Gross, painless hematuria is the primary symptom in 85% of patients with a newly

diagnosed bladder tumor, and microscopic hematuria occurs in virtually all patients
(Khadra et al, 2000; Alishahi et al, 2002; Edwards et al, 2006). The hematuria is usually
intermittent and can be related to Valsalva maneuvers; therefore any episode of gross
hematuria should be evaluated even if subsequent urinalysis is negative. Fifty percent of
patients with gross hematuria will have a demonstrable cause, 20% will have a urologic
malignancy, and 12% will have a bladder tumor(Khadra et al, 2000). The risk of
malignancy in patients with recurrent gross or microscopic hematuria who had a full,
negative evaluation is nearly zero within the first 6 years (Khadra et al, 2000). This should be
considered when recommending repeat evaluations for patients with recurrent hematuria.
A full hematuria evaluation for bladder cancer includes cystoscopy, urine cytology, uppertract imaging (primarily a CT scan of the abdomen and pelvis), and a prostate-specific
antigen (PSA) blood test.A PSA blood test is recommended, because 10% of patients with
recurrent gross hematuria will have prostate cancer (Mishriki et al, 2009). Microscopic
hematuria is typically asymptomatic and carries a 5.4% risk of urologic malignancy and a
4.1% risk of bladder cancer (Mishriki et al, 2008). For patients with a negative microscopic
hematuria evaluation, 84.5% never had a recurrence, and of those with repeat microscopic
hematuria, none had a urologic malignancy with a 13-year follow-up (Mishriki et al, 2008).
The AUA guidelines for microscopic hematuria evaluation include a cystoscopy, upper
tract imaging, and urine cytology(Grossfeld et al, 2001). The guidelines recommend
consideration for re-evaluation of low-risk patients with microscopic hematuria, but repeat
evaluation every 6 months with urinalysis, cytology, and blood pressure (to detect renal
disease) is recommended for highrisk patients (Table 8010).
The main diagnostic test for bladder cancer is cystoscopy and biopsy. White light cystoscopy
(WLC) is the gold standard, and flexible office cystoscopy is as reliable as a rigid endoscopy
(Grossfeld et al, 2001). White light cystoscopy has an excellent sensitivity and specificity for
papillary tumors but is relatively poor for CIS. Cystoscopy with porphyrin dye (commonly
referred to as blue light cystoscopy) may be more sensitive in the detection of CIS (Fradet
et al, 2007; Grossman et al, 2007). Porphyrininduced fluorescence cystoscopy uses
photoactive porphyrins, such as hexaminolevulinate, that accumulate preferentially in
neoplastic tissue and emit red fluorescence under blue-wavelength light. This may
improve the detection of small papillary lesions and CIS.A phase III trial evaluating
white and blue light cystoscopy in patients with known or suspected tumors was recently
completed (Grossman et al, 2007). Blue light cystoscopy detected 58% of CIS compared
with 15% using white light. However, at the patient level, the sensitivity of blue light
was 87% and 83% for white light. Blue light cystoscopy has a false-positive rate of
39% (Fradet et al, 2007). The true impact of blue light cystoscopy on the detection of
bladder cancer is unclear and further studies are required to determine its exact clinical
role.
Narrow-band imaging (NBI) is an endoscopic optical image enhancement technique
that enhances the contrast between mucosal surfaces and microvascular structures without
the use of dyes. The depth of light penetration into the bladder wall increases with increasing

wavelength. NBI illuminates the mucosal surface with light of a narrow bandwidth in the
blue (415 nm) and green (540 nm) light spectrum, which are strongly absorbed by
hemoglobin. Consequently, the vascular structures appear dark brown or green against a pink
or white mucosal background. Commercially available systems have integrated NBI and
WLC, allowing activation of the NBI wavelengths with the push of a button. Herr et al.
performed white light cystoscopy with subsequent NBI cystoscopy in 427 consecutive
patients with a history of NMIBC (Herr and Donat, 2008). Of the 103 patients with a tumor
recurrence, 56% had additional tumors identified with NBI compared with use of white
light cystoscopy, and in 12% of patients, the recurrent tumor was only found with NBI.
