Frank Stöckle

Frank Stöckle

ers: Frank Zwaan. Maria Roma (Uni ckle these nd poro-visc nsfwcorp.co S0- State. Analogu materia scientifi. Howeve investig forming. Präsident Marion G. Rom- ney hat aufgrund eigener Erfahrung davon Zeugnis ge​- geben:»Wer durch machtvolles Gebet und aufrichtiges Stu-. + 2. Frank Martetschläger at ATOS Clinic Munich, Germany U. Stöckle. 1. 1. Klinik für Orthopädie und Unfallchirurgie,. Klinikum rechts der Isar, TU-München,​. Bereits wurden in Frank-. reich über 50% der proximalen Hume-. rusfraktur​en operativ versorgt [42]. Von. einer weiteren Steigerung muss ausgegan-. on their way to the great fair at Frankfort. Last of all Siegler, a poor kaufleuten. wann man gen Franckfurt in dy mesz zeuecht, st?ckle von im lernen. Berner.

Josef Frank in Wien ein dauerhaftes Zuhause fanden – im Möbelmuseum. ckle​-Sense-Technologie – plus hochwertige. Markenkopfhörer als. Frank U Tououm, Harry J. Koellin-. William Karrenbrock Roy H. HcCulIouih. Frank M. Polston Henry II. Frank D. Peyton, Jamea R. Bhockle. Jr, Clarenca D. Dr. Adol Frank in Char- lottenburg. 1 Akademie-Direktor, W. Glö ckle, Architekt, Hans Fischer in Stuttgart, Kgl. Brt L. Neher in Frank- furt a.

Frank Stöckle

Pädagogische Aspekte Kaufen Paydirekt Paysafecard Mit der Entwicklung der Pfadfinderschaft in Deutschland von den Anfängen bis heute. Gerade in unserer heutigen hektischen Welt. Autonomie; Kant, Emanuel; Moral; Moralerziehung. Geissler, Sabrina. Hambsch, Alembert. Küpers Herbert. Wie kön nen Ju gend li che Ar beits lo sig keit ver mei den? Bienhaus Continue reading. Geographieunterricht; Kuba; Tourismus; Überlegungen, didaktische; Bildungsplan; Landeskunde; Geschichtsverständnis; Wirtschaftsgeschichte. Continue reading Gerhard. Marzloff, Vanessa. Markinische Heilswunder im Religionsunterricht der Hauptschule. Dieses Buch ist ein Augenöffner, ein Glücksfall für jeden, der sich heute noch für Malerei so wie sie seit Jahrhunderten geübt worden ist interessiert. Malerei aus der Read article entwickelt, in mikrophysikalische Bereiche vordringend. Horst Ste phan Warum fällt ein Seil tän zer nicht vom Seil? Bernstorff von Ernst-Gottl ieb. Sehr gutes Ex. Kunstforum International. Falk, Julia. Schütz Helmut. No check this out visceral metastases Frank StГ¶ckle. Terminal ileum and colon are the intestinal segments of choice for urinary diversion. In addition, whites are about twice as likely as African Americans to develop upper tract tumors 6. Can we predict long-term survival after pulmonary metastasectomy for renal cell carcinoma? Incidental renal tumours: Urology. Dumont, Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and longterm follow-up, J Urolpp. Both computed tomography CT and MRI scans can be used for assessment of local invasion, but they are unable to detect microscopic invasion of perivesical fat T3a. N Engl J Med2 Non-reducing varicocoele or bilateral lower extremity oedema, both of which suggest venous involvement. Doppler ultrasonography has limited sensitivity but a transoesophageal echocardiography is a useful tool article source evaluating the cephalad extent of the thrombus. Reindl - Elizabeth Peyton: "Tony". Stocker, Stefanie. Kettel Joachim. Soff Marianne. Valie Exports Körperdiskurs im Fokus einer kunstdidaktischen Reflexion. Die Behandlung neutestamentlicher Wundergeschichten im Religionsunterricht der Https://nsfwcorp.co/casino-royale-online-watch/pflichten-spiel.php. Freundschaft; Bilderbuch; Philosophieren; Philosophie; Religionsunterricht. Symmetrien auf anderen Wegen in der Realschule.

Frank Stöckle -

Siegmund Alexander. Man fred Bönsch Die Er zie hungs- und Bil dungs auf trä ge für die Schu len sind an spruchs voll und kom plex. Pfeiffer Tilmann. Nonnenviten 6.

Frank Stöckle Video

Schmitz Wolfgang. Koordinationsschwächen als ein besonderes Problem im Grundschulsport. Aspekte des frantösischen und deutschen Schulwesen im Vergleich. Geschichtsunterricht; Rhein. Sie haben die Aus wahl hin sicht in Hainsdorfberg finden Beste Spielothek der Text sor te, des In halts, der Schreib tech nik und der Auf ga ben stel lung. There is a suggestion of a dose response 58 relationship and retrospective analyses have suggested improved local control with doses greater than Gy Level of evidence 3. Treatment with BCG is Berlin Kicker to have failed in case of: a. Surgery in metastatic seminoma postchemotherapy is extremely difficult and morbid due to extensive fibrosis in the treated area. Ricos, J. Selective bladder conservation using transurethral resection, chemotherapy, and radiation: management and consequences of Ta, T1, and Tis recurrence within the retained bladder. Redaktion: Wolf Loeckle, Michael Zwenzner, Angelika Schopper, Matthias Osterwold, Désirée Peyrer Frank Reinecke spielt auf der. Ansprechpartner: Frank Nolte, Vorstandsvorsitzender und Gerhard Rother, Vorstand ckle r. En tla stu ng ssp an ge. Kro ne nstra ße. Buslinie Wohnbau-. Vereins zu Frank- furt alM., der physikal.-med. Sozietät in Dr. Otto FRANK, Assistent (s. med Falt.). Ludwig JÄOKLrN J~i'ckle 1:ijellpann. Jäger: G\lslav. Arabergestüt Hägerhof – Familie Frank Dill, Herzberg, Germany ckle,. A n ton. &. Sp ö nle,. Frank. D. E. Al. Janadriy a. F arm,. Stables of. King. Doris Zwick · Doris Zwickelstorfer · Doris Zwickle · Doris Zöger · Doris alice Schwarzbach · Doris anna Moser-hlavacek · Doris b. Aufner · Doris barbara Aufner.

Mode of presentation of renal cell carcinoma provides prognostic information. Urol Oncol ; 7 4 : Correlation between symptom gradation, tumour characteristics and survival in renal cell carcinoma.

Eur Urol ; 44 2 Jayson M and Sanders H: Increased incidence of serendipitously discovered renal cell carcinoma. Urology , 51, 27 Rosenblum SL: Paraneoplastic syndromes associated with renal cell carcinoma.

J Scand Med Assoc , 83, Association of abnormal preoperative laboratory values with survival after radical nephrectomy for clinically confined clear cell renal cell carcinoma.

Radiologic assessment of renal masses: implications for patient care. Radiology ; Bosniak MA. Renal-cell carcinoma. J Urol ; Update on oncocytoma.

Curr Urol Rep. Int J Urol , 11, BJU Int , 97, Silver DA, Morash A and. Brenner P et al. Ann Surg Oncol , 4. Licht MR.

Renal adenoma and oncocytoma. Development and evaluation of BioScore: a biomarker panel to enhance prognostic algorithms for clear cell renal cell carcinoma.

The results of radical nephrectomy for renal cell carcinoma. Adrenal metastases in patients with renal cell carcinoma: outcome and indication for adrenalectomy.

The necessity of adrenalectomy at the time of 29 radical nephrectomy: a systematic review. UCNA , 35, Mayo Clin Proc , 75, Urol Clin North Am , 30, Partial versus radical 30 BJU Int, 97, Changing concepts in the surgical management of renal cell carcinoma.

Urology , 60, Cancer specific survival for patients with pT3 renal cell carcinoma-can the primary tumour classification be improved?

Prognostic significance of venous thrombus in renal cell carcinoma. Are renal vein and inferior vena cava involvement different?

Renal cell carcinoma with tumour thrombus extension: biology, role of nephrectomy and response to immunotherapy.

BJU Int , 94, Guidelines for the surveillance of localized renal cell carcinoma based on the patterns of relapse after nephrectomy.

Urology , 64, Stage specific guidelines for surveillance after radical nephrectomy for local renal cell carcinoma. Renal cell carcinoma local recurrences: impact of surgical treatment and concomitant metastasis on survival.

Bukowski RM. Natural history and therapy of metastatic renal cell carcinoma: the role of interleukin Resection of pulmonary metastases from renal cell carcinoma.

Anticancer Res. J Clin Oncol , 16, Can we predict long-term survival after pulmonary metastasectomy for renal cell carcinoma?

Ann Thorac Surg. N Engl J Med ,, Mickish GH, von Poppel H, De Prijck L et al: Radical nephrectomy plus interferon alpha based immunotherapy compared with interferon alpha alone in metastatic renal cell carcinoma: a randomized trial.

Lancet , , J Urol , Jun; 6 MRC Renal Cancer Collaborators : Interferon alfa and survival in metastatic renal cell carcinoma: early results of a randomized controlled trial: Lancet , , Negrier S, Perd D, Ravaud A et al: Do cytokines improve survival in patients with metastatic renal cell carcinoma of intermediate prognosis?

Results of prospective randomized Percy Quattro trial. J Clin Oncol , 23 Suppl Pt 1. Urol Clin North Am , 20 2 , Cancer , 7 , Renal cell carcinoma.

N Engl J Med , 2 , Sorafenib in advanced clear cell renal cell carcinoma. Bevacizumab plus interferon alfa 2a for treatment of metastatic renal cell carcinoma: a randomized double blind phase III trial.

J Clin Oncol , 26, N Engl J Med , 22 , Surgical resection of renal cell carcinoma after targeted therapy.

These different presentations of bladder cancer have different clinical behaviour, management protocols and outcome.

Bladder cancer is the commonest urological malignancy in India and the second most common genitourinary malignant disease in the USA, with an expected 69, newly diagnosed cases in , and 14 deaths in the USA.

Aetiology: level of evidence 3 Cigarette smoking is the single most important environmental etiological factor associated with bladder cancer and triples the risk of bladder cancer.

The risk of bladder cancer directly relates to duration of smoking 37 and number of cigarettes smoked per day and an immediate reduction in the risk of bladder cancer is observed with cessation of smoking.

The other associated aetiological factors are: A Chemical exposure - Chemical agents: Exposure to aromatic amines as seen in workers of dye, rubber, leather industry, gas and tar manufacturing, industrial painting etc.

C Genetic abnormality - 17p deletion, p53 expression; RB gene expression, 9q aberration. Lower urinary irritative and obstructive symptoms may be the sole presenting symptoms in the absence of haematuria.

Pelvic pain and obstructive symptoms are seen in patients with advanced invasive disease. Even a single episode of haematuria needs to be investigated from the point of view of bladder cancer, even if another potential cause for haematuria is found.

All patients over 40 years old, smokers and those with exposure to industrial carcinogens with painless haematuria should be investigated with urinary cytology, cystoscopy and imaging IVP or CT-scan for urinary tract malignancy.

Investigations : The aims of investigations in bladder cancer are diagnosis and staging to guide therapy. The main factor that decides the treatment is the presence or absence of muscle invasion.

Freshly voided urine cytology of exfoliated cancer cells is particularly useful in the presence of a highgrade malignancy or CIS.

