Download Applicability of the FISH Test For Bladder Cancer

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Applicability of the FISH Test
For Bladder Cancer
Peggy Ward-Smith, Brenda Miller, Michael Caughron
I
n the U.S., bladder cancer is
estimated to be diagnosed in
70,530 individuals in 2010,
with 14,680 deaths attributed
to this disease (National Cancer
Institute [NCI], 2010). Risks for
bladder cancer include being over
40 years of age, smoking, occupations with known carcinogens in
the workplace, parasite infections,
and previous treatment or exposure to cyclophosphamide or
arsenic. Ethnically, bladder cancer occurs twice as frequently
among Caucasians when compared to African Americans, and
it occurs least frequently among
Asians. Men are two to three
times more likely to be diagnosed
with bladder cancer than women,
and family members are more
likely to get this disease. The
identification of a gene linked to
bladder cancer has yet to be identified.
Bladder Physiology
The bladder is a flexible, muscular organ that receives and
stores urine excreted from the kidneys (Hall & Chang, 2007). The
Peggy Ward-Smith, PhD, RN, is an
Associate Professor, University of Missouri,
School of Nursing, Kansas City, MO.
Brenda Miller, MSN, RN, is a Nurse
Clinician, Urology Outpatient Clinic, Truman
Medical Center, Kansas City, MO.
Michael Caughron, MD, is a Pathologist in
private practice, Kansas City, MO.
Note: Objectives and CNE Evaluation Form
appear on page 222.
Note: The authors reported no actual or
potential conflict of interest in relation to this
continuing nursing education article.
218
Fluorescence in situ hybridization (FISH) analysis is an FDA-approved, urinebased marker that assists in diagnosis and surveillance of invasive urothelial
cancer. This article provides an overview and case study demonstrating the
clinical use of this analysis. As a systematic review of non-randomized and
randomized clinical trials, this article provides Level I evidence.
© 2010 Society of Urologic Nurses and Associates
Urologic Nursing, pp. 218-222, 251.
Key Words: FISH analysis, urothelial cancer, diagnosis, surveillance.
Objectives
1.
Describe the bladder’s physiology.
2.
List the symptoms of bladder cancer.
3.
Discuss the treatment of bladder cancer and its costs.
4.
Explain the FISH test and its clinical application.
primary function of the bladder is
to store urine; normally, a bladder
is capable of retaining between 50
and 500 ml of urine. Once the
parasympathetic nervous system
is stimulated, the smooth muscle
layer of the bladder wall (the
detrusor muscle) contracts, and
urine is released. Anatomically,
the walls of the bladder consist of
several layers of cells. The urothelium consists of transitional cells
that form the surface of the bladder and comes into direct contact
with urine, the lamina propria
(submucosa) is a thin layer of
highly vascular connective tissue,
the muscular propria is a thicker
layer of smooth muscle tissue, and
the detrusor muscle is the smooth
muscle layer of the bladder wall
that initiates voiding. The outermost layer of the bladder is called
the adventia and consists of fatty
tissue that protects and cushions
the bladder. Most of the bladder is
covered by a serosal mesothehal
surface within the abdominal cavity and pelvis (Messing &
Catalona, 2007).
Blood supply to the bladder is
provided by the internal iliac
artery and the superior, middle,
and inferior vesicle arteries (Legg,
2008). Blood is also supplied by
the obturator and inferior gluteal
arteries. In women, the smaller
arteries arising from the uterus
and vagina also provide blood to
the bladder. Lymphatic drainage is
supplied by interstitial vesical
lymphatics (Legg, 2008).
Symptoms of Bladder Cancer
Symptoms associated with
bladder cancer include hematuria
and painful and/or frequent urination. The American Urologic
Association’s (AUA) best practice
guidelines for the evaluation of
microscopic hematuria recommend a full urologic work up for
all high-risk patients or those with
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two or more documented positive
urinalyses (Hall & Chang, 2007).
The diagnostic work up may
include a physical examination,
urine tests, intravenous pyelogram, and cystoscopy. Tissue samples can be obtained during a cystoscopy and are sent to the pathologist for microscopic review.
