Urinary Bladder Pathology

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To my wife Catherine and our daughters Ava and Olivia
for their support and love!
Haijun Zhou, MD, PhD
To my loving wife Cathy and my wonderful son Brian.
Charles C. Guo, MD
To my wife Jungsil and my son’s family (Bobby, Kim, Avery,
and Christian) for their love and support!
Jae Y. Ro, MD, PhD
Preface

Bladder diseases are common in clinical practice. While many inflammatory

conditions and other abnormalities are usually managed clinically, tissue
diagnosis is often needed if neoplastic lesions or non-neoplastic tumoral con-
ditions are suspected. Bladder cancer is one of the top ten most common
cancers in the United States (fourth in men and twelfth in women). Accurate
diagnosis of bladder cancer plays a central role in daily pathology practice,
clinical management, and prognosis. The variety of tumor histologic types
and corresponding mimickers complicate bladder cancer pathologic diagno-
sis. Familiarity with common and uncommon bladder pathologic entities is
vital for successful diagnosis of bladder cancers and subsequent patient
management.
The focus of this book is bladder cancer pathology, including primary
bladder malignancies and other tumor varieties involving the bladder, with an
emphasis on diagnostic pitfalls and clinical relevance. This book also
describes normal bladder histology, benign abnormalities with cancer mim-
ickers, and cancer carcinogenesis – important subject matter for understand-
ing bladder cancers, correct diagnosis, and differential diagnoses. Advances
in immunohistochemistry and molecular pathology have enhanced the accu-
racy of cancer pathology diagnoses. In addition to covering the anatomic and
histologic features of bladder tumors, this book also reviews recent molecular
and immunohistochemical advances in these areas. Recently updated clinical
management information is also presented in this book.
Many experienced genitourinary pathologists, surgical pathologists,
molecular pathologists, and clinical oncologists have contributed to this
book, in addition to many fellows and residents.
We hope this book will be a useful resource for practicing pathologists,
pathology trainees, and other health professionals who treat patients with
bladder cancers.

Houston, TX, USA Haijun Zhou

Houston, TX, USA Charles C. Guo
Houston, TX, USA Jae Y. Ro

vii
Acknowledgment

This book is a result of teamwork with tremendous help and support from
numerous colleagues. We thank our trainees and colleagues for providing
insights in our practice of diagnostic genitourinary pathology and acknowl-
edge the clinical teams in taking care of bladder cancer patients with their
expertise and passion.
We would like to thank Adrienne Winston and Sasha Pejerrey for their
assistance with scientific and editorial working in the preparation of our
book.

ix
Contents

1 Introduction to Urinary Bladder Pathology����������������������������������   1

Haijun Zhou, Charles C. Guo, and Jae Y. Ro
2 Normal Anatomy and Histology of the Urinary Bladder with
Pathologic Correlates����������������������������������������������������������������������   7
Ziad M. El-Zaatari and Jae Y. Ro
3 Flat Urothelial Lesions�������������������������������������������������������������������� 21
Gang Wang
4 Papillary and Inverted Tumors������������������������������������������������������ 35
Haijun Zhou, Charles C. Guo, and Jae Y. Ro
5 Invasive Urothelial Carcinoma with Molecular Types ���������������� 45
Charles C. Guo, Jae Y. Ro, and Bogdan Czerniak
6 Morphological Variants of Invasive Urothelial Carcinoma���������� 63
Kyung En Park, Qihui “Jim” Zhai, and Fang-Ming Deng
7 Other Types of Carcinoma�������������������������������������������������������������� 83
Kosuke Miyai, Hussam Abu-Farsakh, and Jae Y. Ro
8 Mesenchymal Tumors���������������������������������������������������������������������� 97
Michael J. Hwang and Pheroze Tamboli
9 Neuroendocrine Tumors of the Urinary Bladder�������������������������� 113
Ahmed N. Shehabeldin and Jae Y. Ro
10 Bladder Lymphoma and Leukemia������������������������������������������������ 129
Jie Xu, Shaoying Li, and M. James You
11 Secondary Tumors in the Bladder�������������������������������������������������� 141
Miao Zhang
12 Urine Cytology �������������������������������������������������������������������������������� 147
Haijun Zhou
13 Diagnostic Values of Immunohistochemistry in
Bladder Cancer�������������������������������������������������������������������������������� 159
Qihui “Jim” Zhai and Fang-Ming Deng
14 Molecular Pathology������������������������������������������������������������������������ 175
Dilek Ertoy Baydar

