Anatomic Pathology / KERATINS IN INTERSTITIAL CYSTITIS
Keratin Expression Profiling of Transitional Epithelium
in the Painful Bladder Syndrome/Interstitial Cystitis
Pilar Laguna, MD, PhD,1 Frank Smedts, MD, PhD,2 Jörgen Nordling, MD, PhD,4
Thomas Horn, MD, PhD,3 Kirsten Bouchelouche, MD,4 Anton Hopman, PhD,5
and Jean de la Rosette, MD, PhD1
Key Words: Cytokeratins; Bladder; Intermediate filaments; Pelvic pain syndrome
DOI: 10.1309/W342BWMDMDDBCTVH
Abstract
Painful bladder syndrome/interstitial cystitis
(PBS/IC) is a severely debilitating condition. Its cause
is poorly understood; therapy is symptomatic and often
unsuccessful. To study urothelial involvement, we
characterized the keratin phenotype of bladder
urothelium in 18 patients with PBS/IC using a panel of
11 keratin antibodies recognizing simple keratins found
in columnar epithelia (keratins 7, 8, 18, and 20) and
keratins associated with basal cell compartments of
squamous epithelia (keratins 5, 13, 14, and 17). We also
tested 2 antibodies recognizing more than 1 keratin also
directed against basal cell compartments of squamous
epithelia (D5/16 B4 and 34β E12).
Bladder urothelium in PBS/IC showed distinct
differences in the profiles of keratins 7, 8, 14, 17, 18,
and 20 compared with literature reports for normal
bladder urothelium. These were characterized by a shift
from the normal bladder urothelial keratin phenotype to
a more squamous keratin profile, despite the lack of
morphologic evidence of squamous epithelial
differentiation and a loss of compartmentalization of
keratin expression. The severity of these changes varied
between biopsy specimens. Whether these changes are
primary or secondary to another underlying condition
remains to be determined.
Painful bladder syndrome/interstitial cystitis (PBS/IC) is a
poorly defined, infrequent bladder condition mostly diagnosed
in women. It is characterized clinically by bladder pain causing
frequent voiding of small volumes of urine. Pharmacologic
therapy often results in only partial alleviation of symptoms
and, in rare cases, cystectomy of a morphologically normal
bladder may be the final resort.1
The cause of IC is unclear; several explanatory hypotheses revolve around the fact that the bladder urothelium is in
some way “leaky.”2,3 It is hypothesized that this results in a
sterile inflammation in the bladder mucosa.3-5
Epithelial function or adaptation of epithelium to changing
conditions usually is accompanied by transitions in the cytoskeleton of epithelial cells.6 Cytokeratins, the most important components of the cytoskeleton, are filaments with a diameter between
6 and 10 nm; they span the cell between the cytoplasm and
nucleus, providing an internal scaffold that is functional in cell
integrity. There are 20 known soft keratins, each with a specific
molecular weight and biochemical properties. Different combinations of these keratins are present in different types of epithelia, usually up to 6.7 Urothelium is an exceptional type of epithelium containing a mix of simple keratins, ie, 8, 18, and 20, and a
number of complex keratins, ie, 4, 5, and 13.8,9 Keratin expression also is differentiation-related, eg, during squamous metaplasia, keratin 8 will disappear and keratin 14 will be expressed
more extensively as squamous epithelium matures.10
This is a descriptive study of the keratin components of
the urothelial cytoskeleton in women with PBS/IC. Our
objective was to establish whether the keratin phenotype of
urothelium in PBS/IC is in any way altered from what has
been reported for normal urothelium.6-9,11-16 We speculate that
a defect in the cytoskeleton of urothelial cells, manifesting
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Laguna et al / KERATINS IN INTERSTITIAL CYSTITIS
itself in altered keratin expression patterns, may be at the root
of or involved in this condition.
