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Mod Pathol. Author manuscript; available in PMC 2016 September 02.
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Published in final edited form as:

Mod Pathol. 2015 May ; 28(5): 612–630. doi:10.1038/modpathol.2014.158.
Update for the practicing pathologist: The International

Consultation On Urologic Disease-European association of
urology consultation on bladder cancer
Mahul B Amin1,27, Steven C Smith1,27,28, Victor E Reuter2, Jonathan I Epstein3, David J
Grignon4, Donna E Hansel5, Oscar Lin2, Jesse K McKenney6, Rodolfo Montironi7, Gladell P
Paner8, Hikmat A Al-Ahmadie2, Ferran Algaba9, Syed Ali3, Isabel Alvarado-Cabrero10,
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Lukas Bubendorf11, Liang Cheng4, John C Cheville12, Glen Kristiansen13, Richard J

Cote14, Brett Delahunt15, John N Eble4, Elizabeth M Genega16, Christian Gulmann17, Arndt
Hartmann18, Cord Langner19, Antonio Lopez-Beltran20, Cristina Magi-Galluzzi6, Jorda
Merce14, George J Netto3, Esther Oliva21, Priya Rao22, Jae Y Ro23, John R Srigley24, Satish
K Tickoo2, Toyonori Tsuzuki25, Saleem A Umar14, Theo Van der Kwast26, Robert H
Young21, and Mark S Soloway14
1Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles,
CA, USA 2Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY,
USA 3Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA 4Department of
Pathology, Indiana University School of Medicine, Indianapolis, IN, USA 5Department of
Pathology, University of California San Diego, San Diego, CA, USA 6Department of Pathology,
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Cleveland Clinic Foundation, Cleveland, OH, USA 7Section of Pathological Anatomy, Polytechnic
University of Medicine, United Hospitals, Ancona, Italy 8Department of Pathology, University of
Chicago, Chicago, IL, USA 9Pathology Section, Fundacio Puigvert, Universitat Autónoma de
Barcelona, Barcelona, Spain 10Department of Pathology, Mexican Oncology Hospital, Mexico
City, Mexico 11Institute of Pathology, University Hospital Basel, Basel, Switzerland 12Division of
Anatomic Pathology, Mayo Clinic, Rochester, MN, USA 13Institute of Pathology, University
Hospital Bonn, Bonn, Germany 14Department of Pathology, University of Miami Miller School of
Medicine, Miami, FL, USA 15Department of Pathology, Wellington School of Medicine and Health
Sciences, University of Otago, Wellington, New Zealand 16Department of Pathology and
Laboratory Medicine, Tufts Medical Center, Boston, MA, USA 17Department of Pathology,
Beaumont Hospital, Dublin, Ireland 18Institute of Pathology, University Erlangen-Nürnberg,
Erlangen, Germany 19Institute of Pathology, Medical University Graz, Graz, Austria 20Unit of
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Anatomical Pathology, Cordoba University Medical School, Faculty of Medicine, Cordoba, Spain
21James Homer Wright Pathology Laboratories, Department of Pathology, Massachusetts
General Hospital, Harvard Medical School, Boston, MA, USA 22Department of Pathology, The
University of Texas M. D. Anderson Cancer Center, Houston, TX, USA 23Department of Pathology
Correspondence: Dr MB Amin, MD, Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly
Blvd, S. Tower, Rm 8707, Los Angeles, CA 90048, USA. [email protected].
27Co-first authors.
28Current address: Department of Pathology, VCU Health System, Richmond, VA 23298, USA.
Disclosure/conflict of interest
The authors declare no conflict of interest.
Amin et al. Page 2
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and Genomic Medicine, The Methodist Hospital Physician Organization, Weill Cornell Medical
College of Cornell University, Houston, TX, USA 24Department Pathology and Molecular
Medicine, McMaster University, Hamilton, ON, Canada 25Department of Pathology, Japanese Red
Cross Nagoya Daini Hospital, Nagoya, Japan 26Department of Urology, University of Miami Miller
School of Medicine, Miami, FL, USA
Abstract
The International Consultations on Urological Diseases are international consensus meetings,
supported by the World Health Organization and the Union Internationale Contre le Cancer, which
have occurred since 1981. Each consultation has the goal of convening experts to review data and
provide evidence-based recommendations to improve practice. In 2012, the selected subject was
bladder cancer, a disease which remains a major public health problem with little improvement in
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many years. The proceedings of the 2nd International Consultation on Bladder Cancer, which
included a ‘Pathology of Bladder Cancer Work Group,’ have recently been published; herein, we
provide a summary of developments and consensus relevant to the practicing pathologist.
Although the published proceedings have tackled a comprehensive set of issues regarding the
pathology of bladder cancer, this update summarizes the recommendations regarding selected
issues for the practicing pathologist. These include guidelines for classification and grading of
urothelial neoplasia, with particular emphasis on the approach to inverted lesions, the handling of
incipient papillary lesions frequently seen during surveillance of bladder cancer patients,
descriptions of newer variants, and terminology for urine cytology reporting.
The International Consultation on Urological Diseases (ICUD) is a World Health

Organization (WHO)-registered non-governmental organization promoting improvements in
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world health through sponsorship and organization of interdisciplinary international

consultations on the diagnosis, classification, and management of urologic diseases, with
emphasis on provision of evidence-based recommendations. Prior consultations have
spanned the spectrum of neoplastic and non-neoplastic urologic diseases ranging from
benign prostatic hyperplasia and erectile dysfunction to prostate and bladder cancer. Bladder
cancer was previously addressed in 2004 in the 1st International Consultation on Bladder
Tumors in Hawaii with proceedings published in 2005.1 In March 2011 in Vienna, Austria,
bladder cancer was revisited in the 2nd International Consultation on Bladder Cancer to
provide an updated consensus and recommendations. This meeting, co-sponsored by the
European Association of Urology, included a Pathology of Bladder Cancer Work Group
composed of nearly 40 experts in urological pathology among a total of 10 committees
formulated to address key clinical and public health questions. The 2nd Consultation on
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Bladder Cancer resulted in recent publication of the book, Bladder Cancer,2 reporting the
consultation’s proceedings, as well as a number of summary papers.3–7 From the standpoint
of bladder cancer pathology, this consultation, auspiciously occurring a number of years
after the discussion in 1997–1998, introduction,8 modification,9 and formal WHO adoption
in 200410 of the International Society of Urologic Pathology (ISUP) classification and
grading system for urothelial neoplasms of the urinary bladder, offered the opportunity to

