CIS of the bladder: a review of literature/Mesanede karsinoma in situ: literatür derlemesi

Headnote

ABSTRACT

Carcinoma in situ (CIS) of the bladder poses a clinical challenge to urologists worldwide. The clinical course of CIS ranges from benign, indolent tumor growth to highly progressive tumor proliferation with deleterious effects on patient outcome and increased disease-specific mortality. The aim of our review was to outline the natural history of bladder CIS in a single concise source for young urologists. We performed a PubMed review of the literature on CIS of the bladder. We used CIS, BCG and superficial bladder cancer as the keywords for our search. Following a group discussion, the authors selected 77 important publications to be included in our review article. The presence of bladder CIS increases the risk of panurothelial disease involving the prostate, urethra or upper urinary tracts. Urine cytology is the primary approach for the di- agnosis of CIS. Intravesical BCG remains the gold standard for the initial treatment of CIS. Early radical cystectomy for cases that present BCG failure showed a higher rate of success with long-term cure. Frozen section biopsy of the distal ureter should be performed when CIS of the bladder has been preoperatively diagnosed. Whether frozen section biopsy was performed and regardless of the condition of the distal ureter at the time of cystectomy, postoperative follow-up with cytology, endoscopy of the new pouch and ureteros- copy of the ureters is recommended for early detection of possible recurrence.

Key words: BCG; carcinoma in situ; intravesical chemotherapy

ÖZET

Mesanede karsinoma in situ (KIS) ttim dtinyada iirologlar için bir klinik sorun olugturmaktadir. Tembel bir tiimörden, hastanm akibeti tizerine zararli etki ve hastaliga özgii mortalité arti§i ile birlikte oldukça progresif bir tiimöre kadar degigen geni§ bir klinik seyre sahiptir. Derlememizin amaci genç iirologlarin mesane KIS'in dogal seyrini anlamalari için özet bir kaynak saglamaktir. Mesane KIS çaligilan literatiirlerin bir pubmed derlemesini yaptik. Tarama sirasinda anahtar sözciikler olarak "CIS", "BCG" ve "superficial bladder cancer" kullandik. Grup tarti§masim takiben, yazarlar 77 önemli yayimn derleme makalemize dahil edilmesine ka- rar verdi. Mesane KIS mevcudiyeti prostat, uretra veya Ust idrar yollarim tutan panurotelial hastalik riskini artirmaktadir. Idrar sitolojisi KIS tamsi için baglica dayanaktir. Intravezikal BCG KIS baglangiç tedavisi için altin standart olmayi stirdtirmektedir. BCG'nin bagarisiz oldugu olgular için erken radikal sistektomi uzun dönemli ktir oranlari ile daha yiiksek ba§ari göstermigtir. Mesanede KIS tamsi ameliyat öncesi konuldu- gunda, distal ureterin (frozen section) biyopsisi yapilmalidir. Sistektomi sirasinda distal ureterin durumuna veya frozen kesit yapilip yapilmadigina bakilmaksizin, olasi rektirrensin erken saptanmasi için sitoloji, yeni kesenin endoskopisi ve ureterlerin ureteroskopisi ile ameliyat sonrasi takip önerilmektedir.

Anahtar sözciikler: BCG; karsinoma in situ; intravezikal kemoterapi

Introduction

Definition

Carcinoma in situ (CIS) is defined as flat (non- papillary), high-grade and involving either the entire thickness or part of the urothelium.1'

Using the 2002 TNM classification system, CIS is classified, together with Ta and T1 papillary tumors, as superficial tumors of the bladder.121

Historical review

CIS of the bladder was first described in 1952 by Melicow, who evaluated grossly normal appearing mucosa of tumor-bearing bladders, identified foci of cellular activity and diag- nosed the foci as malignant with invasive potential, rather than precancerous lesions.13 41

The 1998 WHO/ International Society of Urological Pathology consensus expanded the definition of CIS to include lesions previously designated as severe dysplasia or marked atypia.151

Risk of CIS

The natural history indicates a greater than 50% 5-year progres- sion rate to invasive disease and higher recurrence rate.1671 If CIS is associated with T1 papillary tumor of the bladder, the progression rate increases to 80% for cases treated by resec- tion only (TURBT).181 CIS of the bladder is associated with a 3- 4-fold higher risk for CIS of the upper urinary tract (UUT) than invasive bladder tumors.19101

Salsona et al.[U1 reported that in patients undergoing cystectomy, the incidence of UUT TCC was higher among cases with blad- der CIS (8 of 46, 17.4%) than among cases with invasive blad- der cancer (7 of 179, 3.9%) (p<0.01).

