yu et al.
(≥ pT2) bladder carcinoma at cystectomy (sensitivity studied 311 patients with a pT2 tumour and, when
81%; specificity 83%; positive predictive value 95%; controlling for lymph node status, found no signifi-
negative predictive value 56%).63 Furthermore, cant difference in outcome between superficial and
although Chang et al.47 recommended a 1-mm cut- deeply invasive tumours.101 Similarly, in studies of
off, they also found clinical significance in the 1.5- 790 pT2N0 patients and 148 pT2N0 patients, there
mm cut-off. Using this criterion, of 83 consecutive were no significant differences in outcome between
pT1 patients, the 5-year progression-free survival pT2a and pT2b patients.99,100 Indeed, even in 1978
was significantly worse in tumours with ≥ 1.5 mm enough evidence weighing against the utility of
(67 versus 93%).54 Finally, Brimo et al.70 found that pT2a/b subdivision had mounted that Jewett deter-
quantifying invasion using cut-offs for depth of mined: ‘it seems probable that our arbitrary dividing
3 mm and diameter of 6 mm significantly correlated line drawn 30 years ago at the halfway level to sepa-
with outcome and, very recently, Leivo et al.90 rec- rate B1 (pT2a) from B2 (pT2b) tumours was too
ommended using a cut-off of ≥ 2.3 mm as the best superficial’.104
predictor of progression. In practical terms, 2.3 mm This admission of error by Jewett may have been
is approximately equivalent to one 910 microscopic premature, however, as several recent, large studies
field. found clinical utility in the current pT2a/b staging
The cumulative data of these studies clearly weighs classification.105–108 Gakis et al. studied 252 patients
in favour of the utility of a linear cut-off to substage with pT2 tumours and found a significant difference
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.
 Staging of bladder cancer 121

A B

C D

Figure 8. Advanced stage urothelial carcinoma. A, T2 invasive urothelial carcinoma. B, pT3 urothelial carcinoma with perivesical fat inva-
sion. C, Adipose tissue can be seen in the lamina propria. Fat invasion in the transurethral resection specimen does not indicate pT3 cancer.
D, pT4 urothelial carcinoma invading into the prostate. E, pT4 urothelial carcinoma invading into the seminal vesicles.

in recurrence-free survival (85.9 versus 37.5%, patients.108 Additionally, pT2 substratification was
respectively) and cancer-specific survival (84.8 versus the only risk factor of recurrence and cancer-specifi-
59.6%, respectively) between pT2aN0 and pT2bN0 city.108 Similarly, Tilki et al. studied 565 pT2
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.
122 M J Magers et al.

tumours from six different institutions and found sig- AJCC Staging Manual 8th edition.2 The distinction of
nificantly better recurrence-free survival (73.2 versus pT2b versus pT3a has important therapeutic implica-
58.7%, respectively) and cancer-specific survival tions, and a clear, consistent definition of microscopic
(78.0 versus 65.1%, respectively) in pT2a versus extravesical extension is needed.110,111 The ambiguity
pT2b patients.105 Another multi-institutional study of pT2b versus pT3a is a probable cause of the con-
by Sonpavde et al. included 707 pT2N0 patients from flicting results of outcome studies between the two
nine different institutions found that recurrence-free groups.100,112–114
survival was worse in pT2b patients compared to Adipose tissue is always present within the mus-
pT2a patients.106 Finally, a study by Ghoneim et al. cularis propria and is found frequently within the
found significantly better 5- and 10-year survival in lamina propria (Figure 8C).115 Thus, the presence of
pT2a patients than pT2b patients, both with and tumour admixed with fat in a biopsy or TUR speci-
without lymph node metastases, although this cohort men does not necessarily indicate extravesical exten-
included a relatively large number of squamous cell sion, or even muscle invasion, and stage pT3 should
carcinomas (54%) and adenocarcinomas (11%).107 not be assigned to these transurethral specimens.
In summary, of the studies regarding pT2 subclas- Even so, it may be possible to identify patients at
sification there may be utility in using the middle of risk for extravesical extension based on a TUR or
the muscularis propria as the cut-off. This, however, biopsy. For example, in a study of 90 patients the
is not definite, and future studies should elucidate this depth of invasion in the TUR specimen was found to
point further. Alternative methods of subclassifying be predictive of extravesical extension, with a depth
pT2, such as tumour size, should also be explored of invasion > 4 mm from the basement membrane
further. of the surface urothelium having a sensitivity, speci-
ficity, positive predictive value, and negative predic-
tive value of 54, 90, 81 and 72%, respectively, for
predicting stage pT3b.115 The overall accuracy of
Stage pT3 carcinoma
invasion depth for predicting extravesical extension,
Stage pT3 urinary bladder cancer is defined as measured by the area under the receiver operating
tumour invading perivesical soft tissue (i.e. tumour curve, was 0.81 [standard error (SE) = 0.045]. Zarei
invades perivesical fat outside of the muscularis pro- et al. demonstrated similar findings in a study of
pria) (Figure 8B). This is subdivided further into pT3a 206 patients with pT3N0 following radical cystec-
(i.e. microscopic invasion of perivesical soft tissue) tomy,100 as patients with < 4.5-mm tumour inva-
and pT3b (i.e. macroscopic invasion of perivesical soft sion from the base of the muscularis propria had
tissue). significantly better cancer-specific survival than
A challenge in determining extravesical extension patients with ≥ 4.5-mm tumour invasion (53 versus
is the irregular arrangement of muscularis propria 40%). It may be that a more objective parameter,
muscle bundles and admixture of adipocytes within such as measurement of thickness of invasive dis-
the muscularis propria, which result in the border ease from the basement membrane of the surface
between the muscularis propria and the perivesical urothelium or base of the muscularis propria, strati-
soft tissue being ill-defined. A recent survey of prob- fies patients with pT2 and/or pT3 disease more
lematic pT2b versus pT3a cases conducted by Anan- clearly, and application of this measurement to TUR
thanarayanan et al. demonstrated merely fair may be clinically valuable.
interobserver agreement (j = 0.286) among 17 The prognostic significance of pT3 substaging as
expert urological pathologists.109 This study also pT3a or pT3b has been a matter of debate, with
highlighted three distinct approaches to defining the numerous studies demonstrating conflicting results.
outer boundary of the muscularis propria: (1) the pre- For example, Quek et al. examined 236 patients (me-
cise edge of the muscle bundle; (2) an irregular, dian follow-up = 8.9 years) with pT3 urinary bladder
imaginary line between adjacent muscle bundles; and cancer and found no significant difference in recur-
(3) a straight, imaginary line along the outermost rence or survival rates between patients with pT3a
muscle bundle. Approximately half (nine of 17, 53%) and pT3b tumours;116 lymph node and surgical mar-
of expert urological pathologists utilise the irregular, gin status were the only factors to impact patient
imaginary line between adjacent muscle bundles, and prognosis significantly among pT3 patients. Other
application of this definition results in higher median studies have also demonstrated similar find-
agreement (j = 0.696). LVI alone should be not con- ings.100,117,118 Conversely, several recent, large stud-
sidered pT3a, although this is not specified in the ies have found that pT3b is associated with worse
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.
 Staging of bladder cancer 123

outcome compared to pT3a.112–114,119 For example, receive neoadjuvant or adjuvant chemotherapy.113 In

Tilki et al.120 included 808 patients who underwent a study of 903 patients, Neuzillet et al. found no sig-
radical cystectomy with stage pT3 and found that nificant difference in outcome between patients with
although there was no significant difference overall pT3apN0 and pT3bpN0 who had received adjuvant
in outcome of pT3a versus pT3b patients, of the chemotherapy while patients with pT3bpN0 had sig-
patients without lymph node metastasis (pN0) pT3b nificantly worse metastasis-free survival compared to
was associated with significantly worse 5-year recur- pT3apN0 (42 versus 68%, respectively).113
rence-free survival (47.9 versus 60.7%) and cancer-
specific survival (55.0 versus 64.4%) compared to
pT3apN0 patients. Thus, careful assessment of the
Stage pT4 carcinoma
presence or absence of macroscopic perivesical inva-
sion should be performed and report. According to the AJCC Staging Manual 8th edition,
Although gross diagnosis of macroscopic perivesical stage pT4 urinary bladder cancer is defined as extrav-
soft tissue invasion is a critical component of the esical tumour directly invading adjacent organs.2
AJCC Staging Manual 8th edition and appears to This is subdivided further into pT4a (i.e. direct inva-
have prognostic implications in a subset of pT3 sion into prostatic stroma, uterus, or vagina) and
patients, it is not always straightforward and hinges pT4b (i.e. direct invasion into pelvic wall or abdomi-
heavily on the thoroughness and accuracy of the pro- nal wall).
sector.2 Unfortunately, assessment of extravesical
extension of the tumour is not always documented in
PROSTATIC INVASION
the prosector’s gross description, and a recent study
from a large tertiary care academic institution found Invasion of the prostate by urinary bladder urothelial
that this was missing in 17% of reports.121 Most of carcinoma (Figure 8D) may occur in three ways: (1)
these cases were staged as pT3a, and it is plausible intra-urethral, (2) extravesical and (3) bladder neck
that failure to document macroscopic extension invasion.122–124 Spread of urothelial carcinoma
resulted in understaging these tumours. Importantly, through the urethra with subsequent invasion into
the authors also found that educational intervention prostatic stroma is not considered direct invasion of
increased the rate of reporting presence or absence of the prostate; rather, this situation is staged using the
extravesical extension. Conversely, extravesical exten- urethral cancer staging system for the urethral/pro-
sion can also be mimicked macroscopically by reac- static tumour and a separate stage for the urinary
tive changes (e.g. inflammation and fibrosis), and bladder tumour (Table 2). The extravesical and blad-
microscopic confirmation is necessary. Because of der neck pathways into the prostate occur less fre-
these difficulties, it is not unexpected that the data quently than intra-urethral spread.123–130 The
regarding pT3a/pT3b may be muddied by inexact or reported incidence of direct involvement of the pros-
incomplete gross descriptions. Another reason for tate by urinary bladder cancer is somewhat variable,
these disparate findings may be that some patients due probably to differences in patient populations and

