urinary bladder urothelial cell carcinoma ( bc ) is one of the most commonly diagnosed cancers . after prostate , lung and colon cancers , bc rates as the fourth most common cancer in men in the world . approximately 75% of over 330 000 diagnosed bc cases in males in 2015 can be at the non - invasive stage ( i.e. without infiltration of the muscularis mucosae : stages ta , t1 , tis ) , and could thus be successfully treated endoscopically [ 2 , 3 ] . due to the combined effect of intensive routine follow - up , and multiple therapeutic procedures , the treatment costs of non - muscle - invasive bc are very high . therefore , bc is a considerable burden for both patient and national health funds . owing to high overall bc one - year and five - year recurrence rates ( 61% and 78% , respectively ) , the frequent need for repeated turb procedures and life - long endoscopic follow - up has elevated the cost of bc treatment to one of the highest of all cancer treatments [ 5 , 6 ] . the natural course of urothelial bc may vary , ranging from low - grade tumors , which recur after transurethral resection of bladder ( turb ) in one - third of cases , to high - grade tumors , which tend to have high recurrence rates and often progress to incurable metastatic disease . however , progression rates depend on a variety of factors . according to eau guidelines , in order to predict short- and long - term recurrence and progression risks , the european organization for research and treatment of cancer ( eortc ) has developed a scoring system . the system is based on the six most significant clinical and pathological factors characterizing bc . a corresponding scoring model for bcg - treated patients has been published by the club urolgico espaol de tratamiento oncolgico ( cueto ) . subtle urothelial changes or small structural bladder pathologies can not be detected by ultrasound or other imaging techniques including computed tomography [ ct ] or magnetic resonance imaging [ mri ] . therefore , bc detection and staging is based on an endoscopic examination , namely white light cystoscopy ( wlc ) , aided by secondary procedures . a medline and web of science database search was performed in september 2015 , without setting time limits , using the terms  bladder cancer in conjunction with fluorescence ,  blue - light ,  pdd ,  narrow band imaging ,  molecular imaging ,  optical coherence tomography or confocal laser endomicroscopy. boolean operators ( not , and , or ) were also used in succession to narrow and broaden the search . autoalerts in medline were also run , and reference lists of original articles , review articles , and book chapters were searched for further eligible articles . articles that did not address the topics were excluded , and the full text of the remaining articles was subsequently reviewed . in this article we present a review of literature concerning modern optical diagnostic techniques for non - muscle - invasive bladder cancer . we present currently available technology with its advantages and disadvantages , and studies regarding its effectiveness . firstly , wlc does not allow for cancer grading or determination of infiltration status . secondly , while sufficient in identifying papillary lesions of over 0.5 cm in diameter , wlc can sometimes be inadequate in identifying small or flat solid tumors , including carcinomas in situ ( cis ) , whose detection rates in wlc do not exceed 5868% [ 9 , 10 ] . the high risk of cis oversight may lead to incorrect , conservative treatment rather than a radical approach ; this may ultimately lead to progression of bc into incurable metastatic disease . finally , the use of wlc does not allow for thorough examination of surgical margins and the detection of small or satellite tumors , contributing to 4070% rates of residual tumors found in the revision turb performed 46 weeks after primary procedure [ 11 , 12 ] . on the other hand , the high rate of incomplete resection may also be a result of technical difficulty and lack of training in turb . passing a straight instrument into an oval structure poses a challenge in removing some tumors because of their location and the desire to avoid bladder perforation . limitations of wlc have led to the emergence of new optical imaging techniques , which optimize bc detection and resection . some of them , such as fluorescence cystoscopy ( fc ) , also known as photodynamic diagnosis ( pdd ) , have already become well - established diagnostic methods , while others are still undergoing clinical trials . the new imaging techniques can be classified according to their scope as macroscopic , microscopic and molecular . macroscopic techniques , such as pdd and narrow band imaging ( nbi ) , are similar to wlc ; however , they help to