Wang et al.[121 compared UUT TCC recurrence rates after pri- mary invasive bladder cancer with those after CIS and identi- fied a higher incidence after CIS. The incidence of UUT TCC recurrence after CIS of the bladder was 11 out of 56 (19.6%), whereas following invasive bladder tumor, the incidence was 11 out of 420 (2.6%) (p-value=0.007).

Nixon et al.[131 reviewed 192 consecutive radical cystectomy specimens and noted that in specimens from patients with CIS in the bladder, 31.3% had prostatic urethral involvement. The authors concluded that the risk of prostatic urethral involve- ment is 12-15-fold higher when CIS or multifocality of bladder urothelial carcinoma is present.

Iba et al.[141 published a case report of CIS of the bladder neck, which invaded the prostatic stroma and was difficult to diag- nose, except by TRUS-guided biopsy.

Millan et al.[101 detected that out of 1529 patients who underwent random biopsy of the bladder and prostatic urethra, 19% had CIS of the bladder and 2.7% had CIS of the prostatic urethra.

In contrast to testicular CIS and prostatic intraepithelial neo- plasia, CIS of the bladder is a dangerous disease with a narrow window between successful treatment and progression or even disease-specific mortality. Shariat et al.1151 demonstrated 3-year bladder cancer-specific survival rates of 65% and 37% for patients with de novo invasive tumor and patients with tumor progression beyond the CIS criteria, respectively.

Schrier et al.1161 demonstrated that patients experiencing disease progression from CIS to muscle-invasive tumors have a signifi- cantly worse prognosis compared with stage- and age-matched patients with de novo invasive tumors.

Masood et al.1171 demonstrated that 55% of patients with clinically high grade T1 bladder cancer and concomitant CIS experienced upstaging at cystectomy compared with only 6% of patients with clinically high grade T1 of the bladder without CIS.

Focal CIS may exist for years and progresses in as few as 8% of patients.171

Incidence

Primary CIS constitutes 1-3% of all urothelial neoplasms.111 Secondary CIS is detected during follow-up in 90% of cases with urothelial neoplasms.171

Also, 45-65% of invasive urothelial carcinoma and 7-15% of superficial papillary carcinoma are accompanied by CIS.111

CIS is noted predominantly in male smokers in the sixth and seventh decades of life.1181

Kaasinen et al.1191 reported that 5% of patients with superficial bladder cancer had concurrent CIS. Palou et al.1201 reported a 19% incidence of concurrent CIS.

Clinical types

According to Lamm et al.,1211 bladder CIS can be classified into 3 clinical types:

1. Primary CIS: isolated CIS with no previous or concurrent papillary tumor

2. Secondary CIS: CIS detected during the follow-up of patients with a previous papillary tumor

3. Concurrent CIS: CIS in association with a papillary tumor

Genetic changes

There are several genetic changes that may predispose patients to develop CIS of the bladder and allow disease progression to invasive bladder tumor growth.

The most important genetic changes are deletion/ mutation of the P53 gene located on 17pl3.1, loss of cyclin-dependent kinase inhibitor (CDKN2/pl6) and deletion of 9q.122 24

Clinical presentations

CIS presents with irritative bladder symptoms in the form of dysuria, frequency and urgency. Hematuria, if present, is typi- cally microscopic.11251

Diagnosis

1) Urine cytology: CIS is associated with loss of cell cohe- sion in the epithelial lining of the bladder; therefore, a large number of floating cells are found in urine. Therefore, CIS is nearly always detected by urine cytology with a sensitiv- ity and specificity of over 90%. Cytology can be performed on voided urine or bladder wash (barbotage) during cystos- copy; however, the EAU guidelines recommend performing cytology on voided urine, unless a bladder wash is per- formed at the time of cystoscopy.1261 The recent European guidelines insist on performing cytology on fresh urine with adequate fixation and also state that morning urine is unsuitable because cytolysis may be present.1271 Cellular anaplasia, loss of polarity, discohesion, nuclear enlarge- ment, hyperchromasia, pleomorphism and atypical mitoses are the histopathological hallmarks of CIS.1181

However; Sharkey1281 found a considerable discrepancy between local and review pathology, in which 22% of the cases with CIS were downgraded to dysplasia, whereas 30% of the reports of dysplasia were upgraded to CIS.