xi
xii Contents

15 Surgical Treatment in Urinary Bladder Cancer �������������������������� 189

Dalsan You, Bumjin Lim, and Choung-Soo Kim
16 Medical Treatment with Targeted Therapy for Metastatic
Urothelial Bladder Carcinoma ������������������������������������������������������ 199
Omar Alhalabi and Jianjun Gao
17 Bladder Cancer: Specimen Handling and Reporting������������������ 211
Yong Mee Cho and Jae Y. Ro
18 AJCC Staging of Bladder Cancers������������������������������������������������ 229
Euno Choi, Sanghui Park, and Jae Y. Ro
19 Conclusion and Remarks���������������������������������������������������������������� 249
Haijun Zhou, Charles C. Guo, and Jae Y. Ro
Index���������������������������������������������������������������������������������������������������������� 253
Contributors

Hussam Abu-Farsakh, MD, FCAP Department of Pathology, First Medical

Lab, Amman, Jordan
Omar Alhalabi, MD Department of Genitourinary Medical Oncology,
University of Texas MD Anderson Cancer Center, Houston, TX, USA
Dilek Ertoy Baydar, MD Department of Pathology, Koc University
Hospital, Istanbul, Turkey
Yong Mee Cho, MD, PhD Department of Pathology, Asan Medical Center,
University of Ulsan College of Medicine, Seoul, South Korea
Euno Choi, MD Department of Pathology, Ewha Womans University/Mok-­
dong Hospital, Seoul, South Korea
Bogdan Czerniak, MD, PhD Department of Pathology, The University of
Texas MD Anderson Cancer Center, Houston, TX, USA
Fang-Ming Deng, MD, PhD Department of Pathology, New York University
Langone Health, New York, NY, USA
Ziad M. El-Zaatari, MD Department of Pathology and Genomic Medicine,
Houston Methodist Hospital, Houston, TX, USA
Jianjun Gao, MD, PhD Department of Genitourinary Medical Oncology,
The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Charles C. Guo, MD Department of Pathology, The University of Texas
MD Anderson Cancer Center, Houston, TX, USA
Michael J. Hwang, MD, PhD Department of Pathology and Laboratory
Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
Choung-Soo Kim, MD, PhD Department of Urology, Asan Medical Center,
Seoul, South Korea
Shaoying Li, MD Department of Hematopathology, The University of Texas
MD Anderson Cancer Center, Houston, TX, USA
Bumjin Lim, MD Department of Urology, Asan Medical Center, Seoul,
South Korea
Kosuke Miyai, MD, PhD National Defense Medical College, Department
of Basic Pathology, Saitama, Japan