visualize even very small lesions in the bladder mucosa by the addition of contrast enhancement . microscopic imaging techniques , such as optical coherence tomography ( oct ) and confocal laser endomicroscopy ( cle ) , provide high - resolution cross - sectional views of vesicular tissues . therefore , microscopic imaging techniques are referred as  optical biopsy. by combining optical imaging with fluorescent labelling of elements such as antibodies , molecular imaging methods offer highly specific real - time visualization of cancer cells and their differentiation from healthy tissue . fc or pdd , also known as blue - light cystoscopy ( blc ) , offers fluorescent images of the inner bladder walls . all urothelial cells absorb this agent ; however , it is excessively accumulated by cancer cells . following exposure to blue light ( wave lengths of 380480 nm ) , cancer cells emit a characteristic red fluorescence , which is easily discernible against the blue background of healthy urothelium . in the human body , endogenous 5-ala is the first component in the heme biosynthesis pathway and does not fluoresce itself . administration of exogenous 5-ala overwhelms the metabolic capacity of the physiological pathways , resulting in accumulation of protoporphyrin ix  a fluorescent precursor of the heme molecule . protoporphyrin ix is mainly accumulated in cancer cells , as cancer cells express lower levels of the ferrochelatase , the enzyme , which inserts iron into protoporphyrin ix to form the heme molecule . bc detection using pdd , with 5-aminolevulinic acid ( 5-ala ) as a photosensitizer , is a well - known method and has been reported in a number of publications since the early 1990s . a number of clinical studies have demonstrated the efficacy of pdd with 5-ala as a diagnostic technique that increases detection rates of bc , including residual tumors and cis . unfortunately , the disadvantages associated with 5-ala , such as its hydrophilicity at physiological ph and low solubility in fats leading to poor bioavailability , result in a non - uniform distribution of protoporphyrin ix across tissues . the need for long - lasting bladder 5-ala instillations before cystoscopy , together with the rapid disappearance of tissue fluorescence ( photobleaching ) during cystoscopy , considerably limit the use of 5-ala in everyday practice . these limitations have been overcome with the introduction of the hexyl ester derivative of ala ( hexyl aminolevulinic acid , hal , hexvix ) . hexvix is characterized by better physicochemical properties , including higher fat solubility . following its relatively rapid and uniform absorption by urothelial cells , hal is transformed into 5-ala by an esterase , allowing pdd to be performed . over the last two decades , more than 200 studies on fc have been published . there have been six meta - analyses on pdd with either hal or 5-ala based on over 80 randomized , prospective and retrospective cohort clinical trials . in 2013 two new meta - analyses and one systematic review summarizing studies of the use of hal - blc [ 4 , 17 , 18 ] have been published . all these analyses demonstrated pdd to be significantly more effective than wlc in terms of bc detection and recurrence reduction . despite the fact that pdd does not differentiate between high - grade and low - grade tumors , a number of studies showed this technique to have a significantly higher rate of cis detection than conventional cystoscopy [ 10 , 18 ] . the meta - analysis by burger et al . showed that 22.6% patients had tumors that had been previously undetected by wlc . the same meta - analysis found that patients at low risk of recurrence also benefit from hal - pdd . the use of this technique prevents recurrence in one in six low risk patients over a period of 12 months . therefore , establishing the final diagnosis during the first turb procedure with pdd may affect further treatment , including the need for bcg immunotherapy or cystectomy . furthermore , higher rates of tumor detection may reduce the number of patients requiring another turb procedure and the need for histopathological evaluations . on the basis of these findings , hal - pdd is currently recommended by the european association of urology ( eau ) and international consultation on urological diseases ( icud ) experts , as well as the individual national associations of germany , scandinavia , and the uk [ 10 , 1823 ] . accordingly , hal - pdd should be used in every patient with primary non - muscle - invasive bc ( nmibc ) undergoing first - time turb . the purpose of blc is to improve the quality of turb procedures and to reduce the risk of recurrence , thus decreasing rates of repeated turb and re - hospitalization . all guidelines emphasize the role of pdd in follow - up of high - risk patients ; those with high - grade bc , cis , and multifocal tumors . a further benefit can be achieved in all patients presenting with positive urine cytology and negative wlc . in these patients , hal - pdd , instead of the usually fruitless current literature shows , that the use of pdd with the first turb is cost - effective . it is possible , that its use with subsequent turb procedures would also be recognized as advantageous , but as of now , there has not been available data to support this hypothesis . if no lesion has been found during pdd cystoscopy , the upper urinary tract or the prostate urethra may need to be examined for urothelial cancer . it should be mentioned , that almost half of late recurrences of bc after failed bcg therapy are not located in the bladder , but rather in the upper urinary tract or urethra . hal - pdd is practically free from side effects ; however , the rate of false - positive diagnoses reaches 1012% and may have lower specificity than wlc . this phenomenon is caused by both autofluorescence by endogenous tissue fluorophores and the high capability of immune cells to accumulate the photosensitizing agent . due to photosensitizer accumulation , tissues with inflammatory and postinflammatory lesions may yield false results following intravesical treatment . hence , the use of pdd shortly after ( 612 weeks ) intravesical chemotherapy or immunotherapy is not recommended [ 19 , 20 ] . results can be also misrepresented in case of bleeding during the procedure or when evaluating tangential sections . nonetheless , it is believed that the rate of misdiagnoses , including those following intravesical therapy , depends on the examiner 's experience and decreases rapidly as the learning curve rises . nowadays , numerous high - quality studies supporting the positive effects of hal - pdd on patients quality of life and treatment cost reduction are available . these reports evaluate not only the one - time intravesical fluorophore administration , but also the cost of pdd equipment [ 6 , 2528 ] . based on the data obtained from insurance providers , public health care facilities , and specially developed calculation models , it has been demonstrated , that the use of hal - pdd with the turb procedure provides cost reduction and a rise in quality - adjusted life years ( qaly ) . although pdd implementation does not bring savings immediately , it helps to reduce the number of procedures and hospitalizations in the long follow - up . nbi is a relatively new macroscopic technique of endoscopic imaging that improves tumor detection without the need for intravesical contrast administration . by using special filters , the light spectrum is reduced to its blue ( 415 nm ) and green ( 540 nm ) components , which are well absorbed by haemoglobin . as a result , enhanced contrast between the mucosa and blood vessels is achieved and pathologicaly well - vasculated lesions are clearly visible . like wlc and pdd , nbi does not allow for tumor grade differentiation and determination of infiltration status , yet , it improves detection of non - invasive bc . tokyo ) is available both in the form of integrated videocystoscope and as a camera that can be attached to a regular cystoscope . operating this equipment is very simple : during the examination , the urologist can switch repeatedly between nbi and white light . however , there have only been a few studies published examining its effectiveness . in 2007 , bryan et al . were the first to publish nbi cystoscopy findings in 29 patients with recurrent bladder tumors . the authors found 15 additional tumors in 12 patients , in comparison to those detected with wlc . a prospective randomized single - centre study of 220 cases demonstrated better non - invasive carcinoma detection rates than those achieved with wlc ( 95% vs. 68% , respectively ) . the effect of nbi on therapeutic outcomes has not yet been confirmed ; however , it seems obvious that better visualization would offer better local control , and fewer recurrences . additionally , the use of new technologies forces the urologist to perform better and more careful cystoscopies with higher detection rates of tumors even with wlc . an ongoing large prospective international study of the clinical research office of the endourological society ( croes ) aims to evaluate the effectiveness of nbi . the addition of different colours ( e.g. orange or violet ) to the image obtained by reflected blue- and green - spectrum light offers three different viewing options depending on needs in various clinical situations . microscopic imaging techniques , including oct and cle , are currently in the early stages of experimental research . the oct technique provides real - time high - quality