Table 2. Involvement of prostate by urothelial carcinoma

Route of spread

Directly from prostate through Intraurethral

bladder neck or soft tissue

Tumour cells within prostatic glands Bladder component: pT4a Bladder component: pTX
Urethral component: NA Urethral component: pTis

Tumour invasive into subepithelial connective tissue Bladder component: pT4a Bladder component: pTX
underlying urethra Urethral component: NA Urethral component: pT1

Into prostatic stroma Bladder component: pT4a Bladder component: pTX

Urethral component: NA Urethral component: pT2

Into periprostatic tissue Bladder component: ≥ pT4a Bladder component: pTX

Urethral component: NA Urethral component: ≥ pT3

NA, not applicable.

© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.

124 M J Magers et al.

method of processing the cystoprostatectomy speci- to prostatic involvement by urinary bladder urothelial
mens, but it is not rare, occurring in 7–38% of male carcinoma, direct invasion of the vagina or uterus (i.e.
patients who underwent radical cystoprostatec- without urethral involvement) is rare, occurring in
tomy.123–130 The distinction between invasion of pro- approximately 3–6% of females undergoing radical
static stroma by a urethral tumour (i.e. pT2) versus cystectomy.137–141 In addition to direct invasion by
invasion of prostatic stroma by a urinary bladder urinary bladder carcinoma, the female gynaecological
tumour is critical (i.e. pT4a), due to significantly tract may be involved by urothelial carcinoma either
worse outcomes in the latter group.123,125,127– via pagetoid or metastatic spread and, although this
129,131,132
This is best achieved by correlation with would not be considered stage pT4a, is associated with
the clinical and gross findings. For example, if a poor outcomes.142 Anatomical differences in staging
tumour is grossly present in the urethra, it is proba- also result ultimately in differences in outcomes follow-
bly a urethral tumour invading the prostatic stroma. ing radical cystectomy. Several studies have demon-
If, however, no urethral tumour is present and a uri- strated worse recurrence-free survival and cancer-
nary bladder mass, perhaps arising in the trigone or specific survival in pT4a females following radical cys-
bladder neck, is grossly deeply invasive into the pros- tectomy compared to pT4a males.22,143,144
tate or perivesical soft tissue, it is probably a urinary
bladder tumour invading the prostatic stroma.
Distinction between pT2 urethral cancer and pT4a INVASION OF THE PELVIC OR ABDOMINAL WALL

urinary bladder cancer is critical, because assignment Direct invasion of urinary bladder urothelial carci-
of a pathological stage to a TUR specimen is problem- noma into the pelvic wall or abdominal wall is
atic. Assignment of stage ≥ pT2 with an accompany-
ing note describing the difference between urethral
A
pT2 and urinary bladder pT4a is appropriate.87

SEMINAL VESICLE INVASION

Seminal vesicle invasion by urinary bladder cancer is

staged as pT4 in the AJCC Staging Manual 8th edi-
tion, but the staging manual does not subclassify it
as pT4a or pT4b (Figure 8E).2 Nonetheless, compared
to prostatic stromal invasion (i.e. pT4a), seminal vesi-
cle invasion by urinary bladder cancer is associated
with a worse prognosis.133–136 In one large study of
1682 patients who underwent radical cystectomy
and pelvic lymphadenectomy for urinary bladder can-
cer, 5-year survival for patients with seminal vesicle
invasion was 10%, similar to pT4b patients (7%) and B
significantly worse than patients with prostatic stro-
mal invasion (38%).133 Seminal vesicle invasion by
urinary bladder urothelial carcinoma is a poor prog-
nostic indicator and portends a prognosis similar to
stage pT4b patients, even if current staging systems
do not subclassify it as such.

INVASION OF THE FEMALE GYNAECOLOGICAL

TRACT

Anatomical differences between males and females

necessitate differences in staging. In females, invasion
of the uterus or vagina by a urinary bladder cancer
warrants a stage of pT4a (Figure 9). When extravesi-
cal extension is present in females, the most commonly Figure 9. pT4 urothelial carcinoma invading into the uterus. A,
involved organs are the vagina and uterus.107 Relative gross appearance. B, microscopic appearance.

© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.

 Staging of bladder cancer 125

regarded as stage pT4b. Stage pT4b is a rare finding at ideal.152,155 In the opinion of the authors, removal of
radical cystectomy, accounting for only 14% of pT4 at least 12 lymph nodes, which parallels recommen-
tumours and 2% of all resected tumours, probably dations made for colorectal tumours and meets the
because many of these patients are not surgical candi- minimum criteria of the studies discussed above, is
dates.145 Although rarely present at radical cystec- probably adequate. Some investigators recommended
tomy, pT4b tumours are associated with significantly that a minimum of 25 lymph nodes should be
worse outcomes than pT4a tumours.145–147 Liberman obtained in radical cystectomy with bilateral pelvic
et al. found that 5-year cancer-specific mortality in lymphadenectomy.151,157
pT3, pT4a and pT4b patients is 53.9, 57.6 and 81.7%, The presence of lymph node metastasis is associated
demonstrating the drastic increase in mortality when with markedly worse prognosis compared to patients
comparing pT4b versus pT4a patients relative to the without lymph node metastasis, but a subset of patients
same comparison in pT4a versus pT3 patients.146 experience long-term survival following resection of
lymph nodes possessing metastatic tumour.89,148,158–
161
Thus, stratification of patients with nodal disease is
Lymph node staging vital. The AJCC Staging Manual 7th edition staged
nodal disease based on the anatomical location and
In the AJCC Staging Manual 8th edition, regional number of positive lymph nodes rather than based on
lymph node staging is categorised as: lymph nodes size, as the AJCC Staging Manual 6th edition had previ-
cannot be assessed (Nx); no lymph node metastasis ously done.162,163 This change occurred following
(N0); single regional lymph node metastasis in the reports outlining the inefficiency in stratifying patients
true pelvis (N1); multiple regional lymph node metas- based on size.148,164 This was maintained in the 8th edi-
tasis in the true pelvis (N2); and lymph node metas- tion, and it accurately stratifies many patients, particu-
tasis to the common iliac lymph nodes (N3) larly with respect to pN1 disease, although pN3 disease
(Table 1).2 Metastases to lymph nodes beyond the remains relatively heterogeneous and may not be signif-
iliac lymph nodes are considered distant metastases icantly different to pN2.165
and assigned M1a. Regional lymph nodes include Indeed, there is evidence that better separation of
perivesical, obturator, iliac (internal and external), prognostic groups may occur using only the number
sacral (lateral and sacral promontory) and common of lymph nodes involved, irrespective of anatomical
iliac lymph nodes. The inclusion of perivesical lymph location. Pedrosa et al. demonstrated recently that in
nodes in what are formally considered regional 244 patients with metastases to lymph nodes who
lymph nodes is the only change in lymph node stag- underwent radical cystectomy and pelvic lymph node
ing relative to the previous edition. Although not dissection, a three-tiered classification system of:
part of the formal staging system, the AJCC Staging N1 = metastasis in a single lymph node; N2 = metas-
Manual 8th edition also recommends reporting the tasis in two to five lymph nodes; and N3 = metastasis
presence or absence of extranodal extension as well in more than five lymph nodes was able to stratify
as the total number of lymph nodes present. Extran- patients with statistical significance.166 Thus, it is
odal extension has been found by some to be associ- clear that the current AJCC Staging Manual recom-
ated with reduced disease-specific survival and mendations are improved relative to previous schema,
recurrence-free survival, but others have not found but further refinement is necessary.
any prognostic difference (Figure 10A).148–150
Agreed-upon criteria for the minimum number of
lymph nodes identified do not currently exist, and
the number of lymph nodes identified in a case varies Distant metastasis
based on the surgical procedure performed (e.g. en Distant metastases are now subdivided into M1a and
bloc resection of lymph nodes with the urinary blad- M1b, according to the AJCC Staging Manual 8th edi-
der versus separate pelvic lymph node dissection) as tion (Table 1).2 Distant metastases limited to lymph
well as the meticulousness of the gross dissection.151 nodes beyond the common iliac lymph nodes are con-
Nonetheless, multiple studies demonstrate that a sidered M1a, and non-lymph node metastases are
greater number of dissected lymph nodes is associ- considered M1b (Figure 10B). This distinction is
ated with improved outcome, even in pN0 dis- important, as patients with metastases limited to non-
ease.152–156 Specifically, Herr et al. recommended regional lymph nodes have a significantly better out-
removal of ≥9 lymph nodes, while Wright et al. come than patients with visceral or bone metas-
found that removal of >10 lymph nodes is tases.167
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.
126 M J Magers et al.