For white light and NBI cystoscopy, the overall sensitivity was 87% and 100% and the
overall specificity 85% and 82%, respectively.A recent study suggests that NBI more
accurately detects tumor recurrence after BCG therapy than do urine cytology or white light
cystoscopy, and NBI can obviate the need for random bladder biopsies in post-BCG bladders
(Herr, 2008). NBI detected tumor recurrence in 21 of 22 patients with tumor recurrence after
BCG, but another 10 patients had a falsepositive NBI resulting in unnecessary biopsies.
Because the NBI and white light cystoscopy is performed by the same urologist,
observation bias may skew these results.
Random bladder biopsies are recommended to detect unsuspected CIS or small
papillary tumors in endoscopically normal urothelium. Overall, there is a 2.5% detection
rate of CIS or small papillary tumors in random biopsies of patients with known or suspected
bladder tumors (Fradet et al, 2007). For patients with concurrent bladder tumors, a
random biopsy will detect dysplasia or CIS in up to 23% of cases (Mufti and Singh, 1992). It
is reasonable to perform random biopsies in high-risk individuals, such as for those
given postintravesical therapy or for those with a positive cytology and an
endoscopically negative bladder. Urine cytology, first introduced by Papanicolaou in
1945, evaluates the morphologic changes associated with bladder cancer and is the gold
standard urinary marker against which other markers are held (Papanicolaou and Marshall,
1945). Overall, the sensitivity and specificity for cytology in detecting bladder cancer is
40% to 62% and 94% to 100%, respectively (van Rhijn et al, 2005; Volpe et al, 2008).
Positive urine cytology is virtually diagnostic of a bladder tumor, though there are cases in
which the tumor is not endoscopically visible. The sensitivity and specificity of urine
cytology is dependent on the cytopathologist, number of samples evaluated, and the stage and
grade of the tumor (Volpe et al, 2008). Instrumented urine during cystoscopy has improved
sensitivity and specificity, but an invasive procedure is required (Badalament et al, 1987).
Fifteen percent of patients with atypical cytology that is not diagnostic of cancer will have
an underlying malignancy (Novicki et al, 1998). Thus patients with an atypical cytology
need more frequent evaluation or repeat random bladder biopsies.
Urine Markers for Urothelial Cancer
Van Rhijn and colleagues (2005) did a systematic literature review evaluating urine marker
studies for surveillance only and included those markers that had at least two studies
published from two separate institutions (Table 8011). We will discuss the markers that
had at least 70% sensitivity and specificity plus novel markers that may be important in the

future. The sensitivity and specificity of these tests are lower in patients undergoing
surveillance evaluations with no active tumor or those with low-grade cancers (van Rhijn et
al, 2005; Zwarthoff, 2008).NMP-22 is a nuclear matrix protein that is used to form the cell
nuclei. NMP-22 is shed into the urine and has a 20-times higher concentration in the urine
of bladder cancer patients than in noncancer controls (Keesee et al, 1996). There are a
variety of NMP-22 cutoff levels for bladder cancer detection, but typically10 units/mL
is used to identify patients with or without cancer (Soloway et al, 1996; Grossman et al,
2006). A lower cutoff level of 5 units/mL improves the sensitivity but significantly worsens
the specificity. The cutoff level does not appear to be related to stage or grade of the
disease. False positives with NMP-22 can occur from patients with an active urinary tract
infection or significant hematuria (Atsu et al, 2002). Grossman and colleagues (2006)
reported a large multi-institutional study evaluating the efficacy of using NMP-22
(Grossman et al, 2006) as a marker. Using a cutoff level of 10 units/mL, the overall
sensitivity and specificity for detecting urothelial cancer was 49% and 87%,
respectively.The sensitivity for Ta, T1, and T2 tumors was 36%, 65%, and 88%, respectively.
A combination of cystoscopy and NMP-22 detected all but one of the 103 tumorsseen in this
study. NMP-22 picked up eight of the nine tumors missed by white light cystoscopy.