xiii
xiv Contributors

Kyung En Park, MD Department of Pathology, New York Langone Medical

Health, New York, NY, USA
Sanghui Park, MD, PhD Department of Pathology, Ewha Womans
University/Mok-dong Hospital, Seoul, South Korea
Jae Y. Ro, MD, PhD Department of Pathology and Genomic Medicine,
Weill Medical College of Cornell University/Houston Methodist Hospital,
Houston, TX, USA
Ahmed N. Shehabeldin, MD Department of Pathology and Genomic
Medicine, Houston Methodist Hospital, Houston, TX, USA
Pheroze Tamboli, MBBS Department of Pathology, The University of
Texas MD Anderson Cancer Center, Houston, TX, USA
Gang Wang, MD, PhD Department of Pathology and Laboratory Medicine,
British Columbia Cancer Vancouver Centre, Vancouver, BC, Canada
Jie Xu, MD, PhD Department of Hematopathology, The University of Texas
MD Anderson Cancer Center, Houston, TX, USA
Dalsan You, MD, PhD Department of Urology, Asan Medical Center,
University of Ulsan College of Medicine, Seoul, South Korea
M. James You, MD, PhD Department of Hematopathology, The University
of Texas MD Anderson Cancer Center, Houston, TX, USA
Qihui “Jim” Zhai, MD Lab Medicine and Pathology, Mayo Clinic Florida,
Jacksonville, FL, USA
Miao Zhang, MD, PhD Department of Pathology, MD Anderson Cancer
Center, Houston, TX, USA
Haijun Zhou, MD, PhD Department of Pathology and Genomic Medicine,
Weill Medical College of Cornell University/Houston Methodist Hospital,
Houston, TX, USA
 Introduction to Urinary Bladder
Pathology 1
Haijun Zhou, Charles C. Guo, and Jae Y. Ro

The urinary bladder is a sac-like organ that func- low-grade neoplasms or high-grade malignan-
tions in urine storage and urination. From the cies. These pathologic features from different
innermost epithelium (urothelium) to the outer entities will be discussed in the following
muscle layer, many diseases and conditions can chapters.
originate from the bladder. Inflammatory condi-
tions, such as cystitis, are the most common, with
a clinical presentation of urinary urgency and fre- Bladder Cancer Epidemiology
quency. Congenital and acquired anomalies, such
as diverticulum, exstrophy, vesicoureteral reflux, Globally, bladder cancer is the tenth most common
and urachal cysts, are also common clinically. type of cancer, with approximately 550,000 new
Hematuria, obstruction, and radiologically cases diagnosed worldwide in 2018 [1]. The prev-
abnormal findings would prompt further evalua- alence of bladder cancer is considerably higher in
tion with cytology and cystoscopy with patho- the Western countries than in the developing world
logic examination to rule out potential malignant [2]. In the United States, the lifetime risk of receiv-
processes. Pathological evaluation is critical for ing a diagnosis of bladder cancer is 3.9% for males
further clinical management and is key to differ- and 1.2% for females, respectively [3]. An esti-
entiate benign or reactive processes from malig- mated of 81,400 new cases of bladder cancer will
nant conditions. Pathological findings can range be diagnosed and an estimated 17,980 people will
from inflammatory or metaplastic changes to die from bladder cancer in 2020: 13,050 males and
4930 females, respectively, in the United States
[4].
Multiple risk factors have been established
for bladder cancer. Cigarette smoking is the most
significant environmental risk factor for bladder
H. Zhou (*) · J. Y. Ro
Department of Pathology and Genomic Medicine, cancer, and it is estimated to cause up to half of
Weill Medical College of Cornell University/Houston all cases in the United States [4], and smokers
Methodist Hospital, Houston, TX, USA have two to five times greater risk of develop-
e-mail: [email protected];
ing bladder cancer than the general population
[email protected]
[5]. The risk of bladder cancer is also increased
C. C. Guo
among persons with hazardous industrial expo-
Department of Pathology, The University of Texas
MD Anderson Cancer Center, Houston, TX, USA sures to aniline dyes and aromatic amines [6],
e-mail: [email protected] as well as among persons who have consumed