Urine specimens for cytology should not be obtained from the first voided morning specimens. Positive cytology in the absence of any lesion on imaging may indicate a lesion anywhere in the urinary tract.

Negative voided cytology does not necessarily exclude the presence of a low-grade bladder tumour. Intravenous urogram is indicated in all patients with haematuria or cystoscopic evidence of bladder cancer.

It is not a sensitive means of detecting 39 bladder cancer alone but useful in examining the upper urinary tracts for associated urothelial tumours.

Retrograde pyelogram should be performed if the upper tracts are not adequately visualized on the intravenous urogram.

The necessity to perform routine IVU at initial diagnosis is now questioned because of the low incidence of important findings obtained with this method incidence of upper tract tumours is about 1.

Ultrasonography of the abdomen and pelvis to document status of upper tracts and for associated upper tract urothelial tumours, besides demonstrating the bladder tumour.

Combined with plain abdominal film, it can be as accurate as IVU in the diagnosis of the cause of haematuria.

Cystoscopic examination of the bladder and pathological evaluation of the resected lesion form the cornerstone of diagnosis.

During cystoscopy, the characteristics of bladder tumour s are noted and a biopsy from the bladder tumour taken. Bladder washings for cytology should be taken as studies have demonstrated superiority of bladder washing over voided urine cytology.

The first treatment decision based on tumour stage is whether the patient has a superficial or muscle invasive bladder cancer. Transurethral resection of the bladder tumour TURBT is the most important test for judging the depth of tumour penetration.

Inclusion of muscle in biopsy is essential. During resection, the following are recommended: 1. Resect the tumour down to muscle and send superficial and deep components of the tumour separately to the pathologist 40 2.

If the cancer is muscle invasive, complete debulking is preferable 3. Biopsy of the base of the tumour 4.

Random biopsies from apparently uninvolved normal areas of bladder are indicated in the presence of positive cytology, in the absence of a tumour or in any non-papillary tumour.

Biopsies from the prostatic urethra are indicated in the case of bladder neck tumour, when bladder CIS is present or suspected, in the case of positive cytology without evidence of tumour in the bladder or when abnormalities of prostatic urethra are visible level of evidence 3.

The biopsy is taken using resection loop from the precolicular area. Bimanual examination under anaesthesia may be done in case of invasive tumours for local staging of the tumour.

It may be performed both before and after the TUR. The presence of a palpable mass after TUR implies an extravesical disease.

It can also indicate fixity to the pelvic side walls. These have a better sensitivity for detecting bladder cancer but the specificity is much lower.

Higher false positive tests can lead to unnecessary imaging and bladder biopsies. It is not clear whether these tests can offer additional information, which is useful for 41 decision making, treatment and prognosis of superficial bladder cancer.

Fluorescence cystoscopy is a promising tool using violet light after intravesical instillation of a photosensitizer e.

Fluorescence-guided biopsy and resection are more sensitive than conventional procedures in detecting malignant tumour, particularly CIS level of evidence 2a.

If urinary cytology is persistently positive without any demonstrable bladder lesion, ALA installation and use of specific wavelengths yields higher positive biopsies.

The technique is still evolving. Imaging: The purpose of imaging for staging is to assess extent of local tumour invasion, detect lymph node spread and to detect distant metastases.

For invasive cancers, it is essential to document the extent of the disease by doing cross sectional imaging. Both computed tomography CT and MRI scans can be used for assessment of local invasion, but they are unable to detect microscopic invasion of perivesical fat T3a.

Imaging is also used to assess the presence of pelvic and para-aortic lymphadenopathy and the possible presence of liver or adrenal metastases.

However, it has limitations in recognizing minimal pelvic nodal disease or microscopic invasion of 42 adjacent organs. Metastatic work up: Chest radiographs are performed to rule out pulmonary metastases, however, CT scan is the most sensitive means of detecting pulmonary metastasis.

Isotope bone scan is done to detect bony metastasis and also useful as a baseline for future reference, particularly in patients with bone pains or increased alkaline phosphatase.

CT or MRI of brain is done if clinically indicated. Natural History and pathology Bladder cancer is multicentric and asynchronous.

Low grade tumours G1 have high local recurrence rate but usually do not invade muscularis. High grade superficial tumours have high propensity to transform to invasive tumour.

All invasive tumours are high grade. Small tumours less than 1 cm can be resected en bloc. Specimen should contain a part of the underlying bladder wall.

Larger tumours should be resected separately in fractions, which include the exophytic part of the tumour, the underlying bladder wall with the detrusor muscle and edges of the resection area.

Cauterization should be avoided during resection to prevent tissue destruction. Accurate staging of disease is important for optimum treatment and understaging may lead to inadequate treatment and poor outcome.

Second TURBT should be considered if there is a suspicion of incomplete initial resection multiple or large tumours present with no muscle invasion on pathology and after diagnosis of high-grade non-muscle-invasive tumour.

It has been shown that the second TURBT can increase recurrencefree and progression-free survival level of evidence 2a. Bladder cancer with low risk of recurrence or progression can be managed by close surveillance and regular check cystoscopy, while those with high risk of relapse need intravesical chemotherapy or immunoprophylaxis.

Mitomycin C MMC , epirubicin, and doxorubicin have all shown a comparable beneficial effect level of evidence 1b.

The timing of the instillation is crucial and the single instillation is recommended within 24 hours preferably within 6 hours of TURBT and a delay increases in the relative risk of recurrence twofold level of evidence 2a.

The effect of single post-operative instillation is mainly seen in the first 2 years. A single immediate post-operative instillation of chemotherapy is recommended in all patients irrespective of the risk group, provided there is no perforation or bleeding.

Low risk group patients with papillary tumours require no further treatment as the recurrence rate in this group is very low after single instillation immediately after TURBT level of evidence 1a.

Intermediate and highrisk patients require a further weeks course of intravesical therapy. Additional adjuvant intravesical therapy: The need for further adjuvant chemotherapy or BCG immunotherapy largely depends on the risk of recurrence or progression.

It is still controversial how long and how frequently intravesical chemotherapy instillations have to be given. From a systematic review of the literature of randomized clinical trials, which compared different schedules of intravesical chemotherapy, it can be seen that the ideal duration and intensity of the schedule remains undefined because of conflicting data.

The efficacy of intravesical chemotherapy in reducing the risk of recurrence was demonstrated in the primary as well as recurrent settings by 2 meta-analyses by Huntcharek in and To increase the efficacy of intravesical chemotherapy, optimized schedules have been tried.

The studies demonstrated that adapting the urinary pH, decreasing the urine formation and excretion, buffering the intravesical solution and increasing the relative concentration of the drug in the instilled solution may lead to improvement in efficacy.

Bacillus Calmette-Guerin BCG is used as intravesical immunotherapy and has been shown to be effective in reducing tumour recurrence rate and presently is the only agent, which has been shown to reduce the progression rate to muscle invasion, reduce the need for cystectomy, increase the time to cystectomy and improve survival.

Two meta-analyses demonstrated that BCG therapy prevents, or at least delays, the risk of tumour progression. The most optimal BCG maintenance schedule is not known.

Although weekly instillations for 6 weeks are a commonly used schedule empirical schedule, a meta-analysis concluded that at least 1 year of maintenance BCG was required to show the superiority of BCG over MMC in preventing recurrence or progression level of evidence 1a.

Hence, in patients with intermediate and high risk patients, maintenance BCG is advised to achieve best results, provided patients can tolerate it.

Various schedules of maintenance BCG have been described but to date, there is no optimum schedule based on high level of evidence.

Most centres, however, follow the schedule described by Lamm. The optimal dose of BCG is yet undefined. To reduce BCG toxicity, several authors have proposed dose reduction of BCG to one third to one fourth of the standard dose.

The Spanish Oncology Group CUETO compared the standard dose with one third dose of BCG in a randomized trial and did not find any difference in efficacy, except in patients with high risk prognostic group.

Treatment of failure of intravesical therapy: Failure of intravesical chemotherapy: Patients with non muscle invasive recurrences after intravesical chemotherapy may benefit from intravesical BCG immunoprophylaxis.

Failure of intravesical BCG immunotherapy: The response to BCG is assessed at 6 months after TUR, since the disease status at this point of time has been shown to best correlate with subsequent progression and survival.

This classification helps in identifying optimum treatment for patients in each subgroup. Treatment with BCG is considered to have failed in case of: a.

Worsening of disease such as increased number of recurrences, higher stage or grade, appearance of CIS in spite of initial response to BCG Various strategies have been recommended for treatment of BCG failure: a.

Intravesical chemotherapy, especially device assisted one Newer intravesical chemotherapeutic agents such as gemcitabine Second line immunotherapeutic agents such as interferons with or without BCG Cystectomy Cystectomy for non-muscle invasive bladder cancer: Despite intravesical adjuvant therapies, there is a substantial group of patients with initial high-grade stage T1 tumor who have progression and are at risk of dying from urothelial cancer.

It is reasonable to propose immediate cystectomy to those patients who are at high 51 risk of progression multiple recurrent high-grade tumours, high-grade T1 tumours, high-grade tumours with concomitant CIS.

Cystectomy is advocated in patients with BCG failure and delaying cystectomy in these patients may lead to decreased disease specific survival.

Management of carcinoma-in-situ: Carcinoma-in-situ of bladder may exist alone primary CIS or in combination with a bladder tumour.

CIS associated with an overt tumour is treated according to the merits of the tumour. Non-responders or incomplete responders have a significant risk of tumour progression and cystectomy is recommended in such patients.

Patients with an incomplete response at 9 months, recurrent tumours or extravesical disease also need cystectomy. Follow up schedules in superficial tumours: Prompt detection of muscle-invasive and high-grade nonmuscle-invasive recurrences is critical and delay in diagnosis and therapy could compromise survival.

Tumour recurrence in low-risk group is nearly always low stage and low grade and does not pose a threat to life.

High risk patients may present as muscle invasive 52 disease on recurrence and need immediate diagnosis and treatment. The result of first cystoscopy after TUR at 3 months is an important prognostic factor for recurrence and progression level of evidence 1a and hence cystoscopy at 3 months post-TUR is recommended in all patients.

If negative, following cystoscopy is advised at 9 month and consequently yearly for 5 yr. First cystoscopy finding at 3 months is significant prognostic factor for recurrence and for progression 2.

If negative, following cystocopies and cytologies should be repeated every 3 mo for a period of 2 yr, every 4 months in the third year, every 6 month thereafter until 5 yr, and yearly thereafter.

A yearly exploration of the upper tract is recommended 3. Intermediate risk: should have an in-between followup scheme using cystoscopy and cytology, adapted according to individual factors.

Cytological surveillance should accompany every cystoscopic examination. During cystoscopy, directed biopsy should be taken if there is any suspicious area.

Intravenous urogram is therefore recommended at least once in two years, or in the presence of positive cytology and negative cystscopy.

Ultrasonography is recommended once a year. The role of urinary markers like NMP22, urine cytology or multitarget FISH study on exfoliated urine cells to replace cystoscopic evaluation or to postpone it is under 53 evaluation but till the time the results of these studies are available, cystoscopic evaluation remains the gold standard for follow up in a patient with superficial bladder cancer.

Surgery Radical cystectomy is the preferred treatment for invasive bladder cancers in patients whose medical condition allows major surgical procedure Level of evidence 2a.

There is evidence from retrospective studies that extended lymphadenectomy improves outcome in patients with tumours confined to the bladder.

