bladder cancer is the ninth most common cancer worldwide , with 380,000 new cases reported annually .
the ratio of male : female bladder cancer patients is 3.8:1 . according to data from the united states ,
15,250 deaths from bladder cancer are expected to occur in 2013 . moreover , according to the surveillance , epidemiology and end results database , there has been no significant change in bladder cancer deaths over the last 30 years .
bladder cancer is a heterogeneous disease , with 70% of patients presenting with superficial tumors that tend to recur , but are generally not life threatening , and 30% presenting as muscle - invasive disease associated with a high risk of death from distant metastases .
transitional cell carcinoma accounts for more than 90% of all bladder cancers , followed by squamous cell carcinomas ( 5% ) , adenocarcinomas ( 2% ) , and undifferentiated cancers ( < 1% ) .
however , this only provides a 5-year survival in about 50% of patients . although radical cystectomy is the preferred treatment for muscle invasive disease , metastases develop in about 25% of cases with tumors only invading the muscular layer , and in about 50% with tumors extending into the perivesical tissue .
the main cause of death in this malignancy is the metastases . despite radical treatments ,
however , it is not clear if the reason for this is the progressive or unpredictable biological behavior of the disease or micrometastases remaining undiagnosed at the time of diagnosis .
although answer to this question is not clear , the relationship between survival and stage of the disease in cases of radical cystectomy indicates that metastases undiagnosed at the time of diagnosis significantly influence survival .
indeed , the survival rate for stage t2 was 60% to 70% in cases of radical cystectomy investigated by stein et al .
thus , failure of clinical staging is the biggest barrier to predicting the survival and planning additional treatment protocols .
clinical staging using bimanual palpation , computed tomography ( ct ) or magnetic resonance imaging ( mri ) may result in over- and understaging , as indicated by a staging accuracy of only 70% .
pelvic nodes > 8 mm and abdominal nodes > 10 mm in maximum short - axis diameter that are detected by ct or mri should be regarded as pathologically enlarged .
ct and mri have low sensitivity ( 48%-87% ) for lymph node metastasis because they evaluate the lymph node based on its size , and it is well known that metastasis may exist in normal - sized lymph nodes .
accordingly , positron emission tomography / computed tomography ( pet / ct ) is added upon detection of abnormal nodes because the anatomic views provide more accurate data .
furthermore , tests with high sensitivity and specificity are needed in these patients to predict residual disease and monitor treatment response . in this context , f - fluorodeoxyglucose - positron emission tomography / computed tomography ( f - fdg - pet / ct ) , in which particularly functional and anatomic images are processed , is the most important diagnostic tool . therefore , the present study was conducted to retrospectively review the contribution of f - fdg - pet / ct to detection of metastatic bladder cancer .
the histology of the lesions ( if available ) , or all of the clinical and radiological investigations ( ct , mri ) were used as references .
a total of 7,938 patients were evaluated and 10,553 f - fdg - pet / ct scans were performed in the department of nuclear medicine , sifa university , izmir , turkey between july 2007 and april 2013 . of this group
, 79 patients underwent f - fdg - pet / ct because of suspicion of metastatic bladder cancer .
sixty - nine of these patients ( 87.3% ) were male and ten ( 12.7% ) were female .
the mean age was 66.1 years and the standard deviation was 10.7 years ( range , 21 to 85 years ) .
all procedures were conducted in accordance with the ethical standards of the responsible committee on human experimentation and with the helsinki declaration of 1975 , as revised in 2000 .
additional informed consent was obtained from all patients for which identifying information is included in this article .
data on histological sub - types of bladder cancer based on pathological and immunohistochemical investigations were available for 75 patients ( 94.9% ) .
overall , 69 patients ( 87.3% ) had high - grade transitional cell carcinoma ( tcca ) , three ( 3.8% ) had low - grade tcca , two ( 2.5% ) had undifferentiated carcinoma , one ( 1.2% ) had squamous cell carcinoma , and data on histological sub - type were unavailable for four patients ( 5% ) .
these patients were retrospectively evaluated and their pathological and f - fdg - pet / ct findings were recorded .
f - fdg was synthesized using an in - house cyclotron ( rds 111 cyclotron , siemens healthcare , erlangen , germany ) and an automated synthesis system according to a previously authorized procedure . after five hours of fasting ,
the blood glucose level of each patient was measured and the patient was then intravenously injected with 370 mbq of f - fdg .