Yin et al.1291 suggested that the combined use of cytokeratin 20 (CK20) and Ki-67 is sufficient to allow discrimination of CIS from dysplastic cells.

2) Urine markers: Over the last decade, many markers became available to aid in CIS diagnosis and its discrimina- tion from urothelial dysplasia. Schwarts et al.1301 and Nese et al.1181 demonstrated the promising role of UroVysion fluorescent in situ hybridization (FISH) in clearly differ- entiating patients with CIS from patients with dysplasia or reactive atypia; detecting polysomic cells (of chromosomes 3, 7 and 17) and deletion of the 9p chromosome, which are particularly present in CIS and invasive urothelial tumors. Kageyama et al.1311 reported the high sensitivity of calreticu- lin (CRT) in detecting bladder cancer cells, but CRT has low specificity.

Sullivan et al.1321 reported a higher sensitivity of ImmunoCyte compared with both urine cytology and UroVysion in detect- ing bladder cancer but a lower specificity; the specificity was 97%, 63% and 90% for urine cytology, ImmunoCyte and UroVysion, respectively. Mian et al.1331 confirmed the particularly high sensitivity of ImmunoCyte in detecting CIS of the bladder and concluded that combining both cytology and ImmunoCyte can detect 100% of cases with bladder CIS during follow-up of bladder cancer patients. Shariat et al.1341 incorporated nuclear matrix protein 22 (NMP22) in a nomogram to predict disease recurrence and progression in patients with Ta, TI or CIS of the bladder.

3) Standard (white light; WL) cystoscopy: This method may reveal no visible abnormalities, edema of the wall or red velvet-like patches. Witjes1351 concluded that cystoscopic diagnosis of CIS with WL cystoscopy is not optimal and can miss many cases. In a European multicenter study,1361 only 58% of all CIS lesions were detected with WL cystos- copy. Considering the optimal conditions of such a study (high-risk patients and trained investigators), the number of undetected cases can be even higher in normal daily prac- tice. Zaak et al.1371 found that WL cystoscopy failed to detect 53% of specimens with CIS.

Uchikoba et al.1381 reported a new technique for improving the detection of CIS with WL cystoscopy, which involved instillation of pirarubicine hydrochloride into the bladder. After 5 minutes, the bladder was examined using WL cys- toscopy, and increased uptake was clearly noted in cases of CIS. However, the authors noted false positive results due to increased uptake, as well as for cases with urothelial hyperplasia.

4) Fluorescence cystoscopy: This procedure is used to reveal areas in the bladder that are suspicious for CIS and unde- tected by WL cystoscopy, and it improves the detection of CIS to more than 95%.12636391 The feasibility and superiority of photodynamic diagnosis (PDD) using 5 aminolevulinic acid (5-ALA) over WL cystoscopy for the diagnosis of CIS has been well-documented.13740 421 A recognized limitation to PDD cystoscopy is the increased rate of false positive patients compared with WL cystoscopy, especially for cases with chronic bladder inflammation and post instillation of chemotherapy into the bladder. However, Colombo et al.1431 demonstrated improved detection of CIS compared with WL cystoscopy during follow-up of patients on BCG instil- lation therapy. In addition, the higher cost of the initial use of PDD cystoscopy for cases with bladder tumor has been considered. A group from Germany studied that issue over a series of 301 patients and concluded that PDD significantly cut costs related to recurring cystoscopy.1441 Thus, although PDD can be more expensive for an initial diagnosis, PDD can still be cost-effective because of the lower recurrence rate and the lower rate of follow-up cystoscopy and resec- tion of bladder tumors. Another group from Sweden studied the budget impact of using HAL combined with WL cystos- copy for the management of bladder cancer and concluded that the combination may reduce invasive, time-intensive and high-cost procedures, such as cystectomy and TURB, compared with WLC alone.1451 Inoue et al.1461 confirmed mild bladder irritability and absence of systemic side effects from applying PDD, and the authors recommended that PDD be used as the gold standard for the detection of blad- der tumors.