Amin et al. Page 3
examine the state of the art and begin to address a number of key questions regarding
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bladder cancer pathology and the pathologist’s diagnostic approach.
As new findings and better data have become available about important areas of recurrent
interest since the 2004 Blue Book, the proceedings of this bladder cancer pathology
committee and working group provide guidance on a number of areas of value to practicing
pathologists. The consultation’s proceedings are publicly available in toto in electronic and
print form2 and provide a compendium of the state of the art for this disease; the pathology
section proceedings alone number >100 pages with >700 references. In particular, sections
describing the microanatomy of the bladder and normal, reactive, and metaplastic epithelial
changes provide a useful review, as does the review of the use of immunohistochemistry.
However, as these proceedings have seen relatively limited coverage in the mainstream
pathology literature, herein we have endeavored to distill a ‘high yield’ review of selected
topics of the proceedings most relevant to the practice of urologic surgical pathology.
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Specifically, we cover four areas of the ICUD’s recommendations: (i) the classification and
grading of urothelial neoplasia with a focus on application of the grading system in routine
practice, including for neoplasms with inverted morphology or those with grade
heterogeneity; (ii) the diagnostic approach for incipient lesions, often seen in patients under
surveillance for urothelial neoplasia, which are not accurately classifiable as per the current
schema; (iii) an update on the variants of urothelial carcinoma, particularly from the
perspective of newer variants or established variants with increased understanding of clinical
significance; and (iv) a consensus language for urine cytology. These key offerings of the
ICUD proceedings are bulleted in Summary Box 1.
A historical perspective of classification and grading

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Building on the longstanding efforts of the WHO in study and classification of tumors
(reviewed in Mostofi et al9) and the first and second series of the Armed Forces Institute of
Pathology (AFIP) Fascicles,11 the WHO in 1973 published the first international, systematic
approach to the grading of urothelial neoplasia.12 The WHO 1973 system provided a
classification of what was then called ‘transitional cell carcinoma’ of the bladder into three
grades. Although this classification provided the modern foundation for approaching these
lesions, it suffered limitations, particularly pertaining to a lack of clearly defined criteria for
each grade, referring only to the degree of anaplasia and thereby resulting in diagnosis of a
high prevalence of grade II ‘intermediate grade’ carcinomas. A number of authors have
argued that from a clinical standpoint, the 1973 system was limited by focusing on
morphology (without clear criteria) rather than targeted to classifying tumors into categories
more relevant to management.13–15
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In 1994, based largely on a study by Jordan et al,16 the 3rd Series AFIP fascicle proposed a
classification of bladder carcinoma as ‘papilloma,’ lowgrade, and high-grade transitional cell
carcinoma,17 adapting a broader definition of ‘papilloma’ to include most WHO 1973 Grade
I transitional cell carcinomas. In fall 1997, anticipatory of the next WHO monograph, to be
published in 1999, Dr FK Mostofi assembled a team of experts at the AFIP in Washington
DC to discuss terminology used in bladder cancer and make recommendations to the WHO.
Of particular interest was the issue of the nomenclature of Grade I transitional cell

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carcinoma, given the growing appreciation at the time that a majority of tumors in this
category did not progress.16,17 At the AFIP meeting, the term papillary urothelial neoplasm
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of low malignant potential (PUNLMP) was proposed to the WHO committee, to prevent
assigning these more indolent lesions the label of carcinoma but not categorically
designating them as a benign lesion (papilloma) because of the presence of a distinct subset
of cases that show recurrence and grade progression.
Pursuant to this important step, in March 1998, a follow-up meeting, organized under the
auspices of the International Society of Urologic Pathology (ISUP), was convened at the
United States and Canadian Academy of Pathology (USCAP) meeting in Boston in March,
1998, where the classification, terminology, and, importantly, criteria were refined and
modified (drawing significantly from influential approaches that had been reported by
Malmstroöm et al18 and Murphy et al17). The proceedings of this meeting were published as
the WHO/ISUP Consensus Classification of Urothelial Neoplasms of the bladder at the end
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of that year8 in hopes of providing a ‘universally acceptable classification system’ for

urothelial neoplasia. Additional contributions included the formal endorsement of the term
‘urothelial’ to replace ‘transitional cell’ in description of the epithelium of the urinary tract
and tumors therefrom. The flat intraepithelial lesions with non-reactive atypia were
essentially compressed from a multi-tier system of mild, moderate, severe, and carcinoma in
situ (CIS), to essentially a two tier system of dysplasia and CIS. In 1999, the WHO,
maintaining papilloma and PUNLMP as diagnostic categories, re-appropriated the labels of
Grade I, Grade II, and Grade III urothelial carcinoma,9 but used them to label lesions
defined by criteria different from those of the 1973 WHO system.
Subsequently, after a conference in Lyon, France, during 14–18 December 2002, the WHO,
in its revised 2004 ‘Blue Book,’ Pathology and Genetics of Tumours of the Urinary System,
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formally adopted the 1998 ISUP system, with its four categories of papilloma, PUNLMP,
low-grade, and high-grade papillary urothelial carcinoma (the latter with option to comment
on diffuse anaplasia if present). This system has been termed the WHO (2004)/ISUP system,
herein the ‘WHO/ISUP System,’ and has provided a number of advantages to the field of
bladder cancer pathology (Summary Box 2). It is this system that the ICUD recommends for
contemporary use, consistent with the endorsement by the 4th Series Armed Forces
Institutes of Pathology Fascicle on the Urinary Bladder,19 the 7th edition AJCC Cancer
Staging Manual,20 and several American (Association of Directors of Anatomic and
Surgical Pathology, the College of American Pathologists21), and European protocols.22 Two
additional areas relevant to grading where the ICUD made recommendations applicable to
daily practice include the application of the WHO/ISUP system to tumors with inverted
architecture and the approach to the diagnosis and reporting of incipient urothelial neoplasia.
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Overall ICUD recommendation: grading by WHO/ISUP system

A System Linking Histopathologic Criteria to Risk
The ISUP 1998 consensus classification, adopted by the WHO in 2004 as the WHO/ISUP
system, stressed the use of diagnostic criteria for papillary lesions summarized briefly as
follows. Urothelial papilloma was defined as a papillary lesion showing a urothelium of
normal thickness, cellularity and polarization, lining on fibrovascular stalks, a diagnosis

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implying an unequivocally benign lesion of low risk of recurrence and no risk for
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progression. Essentially similar features, seen in flat, nonpapillary mucosa, would be

regarded as normal urothelium. The PUNLMP category of lesions was defined as showing
normal to thickened and hyperplastic-appearing (increased number of layers and cells per
unit area) urothelium with minimal architectural abnormality and minimal cellular atypia.
This group was intended to imply a substantial risk of recurrence (<50%) in some series
approximating that of low-grade papillary carcinoma, but with low risk of progression
(<5%) such that patients could be spared a cancer diagnosis. Lesions showing this range of
features in a nonpapillary lesion or biopsy would be regarded as flat urothelial hyperplasia.
Lesions showing a urothelium with distinct cytologic atypia (nucleomegaly, irregular nuclear
contours, and irregular chromatin distribution) and variable loss of polarity, arrayed on a
discrete fibrovascular core, were defined as low-grade papillary urothelial carcinoma. This
category implies a high risk of recurrence of ~50% and low risk of progression of ~5–10%,
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both greater than in PUNLMP. When encountered in a non-papillary lesion, these histologic
changes would be diagnosed as urothelial dysplasia. Finally, tumors demonstrating
urothelium with moderate to severe cytologic atypia (nuclear pleomorphism, prominent
nucleoli, and mitoses, including atypical forms, in mid to higher layers of the urothelium),
arrayed on fibrovascular cores, with variable, often significant loss of polarity and
discohesion, were defined as high-grade papillary urothelial carcinoma. High-grade
papillary carcinomas have relatively greater risk of recurrence than low-grade carcinomas, as
well as a significant risk of progression to invasive disease (15–40%). The same degree of
cytologic atypia, encountered in a biopsy of flat urothelium, would be regarded as urothelial
CIS.
ICUD Recommendation—Update for Grading Invasive Carcinoma