NMP-22 appears to be an adjunct to white light cystoscopy in approximately 10% of
patients.The Lewis blood group antigen X is usually absent from urothelial cells in adults
except for occasional umbrella cells (Sheinfeld et al, 1990). There is increased Lewis X
expression in bladder cancers, and it is independent of secretor status, grade, and stage. The
sensitivity and specificity for the detection of bladder cancer is 75% and 85%, respectively.
There is no commercially available test to date. CK 20 and CYFRA 21.1 are fragments of
cytoskeletal proteins that can be detected in the urine of bladder cancer patients by
either protein or mRNA detection (Ramos et al, 2003). CK 20 has a sensitivity and specificity
of 85% and 76%, respectively. A recent multicenter study of 446 patients evaluating the role
of CYFRA 21.1, with a cutoff value of 4 ng/mL, found a sensitivity and specificity of 43%
and 68%, respectively (FernandezGomez et al, 2007). Unfortunately, none of the Ta
tumors were identified at the 4 ng/mL cutoff. Decreasing the CYFRA 21.1 cutoff to 1.5
ng/mL increased Ta detection to 33%, but the specificity dropped to an unacceptable
43%. Therefore it is not felt to be a useful marker in the current form, or at least for lowgrade disease.Fluorescence in-situ hybridization (FISH) identifies fluorescently labeled DNA
probes that bind to intranuclear chromosomes. The current commercially available
probes evaluate aneuploidy for chromosomes 3, 7, and 17 and homozygous loss of 9p
21(Zwarthoff, 2008). The median sensitivity and specificity of FISH analysis is 79% and
70%, respectively (van Rhijn et al, 2005). A recent prospective study of 250 patients
evaluated the role of FISH analysis for identifying recurrent urothelial cancer (Yoder et al,
2007). FISH detected 25 of 39 concurrent tumors, and 35 tumors occurred later in 56
patients who initially had a positive FISH test. The authors suggested that this was an
anticipatory finding. Another study by Moonen and colleagues (2007) evaluated 105 patients
with urothelial cancer. The sensitivity for Ta, T1, and T2 tumors was 26.7%, 60%, and 50%,
respectively. These lower sensitivity findings were confirmed (Gudjonsson et al, 2008). It
appears FISH analysis is moderately useful for high-grade disease and may be anticipatory
of new tumor formation; however, because of the recurrent nature of noninvasive bladder

cancer, it is difficult to tell if the FISH test was identifying chromosomal abnormalities
present in normal-appearing urothelium or if it was false-positive test.There are multiple
markers available to identify short DNA repeats present throughout the chromosomes
that are lost in some tumor cells. Microsatellite analysis amplifies these repeats in the
genome that are highly polymorphic, and PCR amplification can detect tumor-associated
loss of heterozygosity by comparing the peak ratio of the two alleles in tumor DNA in the
urine sample with the presence of the alleles in a blood sample from the same
individual(Steiner et al, 1997, Wang et al, 1997). The sensitivity and specificity of
microsatellite analysis for the detection of urothelial carcinoma range from 72% to 97% and
80% to 100%, respectively (Steiner et al, 1997; Wang et al, 1997). A recent European study
evaluated microsatellite analysis in voided urine samples for the detection of low
malignant potential nonmuscle-invasive urothelial carcinoma (van der Aa et al, 2009).
They report sensitivity and specificity of 58% and 72%, respectively. Microsatellite
analysis missed only one T1 high-grade urothelial cancer. Interestingly, if the microsatellite
analysis is persistently positive, there was an 83% 2-year recurrence rate, but if the
analysis was persistently negative, only 22% of patients had recurrent tumors.Hopefully,
standardization of the test will allow analysis without a blood sample, and this will
significantly improve the patients acceptance.