Figure 11. Diverticulum. Note the absence of muscularis propria.

Table 3. Staging of urothelial carcinoma arising in a diver-

ticulum

Primary tumour (T)

TX Primary tumour cannot be assessed

T0 No evidence of primary tumour

Ta Non-invasive papillary carcinoma

Tis Carcinoma in situ: ‘flat tumour’

C T1 Tumour invades subepithelial connective tissue

T2 Not applicable

T3 Tumour invades perivesical tissue

pT3a Microscopically
pT3b Macroscopically (extravesical mass)

T4 Tumour invades any of the following: prostatic stroma,

seminal vesicles, uterus, vagina, pelvic wall,
abdominal wall

T4a Tumour invades prostatic stroma, uterus, vagina

T4b Tumour invades pelvic wall, abdominal wall

Figure 10. A, Lymph node metastasis with extranodal extension. B, invasive tumours, and incorporation of LVI into
Distant (liver) metastasis. C, Lymphovascular invasion. future staging systems may help to guide therapeutic
decisions.2,26,168,169 For example, patients with
LVI present in a TURBT specimen may receive
Lymphovascular invasion aggressive treatment, such as early radical cystec-
Lymphovascular invasion (LVI) is the unequivocal tomy or peri-operative chemotherapy (e.g. neoadju-
presence of neoplastic cells within a lymphatic or vant chemotherapy).17
blood vessel (Figure 10C).1 It is not a formal compo- Identification of LVI, however, is often difficult,
nent of the AJCC Staging Manual 8th edition, but owing to the propensity of urothelial carcinoma to
it has been associated with worse outcomes in demonstrate stromal retraction artefact. The use of
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.
 Staging of bladder cancer 127

Table 4. Staging of urachal carcinoma

Sheldon system Mayo system Ontario system

Confined to urachus, I. Confined to urachal mucosa I. Confined to urachus and/or T1. Invasion limited to
bladder and perivesical bladder submucosa
soft tissue
II. Invasion confined to urachus II. Extension beyond urachus T2. Invasion limited to muscularis
and/or bladder propria of urachus and/or
bladder

IIIA. Extension into bladder

Spread beyond urachus, IIIB. Extension into abdominal wall III. Involvement of regional T3. Invasion into peri-urachal or
bladder and perivesical lymph nodes perivesical soft tissue
soft tissue IIIC. Extension into peritoneum

IIID. Extension into viscera other than

the bladder

IVA. Metastasis to regional lymph IV. Involvement of non-regional T4. Invasion into adjacent organs
nodes lymph nodes and/or distant including abdominal wall
sites
IVB. Metastasis to distant sites

histochemistry (e.g. elastica van Gieson) and

immunohistochemistry (e.g. antibodies to CD31,
CD34 and podoplanin) can often resolve this
dilemma, but these are not performed rou-
tinely.170,171 Additionally, the sensitivity of TURBT to
detect LVI may be limited by the specimen’s relatively
small size, with reported rates of sensitivity ranging
from 18 to 79%.172,173 Nonetheless, finding LVI in a
TURBT does correlate well with finding LVI at radical
cystectomy, with specificity rates ranging from 62 to
90%.172,173 Thus, LVI should be reported when pre-
sent in order to stratify patients for appropriate man-
agement, particularly in patients with stage pT1
urothelial carcinoma.26

Figure 12. Urachal adenocarcinoma involving full thickness of the

Tumour arising in a diverticulum bladder wall.

Approximately 1% of all urinary bladder tumours

occur within a diverticulum, and up to 14% of diver- There are limited data comparing outcome of intradi-
ticula harbour a malignancy.174,175 Most urinary verticular tumours with non-diverticular tumours,
bladder diverticula are acquired and lack muscularis but their outcomes appear similar based on the few
propria (Figure 11).176 Thus, intradiverticular studies available.177,180
tumours invade directly from the subepithelial con-
nective tissue (i.e. pT1) into the perivesicular soft
tissue (i.e. pT3) without invading muscularis propria,
Tumour arising in a urachal remnant
and the AJCC Staging Manual 8th edition for- The AJCC Staging Manual 8th edition does not include
mally recommends excluding pT2 as a staging cate- a formal staging system for tumours which arise
gory for intradiverticular tumours (Figure 1, within a urachal remnant, although several urachal-
Table 3).2,174,177–179 Essentially, staging for intradi- specific staging systems have been proposed (Figure 1,
verticular tumours is the same as for non-diverticular Table 4).2,181–185 Recently, the nomenclature and clas-
tumours, with the exception of the exclusion of mus- sification regarding urachal neoplasms has been
cularis propria invasion (i.e. pT2a/b) as a category. updated and generally accepted.24,186,187
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.
128 M J Magers et al.