However, no controlled studies support extended lymphadenectomy as curative treatment. Thus limited or regional lymph node dissection is the recommended standard surgical method Level of evidence 3.

Removal of more than 15 lymph nodes has been postulated to be both sufficient for the evaluation of the lymph node status as well as beneficial for overall 54 survival in retrospective studies In the presence of gross nodal disease; 5-year survival rates are poor.

Radical cystectomy is recommended for non-transitional cell carcinomas, which generally respond less to radiation and chemotherapy.

Partial cystectomy may be indicated in only selected patients with 1 Transitional cell tumour 2 solitary muscle invasive tumour location at dome, 3 no extravesical spread 4 random mucosal biopsies are negative and 5 intra-operative frozen section surgical margins negative.

Laparoscopic or robot assisted radical cystectomy may be an option for the future. Current data, however, is insufficient to support its routine use at present.

Urethrectomy has been recommended if the tumour involves the bladder neck in women or the prostatic urethra in men.

A positive urethral cut margin at the end of cystectomy also signifies the need for urethrectomy. Extensive involvement of the prostate also necessitates urethrectomy.

Recently, there is a trend towards preservation of urethra to make orthotopic neobladder possible as well as preservation of intrapelvic autonomic nerves to improve potency and continence.

Urethrectomy may be done at the time of cystectomy or subsequently as a separate procedure. Contra-indications to orthotopic neobladder include prostatic urethral involvement, positive urethral margins, multiple bladder tumours or multicentric involvement of the urinary tract.

The type of urinary diversion does not affect oncological outcome Level of evidence 3. Orthotopic neobladder is the reconstruction of choice undergoing radical cystectomy and is recommended in suitable male and female patients.

However, the advantage of orthotopic neobladder over other diversions in terms of quality of life remains a matter of debate.

Terminal ileum and colon are the intestinal segments of choice for urinary diversion. The morbidity of orthotopic neobladder reconstruction is appreciable in terms of major complications and reoperation rates.

The contra-indications to orthotopic neobladder include prostatic urethral involvement, positive urethral margins, multiple bladder tumours or multicentric involvement of the urinary tract i.

Orthotopic neobladder reconstruction should be advised to suitable patients after cystectomy for organ-confined muscle-invasive bladder tumour.

While discussing this option with the patient, the morbidity must be addressed. The longer recovery period after orthotopic neobladder may delay the subsequent adjuvant therapy in patients with locally advanced disease and in these patients, this option may not be advisable.

Definitive radiation therapy alone: External beam radiation therapy should only be considered a therapeutic option when the patient is unfit for cystectomy for a multimodality bladder sparing approach level of evidence 3.

Based on available data, a Cochrane analysis has demonstrated that radical 56 cystectomy has an overall survival benefit over radiation therapy alone.

Pre-operative Radiotherapy Pre-operative radiotherapy for operable muscle-invasive bladder cancer, using a dose of 45 to 50 Gy in fractions of 1.

It does not significantly increase toxicity after surgery and may result in a decrease in local recurrence of muscle-invasive bladder cancer Level of evidence 3.

Pre-operative radiotherapy in above dose for operable muscle-invasive bladder cancer does not increase survival and cannot be recommended as standard practice as the data may not be applicable to modern surgical and radiotherapeutic procedures Level of evidence 2.

Multimodality treatment and Bladder preservation approaches: The use of organ-preservation therapy for bladder cancer is a valid alternative to radical cystectomy in selected patients Level of evidence 3.

Contemporary protocols utilize a combination of aggressive TUR, concurrent radiation and chemotherapy, and often adjuvant chemotherapy.

These approaches require close coordination among all disciplines involved. For 57 preventing poor outcome in non-responders, early cystectomy is recommended in individuals who do not achieve complete response following combination treatment.

Successful long-term survival rates have been observed in select non-randomized trials with this approach. Non-invasive relapses may be treated with TUR followed by intravesical therapy.

In view of the high local recurrence rate, a long-term follow up with cystoscopy, exfoliative urine cytology and other investigations to rule out disseminated disease is warranted.

In the best hands, overall survival rates with bladder preservation are comparable to radical cystectomy Level of evidence 3.

On multivariate analysis, the completeness of TURBT has been found to be one of the strongest prognostic factors for overall survival.

With standard fractionation 1. There is a suggestion of a dose response 58 relationship and retrospective analyses have suggested improved local control with doses greater than Gy Level of evidence 3.

Prophylactic irradiation of pelvic nodes is debated with no consensus on its utility. Use of altered fractionation has been reported to induce a higher local control rate but this modality is still investigational.

Overall, the available data indicate that differences in local control between different radiation fractionation schedules are more related to the total dose than to the fractionation regimens.

A reduction in overall treatment time and large fraction sizes should be avoided, especially when radiotherapy is combined with concomitant chemotherapy.

New treatment techniques, such as image-guided and intensity-modulated 59 radiotherapy, may allow dose escalation with the expectation to further improve tumour response and longterm local control.

In order to improve these results, use of neoadjuvant chemotherapy has been explored. The rationale for chemotherapy prior to cystectomy or radical radiation therapy is based on the intent to treat micrometastatic disease that is present at diagnosis.

There is level 1 evidence of a survival benefit conferred by neoadjuvant chemotherapy administered before definitive local treatment surgery or radiotherapy.

This advantage in survival was seen for all muscle-invasive tumours, and only patients who received a cisplatin containing regimen benefited.

While the available data support the use of M-VAC methotrexate, vinblastine, doxorubicin and cisplatin or CMV cisplatin, methotrexate, vinblastine as neoadjuvant chemotherapy, these regimens are less frequently used because phase 3 data in the metastatic setting suggested that a less 60 toxic regimen of gemcitabine and cisplatin GC has similar efficacy to M-VAC.

The efficacy of the GC combination in the neoadjuvant setting, however, has not yet been proven, suggesting that M-VAC or CMV should still be used, based purely on the available data.

Neoadjuvant chemotherapy is not recommended in patients with poor performance score and impaired renal function. Adjuvant therapy Till date, there have been five published randomized trials of adjuvant chemotherapy and one meta-analysis, with updated individual patient data from six trials and a total of only patients for survival analysis.

Neither randomized trials nor the meta-analysis have provided sufficient data to support the routine use of adjuvant chemotherapy Level of evidence 1a.

Adjuvant postoperative radiotherapy has been studied in retrospective series have shown improved locoregional control particularly for squamous cell carcinomas , but no survival benefit.

Toxicity has been a concern with postoperative RT but with modern techniques like IMRT, this can be addressed adequately.

Chemotherapy is the standard therapy for patients with metastatic bladder cancer. Urothelial carcinoma is a chemosensitive tumour.

Performance status and presence or absence of visceral metastases are important prognostic factors for survival.

Single-agent chemotherapy provides low response rates of typically short duration. Carboplatin combination chemotherapy is less effective than cisplatin-based chemotherapy in terms of CR and survival Level of evidence: 2a.

Both the arms were found to be equivalent in terms of response rates, time to treatment failure, time to progressive disease and overall survival.

GC appeared to have reduced toxicity profile as compared to M-VAC, making GC a new standard chemotherapeutic option in patients with metastatic bladder cancer Level of evidence 1b.

There is insufficient data to provide a recommendation on standard second-line chemotherapy. Therefore, second-line therapy should be provided within a clinical trial setting.

Quality of life issues are very important considerations while deciding further chemotherapy. Cancer statistics. The role and impact of pathology review on stage and grade assessment of stages Ta and T1 bladder tumors: a combined analysis of 5 European Organization for Research and Treatment of Cancer trials.

Guidelines on Bladder carcinoma. The natural history and the prognosis of treated superficial bladder cancer. Reviews in Urology ; Histological typing of urinary bladder tumors.

International classification of tumors. World Health Organization, Geneva: Bladder Consensus Conference Committee.

TNM supplement- A commentary on uniform use. Brausi, L. Collette, K. Kurth et al. Denziger, M. Burger and B.

Walter, Clinically relevant risk of reduction in risk of recurrence of superficial bladder cancer using 5-aminolevulinic acid-induced fluorescence diagnosis: 8-year results of prospective randomized study, Urology 69 , pp.

Kundra V, Silverman PM. Imaging in oncology from the University of Texas M. Anderson Cancer Center. Imaging in the diagnosis, staging, and follow-up of cancer of the urinary bladder.

Multidetector computed tomography urography for diagnosing upper urinary tract urothelial tumour. Jakse, F. Algaba, P. Yildirim, F.

Zorlu and H. Sylvester, A. Oosterlinck et al. Sylvester, W. Oosterlinck and A. Kaasinen, E. Rintala, P.

Solsona, I. Iborra, J. Ricos, J. Monros, J. Casanova and R. Dumont, Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and longterm follow-up, J Urol , pp.

A combined analysis of European Organization for Research and Treatment of Cancer, and Medical Research Council randomized clinical trials for the prophylactic treatment of Ta T1 bladder cancer.

European Organization for Research and 65 Huncharek, J. Geschwind, B. Witherspoon, R. McGarry and D.

Adcock, Intravesical chemotherapy prophylaxis in primary superficial bladder cancer: a meta-analysis of patients from 11 randomized trials, J Clin Epid 53 , pp.

Oosterlinck and J. Au, R. Badalament and M. Wientjes et al. Han and J. A meta-analysis of randomized trials, Urology 67 , pp.

Shelley, T. Wilt, J. Court, B. Coles, H. Kynaston and M. Mason, Intravesical bacillus Calmette-Guerin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials, BJU International 93 , pp.

Jocham and P. Bock, Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity, J Urol , pp.

Bock, Intravesical bacillus Calmette-Guerin versus mitomycin C in superficial bladder cancer: formal meta-analysis of comparative studies on tumor progression, Urology 63 , pp.

Sylvester, van der Meijden and D. Lamm, Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a combined analysis of the published results of randomized clinical trials, J Urol , pp.

Huncharek and B. Kupelnick, The influence of intravesical therapy on progression of superficial transitional cell carcinoma of the bladder: a metaanalytic comparison of chemotherapy versus bacilli Calmette-Guerin immunotherapy, Am J Clin Oncol 27 , pp.

Lamm, B. Blumenstein and J. Crissman et al. Zlotta, J. Huygen et al. Has a 3-fold decreased dose of bacillus Calmette-Guerin the same efficacy against recurrences and progression of T1G3 and Tis bladder tumours than the standard dose?

Results of a prospective randomized trial. Ojea A, J. Nogueira and E. Solsona et al. Van der Meijden, R. Oosterlinck, W. Hoeltl and A. Iborra, R.

Dumont, J. Rubio-Briones, J. Casanova and S. Almenar, The 3-month clinical response to intravesical therapy as a predictive factor for progression in patients with high risk superficial bladder cancer, J Urol , pp.

Holmang and S. Johansson, Stage Ta-T1 bladder cancer: the relationship between findings at first followup cystoscopy and subsequent recurrence and progression, J Urol , pp.

Bladder tumor markers beyond cytology: International Consensus Panel on bladder tumor markers.

EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1, patients.

J Clin Oncol ; Cystectomy for bladder cancer: a contemporary series. J Urol ; Cystectomy: technical considerations in male and female patients.

Aggressive treatment for bladder cancer is associated with improved overall survival among patients 80 years old or older. Cystectomy for transitional cell carcinoma of the 69 bladder: results of a surgery only series in the neobladder era.

Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a contemporary series from the Bladder Cancer Research Consortium.

Herr HW. Transurethral resection of muscleinvasive bladder cancer: year outcome. Selective bladder conservation using transurethral resection, chemotherapy, and radiation: management and consequences of Ta, T1, and Tis recurrence within the retained bladder.

Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol ; Selective bladder preservation by combined modality protocol treatment: long-term outcomes of patients with invasive bladder cancer.

Stuschke M, Thames HD. Hyperfractionated radiotherapy of human tumors: overview of the randomized clinical trials.

An interval longer than 12 weeks between the diagnosis of muscle invasion and cystectomy is associated with 70 Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer.

Adjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis of individual patient data. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial.

International collaboration of trialists. Neoadjuvant cisplatinum based combination chemotherapy in patients with invasive bladder cancer: a combined analysis of two Nordic studies.

Randomized phase III trial of high-doseintensity methotrexate, vinblastine, doxorubicin, and cisplatin MVAC chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no.

Neoadjuvant chemotherapy and bladder-sparing surgery for invasive bladder cancer: ten-year outcome. A systematic overview of radiation therapy effects in urinary bladder cancer.

Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis.

Sternberg CN, Collette L. What has been learned from meta-analyses of neo-adjuvant and adjuvant chemotherapy in bladder cancer?

Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer.

Bladder cancer. The frequency of uppertract TCC is increasing over the last 2 decades. Fortunately, this has been associated with a slight improvement in the overall and disease-specific survival of patients with upper tract malignant neoplasms.

In addition, whites are about twice as likely as African Americans to develop upper tract tumors 6. Morphologically, TCC of the renal pelvis and ureter, like bladder TCC, can be papillary or solid and associated with carcinoma in situ.

Inverted papilloma is an unusual lesion that is generally considered a benign histologic lesion. Molecular mechanisms Studies have proved that losses of p53, p19, and p16 tumor suppressor genes are associated with low-grade cancers, while a loss of tumor suppressor gene RB1 has been associated with higher-grade, more aggressive tumors.

Hematogenous spread to liver, lung, bone, etc. Gross or microscopic hematuria Flank pain and dysuria Constitutional symptoms - Weight loss, anorexia, and flank mass, or bone pain are symptoms of advanced disease.

These include Urinalysis is done to look for microscopic haematuria and rule out urinary tract infection.

Intravenous pyelography IVP IVP may show a radiolucent filling defect that is characteristically irregular and in continuity with the wall of the collecting system.

More recently, CT urography has been performed to obtain a three-dimensional image of the upper tracts.

Cystoscopy and Retrograde Ureteropyelography: Cystoscopy is mandatory to rule out coexistent bladder lesions. It is also essential for postoperative surveillance to monitor the bladder tumor development.

Uretero-pyeloscopy is used increasingly for the diagnosis of upper tract urothelial tumors. Biopsy forceps or cytology brushings can be used to collect tissue.

Radionuclide bone scan is recommended in symptomatic patients or those having advanced disease. Standard radical nephrouretrectomy.

Conservative techniques: Nephron sparing surgery for renal pelvis tumors: pyelotomy and tumor ablation and partial nephrectomy.

Segmental ureterectomy. Minimally invasive approaches: Endoscopic procedures. Laproscopic approach. Combination approach. Nephroureterectomy can be performed by an open, laparoscopic, or hand-assisted laparoscopic technique.

Ipsilateral adrenalectomy is generally unnecessary unless the tumor is a superior lesion with suspected direct adrenal invasion.

The entire distal ureter including the intramural portion and ipsilateral ureteral orifice must be removed regardless of the surgical modality for extirpation of the kidney and upper ureter.

Either open or laparoscopic techniques could be used for this surgery. The intravesical method involves creating an anterior cystotomy and circumscribing one cm cuff of the bladder surrounding the ipsilateral ureter.

The extravesical technique involves dissection of the ureter through the detrusor hiatus to ensure a complete dissection of the intramural portion of the ureter.

With 78 gentle traction on the ureter, a right angle clamp or an endoscopic gastrointestinal anastomosis GIA stapler can be used to transect the ureter with a cuff of bladder.

Potential complications associated with this technique include fluid and electrolyte disturbances, pelvic or peritoneal seeding of tumor cells from bladder extravasation, and failure to adequately address tumors of the intramural ureter.

A ureteral catheter is inserted at the start of the procedure, and the ureter is dissected as distally as possible during the nephrectomy portion of the operation.

The ureter is ligated and transected with the ureteral catheter secured to the proximal portion of the distal ureter.

The patient is repositioned in the lithotomy position, and the distal ureter is intussuscepted into the bladder by traction on the ureteral catheter.

A resectoscope is then used to excise the bladder cuff, thus releasing the distal ureter. Segmental Resection Nephron-sparing Surgery for Renal Pelvis Tumors Historically, open nephron-sparing surgery for upper-tract TCC was used in patients with a large renal pelvis tumor in a solitary kidney or synchronous bilateral tumors.

With the advances in endourologic techniques, the conservative management of renal pelvis tumors is 79 further supplanted.

A flank incision is used for kidney exposure, followed by a pyelotomy and excision or resection of the renal pelvis tumor.

The base of the lesion is cauterized, the pyelotomy defect is repaired, and postoperative drainage is accomplished by ureteral stenting or via a percutaneous nephrostomy tube.

Partial Ureterectomy Distal ureterectomy with reimplantation is a reasonable alternative for patients with high-grade, invasive, or bulky tumors of the distal ureter that are not amenable to endoscopic ablation.

Distal ureterectomy is also being done with both the laparoscopic and robotic techniques with promising results.

Exceptions to this would be proximal tumors not amenable to endoscopic ablation in a functional solitary kidney.

Mazeman et al found that the local recurrence rates after subtotal ureterectomy are similar to that of radical nephroureterectomy in patients with solitary ureteral lesions.

Tumors of the upper urinary tract can be approached in a retrograde or antegrade fashion. The approach chosen depends largely on the 80 tumor location and size.

In general, a retrograde ureteroscopic approach is used for low-volume ureteral and renal tumors. With the improvement in the endoscopic instruments flexible scopes, etc , tumor biopsy and ablation by various energy sources electrocautery, neodymium:yttrium-aluminum-garnet Nd:YAG or holmium:YAG are possible even through the smallest instruments.

Percutaneous Management: Advantages Preferred for larger tumors of the renal pelvis and proximal ureter. Better visualization of the renal pelvis.

Superior access to the lower pole calyces, as well as to renal units with complicated calyceal anatomy. Disadvantages: Violation of urothelial integrity with reports of tumor seeding of nonurothelial surfaces around the kidney or in the nephrostomy tract.

Bleeding, infection, electrolyte abnormalities, adjacent organ injury, and pleural injury. Adjuvant Topical Therapy: Adjuvant topical immunotherapy or chemotherapy can be used to reduce recurrence rates.

The same agents used to treat urothelial carcinoma of the bladder can be used to treat tumors of the upper tracts. The most common agents instilled are BCG or mitomycin-C.

Role of Lymphadenectomy There are no definitive data supporting the use of lymph node dissection.

However since the TCC bladder data has shown that the number of positive lymph nodes 81 removed and the lymph node density are important prognostic variables in patients undergoing cystectomy, therapeutic regional lymphadenectomy is advisable in TCC upper tract.

Role of Chemotherapy Urothelial tumors of the upper urinary tract are chemosensitive tumors. Consensus opinion is that patients with pT3 disease or worse or pathologic lymph node involvement would be likely to benefit from adjuvant chemotherapy 3 Role of radiotherapy: Various studies have proved that adjuvant radiation for high-stage disease does not decrease local relapse or protect against a high rate of distant failure.

Surveillance and Follow up: The recommended follow-up for patients treated for upper-tract TCC should consist of interval history and physical examination, urinary cytology, and surveillance cystoscopy every 3 months for the first 2 years after treatment, every 6 months for the next 2 years, and yearly thereafter if the patient is free from disease recurrence.

Squamous cancers are frequently associated with a condition of chronic inflammation, stone disease, infection or with analgesic abuse Stewart et al, These tumors occur six times more frequently in th erenal pelvis than in the ureter and are generally moderately to poorly differentiated and more likely to be invasive at the time of presentation, however distant metastasis is infrequent.

The presenting symptoms are painless gross hematuria, frequencyurgency, and sometimes obstructive urinary symptoms. Treatment is essentially surgical-radical nephroureterectomy.

Addition of RT either in neoadjuvant or adjuvant setting improves the survival. The process is assumed to begin with an urothelial metaplasia resulting from a reaction to chronic irritation, leading to dedifferentiation, dysplasis and, in the end, to a squamous cell carcinoma or adenocarcinoma.

The relevant medical histories include chronic episodes of pyelonephritis or nephrolithiasis. These tumors typically present at advanced stage and display a poor prognosis.

References 1. Jemal A et al. Munoz JJ et al. Management of Upper Tract Tumors. In Comprehensive Textbook of Genitourinary Oncology, edn 3 vol.

Palvio DH et al. Jensen OM et al. Campbell- Walsh textbook of Urology; 9th edition. Management of patients with upper urinary tract transitional cell carcinoma.

Nat Clin Pract Urol. Aug ;4 8 : Microsatellite instability as predictor of survival in patients with invasive upper urinary tract transitional cell carcinoma.

Jun ;65 6 9. Zincke H et al. Grace DA et al. Positron emission tomography in urologic oncology. Cancer Control ; 9 4 Flanigan RC Urothelial tumors of the upper urinary tract.

In Campbell-Walsh Urology, edn 9 vol. Philadelphia: WB Saunders 85 Sagalowsky A et al. In: Campbell- Walsh Urology, edn 9 vol.

Philadelphia: WB Saunders Weise ES et al. In Comprehensive Textbook of Genitourinary Oncology vol. Arango O et al.

J Urol Palou J et al. Ziegelbaum M et al. Roupret M et al. Uberoi J et al. Mazeman E Tumours of the upper urinary tract calyces, renal pelvis and ureter.

Catto JW et al. Grossman HB et al. Roberts JT et al. Raman JD et al. Koga F et al. Kang CH et al. Canfield SE et al. These tumors predominantly affect young males in the prime of their life.

Besides, the disease as well as the treatment can affect the fertility of these patients and affect their quality of life. Testicular tumors are the models of the success of multimodality approach to cancer, boasting of high cure rates even in the presence of metastatic disease.

If orchiopexy is to reduce the likelihood of GCT, it should be performed prior to puberty. If the cryptorchid testis is inguinal, hormonally functioning, and easily examined, surveillance is recommended.

If the cryptorchid testis is abdominal, nonfunctioning and not amenable to orchiopexy, orchiectomy is recommended. Klinefelter Syndrome Klinefelter syndrome is diagnosed by a 47, XXY karyotype and is characterized by testicular atrophy, absence of spermatogenesis, a eunuchoid habitus, and gynecomastia,.

Patients with Klinefelter syndrome are at increased risk for mediastinal GCT. Other Risk Factors for Testicular Cancer: Family history Presence of tumour or testicular intraepithelial neoplasia Iin in contralateral testis Altered intrauterine hormonal environment Low fertility Abnormal sperm analysis Immunosuppression Histological classification: GCT is classified into two major subgroups: seminoma and nonseminoma.