© Springer Nature Switzerland AG 2021 1

H. Zhou et al. (eds.), Urinary Bladder Pathology, https://doi.org/10.1007/978-3-030-71509-0_1
2 H. Zhou et al.

a high level of arsenic in their drinking water distant metastases. This pathway is associated
[7]. Certain bladder congenital defects, parasitic with many tumor suppressors [16, 17], including
infection (schistosomiasis), or long-term urinary p53 [18, 19], retinoblastoma gene (RB) [18], and
tract irritation (such as catheters or stone) are also phosphatase and tensin homolog (PTEN) [19].
risk factors. This pathway is genetically unstable, and inacti-
vating mutations of TP53 are identified in about
60% of these tumors. Of note, approximately
Bladder Urothelial Carcinogenesis 10–15% of low-grade papillary tumors can prog-
ress to high-grade invasive carcinoma, which is
Bladder cancer is a heterogeneous group of neo- often preceded by the development of flat CIS
plasms. More than 90% bladder cancer cases are within papillary lesions or in the adjacent urothe-
urothelial (transitional cell) carcinoma, which lial mucosa of papillary tumors [20].
arise from the bladder urothelial epithelium. Early genetic events, such as loss of hetero-
Other primary tumors, such as adenocarcinoma, zygosity (LOH), predispose the urothelium to
squamous cell carcinoma, and small cell carci- develop neoplasms. LOH of chromosome 9q21
noma, and mesenchymal tumors are less locus of the cyclin-dependent kinase inhibitor 2A
common. gene (CDKN2A) that encodes the p16INK4A
Bladder urothelial neoplasms morphologically protein is one of the earliest molecular changes
originate from two distinct precursor lesions: seen in the development of both noninvasive pap-
low-grade noninvasive papillary tumors and flat illary carcinoma and flat urothelial CIS [21–23].
noninvasive urothelial carcinoma (carcinoma in A variety of chromosomal abnormalities have
situ (CIS)), respectively. been reported in association with urothelial car-
Low-grade papillary tumors arise from cinoma [24]. Aneuploidy of chromosomes 3,
a hyperplastic carcinogenesis pathway that 7, and 17 and the loss of the 9p21 locus have
accounts for about 80% of urothelial tumor cases been incorporated into a FISH test in urine
[8]. This pathway initiates from urothelial hyper- (UroVysion), which may be used alone or cou-
plasia and then progresses to low-grade papillary pled with cytology for bladder cancer screening
urothelial carcinoma (LGUC). In this pathway, and surveillance.
the most frequent genetic abnormalities are Multifocal occurrence is a common character-
mutations of fibroblast growth factor receptor 3 istic of urothelial malignancy, which is explained
(FGFR3) [9, 10], H-ras oncogene [11–13], and by two proposed theories: the monoclonal theory
phosphatidylinositol-4,5-bisphosphate 3-kinase and the field cancerization theory [20, 21, 25–27].
catalytic subunit alpha (PIK3CA) genes [9, 14]. Understanding monoclonal versus oligoclonal
These hyperplastic pathway papillary tumors are early tumor development is important for deter-
genetically stable with nonaggressive behavior mining treatment strategies and the detection of
and a characteristically high recurrence rate [15]. recurrent or residual disease when molecular
Flat noninvasive urothelial carcinoma/CIS diagnostic information is used.
originates from the dysplastic pathway, which is The dual-track molecular carcinogenesis the-
less common than the hyperplastic pathway and ory is supported by in vitro studies and animal
is responsible for approximately 20% of urothe- models; however, it is still unclear how molecu-
lial carcinoma cases. This pathway starts with lar alterations contribute to the development of
dysplasia and then leads to high-grade urothelial these two morphologically distinct bladder can-
carcinoma (HGUC), including high-grade papil- cer types [20]. This model may be oversimplified
lary carcinoma or flat urothelial CIS. HGUC can compared to the genomic complexity of urothe-
progress to muscle-invasive, high-stage tumors lial cancer. More detailed information can be
with regional lymph node involvement and/or found in Chap. 14.
1 Introduction to Urinary Bladder Pathology 3