The first staging system for urachal carcinoma was References

proposed in 1984 by Sheldon et al.185 (the Sheldon
1. Cheng L, Montironi R, Davidson DD, Lopez-Beltran A. Staging
system). A major detriment of this system is that the
and reporting of urothelial carcinoma of the urinary bladder.
majority of tumours are at least stage III, with little Mod. Pathol. 2009; 22(Suppl. 2); S70–S95.
stratification of urachal carcinoma among different 2. Amin MB, Edge SB, Greene FL, Schilsky RL, Gaspar LE, Wash-
stage groups, because of the indistinct boundary ington M. AJCC cancer staging manual. New York, NY:
between the urachus and urinary bladder (Fig- Springer, 2017.
3. Paner GP, Stadler WM, Hansel DE, Montironi R, Lin DW,
ure 12). Subsequently, Ashley et al.183 (Mayo system)
Amin MB. Updates in the eighth edition of the Tumor–Node–
and Pinthus et al.184 (Ontario system) both published Metastasis Staging Classification for Urologic Cancers. Eur.
alternative staging systems. The Ontario system par- Urol. 2018; 73; 560–569.
allels the AJCC staging system for urinary bladder 4. Delahunt B, Egevad L, Samaratunga H et al. UICC drops the
cancer, while the Mayo system achieves the greatest ball in the 8th edition TNM staging of urological cancers.
Histopathology 2017; 71; 5–11.
stratification of cases into stages I or II by considering
5. Brierley J, Gospodarowicz MK, Wittekind C. TNM classification
urachal carcinoma limited to the urachus and/or uri- of malignant tumours. 8th ed. Chichester, West Sussex, UK/
nary bladder to be stage I and extension of urachal Hoboken, NJ: John Wiley & Sons Inc, 2017.
carcinoma beyond the muscular layer of the urachus 6. Tilki D, Svatek RS, Novara G et al. Stage pT0 at radical cys-
or urinary bladder to be stage II.2,183,184 While some tectomy confers improved survival: an international study of
4,430 patients. J. Urol. 2010; 184; 888–894.
data suggest that these systems have value, the major
7. Dalbagni G, Genega E, Hashibe M et al. Cystectomy for blad-
distinction appears to be whether the tumour is con- der cancer: a contemporary series. J. Urol. 2001; 165; 1111–
fined to the resection specimen (i.e. confined to the 1116.
urachus, urinary bladder and perivesical soft tissue) 8. Palapattu GS, Shariat SF, Karakiewicz PI et al. Cancer speci-
or has spread to the peritoneum and/or other fic outcomes in patients with pT0 disease following radical
cystectomy. J. Urol. 2006; 175; 1645–1649; discussion
organs.181–184,188–190 Thus, although no particular
1649.
staging system has been formally recommended, the 9. Kassouf W, Spiess PE, Brown GA et al. P0 stage at radical cys-
Mayo system can be easily utilised to stratify cases tectomy for bladder cancer is associated with improved out-
into either stages I and II (i.e. lacking spread beyond come independent of traditional clinical risk factors. Eur. Urol.
the perivesical soft tissue) or stages III and IV (i.e. 2007; 52; 769–774.
10. Thrasher JB, Frazier HA, Robertson JE, Paulson DF. Does a
with spread beyond the perivesical soft tissue includ-
stage pT0 cystectomy specimen confer a survival advantage
ing regional lymph nodes).183 in patients with minimally invasive bladder cancer? J. Urol.
1994; 152; 393–396.
11. Volkmer BG, Kuefer R, Bartsch G Jr et al. Effect of a pT0 cys-
Summary tectomy specimen without neoadjuvant therapy on survival.
Cancer 2005; 104; 2384–2391.
Bladder cancer is a heterogeneous disease with a 12. Yiou R, Patard JJ, Benhard H, Abbou CC, Chopin DK. Out-
spectrum of clinical outcomes, ranging from extre- come of radical cystectomy for bladder cancer according to
the disease type at presentation. BJU Int. 2002; 89; 374–
mely favourable (i.e. pT0 tumours) to extremely poor
378.
(i.e. pT4). Therapeutic decisions and prognostic 13. Petrelli F, Coinu A, Cabiddu M, Ghilardi M, Vavassori I, Barni
expectations are based largely on the stage of the S. Correlation of pathologic complete response with survival
tumour in a biopsy, transurethral and/or cystectomy after neoadjuvant chemotherapy in bladder cancer treated
specimen. For example, the presence of muscularis with cystectomy: a meta-analysis. Eur. Urol. 2014; 65; 350–
357.
propria invasion or LVI are indicative of aggressive
14. Lavery HJ, Stensland KD, Niegisch G, Albers P, Droller MJ.
disease, and early radical cystectomy or NAC may be Pathological T0 following radical cystectomy with or without
considered in these patients. The AJCC Staging Man- neoadjuvant chemotherapy: a useful surrogate. J. Urol. 2014;
ual 8th edition provides a basis for staging bladder 191; 898–906.
cancer, but further refinement, such as for pT1 sub- 15. Kim HS, Jeong CW, Kwak C, Kim HH, Ku JH. Pathological T0
following cisplatin-based neoadjuvant chemotherapy for mus-
staging and possible incorporation of LVI, is neces-
cle-invasive bladder cancer: a network meta-analysis. Clin.
sary. Incorporation of molecular and genomic Cancer Res. 2016; 22; 1086–1094.
information into treatment algorithms and possibly 16. Pokuri VK, Syed JR, Yang Z et al. Predictors of complete
staging systems is also likely to occur in the future. pathologic response (pT0) to neoadjuvant chemotherapy in
muscle-invasive bladder carcinoma. Clin. Genitourin. Cancer
2016; 14; e59–e65.
17. Mathieu R, Lucca I, Roupret M, Briganti A, Shariat SF. The
Conflicts of interest prognostic role of lymphovascular invasion in urothelial carci-
noma of the bladder. Nat. Rev. Urol. 2016; 13; 471–479.
No conflicts of interest are declared.
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.
 Staging of bladder cancer 129

18. MacLennan GT, Kirkali Z, Cheng L. Histologic grading of non- grading classification in primary T1 non-muscle-invasive
invasive papillary urothelial neoplasms. Eur. Urol. 2007; 51; bladder cancer. A step forward or back? BJU Int. 2015; 115;
889–897; discussion 897–898. 267–273.
19. Shariat SF, Palapattu GS, Amiel GE et al. Characteristics and 37. Soukup V, Capoun O, Cohen D et al. Prognostic perfor-
outcomes of patients with carcinoma in situ only at radical mance and reproducibility of the 1973 and 2004/2016
cystectomy. Urology 2006; 68; 538–542. World Health Organization Grading Classification Systems
20. Babjuk M, Bohle A, Burger M et al. EAU Guidelines on non- in non-muscle-invasive bladder cancer: a European Associa-
muscle-invasive urothelial carcinoma of the bladder: update tion of Urology Non-muscle Invasive Bladder Cancer Guide-
2016. Eur. Eurol. 2017; 71; 447–461. lines Panel Systematic Review. Eur. Eurol. 2017; 72; 801–
21. Chade DC, Shariat SF, Godoy G et al. Clinical outcomes of pri- 813.
mary bladder carcinoma in situ in a contemporary series. J. 38. Farrow GM, Utz DC, Rife CC. Morphological and clinical
Urol. 2010; 184; 74–80. observations of patients with early bladder cancer treated
22. Tilki D, Reich O, Svatek RS et al. Characteristics and out- with total cystectomy. Cancer Res. 1976; 36; 2495–2501.
comes of patients with clinical carcinoma in situ only treated 39. Farrow GM, Utz DC, Rife CC, Greene LF. Clinical observations
with radical cystectomy: an international study of 243 on sixty-nine cases of in situ carcinoma of the urinary blad-
patients. J. Urol. 2010; 183; 1757–1763. der. Cancer Res. 1977; 37; 2794–2798.
23. Moschini M, Shariat SF, Abufaraj M et al. The presence of 40. Amin MB, Gomez JA, Young RH. Urothelial transitional cell
carcinoma in situ at radical cystectomy increases the risk of carcinoma with endophytic growth patterns: a discussion of
urothelial recurrence: implications for follow-up schemes. patterns of invasion and problems associated with assessment
Urol. Oncol. 2017; 35; 151.e17–151.e23. of invasion in 18 cases. Am. J. Surg. Pathol. 1997; 21; 1057–
24. Cheng L, Lopez-Beltran A, Bostwick DG. Bladder pathology. 1068.
Hoboken, NJ: Wiley-Blackwell, 2012. 41. Lopez-Beltran A, Cheng L, Andersson L et al. Preneoplastic
25. Lopez-Beltran A, Cheng L. Stage pT1 bladder carcinoma: diag- non-papillary lesions and conditions of the urinary bladder:
nostic criteria, pitfalls and prognostic significance. Pathology an update based on the Ancona International Consultation.
2003; 35; 484–491. Virchows Arch. 2002; 440; 3–11.
26. Andius P, Johansson SL, Holmang S. Prognostic factors in 42. van der Aa MN, van Leenders GJ, Steyerberg EW et al. A new
stage T1 bladder cancer: tumor pattern (solid or papillary) system for substaging pT1 papillary bladder cancer: a prog-
and vascular invasion more important than depth of invasion. nostic evaluation. Hum. Pathol. 2005; 36; 981–986.
Urology 2007; 70; 758–762. 43. McKenney JK, Gomez JA, Desai S, Lee MW, Amin MB. Mor-
27. Jimenez RE, Keane TE, Hardy HT, Amin MB. pT1 urothelial phologic expressions of urothelial carcinoma in situ: a detailed
carcinoma of the bladder: criteria for diagnosis, pitfalls, and evaluation of its histologic patterns with emphasis on carci-
clinical implications. Adv. Anat. Pathol. 2000; 7; 13–25. noma in situ with microinvasion. Am. J. Surg. Pathol. 2001;
28. Mhawech P, Iselin C, Pelte MF. Value of immunohistochem- 25; 356–362.
istry in staging T1 urothelial bladder carcinoma. Eur. Eurol. 44. Farrow GM, Utz DC. Observation on microinvasive transi-
2002; 2; 459–463. tional cell carcinoma of the urinary bladder. Clin. Oncol.
29. Tamas EF, Epstein JI. Detection of residual tumor cells in blad- 1982; 1; 609–615.
der biopsy specimens: pitfalls in the interpretation of cytoker- 45. Bertz S, Denzinger S, Otto W et al. Substaging by estimating
atin stains. Am. J. Surg. Pathol. 2007; 31; 390–397. the size of invasive tumour can improve risk stratification in
30. Bol MG, Baak JP, Buhr-Wildhagen S et al. Reproducibility and pT1 urothelial bladder cancer – evaluation of a large hospi-
prognostic variability of grade and lamina propria invasion in tal-based single-centre series. Histopathology 2011; 59; 722–
stages Ta, T1 urothelial carcinoma of the bladder. J. Urol. 732.
2003; 169; 1291–1294. 46. van Rhijn BW, van der Kwast TH, Alkhateeb SS et al. A new
31. van Rhijn BW, van der Kwast TH, Kakiashvili DM et al. and highly prognostic system to discern T1 bladder cancer
Pathological stage review is indicated in primary pT1 bladder substage. Eur. Eurol. 2012; 61; 378–384.
cancer. BJU Int. 2010; 106; 206–211. 47. Chang WC, Chang YH, Pan CC. Prognostic significance in
32. Giunchi F, Panzacchi R, Capizzi E et al. Role of inter-observer substaging ofT1 urinary bladder urothelial carcinoma on
variability and quantification of muscularis propria in the transurethral resection. Am. J. Surg. Pathol. 2012; 36; 454–
pathological staging of bladder cancer. Clin. Genitourin. Cancer 461.
2016; 14; e307–e312. 48. Dem V, Cerruto MA, D’Elia C et al. Prognostic role of substag-
33. Van Der Meijden A, Sylvester R, Collette L, Bono A, Ten ing in T1G3 transitional cell carcinoma of the urinary blad-
Kate F. The role and impact of pathology review on stage der. Mol. Clin. Oncol. 2014; 2; 575–580.
and grade assessment of stages Ta and T1 bladder tumors: 49. Patriarca C, Hurle R, Moschini M et al. Usefulness of pT1 sub-
a combined analysis of 5 European Organization for staging in papillary urothelial bladder carcinoma. Diagn.
Research and Treatment of Cancer Trials. J. Urol. 2000; Pathol. 2016; 11; 6.
164; 1533–1537. 50. Nishiyama N, Kitamura H, Maeda T et al. Clinicopathological
34. Tosoni I, Wagner U, Sauter G et al. Clinical significance of analysis of patients with non-muscle-invasive bladder cancer:
interobserver differences in the staging and grading of superfi- prognostic value and clinical reliability of the 2004 WHO
cial bladder cancer. BJU Int. 2000; 85; 48–53. classification system. Jpn. J. Clin. Oncol. 2013; 43; 1124–
35. Cheng L, MacLennan GT, Lopez-Beltran A. Histologic grading 1131.
of urothelial carcinoma: a reappraisal. Hum. Pathol. 2012; 51. Lawless M, Gulati R, Tretiakova M. Stalk versus base invasion
43; 2097–2108. in pT1 papillary cancers of the bladder: improved substaging
36. Pellucchi F, Freschi M, Moschini M et al. Oncological system predicting the risk of progression. Histopathology 2017;
predictive value of the 2004 World Health Organisation 71; 406–414.

© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.

130 M J Magers et al.

52. Nieder AM, Brausi M, Lamm D et al. Management of stage T1 urothelial carcinoma. Am. J. Surg. Pathol. 2007; 31; 1420–
tumors of the bladder: International Consensus Panel. Urology 1429.
2005; 66; 108–125. 70. Brimo F, Wu C, Zeizafoun N et al. Prognostic factors in T1
53. Cheng L, Bostwick DG. Progression of T1 bladder tumors: bet- bladder urothelial carcinoma: the value of recording millimet-
ter staging or better biology? Reply. Cancer 1999; 86; 910– ric depth of invasion, diameter of invasive carcinoma, and
912. muscularis mucosa invasion. Hum. Pathol. 2013; 44; 95–
54. Cheng L, Neumann RM, Weaver AL, Spotts BE, Bostwick DG. 102.
Predicting cancer progression in patients with stage T1 blad- 71. Fransen van de Putte EE, Behrendt MA, Pigot GL, van der
der carcinoma. J. Clin. Oncol. 1999; 17; 3182–3187. Kwast TH, van Rhijn BW. Prognostic significance of substage
55. Soloway MS, Lee CT, Steinberg GD, Ghandi AA, Jewett MA. and WHO classification systems in T1 urothelial carcinoma of
Difficult decisions in urologic oncology: management of high- the bladder. Curr. Opin. Urol. 2015; 25; 427–435.
grade T1 transitional cell carcinoma of the bladder. Urol. 72. Smits G, Schaafsma E, Kiemeney L, Caris C, Debruyne F, Wit-
Oncol. 2007; 25; 338–340. jes JA. Microstaging of pT1 transitional cell carcinoma of the
56. Soloway MS, Sofer M, Vaidya A. Contemporary management bladder: identification of subgroups with distinct risks of pro-
of stage T1 transitional cell carcinoma of the bladder. J. Urol. gression. Urology 1998; 52; 1009–1013; discussion 1013–
2002; 167; 1573–1583. 1014.
57. Ro JY, Ayala AG, el-Naggar A. Muscularis mucosa of urinary 73. Kondylis FI, Demirci S, Ladaga L, Kolm P, Schellhammer PF.
bladder. Importance for staging and treatment. Am. J. Surg. Outcomes after intravesical bacillus Calmette-Guerin are not
Pathol. 1987; 11; 668–673. affected by substaging of high grade T1 transitional cell carci-
58. Angulo JC, Lopez JI, Grignon DJ, Sanchez-Chapado M. Muscu- noma. J. Urol. 2000; 163; 1120–1123.
laris mucosa differentiates two populations with different 74. Shariat SF, Weizer AZ, Green A et al. Prognostic value of P53
prognosis in stage T1 bladder cancer. Urology 1995; 45; 47– nuclear accumulation and histopathologic features in T1
53. transitional cell carcinoma of the urinary bladder. Urology
59. Hasui Y, Osada Y, Kitada S, Nishi S. Significance of invasion 2000; 56; 735–740.
to the muscularis mucosae on the progression of superficial 75. Bernardini S, Billerey C, Martin M, Adessi GL, Wallerand H,
bladder cancer. Urology 1994; 43; 782–786. Bittard H. The predictive value of muscularis mucosae
60. Hermann GG, Horn T, Steven K. The influence of the level of invasion and p53 over expression on progression of stage
lamina propria invasion and the prevalence of p53 nuclear T1 bladder carcinoma. J. Urol. 2001; 165; 42–46; discussion
accumulation on survival in stage T1 transitional cell bladder 46.
cancer. J. Urol. 1998; 159; 91–94. 76. Orsola A, Trias I, Raventos CX et al. Initial high-grade T1
61. Platz CE, Cohen MB, Jones MP, Olson DB, Lynch CF. Is urothelial cell carcinoma: feasibility and prognostic signifi-
microstaging of early invasive cancer of the urinary bladder cance of lamina propria invasion microstaging (T1a/b/c) in
possible or useful? Mod. Pathol. 1996; 9; 1035–1039. BCG-treated and BCG-non-treated patients. Eur. Eurol. 2005;
62. Younes M, Sussman J, True LD. The usefulness of the level of 48; 231–238; discussion 238.
the muscularis mucosae in the staging of invasive transitional 77. Mhawech-Fauceglia P, Fischer G, Alvarez V Jr, Ahmed A,
cell carcinoma of the urinary bladder. Cancer 1990; 66; 543– Herrmann FR. Predicting outcome in minimally invasive (T1a
548. and T1b) urothelial bladder carcinoma using a panel of
63. Cheng L, Weaver AL, Neumann RM, Scherer BG, Bostwick biomarkers: a high throughput tissue microarray analysis.
DG. Substaging of T1 bladder carcinoma based on the depth BJU Int. 2007; 100; 1182–1187.
of invasion as measured by micrometer: a new proposal. Can- 78. Orsola A, Cecchini L, Raventos CX et al. Risk factors for posi-
cer 1999; 86; 1035–1043. tive findings in patients with high-grade T1 bladder cancer
64. Dixon JS, Gosling JA. Histology and fine structure of the mus- treated with transurethral resection of bladder tumour (TUR)
cularis mucosae of the human urinary bladder. J. Anat. 1983; and bacille Calmette-Guerin therapy and the decision for a
136; 265–271. repeat TUR. BJU Int. 2010; 105; 202–207.
65. Keep JC, Piehl M, Miller A, Oyasu R. Invasive carcinomas of 79. Faivre d’Arcier B, Celhay O, Safsaf A et al. T1 bladder car-
the urinary bladder. Evaluation of tunica muscularis mucosae cinoma: prognostic value of the muscularis mucosae inva-
involvement. Am. J. Clin. Pathol. 1989; 91; 575–579. sion (T1a/T1b). A multicenter study by the French
66. Engel P, Anagnostaki L, Braendstrup O. The muscularis Urological Association (CCAFU). Prog. Urol. 2010; 20; 440–
mucosae of the human urinary bladder. Implications for 449.
tumor staging on biopsies. Scand. J. Urol. Nephrol. 1992; 26; 80. Lee JY, Joo HJ, Cho DS, Kim SI, Ahn HS, Kim SJ. Prognostic
249–252. significance of substaging according to the depth of lamina
67. Holmang S, Hedelin H, Anderstrom C, Holmberg E, Johansson propria invasion in primary T1 transitional cell carcinoma of
SL. The importance of the depth of invasion in stage T1 blad- the bladder. Korean J. Urol. 2012; 53; 317–323.
der carcinoma: a prospective cohort study. J. Urol. 1997; 81. Palou J, Sylvester RJ, Faba OR et al. Female gender and carci-
157; 800–803; discussion 804. noma in situ in the prostatic urethra are prognostic factors
68. Sozen S, Akbal C, Sokmensuer C, Ekici S, Ozen H. Microstag- for recurrence, progression, and disease-specific mortality in
ing of pT1 transitional cell carcinoma of the bladder. Does it T1G3 bladder cancer patients treated with bacillus Calmette-
really differentiate two populations with different prognoses? Guerin. Eur. Eurol. 2012; 62; 118–125.
(pT1 subcategory). Urol. Int. 2002; 69; 200–206. 82. Roupret M, Seisen T, Comperat E et al. Prognostic interest in
69. Paner GP, Ro JY, Wojcik EM, Venkataraman G, Datta MW, discriminating muscularis mucosa invasion (T1a vs T1b) in
Amin MB. Further characterization of the muscle layers and nonmuscle invasive bladder carcinoma: French national mul-
lamina propria of the urinary bladder by systematic histologic ticenter study with central pathology review. J. Urol. 2013;
mapping: implications for pathologic staging of invasive 189; 2069–2076.

© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.

 Staging of bladder cancer 131

83. Nguyen-Huu Y, Delorme G, Lillaz J et al. Muscularis mucosae 100. Zarei S, Frank I, Boorjian SA et al. Prognostic significance of
invasion: prognostic factor for intravesical BCG immunother- measured depth of invasion of urothelial carcinoma of the
apy failure for T1 bladder carcinoma. Prog. Urol. 2012; 22; bladder compared to the 2010 American Joint Committee on
284–290. Cancer pT2 and pT3 classifications. J. Urol. 2012; 188;
84. Olsson H, Hultman P, Rosell J, Jahnson S. Population-based 1706–1711.
study on prognostic factors for recurrence and progression in 101. Yu RJ, Stein JP, Cai J, Miranda G, Groshen S, Skinner DG.
primary stage T1 bladder tumours. Scand. J. Urol. 2013; 47; Superficial (pT2a) and deep (pT2b) muscle invasion in patho-
188–195. logical staging of bladder cancer following radical cystectomy.
85. Soukup V, Duskova J, Pesl M et al. The prognostic value of J. Urol. 2006; 176; 493–498; discussion 498–409.
T1 bladder cancer substaging: a single institution retrospec- 102. Herranz Amo F, Verdu Tartajo F, Diez Cordero JM et al. Dif-
tive study. Urol. Int. 2014; 92; 150–156. ferences in survival of patients with bladder cancer depending
86. Orsola A, Werner L, de Torres I et al. Reexamining treatment on depth of muscle infiltration. Actas Urol. Esp. 2001; 25;
of high-grade T1 bladder cancer according to depth of lamina 110–114.
propria invasion: a prospective trial of 200 patients. Br. J. 103. Bowles WT, Cordonnier JJ. Total cystectomy for carcinoma of
Cancer 2015; 112; 468–474. the bladder. J. Urol. 1963; 90; 731–735.
87. Paner GP, Montironi R, Amin MB. Challenges in pathologic 104. Jewett HJ. Comments on the staging of invasive bladder cancer
staging of bladder cancer: proposals for fresh approaches of two B’s or not two B’s: that is the question (apologies to Shake-
assessing pathologic stage in light of recent studies and obser- speare, Hamlet. Act III, sc. I, 1. 56). J. Urol. 1978; 119; 39.
vations pertaining to bladder histoanatomic variances. Adv. 105. Tilki D, Reich O, Karakiewicz PI et al. Validation of the AJCC
Anat. Pathol. 2017; 24; 113–127. TNM substaging of pT2 bladder cancer: deep muscle invasion
88. Hu Z, Mudaliar K, Quek ML, Paner GP, Barkan GA. is associated with significantly worse outcome. Eur. Eurol.
Measuring the dimension of invasive component in pT1 2010; 58; 112–117.
urothelial carcinoma in transurethral resection specimens can 106. Sonpavde G, Khan MM, Svatek RS et al. Prognostic risk strati-
predict time to recurrence. Ann. Diagn. Pathol. 2014; 18; 49– fication of pathological stage T2N0 bladder cancer after radi-
52. cal cystectomy. BJU Int. 2011; 108; 687–692.
89. Cheng L, Weaver AL, Bostwick DG. Predicting extravesical 107. Ghoneim MA, Abdel-Latif M, el-Mekresh M et al. Radical cys-
extension of bladder carcinoma: a novel method based on tectomy for carcinoma of the bladder: 2,720 consecutive
micrometer measurement of the depth of invasion in transur- cases 5 years later. J. Urol. 2008; 180; 121–127.
ethral resection specimens. Urology 2000; 55; 668–672. 108. Gakis G, Schilling D, Renninger M, Seibold J, Sievert KD,
90. Leivo MZ, Sahoo D, Hamilton Z et al. Analysis of T1 bladder Stenzl A. Comparison of the new American Joint Committee
cancer on biopsy and transurethral resection specimens: com- on Cancer substratification in node-negative pT2 urothelial
parison and ranking of T1 quantification approaches to pre- carcinoma of the bladder: analysis of patient outcomes in a
dict progression to muscularis propria invasion. Am. J. Surg. contemporary series. BJU Int. 2011; 107; 919–923.
Pathol. 2018; 42; e1–e10. 109. Ananthanarayanan V, Pan Y, Tretiakova M et al. Influence
91. Jewett HJ. Carcinoma of the bladder: influence of depth of of histologic criteria and confounding factors in staging
infiltration on the 5-year results following complete extirpa- equivocal cases for microscopic perivesical tissue invasion
tion of the primary growth. J. Urol. 1952; 67; 672–680. (pT3a): an interobserver study among genitourinary patholo-
92. Bayraktar Z, Gurbuz G, Tasci AI, Sevin G. Staging error in gists. Am. J. Surg. Pathol. 2014; 38; 167–175.
the bladder tumor: the correlation between stage of TUR and 110. Alfred Witjes J, Lebret T, Comperat EM et al. Updated 2016
cystectomy. Int. Urol. Nephrol. 2001; 33; 627–629. EAU Guidelines on muscle-invasive and metastatic bladder
93. Herr HW. Staging invasive bladder tumors. J. Surg. Oncol. cancer. Eur. Eurol. 2017; 71; 462–475.
1992; 51; 217–220. 111. Milowsky MI, Rumble RB, Booth CM et al. Guideline on Mus-
94. Herr HW. A proposed simplified staging system of invasive cle-Invasive and Metastatic Bladder Cancer (European Associ-
bladder tumors. Urol. Int. 1993; 50; 17–20. ation of Urology Guideline): American Society of Clinical
95. Hall RR, Prout GR. Staging of bladder cancer: is the tumor, Oncology Clinical Practice Guideline Endorsement. J. Clin.
node, metastasis system adequate? Semin. Oncol. 1990; 17; Oncol. 2016; 34; 1945–1952.
517–523. 112. Scosyrev E, Yao J, Messing E. Microscopic invasion of perivesi-
96. Skinner DG. Current state of classification and staging of blad- cal fat by urothelial carcinoma: implications for prognosis
der cancer. Cancer Res. 1977; 37; 2838–2842. and pathology practice. Urology 2010; 76; 908–913; discus-
97. Cheng L, Neumann RM, Scherer BG et al. Tumor size predicts sion 914.
the survival of patients with pathologic stage T2 bladder car- 113. Neuzillet Y, Lebret T, Molinie V et al. Perivesical fat invasion
cinoma: a critical evaluation of the depth of muscle invasion. in bladder cancer: implications for prognosis comparing
Cancer 1999; 85; 2638–2647. pT2b, pT3a and pT3b stages and consequences for adjuvant
98. Tokgoz H, Turkolmez K, Resorlu B, Kose K, Tulunay O, Beduk chemotherapy indications. BJU Int. 2012; 110; 1736–1741.
Y. Pathological staging of muscle invasive bladder cancer. Is 114. Bastian PJ, Hutterer GC, Shariat SF et al. Macroscopic, but
substaging of pT2 tumors really necessary? Int. Braz. J. Urol. not microscopic, perivesical fat invasion at radical cystectomy
2007; 33; 777–783; discussion 783–784. is an adverse predictor of recurrence and survival. BJU Int.
99. Boudreaux KJ Jr, Clark PE, Lowrance WT et al. Comparison of 2008; 101; 450–454.
American Joint Committee on Cancer pathological stage T2a 115. Philip AT, Amin MB, Tamboli P, Lee TJ, Hill CE, Ro JY.
versus T2b urothelial carcinoma: analysis of patient outcomes Intravesical adipose tissue: a quantitative study of its presence
in organ confined bladder cancer. J. Urol. 2009; 181; 540– and location with implications for therapy and prognosis.
545; discussion 546. Am. J. Surg. Pathol. 2000; 24; 1286–1290.

© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.