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One key area where the recommendations of the ICUD differ, indirectly, from the WHO/
ISUP system concerns the approach to histologic grading of invasive lesions. In principle,
the WHO 1973, ISUP 1998, WHO 1999, and WHO(2004)/ISUP systems all recommended
grading invasive carcinoma by the same system under which non-invasive carcinomas are
graded; indeed, the 2004 WHO Blue Book recommends their grading by ‘the degree of
nuclear anaplasia and…architectural abnormalities.’ Emerging understanding in the
intervening years suggests that among tumors showing any extent of invasion of the
basement membrane (pT1 or greater), the histologic grade is both less important
prognostically, as reviewed recently,2,3 as well as nearly operationally irrelevant, given the
overwhelming predominance of high-grade histology (per WHO (2004)/ISUP criteria). For
instance, in a study by Cao et al,23 41/42 tumors showing stromal invasion were graded as
high-grade under the current WHO/ISUP system. Thus, the prevalence of ‘low-grade’ pT1
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was too low to evaluate, whereas even application of the 1973 criteria resulted in a non-
significant difference in recurrence-free, progression-free, and overall survival. Similarly, in
a larger cohort, Otto et al24 found that of over 300 pT1 stage tumors, 96% were graded as
high-grade under the WHO/ISUP system, whereas recurrence-free, cancer-free, and overall
survival again did not differ between low- and high-grade (stage pT1 invasive) carcinomas.

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In the end, this finding should not be surprising in that the criteria involved in recognizing
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stromal (or muscularis propria) invasion (retraction artifact, single cells, irregularly shaped
clusters, paradoxical inverse maturation) essentially by definition exclude retention of the
architectural features necessary for a low-grade designation (preservation of a modicum of
polarity within the urothelium). Even tumors at the lower end of the spectrum of cytologic
atypia in invasive tumors, the so-called ‘deceptively bland’ variants (nested etc), once
muscle invasive show overall prognoses similar to stage-matched tumors with conventional
morphology.
Thus, based on the growing experience and understanding of criteria subsequent to the
introduction of the WHO (2004)/ISUP system, the ICUD recommends that invasive
urothelial carcinomas, independent of the degree of invasion, be generally graded as high-
grade. This recommendation comes with the understanding that there are uncommon
variants of invasive urothelial carcinoma that may demonstrate idiosyncratic low-grade
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cytologic features (including the small and large nested variants—see below) and which
require careful consideration and communication with clinical colleagues. Additionally, this
ICUD recommendation comes with the consideration voiced by some panelists, especially
European colleagues, that a number of protocols and institutional standard practices ascribe
grades to invasive carcinomas using criteria from prior grading systems—principally WHO
1973 defined solely on degree of ‘anaplasia.’12 Thus, while recognizing that, in any case,
stage trumps grade, grading of invasive urothelial carcinoma may be resorted to in very
select situations based on existing institutional or clinical protocols.
ICUD Recommendation—Update for Grading Inverted Neoplasms

One of the themes in the approach to grading urothelial neoplasms in general, considered at
length in the deliberations of the ICUD, was the analogy between morphologic features of
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papillary and flat lesions (Table 1). For instance, beginning with the descriptions and criteria
first proposed in the 1998 ISUP Consensus Classification, there was an appreciation that
similar degrees of cytologic changes were appreciable between flat and papillary non-
invasive lesions, such that normal urothelium and papilloma were analogous, flat urothelial
hyperplasia and PUNLMP were analogous, dysplasia and low-grade papillary urothelial
carcinoma were analogous, and urothelial CIS and high-grade papillary urothelial carcinoma
were analogous. Although the 1998 ISUP included a definition of inverted papilloma and
referenced a contemporary report of urothelial neoplasms with inverted or endophytic
architecture,25 it did not address the applicability of the grading system to inverted
neoplasms. For that matter, the WHO (2004) /ISUP system,10 despite recognizing the
existence of inverted papilloma, did not address grading any other inverted lesions and only
considered the issue that inverted/endophytic growth patterns may simulate invasion.25,26
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Inverted neoplasms have been the source of some difficulty in urological pathology, as
already recognized in the 1998 WHO/ISUP Consensus.8 In ICUD deliberations, it became
apparent that a formal approach for grading neoplasms showing an inverted growth pattern,
particularly those demonstrating predominant or exclusive inverted growth,27 was not
available under the existing grading systems. The ICUD proceedings note that this
deficiency has resulted in these neoplasms, especially ones with features of PUNLMP but

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with inverted growth, being reported under a number of terminologies.25,26,28–30 Thus, a

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recommendation was made to appropriate the existing WHO/ISUP system criteria and
analogy between flat and exophytic papillary neoplasms to inverted/endophytic papillary
lesions.
Although data to support the validity of the application of the WHO/ISUP System of
histologic grading to inverted neoplasms, particularly PUNLMP,31,32 have only begun to
accumulate, the ICUD recommends use of the criteria of the WHO/ISUP system to grade
inverted lesions, which include inverted papilloma (Figure 1a and b), inverted PUNLMP
(Figure 1c and d), inverted papillary urothelial carcinoma, low-grade (Figure 2a and b), and
inverted papillary urothelial carcinoma, high-grade (Figure 2c and d, which may be invasive
or noninvasive); see Table 1. Though the ICUD noted that the limited understanding of the
prospective significance of such diagnoses should be recognized and conveyed to clinicians,
the use of standardized criteria and terminology will enable the future studies necessary to
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better understand these neoplasms going forward. For that matter, in clinical practice, it is
not uncommon to see tumors with both exophytic/papillary and endophytic/inverted growth;
it is only when the inverted pattern is prominent or predominant that this proposed
terminology should be used.
ICUD Recommendation: Update for Grading Papillary Neoplasia with Grade Heterogeneity
Heterogeneity in the grade of urothelial neoplasms is not infrequent, with some studies
reporting as much as ~40%.33–36 Under the current (and ICUD recommended) WHO/ISUP
system, the recommendation was made to render a grade based on the highest grade area
identified in the tumor.10 The ICUD workgroup acknowledged that some studies have
promulgated ignoring less than 5% of a higher grade neoplasm,34,36 though it did not
endorse this approach. Additionally, the proceedings reviewed the results of studies that have
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identified significant differences between the prognosis of non-invasive papillary carcinomas

with predominant high-grade histology and carcinomas with admixed low-grade
components.33,35,36 Overall, the proceedings acknowledged that prospective studies of grade
heterogeneity, approaches to its reporting, and the relationship of these parameters to
outcomes are needed.
Heterogeneity in lesions that show morphology varying between PUNLMP and papillary
urothelial carcinoma, low-grade, pose a less critical clinical distinction given their relatively
similar recurrence rates. In contrast, the implications of mixed low-grade and high-grade
morphology are more clinically important, though both PUNLMP/low-grade and low-grade/
high-grade mixed patterns are encountered.36 More importantly, one of the documented
reasons behind the interobserver variability in the diagnosis of high-grade papillary
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carcinoma is that a focus of higher grade histology may be counted as sufficient for
diagnosis by one observer but not another.15 To provide a more complete diagnostic
description of such a process, the ICUD noted that some authors use terminology such as,
‘high-grade papillary urothelial carcinoma arising in a background of low-grade papillary
urothelial carcinoma.’
Because the distinction of low-grade and high-grade tumors is clinically significant, the
ICUD recommends that when assigning a grade to a borderline lesion (between low- and