cross - sectional images of superficial tissues . similarly to ultrasonography , this technique utilizes the signal created by waves reflected from various tissue surfaces . in contrast , however , it uses the waves of the near - infrared light spectrum ( 8901,300 nm ) . this allows for tissue imaging at 1020 mm resolution and up to 2 mm in depth , which is sufficient to identify most urothelial tumors . oct differentiates between abnormal and healthy urothelium , and although it does not differentiate tumor grades , it allows for assessment of tissue infiltration status . thanks to the probe , compatible with the cystoscopy equipment , tumor stage assessment can be conducted during cystoscopy and turb procedures . several available studies estimated the sensitivity of the technique at 90 - 100% and specificity at 65 - 89% [ 33 , 34 ] . despite the initially promising findings , oct is difficult to use in its present form in everyday practice . reported a significant improvement in both sensitivity and specificity of the examination with the use of oct combined with pdd . cle uses a fiber optic probe bundle inserted into the lumen of an operating cystoscope and a fluorescent agent administered intravesically to obtain real - time microscopic images of the examined tissue . cle has already been successfully used in the diagnostic endoscopy of gastrointestinal tumors . with the reduced calibre of the probe because of its high resolution ( 25 m ) and depth of imaging penetration ( 240 m ) , cle helps to achieve detailed images of tissue structure and evaluate the appearance of individual cells . this technology makes it possible to obtain data on tissue differentiation status and thus distinguish high - grade and low - grade urothelial carcinomas , as well as identify non - invasive carcinomas during cystoscopic examination . however , it does not improve tumor visualization of occult lesions . in upper tract tumors cle may be complementary to a bad quality biopsy , yet , in bc , suspected areas must be resected by turb to make an accurate diagnosis . the first atlas created to determine diagnostic and tumor grading criteria , based on cle images from 66 patients with bladder tumors , is already available . as in the case of oct , a limitation of this technique is the fact that it offers a very small field of view with limited tissue penetration . raman spectroscopy ( rs ) relies on the inelastic scattering of photons following interaction with intramolecular bonds . rs uses infrared light ( 785845 nm ) to excite intrinsic chemical bonds in order to create optical contrast . in ex vivo studies , rs was able to differentiate the normal bladder wall and low-/high - grade bc , and determine bc invasiveness . limitations include time shift ( 15 seconds ) , weak signals and a narrow view area . recently , surface - enhanced raman scattering ( sers ) nanoparticles have been shown to enhance the signals from cars . autofluorescence of cells and extracellular matrix components in multiphoton microscopy ( mpm ) is obtained after the simultaneous absorption of two or more photons of lesser energy . mpm makes use of intrinsic tissue fluorophores such as nadh , fad or collagen . in a recent study , limitations of mpm include lack of visualization of nuclear morphology and shallow penetration , thus not allowing formal cancer staging . scanning fiber endoscopy ( sfe ) the image is generated by red , green and blue laser scanning of tissues and analysis of backscattered light . sfe can be used in automatic devices to create a panoramic view of the mucosa . ultraviolet autofluorescence is designed to distinguish normal , inflammatory and cancerous urothelium by discriminating variances in their molecular contents . after exposure to uv laser radiation , endogenous fluorophores ( e.g. nad and tryptophan ) emit autofluorescence diagnostic signals that are converted into an intensity ratio between different wavelengths . a recent in vivo pilot study demonstrated the feasibility of this method in differentiating bc from normal mucosa . however , further studies are needed to establish this method 's role in bc detection . molecular imaging is achieved by combining optical ( macroscopic and microscopic ) imaging and intravesical administration of fluorescent - labeled elements , such as antibodies , peptides , and other molecules , which selectively bind to cancer cells . a recently published study demonstrated the use of the fluorescent - labeled antibody cd47 to detect bladder cancer by combined cle and pdd techniques . given that the monoclonal antibody cd47 is currently being evaluated for its possible use in targeted therapy against urothelial carcinoma , this may be an attractive prospect of combining targeted therapy and targeted