 ladder Cancer Clinical Course

B for cancer progression [29, 30] and is common
and Management in urothelial cancer. Therefore, timely follow-
up care is extremely important for all bladder
The majority of bladder cancer patients experi- cancer patients. Subsequent bladder cancer can
ence either gross or microscopic hematuria. typically be identified during surveillance due
Other symptoms, including increased frequency to the multifocal features of bladder cancer
or urgency of urination or dysuria, can be seen carcinogenesis.
alone or in combination in a significant propor-
tion of patients.
Urine cytology and cystoscopy should be Pathology Prospective
initiated for the evaluation of bladder mucosal
lesions. Visible small lesions (such as papillary Pathologic evaluation plays a central role in the
tumors) and flat lesions suspected of CIS under screening, diagnosis, treatment, and surveillance
cystoscopy are sampled with cold-cup biopsy of bladder cancer. Urine cytology and cystoscopy-­
forceps. Tumor grading and invasiveness are based biopsy are critical in the initial evaluation
evaluated microscopically. The presence of mus- of the disease. Morphologic evaluation gives
cularis propria is important for tumor staging and vital firsthand information: normal with variation
management and should be included in biopsies versus disease, nonneoplastic versus neoplastic,
whenever possible [28]. benign changes versus malignancy, noninvasive
Surgical resection is the most common treat- versus invasive, flat versus papillary, urothelial
ment option for bladder cancer patients, as versus non-urothelial tumor, nonmuscle-invasive
approximately 75% of new urothelial carcinoma versus muscle-invasive, and primary malignancy
cases are nonmuscle-invasive. Suspicious lesions versus secondary metastasis. All pertinent mor-
should be resected transurethrally as com- phologic information will determine the next
pletely as possible at initial clinical evaluation. steps for the management of the patient. The
Pathology-confirmed early-stage nonmuscle-­ pathologic evaluation of resection cystectomy
invasive carcinoma (Ta/Tis/T1 lesions) may be specimens will help to determine the precise
treated by removing the tumor and then adminis- pathology stage and the efficacy of neoadjuvant
tering immunotherapy [bacillus Calmette-Guérin chemotherapy. Subsequent surveillance will rely
(BCG)] or chemotherapy drugs directly into the on scheduled cytology and biopsy.
bladder (intravesical therapy). More advanced The advances of pathology techniques
muscle-invasive tumors (T2 and above) may help to further classify urothelial carcinomas.
require cystectomy either with or without regional Immunohistochemical markers have been used
lymph node dissections and neoadjuvant or adju- to classify urothelial carcinoma into luminal
vant chemotherapy. Metastatic bladder cancer carcinomas (CK20+, GATA3+, CK5/6-) and
patients are typically treated with chemotherapy. basal-­like carcinomas (CK5/6+, CD44+, CK20-)
Outcomes in patients with muscle-­invasive uro- [31]. Luminal carcinomas share a similar gene
thelial carcinoma are improved with the use of expression profile with superficial papillary
neoadjuvant chemotherapy before cystectomy. tumors. Basal-like carcinomas express genes
Immunotherapy and targeted therapy drugs are more characteristic of urothelial basal cells and
new options for patients with an advanced stage have a significantly worse prognosis than lumi-
of urothelial carcinoma in conjunction with che- nal carcinomas but may be more responsive to
motherapy and/or radiation. neoadjuvant chemotherapy. Luminal type can be
The 5-year relative survival rate for bladder subdivided into a p53-like tumor type, which is
cancer is 77%, and for noninvasive urothelial resistance to chemotherapy [32].
carcinoma cases, the 5-year survival rate is 96% With the advance of immune checkpoint
[4]. Tumor recurrence is a significant risk factor inhibitor therapy in the treatment of bladder
4 H. Zhou et al.

