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Histology of bladder cancer

Tumors found in the urinary tracts are classified according to WHO/ISUP 2004 guidelines (5). More than 99 % of the tumors found in the urinary tracts originate from the urothelium, which covers mucosa of the calyses, renal pelvis , ureters, urinary bladder and the upper part of the urethra.

Benign tumors are uncommon; urothelial papillomas may be papillary or inverted . Infection with the Human Papillomavirus may cause squamous cell papillomas .

More than 95% of urothelial tumors are malignant and are known as urothelial carcinomas. They are either non-invasive and papillary, or invasive (images 1 and 2).

Image 1: Low-grade, papillary non-invasive carcinoma. Click to enlarge.
Image 2: High-grade invasive urothelial carcinoma. Click to enlarge. 

Different variants of urothelial carcinomas exist (images 3,4) and some of these are very aggressive (micropapillary and sarcomatoid type). High-grade urothelial carcinomas can have both squamous differentiation and glandular differentiation. Primary adenocarcinomas in the bladder occur, which are often associated with intestinal metaplasia in the urothelium and adenocarcinoma in situ . Adenocarcinomas originating from embryonal remains in the urachus often produce mucus. 

Primary squamous cell carcinomas in the bladder are uncommon in Norway, but do occur in patients with chronic infections and keratinizing squamous metaplasia in bladder mucosa. In countries with endemic infections with Schistosoma haematobium, squamous cell carcinomas in the bladder are much more common . Small-cell carcinomas in the bladder are very aggressive tumors. This diagnosis is confirmed by immunohistochemistry . Correct classification of this tumor type is crucial because patients are treated primarily with chemotherapy and not surgery.

Image 3: Photomicroscopic image of micropapillary urothelial carcinoma. Click to enlarge.
Image 4: Photomicroscopic image of urothelial carcinoma, sarcomatoid type. Click to enlarge. 

Tumors occuring in supporting connective tissue are uncommon (images 5-8); they may be benign (leiomyoma) or malignant (sarcomas of different types). Malignant tumors which occur in lymphoid tissue are called lymphomas; these can originate primarily in the urinary tracts, but are uncommon. Metastases occur also in the urinary tracts despite the more common direct invasion from malignant tumors into adjacent organs (prostate, uterus or rectum). 

Image 5: Photomicroscopic image of leiomyosarcoma of the urinary bladder. Click to enlarge.
Image 6: Photomicroscopic image of leiomyoma of the urinary bladder. Click to enlarge.

 

Image 7: Specimen from a radical cystectomy of the urinary bladder with leiomyosarcoma. Click to enlarge.
Image 8: Photomicroscopic image of leieomyosarcoma of the urinary bladder. Click to enlarge.

Histological diagnostics 

If the patient has hematuria with suspicion of a urinary tract tumor, the diagnosis must be verified by histological diagnostics before treatment is started. The pathologist plays a key role in diagnosing tumors of the urinary tracts. The pathologist must inspect the tissue samples and surgical specimens by microscopy to determine whether the tumor is benign or malignant, as well as the malignancy potential. It is also necessary to confirm whether the tumor in the urinary tracts represents spread from other tumors. Typing, grading and description of extent of tumor spread is time-consuming and of great significance for choice of treatment and the patient's prognosis. The pathologists work together in a team, and there are often multiple pathologists assessing the tissue sample before the final diagnosis is made. Additional analyses such as immunohistochemical and molecular analysis may be necessary to sub-classify the tumor. The diagnosis is made on mucosal biopsies from the urinary tract taken by cystoscopy, TUR-B or larger surgical specimens .

Mucosal biopsies from the bladder 

The urologist may take selected mucosal biopsies from the bladder to determine pre-stages (dysplasia and carcinoma in situ) for classification of small tumors or to detect recurrence of tumors . Mucosal biopsies rarely contain tissue from the bladder wall musculature, which inhibits staging of infiltrating carcinomas.

Transurethral Bladder Resection (TUR-B)

With this procedure, much more tissue of the bladder and urinary tracts can be examined. The urologist shaves away tumor tissue with laser via a cystoscope. The pathologist receives multiple tissue samples preserved in formalin. After fixation, the material is weighed and random shavings are cast for examination with a photomicroscope (up to 8 blocks). When the pathologist examines these shavings using a photomicroscope, the presence of papilloma, carcinoma, or carcinoma in situ in flat mucosa is indicated. The type and grade of tumor tissue must also be determined. The pathologist must also indicate if there is infiltration of the lamina propria and muscularis propria. In some instances, there may be too much thermal damage and the pathologist is not able to make a reliable diagnosis . If infiltrating carcinoma is present and the material lacks muscle from the bladder wall, a new tissue sample must be taken from the tumor area (TUR-B) before final staging can be done.

Partial or radical cystectomy

Patients with carcinoma in situ, high-grade and muscle-invasive carcinomas are candidates for partial or radical cystectomy. In men, the bladder is removed with surrounding adipose tissue, the prostate, and seminal vesicles. In women, the uterus as well as both ovaries, fallopian tubes and parts of the vagina are removed. 

If there is carcinoma in situ, the pathologist will often not see any changes in the bladder mucosa (image 9). Bladder carcinomas may grow exophytic (image 10) or infiltrating (image 11) and they may originate from bladder diverticula .

The pathologist removes many sections from the bladder wall with surrounding tissue to investigate the extent of the tumor. The pathologist will then determine the type of tumor, whether the tumor has infiltrated the bladder wall and into adipose tissue, the status of the resection renders, and the presence of growth into vessels or spread to lymph nodes or adjacent organs. 

Image 9: Specimen from a radical cystectomy without visible tumor tissue. Click to enlarge.
Image 10: Specimen from a radical cystectomy with papillary bladder cancer. Click to enlarge.
Image 11: Infiltrating bladder carcinoma. Click to enlarge.

Grading

In 2004, a new grading system was introduced for urothelial tumors (WHO/ISUP) (5,6). This system includes a new category of papillary urothelial neoplasm of low malignant potential (PUNLUMP - see table). These tumors have a thicker, more disorderly urothelium with mild nuclear pleomorphia compared to papillomas, but not as pronounced nuclear atypia as observed in the low-grade non-invasive urothelial carcinomas. High-grade urothelial carcinomas have a thickened, disordered urothelium with moderate to severe nuclear atypia over the entire thickness of the urothelium, with increased amount of mitoses high up in the urothelium.

The new classification system is now used by all pathology laboratories in Norway (7). The hope is that the new system will facilitate in diagnosing malignant tumors with good versus poor prognoses and provide grounds for choice of treatment strategies. It has been important to reduce the amount of tumors which were previously classified as WHO grade 2, which have been a very heterogeneous group. The morphological criteria are now better characterized than previously. Some of the tumors that were previously classified as WHO grade 2 are now graded as low-grade, while some are graded as high-grade (see table). Pathologists no longer differentiate between tumors having moderate and severe nuclear atypia; they are now classified as high-grade. Pre-stages are not graded; they are separated into low-grade dysplasia and carcinoma in situ (which are are no longer graded) (5,6,8).

 

Grading of Urothelial Tumors (click to enlarge images)

WHO 1973
(old classification)

 

WHO/ISUP 2004
(new classification)

Papilloma

Papilloma

Urothelial carcinoma grade 1

Papillary urothelial neoplasm 
of low malignant potential
(PUNLUMP)

Urothelial carcinoma grade 1

Urothelial carcinoma grade 2

Low-grade urothelial carcinoma

Urothelial carcinoma grade 2

Urothelial carcinoma grade 3

High-grade urothelial carcinoma

 

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