molecular imaging . fc or pdd , also known as blue - light cystoscopy ( blc ) , offers fluorescent images of the inner bladder walls . prior to cystoscopy all urothelial cells absorb this agent ; however , it is excessively accumulated by cancer cells . following exposure to blue light ( wave lengths of 380480 nm ) , cancer cells emit a characteristic red fluorescence , which is easily discernible against the blue background of healthy urothelium . in the human body , endogenous 5-ala is the first component in the heme biosynthesis pathway and does not fluoresce itself . administration of exogenous 5-ala overwhelms the metabolic capacity of the physiological pathways , resulting in accumulation of protoporphyrin ix  a fluorescent precursor of the heme molecule . protoporphyrin ix is mainly accumulated in cancer cells , as cancer cells express lower levels of the ferrochelatase , the enzyme , which inserts iron into protoporphyrin ix to form the heme molecule . bc detection using pdd , with 5-aminolevulinic acid ( 5-ala ) as a photosensitizer , is a well - known method and has been reported in a number of publications since the early 1990s . a number of clinical studies have demonstrated the efficacy of pdd with 5-ala as a diagnostic technique that increases detection rates of bc , including residual tumors and cis . unfortunately , the disadvantages associated with 5-ala , such as its hydrophilicity at physiological ph and low solubility in fats leading to poor bioavailability , result in a non - uniform distribution of protoporphyrin ix across tissues . the need for long - lasting bladder 5-ala instillations before cystoscopy , together with the rapid disappearance of tissue fluorescence ( photobleaching ) during cystoscopy , considerably limit the use of 5-ala in everyday practice . these limitations have been overcome with the introduction of the hexyl ester derivative of ala ( hexyl aminolevulinic acid , hal , hexvix ) . hexvix is characterized by better physicochemical properties , including higher fat solubility . following its relatively rapid and uniform absorption by urothelial cells , hal is transformed into 5-ala by an esterase , allowing pdd to be performed . over the last two decades , there have been six meta - analyses on pdd with either hal or 5-ala based on over 80 randomized , prospective and retrospective cohort clinical trials . in 2013 two new meta - analyses and one systematic review summarizing studies of the use of hal - blc [ 4 , 17 , 18 ] have been published . all these analyses demonstrated pdd to be significantly more effective than wlc in terms of bc detection and recurrence reduction . despite the fact that pdd does not differentiate between high - grade and low - grade tumors , a number of studies showed this technique to have a significantly higher rate of cis detection than conventional cystoscopy [ 10 , 18 ] . the meta - analysis by burger et al . showed that 22.6% patients had tumors that had been previously undetected by wlc . the same meta - analysis found that patients at low risk of recurrence also benefit from hal - pdd . the use of this technique prevents recurrence in one in six low risk patients over a period of 12 months . therefore , establishing the final diagnosis during the first turb procedure with pdd may affect further treatment , including the need for bcg immunotherapy or cystectomy . furthermore , higher rates of tumor detection may reduce the number of patients requiring another turb procedure and the need for histopathological evaluations . on the basis of these findings , hal - pdd is currently recommended by the european association of urology ( eau ) and international consultation on urological diseases ( icud ) experts , as well as the individual national associations of germany , scandinavia , and the uk [ 10 , 1823 ] . accordingly , hal - pdd should be used in every patient with primary non - muscle - invasive bc ( nmibc ) undergoing first - time turb . the purpose of blc is to improve the quality of turb procedures and to reduce the risk of recurrence , thus decreasing rates of repeated turb and re - hospitalization . all guidelines emphasize the role of pdd in follow - up of high - risk patients ; those with high - grade bc , cis , and multifocal tumors . a further benefit can be achieved in all patients presenting with positive urine cytology and negative wlc . in these patients , hal - pdd , instead of the usually fruitless current literature shows , that the use of pdd with the first turb is cost - effective . it is possible , that its use with subsequent turb procedures would also be recognized as advantageous , but as of now , there has not been available data to support this hypothesis . if no lesion has been found during pdd cystoscopy , the upper urinary