Materials and Methods
Cases
From the files of the Department of Pathology, Herlev
University Hospital, Copenhagen, Denmark, we selected formalin-fixed, paraffin-embedded bladder biopsy specimens
from 18 consecutive patients diagnosed with PBS/IC or
patients in whom PBS/IC was suspected. For comparison, we
used “normal” archival random bladder biopsy specimens
from 4 female patients with noninvasive low-grade urothelial
tumors, without an invasive component. Follow-up in these
patients was uneventful, and there were no symptoms suggestive of PBS/IC.
Selection criteria included bladder pain on filling that was
relieved by voiding, frequency, nocturia, urgency, and hematuria. Urodynamic studies included filling cystometry, residual bladder volume measurement with registration of
decreased bladder capacity, detrusor instability, or possible
incomplete bladder emptying. Cystoscopy with hydrodistention was performed to ascertain the presence of a Hunner ulcer
and/or glomerulations. After hydrodistention, a cold-cup biopsy specimen was obtained from the lateral bladder wall.
Bladder infection was excluded, as were preneoplastic, neoplastic, and benign conditions, ie, unstable bladder that may
mimic painful bladder syndrome. All patients were classified
according to the National Institute of Diabetic and Digestive
and Kidney Diseases (NIDDK) criteria for IC.16
For tissue processing and evaluation, we cut 4-µm-thick
sections and stained them with H&E. A Leder stain was performed for estimation of the number of mast cells in the bladder wall. AZAN staining was performed to evaluate fibrosis in
the bladder wall.
Inflammation, if present, was graded semiquantitatively
as follows: –, no inflammation; 1+, mild inflammation signifying dispersed inflammatory cells in the mucosa; 2+, moderate inflammation signifying a patchy infiltrate not filling a
high-power field (×40); or 3+, severe inflammation, consisting
of at least 1 ×40 high-power field of inflammatory cells.
Immunohistochemical Analysis
Sections were mounted on coated slides, deparaffinized,
and subjected to the appropriate antigen-retrieval step followed
by immunostaining with one of the monoclonal keratin antibodies ❚Table 1❚. Transitional epithelium was divided into 3
layers: the basal cell layer directly above the basal membrane,
an intermediate layer constituting most of the thickness of the
urothelium, and the highly characteristic superficial umbrella
cell layer. Immunoreactivity was reported for each cell layer.
The staining distribution pattern was recorded and compared
with findings reported in literature and the control cases.
Results
Patients
The average age of the 18 women with PBS/IC at the
time of biopsy was 56 years; the age of the control subjects
was 52 years. A schematic representation comparing the keratin profiles of the patients with PBS/IC with findings from
the literature is shown in ❚Figure 1❚. Ten cases fulfilled the
NIDDK criteria, and 8 did not. In 4, glomerulations were not
present on hydrodistention. Bladder capacity at cystometry
was more than 350 mL in 1 patient. Three patients did not fulfill more than 1 criterion: 1 had a bladder capacity of more
than 350 mL and no nocturia, 1 had a bladder capacity of more
than 350 mL and no glomerulations on hydrodistention, and 1
had no nocturia, no glomerulations on hydrodistention, and a
bladder capacity of more than 350 mL.