CpG dinucleotide islands cluster around promoters in an unmethylated state to allow
gene expression (Knowles, 2007). Methylation of the CpG islands shuts down the
promoter, and if the promoter in question is part of a tumor suppressor gene then cancer
can form.Examples of promoter methylation of CpG islands causing epigenetic changes in
urothelial cancer include the P16/CDKN2Agene (Gonzalez-Zulueta et al, 1995). The
sensitivity of gene methylation for the detection of bladder cancer is 75%; however,
methylated CpG islands can be found in the normal urothelial cells of older patients (Yates et
al, 2006). FGFR-3point mutations are found in 75% of nonmuscleinvasive bladder cancer,
particularly in Ta tumors (van Rhijn et al, 2004; Wolff et al, 2005). Unfortunately, there are
over 11 different point mutation sites within this gene, and therefore identification of all
possible mutations is difficult in a single urine sample. Single-strand conformational
polymorphism can detect these point mutations, and a snapshot assay has been
produced that holds the possibility for rapid identification of FGFR-3mutations (van Oers et
al, 2005). Surface-enhanced laser desorption ionization (SELDI) mass spectroscopy of urine
samples has a sensitivity and specificity for detecting bladder cancer of 50% to 90%
and 60% to 90%, respectively (Vlahou et al, 2001). Tumor grade, patient age, and type of
analysis are confounders of SELDI analysis, and a multi-institutional trial is needed to
determine its effectiveness in identifying urothelial carcinoma. Survivin is an
antiapoptotic protein that has a high expression in urothelial cancer (Smith et al, 2001).
Survivin is found in 10% to 30% of bladder cancers and is readily shed into the urine.
The sensitivity and specificity of survivin in the detection of urothelial tumors is 64% to
100% and 87% to 93%, respectively (Smith et al, 2001; Shariat et al, 2004). This test
may be useful in predicting which patients will respond to intravesical therapy
(Hausladen et al, 2003). Survivin was relatively poor at detecting advanced-stage or highgrade tumors, with a sensitivity of 71% for stage T2 tumors and 80% for high-grade cancers

(Shariat et al, 2004). Hylauronic acid controls intercellular communications and cell
replication. Urothelial cancer induces hylauronic acid production from fibroblasts, and the
amount correlates with the stage of the disease. The sensitivity and specificity of
hylauronic acid for detection of bladder cancer is 91% to 100% and 84% to 90%,
respectively (Pham et al, 1997; Lokeshwar et al, 2002). The sensitivity and specificity for
discriminating between low-grade and high-grade lesions is unclear. Telomerase resides at
the terminal ends of the chromosomes and duplicates random DNA repeats to prevent cell
death (Rhyu, 1995). Telomerase activity is measured in telomeric repeat application protocol
(TRAP) and is detected in 80% of urine from patients with bladder cancer with no grade
differential. The sensitivity and specificity is 90% and 88%, respectively (Sanchini et al,
2005). The ImmunoCyt test (Diagnocure, Qubec, Canada) detects mucin-based antigens
that are present on most bladder cancer cells. The sensitivity and specificity is 61% to 92%
and 71% to 90%, respectively (Halling et al, 2000; Pfister et al, 2003).
Virtually all patients complain of pain and discomfort with an office cystoscopy. Urine
markers studies could forgo this pain in select situations as described above. However,
patients reported that a urine marker study would need 90% sensitivity in order to replace
office cystoscopy(Vriesema et al, 2000). The primary concern is missing tumor cells by
relying on the urinary marker. None of the currently available urinary markers meet this
90% sensitivity on a reliable basis, and therefore a combination of cystoscopy with urine
markers, in select situations, is appropriate for surveillance of patients with non
muscle-invasive bladder cancer.
Gross hematuria yang tidak nyeri adalah gejala utama dalam 85% pasien dengan tumor
kandung kemih yang baru didiagnosis, dan hematuria mikroskopik terjadi pada hampir semua
pasien (Khadra et al, 2000; Alishahi et al, 2002; Edwards et al, 2006). Hematuria biasanya
intermiten dan dapat berhubungan dengan Valsava manuver; Oleh karena itu setiap episode
gross hematuria harus dievaluasi bahkan jika hasil negatif pada pemeriksaan urine
berikutnya. Lima puluh persen dari pasien dengan gross hematuria akan memiliki penyebab,
20% akan memiliki keganasan urologi, dan 12% akan memiliki tumor kandung kemih
(Khadra et al, 2000).
