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|Non-Muscle-Invasive Bladder Cancer|
First read about staging.
Benign Papilloma or low-grade papillary tumor-what is the difference? see below
Non-muscle-invasive bladder cancer, stage Ta, grade 1
There are different degrees of risk according to several known prognostic factors, the most important of which are grade (aggressiveness of the tumor cells) and depth of invasion (stage Ta vs. T1). Low grade, Ta tumors larger than 3 cm, and/or the presence of multiple tumors have been shown to pose risk of recurrence (see graph below).
Upon initial diagnosis of a non-invasive Ta, low grade, well differentiated tumor, surveillence with no further treatment after transurethral resection has long been standard. Follow up cystoscopies are important; if no tumor recurrence is seen after one year, follow ups may be lengthened.
Recurrence, which may be expected in 50% to 75% of cases but is usually of the same grade and stage, can then again be successfully treated by repeat TUR. There is evidence that one instillation of intravesical (instilled in the bladder) chemotherapy can delay the time between recurrences. [See also: intravesical chemo]
Ta, low grade papillary tumors progress in grade or become invasive less than 5% of the time, and are high in grade in only 1% to 3% of cases. In contrast, stage T1 tumors may be high grade in 30% to 50% of cases and are rarely low grade.1 Carcinoma in situ is considered a high risk form of bladder cancer with a widely variable outcome. Although all three kinds of tumors are considered non-invasive (formerly referred to as "superficial"), their outcomes are clearly different.
Update 2006: New data support 'watchful waiting' instead of automatic removal of low grade, Ta non-invasive bladder tumors, see,
Evaluation of Risk
click here for more graphs: Predicting recurrence and progression in stage Ta-T1 bladder cancer: the use of the EORTC risk tables
Risk factors for superficial recurrences include multiple tumors, tumors larger than 3 to 4 cm. positive urine cytology, tumors involving the submucosa (stage T1) and dysplasia (abnormal cell appearance) in random mucosal biopsy specimens.
“Recognition that a significant percentage of transitional cell neoplasms are benign is more than an exercise in semantics. Patients presenting with these lesions have a low risk (<10%) of ever developing a life-threatening bladder cancer and probably will not benefit from prophylactic therapy with topical agents. Long-term follow-up is, of course, necessary but it need not be aggressive, especially after the first 2 years. Patients can take comfort in having a benign tumour rather than a bladder cancer.” 8
Other reports have suggested prognostic distinctions among tumors that penetrate the lamina propria only microscopically (stage T1a), those that penetrate more extensively up to the layer of the muscularis mucosae (stage T1b), and those that penetrate through the muscularis mucosae to involve extensively the deeper portions of the lamina propria (stage T1c). These distinctions have not been incorporated into the commonly accepted staging system. 1
Stage T1 - not exactly "non-muscle-invasive" anymore?
Recent data has suggested that stages Ta and T1 are of different biological origins, and in many cases are indeed separate tumor entities with marked genetic differences. Independent of treatment, true bioligical progression of Ta, low grade tumors is very rare, while in a significant amount of cases, pT1 carcinomas are early stages of potentially highly malignant tumors that will consequently need surgical intervention. The distinction is critical because of an increasing tendency of urologists to perform early cystectomy for recurrent pT1 carcinomas, though as of yet there is no proven accepted method of distinguishing which T1 tumors will definitely become invasive.7
T1 disease, irrespective of grade, has already demonstrated the biological ability to invade, and has a reported progression rate of 29%. If a T1 tumor is extensive, multiple, recurrent, high grade, or has shown p53 overexpression, the risk of invasion is higher. Therefore, the diagnosis of high grade T1 tumors and CIS may justify the use of intravesical chemotherapy to prevent progression to muscle invasion. 6
Second TUR? New data is appearing suggesting that a second TUR be performed after a T1 diagnosis as this can catch residual tumor and improve outcome (see sidebar for reference).
Controversy: There is ongoing debate about the best management of Grade III, pT1 tumors, whether early radical therapy (cystectomy) is indicated or if it is safe to delay treatment until definite recurrence has been identified. Molecular biomarkers are being actively investigated as a means of determining treatment strategies, but are not yet in everyday practice. See also; Biomarkers
CIS-carcinoma in situ, is relatively rare, comprising approximately 10% of cases and is also considered a superficial tumor (does not penetrate the bladder lining), and is usually associated with concomitant high grade, invasive TCC in adjacent or distant urothelium (secondary CIS). Carcinoma in situ is a high-grade and aggressive manifestation of TCC that has a highly variable course. The treatment of CIS has undergone dramatic changes since this malignancy was first recognized. While cystectomy was once recommended as the initial treatment of choice, recognition of the highly variable prognosis and the uniformly high response rate to intravesical BCG has prompted a more conservative approach to management. 2
The symptoms of bladder CIS may be mistaken for urinary tract infection, prostate disease, or neurogenic bladder incontinence (leaky bladder due to defects in the nervous system). CIS may involve nearby organs such as the urethra, periurethral glands (glands around the urethra), and prostate. In fact, because CIS can be dangerously silent within the prostate, many doctors recommend routine biopsy of the prostate in male CIS patients.