cancer, the evaluation of the expression levels grading, and diagnosis. Urology. 2005;66(6 Suppl 1):
4–34.
of programmed cell death-1/programmed cell 8. Knowles MA, Hurst CD. Molecular biology of blad-
death-1 ligand (PD-1/PD-L1) in tissue blocks der cancer: new insights into pathogenesis and clini-
with immunohistochemical stains is now critical cal diversity. Nat Rev Cancer. 2015;15(1):25–41.
for qualifying patients for immunotherapy (using 9. Lopez-Knowles E, Hernandez S, Malats N, Kogevinas
M, Lloreta J, Carrato A, et al. PIK3CA mutations are
drugs such as atezolizumab, pembrolizumab, an early genetic alteration associated with FGFR3
nivolumab, durvalumab, and avelumab) [33, 34]. mutations in superficial papillary bladder tumors.
The suggested pathology cutoffs for evaluat- Cancer Res. 2006;66(15):7401–4.
ing available PD-L1 immunostaining are drug-­ 10. van Rhijn BW, Montironi R, Zwarthoff EC, Jobsis
AC, van der Kwast TH. Frequent FGFR3 mutations in
specific and will be discussed in Chap. 13. urothelial papilloma. J Pathol. 2002;198(2):245–51.
11. Boulalas I, Zaravinos A, Karyotis I, Delakas D,
Spandidos DA. Activation of RAS family genes in
Summary urothelial carcinoma. J Urol. 2009;181(5):2312–9.
12. Mo L, Zheng X, Huang HY, Shapiro E, Lepor H,
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incorporated into bladder cancer treatment; how- 13. Oxford G, Theodorescu D. The role of Ras superfam-
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pathology trainees alike. This chapter illustrates pathways. Nat Rev Cancer. 2005;5(9):713–25.
many aspects of bladder pathologic diagnostics 15. Amin MB, Smith SC, Reuter VE, Epstein JI, Grignon
DJ, Hansel DE, et al. Update for the practicing pathol-
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 Normal Anatomy and Histology
of the Urinary Bladder 2
with Pathologic Correlates

Ziad M. El-Zaatari and Jae Y. Ro

Urinary Bladder Anatomy left ureteral orifices laterally and the urethral
opening inferiorly. The mucosal surface of the
Basic Anatomic Structure trigone appears smooth and flat, unlike the
remainder of the bladder mucosa, which nor-
The urinary bladder is a hollow viscus pelvic mally displays mucosal folds. The bladder neck
organ shaped like an inverted pyramid. The uri- is the region opening into the urethra and merges
nary bladder’s function is the storage of urine and with the prostate tissue below in males. The blad-
participating in the expulsion of urine during der neck rests anteriorly and laterally on the
micturition. Anatomically, the urinary bladder is internal obturator and levator ani muscles, in
divided into three main portions: the dome, the addition to the pubic bone. Invasion of these
midportion, and the base. The dome is located structures with carcinoma may render the
superiorly and is lined by peritoneum on its outer patient’s tumor inoperable [1]. The midportion of
surface. The dome’s tip, known as the apex, is the bladder occupies the majority of the bladder
located anterior-superiorly. The median umbili- area and is located between the dome and the
cal ligament, a remnant of the fetal urachus, apex. The midportion consists of anterior and
attaches to the bladder apex. The urachus is a posterior and lateral (left and right) walls.
tract present during fetal life that connects the The bladder is situated among other pelvic
bladder and umbilicus. Failure of the urachus to organs, including the distal bowels (rectum) and
obliterate may lead to anomalies known as ura- organs from the male and female genital tracts. In
chal remnants (see section “Urachal Remnants”). males, the seminal vesicles and the ampullae of
The base of the bladder is located posteriorly and the vasa deferentia are located between the blad-
inferiorly. Within the base is an area known as the der and the rectum, and the prostate is located
trigone: a triangular area between the right and inferior to the bladder. In females, the uterine cer-
vix and the upper vagina are between the bladder
and the rectum. The anterior surface of the uter-
Z. M. El-Zaatari (*) ine corpus lies against the superior-posterior sur-
Department of Pathology and Genomic Medicine,
Houston Methodist Hospital, Houston, TX, USA face of the bladder. Knowledge of organs adjacent
e-mail: [email protected] to the bladder is important for staging bladder
J. Y. Ro tumors, which may extend to and invade sur-
Department of Pathology and Genomic Medicine, rounding structures. Any tumor which invades
Weill Medical College of Cornell University/Houston beyond the bladder wall and adjacent fat into
Methodist Hospital, Houston, TX, USA adjacent organs is designated as T4 stage.
e-mail: [email protected]