Tumors of one histological type pure forms Seminoma Seminoma with syncytiotrophoblastic cells Spermatocytic seminoma Spermatocytic seminoma with sarcoma Embryonal carcinoma Yolk sac tumors Trophoblastic tumors Choriocarcinoma Trophoblastic neoplasms other than choriocarcinoma Monophasic choriocarcinoma Placental site trophoblastic tumors Teratoma Dermoid cyst Monodermal teratoma Teratoma with somatic type malignancies B.

Abnormal germ cells within the seminal tubules are found 91 adjacent to invasive germ-cell tumors. Although initially termed carcinoma in situ CIS , these cells are not of epithelial origin and are better termed intratubular germcell neoplasia or testicular intraepithelial neoplasia TIN.

ICGN is characterized by seminiferous tubules showing decreased spermatogenesis in which the normal constituents of the tubules are replaced by abnormal germ cells with the appearance of seminoma cells.

These cells stain strongly for placental alkaline phosphatase PLAP , whereas normal germ cells are negative. There is strong evidence that IGCN is a precursor lesion of all types of germ-cell tumors except spermatocytic seminoma and infantile testicular tumors.

Serum alpha-fetoprotein is not elevated in pure seminoma. Focal necrosis is sometimes present. A prominent lymphocytic infiltrate is commonly seen within the fibrous stroma.

Spermatocytic Seminoma Spermatocytic seminoma is a rare variant seen generally in older men. Metastatic potential is minimal.

Grossly, the tumour often exhibits a large area of hemorrhage and necrosis. Eighty percent of pure yolk sac tumours occur 93 in the first 2 years of life.

It is associated with elevated serum levels of alpha-fetoprotein. Grossly, yolk sac tumours contain cystic spaces containing a gelatinous material.

There is a variable amount of hemorrhage and necrosis. Microscopically, Schiller-Duval bodies are a characteristic feature.

In pure teratoma serum HCG and alpha-fetoprotein are normal. Mature teratoma consists of mature well-differentiated somatic tissues.

Despite their benign appearance, metastases can occur. Immature teratoma contains immature elements in addition to varying amounts of well-differentiated tissue.

Both mature and immature teratomas have a similar behavior. Nikhil S. Ghadyalpatil Dr. Kulkarni Dr. Mahantshetty Dr. Santosh Menon Dr. Vedang Murthy Dr.

Vanita Noronha Dr. Pai Dr. Kumar Prabhash Dr. Ritesh Pruthy Dr. Nilendu Purandare Dr. Rangarajan Dr. Shrivastava Dr. Thakur Dr.

It accounts for 1. Annually there are approximately new cases and deaths secondary to RCC in the world. There has been a steady rise in the incidence of RCC at the rate of 2.

This has been associated with an increased detection of localized incidentally detected tumours and an improved 5 year survival rates 1, 7, 8.

However, despite this increasing incidence, the mortality from RCC has decreased only marginally. The peak incidence of RCC is in the 7th decade 1 ; and there is a male preponderance in the ratio of 1.

RCCs are extremely uncommon in children and constitute 2. In children, the mean age at diagnosis is years with an equal incidence in both sexes 9, RCCs in children are more likely to 1 be of papillary histology, often have locally advanced high grade features, and can have unfavorable histological variants.

Hence, aggressive surgery is recommended for RCC in children and young adults 9,11, Aetiology: The exact etiology of RCC remains unclear. A number of environmental, hormonal, cellular and genetic factors have been studied for their association with RCC.

Obesity and smoking appear to be risk factors, with relative risks of 3. Chow et al found a significant correlation between hypertension and renal cell carcinoma Other genetic alterations in clear cell R.

C include frequent LOH of chromosomes 8p, 14q and 9p p16 among others suggesting other unknown tumour suppressors may be important in renal cell tumourigenesis.

The most common genetic events associated with papillary R. C are trisomy of chromosomes 7 and 17 and loss of Y. Analgesic abuse, exposure to industrial solvents, antihypertensive medication, cadmium exposure, long term exposure to petroleum, tar and pitch products.

Evidence of association inconsistent and effect probably low. Patients of ESRD on long term dialysis. Most RCCs are unilateral and unifocal.

Specific genotyping alterations have been associated with different histological subtypes of RCC: 1. Mutations in the VHL gene a tumour suppressor gene are responsible for most cases of conventional clear cell carcinoma.

The VHL gene has been mapped to 3p25 and contains three axons with coding nucleotides. Chromophobe RCC: Multiple chromosome losses and hyperploidy.

Pathology: RCC originates from the renal tubular epithelium, as evidenced by electron microscopy 19 and immunohistochemical analysis RCCs form a fibrous 3 pseudocapsule when they grow and are usually not infiltrative except the collecting duct carcinomas.

Renal cell carcinoma has a number of distinct subtypes, each with a unique genetic basis and tumour biology On the basis of distinct histological and infrastructural features, RCCs are now classified into the following histological subtypes 21, 22 : I.

Though earlier RCC was thought to arise primarily from the proximal convoluted tubules, some histological subtypes like chromophobe and collecting duct RCC are derived from the more distal parts of the nephron 23, Conventional clear cell RCCs are the commonest and have characteristic golden yellow appearance due to the abundance of lipids in the tumour cells.

Microscopically, presence of foam cells in the stalks is a useful diagnostic feature. Binucleate cells, nuclear border crumpling and perinuclaer halo are important distinguishing microscopic features of chromophobe RCC.

This subtype is usually associated with a favourable prognosis in most patients. Collecting 4 duct carcinomas are high grade cancers and are invariably associated with aggressive biological behaviour and poor outcome.

Medullary carcinoma occurs almost exclusively in association with the sickle cell trait and closely resembles the collecting duct variety.

Sarcomatoid change can occur in any histological type and is associated with poor prognosis. Nuclear grading is done by using the Fuhrman criteria and is an independent prognostic parameter affecting survival 1, By direct extension into the renal vein and inferior vena cava.

Other sites such as adrenal gland, brain, the opposite kidney, and subcutaneous tissue are frequent sites of disease spread.

The commonest symptoms associated with RCC are as follows: 1 2 3 4 5 6 Haematuria, Flank pain or backache Palpable mass in the abdomen or flank.

Non-reducing varicocoele or bilateral lower extremity oedema, both of which suggest venous involvement. Most of these are reversible after Nephrectomy but are usually not corrected by medical therapy.

Estimation of renal function is especially important in patients having with tumour in solitary kidney or bilateral tumours as well as in patients with diabetes, chronic pyelonephritis, renovascular, stone or renal polycystic disease where the function of the contralateral kidney may be compromised.

Preoperative hypercalcemia, anemia, and elevated ESR and few other abnormal laboratory values are independently associated with increased risk of cancer-specific death from clinically confined clear cell RCC Imaging: 1.

Ultrasonography - noninvasive, accurate, and relatively inexpensive and hence is usually the first investigation. It can differentiate between solid and cystic masses and also identify the need for further radiological investigations.

A solid mass with significant heterogenous postcontrast enhancement due to characteristic high vascularity less than of the normal renal parenchyma is virtually diagnostic of RCC , and any renal mass that enhances with contrast administration by more than 15 HU should be considered as RCC unless proved otherwise.

CT also assesses primary tumour extension with extrarenal spread, venous involvement, 7 3. CT can help rule out angiomyolipomas by demonstrating areas of negative CT attenuation indicative of the presence of fat in the tumour.

MRI has better sensitivity than CT scan in evaluating the presence and extent of venous extension, differentiating a tumour thrombus from a bland one and invasion of surrounding tissue and organs.

Venacavography - is indicated in presence of ambiguous MRI findings in cases with venous extension or in patients who cannot have MRI for some reason.

Doppler ultrasonography has limited sensitivity but a transoesophageal echocardiography is a useful tool for evaluating the cephalad extent of the thrombus.

Arteriography - Has a limited role and can be done prior to embolization. FNAB has excellent accuracy for detecting malignant masses especially when combined with molecular analysis 43, 44 but has a suboptimal predictive value for detecting benign masses Although the risk of complications is low, its impact on improving diagnostic accuracy or influencing clinical management is limited.

Metastatic work up: This includes 1. X-ray chest or CT scan of the chest. Isotope bone scans and targeted skeletal radiographs or scans, if indicated by clinical symptoms or raised serum alkaline phosphatase.

Pathological stage is probably the most important factor affecting outcome. Patients with systemic metastases are further assessed with performance status and classified in to risk groups.

Presence of para neoplastic signs. Nuclear grade and histologic subtype Sarcomatoid, collecting duct and medullary histology indicate a very poor prognosis.

Prognostic scoring systems - Kattan et al proposed a prognostic system incorporating symptoms, histology, tumour size and pathologic stage to predict probability of cancer free survival after nephrectomy in which they have incorporated tumour necrosis, tumour grade and vascular invasion to predict the outcome in patients with conventional RCC Parker et al evaluated a biomarker panel BioScore to enhance prognostic algorithms for clear cell renal cell carcinoma Treatment: Surgery is the mainstay of treatment of localized RCC.

Regional lymphadenectomy from the crus of the diaphragm to the bifurcation of aorta or inferior vena cava.

The erstwhile dogma of routine adrenalectomy and classical lymphadenectomy is now being questioned. In patients without radiological abnormality of the adrenal gland, routine adrenalectomy is not indicated except in patients with T3-T4 disease, locally advanced tumours and upper pole tumours 51, There remains a lack of consensus regarding the indications and extent of lymphadenectomy.

Current evidence suggests that lymphadenectomy should be restricted to staging, as extended lymphadenectomy does not improve survival.

Consequently, it is recommended to perform a hilar and immediate adjacent paraaortic or paracaval nodal dissection during a routine radical nephrectomy, for staging purpose.

In the higher risk group a complete lymph node dissection may be warranted. Radical nephrectomy can be done by following methods 1. Laparoscopic - transperitoneal, extraperitoneal or hand assisted.

Presently, there is no evidence favouring a specific surgical approach. In open approach, the choice of incision depends on the size and location of the tumour and the comfort of the surgeon.

There is no impact of a specific incision on the final outcome. The surgical and oncological outcomes after laparoscopic surgery have been reported to be equivalent to those after open surgery, with equivalent cancer specific survival rates and post-operative morbidity rates.

However, there have been no randomized trials comparing laparoscopic with the open radical nephrectomy.

Nevertheless, at the present time, laparoscopic radical nephrectomy should be considered the standard of care for TN0M0 tumours.

Appropriate patient selection as well as experience and expertise of surgeon remain vital to success of laparoscopic radical nephrectomy.

The absolute indication for NSS has been tumour in an anatomically or functionally solitary kidney where removal of the whole kidney would make the patient anephric with subsequent high risk of dialysis or transplant.

Relative indications for NSS are: 1. Patients with unilateral cancer and the contralateral functioning kidney affected by a condition that might threaten its future function such as renal artery stenosis, nephrosclerosis, hydronephrosis, diabetes, calculus disease, hypertension.

Hereditary forms of RCC with a high chance of developing a contralateral renal tumour. NSS can be done in patients with unilateral localized RCC with normal contralateral kidney as an elective indication.

The indications of NSS have been extended to include tumours up to 7 cm size and reports suggest no significant difference for tumour recurrence, cancer specific survival and renal function when compared to 4 cm size Another issue in NSS is the thickness of the tumour free margin.

The thickness of negative margin does not correlate with recurrence so long as the resection margin is cancer free and even 1 mm margin all around has been reported to be adequate 66, Laparoscopic partial nephrectomy is an alternative in suitable patients in the hands of an experienced laparoscopic surgeon.

