Nonneoplastic Diseases of the Urinary Bladder

Clinical Features

The urothelium may exhibit a host of morphologic variations, including von Brunn nests, cystitis cystica, and cystitis glandularis. They are extremely common findings that are present in 85% to 95%, 60%, and 71% of bladders, respectively, in several autopsy studies. They represent a continuum of reactive proliferative changes seen along the entire urinary tract, and all three are commonly seen in the same specimen. They are considered as variants of normal urothelial histology. They may also occur as a result of local inflammation. Several reports exist of association between pelvic lipomatosis and the proliferative changes of the urothelium. No association is found between these proliferative changes and urothelial carcinoma.

Pathologic Features

Microscopic Findings

von Brunn nests are solid nests of urothelial cells that lie beneath the urothelium and may be connected to the surface urothelium. These nests usually are similar in size and shape and have a smooth round contour and orderly spatial arrangement ( Fig. 3-6 ). The depth of growth into the lamina propria is usually uniform, which often gives a somewhat band-like appearance. The cells in the von Brunn nests lack cytologic atypia, although they may have slightly larger nuclei when compared with the overlying urothelial cells. Cystitis cystica consists of von Brunn nests that become cystically dilated and acquire a luminal space as a result of degeneration of central cells ( Fig. 3-7 ). The cysts are filled with eosinophilic fluid and may contain some inflammatory cells. Cystitis glandularis resembles cystitis cystica except that the cystic spaces are lined with cuboidal or columnar cells ( Fig. 3-8 ). If the columnar epithelium acquires intestinal-type goblet cells, this variant is termed cystitis glandularis with intestinal or colonic metaplasia ( Fig. 3-9 ), as opposed to the nonmucinous, typical type of cystitis glandularis. Rarely von Brunn nests, cystitis cystica, and glandularis are so prominent that they form grossly visible mass lesion ( Fig. 3-10 ).

Ancillary Studies

Differential Diagnosis

Florid von Brunn nests can be differentiated from nested variant of urothelial carcinoma by its lobular or linear array of the nests, flat noninfiltrative base, and lack of cytologic atypia. von Brunn nests in the bladder in general are also larger and have a smooth rounded contour and regular spacing. Cyst formation is often more pronounced, and apical glandular differentiation and eosinophilic secretions are also more common. When von Brunn nests are numerous and crowded, their distinction from inverted papilloma may be difficult and arbitrary. Urothelial carcinoma in situ may involve von Brunn nests and should not be mistaken as invasive urothelial carcinoma. Florid cystitis glandularis, especially of the intestinal type, may be confused with invasive adenocarcinoma. An irregular haphazard arrangement of glands in the deeper lamina propria or muscularis propria and cytologic atypia should raise the suspicion for adenocarcinoma. Mucin extravasation may be striking in cases of cystitis glandularis with extensive intestinal metaplasia (intestinal type). In contrast to colloid carcinoma, clusters of epithelial cells are not seen floating in the mucin, and the lining epithelium of cysts is not atypical.

Prognosis and Treatment

Considered as variants of normal histology or reactive changes in response to local inflammation, von Brunn nests, cystitis cystica, and glandularis are entirely benign and do not necessitate therapy.

Clinical Features

The two types of squamous metaplasia of the urothelium are nonkeratinizing and keratinizing. The former is considered as a normal finding in females and is present in the trigone and bladder neck in up to 85% of women of reproductive age and in 75% of postmenopausal women. Very rare in men, this type of squamous metaplasia has been described in men undergoing estrogen therapy for prostatic carcinoma. Keratinizing squamous metaplasia, also termed leukoplakia, on the other hand, is more common in men and is usually associated with chronic irritation, such as indwelling catheters, calculi, and schistosomiasis. Vitamin A deficiency can induce keratinizing squamous metaplasia of the urothelium as well in a variety of epithelia. It has been recognized as a significant risk factor for the development of carcinoma of the urinary mucosa, most of which are squamous cell carcinoma.

Pathologic Features

Gross Findings

Cystoscopically, areas of squamous metaplasia appear gray-white ( Fig. 3-11 ). An extensively keratinizing lesion may have a bulky irregular appearance similar to carcinoma.