❚Table 1❚
Keratin Antibodies Used in the Study, Including the Specific Keratin Subtypes With Which They React and the Antigen-Retrieval
Step Used for Immunostaining
Clone
Keratin Detected
D5/16B4
34βE12
RCK103
OV-TL 12/30
CAM 5.2
1C7
LL002
E3
RCK106
RCK108
IT.Ks 20.8
106
106
5, 6
1, 5, 10, 14
5
7
8 (7)
13
14
17
18
19
20
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Antigen-Retrieval Step
Citrate, pH 7.3
Citrate, pH 6.0
Citrate, pH 7.3
Protease
Protease
Citrate, pH 6.0
Citrate, pH 6.0
Citrate, pH 6.0
Citrate, pH 6.0
Protease
Protease
Source
Boehringer Mannheim, Mannheim, Germany
DAKO, Glostrup, Denmark
Mubio, Maastricht, the Netherlands
BioGenex, San Ramon, CA
Becton Dickinson, Franklin Lakes, NJ
Neomarkers, Fremont, CA
BioGenex
Neomarkers
Mubio
Mubio
Neomarkers
© American Society for Clinical Pathology
Anatomic Pathology / ORIGINAL ARTICLE
Normal urothelium
RCK103 K13 K19
K7
K8
K18 K20 34βE12 K5/6 K14 K17
U
+
+
+
+/–
+
+
+
–
–
–
–
I
+
+
+
+/–
+
+
–
–
–
–
–
B
+
+
+
+/–
+
+
–
+
+
–
+
K7
K8
K18 K20 34βE12 K5/6 K14 K17
Urothelium in PBC/IC
RCK103 K13 K19
U
+
+
+
+
+/–
+/–
+/–
+/–
+/–
+/–
+/–
I
+
+
+
+
+/–
+/–
+/–
+/–
+/–
+/–
+/–
B
+
+
+
+
+/–
+/–
+/–
+/–
+/–
+/–
+/–
❚Figure 1❚ Schematic representation of the keratin profiles in normal and painful bladder syndrome/interstitial cystitis (PBS/IC)
urothelium. In patients with PBS/IC, the most frequent staining pattern is indicated. B, basal urothelial layer; I, intermediate cell
layer; U, umbrella cell layer; –, no staining; +/–, erratic staining with positive and negative areas with variable immunostaining
intensity; +, staining of all cells, usually quite intense.
Biopsy Specimens
All biopsy specimens had intact urothelium, and none
showed light microscopic evidence of urothelial cell damage,
such as denudation or degenerative cellular damage. In 12
biopsy specimens, some degree of inflammation was present;
8 of these cases fulfilled the NIDDK criteria.
Keratin Expression Patterns
Considerable differences in keratin expression were noted
for 8 of 11 keratin antibodies. These were striking when the
PBS/IC-urothelial keratin phenotype was compared with literature reports for normal urothelium. Differences were a little
less striking when PBS/IC keratin expression patterns were
compared with the keratin profiles of the control samples.
For 3 of 11 keratin antibodies, ie, RCK103 (keratin 5+), 1C7
(keratin 13), and RCK108 (keratin 19), keratin expression in the
patients was identical to that described in the literature and observed
in the control samples. These antibodies showed full-thickness
immunostaining of the urothelium ❚Image 1A❚ and ❚Image 1B❚.
Simple Keratins
Keratin 7.—The specific staining pattern reported in the
literature consisting of alternating areas showing full-thickness
staining and areas in which one or more layers of the urothelium did not stain8 was noted in 4 cases of PBS/IC ❚Image 1C❚.
In the other 13 cases, the full-thickness of the urothelium
stained ❚Image 1D❚; 1 case showed only sporadic staining of a
few cells ❚Image 1E❚. Two control samples showed the normal
pattern (Image 1C), and the other 2 showed full-thickness
staining.
Keratin 8.—This keratin, normally present through the
full thickness of the urothelium,8,9 showed lower levels of
expression in the PBS/IC group. Five cases showed moderate
full-thickness expression ❚Image 1F❚; in 8, the number of cells
staining in the respective layers varied from 50% to 100% and
the intensity was usually low. In 5 cases, entire cell layers
were negative, with only umbrella cells staining in 2 cases
❚Image 1G❚. Control samples showed intense, full-thickness
immunostaining.
Keratin 18.—The normal pattern of immunoreactivity
characterized by full-thickness intense immunostaining8,9 was
noted in only 4 cases ❚Image 1H❚; reactivity levels were low.
In the others, staining was variable in intensity and the number of cells staining, with some layers showing no immunoreactivity ❚Image 1I❚. In the control samples, full-thickness
staining was noted, but not all cells stained.