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high-grade), a number of additional factors, including historical data (grade of prior

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urothelial neoplasia, frequency of recurrence), as well as salient clinical (size, focality/

multifocality) and pathologic (concurrent CIS, urine cytology results) observations may be
considered. The ICUD recommends consideration of the presence or absence of such factors
as part of the pathologist’s decision whether or not to ‘upgrade’ a borderline lesion to a
higher grade, which is reasonable in light of the ICUD noting that urologists often approach
management of a case based on such factors. In reviewing cases with ‘cusp’ patterns, it is
important to make the assessment on thin, well stained H&E sections, and judicious ordering
of recuts may be helpful in such cases. Finally, the sharing of difficult or borderline cases
with colleagues is strongly recommended, especially as there are no reliable
immunohistochemical or molecular markers that may be recommended, at present, as
validated adjuncts to help make this important determination. A number of experts have
raised concerns regarding increased tendency of practicing pathologists to grade noninvasive
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lesions as high-grade; future efforts such as the upcoming new edition of the WHO ‘Blue
Book’ will likely focus on tightening diagnostic criteria.
ICUD recommendation: approach and terminology for incipient lesions

encountered during surveillance
A recurring difficulty concerns what terminology to use in cases of incipient lesions or
‘formes frustes’ of papillary urothelial neoplasia that present in the form of generally small,
proliferative, and hyperplastic lesions as are encountered with some frequency in patients
under endoscopic surveillance for urothelial neoplasia.37 For instance, papillary urothelial
hyperplasia, described as lesions showing a urothelium with increased thickness or cell
density and an undulated or ‘tented’ border (importantly, lacking fibrovascular cores or
cytologic atypia) were described,38 confirmed as a clonal process39 and formally adopted as
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a diagnostic category in the 1998 WHO/ISUP Consensus.8 In the 2004 WHO ‘Blue Book,’
papillary urothelial hyperplasia was not specifically identified as a distinct category, but
mentioned as a morphologic variation in the spectrum of hyperplasia.10 The ICUD
Consultation endorsed this entity and term.2,3 However, it bears consideration that the
definition of papillary hyperplasia excludes lesions with cytologic atypia, raising the
question of how to diagnostically approach lesions with low- or high-grade cytologic atypia
or even abortive or rudimentary fibrovascular core formation, such as those sampled during
surveillance.
A number of reports have described similar changes in urothelial neoplasia induced by

intravesical therapies, termed as ‘truncated papillae of treated papillary carcinoma’40 or as
‘atypical papillary urothelial hyperplasia.’41 Such changes may be induced by the local
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abrasive effect of intravesical agents.40 Under increased clinical scrutiny and sampling of
patients following contemporary protocols, such lesions pose a challenge to the practicing
pathologist regarding diagnostic approach and terminology. Unfortunately, there is no
molecular or immunohistochemical biomarker that may be recommended at this time to help
sort out any given case definitively. Thus, based on the experience of the bladder pathology
workgroup members, the ICUD recommends a general approach to apply when such lesions
are encountered rather than a particular terminology.

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First, the consultation recommends the use of strict criteria for diagnosis of flat urothelial
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hyperplasia as opposed to focal or incipient papillary urothelial neoplasia, in particular,

requiring the complete lack of true fibrovascular cores to render a straightforward diagnosis
of flat hyperplasia. Thin fibrovascular cores are a hallmark of urothelial neoplasia,17 and
their presence, even in rudimentary form, in a biopsy under surveillance, is worrisome for
neoplastic persistence or recurrence. Second, reflective of the desire to employ standardized
criteria, the ICUD recommends use of the criteria and terminology of the WHO/ISUP
system to describe the degree of atypia of the proliferative or hyperplastic flat urothelium
such that cases be described in terms of dysplasia or CIS, based on the degree of the
cytologic atypia of the urothelium.
Perhaps most importantly, correlation with the clinical setting, particularly the cystoscopic
impression, is essential to determine whether such a forme fruste lesion was thought to be a
papillary lesion. For instance, in the appropriate clinical scenario, which might include a
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prior non-invasive low-grade papillary urothelial carcinoma diagnosis and a clinically

exophytic lesion identified, a patch of hyperplastic urothelium with distinct but mild
cytologic atypia and mild-to-moderate loss of polarity, with only focally to poorly formed
fibrovascular cores may be interpreted as a small low-grade papillary urothelial carcinoma.
However, in the absence of histologic documentation of well-formed exophytic growth and
in the absence of clinical documentation of a papillary lesion, descriptive terminology such
as ‘dysplasia with early papillary formations’ (Figure 3a and b) or ‘CIS with early papillary
formations’ to describe low- and high-grade cases (Figure 3c and d), is recommended. The
fact that these terms are descriptive diagnoses needs to be communicated with the treating
urologist, in as much as there are limited data supporting their validity as entities or their
prognostic significance.
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ICUD recommendation: update on approach to variants and new patterns

Overall recommendation
The remarkable morphologic plasticity of urothelial carcinoma has been studied in detail,
with numerous patterns of variant morphology and differentiation reported, as reviewed
recently,42,43 and as considered exhaustively by the ICUD proceedings.2 A comprehensive
review of the full range of variants of urothelial carcinoma is beyond the scope of this
review; instead, we provide a focused update regarding variants of urothelial carcinoma that
are not detailed in the 2004 WHO Blue Book,10 including the large nested variant, urothelial
carcinoma with small tubules, urothelial carcinoma with rhabdoid features, and urothelial
carcinoma with chordoid features. Additionally, we provide an update on one key variant,
micropapillary urothelial carcinoma, where new diagnostic, clinical, and molecular data are
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available and increasingly relevant to ongoing practice of urologic surgical pathology.
Importantly, the ICUD makes a general recommendation in favor of reporting variant

morphology for urothelial carcinoma, especially as recent studies suggest it may be
underreported in routine practice.44 Reporting of variants will not only inform clinicians but
also enable prospective study and allow correlation with any subsequent recurrence.45
Additionally, similar to the College of American Pathologists reporting approach, in cases

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where multiple variant morphologies coexist, the recommendation is made to report each
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variant and the estimated percentage of each variant present.
The Large Nested Variant of Urothelial Carcinoma

