squamous lesions of the bladder

MINI-SYMPOSIUM: PATHOLOGY OF BLADDER TUMOURS

Squamous lesions of thebladderLing Wang

Ahmed Shabaik

Donna E Hansel

AbstractSquamous lesions of the bladder encompass a broad range of benign and

malignant lesions. Many of the squamous lesions restricted to the urothe-

lial surface are generally indolent, such as squamous metaplasia, squa-

mous papilloma and condyloma acuminatum. However, some superficial

lesions such as verrucous squamous hyperplasia and squamous cell car-

cinoma in situ may precede the development of invasive squamous cell

carcinoma. Squamous lesions present within the wall of the bladder are

often malignant and include classic squamous cell carcinoma and the ver-

rucous squamous cell carcinoma and basaloid squamous cell carcinoma

variants. One exception, however, is pseudoepitheliomatous (pseudocar-

cinomatous) hyperplasia, which is a benign mimicker of invasive squa-

mous cell carcinoma. Our review summarizes the available data on

clinical presentation, histopathologic features, differential diagnosis and

ancillary tests of the squamous lesions of the bladder.

Keywords bladder; pathology; review; squamous; urothelium

Introduction

The bladder is lined by urothelium that can undergo a variety of

metaplastic and neoplastic processes including transition into

squamous lesions that range from benign to malignant in nature.

The first part of this reviewwill focus on lesions that are confined to

the surface of the bladder and may be either flat or exophytic in

nature. The second part of this review will focus on squamous le-

sions that penetrate below the surface lining and range from benign

mimickers of malignant squamous processes to true invasive squa-

mous cell carcinoma (SCC). The differential diagnosis and ancillary

tests recommended for diagnosis will be discussed as are relevant.

Superficial squamous lesions

Nonkeratinizing and keratinizing squamous metaplasia

Squamous metaplasia of the bladder can occur in non-

keratinizing and keratinizing forms. Nonkeratinizing squamous

Ling Wang MD PhD Department of Pathology, University of California at

San Diego, La Jolla, CA, USA. Conflicts of interest: none declared.

Ahmed Shabaik MD Department of Pathology, University of California at

San Diego, La Jolla, CA, USA. Conflicts of interest: none declared.

Donna E Hansel MD PhD Department of Pathology, University of Cali-

fornia at San Diego, La Jolla, CA, USA. Conflicts of interest: none

declared.

DIAGNOSTIC HISTOPATHOLOGY 19:10 376

metaplasia occurs normally in the trigone and bladder neck re-

gion of 50e70% of women and may be influenced by hormonal

status.1 In addition, nonkeratinizing squamous metaplasia is also

seen following injury to the bladder and is within the spectrum of

reparative changes in this organ. Generally, nonkeratinizing

squamous metaplasia is considered a benign finding at this

location.

In contrast, keratinizing squamous metaplasia can occur

secondary to injury, chronic inflammation or other insult to the

bladder and may be associated with subsequent or consequent

invasive SCC2 (Figure 1). Keratinizing squamous metaplasia

more commonly affects men and is often identified on workup

for non-specific urinary tract symptoms or in association with

chronic injury, such as long-term catheterization or recurrent

urinary calculi.3 On cystoscopy, the surface keratinization makes

the lesion appear as white and flaky (leukoplakia). No specific

site within the bladder appears to be preferentially affected.

Although many cases of keratinizing squamous metaplasia

follow a benign course, a subset has been associated with inva-

sive urothelial and/or squamous cell carcinoma.2,3 In biopsies or

transurethral resection (TUR) specimens in which keratinizing

squamous metaplasia is identified, it is important to carefully

evaluate the epithelium for atypia to rule out squamous dysplasia

or carcinoma in situ and to assess the base of the lesion for in-

vasion in such instances. A recommendation for repeat biopsy or

TUR may be important in cases of extensive keratinizing squa-

mous metaplasia or in superficial specimens that prevent reliable

assessment of the base of the lesion.