Microscopic Findings

In nonkeratinizing squamous metaplasia, the normal urothelium is replaced with squamous epithelium with clear, glycogenated cytoplasm that resembles the vaginal squamous epithelium ( Fig. 3-12 , A ). The keratinizing squamous metaplasia features a squamous epithelium with hyperkeratosis and occasionally parakeratosis and even a granular layer ( Fig. 3-12 , B ). In most cases, no nuclear atypia is found. However, atypia as severe as carcinoma in situ can be seen.

Prognosis and Treatment

Nonkeratinizing squamous metaplasia is essentially a normal finding in female and necessitates no treatment. Keratinizing

squamous metaplasia, on the other hand, is a significant risk factor for bladder carcinoma and complications, such as bladder contracture and ureteral obstruction. The wide variation in lag time to the development of complications necessitates indefinite follow-up periods. Cystectomy may be offered to selected patients with extensive bladder involvement and long life expectancy.

Clinical Features

Intestinal metaplasia is used to describe the presence of isolated or aggregated goblet cells in cystitis glandularis, but this term often refers to replacement of urothelium by epithelium resembling colonic mucosa. It usually occurs in chronically irritated bladders, such as those in patients with paraplegia or in patients with stones or long-term catheterization.

Pathologic Features

The surface of the bladder mucosa and glands in the lamina propria are lined with single layer of mucin-producing goblet cells ( Fig. 3-13 ). Paneth cells may be identified at the base of crypt-like glands. The cells in intestinal metaplasia may exhibit minimal reactive cytologic atypia, but moderate-severe atypia is absent. Florid cases may minimally involve superficial muscularis propria and have mucin extravasation; however, the change is usually focal, and there are no free-floating cells in the mucin pools.

Differential Diagnosis

Diffuse intestinal metaplasia may be confused with invasive adenocarcinoma. Distinguishing the latter from intestinal metaplasia is the finding in adenocarcinoma of an infiltrative architectural pattern, extensive muscle invasion, and most importantly moderate-severe cytologic atypia.

Prognosis and Treatment

The association between diffuse intestinal metaplasia and bladder cancer is uncertain. Genetic associations are found between intestinal metaplasia and bladder cancer. These include telomeric shorting, allelic imbalance of TP53, and loss of heterozygosity of D2S123 locus. In contradiction of this, no such link was found in a recent study of 53 cases with long-term follow-up periods. Given these conflicting data, patients with intestinal metaplasia, particularly those showing dysplasia, were suggested to undergo regular follow-up examinations until more conclusive information is available.

Clinical Features

Nephrogenic adenoma (nephrogenic metaplasia) is characterized by small tubular and papillary proliferation along the urothelial lining of the urinary tract. It often arises in the setting of an inflammatory insult and local injury, such as prior surgery, calculi, trauma, or infection. Eight percent of patients have a history of renal transplantation. Approximately two thirds of the patients are male, and one third is younger than 30 years of age. Nephrogenic adenoma is often asymptomatic and detected incidentally, although it may present as a mass lesion simulating cancer. Named for its resemblance to the renal tubules, nephrogenic adenoma is considered as a metaplastic process of the urothelium in response to injury. However, a recent study showed that at least in renal transplant recipients these lesions are derived from shed renal tubular cells.

Pathologic Features

Gross Findings

Nephrogenic adenoma is found throughout the urinary tract, with 55% localized in the bladder, 41% in the urethra, and the remaining 4% in the ureter and occasionally in the renal pelvis. It may present as a papillary or polypoid exophytic mass or velvety lesion ( Fig. 3-14 ) most often less than 1 cm, although larger lesions may occasionally be seen.

Microscopic Findings

Nephrogenic adenoma has a broad histologic spectrum. It may consist of papillae, small tubules, large cystically dilated tubules with eosinophilic or basophilic intraluminal secretions, flat epithelium covering the urothelial surface, cords of cells or single cells, and diffuse and solid cell growth ( Fig. 3-15 , A to D ). Tubules are often surrounded by a layer of hyalinized basement membrane. A variable degree of acute and chronic inflammation and stromal edema are common in the background. The tubules and papillae are lined with cuboidal or low columnar epithelium. Prominent nucleoli can be present, although nuclear atypia and mitoses are virtually absent. One characteristic finding is cystically dilated tubules lined with hobnail cells that resemble endothelial-lined vascular spaces (see Fig. 3-15 , C ). Cells with oxyphilic or clear cytoplasm or signet-ring–like cells may also be seen. Different patterns are often admixed, although one pattern may predominate.