The large nested variant of urothelial carcinoma,46 along with the (small) nested variant of
urothelial carcinoma,47 is one of the variants that may present a ‘pseudo benign’
(deceptively bland) appearance. Though the potential of benign proliferations such as von
Brunn’s nests to simulate carcinoma is well known,48 awareness of the large nested variant
is important given that it may simulate a urothelial neoplasm with inverted growth despite
being invasive, often deeply, of the bladder wall. These carcinomas are composed of large
nests of cells that are cytologically bland (see Figure 4a – c). They show a broad, pushing
pattern of invasion, sometimes evocative of the pattern of verrucous carcinomas. In contrast
to the small nested variant, a surface component has been identified with some frequency,
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which also often appears low-grade. In the series reported by Cox et al,46 follow-up data
were obtained in 17/23 patients with large nested variant urothelial carcinoma, showing
persistent/progressive disease in 6/17, suggesting that the low-grade appearance is deceptive.
Larger, additional cohorts will be necessary to better understand this variant, its prevalence,
and its prognostic significance;49 however, a number of features have been identified to
assist in its discrimination from potential simulants. First, although these lesions appear low
grade compared with ‘garden variety’ invasive urothelial carcinoma, the degree of atypia is
more in keeping with a low-grade urothelial carcinoma and generally exceeds that of nests
of von Brunn, even in a reactive setting. In the case of small nested carcinoma, the degree of
atypia is usually greater at the deeper aspect of these lesions, somewhat the opposite of that
expected for benign proliferative lesions. Features to consider in support of a large nested
carcinoma include the haphazard and irregular distribution of the nests in the wall of the
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bladder (Figure 5a), which is unexpected for embryologic duct remnants (urachal, etc) or
even orifices of duplicated or tangentially sectioned ureteral collecting systems. The
infiltrative appearance of the nests in the wall, especially deep in the muscularis propria,
directly juxtaposed to large caliber bundles of muscularis propria (Figure 5b), is very useful,
because non-invasive inverted urothelial neoplasia should not invade the muscularis propria.
Finally, observation of foci of conventional invasion, apparent in approximately one third of
cases reported previously,46 can be helpful to confirm invasion (Figure 5c).
Urothelial Carcinoma with Small Tubules

Urothelial carcinoma with small tubules50–52 is a rare neoplasm characterized by infiltrative,
small tubules which may be admixed with solid small nests, often showing the low-grade
morphology described in nested cases (Figure 6a – c). The epithelium may be attenuated and
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does not show overt glandular or columnar differentiation, and a surface component may not
be present. Given the smaller size of these tubules, generally smaller than that observed in
microcystic urothelial carcinoma,53 this variant may be mistaken for nephrogenic adenoma,
adenocarcinoma of the prostate,54 or even cystitis cystica et glandularis, though generally
these carcinomas show a degree of infiltrative growth, often involving the muscularis
propria, and cytologic atypia, at least focally, exceeding that allowable in nephrogenic
adenoma or other benign lesions in the differential. Also in the differential diagnoses are

Amin et al. Page 11
primary adenocarcinomas of the bladder (which generally show more explicit glandular
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features, higher grade, variability in acinar size, mucin, and surface/precursor lesions) and
prostatic adenocarcinoma (which may be readily excluded by use of
immunohistochemistry). The importance of this variant remains its recognition and
distinction from benign or malignant processes, as sufficient cases have not yet been studied
to estimate its biologic potential or treatment implications.
Urothelial Carcinoma with Rhabdoid Features

Urothelial carcinoma with rhabdoid features55,56 is another infrequent variant at the
undifferentiated end of the spectrum of urothelial carcinoma. These tumors merit distinction
from malignant extrarenal rhabdoid tumors of soft tissue, which are pathogenetically
unrelated sarcomas generally of the pediatric population,57 with which they share
histomorphologic features. These tumors are rare and often present as a pattern observed in
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an otherwise poorly differentiated to undifferentiated urothelial carcinoma. Generally,

carcinomas with rhabdoid features show a friable, discohesive appearance composed of
sheets of cells with characteristic high-grade features, eccentrically located vesicular nuclei
with prominent nucleoli and hyaline cytoplasmic inclusions; identification of a conventional
urothelial component or contemporary urothelialassociated markers58–61 may be helpful
(Figure 7a – c). In the differential diagnosis, one must consider the rare malignant extrarenal
rhabdoid tumors of soft tissue that have been reported in the bladder;62 these tumors do not
express immunohistochemical markers associated with urothelial carcinoma58 and show
prevalent alteration or loss of expression of the gene SMARCB1 (INI1).63
Invasive Urothelial Carcinoma with Chordoid Features

Urothelial carcinoma with chordoid features64 were noted during a retrospective review of
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>160 urothelial carcinomas to identify cases with a morphology reminiscent of chordoma,

extraskeletal myxoid chondrosarcoma, myoepithelioma of soft tissue, or yolk sac tumor.
Though at least focal identifiable conventional urothelial carcinoma was seen in all cases, a
striking pattern of cellular cording was present within an abundant myxoid matrix64 (Figure
8a – c). This stromal change, which may be prominent in conventional urothelial carcinoma
and has been described as ‘urothelial carcinoma with prominent myxoid stroma,’65 suggests
that tumors reported as ‘with chordoid features,’ or ‘associated with prominent myxoid
stroma’ are within a similar spectrum of histopathology. Given the lesions in the differential
diagnosis, all these neoplasms show expression of urothelial-associated markers such as p63
and high molecular weight cytokeratin, which may be useful to confirm the diagnosis. In
contrast, markers associated with tumors in the differential, including calponin, glial
fibrillary acidic protein (myoepithelioma), glypican-3 (yolk sac), and brachyury (chordoma)
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are negative. Three quarters of the tumors characterized by Cox et al64 showed extension
into perivesical fat or adjacent organs and lymph node metastases. The majority of patients
had persistent disease or died of disease at follow-up.
Micropapillary Urothelial Carcinoma

Though covered in the 2004 WHO Blue Book, recent years have seen several developments
in our understanding of the micropapillary variant of urothelial carcinoma. Although other
variant morphologies have been reported to be associated with aggressive course, especially

Amin et al. Page 12
high-stage disease,42 micropapillary urothelial carcinoma remains the variant where the
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prognostic implications are more clearly defined and where therapeutic, and, recently,
molecular considerations are most salient. The ICUD noted that there is not a firm criterion
for the proportion of micropapillary histology required to designate a case as micropapillary;
series have studied cases ranging from focal to almost pure micropapillary histology.66,67
There are indications that the extent of micropapillary differentiation is prognostically
significant, with the proportion of micropapillary morphology identified on transurethral
resection shown to predict stage,68 disease-specific survival,66 or both.69 For this reason, the
general ICUD recommendation is to both report this variant morphology and estimate its
proportion (as above).
These carcinomas were originally described as reminiscent of papillary serous

adenocarcinomas of the ovary,70 a differential diagnostic consideration which, along with
micropapillary variant carcinomas of the breast and other sites, remains salient today. The
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morphology is described as slender, delicate filiform processes or small clusters of cells,