Squamous dysplasia and squamous cell carcinoma in situ

Once the urothelium has undergone squamous metaplasia, pro-

gressive changes that lead to squamous dysplasia or squamous

cell carcinoma in situ can occur. Similar to other in situ lesions,

symptoms may be absent or non-specific. On cystoscopy ap-

pearances may vary from white plaque-like lesions associated

with keratin formation to reddened patches that can mimic

urothelial carcinoma in situ.4 Microscopically, the squamous

epithelium often shows parakeratosis and hyperkeratosis, with

varying degrees of nuclear atypia (Figure 2). Occasionally,

squamous cell carcinoma in situ can appear similar to urothelial

carcinoma in situ with only small areas of squamous differenti-

ation or dyskeratotic cells identified. Approximately one-third of

all invasive SCC are associated with squamous cell carcinoma in

situ.2 Of patients diagnosed with squamous cell carcinoma in situ

on biopsy, a significant proportion appear to progress to invasive

disease over several months.4 These findings suggest that careful

evaluation of flat squamous lesions of the bladder for dysplastic

changes should be undertaken, especially in cases of keratinizing

squamous metaplasia or squamous metaplasia in the absence of

known inciting factors in male patients.2

Squamous papilloma

Squamous papilloma of the bladder is a rare entity, reported as

small series in the literature, which rarely recur and generally do

not progress.5 In support of the indolent nature of these lesions,

squamous papillomas have been shown to be diploid and lack

nuclear p53 accumulation,5 which is common in high grade

urothelial carcinomas. At cystoscopy, these lesions may appear

exophytic depending on the size of the lesion. Microscopically,

� 2013 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.mpdhp.2013.08.007

Figure 1 Keratinizing squamous metaplasia shows parakeratosis and

hyperkeratosis.

Figure 2 Squamous cell carcinoma in situ showing dyskeratosis and nu-

clear atypia.


squamous papillomas show mature squamous epithelium lining

a central fibrovascular core. In contrast to condylomas, squa-

mous papillomas lack koilocytic change and have been negative

for human papillomavirus (HPV) in published cases.4,5 In chal-

lenging cases, assessment of HPV subtypes in these lesions is

recommended.

Condyloma acuminatum

Figure 3 Verrucous squamous hyperplasia is characterized by repetitive

upward tenting of the surface and dramatic hyperkeratosis.

Condyloma acuminatum of the bladder occurs in association

with HPV infection of the anogenital region and often results via

direct colonization of the urothelium at the urethral orifice with

secondary spread to the bladder surface. Bladder condylomata

are more frequent in women than men (2:1 ratio) and are more

commonly seen in patients under 50 years of age. An altered

immune response may be associated with the development of

condylomata at this location, as up to a third of patients in one

series occurred in association with immunosuppression4 and

association with human immunodeficiency virus (HIV) has been

also reported.6 Typically, condylomata affecting the bladder have

been reported primarily in the context of low-risk variants of

HPV.7


On cystoscopy, condylomata may be solitary or multiple

exophytic lesions, with occasional diffuse involvement of the

bladder mucosa. Microscopically, these lesions are distinguished

by the presence of koilocytes, although ancillary testing for HPV

may be of value in cases that lack overt features. In a small

number of cases, bladder condylomata have been associated

with concurrent or subsequent SCC.2,4 In the majority of patients,

however, recurrence is a common outcome with many patients

proving refractory to conservative therapy.

Verrucous squamous hyperplasia

Verrucous squamous hyperplasia (VSH) is a recently described

entity that has been associated with the development of SCC of

the bladder.2,4 On cystoscopy, these lesions have a thickened,

white, plaque-like appearance which, if large, may appear exo-

phytic. Microscopically, these lesions have a striking appearance

that consists of repetitive spike-like projections of the bladder

surface accompanied by squamous metaplasia and marked hy-

perkeratosis and parakeratosis (Figure 3). Although studies on

VSH are limited in the literature, it appears that these lesions may

be associated with invasive SCC in many instances.2,4 Careful

assessment of these lesions for dysplastic alterations and/or in-

vasion at the base of the lesion is necessary to exclude malig-

nancy. In instances in which the lesion is only superficially

sampled, a recommendation for repeat sampling and careful

followup of the patient is recommended, with a comment that a

subset of these lesions may demonstrate subsequent develop-

ment of carcinoma.

Squamous lesions involving the superficial or deep bladder wall

Pseudoepitheliomatous (pseudocarcinomatous) hyperplasia

This benign mimicker of invasive SCC can be found in associa-

tion with radiation cystitis, as well as other forms of bladder

injury and can mimic superficially invasive SCC. Microscopi-

cally, this lesion shows irregular tongues of squamous epithe-

lium dipping into the lamina propria often associated with




marked inflammation and reactive atypia of the superficial uro-

thelium (Figure 4). Minimal to no mitotic activity is present.8

Classic squamous cell carcinoma

Figure 5 Classic squamous cell carcinoma showing keratin production.