5) Bladder biopsy: European guidelines have recommended that whenever positive cytology is present, random biopsies should be taken from the bladder and prostatic urethra, and a bladder diagram should be used to identify the exact loca- tion of the biopsied areas.1261

In a recent study, a Japanese group detected 11.8% cases with CIS in intermediate and high-risk cancer cases without abnormal cystoscopy and positive cytology. Because of this finding, they recommended routine random biopsies from normal looking sites whenever there is positive cytology, regardless of the cystoscopic findings.1471 Either cold cup biopsies or resection loop can be used to take the random biopsies, and it is advised that the biopsies be sent for assessment in separate containers.1451

6) Upper tracts studies: Whenever positive cytology is detected along with an absence of visible tumor on cystos- copy and IVU and normal biopsies from the bladder and prostatic urethra, CIS in the upper urinary tracts should be suspected.1111 Diagnosis of the affected renal unit can be made by selective cytology using a ureteral catheter in combination with ureteroscopy and brush sampling.1261

Treatment

1) Intravesical chemotherapy: Lamm 1211 reported that intra- vesical chemotherapy produced a complete response rate of 38% in patients treated with Thiotipa, 48% in patients treated with doxorubicine and 53% in patients treated with mitomycin C. Sylvester et al.1481 demonstrated that no single drug has superior efficacy compared with the others, and all have a beneficial effect when given as an adjuvant single instillation following transurethral resection of the blad- der tumor (TURBT). However, in the study by Sylvester, all patients with high-risk bladder tumors were included whether they had CIS or not. Conversely, in another study by the same group, mitomycin C was superior to other chemotherapeutic agents in treating CIS with no superior effect on Ta and T1 lesions.1491 Severe complications have been reported in cases of drug extravasation.1501 Therefore, EAU guidelines1271 recommend omitting the immediate instillation of chemotherapy in cases of extensive TUR pro- cedures, which are suspicious for intra- or extra-peritoneal perforation. Campodonico et al.1511 considered Gemcitabine to be the best drug for single instillation following TURBT. Whatever the drug used, it should be diluted in sterile water and not saline, and the highest efficacy is achieved when administered within 6 hours post-resection. Sylvester1481 showed that the best results can still be achieved with delayed instillation for up to 24 hours. EAU guidelines1271 recommend using the drug at its optimal pH and to maintain the concentration of the drug by decreasing fluid intake. The optimal schedule and duration of treatment is unclear, but it should be maintained for 6-12 months. Intravesical chemotherapy acts by decreasing recurrence with no effect on tumor progression.1521 The results from using intravesical chemotherapy, however, remains unpromising. Valrubicin is the only FDA-approved drug for patients with CIS; it showed a 21% and 8% complete response after 1 and 2 years, respectively.1531 Dalbagni et al.1541 demonstrated a complete response of 21% after 1 year of applying intra- vesical Gemcitabine for CIS cases. A recent paper1551 studied the effect of a combination of intravesical hyperthermia and mitomycin C instillation. The initial cure rate after 3 months was 92% and persisted at over 50% after 2 years.

2) Intravesical Immunotherapy: BCG was approved by the FDA for the treatment of CIS in 1990. Immunotherapy with Bacillus Calmette Guerine (BCG) for patients with CIS has been shown to provide a favorable short-term outcome, reaching a 70% complete response.1491 Gofrit et al.1561 dem- onstrated that 77% of the biopsy-proven BCG responders remained progression-free 10 years later, and only 14% of them died from metastatic disease. A strong insight into the impact of BCG on CIS was achieved in two SWOG studies; the first study1571 demonstrated a 70% complete response. The median response duration was 39 months, and 64% of patients who responded to BCG remained disease-free for 5 years. The second subsequent study compared a single 6-week course of BCG with an additional 3-week course at 3 months, and the complete response rate increased by 14% with the "6+3" BCG regimen.158591 In patients who demonstrated complete response, maintenance BCG immu- notherapy, consisting of 3 treatments at 1-week intervals for 6 month and every 6 months for 3 years, resulted in a 5-year disease-free status of more than 75%. EAU Guidelines1271 confirm the role of maintenance therapy with BCG in achieving a better cure rate in such cases. Sylvester et al.1601 demonstrated that maintenance BCG was able to prevent or delay progression to muscle-invasive tumor in patients with CIS. Davis et al.1611 demonstrated 10-year progression-free survival rates following maintenance BCG therapy of 55%, 77% and 62% for patients with CIS, high-grade Ta and Tl, respectively. Van Gils-Gielen et al.1621 reported that patients with extensive CIS, defined as three or more positive biop- sies or CIS associated with papillary tumors, tended to have a lower response rate, shorter time to recurrence and higher incidence of progression. In a recent study, Takynaka et al.1631 used multivariate analysis to show that the extent of CIS is the only independent factor that can predict disease progression.