132 M J Magers et al.

116. Quek ML, Stein JP, Clark PE et al. Microscopic and gross 133. Daneshmand S, Stein JP, Lesser T et al. Prognosis of seminal
extravesical extension in pathological staging of bladder can- vesicle involvement by transitional cell carcinoma of the blad-
cer. J. Urol. 2004; 171; 640–645. der. J. Urol. 2004; 172; 81–84.
117. Boudreaux KJ Jr, Chang SS, Lowrance WT et al. Comparison 134. Volkmer BG, Kufer R, Maier S et al. Outcome in patients with
of American Joint Committee on Cancer pathologic stage T3a seminal vesicle invasion after radical cystectomy. J. Urol.
versus T3b urothelial carcinoma: analysis of patient out- 2003; 169; 1299–1302.
comes. Cancer 2009; 115; 770–775. 135. May M, Brookman-May S, Burger M et al. Concomitant semi-
118. Dincel C, Kara C, Balci U et al. Comparison of microscopic nal vesicle invasion in pT4a urothelial carcinoma of the blad-
(pT3a) and gross extravesical extension (pT3b) in pathologi- der with contiguous prostatic infiltration is an adverse
cal staging of bladder cancer: analysis of patient outcomes. prognosticator for cancer-specific survival after radical cystec-
Int. Urol. Nephrol. 2013; 45; 387–393. tomy. Ann. Surg. Oncol. 2014; 21; 4034–4040.
119. Sonpavde G, Khan MM, Svatek RS et al. Prognostic risk strati- 136. You D, Kim SC, Jeong IG et al. Urothelial carcinoma of the
fication of pathological stage T3N0 bladder cancer after radi- bladder with seminal vesicle invasion: prognostic significance.
cal cystectomy. J. Urol. 2011; 185; 1216–1221. BJU Int. 2010; 106; 1657–1661.
120. Tilki D, Svatek RS, Karakiewicz PI et al. pT3 Substaging is a 137. Chen ME, Pisters LL, Malpica A, Pettaway CA, Dinney CP.
prognostic indicator for lymph node negative urothelial carci- Risk of urethral, vaginal and cervical involvement in patients
noma of the bladder. J. Urol. 2010; 184; 470–474. undergoing radical cystectomy for bladder cancer: results of a
121. Tretter EM, Ebel JJ, Pohar KS, Zynger DL. Does the gross pros- contemporary cystectomy series from M. D. Anderson Cancer
ector impact pT3 subclassification or lymph node counts in Center. J. Urol. 1997; 157; 2120–2123.
bladder cancer? Hum. Pathol. 2017; 61; 190–198. 138. Salem H, El-Mazny A. A clinicopathologic study of gyneco-
122. Donat SM, Genega EM, Herr HW, Reuter VE. Mechanisms of logic organ involvement at radical cystectomy for bladder
prostatic stromal invasion in patients with bladder cancer: cancer. Int. J. Gynaecol. Obstet. 2011; 115; 188–190.
clinical significance. J. Urol. 2001; 165; 1117–1120. 139. Varkarakis IM, Pinggera G, Antoniou N, Constantinides K,
123. Esrig D, Freeman JA, Elmajian DA et al. Transitional cell car- Chrisofos M, Deliveliotis C. Pathological review of internal
cinoma involving the prostate with a proposed staging classi- genitalia after anterior exenteration for bladder cancer in
fication for stromal invasion. J. Urol. 1996; 15; 1071–1076. women. Evaluating risk factors for female organ involvement.
124. Montironi R, Cheng L, Mazzucchelli R et al. Critical evalua- Int. Urol. Nephrol. 2007; 39; 1015–1021.
tion of the prostate from cystoprostatectomies for bladder can- 140. Ali-El-Dein B, Abdel-Latif M, Mosbah A et al. Secondary
cer: insights from a complete sampling with the whole mount malignant involvement of gynecologic organs in radical cys-
technique. Eur. Eurol. 2009; 55; 1305–1309. tectomy specimens in women: is it mandatory to remove
125. Knoedler JJ, Boorjian SA, Tollefson MK et al. Urothelial carci- these organs routinely? J. Urol. 2004; 172; 885–887.
noma involving the prostate: the association of revised 141. Groutz A, Gillon G, Konichezky M et al. Involvement of inter-
tumour stage and coexistent bladder cancer with survival nal genitalia in female patients undergoing radical cystec-
after radical cystectomy. BJU Int. 2014; 114; 832–836. tomy for bladder cancer: a clinicopathologic study of 37
126. Barocas DA, Patel SG, Chang SS, Clark PE, Smith JA Jr, Cook- cases. Int. J. Gynecol. Cancer 1999; 9; 302–306.
son MS. Outcomes of patients undergoing radical cystoprosta- 142. Reyes MC, Park KJ, Lin O et al. Urothelial carcinoma involv-
tectomy for bladder cancer with prostatic involvement on ing the gynecologic tract: a morphologic and immunohisto-
final pathology. BJU Int. 2009; 104; 1091–1097. chemical study of 6 cases. Am. J. Surg. Pathol. 2012; 36;
127. Njinou Ngninkeu B, Lorge F, Moulin P, Jamart J, Van Cangh 1058–1065.
PJ. Transitional cell carcinoma involving the prostate: a clini- 143. Aziz A, Shariat SF, Roghmann F et al. Prediction of cancer-
copathological retrospective study of 76 cases. J. Urol. 2003; specific survival after radical cystectomy in pT4a urothelial
169; 149–152. carcinoma of the bladder: development of a tool for clinical
128. Pagano F, Bassi P, Ferrante GL et al. Is stage pT4a (D1) reli- decision-making. BJU Int. 2016; 117; 272–279.
able in assessing transitional cell carcinoma involvement of 144. May M, Bastian PJ, Brookman-May S et al. Gender-specific differ-
the prostate in patients with a concurrent bladder cancer? A ences in cancer-specific survival after radical cystectomy for
necessary distinction for contiguous or noncontiguous patients with urothelial carcinoma of the urinary bladder in
involvement. J. Urol. 1996; 155; 244–247. pathologic tumor stage T4a. Urol. Oncol. 2013; 31; 1141–1147.
129. Ayyathurai R, Gomez P, Luongo T, Soloway MS, Manoharan 145. Tilki D, Svatek RS, Karakiewicz PI et al. Characteristics and
M. Prostatic involvement by urothelial carcinoma of the blad- outcomes of patients with pT4 urothelial carcinoma at radical
der: clinicopathological features and outcome after radical cystectomy: a retrospective international study of 583
cystectomy. BJU Int. 2007; 100; 1021–1025. patients. J. Urol. 2010; 183; 87–93.
130. Shen SS, Lerner SP, Muezzinoglu B, Truong LD, Amiel G, 146. Liberman D, Alasker A, Sun M et al. Radical cystectomy for
Wheeler TM. Prostatic involvement by transitional cell carci- patients with pT4 urothelial carcinoma in a large population-
noma in patients with bladder cancer and its prognostic sig- based study. BJU Int. 2011; 107; 905–911.
nificance. Hum. Pathol. 2006; 37; 726–734. 147. Nuhn P, May M, Fritsche HM et al. External validation of dis-
131. Vallo S, Gilfrich C, Burger M et al. Comparative analysis of ease-free survival at 2 or 3 years as a surrogate and new pri-
the effect of prostatic invasion patterns on cancer-specific mary endpoint for patients undergoing radical cystectomy for
mortality after radical cystectomy in pT4a urothelial carci- urothelial carcinoma of the bladder. Eur. J. Surg. Oncol. 2012;
noma of the bladder. Urol. Oncol. 2016; 34; 432.e1–432.e8. 38; 637–642.
132. Patel AR, Cohn JA, Abd El Latif A et al. Validation of new 148. Fleischmann A, Thalmann GN, Markwalder R, Studer UE.
AJCC exclusion criteria for subepithelial prostatic stromal Extracapsular extension of pelvic lymph node metastases from
invasion from pT4a bladder urothelial carcinoma. J. Urol. urothelial carcinoma of the bladder is an independent prog-
2013; 189; 53–58. nostic factor. J. Clin. Oncol. 2005; 23; 2358–2365.

© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.