tract or the prostate urethra may need to be examined for urothelial cancer . it should be mentioned , that almost half of late recurrences of bc after failed bcg therapy are not located in the bladder , but rather in the upper urinary tract or urethra . hal - pdd is practically free from side effects ; however , the rate of false - positive diagnoses reaches 1012% and may have lower specificity than wlc . this phenomenon is caused by both autofluorescence by endogenous tissue fluorophores and the high capability of immune cells to accumulate the photosensitizing agent . due to photosensitizer accumulation , tissues with inflammatory and postinflammatory lesions may yield false results following intravesical treatment . hence , the use of pdd shortly after ( 612 weeks ) intravesical chemotherapy or immunotherapy is not recommended [ 19 , 20 ] . results can be also misrepresented in case of bleeding during the procedure or when evaluating tangential sections . nonetheless , it is believed that the rate of misdiagnoses , including those following intravesical therapy , depends on the examiner 's experience and decreases rapidly as the learning curve rises . nowadays , numerous high - quality studies supporting the positive effects of hal - pdd on patients quality of life and treatment cost reduction are available . these reports evaluate not only the one - time intravesical fluorophore administration , but also the cost of pdd equipment [ 6 , 2528 ] . based on the data obtained from insurance providers , public health care facilities , and specially developed calculation models , it has been demonstrated , that the use of hal - pdd with the turb procedure provides cost reduction and a rise in quality - adjusted life years ( qaly ) . although pdd implementation does not bring savings immediately , it helps to reduce the number of procedures and hospitalizations in the long follow - up . nbi is a relatively new macroscopic technique of endoscopic imaging that improves tumor detection without the need for intravesical contrast administration . by using special filters , the light spectrum is reduced to its blue ( 415 nm ) and green ( 540 nm ) components , which are well absorbed by haemoglobin . as a result , enhanced contrast between the mucosa and blood vessels is achieved and pathologicaly well - vasculated lesions are clearly visible . like wlc and pdd , nbi does not allow for tumor grade differentiation and determination of infiltration status , yet , it improves detection of non - invasive bc . tokyo ) is available both in the form of integrated videocystoscope and as a camera that can be attached to a regular cystoscope . operating this equipment is very simple : during the examination , the urologist can switch repeatedly between nbi and white light . however , there have only been a few studies published examining its effectiveness . in 2007 , bryan et al . were the first to publish nbi cystoscopy findings in 29 patients with recurrent bladder tumors . the authors found 15 additional tumors in 12 patients , in comparison to those detected with wlc . a prospective randomized single - centre study of 220 cases demonstrated better non - invasive carcinoma detection rates than those achieved with wlc ( 95% vs. 68% , respectively ) . the effect of nbi on therapeutic outcomes has not yet been confirmed ; however , it seems obvious that better visualization would offer better local control , and fewer recurrences . additionally , the use of new technologies forces the urologist to perform better and more careful cystoscopies with higher detection rates of tumors even with wlc . an ongoing large prospective international study of the clinical research office of the endourological society ( croes ) aims to evaluate the effectiveness of nbi . the addition of different colours ( e.g. orange or violet ) to the image obtained by reflected blue- and green - spectrum light offers three different viewing options depending on needs in various clinical situations . microscopic imaging techniques , including oct and cle , are currently in the early stages of experimental research . the oct technique provides real - time high - quality cross - sectional images of superficial tissues . similarly to ultrasonography , this technique utilizes the signal created by waves reflected from various tissue surfaces . in contrast , however , it uses the waves of the near - infrared light spectrum ( 8901,300 nm ) . this allows for tissue imaging at 1020 mm resolution and up to 2 mm in depth , which is sufficient to identify most urothelial tumors . oct differentiates between abnormal and healthy urothelium , and although it does not differentiate tumor grades , it allows for assessment of tissue infiltration status . thanks to the probe , compatible