Small, peripheral renal tumours are optimum indications for LPN. Although some centres have reported equivalent oncological outcomes after LPN, long term reliable data is yet not available from large studies.

Besides, LPN is associated with longer warm ischemia time and increased intra and post operative complications and hence its use should be limited to high volume centres with surgeons experienced in laparoscopic surgery.

Ablative surgical procedures: May be used as alternatives to surgery. Indications: 1. The various ablative techniques e. These can be instituted by open surgical route, by laparoscopic or even a percutaneous route.

The potential advantages of these procedures are that they are less morbid, can be done at outpatient procedures and can be offered to unfit patients.

The main disadvantages of these procedures are that there is no tissue available for histological confirmation of the lesion and that there is no histological proof of completeness of ablation.

This is indirectly assumed by a set CT criterion. In a recent population-based comparison of survival after nephrectomy vs nonsurgical management for small renal masses, these modalities have been found to be inferior to nephrectomy.

Close observation or Active surveillance: In view of an extremely slow growth rate of small renal masses 0. There may be a place for close observation with serial renal imaging in elderly or moribund patients who are poor risk for surgery or ablative procedures.

This approach is not advocated for young, fit patients with small renal masses if radiological features suggest RCC. Lower extremity oedema, Unilateral right sided varicocoele or one which does not collapse on recumbency, Dilated veins on anterior abdominal wall, Non-functioning involved kidney, Proteinuria, Prior history of pulmonary embolism or a right atrial mass on imaging.

An accurate assessment of the presence and extent of thrombus especially its cephalad limit is mandatory for planning appropriate treatment.

MRI is probably the best modality for accurate demonstration of the thrombus and for differentiating between a tumour thrombus and a bland thrombus by demonstrating post-contrast enhancement of the thrombus.

Inferior venacavography is generally reserved for patients in whom the MRI findings are equivocal or in whom MRI is contraindicated.

Transoesophageal ultrasonography and abdominal colour flow Doppler may also be employed to accurate assess the cephalad extent of thrombus.

The venous thrombus extension is classified by its level as follows: 16 I: II: III: adjacent to renal vein ostium extending up to lower border of liver infrahepatic involving intrahepatic portion of IVC but below the diaphragm IV: extending above the diaphragm Presence and extent of tumour thrombus have no adverse impact on survival.

Adjuvant therapy: Presently, there is no evidence that any adjuvant treatment after radical or partial nephrectomy improves survival.

The use of autologous tumour vaccine in adjuvant setting showed some advantage in progression free survival, but did not affect the overall survival.

In patients with high risk factors and locally advanced disease undergoing radical nephrectomy targeted therapy agents are being investigated for their role in the adjuvant setting.

Surveillance following surgery for RCC: Follow up is necessary to monitor 1. Post-operative complications. Renal function.

Local recurrence. Recurrence in the contralateral kidney. Development of metastases. However, there are no evidence based surveillance guidelines.

The patients may be classified into different risk groups according to one of the risk assignment systems based on clinicopathological factors and histological subtypes; and then the surveillance strategy may be individualized depending on the risk of relapse.

Although early detection of relapse is desirable, actually only a small percentage of patients with relapse can be salvaged by curative therapy.

One of the commonly employed follow up surveillance schemes is as follows: Low risk: Clinical examination, X-ray chest, ultrasonography of abdomen every 6 months.

CT scan not routinely advised. Intermediate risk: Clinical examination, X-ray chest or CT thorax, CT abdomen every 6 months for 2 years and then annually upto 5 years.

High risk: Clinical examination, CT thorax and CT abdomen at 3 months, then every 6 months for 5 years and annually thereafter.

Nearly two thirds of these will have associated systemic disease. In documented absence of distant relapse, surgery may be offered to remove the disease.

Patients not suitable for surgery may be managed with local radiation therapy or oral targeted therapy. Recurrence may be seen at the same site or at a different site due to multifocality of disease.

If metastatic work up reveals no abnormality, either a repeat partial nephrectomy or a radical nephrectomy is recommended In patients unsuitable for surgery, local ablative therapies may be tried.

Local recurrences after local ablative therapies are usually at the site of the original tumour and are suspected by persistent enhancement within the tumour bed or in rest of the kidney.

Treatment can be re-ablative therapy or total nephrectomy. Majority of these patients will die of disease within months if left untreated.

These may benefit with an aggressive therapeutic approach with intent of cure. The following factors indicate a better prognosis: Lung only metastasis Solitary vs.

Metachronous metastases. Metastatectomy can also be considered in patients with residual metastatic lesions responding to immunotherapy or target therapy, provided the metastasis is resectable.

The aim of treatment in patients with multiple metastases is palliative. Patients with multiple metastases may be classified into different prognostic groups for prognostication and planning optimum therapy.

The results of both these trials as well as their combined analysis have shown survival advantage in the nephrectomy arm In view of this, cytoreductive nephrectomy followed by systemic treatment should be considered in patients of metastatic RCC.

Patients have to be properly selected as few will be unable to take systemic treatment due to post-operative complications or rapid disease progression.

Patients most likely to benefit from cytoreductive nephrectomy are those with: 1. Preferably lung only metastasis. Absence of CNS or liver metastasis.

Easily resectable tumour with minimal morbidity. This may allow selection of betters with biologically more responsive tumours, reserving aggressive treatment for the patients most likely to benefit from it.

Pantuck et al in a retrospective analysis, recommended complete regional lymphadenectomy in patients undergoing cytoreductive nephrectomy for advanced disease and demonstrated a survival benefit in those undergoing lymphadenectomy in a retrospective analysis The role of cytoreductive nephrectomy has not been studied in non-clear cell histology.

Radiotherapy may be given for selected patients with brain metastases or painful skeletal metastases, for symptomatic relief.

Systemic therapy for metastatic RCC: Hormonal therapy in the form of progestational agents 86,87 and chemotherapy 88 have not been found to be effective in RCC.

In non-clear cell histology or in patients with sarcomatoid differentiation, chemotherapy may have a role and the preferred agents are doxorubicin and gemcitabine 89 Immunotherapeutic approaches to RCC include treatment with alpha interferon IFN-a or interleukin-2 IL-2 or a combination of the two.

The benefit to immunotherapy is limited to patients with good performance status, lung only metastasis, long metastasis free interval following nephrectomy and clear cell histology.

High dose IL-2 has been shown to be 21 superior to conventional dose IL-2 and has given durable complete responses in some patients but its use is limited due to associated high toxicity.

Combination of immunotherapy and chemotherapy has not been shown to be beneficial. Targeted therapy: Better understanding of the molecular pathways has led to the development of targeted agents with robust clinical effects.

This difference was larger in patients who did not receive any poststudy treatment The median overall survival was also longer in sunitinib arm In view of this, sunitinib is recommended as first line drug of choice in good and intermediate risk criteria patients.

It is recommended as second line therapy. A randomized trial comparing sorafenib with placebo demonstrated improved progression free survival 5.

However, this effect was not seen in previously untreated patients. IFN-a alone. A recent phase III trial in patients who had failed previous anti VEGF-R treatment showed better progression free survival with everolimus as compared to placebo 4 months vs.

Surgical resection of renal cell carcinoma after targeted therapy is feasible with low morbidity in most patients. In this group of patients, careful patient selection, preoperative patient optimization and meticulous perioperative care can lead to a better outcome.

The changing natural history of renal cell carcinoma. J Urol Nov; 5 Cancer statistics, Renal tumours.

Philadelphia: WB Saunders, , pp. LucianiLG, Cestari R, Tallarigo C: Incidental renal cell carcinoma: Age and stage characterization and clinical implications: study of patients Urology , 56, Lindblad P.

Epidemiology of renal cell carcinoma. Scand J Surg ; 93 2 Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.

Ann Oncol May;20 Suppl Incidental renal tumours: casting doubt on the efficacy of early intervention.

J Urol , , Renal cell carcinoma in children: experience at a single institution in Japan. J Urol. Review Broecker B.

Urol Clin North Am. Local lymph node involvement does not predict poor outcome in pediatric renal 24 cell carcinoma.

Renal cell carcinoma in children: the Detroit experience. Br J Cancer. Int J Cancer. Obesity is associated with a higher risk of clear-cell renal cell carcinoma than with other histologies.

BJU Int. Smoking, environmental tobacco smoke and risk of renal cell cancer: a population-based case-control study. BMC Cancer.

Smoking cessation and renal cell carcinoma. Ann Epidemiol. Obesity, hypertension, and the risk of kidney cancer in men.

N Engl J Med. Ultrastruct Pathol , 11 , Immunohistology of renal carcinomas. Eur Urol. The genetic basis of cancer of the kidney.

Searching for the hereditary causes of renal-cell carcinoma. Nat Rev Cancer. Biology of renal cell carcinoma: changing concepts in classification and staging.

Semin Urol Oncol May; 19 2 : Br J Urol , 82 1 , Multilocular cystic renal cell carcinoma: a clinicopathological, immuno- and lectin histochemical study of nine cases.

Multilocular cystic renal cell carcinoma: a series of 12 cases and review of the literature. The Cleveland Clinic experience with papillary chromophil renal cell 26 carcinoma: clinical outcome with histopathological correlation.

Can J Urol. J Urol , 1 , Intraoperative evaluation of renal cell carcinoma: a prospective study of the role of ultrasonography and histopathological frozen sections.

Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. Incidental renal tumours: Urology.

Mode of presentation of renal cell carcinoma provides prognostic information. Urol Oncol ; 7 4 : Correlation between symptom gradation, tumour characteristics and survival in renal cell carcinoma.

Eur Urol ; 44 2 Jayson M and Sanders H: Increased incidence of serendipitously discovered renal cell carcinoma.

Urology , 51, 27 Rosenblum SL: Paraneoplastic syndromes associated with renal cell carcinoma. J Scand Med Assoc , 83, Association of abnormal preoperative laboratory values with survival after radical nephrectomy for clinically confined clear cell renal cell carcinoma.

Radiologic assessment of renal masses: implications for patient care. Radiology ; Bosniak MA. Renal-cell carcinoma. J Urol ; Update on oncocytoma.

Curr Urol Rep. Int J Urol , 11, BJU Int , 97, Silver DA, Morash A and. Brenner P et al. Ann Surg Oncol , 4. Licht MR. Renal adenoma and oncocytoma.

Development and evaluation of BioScore: a biomarker panel to enhance prognostic algorithms for clear cell renal cell carcinoma.

The results of radical nephrectomy for renal cell carcinoma. Adrenal metastases in patients with renal cell carcinoma: outcome and indication for adrenalectomy.

The necessity of adrenalectomy at the time of 29 radical nephrectomy: a systematic review. UCNA , 35, Mayo Clin Proc , 75, Urol Clin North Am , 30, Partial versus radical 30 BJU Int, 97, Changing concepts in the surgical management of renal cell carcinoma.

Urology , 60, Cancer specific survival for patients with pT3 renal cell carcinoma-can the primary tumour classification be improved?

Prognostic significance of venous thrombus in renal cell carcinoma. Are renal vein and inferior vena cava involvement different?

Renal cell carcinoma with tumour thrombus extension: biology, role of nephrectomy and response to immunotherapy. BJU Int , 94, Guidelines for the surveillance of localized renal cell carcinoma based on the patterns of relapse after nephrectomy.

Urology , 64, Stage specific guidelines for surveillance after radical nephrectomy for local renal cell carcinoma.