Pathologically, most malignant
bladder cancers begin in the cells
that line the bladder wall. These
cancers are named for the type
of cell present (transitional,
squamous, or adenocarcinoma)
(Messing & Catalona, 2007). If the
initial review determines that the
tissue obtained is cancerous, further diagnostic testing may be warranted. This may include computerized tomography (CT) or magnetic resonance imaging (MRI)
scans, sonograms, intravenous
pyelogram, bone scan, and a chest
X-ray. These tests determine if the
bladder cancer is present locally
or elsewhere in the body and are
necessary to stage the disease
(Pashos, Botteman, Laskin, &
Redaelli, 2002). There are five
stages for bladder cancer (0 to IV)
associated with the extent of the
disease within the bladder, surrounding tissues, or other organs.
Treatments for bladder cancer
consist of surgery, radiation therapy, chemotherapy, and biological
therapy (NCI, 2010).
Cost and Clinical Treatment
Of Bladder Cancer
Estimated costs associated
with the diagnosis and subsequent treatments of bladder cancer have been determined by
Arritscher and associates (2006).
These researchers performed a
retrospective medical record chart
review of 208 patients diagnosed
and treated for bladder cancer
between 1991 to 1999, and inflated costs to 2006 U.S. dollars.
Future costs were estimated based
on best-case and worst-case scenarios, where the bladder cancer
recurs and if the patient dies of
disease. The results of this study
indicate that the average lifetime
cost to treat bladder cancer is
$65,158.00. Sixty percent of
these costs ($39,393.00) were
associated with surveillance and
treatment of recurrences, with
30% ($19,811.00) of these costs
contributed to treatment/prevention of complications.
According to the AUA Best
Practice Guidelines (Hall & Chang,
2007), the potential for disease
recurrence and progression typically necessitates follow-up strategies. According to The Committee
for Establishment of the Clinical
Practice Guidelines for the
Management of Bladder Cancer
and the Japanese Urological
Association (2010), recurrence
rates for bladder cancer at low risk
for recurrence and progression
have a 45% reported recurrence
rate. Follow up is recommended
every month for the first two years,
every six months for the next two
years, and then annually thereafter
(Liou, 2006). Cytology and urine
cytology provide the present standard of care, yet each of these tests
has limitations. Better surveillance
strategies would identify recurrence/progression, and thus,
include cost effectiveness with
appropriate treatment.
Presently, six U.S. Food and
Drug Administration (FDA)approved, urine-based markers
can be used to assist in the diagnosis and surveillance of invasive urothelial cancer. These
markers tests include 1) the bladder tumor antigen STAT test
(Bard Diagnostics, Redmond, WA,
U.S.), 2) the BTA TRAK test (Poly
Med Co, Cortlandt Manor, NY,
U.S.), 3) the nuclear matrix protein (NMP) 22, 4) NMP22
BladderChek assays (Matritech,
Newton,
MA,
U.S.),
5)
ImmunoCyt test (Diagnocure Inc,
Quebec City, Quebec, Canada),
and 6) fluorescence in situ
hybridization (FISH) analysis
(Urovysion Systems Vysis, Abbott
Laboratories, Abbott Park, IL,
U.S.) (Gaston & Pruthi, 2004).
Other recently investigated tests
and identified markers include
Quanticyt (Gentian Scientific,
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Niawer,
The
Netherlands),
BLCA-4, hyaluronic acid, telomerase, LewisX blood group antigens, microsatellite polymorphism analysis, cytokeratins, and
survivin (Konety, 2006). The
potential for these urine-based
markers to support or replace
cytology or cystoscopy has yet to
be determined. Using a case
study, this article presents the
challenges associated with using
FISH analysis of voided urine in
diagnostic activities and the role
of the nurse when this diagnostic
tool is used.
The FISH Test
The FDA approved FISH
analysis in 2001 for use in conjunction with cystoscopy to monitor for recurrence among those
with previously diagnosed bladder cancer. Since then, a multitude of studies have confirmed
the usefulness of including FISH
analysis when monitoring for
recurrence (Skacel et al., 2003). A
systematic review of the use of
urine markers for bladder cancer
surveillance was performed by
van Rhijn, van der Poel, and van
der Kwast (2005). Comparing the
results of 64 articles that used 18
different marker analyses, six different assays (including FISH)
were identified as the most promising in identifying recurrence.