one hour after f - fdg injection , a ct scan of the area from the vertex to the proximal thigh was performed without contrast agent , and these images were then used for attenuation correction and image fusion .
this was followed by whole - body three - dimensional pet acquisition with eight bed positions that each consisted of 3 minutes of emission scan time using a dedicated pet / ct scanner ( hi - rez biograph 6 , siemens healthcare ) .
this scanner provides an in - plane spatial resolution of 4.8 mm and an axial field view of 16.2 cm .
the pet data were then reconstructed using a gaussian filter with an ordered - subset expectation maximization algorithm ( 3 iterations , 8 subsets ) , reoriented in transverse , coronal and sagittal planes , and assessed by comparison with corresponding ct images .
pet scans were analyzed visually and semi - quantitatively using maximum standardized uptake value ( suvmax ) measurement .
suv was expressed in terms of body weight ( suvbw , g / ml ) .
parameters such as patient 's weight ( kg ) , height ( cm ) , radioactivity during injection ( mbq ) , residual radioactivity ( mbq ) after the injection , starting time of injection , and half life of the radioisotope ( taken to be 109.8 minutes for f - fdg ) were calculated automatically by the software .
two physicians experienced in nuclear medicine blindly and independently reviewed the hybrid f - fdg - pet / ct scans to determine if they were positive or negative for primary tumor sites .
every focal tracer uptake that deviated from physiological distribution was considered to favor disease spread .
the background deviation and difference in activity between suspected lesions and the surrounding tissues were used to differentiate benign from malignant lesions .
f - fdg was synthesized using an in - house cyclotron ( rds 111 cyclotron , siemens healthcare , erlangen , germany ) and an automated synthesis system according to a previously authorized procedure . after five hours of fasting ,
the blood glucose level of each patient was measured and the patient was then intravenously injected with 370 mbq of f - fdg .
one hour after f - fdg injection , a ct scan of the area from the vertex to the proximal thigh was performed without contrast agent , and these images were then used for attenuation correction and image fusion .
this was followed by whole - body three - dimensional pet acquisition with eight bed positions that each consisted of 3 minutes of emission scan time using a dedicated pet / ct scanner ( hi - rez biograph 6 , siemens healthcare ) .
this scanner provides an in - plane spatial resolution of 4.8 mm and an axial field view of 16.2 cm .
the pet data were then reconstructed using a gaussian filter with an ordered - subset expectation maximization algorithm ( 3 iterations , 8 subsets ) , reoriented in transverse , coronal and sagittal planes , and assessed by comparison with corresponding ct images .
pet scans were analyzed visually and semi - quantitatively using maximum standardized uptake value ( suvmax ) measurement .
suv was expressed in terms of body weight ( suvbw , g / ml ) .
parameters such as patient 's weight ( kg ) , height ( cm ) , radioactivity during injection ( mbq ) , residual radioactivity ( mbq ) after the injection , starting time of injection , and half life of the radioisotope ( taken to be 109.8 minutes for f - fdg ) were calculated automatically by the software .
two physicians experienced in nuclear medicine blindly and independently reviewed the hybrid f - fdg - pet / ct scans to determine if they were positive or negative for primary tumor sites .
every focal tracer uptake that deviated from physiological distribution was considered to favor disease spread .
the background deviation and difference in activity between suspected lesions and the surrounding tissues were used to differentiate benign from malignant lesions .
f - fdg - pet / ct imaging was negative in 24 patients ( 30.4% ) and positive in 55 ( 69.6% ) .
there were widespread metastases with high suv values ( mean , 8.3 ; range , 3.3 to 20.9 ) involving at least three organs ( i.e. , lungs or liver , bones , lymph nodes ) in ten patients ( 12.7% ) , lymph node metastases in 24 ( 30.3% ; mean suvmax , 8.1 ) , lung metastases in 18 ( 22.8% ; mean suvmax , 7.5 ) , bone metastases in 15 ( 19% ; mean suvmax , 7.8 ) , soft - tissue metastases in four ( 5% ; mean suvmax , 11.4 ) , liver metastases in three ( 3.8% ; mean suvmax , 8.3 ) , peritonitis carcinomatosa in two ( 2.5% ; mean suvmax , 6.6 ) , cerebral metastasis in one ( 1.2% ; mean suvmax , 11 ) and concomitant upper tract urothelial carcinoma ( utuc ) in one ( 1.2% ; mean suvmax , 14 ) .