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A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Q
R
S
T
❚Image 1❚ Immunohistochemical staining of urothelium in a woman with painful bladder syndrome/interstitial cystitis. A and B,
Keratin 19 (A, ×400) and keratin 13 (B, ×400) found through the full urothelial thickness. C, D, and E, Keratin 7 antibody staining
showing the typical pattern with focal loss of immunoreactivity (C, ×400), the full-thickness staining noted in a considerable
number of patients (D, ×400), and only sporadic staining of a few cells (E, ×400). F and G, Keratin 8 antibody showing the fullthickness staining noted in most cases (F, ×400) and a case in which only the umbrella cells stained (G, ×400). H and I, Keratin
18 antibody showing weak staining through the full thickness of the urothelium (H, ×400) and sporadic staining limited to most
umbrella cells (I, ×400). J, K, and L, Keratin 20 staining. Typically, keratin 20 is restricted to umbrella cells (J, ×500); however, in
some cases there is focal full-thickness immunoreactivity (K, ×400). In 3 cases, the umbrella cells were not immunoreactive
(L, ×400). M and N, 34βE12. In some cases, staining was located only basally (M, ×400); in most, staining reached into higher
urothelial layers up to full thickness (N, ×400). O and P, The keratin 5/6 antibody showed moderate, mainly basally located
staining (O, ×400) compared with other cases in which weak immunoexpression reached up into the higher urothelial layers
(P, ×400). Q and R, Staining for keratin 14. A typical case showing limited immunoreactivity (Q, ×400); a small number of cases
did not stain for the antibody (R, ×400). S and T, Keratin 17 antibody. Expression was limited in the basal cell compartment of
most cases (S, ×400) with higher levels of immunoreactivity in others (T, ×400).
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© American Society for Clinical Pathology
Anatomic Pathology / ORIGINAL ARTICLE
Keratin 20.—This keratin constituent is reported to be
exclusively present in umbrella cells in the normal bladder.11
Fifteen cases usually showed this pattern characterized by
intense staining of the umbrella cells ❚Image 1J❚; however,
variable staining of underlying cells also was noted, which, in
1 case, reached through the full epithelial thickness ❚Image
1K❚. Three cases, each with umbrella cells, were entirely negative ❚Image 1L❚. The majority but not all umbrella cells in the
control cases stained.
Basal Cell/Squamous Cell Keratins
34βE12.—This basal cell keratin marker is reported to be
present in the basal cell compartment of urothelium only.17 In
only 2 cases of PBS/IC this pattern was noted ❚Image 1M❚,
also with some weak umbrella cell immunoreactivity. Thirteen
cases showed mild to moderate staining through the full
urothelial thickness, with most cells staining in the respective
layers ❚Image 1N❚. In 3 cases, basal and intermediate cell layers failed to display immunoreactivity. In 2 controls intense
expression was present through the full urothelial thickness,
and in the other 2 the number of cells staining and the
immunoreactivity decreased toward the urothelial surface.
Keratin 5/6.—Literature reports on the distribution of
keratin 5/6 in normal bladder are not comprehensive and only
report this keratin combination in the basal cell compartment
of urothelium.18 In 8 cases, weak basal staining was noted
❚Image 1O❚, and in the 10 other cases, weak staining was
found irregularly through the full urothelial thickness ❚Image
1P❚. In the control cases, most basal cells stained, however,
and overlying cells also usually stained in 3 cases; in 1 case,
the full epithelial thickness stained.
Keratin 14.—The antibody to this keratin is reported not to
stain normal urothelium.19 Of 18 PBS/IC cases, 11 showed
some positivity with this marker. Staining, however, was weak
with only small numbers of cells staining, usually in one or
more cell layers above the basal cell layer ❚Image 1Q❚. Seven
cases were not immunoreactive ❚Image 1R❚, and the control
cases were also negative.
Keratin 17.—Phenotyping studies explicitly report that this
keratin is present in the basal cell layer of urothelium.20 In 15 of
18 PBS/IC cases, the antibody weakly stained the basal cells
❚Image 1S❚; however, there often was additional, sometimes
intense staining of the higher cell layers ❚Image 1T❚. There was
full-thickness staining in 3 cases. In 3 of the control samples,
there was moderate staining of most basal cells and very limited
staining of the overlying cells; 1 control sample was negative.