generally without true fibrovascular cores (hence the ‘micro’), which appear tightly
clustered in lacunar spaces arrayed in an infiltrative growth pattern70 (Figure 9a).
Particularly when this morphology is extensive, lymphovascular invasion is almost
invariably present, showing a similar pattern of clustered micropapillae present within
vascular spaces.71 Proceeding from data that variants of urothelial carcinoma, including
micropapillary, may be under44 or over-recognized in the practice of surgical pathology and
a desire to better characterize its diagnostic features, Sangoi et al72 performed an
interobserver reproducibility study of micropapillary urothelial carcinomas, sharing cases
among a number of experts of the field. Although a number of features were identified as
sensitive markers of micropapillary carcinoma, especially prominent retraction artifact,
which may be seen in conventional urothelial carcinomas that do not meet criteria for the
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micropapillary variant (Figure 9b), the features that were identified as most specific to
consensus micropapillary cases studied were the features of ‘multiple nests in the same
lacuna’ (Figure 9c), ‘intracytoplasmic vacuolization,’ and related ‘epithelial ring forms’
(Figure 9d).72 These features will be of use for prospective evaluation of clinical cases.
Lastly, the clinical significance of micropapillary urothelial carcinoma has evolved

substantially in the past few years. Consistent with observations of predominant high-stage
disease, including deep, extensive invasion and positive lymph nodes,66–70 the
recommendation for early cystectomy (rather than trial of intravesical therapy) has been
advocated by some, even when muscle invasion has not been documented.73 However, other
groups have retrospectively reviewed their experience with micropapillary cases and noted
locally advanced disease with nodal metastasis, even in cases without pre-cystectomy
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documentation of muscle invasion, suggesting consideration of neoadjuvant chemotherapy.74

In contrast, other groups have questioned the need for aggressive management (by whatever
means) particularly in cases showing a low percentage of micropapillary morphology, lack
of associated CIS, and lack of muscle invasion.68,75 There is far from a consensus regarding
the clinical implications of diagnosis of micropapillary urothelial carcinoma and its most
appropriate management algorithm. This variant should be approached with clear criteria
and documentation of the percentage of micropapillary component (as with other
morphologic variants), emphasis on careful communication with clinicians, and awareness

Amin et al. Page 13
that implications may be significant, depending on institutional practices. Most promising

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for this disease, going forward, are recent molecular observations, which suggest a high
prevalence of lesions involving ERBB2, the HER2 oncogene, which may be amplified76,77
or mutated,78 providing a therapeutically tractable target. Of note, ERBB2 abnormalities in
urothelial neoplasms are not limited to micropapillary carcinoma. In a recent integrative
analysis of 97 high-grade invasive urothelial carcinomas, none of the five tumors harboring
amplification exhibited any micropapillary histology.79
ICUD recommendation: urine cytology reporting

One final area where the ICUD consultation proceedings impact directly on practice in
pathology concerns urine cytology. We recommend the reader to review the consultation’s
proceedings and related summaries for coverage of its recommendations for the role of
cytology in screening and monitoring bladder cancer patients, as well as for commentary
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regarding the role for molecular assays in cytology.2,3 The ICUD recommends a specific
approach and terminology for reporting urine cytology results, which is summarized in
Table 2. This approach, which is modeled after the Papanicolaou Society of Cytopathology
Practice and Guidelines Task Force recommendations, provides a format that mimics the
Bethesda 2001 System for reporting cervical cytology.80 In particular, the recommendations
emphasize inclusion within the diagnostic section of a statement documenting the anatomic
site of origin of the urinary tract specimen (bladder, urethra, ureter, or renal pelvis), as well
as a statement documenting the technique whereby the sample was obtained (voided urine,
washings, brushings, etc). Finally, the recommendation is made to employ a comment
section, which could be used at the discretion of the cytopathologist, to list additional
findings or to clarify any findings listed in the diagnostic categories.
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The ICUD proceedings specifically addressed issues regarding several of the recommended
diagnostic terms. In particular, in the group of diagnoses related to epithelial cell
abnormalities, the relationship of the diagnostic categories atypical urothelial cells and low-
grade urothelial carcinoma was addressed. The consultation clarified that because of the lack
of specific criteria for identification of low-grade urothelial carcinoma, most such cases
would be included within the atypical urothelial cells group. Additionally, as regards the
atypical urothelial cells diagnostic category, the ICUD acknowledged that there remains a
lack of consensus as to what criteria are appropriate to define inclusion in this category.
Despite this lack of clarity, the consultation noted that recent reports suggest that this
category may be substratified into two classes, implying differential acuity of follow-up.
These two subclasses are atypical urothelial cells of undetermined significance, the
implication being to follow with repeat urine cytology, as compared with atypical urothelial
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cells, cannot rule out high-grade carcinoma or atypical urothelial cells, favor neoplasm,
which imply the need for endoscopic evaluation.81,82
Subsequent to the published ICUD proceedings, the International Academy of Cytology

(IAC) in its 2013 congress in Paris proposed new consensus guidelines for urologic cytology
samples, which includes reporting urinary cytopathology. These guidelines will be known as
‘The Paris System for Reporting Urinary Cytopathology’ and will be published in 2016.

Amin et al. Page 14
Conclusion
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The Second International Consultation on Bladder Cancer, conducted nearly 10 years since
the first consultation and the WHO Blue Book update in 200410 represents a body of work
and consensus, developed over a decade, the summary of which is provided here (Summary
Box 1), available online, and in other summaries. We recommend that surgical pathologists
in practice avail themselves not only to the review of the state of the art of bladder cancer
pathology provided in the document, but also to reviews and recommendations regarding
screening and surveillance protocols, molecular biomarkers, stage-specific clinical
guidelines, chemotherapy, and non-urothelial bladder cancers. The entire consultation text is
available as a downloadable document file at no cost, providing a comprehensive textbook of
the disease. Given the ICUD’s stressing evidence-based recommendations, areas where
evidence or consensus is lacking are noted and represent opportunities for future clinical and
translational investigation.
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Finally, it bears consideration that the updated WHO ‘Blue Book’ classification of the
pathology of tumors of urinary system and male genital organs, including as it did in 2004 a
classification of tumors of the bladder,10 is rapidly approaching. As deliberations occur and
result in a revised WHO monograph to be widely available within the next 2 years, the
ICUD recommendations can provide an interim update for use in practice and for
consideration for formal adoption.
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Amin et al. Page 19
Summary Box 1: Key ICUD updates and recommendations

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1. The grading system of choice for papillary and flat non-invasive

urothelial neoplasia is the WHO (2004)/ISUP System.
2. Generally, invasive urothelial carcinoma should be graded as high-

grade, irrespective of the depth of invasion. Recognizing that this issue
is not completely resolved, invasive tumors may be further graded as
required by institutional or clinical trial protocols.
3. The criteria used in the WHO/ISUP System can be extrapolated to
inverted neoplasia, which are classified as inverted papilloma; inverted
PUNLMP; inverted urothelial carcinoma, low-grade, non-invasive;
inverted urothelial carcinoma, high-grade, non-invasive; inverted
urothelial carcinoma, high-grade, invasive.
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4. Diagnostic terminology for incipient papillary lesions not accurately

classifiable per the current system seen in patients under surveillance
include dysplasia with early papillary formations and carcinoma in situ
with early papillary formations. Correlation with cystoscopic findings
is a prerequisite.
5. Approach for neoplasms with grade heterogeneity:
a. Assign by highest grade component, as per the WHO/

ISUP System.
b. In equivocal cases, consider key clinicopathologic data,

including focality/multifocality, grade of prior
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diagnoses, size of lesions, frequency of recurrence,

presence/absence of concurrent CIS, cytologic
impressions; these parameters may help in deciding
whether to ‘upgrade’ an equivocal lesion.
c. There is no established role for immuno-histochemical

or molecular assays in this setting.
6. Variants of urothelial carcinoma not reviewed in the WHO 2004

include:
a. Large nested variant.
b. Urothelial carcinoma with small tubules.