A recent investigational study showed that intravesical application of a non-viable mycobacteria (M Pheli) prepara- tion had a promising effect for cases of documented BCG failure.1641 Watanabe et al.[651) recommended the measure- ment of urinary interleukin 2 (IL 2) as a marker of BCG treatment response. Torti et al.1661 demonstrated that interfer- on alpha (INF-a) monotherapy is efficient for the treatment of CIS. In a more recent study, Lam et al.1671 demonstrated that combined BCG plus INF-a2B therapy may be more effective and produce a more complete response to CIS than either therapy alone.

3) Radical Cystectomy: EAU Guidelines recommend early cystectomy for cases that show BCG failure.1271 Delayed cystectomy in these patients may result in decreased dis- ease-specific survival.1681 Huang et al.1691 did a retrospective study on cases that underwent radical cystectomy for CIS only of the bladder and showed excellent long-term survival outcome. The authors strongly recommended radical cystec- tomy for all patients who show failure of intravesical ther- apy. The same study also showed that patients who under- went cystectomy after failed intravesical therapy were more likely to be understaged than those that were initially man- aged by cystectomy. Denzinger et al.[701 emphasized timely radical cystectomy for cases with CIS, whether alone or combined with papillary tumor, because of the deleterious effect of CIS on cancer-specific survival. Hassan et al.[711 confirmed the excellent disease-specific survival for cases with CIS treated by early cystectomy and demonstrated that these patients still exhibited a higher rate of recurrence if their disease extended into the proximal urethra.

CIS of lower ureter at the time of cystectomy

Salsona et al. found that CIS in the cystectomy specimen predicted progression to panurothelial disease (panurothelial disease is defined as the involvement of two urothelial sites, typically bladder and another site).1721

The frequency of concomitant CIS of the upper urinary tracts at the time of cystectomy was estimated to be 8-11%.173741A recent study concluded that the presence of bladder CIS can indicate concomitant ureteral CIS, and the authors recommended frozen section biopsy at the time of cystectomy in that case.1741 These researchers added that additional resection of the upper ureteral segment decreased tumor development in the upper urinary tract. Salsona et al.1721 described the elevated incidence of upper tract recurrence and increased mortality for cases with distal ureteric CIS.

Wagner et al.1751 recommended that, regardless of whether exci- sion of the distal ureter with CIS was performed, an aggressive follow-up protocol, including ureteroscopy and selective cytol- ogy, should be performed at the time of cystectomy.

Few studies in the literature described the possibilities of recur- rent CIS in the neobladder, either ileal or sigmoid, as well as ileal conduit. 176 771 Therefore, follow-up by cytology and endoscopy is highly recommended for patients after radical cystectomy.

In conclusion, CIS of the bladder can occur either de novo, secondary or concomitant to papillary tumors of the bladder. The presence of bladder CIS increases the risk of panurothelial disease involving the prostate, urethra or upper urinary tracts.

Urine cytology is the primary approach for CIS diagnosis, and it can be the only positive test for diagnosis, regardless of the inter-observer variability. Fluorescent cystoscopy should be applied whenever CIS is suspected. Wight Light cystoscopy is not sufficient for curative treatment of CIS and, when used alone, may miss multifocal CIS and increase the chance of recurrence.

Intravesical BCG remains the gold standard for the initial treatment of CIS, and a 6-week induction course alone is not adequate to establish a high cure rate for the disease; therefore, maintenance therapy with BCG should be applied for all cases.

In cases of BCG failure, there is controversy in the literature regarding the treatment choice between intravesical chemother- apy with or without hyperthermia, the addition of interferons to BCG or radical cystectomy. However; early radical cystectomy for cases that presented BCG failure showed a higher rate of success with long-term cure.

Frozen section biopsy of the distal ureter should be performed when CIS of the bladder is preoperatively diagnosed or sus- pected. The presence of CIS of the distal ureter necessitates its removal until a free upper margin of the ureter is reached because this approach was found to decrease the incidence of recurrent tumors of the upper urinary tracts.

Regardless of whether frozen section biopsy was performed and regardless of the condition of the distal ureter at time of cystec- tomy, postoperative follow-up with cytology, endoscopy of the new pouch and ureteroscopy of the ureters is recommended for the early detection of possible recurrence.

Conflict of interest

No conflict of interest was declared by the authors.

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