Evaluasi hematuria penuh untuk kanker kandung kemih meliputi cystoscopy, sitologi urine,
CT scan abdomen dan panggul, dan tes PSA . pemeriksaan Tes PSA spesifik prostat
dianjurkan, karena 10 % pasien dengan gross hematuria berulang akan memiliki kanker
prostat (Mishriki et al, 2009). Hematuria mikroskopik biasanya tanpa gejala dan membawa
risiko 5,4% dari keganasan urologi dan risiko 4,1% dari kanker kandung kemih (Mishriki et
al, 2008). Untuk pasien dengan evaluasi hematuria mikroskopik negatif, 84,5% tidak pernah
kambuh, dan dari orang-orang dengan hematuria mikroskopik ulangi, tidak memiliki
keganasan urologi dengan 13 tahun follow-up (Mishriki et al, 2008). Guideline dari AUA
untuk evaluasi hematuria mikroskopik termasuk cystoscopy, pencitraan saluran atas, dan urin
sitologi (Grossfeld et al, 2001). guideline merekomendasikan pertimbangan untuk evaluasi
ulang pasien berisiko rendah dengan hematuria mikroskopik, tapi mengulang evaluasi setiap
6 bulan untuk urinalisis, sitologi, dan tekanan darah (untuk mendeteksi penyakit ginjal)
dianjurkan untuk pasien berisiko tinggi.

Tes diagnostik utama untuk kanker kandung kemih adalah cystoscopy dan biopsi. White light
cystoscopy (WLC) adalah Gold Standard, dan Flexible Office cystoscopy adalah pilihan
sebagai endoskopi kaku (Grossfeld et al, 2001). White light cystoscopy memiliki sensitivitas
dan spesifisitas yang sangat baik untuk tumor papillary tetapi relatif rendah untuk CIS.
Cystoscopy dengan porfirin dye (sering disebut sebagai cahaya biru cystoscopy) mungkin
lebih sensitif dalam mendeteksi CIS (Fradet et al, 2007; Grossman et al, 2007). Cystoscopy
fluoresensi Porphyrininduced menggunakan porfirin photoactive, seperti hexaminolevulinate,
yang menumpuk dalam jaringan neoplastik dan memancarkan fluoresensi merah di bawah
sinar biru panjang gelombang. Hal ini dapat meningkatkan deteksi lesi papillary kecil dan
CIS. Blue Light cystoscopy mendeteksi 58% dari CIS dibandingkan dengan White light
cystoscopy yang hanya 15%. Blue Light cystoscopy memiliki tingkat positif palsu sebanyak
39% (Fradet et al, 2007).
Narrow band imaging (NBI) adalah teknik endoskopi yang meningkatkan kontras antara
permukaan mukosa dan struktur mikrovaskuler tanpa menggunakan pewarna. Kedalaman
penetrasi cahaya ke dinding kandung kemih meningkat dengan meningkatnya panjang
gelombang. NBI menerangi permukaan mukosa dengan cahaya dari bandwidth yang sempit
di biru (415 nm) dan hijau (540 nm) spektrum cahaya dimana hemoglobin sangat menyerap
gelombang tersebut. Akibatnya, struktur pembuluh darah tampak bewarna coklat gelap atau
hijau terhadap merah muda atau latar belakang mukosa putih. penelitian terbaru menunjukkan
bahwa NBI lebih akurat mendeteksi kekambuhan tumor setelah terapi BCG dibandingkan
sitologi urin atau White light cystoscopy (Herr, 2008).