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c. Undifferentiated carcinoma with rhabdoid features.
d. Urothelial carcinoma with chordoid features.
7. Micropapillary urothelial carcinoma has received much attention for:
a. Refined criteria for increased diagnostic repro-

ducibility; key features include ‘multiple nests in the
same lacuna’ and ‘epithelial ring forms’

Amin et al. Page 20
b. Clinical implications: controversy over role for early

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cystectomy.
c. Distinctive molecular features: ERBB2 mutation and

amplification.
8. Recommendation of diagnostic terminology for urine cytology:
a. Document anatomic source/site of specimen in

diagnosis.
b. Document technique used for sampling.
c. Recommended diagnostic terminology—See Table 2.

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Amin et al. Page 21
Summary Box 2: Major contributions of the WHO (2004)/ISUP System

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1. Establishment of uniform terminology, definitions, and criteria for

papillary neoplasia, removing ambiguity of the WHO 1973 system (eg,
transitional cell carcinoma grade I-II, transitional cell carcinoma grade
II-III)
2. Simplification of flat urothelial lesions with non-reactive atypia into

dysplasia and CIS
3. Application of similar overall criteria, by analogy, between papillary

and flat lesions, underpinning of the ICUD recommendation for use in
inverted lesions
4. Creation of a category of tumor that identifies a tumor with a negligible

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risk of progression (PUNLMP), whereby patients avoid the label of

carcinoma but are not given ‘benign’ diagnosis obviating follow-up
5. Identification of a clinically high risk group who are candidates for

intravesical management (high-grade papillary urothelial carcinoma,
urothelial CIS)
6. Identification of a larger group of patients, relative to WHO 1973 grade

III, who are at increased risk for invasive disease and merit closer
follow up
7. Overall stratification of bladder tumors into prognostically significant

categories
8. The classification system has been widely accepted by the ICUD,

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UICC, AJCC, AFIP Fascicles, and American (CAP, ADASP) and

European protocols.
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Amin et al. Page 22
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Figure 1.
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Inverted papilloma and inverted papillary urothelial neoplasm of low malignant potential
(PUNLMP). (a) An inverted urothelial papilloma shows endophytic growth of non-
hyperplastic, non-atypical urothelium. (b) Often a suggestion of peripheral palisading is
apparent, while the epithelium may frequently take on a bland, spindled appearance. (c) An
inverted PUNLMP, similar to exophytic PUNLMP is composed of a hyperplastic (increased
cells per unit area and/or increased thickness) urothelium growing in an endophytic pattern.

Amin et al. Page 23
(d) By definition, PUNLMP demonstrates no more than mild atypia and rare mitoses within
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a urothelium with preserved polarity.

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Amin et al. Page 24
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Figure 2.
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Inverted papillary urothelial carcinoma, low-grade and high-grade. (a) Papillary urothelial
carcinoma, low-grade, with predominant inverted growth shows a degree of cellularity and
loss of polarity beyond that allowable in a PUNLMP. (b) Distinct, mild to moderate
cytologic atypia is apparent. (c) Papillary urothelial carcinoma, high-grade, with
predominant inverted growth shows even greater loss of order in the epithelium. This
example showed foci of lamina propria invasion (asterisked), more extensive in adjacent
fields, illustrated here to mainly contrast with the predominantly non-invasive component.

Amin et al. Page 25
(d) Loss of polarization with respect to the basement membrane is increased, while greater
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nuclear atypia is apparent; an atypical mitosis is identified.

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Amin et al. Page 26
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Figure 3.
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Update on ‘formes frustes’ of papillary neoplasia. (a and b) Two examples of lesions that, if
encountered in a biopsy of a patient under surveillance for papillary urothelial neoplasia,
without a clinical impression of a papillary lesion may be termed ‘urothelial dysplasia with
early papillary formations.’ Correlation with cystoscopic impression is key, as a lesion such
as (b) may be diagnosed outright as papillary carcinoma, low-grade if clinically documented
as a tumor. (c and d) Two examples of lesions that, if encountered in a similar scenario
would be termed ‘urothelial carcinoma in situ with early papillary formations’; the lesion in

Amin et al. Page 27
(d) is better developed such that it may be considered sufficient to diagnose papillary
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urothelial carcinoma, high-grade, particularly if there is any endoscopic suspicion for a

lesion. The ICUD notes that clinicopathologic correlation is essential to use these diagnostic
terms.
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Amin et al. Page 28
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Figure 4.
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(a) The large nested variant of urothelial carcinoma may be high stage, as illustrated by deep
muscularis propria invasion. (b) Despite the aggressive growth pattern, a well-polarized
epithelium is preserved. (c) Atypia is less than expected for invasive carcinoma and raises
consideration of low-grade inverted neoplasia.

Amin et al. Page 29
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Figure 5.
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Difficulties in diagnostic approach to large nested lesions. (a) This example of a muscularis
propria invasive large nested urothelial carcinoma illustrates the diagnostic challenges, given
cautery and crush artifacts and the low-grade appearance. If the lesions were not
multifocally involving the muscularis propria, benign mimics such as urachal remnants or
orifices of duplicated or tangentially sectioned ureters could be considered. (b) In another
large nested case, the haphazard pattern of the nests is helpful in exclusion of benign
anatomic or vestigial structures, as is their direct juxtaposition to large compact muscle

Amin et al. Page 30
bundles of muscularis propria (asterisked). Noninvasive inverted neoplasms should not

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generally extend into the muscularis propria. (c) Observation of a focus of conventional-type
invasion (bracketed), consisting of irregularly sized and shaped invasive cell clusters, can be
very helpful to exclude a non-invasive inverted neoplasm.
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Amin et al. Page 31
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Figure 6.
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(a) Urothelial carcinoma with small tubules presents an infiltrative pattern of variably sized
small tubules. (b) The epithelium lining the tubules is frequently attenuated, prompting
consideration of nephrogenic adenoma or other processes. (c) These lesions may be deeply
invasive of muscularis propria despite the low-grade appearance.

Amin et al. Page 32
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Figure 7.
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(a) Urothelial carcinoma with rhabdoid features is a pattern on the spectrum of poorly
differentiated to undifferentiated urothelial carcinoma showing ‘rhabdoid’ morphology of
discohe-sive cells with eccentric nuclei with prominent nucleoli and inclusion-like
eosinophilic cytoplasmic inclusions. (b) Identification of a recognizable conventional
urothelial carcinoma is helpful. (c) Expression of the urothelial carcinoma-associated
marker, S100P, was diffuse, as were uroplakin II and GATA3 in this case.