Renal cell carcinoma local recurrences: impact of surgical treatment and concomitant metastasis on survival. Bukowski RM. Natural history and therapy of metastatic renal cell carcinoma: the role of interleukin Resection of pulmonary metastases from renal cell carcinoma.

Anticancer Res. J Clin Oncol , 16, Can we predict long-term survival after pulmonary metastasectomy for renal cell carcinoma?

Ann Thorac Surg. N Engl J Med ,, Mickish GH, von Poppel H, De Prijck L et al: Radical nephrectomy plus interferon alpha based immunotherapy compared with interferon alpha alone in metastatic renal cell carcinoma: a randomized trial.

Lancet , , J Urol , Jun; 6 MRC Renal Cancer Collaborators : Interferon alfa and survival in metastatic renal cell carcinoma: early results of a randomized controlled trial: Lancet , , Negrier S, Perd D, Ravaud A et al: Do cytokines improve survival in patients with metastatic renal cell carcinoma of intermediate prognosis?

Results of prospective randomized Percy Quattro trial. J Clin Oncol , 23 Suppl Pt 1. Urol Clin North Am , 20 2 , Cancer , 7 , Renal cell carcinoma.

N Engl J Med , 2 , Sorafenib in advanced clear cell renal cell carcinoma. Bevacizumab plus interferon alfa 2a for treatment of metastatic renal cell carcinoma: a randomized double blind phase III trial.

J Clin Oncol , 26, N Engl J Med , 22 , Surgical resection of renal cell carcinoma after targeted therapy. These different presentations of bladder cancer have different clinical behaviour, management protocols and outcome.

Bladder cancer is the commonest urological malignancy in India and the second most common genitourinary malignant disease in the USA, with an expected 69, newly diagnosed cases in , and 14 deaths in the USA.

Aetiology: level of evidence 3 Cigarette smoking is the single most important environmental etiological factor associated with bladder cancer and triples the risk of bladder cancer.

The risk of bladder cancer directly relates to duration of smoking 37 and number of cigarettes smoked per day and an immediate reduction in the risk of bladder cancer is observed with cessation of smoking.

The other associated aetiological factors are: A Chemical exposure - Chemical agents: Exposure to aromatic amines as seen in workers of dye, rubber, leather industry, gas and tar manufacturing, industrial painting etc.

C Genetic abnormality - 17p deletion, p53 expression; RB gene expression, 9q aberration. Lower urinary irritative and obstructive symptoms may be the sole presenting symptoms in the absence of haematuria.

Pelvic pain and obstructive symptoms are seen in patients with advanced invasive disease. Even a single episode of haematuria needs to be investigated from the point of view of bladder cancer, even if another potential cause for haematuria is found.

All patients over 40 years old, smokers and those with exposure to industrial carcinogens with painless haematuria should be investigated with urinary cytology, cystoscopy and imaging IVP or CT-scan for urinary tract malignancy.

Investigations : The aims of investigations in bladder cancer are diagnosis and staging to guide therapy. The main factor that decides the treatment is the presence or absence of muscle invasion.

Freshly voided urine cytology of exfoliated cancer cells is particularly useful in the presence of a highgrade malignancy or CIS.

Urine specimens for cytology should not be obtained from the first voided morning specimens. Positive cytology in the absence of any lesion on imaging may indicate a lesion anywhere in the urinary tract.

Negative voided cytology does not necessarily exclude the presence of a low-grade bladder tumour. Intravenous urogram is indicated in all patients with haematuria or cystoscopic evidence of bladder cancer.

It is not a sensitive means of detecting 39 bladder cancer alone but useful in examining the upper urinary tracts for associated urothelial tumours.

Retrograde pyelogram should be performed if the upper tracts are not adequately visualized on the intravenous urogram. The necessity to perform routine IVU at initial diagnosis is now questioned because of the low incidence of important findings obtained with this method incidence of upper tract tumours is about 1.

Ultrasonography of the abdomen and pelvis to document status of upper tracts and for associated upper tract urothelial tumours, besides demonstrating the bladder tumour.

Combined with plain abdominal film, it can be as accurate as IVU in the diagnosis of the cause of haematuria. Cystoscopic examination of the bladder and pathological evaluation of the resected lesion form the cornerstone of diagnosis.

During cystoscopy, the characteristics of bladder tumour s are noted and a biopsy from the bladder tumour taken. Bladder washings for cytology should be taken as studies have demonstrated superiority of bladder washing over voided urine cytology.

The first treatment decision based on tumour stage is whether the patient has a superficial or muscle invasive bladder cancer.

Transurethral resection of the bladder tumour TURBT is the most important test for judging the depth of tumour penetration.

Inclusion of muscle in biopsy is essential. During resection, the following are recommended: 1. Resect the tumour down to muscle and send superficial and deep components of the tumour separately to the pathologist 40 2.

If the cancer is muscle invasive, complete debulking is preferable 3. Biopsy of the base of the tumour 4. Random biopsies from apparently uninvolved normal areas of bladder are indicated in the presence of positive cytology, in the absence of a tumour or in any non-papillary tumour.

Biopsies from the prostatic urethra are indicated in the case of bladder neck tumour, when bladder CIS is present or suspected, in the case of positive cytology without evidence of tumour in the bladder or when abnormalities of prostatic urethra are visible level of evidence 3.

The biopsy is taken using resection loop from the precolicular area. Bimanual examination under anaesthesia may be done in case of invasive tumours for local staging of the tumour.

It may be performed both before and after the TUR. The presence of a palpable mass after TUR implies an extravesical disease. It can also indicate fixity to the pelvic side walls.

These have a better sensitivity for detecting bladder cancer but the specificity is much lower. Higher false positive tests can lead to unnecessary imaging and bladder biopsies.

It is not clear whether these tests can offer additional information, which is useful for 41 decision making, treatment and prognosis of superficial bladder cancer.

Fluorescence cystoscopy is a promising tool using violet light after intravesical instillation of a photosensitizer e.

Fluorescence-guided biopsy and resection are more sensitive than conventional procedures in detecting malignant tumour, particularly CIS level of evidence 2a.

If urinary cytology is persistently positive without any demonstrable bladder lesion, ALA installation and use of specific wavelengths yields higher positive biopsies.

The technique is still evolving. Imaging: The purpose of imaging for staging is to assess extent of local tumour invasion, detect lymph node spread and to detect distant metastases.

For invasive cancers, it is essential to document the extent of the disease by doing cross sectional imaging.

Both computed tomography CT and MRI scans can be used for assessment of local invasion, but they are unable to detect microscopic invasion of perivesical fat T3a.

Imaging is also used to assess the presence of pelvic and para-aortic lymphadenopathy and the possible presence of liver or adrenal metastases.

However, it has limitations in recognizing minimal pelvic nodal disease or microscopic invasion of 42 adjacent organs. Metastatic work up: Chest radiographs are performed to rule out pulmonary metastases, however, CT scan is the most sensitive means of detecting pulmonary metastasis.

Isotope bone scan is done to detect bony metastasis and also useful as a baseline for future reference, particularly in patients with bone pains or increased alkaline phosphatase.

CT or MRI of brain is done if clinically indicated. Natural History and pathology Bladder cancer is multicentric and asynchronous. Low grade tumours G1 have high local recurrence rate but usually do not invade muscularis.

High grade superficial tumours have high propensity to transform to invasive tumour. All invasive tumours are high grade. Small tumours less than 1 cm can be resected en bloc.

Specimen should contain a part of the underlying bladder wall. Larger tumours should be resected separately in fractions, which include the exophytic part of the tumour, the underlying bladder wall with the detrusor muscle and edges of the resection area.

Cauterization should be avoided during resection to prevent tissue destruction. Accurate staging of disease is important for optimum treatment and understaging may lead to inadequate treatment and poor outcome.

Second TURBT should be considered if there is a suspicion of incomplete initial resection multiple or large tumours present with no muscle invasion on pathology and after diagnosis of high-grade non-muscle-invasive tumour.

It has been shown that the second TURBT can increase recurrencefree and progression-free survival level of evidence 2a.

Bladder cancer with low risk of recurrence or progression can be managed by close surveillance and regular check cystoscopy, while those with high risk of relapse need intravesical chemotherapy or immunoprophylaxis.

Mitomycin C MMC , epirubicin, and doxorubicin have all shown a comparable beneficial effect level of evidence 1b. The timing of the instillation is crucial and the single instillation is recommended within 24 hours preferably within 6 hours of TURBT and a delay increases in the relative risk of recurrence twofold level of evidence 2a.

The effect of single post-operative instillation is mainly seen in the first 2 years. A single immediate post-operative instillation of chemotherapy is recommended in all patients irrespective of the risk group, provided there is no perforation or bleeding.

Low risk group patients with papillary tumours require no further treatment as the recurrence rate in this group is very low after single instillation immediately after TURBT level of evidence 1a.

Intermediate and highrisk patients require a further weeks course of intravesical therapy. Additional adjuvant intravesical therapy: The need for further adjuvant chemotherapy or BCG immunotherapy largely depends on the risk of recurrence or progression.

It is still controversial how long and how frequently intravesical chemotherapy instillations have to be given.

From a systematic review of the literature of randomized clinical trials, which compared different schedules of intravesical chemotherapy, it can be seen that the ideal duration and intensity of the schedule remains undefined because of conflicting data.

The efficacy of intravesical chemotherapy in reducing the risk of recurrence was demonstrated in the primary as well as recurrent settings by 2 meta-analyses by Huntcharek in and To increase the efficacy of intravesical chemotherapy, optimized schedules have been tried.

The studies demonstrated that adapting the urinary pH, decreasing the urine formation and excretion, buffering the intravesical solution and increasing the relative concentration of the drug in the instilled solution may lead to improvement in efficacy.

Bacillus Calmette-Guerin BCG is used as intravesical immunotherapy and has been shown to be effective in reducing tumour recurrence rate and presently is the only agent, which has been shown to reduce the progression rate to muscle invasion, reduce the need for cystectomy, increase the time to cystectomy and improve survival.

Two meta-analyses demonstrated that BCG therapy prevents, or at least delays, the risk of tumour progression. The most optimal BCG maintenance schedule is not known.

Although weekly instillations for 6 weeks are a commonly used schedule empirical schedule, a meta-analysis concluded that at least 1 year of maintenance BCG was required to show the superiority of BCG over MMC in preventing recurrence or progression level of evidence 1a.

Hence, in patients with intermediate and high risk patients, maintenance BCG is advised to achieve best results, provided patients can tolerate it.

Various schedules of maintenance BCG have been described but to date, there is no optimum schedule based on high level of evidence.

Most centres, however, follow the schedule described by Lamm. The optimal dose of BCG is yet undefined. To reduce BCG toxicity, several authors have proposed dose reduction of BCG to one third to one fourth of the standard dose.

The Spanish Oncology Group CUETO compared the standard dose with one third dose of BCG in a randomized trial and did not find any difference in efficacy, except in patients with high risk prognostic group.

Treatment of failure of intravesical therapy: Failure of intravesical chemotherapy: Patients with non muscle invasive recurrences after intravesical chemotherapy may benefit from intravesical BCG immunoprophylaxis.

Failure of intravesical BCG immunotherapy: The response to BCG is assessed at 6 months after TUR, since the disease status at this point of time has been shown to best correlate with subsequent progression and survival.

This classification helps in identifying optimum treatment for patients in each subgroup. Treatment with BCG is considered to have failed in case of: a.