Biopsi kandung kemih dianjurkan untuk mendeteksi CIS tak terduga atau tumor papiler kecil
di urothelium dengan menggunakan endoskopi. Untuk pasien dengan tumor kandung kemih,
biopsi akan mendeteksi displasia atau CIS sampai dengan 23% kasus (Mufti dan Singh,
1992). Hal ini wajar untuk melakukan biopsi pada individu yang berisiko tinggi, seperti bagi
mereka yang diberikan terapi postintravesical atau bagi mereka dengan sitologi positif dan
kandung kemih endoskopi negatif. Urine sitologi, pertama kali diperkenalkan oleh
Papanicolaou pada tahun 1945, mengevaluasi perubahan morfologi yang terkait dengan
kanker kandung kemih dan merupakan standar emas penanda kemih terhadap yang penanda
lainnya (Papanicolaou dan Marshall, 1945). Secara keseluruhan, sensitivitas dan spesifisitas
untuk sitologi dalam mendeteksi kanker kandung kemih adalah 40% - 62% dan 94% -100%,
(van Rhijn et al, 2005; Volpe et al, 2008). Positif sitologi urine hampir diagnostik tumor
kandung kemih, meskipun ada kasus di mana tumor tidak terlihat pada endoskopi.

Penanda Urine untuk Kanker Urothelial

NMP-22 adalah protein matriks nuklir yang digunakan untuk membentuk inti sel. NMP-22
ditumpahkan ke dalam urin dan memiliki konsentrasi 20-kali lebih tinggi dalam urin pasien
kanker kandung kemih dibandingkan kontrol noncancer (Keesee et al, 1996). Ada berbagai
NMP-22 tingkat cutoff untuk deteksi kanker kandung kemih, tetapi biasanya 10 unit / mL
digunakan untuk mengidentifikasi pasien dengan atau tanpa kanker (Soloway et al, 1996;
Grossman et al, 2006). Tingkat cutoff rendah dari 5 unit / mL meningkatkan sensitivitas tetapi
secara signifikan memburuk spesifisitas. Tingkat cutoff tidak muncul terkait dengan tahap
atau kelas penyakit. Positif palsu dengan NMP-22 dapat terjadi dari pasien dengan infeksi
saluran kemih aktif atau hematuria yang signifikan (Atsu et al, 2002). Grossman dan rekan
(2006) melaporkan sebuah studi multi-institusi besar mengevaluasi efektivitas menggunakan
NMP-22 (Grossman et al, 2006) sebagai penanda. Menggunakan tingkat cutoff 10 unit / mL,
sensitivitas secara keseluruhan dan spesifisitas untuk mendeteksi kanker urothelial adalah
49% dan 87%. Tidak ada tes yang tersedia secara komersial sampai saat ini. CK 20 dan
CYFRA 21.1 adalah fragmen protein sitoskeletal yang dapat dideteksi dalam urin pasien
kanker kandung kemih (Ramos et al, 2003). CK 20 memiliki sensitivitas dan spesifisitas,
85% dan 76%. Sebuah studi multicenter terbaru dari 446 pasien mengevaluasi peran CYFRA
21.1, dengan nilai cutoff dari 4 ng / mL, menemukan sensitivitas dan spesifisitas 43% dan
68% (FernandezGomez et al, 2007).
Fluorescence in-situ hibridisasi (FISH) mengidentifikasi probe DNA fluorescently
berlabel yang mengikat intranuklear kromosom. Probe tersedia secara komersial saat
mengevaluasi aneuploidi untuk kromosom 3, 7, dan 17 dan kehilangan homozigot dari 9 p 21
(Zwarthoff, 2008). Sensitivitas median dan spesifisitas analisis FISH adalah 79% dan 70%,
masing-masing (van Rhijn et al, 2005). Sebuah studi prospektif baru-baru 250 pasien
dievaluasi peran analisis FISH untuk mengidentifikasi kanker urothelial berulang (Yoder et
al, 2007). FISH mendeteksi 25 dari 39 tumor bersamaan, dan 35 tumor terjadi kemudian di
56 pasien yang pada awalnya memiliki tes FISH positif. Studi lain oleh Moonen dan rekan
(2007) mengevaluasi 105 pasien dengan kanker urothelial. Sensitivitas untuk tumor Ta, T1,
T2 dan adalah 26,7%, 60%, dan 50%, masing-masing.