© Springer Nature Switzerland AG 2021 7

H. Zhou et al. (eds.), Urinary Bladder Pathology, https://doi.org/10.1007/978-3-030-71509-0_2
8 Z. M. El-Zaatari and J. Y. Ro

Involvement of the prostate by carcinoma origi- sure. The bladder is fixed by ligaments at the
nating from the bladder may occur via direct bladder neck, but the rest of the bladder is free to
extension through the bladder wall and/or peri- expand superiorly into the abdomen when filled
vesical adipose tissue or in a pagetoid fashion with urine. A fibromuscular sheath intermingles
along the continuous bladder and the prostatic with the detrusor muscle of the bladder and is
urethra mucosa. In the latter, the tumor is staged fused to the intramural portion of the ureter. This
separately according to the urethral/prostatic ure- arrangement leads to the closure of the ureter ori-
thral system and constitutes T2 disease [2]. fice when the bladder is distended, thus prevent-
ing the reflux of urine [1, 5].
Innervation of the bladder comes from a
 ascular Supply and Lymphatic
V plexus of both sympathetic and parasympathetic
Drainage nerves; however, only the parasympathetic nerves
play a role in micturition. Parasympathetic nerves
The major arterial supply of the urinary bladder stimulate the contraction of the detrusor muscle
comes from the inferior vesical arteries, which and involuntarily open the internal sphincter dur-
are branches of the internal iliac arteries. Other ing micturition. However, initiation of micturi-
arteries participate in the bladder blood supply tion is a voluntary process that occurs by
and include branches of the umbilical arteries, relaxation of the perineal muscles and the exter-
obturator arteries, inferior gluteal arteries, and nal sphincter. The sensation of pain when the
uterine and vaginal arteries in females. Veins bladder is overdistended is due to the presence of
draining the bladder collect into the internal iliac sensory nerves [1, 5].
veins and form the vesical venous plexus, which
communicates with the prostatic venous plexus
in males and the vaginal venous plexus in  ross Evaluation and Handling
G
females. Lymphatics of the bladder drain mainly of Bladder Specimens
into the external and internal iliac nodes. Portions
of the bladder also drain into the sacral or com- Recommendations for the gross evaluation and
mon iliac nodes [1]. N-stage in the current AJCC handling of bladder specimens were communi-
system denotes metastasis to regional lymph cated by the European Society of Uropathology
nodes, including the internal iliac (hypogastric), and the Uropathology Working Group in 2004
obturator, external iliac, presacral, and common [6] and in the most recent College of American
iliac lymph nodes. N3 stage denotes metastasis to Pathologists’ (CAP) Protocols [3, 7]. Types of
common iliac lymph nodes. Excluding the com- specimens that may be encountered include
mon iliac lymph nodes, N1–N2 stage denotes transurethral resection of the bladder (TURB),
metastasis to any of the regional lymph nodes, partial cystectomy, total cystectomy, cystoprosta-
with N1 representing a single metastasis and N2 tectomy, and pelvic exenterations, in addition to
denoting multiple metastases. Any metastasis to resections of diverticula and excision of urachal
non-regional lymph nodes comprises M1 disease carcinomas [3, 6, 7]. In all of these specimens, an
(distant metastasis) [2–4]. adequate number of sections should be submitted
so that the depth of tumor invasion and tumor
characteristics can be assessed. In TURB speci-
Functional Anatomy and Innervation mens, at least one section per centimeter of tumor
should be submitted, and the possibility of sub-
The urinary bladder receives urine from the kid- mitting the entire tumor can be considered. In
ney via the ureters and acts as a reservoir for cystectomy specimens, representative sections of
urine until it is expelled via the urethra. The uri- the tumor, including the full depth of the bladder
nary bladder can accommodate 400–500 mL of wall and especially the area of deepest macro-
urine without an increase in its intraluminal pres- scopic invasion should be submitted. Additionally,
2 Normal Anatomy and Histology of the Urinary Bladder with Pathologic Correlates 9