SCC of the bladder encompasses two distinct epidemiological

groups. The first group of patients with SCC typically develops

the disease following infection with Schistosoma haematobium

and represents a disease process that is primarily present in parts

of the Middle East and northern Africa. In these patients, depo-

sition of parasite eggs within the wall of the bladder incites an

ongoing inflammatory response that may be associated with

increased cell proliferation, prolonged S phase and down-

regulation of the p27 protein.9 Although at one point SCC sec-

ondary to Schistosomal infection accounted for 59e81% of all

bladder cancer cases in Egypt,10 the incidence of this disease has

been declining due to effective parasite control. The second

group of patients with SCC includes those of non-Schistosomal

origin, which are primarily patients in the Western hemisphere

where SCC represents a mere 5% of all bladder cancer cases. Risk

factors for the development of non-Schistosomal SCC include

tobacco smoke, long-term indwelling catheterization, chronic

bladder neck obstruction, bladder calculi, and a nonfunctioning

bladder.11 It is likely that the contribution of chronic inflamma-

tion of the bladder mucosa is a common pathogenic factor in

both groups of patients with SCC.

On gross evaluation, SCC is often solitary, sessile and may

have a white, flaky surface. Ulceration may be present. Lesions

vary in size, but can achieve dimensions over 6 cm.2 The diag-

nosis of SCC rests on the finding that the invasive component

consists of a purely SCC component, which is generally graded as

well, moderately or poorly differentiated depending on the de-

gree of keratinization and nuclear atypia (Figure 5). Additional

histological findings associated with these carcinomas include

necrosis associated with large nest formation, desmoplasia and a

foreign-body giant cell reaction to keratin. Perineural invasion

and angiolymphatic invasion occur in about a quarter of cases.

Morphologic variations that have been described include pres-

ence of bizarre giant tumour cells, sarcomatoid differentiation,

Figure 4 Pseudoepitheliomatous (pseudocarcinomatous) hyperplasia is a

common mimicker of invasive squamous carcinoma but is distinguished

by lack of nuclear atypia and associated reactive changes in the bladder.


clear cell features and prominent cystic change.2 Surface changes

associated with SCC are numerous and can include keratinizing

squamous metaplasia, VSH, squamous dysplasia and carcinoma

in situ, urothelial carcinoma in situ and rarely condylomata,

which may be identified concurrently on specimens harbouring

SCC.2,3,12 Schistosomal-associated SCC shares most of the

morphologic features found in non-Schistosomal cases, with the

exception that calcified eggs and associated granulomatous

inflammation may be identified in the bladder wall.

Alterations in protein expression are numerous in SCC and

include increased expression of epidermal growth factor receptor

(EGFR),13 galectin-7 and high-molecular-weight keratins,14 cav-

eolin-1,15 parathyroid hormone related peptide (PTHrP)16 and

carbonic anhydrase (CA) family.17 Comparison between Schis-

tosomal and non-Schistosomal derived SCC has been more

limited, however, given the low number of non-Schistosomal

SCC patients available for study.

The major differential diagnosis for SCC is urothelial carci-

noma (UCC) with extensive squamous differentiation, which is a

relatively common form of divergent differentiation in UCC.

Although cystectomy specimens afford the ability to extensively

sample the invasive lesion to obtain a more clear-cut diagnosis,

biopsy and transurethral resection specimens may prove more

challenging. In such small specimens, the co-existence of

noninvasive squamous lesions such as keratinizing squamous

metaplasia with or without dysplasia or VSH, may be helpful in

suggesting that a lesion may represent a pure SCC. However, an

acceptable alternative may be to describe the lesion as primarily

squamous in nature, with the differential diagnosis of SCC versus

UCC with extensive squamous differentiation; often final

distinction may only occur at the time of cystectomy. Some

recent studies have used immunohistochemistry to aid in the

distinction of these two entities. Gulmann et al.18 evaluated a

panel of five antibodies with putative specificity for urothelial

epithelium (uroplakin III, GATA3 and S100P) and squamous

epithelium (CK14, Desmoglein-3) in 50 primary urothelial neo-

plasms. They found that pure SCC was often positive for CK14

(100%) and desmoglein-3 (75%) and negative for GATA3 and

uroplakin III. In contrast, UCC was often positive for S100P

(93%), GATA3 (93%) and uroplakin III (67%) and negative for



Figure 6 Verrucous squamous carcinoma is defined by “pushing” invasive

borders.


desmoglein-3. Application of this panel to UCC with squamous

differentiation could help in favouring subtype of bladder cancer

in a subset of cases. Gaisa et al.19 studied a different immuno-

histochemical panel and showed that pure SCC was positive for

CK 5/6 (76.6%) and CK 5/14 (95.8%), focally positive for CK7

(28.9%), and negative for CK20 and uroplakin III. In contrast,

pure UCC was more frequently positive for CK7 (83.6%), CK20

(50.9%) and uroplakin III (21.8%).