Whereas superficial bladder cancer has the appearance of a solid or papillary tumor, in carcinoma in situ, the involved mucosa is reddish and velvety to granular. The areas are patchy and ill defined and sometimes bleed easily.
In some instances, bladder CIS may have features of Paget's disease, an inflammatory form of cancer that affects organs such as the breast. Pagetoid CIS may cause the bladder lining to flake off or slough. In other cases, CIS may involve groups of bladder cells known as von Brunn's nests. Association with von Brunn's nests is important, as it may influence the type of treatment chosen by the physician.3 Patients with CIS involving von Brunn's nests -- that is, pockets of cells that extend more deeply below the bladder surface -- will have tumor cells that are unexposed and, consequently, unaffected by intravesical therapy. Thus, intravesical therapy is not suitable for individuals with von Brunn's CIS.
Occasionally (1% of cases or less), CIS is found without associated invasive TCC (primary CIS). Only one third of primary CIS invades the lamina propria or muscle wall, and the mortality rate is only 7% to 20%, as opposed to 45.2% for secondary CIS.4 5
If carcinoma in situ is localized and not accompanied by irritative symptoms, it may not lead to infiltrating disease. Diffuse symptomatic carcinoma in situ is an early and aggressive form of the disease.
For more information about CIS and it's management see Dr. Lamm's BCG treatment recommendations here at WebCafe.
In case of high grade Ta or T1 tumors either primary or recurrent, BCG (bacillus Calmette-Guerin, an immunotherapy) has been shown to be most effective, especially with carcinoma in situ. Compared with TUR alone in patients with Ta and T1 lesions, treatment with BCG delayed progression to muscle-invasive and/or metastatic disease, improved bladder preservation, and decreased the risk of death from bladder cancer. New evidence is showing that maintentance therapy as defined in Dr. Lamm's protocol has reportedly further lowered risk of recurrence. 8
Cystectomy is advised in the case of large or high grade T1 lesions, or in the case of muscle invasive disease stage T2 and higher. Segmental (partial) cystectomy is appropriate in only a small subset of patients, such as those with a singular papillary tumor near the dome of the bladder, though due to the high recurrence rate, segmental cystectomy is not often advised.
Intravesical immunotherapies include BCG, and Interferon; Key Hole Limpets; Interleukin and Bropirimine, an oral agent, are being actively investigated. BCG is also used in a percutaneous vaccine form.
Photodynamic therapy and intravesical hyperthermia combined with intravesical chemotherapy (also known as electromotive intravesical chemotherapy) are being investigated for use in superficial bladder cancer. Chemoprevention trials are also being conducted. The combined modalities approach may also be considered in cases of high grade T1 tumors.
Benign urothelial papilloma of the bladder: a review of 34 de novo cases Magi-Galluzzi C, Epstein JI The Cleveland Clinic Foundation, Cleveland, OH, and The Johns Hopkins Hospital, Baltimore, MD, USA Mod Pathol. 2004; 17 (suppl 1): 165A Abstract-PubMed
Urothelial papilloma of the bladder is uncommon, and represents less than 3% of papillary bladder tumors. We retrospectively studied 34 patients who were diagnosed with urothelial papilloma of the bladder. In all cases, the diagnosis of papilloma was the first manifestation of urothelial neoplasia.
Editorial Comment- Dr. Athanase Billis Full-Professor of Pathology
....Classification of urothelial (transitional cell) neoplasms of the urinary bladder (Am J Surg Pathol. 1998; 22:1435-48), papilloma is a distinct neoplasm from papillary neoplasm of low malignant potential. The former neoplasm is defined as discrete papillary growth with central fibrovascular core lined by urothelium of normal thickness and cytology, frequent vacuolization of umbrella cells and edema of the stroma. There is no need to count the number of cell layers. It is a rare benign condition comprising less than 3% of papillary urothelial neoplasms. Papillary urothelial neoplasm of low malignant potential is a papillary lesion with minimal architectural abnormalities and minimal nuclear atypia irrespective of cell thickness. In general, the major distinction from papilloma is that in papillary urothelial neoplasm of low malignant potential the urothelium is much thicker and/or nuclei are significantly enlarged. The urothelial papilloma, in contrast, has no architectural or cytological atypia.
Both papilloma and papillary urothelial neoplasm of low malignant potential may develop recurrent or new papillary lesions but only the latter may be associated with invasion or metastases in rare cases. The study by Magi-Galluzzi and Epstein disclosed the clinical behavior of 34 de novo papillomas. The follow-up showed that 6 patients had recurrent disease but none progression to either lamina propria (T1) or muscularis propria (T2) invasion. This paper confirms that papilloma and papillary neoplasm of low malignant potential should be considered separately. The urologist should follow-up patients with papilloma but because they have a low incidence of recurrence and rarely progress to develop noninvasive urothelial carcinoma, it seems reasonable to avoid labeling these patients as having cancer.
For a review of the WHO's classification of the many different types of bladder tumors, see WebCafe's report here
New diagnostic tool: photodynamic diagnosis (PDD), fluourescent cystoscopy
Review of the guidelines of the European Association of Urology (EAU) on superficial bladder tumors, new data which has come available since 2001. It emphasises the data which are evidenced based and clearly explained where still insufficient research is available to make clear recommendations
|Last Updated ( Friday, 14 November 2008 )|