1 . grade and histological sub - types of the bladder cancer and pet / ct results were assessed . according to the grading system of the international society of urological pathology ( isup ) and european association of urology ( eau ) , pet / ct was negative in three patients ( 100% ) with low - grade disease , while it was negative in 18 patients ( 26% ) and positive in 51 patients ( 74% ) in the group of high - grade disease , and negative in all patients in the group of squamous cell carcinoma , positive in all patients in the group of undifferentiated carcinoma , and negative in three patients ( 75% ) and positive in one patient ( 25% ) in the group of carcinoma of unknown histological sub - type ( table 2 ) .
a significant correlation was observed between f - fdg - pet / ct results and histological degree ( p < 0.05 ) .
the sensitivity , specificity , positive predictive value ( ppv ) , negative predictive value ( npv ) , and accuracy of f - fdg - pet / ct were 89% , 78% , 90% , 75% , and 86% , respectively .
metastatic bladder carcinoma has a poor prognosis , and survival decreases parallel to the stage of disease , with a dramatic decrease occurring in the presence of metastatic disease .
overall , 10% to 15% of patients with metastatic cancer are metastatic at the time of diagnosis . additionally , the rate of local recurrence is about 30% after radical cystectomy , and development of metastatic disease is more common in muscular invasive bladder carcinomas .
even though the disease does not begin with metastases , metastasis occurs in 24 months in almost half of the bladder cancers treated with radical methods .
accordingly , making accurate diagnoses and monitoring responses to treatment are of vital importance . currently , there is no diagnostic tool capable of detecting occult metastases with high accuracy . among all metastases ,
those in the visceral organs are markers of very poor prognosis in terms of survival .
however , accurately staging bladder cancer through conventional diagnostic methods is still currently challenging . the success rate of clinical staging (
bimanual exam , ct , mri ) has been reported as 70% in the literature . in patient - based analyses
, it has been shown that f - fdg - pet / ct leads to changes in the therapeutic plan in 68% of patients because it can detect 40% more cases compared to conventional investigations based on ct and mri . moreover , f - fdg - pet / ct has been found to provide additional diagnostic data for clinical management of the disease owing to the high sensitivity and specificity of metastatic muscle - invasive bladder carcinoma ( mibc )   ( figs
evaluated the diagnostic capacity of pet / ct retrospectively in patients with mibc and found that clinical management had changed in 17% of the patients .
conducted a meta - analysis that revealed that diagnostic accuracy was sufficient in staging and restaging with f - fdg - pet / ct in patients with mibc and metastatic bladder cancer in their meta - analysis , while no diagnostic capacity of f - fdg - pet / ct was observed for detecting bladder wall lesions with primary malignancy .
because it is excreted with urine , fdg may not play an important role in evaluation of bladder and detrusor lesions ; however , it was shown to be useful for staging and determining metastatic disease .
overall , tests with high sensitivity and specificity are needed to predict residual disease and monitor treatment response in such patients . in this context , f - fdg - pet / ct in which particularly functional and anatomic images are processed is a very important diagnostic tool . in the present study ,
patients undergoing pet / ct screening upon suspicion of metastatic disease were evaluated retrospectively , and the capacity of pet / ct to detect metastatic disease was investigated .
the most distinctive feature of cancer tissue is that it shows higher glucose metabolism than normal tissues ( warburg effect ) .
high uptake of f - fdg in cancerous lesions of transitional carcinoma was first demonstrated by harney et al .   in rats .
.   found that metabolism - based anatomical information gathered by the addition of f - fdg - pet to ct provided high diagnostic accuracy in preoperative staging of invasive transitional cancers , particularly invasive bladder carcinoma .
f - fdg - pet / ct is now an established standard for preoperative staging and detection of metastatic lesions of bladder cancer . during systemic circulation , f - fdg undergoes glomerular filtration and is not absorbed , but largely excreted in the urine .
this poses a problem to identification of kidney , ureter , bladder , and prostate tumors .
another limitation is the faint f - fdg uptake by some malignant neoplasms , such as renal , prostate , and hepatocellular carcinomas .
an important reason for decreased sensitivity is that primary tumors can express low levels of glucose transporters such as glut-1 , which are responsible for the accumulation of f - fdg .