It has been controversial in the literature whether SCC has

worse or similar outcomes to UCC of the bladder when corrected

for pathologic stage. One large retrospective multicenter analysis

by Rogers et al. showed no significant difference in clinical

progression and mortality between SCC and UCC,20 with similar

findings identified by Abdollah et al. in a study of 12,311 patients

who underwent cystectomy.21 However, a recent study found

SCC histology to be an independent predictor of worsened out-

comes in patients with advanced stages of disease. SCC tumour

grade has also been shown to correlate with patient outcomes,

with one study showing five-year survival for grades 1, 2, and 3

SCC to be 62%, 52%, and 35%, respectively.22 Regional lymph

nodes were involved in 24% of patients at the time of cys-

tectomy.2 Review of a few literature of non-Schistosomal squa-

mous cell carcinoma of the bladder showed overall five-year

disease-free survival ranged from 43 to 57%.2

For both Schistosomal and non-Schistosomal SCC, radical

surgery remains the mainstay of treatment with improved sur-

vival. The five-year overall survival for Schistosomal-associated

SCC is approximately 50%, which is better than non-Schisto-

somal SCC and reflects recent improvements in early diagnosis

and peri-operative outcomes. As to neoadjuvant therapy, Kassouf

et al. reported the application of neoadjuvant chemotherapy and

chemoirradiation to downstage tumour in three out of eight pa-

tients.23 Few complete remissions were also observed in patients

with multimodal systemic treatment. However, unfortunately,

SCC is usually resistant to chemotherapy and radiotherapy. Due

to rarity of the tumour, it would be difficult to conduct a well-

controlled prospective study to draw a conclusion regarding the

effectiveness of the chemotherapy and radiotherapy. Of note,

because of lack of efficient neoadjuvant therapy, the death of

patients with SCC usually results from local pelvic recurrence or

rare distant metastatic disease even in the absence of positive

surgical margins at cystectomy.23

Verrucous squamous carcinoma

Verrucous squamous carcinoma is a unique, well-differentiated

subtype of SCC that is relatively uncommon and is often

associated with Schistosomal infection. Grossly, these lesions

appear exophytic, which is mirrored in the microscopic anal-

ysis that shows an exophytic, somewhat papillary appearance

to the lesion. The surface shows hyperplastic squamous

epithelium with parakeratosis, while the base shows a

rounded, “pushing” form of invasion (Figure 6). Cytologic

atypia and mitoses are generally absent. This form of SCC

appears to have a more favourable prognosis than that of

classic SCC. In instances in which a classic SCC component is

identified in association with verrucous SCC, the lesion should

be classified as a classic SCC given the worsened outcomes

associated with this component.


Basaloid squamous cell carcinoma

Basaloid SCC is another rare variant of SCC with only rare reports

of this entity involving the bladder, ureter and renal pelvis in the

literature. These lesions appear morphologically similar to those

described from other anatomic regions and consist of small,

bluish cells containing scant cytoplasm and frequent mitotic ac-

tivity. These findings can occasionally mimic small cell carci-

noma, although basaloid SCC will lack neuroendocrine markers

and demonstrate keratin in a subset of cases. In one instance,

association with SCC in situ was identified.24 Due to the rarity of

these lesions, additional larger series are needed to better define

outcomes in this disease process.

Conclusions

Squamous lesions of the bladder are uncommon and can be

diagnostically challenging. Although the diagnosis generally rests

on light microscopy findings, ancillary studies can be helpful in a

subset of cases. A

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Practice points

C Squamous lesions are relatively uncommon in the bladder;

care should be taken to assess for squamous atypia and the

base of the lesion should be surveyed for invasion

C Morphologic risk factors in the development of squamous cell

carcinoma include extensive keratinizing squamous meta-

plasia, verrucous squamous hyperplasia, squamous dysplasia

and squamous cell carcinoma in situ

C Invasive squamous cell carcinoma can demonstrate a range of

morphologic findings, such as clear cell features, bizarre giant

cells, and large nest formation

C Squamous cell carcinoma is staged in the same manner as

conventional urothelial carcinoma

C Pseudoepitheliomatous hyperplasia is a benign mimicker of

invasive squamous cell carcinoma


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