(1)
Department of Pathology, Sinai Hospital of Baltimore Pathology, Baltimore, MD, USA
Keywords
UrotheliumTransitionalVon Brunn’s nestPapillaryCarcinoma in situPapillomaNephrogenic adenomaBladder biopsy specimens are usually submitted to rule out a urothelial neoplasm. The procedure may be indicated because of hematuria, abnormal urine cytology, a history of urothelial neoplasm, or a lesion seen on cystoscopy. The cystoscopic impression is important, and you usually do not diagnose a papillary lesion if none was seen by the urologist. The bladder biopsy specimen is typically a tiny tissue fragment, so you should look at each level carefully.
The normal urothelium consists of a stratified nonsquamous epithelium, also called transitional cell epithelium. It consists of a five- to seven-cell-thick layer of uniform cells that do not significantly mature as they reach the surface (unlike squamous epithelium) and that tend to have oblong nuclei oriented perpendicular to the surface (Figure 12.1). The nuclei are about two to three times the size of lymphocytes. Mitoses are usually seen only at the basal layer, but in the presence of inflammation and reactive changes, they may be seen throughout. At the surface is a specialized cell layer called the umbrella cells , large pillowy cells that are wider than the underlying urothelial cells. Umbrella cells may have atypical nuclei and should be ignored when assessing the urothelium for dysplasia.
Figure 12.1.
Normal urothelium. The urothelial cells form a layer five to seven cells thick, with large umbrella cells sitting on top (arrow). The urothelial nuclei are generally polarized and oriented perpendicular to the surface, with the exception of the umbrella cells. The nuclei are two to three times the size of a lymphocyte (arrowhead).
Underneath the urothelium lies the lamina propria, a connective tissue layer that has vessels, lymphatics, occasional smooth muscle fibers, and even occasional fat. Deep to this is the thick muscularis propria, also known as the detrusor muscle . Beyond the muscular wall is either adventitia or, where the bladder lies against the peritoneum, peritonealized serosa.
Normal Variants
Some changes in the bladder are so common that they are essentially normal. One of these changes is the formation of von Brunn’s nests , which are downward invaginations of the urothelium into the lamina propria (Figure 12.2). These can look alarmingly like a urothelial neoplasm that is invading the bladder, but they should have bland urothelium that looks just like normal urothelium (see below for a description of neoplastic urothelium) and have a smooth rounded border. As these nests progress, they may acquire a dilated central lumen ( cystitis cystica ), columnar cell metaplasia ( cystitis glandularis ; see Figure 12.2), and even intestinal metaplasia with mucin production. They are still benign. However, just as high-grade squamous intraepithelial lesions can involve endocervical glands, in situ urothelial carcinoma can grow down into von Brunn’s nests, mimicking invasion. Another normal variant is the formation of squamous metaplasia, especially in the trigone area of the female bladder.
Figure 12.2.
Von Brunn’s nest and cystitis glandularis. The normal urothelium has invaginated down into the lamina propria, forming a rounded von Brunn’s nest (arrow). The center of the nest has acquired a lumen and columnar cell metaplasia (asterisk), which is known as cystitis glandularis.
Inflammation (Cystitis)
There are several types of inflammatory disease that you may see. One is granulomatous cystitis , which once was largely caused by tuberculosis but is now more likely to be secondary to bacillus Calmette-Guerin (BCG) therapy—a topical chemotherapy for urothelial carcinoma. The intravesical injection of BCG causes an intense inflammatory response that may wipe out the carcinoma.
Parasitic infection, most commonly by Schistosoma species , is still common in undeveloped countries but rare in the United States. The inflammatory response is actually not caused by the organisms but by their eggs, which are extruded into the bladder wall and cause intense foreign body reaction. The eggs themselves are dark purple oval bodies with single spines, large enough to be seen at 4×. Polypoid cystitis is similar to an inflammatory polyp of the bladder and is associated with any process that injures the bladder (e.g., indwelling catheters, calculi, fistula from the colon). Interstitial cystitis is a poorly understood disease that is mainly a cystoscopic diagnosis and more a diagnosis of exclusion for the pathologist.
Malakoplakia is one of those mysterious rare entities that most residents do not see, think about, or understand until they are studying for boards. It is a descriptive name for the yellow plaques seen on cystoscopy, which are formed by sheets of epithelioid histiocytes sporting characteristic round inclusions called Michaelis-Gutmann bodie s (they look like archery targets). It is caused by a defective macrophage response to infection.
Urothelial Neoplasms
Urothelial neoplasms are categorized into two cancer pathways: flat and papillary. Both can lead to invasive carcinoma, but the terminology is different. About 90% of bladder carcinomas are urothelial, so this will be the focus of this chapter.
Flat neoplasia does not form an exophytic lesion but may still be visible on cystoscopy as a red area. It progresses through dysplasia (rarely diagnosed) to carcinoma in situ. Flat urothelial carcinoma in situ is just known as carcinoma in situ (CIS) and can go on to deeply invasive carcinoma without ever making an exophytic lesion, so always scrutinize the urothelium at high power, especially in denuded areas. Features of CIS include the following:
Urothelial cells with increased nuclear size. A helpful hint is that the worst nuclei of CIS should be four to five times the size of lymphocyte nuclei (Figure 12.3).