 Staging of bladder cancer 133

149. Jensen JB, Ulhoi BP, Jensen KM. Evaluation of different lymph 167. Galsky MD, Moshier E, Krege S et al. Nomogram for predict-
node (LN) variables as prognostic markers in patients under- ing survival in patients with unresectable and/or metastatic
going radical cystectomy and extended LN dissection to the urothelial cancer who are treated with cisplatin-based
level of the inferior mesenteric artery. BJU Int. 2012; 109; chemotherapy. Cancer 2013; 119; 3012–3019.
388–393. 168. Lotan Y, Gupta A, Shariat SF et al. Lymphovascular invasion
150. Stephenson AJ, Gong MC, Campbell SC, Fergany AF, Hansel is independently associated with overall survival, cause-speci-
DE. Aggregate lymph node metastasis diameter and survival fic survival, and local and distant recurrence in patients with
after radical cystectomy for invasive bladder cancer. Urology negative lymph nodes at radical cystectomy. J. Clin. Oncol.
2010; 5; 382–386. 2005; 23; 6533–6539.
151. Pedrosa JA, Koch MO, Cheng L. Lymph node-positive bladder 169. Kunju LP, You L, Zhang Y, Daignault S, Montie JE, Lee CT.
cancer: surgical, pathologic, molecular and prognostic Lymphovascular invasion of urothelial cancer in matched
aspects. Expert Rev. Anticancer Ther. 2013; 13; 1281–1295. transurethral bladder tumor resection and radical cystec-
152. Herr HW, Bochner BH, Dalbagni G, Donat SM, Reuter VE, tomy specimens. J. Urol. 2008; 180; 1928–1932; discussion
Bajorin DF. Impact of the number of lymph nodes retrieved 1932.
on outcome in patients with muscle invasive bladder cancer. 170. Shariat SF, Bolenz C, Godoy G et al. Predictive value of com-
J. Urol. 2002; 167; 1295–1298. bined immunohistochemical markers in patients with pT1
153. Hollenbeck BK, Ye Z, Wong SL, Montie JE, Birkmeyer JD. urothelial carcinoma at radical cystectomy. J. Urol. 2009;
Hospital lymph node counts and survival after radical cystec- 182; 78–84; discussion 84.
tomy. Cancer 2008; 112; 806–812. 171. Mazzucchelli R, Cheng L, Lopez-Beltran A, Scarpelli M, Mon-
154. Koppie TM, Vickers AJ, Vora K, Dalbagni G, Bochner BH. tironi R. Clinicopathological significance of lymphovascular
Standardization of pelvic lymphadenectomy performed at rad- invasion in urothelial carcinoma. Anal. Quant. Cytopathol.
ical cystectomy: can we establish a minimum number of Histpathol. 2012; 34; 173–179.
lymph nodes that should be removed? Cancer 2006; 107; 172. Streeper NM, Simons CM, Konety BR et al. The significance of
2368–2374. lymphovascular invasion in transurethral resection of bladder
155. Wright JL, Lin DW, Porter MP. The association between tumour and cystectomy specimens on the survival of patients
extent of lymphadenectomy and survival among patients with with urothelial bladder cancer. BJU Int. 2009; 103; 475–
lymph node metastases undergoing radical cystectomy. Cancer 479.
2008; 112; 2401–2408. 173. Resnick MJ, Bergey M, Magerfleisch L, Tomaszewski JE,
156. Morgan TM, Barocas DA, Penson DF et al. Lymph node yield Malkowicz SB, Guzzo TJ. Longitudinal evaluation of the con-
at radical cystectomy predicts mortality in node-negative and cordance and prognostic value of lymphovascular invasion in
not node-positive patients. Urology 2012; 80; 632–640. transurethral resection and radical cystectomy specimens.
157. Capitanio U, Suardi N, Shariat SF et al. Assessing the mini- BJU Int. 2011; 107; 46–52.
mum number of lymph nodes needed at radical cystectomy 174. Walker NF, Gan C, Olsburgh J, Khan MS. Diagnosis and man-
in patients with bladder cancer. BJU Int. 2009; 103; 1359– agement of intradiverticular bladder tumours. Nat. Rev. Urol.
1362. 2014; 11; 383–390.
158. Lerner SP, Skinner DG, Lieskovsky G et al. The rationale for 175. Prakash, Rajini T, Kumar Bhardwaj A, V J, Kalyani Rao P,
en bloc pelvic lymph node dissection for bladder cancer Singh G. Urinary bladder diverticulum and its association
patients with nodal metastases: long-term results. J. Urol. with malignancy: an anatomical study on cadavers. Rom. J.
1993; 149; 758–764; discussion 764–765. Morphol. Embryol. 2010; 51; 543–545.
159. Skinner DG. Management of invasive bladder cancer: a metic- 176. Hansel DE, Paner GP, Nese N, Amin MB. Limited smoothe-
ulous pelvic node dissection can make a difference. J. Urol. lin expression within the muscularis mucosae: validation
1982; 128; 34–36. in bladder diverticula. Hum. Pathol. 2011; 42; 1770–
160. Abdollah F, Sun M, Schmitges J et al. Stage-specific impact of 1776.
pelvic lymph node dissection on survival in patients with 177. Golijanin D, Yossepowitch O, Beck SD, Sogani P, Dalbagni G.
non-metastatic bladder cancer treated with radical cystec- Carcinoma in a bladder diverticulum: presentation and treat-
tomy. BJU Int. 2012; 109; 1147–1154. ment outcome. J. Urol. 2003; 170; 1761–1764.
161. Stein JP, Lieskovsky G, Cote R et al. Radical cystectomy in the 178. Idrees MT, Alexander RE, Kum JB, Cheng L. The spectrum of
treatment of invasive bladder cancer: long-term results in histopathologic findings in vesical diverticulum: implications
1,054 patients. J. Clin. Oncol. 2001; 19; 666–675. for pathogenesis and staging. Hum. Pathol. 2013; 44; 1223–
162. Edge SB, American Joint Committee on Cancer. AJCC cancer 1232.
staging manual, 7th edn. New York: Springer, 2010. 179. Tamas EF, Stephenson AJ, Campbell SC, Montague DK,
163. Greene FL, American Joint Committee on Cancer, American Trusty DC, Hansel DE. Histopathologic features and clinical
Cancer Society. AJCC cancer staging manual, 6th ed. New outcomes in 71 cases of bladder diverticula. Arch. Pathol. Lab.
York: Springer-Verlag, 2002. Med. 2009; 133; 791–796.
164. Herr HW. Superiority of ratio based lymph node staging for 180. Hu B, Satkunasivam R, Schuckman A, Miranda G, Cai J,
bladder cancer. J. Urol. 2003; 169; 943–945. Daneshmand S. Urothelial carcinoma in bladder diverticula:
165. Pedrosa JA, Kaimakliotis HZ, Monn MF et al. Critical analysis outcomes after radical cystectomy. World J. Urol. 2015; 33;
of the 2010 TNM classification in patients with lymph node- 1397–1402.
positive bladder cancer: influence of lymph node disease bur- 181. Dhillon J, Liang Y, Kamat AM et al. Urachal carcinoma: a
den. Urol. Oncol. 2014; 32; 1003–1009. pathologic and clinical study of 46 cases. Hum. Pathol. 2015;
166. Pedrosa JA, Koch MO, Kaimakliotis HZ et al. Three-tiered 46; 1808–1814.
nodal classification system for bladder cancer: a new pro- 182. Molina JR, Quevedo JF, Furth AF, Richardson RL, Zincke H,
posal. Future Oncol. 2015; 11; 399–408. Burch PA. Predictors of survival from urachal cancer: a

© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.

134 M J Magers et al.

Mayo Clinic study of 49 cases. Cancer 2007; 110; 2434– 187. Gopalan A, Sharp DS, Fine SW et al. Urachal carcinoma: a
2440. clinicopathologic analysis of 24 cases with outcome correla-
183. Ashley RA, Inman BA, Sebo TJ et al. Urachal carcinoma: clin- tion. Am. J. Surg. Pathol. 2009; 33; 659–668.
icopathologic features and long-term outcomes of an aggres- 188. Bruins HM, Visser O, Ploeg M, Hulsbergen-van de Kaa CA,
sive malignancy. Cancer 2006; 107; 712–720. Kiemeney LA, Witjes JA. The clinical epidemiology of urachal
184. Pinthus JH, Haddad R, Trachtenberg J et al. Population based carcinoma: results of a large, population based study. J. Urol.
survival data on urachal tumors. J. Urol. 2006; 175; 2042– 2012; 188; 1102–1107.
2047; discussion 2047. 189. Herr HW, Bochner BH, Sharp D, Dalbagni G, Reuter VE. Ura-
185. Sheldon CA, Clayman RV, Gonzalez R, Williams RD, Fraley chal carcinoma: contemporary surgical outcomes. J. Urol.
EE. Malignant urachal lesions. J. Urol. 1984; 131; 1–8. 2007; 178; 74–78; discussion 78.
186. Amin MB, Smith SC, Eble JN et al. Glandular neoplasms of 190. Wright JL, Porter MP, Li CI, Lange PH, Lin DW. Differ-
the urachus: a report of 55 cases emphasizing mucinous cys- ences in survival among patients with urachal and nonu-
tic tumors with proposed classification. Am. J. Surg. Pathol. rachal adenocarcinomas of the bladder. Cancer 2006; 107;
2014; 38; 1033–1045. 721–728.

© 2018 John Wiley & Sons Ltd, Histopathology, 74, 112–134.