Worsening of disease such as increased number of recurrences, higher stage or grade, appearance of CIS in spite of initial response to BCG Various strategies have been recommended for treatment of BCG failure: a.

Intravesical chemotherapy, especially device assisted one Newer intravesical chemotherapeutic agents such as gemcitabine Second line immunotherapeutic agents such as interferons with or without BCG Cystectomy Cystectomy for non-muscle invasive bladder cancer: Despite intravesical adjuvant therapies, there is a substantial group of patients with initial high-grade stage T1 tumor who have progression and are at risk of dying from urothelial cancer.

It is reasonable to propose immediate cystectomy to those patients who are at high 51 risk of progression multiple recurrent high-grade tumours, high-grade T1 tumours, high-grade tumours with concomitant CIS.

Cystectomy is advocated in patients with BCG failure and delaying cystectomy in these patients may lead to decreased disease specific survival.

Management of carcinoma-in-situ: Carcinoma-in-situ of bladder may exist alone primary CIS or in combination with a bladder tumour.

CIS associated with an overt tumour is treated according to the merits of the tumour. Non-responders or incomplete responders have a significant risk of tumour progression and cystectomy is recommended in such patients.

Patients with an incomplete response at 9 months, recurrent tumours or extravesical disease also need cystectomy. Follow up schedules in superficial tumours: Prompt detection of muscle-invasive and high-grade nonmuscle-invasive recurrences is critical and delay in diagnosis and therapy could compromise survival.

Tumour recurrence in low-risk group is nearly always low stage and low grade and does not pose a threat to life.

High risk patients may present as muscle invasive 52 disease on recurrence and need immediate diagnosis and treatment. The result of first cystoscopy after TUR at 3 months is an important prognostic factor for recurrence and progression level of evidence 1a and hence cystoscopy at 3 months post-TUR is recommended in all patients.

If negative, following cystoscopy is advised at 9 month and consequently yearly for 5 yr. First cystoscopy finding at 3 months is significant prognostic factor for recurrence and for progression 2.

If negative, following cystocopies and cytologies should be repeated every 3 mo for a period of 2 yr, every 4 months in the third year, every 6 month thereafter until 5 yr, and yearly thereafter.

A yearly exploration of the upper tract is recommended 3. Intermediate risk: should have an in-between followup scheme using cystoscopy and cytology, adapted according to individual factors.

Cytological surveillance should accompany every cystoscopic examination. During cystoscopy, directed biopsy should be taken if there is any suspicious area.

Intravenous urogram is therefore recommended at least once in two years, or in the presence of positive cytology and negative cystscopy.

Ultrasonography is recommended once a year. The role of urinary markers like NMP22, urine cytology or multitarget FISH study on exfoliated urine cells to replace cystoscopic evaluation or to postpone it is under 53 evaluation but till the time the results of these studies are available, cystoscopic evaluation remains the gold standard for follow up in a patient with superficial bladder cancer.

Surgery Radical cystectomy is the preferred treatment for invasive bladder cancers in patients whose medical condition allows major surgical procedure Level of evidence 2a.

There is evidence from retrospective studies that extended lymphadenectomy improves outcome in patients with tumours confined to the bladder.

However, no controlled studies support extended lymphadenectomy as curative treatment. Thus limited or regional lymph node dissection is the recommended standard surgical method Level of evidence 3.

Removal of more than 15 lymph nodes has been postulated to be both sufficient for the evaluation of the lymph node status as well as beneficial for overall 54 survival in retrospective studies In the presence of gross nodal disease; 5-year survival rates are poor.

Radical cystectomy is recommended for non-transitional cell carcinomas, which generally respond less to radiation and chemotherapy.

Partial cystectomy may be indicated in only selected patients with 1 Transitional cell tumour 2 solitary muscle invasive tumour location at dome, 3 no extravesical spread 4 random mucosal biopsies are negative and 5 intra-operative frozen section surgical margins negative.

Laparoscopic or robot assisted radical cystectomy may be an option for the future. Current data, however, is insufficient to support its routine use at present.

Urethrectomy has been recommended if the tumour involves the bladder neck in women or the prostatic urethra in men.

A positive urethral cut margin at the end of cystectomy also signifies the need for urethrectomy. Extensive involvement of the prostate also necessitates urethrectomy.

Recently, there is a trend towards preservation of urethra to make orthotopic neobladder possible as well as preservation of intrapelvic autonomic nerves to improve potency and continence.

Urethrectomy may be done at the time of cystectomy or subsequently as a separate procedure. Contra-indications to orthotopic neobladder include prostatic urethral involvement, positive urethral margins, multiple bladder tumours or multicentric involvement of the urinary tract.

The type of urinary diversion does not affect oncological outcome Level of evidence 3. Orthotopic neobladder is the reconstruction of choice undergoing radical cystectomy and is recommended in suitable male and female patients.

However, the advantage of orthotopic neobladder over other diversions in terms of quality of life remains a matter of debate.

Terminal ileum and colon are the intestinal segments of choice for urinary diversion. The morbidity of orthotopic neobladder reconstruction is appreciable in terms of major complications and reoperation rates.

The contra-indications to orthotopic neobladder include prostatic urethral involvement, positive urethral margins, multiple bladder tumours or multicentric involvement of the urinary tract i.

Orthotopic neobladder reconstruction should be advised to suitable patients after cystectomy for organ-confined muscle-invasive bladder tumour.

While discussing this option with the patient, the morbidity must be addressed. The longer recovery period after orthotopic neobladder may delay the subsequent adjuvant therapy in patients with locally advanced disease and in these patients, this option may not be advisable.

Definitive radiation therapy alone: External beam radiation therapy should only be considered a therapeutic option when the patient is unfit for cystectomy for a multimodality bladder sparing approach level of evidence 3.

Based on available data, a Cochrane analysis has demonstrated that radical 56 cystectomy has an overall survival benefit over radiation therapy alone.

Pre-operative Radiotherapy Pre-operative radiotherapy for operable muscle-invasive bladder cancer, using a dose of 45 to 50 Gy in fractions of 1.

It does not significantly increase toxicity after surgery and may result in a decrease in local recurrence of muscle-invasive bladder cancer Level of evidence 3.

Pre-operative radiotherapy in above dose for operable muscle-invasive bladder cancer does not increase survival and cannot be recommended as standard practice as the data may not be applicable to modern surgical and radiotherapeutic procedures Level of evidence 2.

Multimodality treatment and Bladder preservation approaches: The use of organ-preservation therapy for bladder cancer is a valid alternative to radical cystectomy in selected patients Level of evidence 3.

Contemporary protocols utilize a combination of aggressive TUR, concurrent radiation and chemotherapy, and often adjuvant chemotherapy.

These approaches require close coordination among all disciplines involved. For 57 preventing poor outcome in non-responders, early cystectomy is recommended in individuals who do not achieve complete response following combination treatment.

Successful long-term survival rates have been observed in select non-randomized trials with this approach. Non-invasive relapses may be treated with TUR followed by intravesical therapy.

In view of the high local recurrence rate, a long-term follow up with cystoscopy, exfoliative urine cytology and other investigations to rule out disseminated disease is warranted.

In the best hands, overall survival rates with bladder preservation are comparable to radical cystectomy Level of evidence 3.

On multivariate analysis, the completeness of TURBT has been found to be one of the strongest prognostic factors for overall survival.

With standard fractionation 1. There is a suggestion of a dose response 58 relationship and retrospective analyses have suggested improved local control with doses greater than Gy Level of evidence 3.

Prophylactic irradiation of pelvic nodes is debated with no consensus on its utility. Use of altered fractionation has been reported to induce a higher local control rate but this modality is still investigational.

Overall, the available data indicate that differences in local control between different radiation fractionation schedules are more related to the total dose than to the fractionation regimens.

A reduction in overall treatment time and large fraction sizes should be avoided, especially when radiotherapy is combined with concomitant chemotherapy.

New treatment techniques, such as image-guided and intensity-modulated 59 radiotherapy, may allow dose escalation with the expectation to further improve tumour response and longterm local control.

In order to improve these results, use of neoadjuvant chemotherapy has been explored. The rationale for chemotherapy prior to cystectomy or radical radiation therapy is based on the intent to treat micrometastatic disease that is present at diagnosis.

There is level 1 evidence of a survival benefit conferred by neoadjuvant chemotherapy administered before definitive local treatment surgery or radiotherapy.

This advantage in survival was seen for all muscle-invasive tumours, and only patients who received a cisplatin containing regimen benefited.

While the available data support the use of M-VAC methotrexate, vinblastine, doxorubicin and cisplatin or CMV cisplatin, methotrexate, vinblastine as neoadjuvant chemotherapy, these regimens are less frequently used because phase 3 data in the metastatic setting suggested that a less 60 toxic regimen of gemcitabine and cisplatin GC has similar efficacy to M-VAC.

The efficacy of the GC combination in the neoadjuvant setting, however, has not yet been proven, suggesting that M-VAC or CMV should still be used, based purely on the available data.

Neoadjuvant chemotherapy is not recommended in patients with poor performance score and impaired renal function.

Adjuvant therapy Till date, there have been five published randomized trials of adjuvant chemotherapy and one meta-analysis, with updated individual patient data from six trials and a total of only patients for survival analysis.

Neither randomized trials nor the meta-analysis have provided sufficient data to support the routine use of adjuvant chemotherapy Level of evidence 1a.

Adjuvant postoperative radiotherapy has been studied in retrospective series have shown improved locoregional control particularly for squamous cell carcinomas , but no survival benefit.

Toxicity has been a concern with postoperative RT but with modern techniques like IMRT, this can be addressed adequately.

Chemotherapy is the standard therapy for patients with metastatic bladder cancer. Urothelial carcinoma is a chemosensitive tumour.

Performance status and presence or absence of visceral metastases are important prognostic factors for survival. Single-agent chemotherapy provides low response rates of typically short duration.

Carboplatin combination chemotherapy is less effective than cisplatin-based chemotherapy in terms of CR and survival Level of evidence: 2a.

Both the arms were found to be equivalent in terms of response rates, time to treatment failure, time to progressive disease and overall survival.

GC appeared to have reduced toxicity profile as compared to M-VAC, making GC a new standard chemotherapeutic option in patients with metastatic bladder cancer Level of evidence 1b.

There is insufficient data to provide a recommendation on standard second-line chemotherapy. Therefore, second-line therapy should be provided within a clinical trial setting.

Quality of life issues are very important considerations while deciding further chemotherapy.

Cancer statistics. The role and impact of pathology review on stage and grade assessment of stages Ta and T1 bladder tumors: a combined analysis of 5 European Organization for Research and Treatment of Cancer trials.

Guidelines on Bladder carcinoma. The natural history and the prognosis of treated superficial bladder cancer.

Reviews in Urology ; Histological typing of urinary bladder tumors. International classification of tumors. World Health Organization, Geneva: Bladder Consensus Conference Committee.

TNM supplement- A commentary on uniform use. Brausi, L. Collette, K. Kurth et al. Denziger, M. Burger and B. Walter, Clinically relevant risk of reduction in risk of recurrence of superficial bladder cancer using 5-aminolevulinic acid-induced fluorescence diagnosis: 8-year results of prospective randomized study, Urology 69 , pp.

Kundra V, Silverman PM. Imaging in oncology from the University of Texas M.

2 comments

Leave a Reply

Deine E-Mail-Adresse wird nicht veröffentlicht. Erforderliche Felder sind markiert *