with the cystoscopy equipment , tumor stage assessment can be conducted during cystoscopy and turb procedures . several available studies estimated the sensitivity of the technique at 90 - 100% and specificity at 65 - 89% [ 33 , 34 ] . despite the initially promising findings , oct is difficult to use in its present form in everyday practice . scanning the entire bladder to search for neoplastic lesions is a laborious task . reported a significant improvement in both sensitivity and specificity of the examination with the use of oct combined with pdd . cle uses a fiber optic probe bundle inserted into the lumen of an operating cystoscope and a fluorescent agent administered intravesically to obtain real - time microscopic images of the examined tissue . cle has already been successfully used in the diagnostic endoscopy of gastrointestinal tumors . with the reduced calibre of the probe because of its high resolution ( 25 m ) and depth of imaging penetration ( 240 m ) , cle helps to achieve detailed images of tissue structure and evaluate the appearance of individual cells . this technology makes it possible to obtain data on tissue differentiation status and thus distinguish high - grade and low - grade urothelial carcinomas , as well as identify non - invasive carcinomas during cystoscopic examination . however , it does not improve tumor visualization of occult lesions . in upper tract tumors cle may be complementary to a bad quality biopsy , yet , in bc , suspected areas must be resected by turb to make an accurate diagnosis . the first atlas created to determine diagnostic and tumor grading criteria , based on cle images from 66 patients with bladder tumors , is already available . as in the case of oct , a limitation of this technique is the fact that it offers a very small field of view with limited tissue penetration . raman spectroscopy ( rs ) relies on the inelastic scattering of photons following interaction with intramolecular bonds . rs uses infrared light ( 785845 nm ) to excite intrinsic chemical bonds in order to create optical contrast . in ex vivo studies , rs was able to differentiate the normal bladder wall and low-/high - grade bc , and determine bc invasiveness . limitations include time shift ( 15 seconds ) , weak signals and a narrow view area . recently , surface - enhanced raman scattering ( sers ) nanoparticles have been shown to enhance the signals from cars . autofluorescence of cells and extracellular matrix components in multiphoton microscopy ( mpm ) is obtained after the simultaneous absorption of two or more photons of lesser energy . mpm makes use of intrinsic tissue fluorophores such as nadh , fad or collagen . in a recent study , limitations of mpm include lack of visualization of nuclear morphology and shallow penetration , thus not allowing formal cancer staging . scanning fiber endoscopy ( sfe ) the image is generated by red , green and blue laser scanning of tissues and analysis of backscattered light . sfe can be used in automatic devices to create a panoramic view of the mucosa . ultraviolet autofluorescence is designed to distinguish normal , inflammatory and cancerous urothelium by discriminating variances in their molecular contents . after exposure to uv laser radiation , endogenous fluorophores ( e.g. nad and tryptophan ) emit autofluorescence diagnostic signals that are converted into an intensity ratio between different wavelengths . a recent in vivo pilot study demonstrated the feasibility of this method in differentiating bc from normal mucosa . however , further studies are needed to establish this method 's role in bc detection . molecular imaging is achieved by combining optical ( macroscopic and microscopic ) imaging and intravesical administration of fluorescent - labeled elements , such as antibodies , peptides , and other molecules , which selectively bind to cancer cells . a recently published study demonstrated the use of the fluorescent - labeled antibody cd47 to detect bladder cancer by combined cle and pdd techniques . given that the monoclonal antibody cd47 is currently being evaluated for its possible use in targeted therapy against urothelial carcinoma , this may be an attractive prospect of combining targeted therapy and targeted molecular imaging . raman spectroscopy ( rs ) relies on the inelastic scattering of photons following interaction with intramolecular bonds . rs uses infrared light ( 785845 nm ) to excite intrinsic chemical bonds in order to create optical contrast . in ex vivo studies , rs was able to differentiate the normal bladder wall and low-/high - grade bc , and determine bc invasiveness . limitations include time shift ( 15 seconds ) , weak signals and a narrow view area . recently , surface - enhanced raman scattering ( sers ) nanoparticles have been shown to enhance the signals from cars . autofluorescence of cells and extracellular matrix components in multiphoton microscopy ( mpm ) is obtained after the simultaneous absorption of two or more photons of lesser energy . mpm makes use of intrinsic tissue fluorophores such as nadh , fad or collagen . in a recent study , limitations of mpm include lack of visualization of nuclear morphology and shallow penetration , thus not allowing formal cancer staging . scanning fiber endoscopy ( sfe ) employs a 1.2 mm wide angle , colour , high - resolution flexible endoscope . the image is generated by red , green and blue laser scanning of tissues and analysis of backscattered light . sfe can be used in automatic devices to create a panoramic view of the mucosa . ultraviolet autofluorescence is designed to distinguish normal , inflammatory and cancerous urothelium by discriminating variances in their molecular contents . after exposure to uv laser radiation , endogenous fluorophores ( e.g. nad and tryptophan ) emit autofluorescence diagnostic signals that are converted into an intensity ratio between different wavelengths . a recent in vivo pilot study demonstrated the feasibility of this method in differentiating bc from normal mucosa . however , further studies are needed to establish this method 's role in bc detection . molecular imaging is achieved by combining optical ( macroscopic and microscopic ) imaging and intravesical administration of fluorescent - labeled elements , such as antibodies , peptides , and other molecules , which selectively bind to cancer cells . a recently published study demonstrated the use of the fluorescent - labeled antibody cd47 to detect bladder cancer by combined cle and pdd techniques . given that the monoclonal antibody cd47 is currently being evaluated for its possible use in targeted therapy against urothelial carcinoma , this may be an attractive prospect of combining targeted therapy and targeted molecular imaging . current advances in endoscopy and endoscopic urogenital surgery are the result of two centuries worth of ingenuity and the perseverance of countless researchers and innovators . these new technologies introduced the concept of minimally invasive surgery and revolutionized treatment not only in bc , but in all urologic neoplasms . the most recent advances in optic imaging of the urinary bladder offer a unique opportunity to improve bladder cancer detection and assessment that can allow for the use of specially - tailored therapies . hal - pdd is currently the only imaging diagnostic technique for bladder cancer approved in both the eu and us , and recommended by most international urological associations for routine diagnosis and treatment of urothelial carcinoma . the emerging new techniques of microscopic and macroscopic imaging , often combined with pdd , may dramatically alter the current management of bladder cancer .
introductionurinary bladder urothelial cell carcinoma is one of the most commonly diagnosed cancers in europe . after prostate , lung and colon cancers , bladder cancer rates as the fourth most common cancer in men in the world.urinary bladder cancer detection , treatment , and staging have traditionally been based on an endoscopic examination  cystoscopy.material and methodsa medline , and web of science database search was performed on september 2015 without setting time limits , using the terms  bladder cancer in conjunction with 
 cystoscopy , 
 diagnosis , 
 detection , 
 fluorescence ,  blue - light ,  pdd ,  narrow band imaging ,  molecular imaging ,  optical coherence tomography or 
 confocal laser endomicroscopy.resultsthe new imaging techniques can be classified according to their scope as macroscopic , microscopic , and molecular . 
 macroscopic techniques , such as narrow band imaging , are similar to white light cystoscopy ; however , they help visualize even very minute lesions in the bladder mucosa by means of contrast enhancement.microscopic imaging techniques , such as optical coherence tomography and confocal laser endomicroscopy , provide high - resolution cross - sectional views of vesicular tissues , which resemble images obtained by histopathological examination . 
 therefore , these are referred as 
 optical biopsy. molecular imaging methods offer highly specific real - time visualization of cancer cells and their differentiation from healthy tissue , by combining optical imaging with fluorescent labeling of elements such as antibodies.conclusionsin this article we present a review of studies and literature concerning modern optical diagnostic techniques for non - muscle - invasive bladder cancer . 
 we present available technology with its advantages and disadvantages , and studies regarding its effectiveness .