While many of these tests are
promising, it was not suggested by
these authors that urine assay testing be substituted for cytoscopic
follow up.
FISH analysis uses a computer algorithm model to evaluate
and compare cells for abnormality. If abnormal, these cells may be
considered suspicious or diagnostic for cancer. The presence of
four or more abnormal cells is
considered diagnostic for bladder
cancer. Thus, a grey area may
exist when there are one to three
abnormal cells present. Clinical
judgment skills, experience with
FISH analysis, knowledge of the
patient’s medical history, and/or
consultation with other patholo-
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gists may be necessary for appropriate diagnosing. Low-grade
bladder cancers rarely demonstrate changes that can be detected by FISH analysis. Thus, a clinical benefit of FISH is its ability to
identify the more aggressive bladder cancers earlier. Identifying the
tumor type that may eventually
become life-limiting allows the
patient and health care providers
to initiate a treatment plan that
includes scheduled surveillance
and pro-active or appropriate
treatment.
Clinical Application of the FISH Test
Gofrit and associates (2008)
followed patients diagnosed with
non-muscle invasive bladder cancer treated by transurethral resection for a median of 13.5 months.
An abnormal FISH result preceded the diagnosis of tumor recurrence in 18 of 21 cases (86%),
including all high-grade recurrences. These data suggest that
FISH assay may be a particularly
useful tool for predicting tumor
recurrence. However, the implementation of FISH analysis or any
other assay as a substitution for
cystoscopy is not recommended
at this time. Gofrit et al. (2008)
suggest that cystoscopy may be
spared and surveillance intervals
widened in patients with a history of low-grade tumors and normal FISH test(s).
The initial clinical testing
using FISH as a diagnostic tool
included 497 patients receiving
care at 23 health care sites
(Sarosdy et al., 2006). Participation in this study was limited to
individuals who presented with
hematuria and had no previous
history of bladder cancer. After
excluding very low-grade tumors,
FISH was able to detect cancer in
25 of 30 (84%) cases; cytology
was detected 15 (50%) cases. The
capability of FISH to detect bladder cancer is somewhat less if the
patient has a smoking history or
presently smokes. In patients with
a greater than 40-pack-per-year
history of smoking, FISH was able
220
to detect cancer 65% of the time.
For those with less than 20 or 20to-40-pack-per-year smoking history, or with no smoking history,
this ability decreased to 13.6% to
24.2%. Overall, the results of this
study indicate that FISH demonstrates a 68.6% clinical sensitivity
and a 77.7% clinical specificity in
detecting bladder cancer. Based
on these results, the FDA
approved Abbott’s UroVysionTM
DNA probe (FISH) as a diagnostic
tool for bladder cancer in 2005.
Presently, FISH is used as an aid in
the initial diagnosis of bladder cancer in patients with hematuria. In
2005, Sarosdy stated; “This...
should allow physicians to make
an earlier diagnosis, with earlier
treatment” (p. 1).
Hajdinjak (2008) identified
and reviewed 14 research articles
that included the FISH assay as a
tool used in diagnosing bladder
cancer. Synthesizing the results of
these studies reveals that the sensitivity of FISH ranges from 69%
to 75% (mean 72%), and the
specificity ranges from 82% to
85% (mean 83%). The overall
performance for FISH was higher
than that obtained using cytology,
yet these differences almost disappear after superficial cancer
cases are excluded. This author
states that a positive FISH result
moderately increases the probability of the presence of any stage
of bladder cancer, and a negative
result reduces this probability by
a small but significant amount.
Thus, while the FISH test results
cannot provide conclusive evidence for the presence or absence
of cancer, both positive and negative results should influence the
probability of the disease.
Ferra and associates (2009)
evaluated the effectiveness of
FISH among 161 patients with
suspicious cytology results. The
aim of this study was to identify
those for whom an aggressive
work up was indicated. These
results indicate that a negative
FISH test did not rule out the
presence of a low- or high-grade
cancer when the urine specimen
was suspicious. Thus, these
authors conclude that an aggressive work up is not indicated
when patients display a suspicious cytology, positive FISH
result, and a negative cystoscopic
evaluation.