use of urinary activity of f - fdg in diagnosis of primary tumors is currently still challenging ; however , oral hyperhydration , forced diuresis with furosemide , evacuating the bladder with a catheter , and taking late pelvic images partially eliminates such problems .
thus , urinary activity of f - fdg was only a limitation of our study as it relates to utucs .
f - fdg activity of the bladder in metastases of pelvic lymph nodes was recorded as a feature partially limiting the evaluations owing to superposition .
diuresis has been shown to effectively decrease background radioactivity in the urinary tract and hence facilitate the identification of hypermetabolic lesions on f - fdg - pet .
found a sensitivity of 54% when f - fdg - pet / ct was applied to detect malignant areas on the bladder wall in 11 patients with mibc . in a similar study , harkirat et al
.   found sensitivity and specificity of 86.7% and 100% , respectively , for detection of primary lesions with f - fdg - pet / ct in 22 patients with mibc .
sensitivity and specificity rates given in both studies were found using late pelvic images taken along with forced diuresis . in a study of 51 patients ,
swinnen et al .   compared the f - fdg - pet / ct results of patients with mibc for whom radical cystectomy was scheduled with pathological results obtained by extended pelvic lymph node dissection .
the sensitivity , specificity , and accuracy of f - fdg - pet / ct were found to be 46% , 97% , and 84% , respectively . in a similar study ,
lodde et al .   found a ppv of 100% for f - fdg - pet / ct applied to detect lymph node metastasis , and a higher specificity rate compared to ct ( 33% vs. 57% ) .
taken together , these previous studies indicate the superiority of f - fdg - pet / ct on ct for detection of lymph node metastasis ( figs . 5 , 6 ) .
found a sensitivity , specificity , ppv , and npv of 70% , 94% , 78% , and 91% , respectively in a f - fdg - pet / ct investigation of 43 patients with stage t2/3n0m0 urothelial cancer .
specifically , they found occult metastatic disease in seven of 42 patients and that preoperative f - fdg - pet / ct might be influential in the decision of whether or not to conduct treatment prior to radical cystectomy .
the relationship between pet findings and survival was also assessed in that study , and the results showed a 24-month recurrence - free survival of 24% among pet - positive patients , compared to a survival of 55% among pet - negative patients .
jensen et al .   compared f - fdg - pet / ct and mri for n - staging prior to radical cystectomy in 18 patients and found specificity rates of 93% and 80% , respectively , which were significantly different .
additionally , the npvs were found to be 87.5% and 80% , respectively , although these values were not statistically significant .
.   found sensitivity , specificity , and accuracy rates of 60% , 88% , and 78% , respectively , for the detection of metastatic disease by f - fdg - pet / ct in 55 patients with mibc . in that series
apolo et al .   evaluated 47 patients for diagnosis of metastatic disease and 135 individual metastatic lesions and found a sensitivity of 88% and specificity of 87% upon organ - based analyses . in that study , f - fdg - pet / ct was found to lead to changes in the therapeutic plan in 68% of the patients because it could detect 40% more cases than conventional investigations using ct and mri .
the authors concluded that f - fdg - pet / ct has excellent sensitivity and specificity for detection of metastatic bladder cancer and provides additional diagnostic information that enhances clinical management relative to ct / mri alone . in the present study , specificity , sensitivity , accuracy rates , ppv , and npv
were found to be 89% , 78% , 90% ( 50/55 ) , 75% ( 18/24 ) , and 86% , respectively , which was in accordance with the results of previous studies .
liu et al .   found a sensitivity of 77% and specificity of 97% for f - fdg - pet / ct when detecting metastatic disease in 46 chemotherapy - negative patients . in a recent systemic review and meta - analysis by lu et al .