Amin et al. Page 33
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Figure 8.
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(a) Urothelial carcinoma with chordoid features shows cords to reticular growth of epithelial
cells in a myxoid stroma evocative of extraskeletal myxoid chondrosarcoma. (b) Another
case shows clustered cells in abundant myxoid stroma. (c) These cases often present with
high stage.

Amin et al. Page 34
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Figure 9.
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Update on features of micropapillary urothelial carcinoma. (a) Micropapillary urothelial

carcinoma with invasion of the muscularis propria. (b) Prominent retraction artifact,
apparent in this conventional urothelial carcinoma, may simulate micropapillary carcinoma.
(c) Two specific features of micropapillary urothelial carcinoma illustrated here are ‘multiple
nests in the same lacuna’ and ‘inverse polarization’ of the epithelium with peripherally

Amin et al. Page 35
oriented nuclei. (d) ‘Epithelial ring forms,’ asterisked at center, are another highly specific
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feature helpful in diagnosis.

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Amin et al. Page 36
Table 1
Analogy for application of WHO/ISUP system to inverted neoplasia

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Degree of atypia Exophytic papillary lesions Flat lesions Endophytic/inverted papillary lesionsa
None Papilloma Normal Inverted papilloma
Minimal PUNLMPb Urothelial hyperplasia Inverted PUNLMPb
Distinct, mild-moderate Papillary urothelial carcinoma, Urothelial dysplasia Inverted papillary urothelial carcinoma,
low-grade, non-invasive low-grade, non-invasive
Moderate-severe Papillary urothelial carcinoma, Urothelial CIS Inverted papillary urothelial carcinoma,
high-grade, non-invasive high-grade, non-invasive
Severe Papillary urothelial carcinoma, Urothelial carcinoma, Inverted papillary urothelial carcinoma,
high-grade, invasive high-grade, invasive high-grade, invasive
a
Inverted lesions may show areas with both exophytic and endophytic growth, but should be at least predominantly inverted to be designated as
such.
b
Papillary urothelial neoplasm of low malignant potential.
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Amin et al. Page 37
Table 2
ICUD recommended format and nomenclature for urine cytology

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I. Adequacy statement (optional)

Satisfactory for evaluation
List any quality factors affecting specimen
Unsatisfactory for evaluation (give reason)
II. General categorization
Negative for epithelial cell abnormality (see Descriptive diagnoses)
Epithelial cell abnormality present (see Descriptive diagnosis)
III. Descriptive diagnosis
Negative for epithelial cell abnormality
Infectious agents
Bacterial organisms
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Fungal organisms
Viral changes (CMV, herpes, adenovirus, polyomavirus)
Nonspecific inflammatory changes
Acute inflammation
Chronic inflammation
Changes consistent with xanthogranulomatous pyelonephritis
Cellular changes associated with:
Chemotherapeutic agents
Radiation
Epithelial Cell Abnormalities
Atypical urothelial cells (*see comment)
Low-grade urothelial carcinoma
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High-grade urothelial carcinoma (invasive carcinoma vs carcinoma in situ)

Squamous cell carcinoma
Adenocarcinoma
Other malignant neoplasms (specify type)
IV. Other—Any molecular findings
V. Comment—Use at cytopathologist discretion to report or clarify other findings
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Published in final edited form as:

Update for the practicing pathologist: The International

Lukas Bubendorf11, Liang Cheng4, John C Cheville12, Glen Kristiansen13, Richard J

The International Consultation on Urological Diseases (ICUD) is a World Health

world health through sponsorship and organization of interdisciplinary international

Mod Pathol. Author manuscript; available in PMC 2016 September 02.

bladder cancer pathology and the pathologist’s diagnostic approach.

A historical perspective of classification and grading

Mod Pathol. Author manuscript; available in PMC 2016 September 02.

of that year8 in hopes of providing a ‘universally acceptable classification system’ for

Overall ICUD recommendation: grading by WHO/ISUP system

Mod Pathol. Author manuscript; available in PMC 2016 September 02.

progression. Essentially similar features, seen in flat, nonpapillary mucosa, would be

ICUD Recommendation—Update for Grading Invasive Carcinoma

Mod Pathol. Author manuscript; available in PMC 2016 September 02.

ICUD Recommendation—Update for Grading Inverted Neoplasms

Mod Pathol. Author manuscript; available in PMC 2016 September 02.

with inverted growth, being reported under a number of terminologies.25,26,28–30 Thus, a

identified significant differences between the prognosis of non-invasive papillary carcinomas

Mod Pathol. Author manuscript; available in PMC 2016 September 02.

high-grade), a number of additional factors, including historical data (grade of prior

urothelial neoplasia, frequency of recurrence), as well as salient clinical (size, focality/

ICUD recommendation: approach and terminology for incipient lesions

A number of reports have described similar changes in urothelial neoplasia induced by

Mod Pathol. Author manuscript; available in PMC 2016 September 02.

hyperplasia as opposed to focal or incipient papillary urothelial neoplasia, in particular,

prior non-invasive low-grade papillary urothelial carcinoma diagnosis and a clinically

ICUD recommendation: update on approach to variants and new patterns

available and increasingly relevant to ongoing practice of urologic surgical pathology.

Importantly, the ICUD makes a general recommendation in favor of reporting variant

Mod Pathol. Author manuscript; available in PMC 2016 September 02.

variant and the estimated percentage of each variant present.

The Large Nested Variant of Urothelial Carcinoma

Urothelial Carcinoma with Small Tubules

Mod Pathol. Author manuscript; available in PMC 2016 September 02.

Urothelial Carcinoma with Rhabdoid Features

an otherwise poorly differentiated to undifferentiated urothelial carcinoma. Generally,

Invasive Urothelial Carcinoma with Chordoid Features

>160 urothelial carcinomas to identify cases with a morphology reminiscent of chordoma,

Micropapillary Urothelial Carcinoma

Mod Pathol. Author manuscript; available in PMC 2016 September 02.

These carcinomas were originally described as reminiscent of papillary serous

morphology is described as slender, delicate filiform processes or small clusters of cells,

Lastly, the clinical significance of micropapillary urothelial carcinoma has evolved

documentation of muscle invasion, suggesting consideration of neoadjuvant chemotherapy.74

Mod Pathol. Author manuscript; available in PMC 2016 September 02.

that implications may be significant, depending on institutional practices. Most promising

ICUD recommendation: urine cytology reporting

Subsequent to the published ICUD proceedings, the International Academy of Cytology

Mod Pathol. Author manuscript; available in PMC 2016 September 02.

2. Soloway, M.; Khoury, S. Bladder Cancer. 2nd. Paris: 2012. EDITIONS 21

Mod Pathol. Author manuscript; available in PMC 2016 September 02.

332. [PubMed: 23088996]

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BJU Int. 2011; 107:532–537. [PubMed: 21091975]

Hum Pathol. 2002; 33:512–517. [PubMed: 12094376]

Mod Pathol. Author manuscript; available in PMC 2016 September 02.

neoplasia. Adv Anat Pathol. 1997; 4:244–251.

cases. Hum Pathol. 2006; 37:168–172. [PubMed: 16426916]