Discussion
We analyzed the keratin phenotype of urothelium in the
enigmatic condition of PBS/IC in an effort to ascertain whether
we could find support for our hypothesis that the cytoskeleton
in some way has a primary or secondary role in this disease.
Our study demonstrated distinct changes in the keratin phenotype of urothelium in patients with PBS/IC that can be categorized as follows: (1) In a considerable number of PBS/IC
cases, the urothelium loses its “keratin-urothelial phenotype,”
and keratin makeup shifts to a phenotype associated with
squamous type epithelium, although this is not evident morphologically. (2) Variability of keratin 20 expression is worth
noting. This may well indicate a defect in the urothelial permeability barrier, impairment of urothelial response to
mechanical stress, or both.
The shift to squamoid differentiation was characterized
by initiation of keratin 14 expression; enhanced expression of
keratin 17; erratic expression of the squamous epithelium
marker 34βE12, recognizing keratins 1, 5, 10, and 14; and the
D5/16B4 antibody recognizing keratin 5/6. This was associated with a loss of expression of keratins characteristic of simple epithelia, ie, keratins 8 and 18.10 Urothelial squamoid phenotype transformation, characterized by keratin 14 expression,
also has been observed in patients with denervation of the
bladder due to spinal cord injury. In this setting, it also occurs
before morphologic squamoid differentiation and is thought to
be reactive to urothelial stress and indicative of susceptibility
of the bladder to future disease.19,21,22 Functionally, the loss of
expression of keratins 8 and 18 is not without meaning and
probably indicates a reduced capacity of the urothelium to
cope with osmotic pressure fluctuation; furthermore, it might
signify impairment of the active uptake and secretion functions of urothelium.23
Keratin 20 is specific for umbrella cells in the normal
bladder and related to the barrier function of urothelium.11 It
is thought that keratin 20 facilitates membrane transport on the
urothelial surface, and there is proof that the matrixes it forms
in the umbrella cells are extremely important in umbrella cell
contraction and reduction of the exposed bladder surface to
urine.21,22,24 Full-thickness expression of keratin 20 in urothelium in fetal studies is thought to signify the fact that fetal
urothelium has not yet developed its barrier function.25
The keratin phenotype was not related to mucosal inflammation, and, in all cases, the urothelium was light microscopically normal; however, electron microscopic studies in IC
report intracellular canals, epithelial edema, and degeneration.3,4 The variability of the changes in keratin phenotype
between cases adds to the diversity of theories that attempt to
explain this condition and the fact that some researchers do
not consider this a single entity.1-5,12-15 This also would
explain the diversity in disease outcome.
Methodologically, the control group is far from ideal.
Because these women had nonrecurrent, low-grade papillary
urothelial carcinoma, we also compared keratin expression in
patients with IC with what is described in the literature. We
found that the control group did not show the same expression
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Laguna et al / KERATINS IN INTERSTITIAL CYSTITIS
patterns as reported in the literature.8,12,17,21 We attribute
this to the fact that these women had low-grade papillary
transitional cell carcinomas elsewhere, and this could be a
field effect.
This study showed that in PBS/IC, the transitional cell
epithelium shows an unpredictable shift in keratin profile,
moving away from its characteristic transitional epithelium
keratin phenotype to a phenotype associated with squamous
epithelium. Furthermore, terminal maturation of the urothelial
cell is incomplete; umbrella cell function and contractility
probably are impaired. These observations underline the theory that this condition is associated with a urothelial cell defect.
From the Departments of 1Urology, Academic Medical Centre,
University of Amsterdam, Amsterdam, the Netherlands;
2Pathology, Foundation of Collaborating Hospitals of Eastern
Groningen, Winschoten, the Netherlands; 3Urology and
4Pathology, Herlev Hospital, University of Copenhagen,
Copenhagen, Denmark; and 5Molecular Cell Biology and
Genetics, University of Limburg, Maastricht, the Netherlands.
Address reprint requests to Dr de la Rosette: Dept of Urology,
Academic Medical Centre, University of Amsterdam, Meibergdreef
9, 1105 AZ Amsterdam, the Netherlands.
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© American Society for Clinical Pathology