sections should include representative mucosa on the anterior wall of the bladder made in an
from various areas (e.g., lateral walls, dome, and inferior-superior direction to visualize the entire
trigone), including away from the grossly visible mucosa [8]. Also, the interureteric ridge, an ana-
carcinoma. The rationale for including these sec- tomic structure with the appearance of a slightly
tions is to assess for microscopic invasive or in raised curve resembling a lip with bulges at either
situ carcinoma and multifocality, which is com- end, can be used to locate the left and right ure-
mon in urothelial neoplasms. The ureteral and teric orifices on the mucosal surface. The orifices
urethral margins of cystectomies should also be will be within the left and right bulges at either
submitted, in addition to sections from the mid- end of the “lip” and can be probed [8]. Finally,
portions of a long segment of the ureter, if pres- sequential sections of the bladder in one direction
ent. In cystoprostatectomy specimens, sections of (our preference is in the superior to inferior direc-
the prostatic urethra with surrounding prostatic tion) should be taken to include the entire thick-
parenchyma should be submitted. This is, again, ness of the bladder wall and surrounding adipose
to assess for possible invasion and/or multifocal- tissue for proper gross assessment of the depth of
ity and to detect pagetoid mucosal extension of tumor invasion [8].
bladder cancer to the prostatic urethra or to the
prostatic ducts or acini. Incidental prostatic carci-
noma may also be found and is actually more Histology
common in cystoprostatectomy specimens for
urothelial carcinoma. In cases of more complex Urothelium
pelvic exenteration specimens, including the rec-
tum, vagina, and/or uterus, targeted sections The urothelium is the epithelial lining of the uri-
should be taken in areas where tumor appears to nary bladder, ureters, renal pelvis, and portions of
infiltrate into these organs [6, 7]. the urethra. It consists of three layers: superficial
Another note when handling urinary bladder “umbrella” cells, intermediate cells, and basal
specimens is to pay careful attention to the mar- cells (Fig. 2.1). The urothelium varies in ­thickness
gins. The margins should be totally submitted, or
at least representative sections of the margins
grossly closest to the tumor. Margins include
deep soft tissue margins and peritoneal surfaces,
soft tissue margins of partial cystectomies, ureter
and urethral margins, and other margins in pelvic
exenterations, such as vaginal cuff margins. In
urachal adenocarcinoma, excision of the urachal
tract and umbilicus is performed, necessitating
attention to the soft tissue margin surrounding the
urachus and to the margin of skin around the
umbilicus [6, 7].
We also recommend the following useful
practices when grossing cystectomy specimens.
The smooth peritoneal surface covering most of
the posterior bladder surface can serve as a land-
Fig. 2.1 Normal urothelium. Cells lining the urothelium
mark for proper orientation of cystectomy speci- are superficially umbrella cells, followed by a layer of
mens during gross evaluation [8]. After opening intermediate cells and a basal cell layer. Intermediate cells
the bladder, careful assessment of the entire blad- are oval-round with nuclear grooves and a vertical orienta-
tion. Umbrella cells have abundant cytoplasm, are hori-
der mucosa should be performed, and any ery- zontally oriented, and cover more than one of the
thematous or fibrotic areas should be well intermediate cells. Basal cells are situated on the base-
sampled. We suggest using a “Y-shaped” incision ment membrane immediately above the lamina propria