Research has demonstrated
the clinical value and diagnostic
significance of FISH, but these
findings are not universal nor
considered confirmative as yet.
Wild and colleagues (2009) state
that the FISH test is capable of
detecting symptoms of malignancy on the molecular level. This
may lead to earlier diagnosis and
therapy, and it may potentially
extend survival. FISH makes it
possible to make decisions in
cases of atypical or unclear cytological findings. According to
Reid-Nicholson and colleagues
(2009), FISH results cannot be
used to definitely diagnose squamous carcinoma or adenocarcinoma, nor can it be used to differentiate the two from urothelial carcinoma. However, it may be useful
as a surveillance tool in established primary and secondary
bladder adenocarcinoma. When
urine specimens are suspicious,
the role of FISH is questionable,
especially in light of the high cost
associated with this test.
According to the AUA (Hall &
Chang, 2007), cystoscopy remains
the gold standard in the diagnosis
and surveillance of bladder cancer.
Case Study
Bob is a 54-year-old Caucasian
factory worker with complaints of
hematuria and frequent/painful
urination for the previous month.
The results of his FISH test are
positive, but his cystoscopy and
histology are negative for cancer.
His physician recommends no further treatment but admits the
inability to explain the symptoms;
other causes (infection, prostate,
and abdominal reasons) have been
ruled out. Bob and his family are
confused and have accessed the
Internet for health care informa-
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tion. According to the information
they have read, the possibility or
probability of cancer in the future
has not been sufficiently ruled
out.
Application of the evidence
needs to include demographic
and employment history data.
Knowing Bob’s ethnicity, the fact
that he has been a cigarette smoker for the past 25 years and works
in the automobile industry
increase his chances for bladder
cancer. His recent test results may
indicate either a false or anticipatory positive FISH result. This is
especially important for Bob,
since his lifestyle choices may
influence FISH results. Research
has reported eventual tumor
recurrence rates between 39%
(Zellweger et al., 2006) and 50%
(Grossman et al., 2006) when follow up is performed between
three and 46 months later. While
Bob’s test results may at present
be negative for a diagnosis of cancer, he is at risk, and routine follow up should be encouraged. In
addition to follow up, Bob should
be instructed to contact his physician if any changes in his health
are noted, particularly if hematuria is noted or urinary function
becomes impaired.
Nursing Implications
While cystoscopy and urine
tests provide the gold standard for
diagnosing bladder cancer, other
procedures that demonstrate the
ability to identify some types of
bladder cancer are available.
Despite the inconsistency of the
results, urine-based markers can
provide important information
that assists in the diagnosis and
surveillance of invasive urothelial
cancer. Nurses need to be aware of
the emerging presence of these
other diagnostic procedures, as
well as their reliability and sensitivity. The potential or actual
diagnosis of bladder cancer
results in an unfamiliar world for
most patients, and interpreting
modern diagnostic test results is
challenging. Thus, providing evi-
dence-based care requires that
nurses are aware of not only the
availability of diagnostic and follow-up tests, but how these tests
apply to each individual patient.
Laboratory tests cannot discriminate or know the specific demographic and lifestyle variables that
accompany every patient. All of
these impact the use and results of
urine-based markers, such as
FISH analysis.
Conclusion
While the research evidence
supports the use of FISH in bladder cancer surveillance activities,
it has been FDA-approved as a
diagnostic test. FISH results provide the ability to diagnose some
bladder cancers while at the
molecular level. This represents
new information that may be confusing and must be coordinated
with other medical information
and specific patient demographic
information. In comparison to
cystoscopy, the results of FISH at
the time of initial diagnosis may
blur the situation. While the
potential exists for under or overdiagnosing bladder cancer, the
potential also exists for diagnosing this life-threatening disease
while it is at an early stage, treatable, and controllable.
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Urologic Nursing Editorial Board Statements of Disclosure
In accordance with ANCC-COA governing rules Urologic Nursing Editorial Board statements of disclosure are published with each CNE offering. The statements of disclosure for
this offering are published below.
Susanne A. Quallich, ANP-BC, NP-C, CUNP, disclosed that she is on the Consultants’
Bureau for Coloplast.
All other Urologic Nursing Editorial Board members reported no actual or potential conflict of interest in relation to this continuing nursing education article.
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FISH Test
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