, a sensitivity of 89% and specificity of 82% were found for detection of metastatic lesions in bladder cancer . in that meta - analysis , the authors found that diagnostic accuracy was sufficient in staging and restaging with f - fdg - pet / ct for patients with mibc and metastatic bladder cancer , while no diagnostic capacity of f - fdg - pet / ct was observed during detection of bladder wall lesions with primary malignancy .
because of its urinary excretion , f - fdg may not play an important role in evaluation of bladder and detrusor lesions ; however , the authors found that it might be useful for staging and in determining metastatic disease . in a study conducted in 2014 , mertens et al .   evaluated the relationship of f - fdg - pet / ct results with mortality in patients with mibc ( n=211 ; median follow - up , 18 months ) . in that study , disease - specific survival was 50 months in pet - negative patients , while it fell to 16 months in pet - positive patients
the presence of extravesical disease was found to be an independent prognostic factor for mortality in pet - positive patients .
studies have also been conducted to investigate the diagnostic performance of alternative diagnostic tools to f - fdg - pet / ct . in a study using choline , golan et al .   evaluated 20 patients for a total of 51 lesions with abnormal activity . for all lesions ,
the ppv was 84.7% for 11choline - pet / ct , while it was 90.7% for f - fdg - pet / ct .
that study indicated that 11choline - pet / ct was not superior to f - fdg - pet / ct for detecting metastatic bladder cancer , despite its histopathological correlation disadvantage .
the diagnostic performance of f - fdg - pet / ct applied to metastatic bladder cancer reported in previous studies is summarized in table 3 .
the metabolic rate of low grade transitional cell carcinomas is close to that of normal tissues .
the increased glucose metabolism in patients with high grade mibc allows visualization of the lesions on the detector due to increased fdg uptake .
false - positive or false - negative findings of fdg uptake can not be explained solely by glucose metabolism of tumor tissue .
previous studies have demonstrated that f - fdg - pet / ct scans can only provide information in the presence of a number of increased tumor cells with abnormal glucose metabolism ( 10 - 10 ) .
such diagnostic failures are particularly important in solid organ metastases , such as those found in the lungs and liver . in general ,
f - fdg - pet / ct can not accurately evaluate metastases measuring less than 5 mm in size .
it is unknown why lung lesions below this threshold do not produce high suvs ; however , it may be caused by motion artifacts and low metabolic activity of the metastatic lesion .
the reduction of motion artifacts using certain techniques , achieving a better spatial resolution and finding a higher cutoff suv values for such lesions can increase diagnostic accuracy .
the findings of pet / ct scans must be verified by histopathological work - up to confirm disease recurrence .
unfortunately , this is seldom possible in daily practice owing to clinical reasons , feasibility of the procedure and effective advantages of this approach in the absence of a radical surgical intent . in our study ,
histological confirmation was available in 14 patients , while all others were compared based on clinical and radiological findings .
additionally , there may have been some selection bias since it is likely that only metastatic bladder carcinoma patients suspected to have recurrence were referred for pet / ct .
the present study retrospectively reviewed the contribution of f - fdg - pet / ct to detection of metastatic bladder cancer and found it to be consistent with the results of previous studies .
the most important parameters limiting the current study and similar ones in the literature were a low correlation of histopathology , inability to prevent respiratory artifacts when detecting lung carcinomas smaller than 5 mm and thus inability to diagnose microscopic disease with high accuracy .
it is believed that f - fdg - pet / ct may be useful in the diagnosis of metastatic bladder cancer owing to its high sensitivity and ppvs .
additionally , it may be useful to evaluation of the response to systemic chemotherapy due to its high performance .
 purposethe purpose of this study was to retrospectively investigate the contribution of 18f - fluorodeoxyglucose - positron emission tomography / computed tomography ( 18f - fdg - pet / ct ) to detection of metastatic bladder cancer.materials and methodsthe present study included 79 patients ( 69 men and 10 women ) undergoing 18f - fdg - pet / ct upon suspicion of metastatic bladder cancer between july 2007 and april 2013 . 
 the mean age was 66.1 years with a standard deviation of 10.7 years ( range , 21 to 85 years ) . 
 patients were required to fast for 6 hours prior to scanning , and whole - body pet scanning from the skull base to the upper thighs was performed approximately 1 hour after intravenous injection of 555 mbq of 18f - fdg . 
 whole body ct scanning was performed in the cranio - caudal direction . 
 fdg - pet images were reconstructed using ct data for attenuation correction . 
 suspicious recurrent or metastatic lesions were confirmed by histopathology or clinical follow-up.resultsthe sensitivity , specificity , positive predictive value , negative predictive value , and accuracy of 18f - fdg - pet / ct were 89% , 78% , 90% , 75% , and 86% , respectively.conclusion18f-fdg-pet/ct can detect metastases with high sensitivity and positive predictive values in patients with metastatic bladder carcinoma . 
Introduction
Materials and Methods
1. Imaging and interpretation of data
Results
Discussion
Conclusion