Ancillary Studies

Differential Diagnosis

Characteristic tubules lined with bland cuboidal or low columnar cells and surrounded by a prominent basement membrane in an inflammatory background readily suggest the correct diagnosis. However, in men, nephrogenic adenomas may be confused with prostatic carcinoma when there are tubules with prominent nucleoli sometimes situated within muscle bundles. Atrophic cytoplasm, associated inflammation, a hyaline rim of connective tissue around some of the glands, other typical patterns of nephrogenic adenoma, immunoreactivity for PAX2/PAX8, and only weak positivity for PSA and PAP should lead to the correct diagnosis. Nephrogenic adenomas should also be differentiated from the papillary and nested variant of urothelial carcinoma. Papillary urothelial neoplasms have delicate fibrovascular cores lined by stratified urothelium in contrast to the edematous and inflamed cores covered with single layer of bland cuboidal or low columnar cells in nephrogenic adenomas. Nested variants of urothelial carcinomas often have deceptively bland cytology; however, they usually exhibit greater atypia and increased mitoses at the deep invasive fronts. Immunoreactivity for PAX2/PAX8 and negative staining for P63, high–molecular-weight cytokeratin (34βE12), and CK5/6 should lead to the correct diagnosis. Nephrogenic adenoma may have a predominance of small tubules with mucin that resemble signet-ring cell carcinoma. However, the thickened basement membrane, lack of nuclear atypia and other patterns, immunoreactivity for PAX2/PAX8, and negative immunoreactivity for CDX2 can lead to the correct diagnosis. In females, nephrogenic adenomas can be differentiated from clear cell adenocarcinoma by the lack of widespread nuclear atypia, absent mitoses, infrequent presence of clear cells, and lack of solid sheets of cells. Finally, nephrogenic adenoma may be confused with a capillary hemangioma because of the vascular space–like dilated tubules; however, nephrogenic adenoma is positive for cytokeratin 7 and negative for endothelial markers, such as CD31.

Prognosis and Treatment

Nephrogenic adenomas are benign yet may recur if the underlying cause persists. Therapy should be directed towards the underlying etiology.

Clinical Features

Polypoid cystitis is an inflammatory mucosal lesion that assumes polypoid configuration cystoscopically and microscopically. It arises as a reaction to any inflammatory insult to the bladder mucosa and is most commonly seen in the clinical setting of indwelling catheters and vesical fistulas. It affects both genders equally with an age range from 20 months to 79 years. Depending on the extent of edema of the lamina propria, there is a continuous morphologic spectrum from papillary cystitis (slender finger-like papillae) to polypoid cystitis (broad-based, thick papillae) to bullous cystitis (papillae with width greater than length).

Pathologic Features

Microscopic Findings

The papillae in polypoid cystitis have thick edematous fibrovascular cores with vascular dilation and acute and chronic inflammation in the lamina propria ( Fig. 3-16 , A and B ). The papillae are simple without branching. The urothelium lining the edematous stalks may be normal or show reactive atypia or squamous metaplasia. Bullous cystitis has

POLYPOID CYSTITIS—FACT SHEET

Definition

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  Inflammatory lesion with lamina propria edema resulting in a polypoid configuration

Gender, Race, and Age Distribution

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  Affects both genders equally

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  Age range 20 months to 79 years

Clinical Features

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  Arises as a reaction to any inflammatory insult to the bladder mucosa

Prognosis and Treatment

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  Benign

• ▪

  No risk for bladder cancer

extensive submucosal edema. Papillary cystitis often has less edematous and more fibrotic papillae.

Differential Diagnosis

Polypoid cystitis should be distinguished from papillary urothelial neoplasms. The fibrovascular cores in polypoid cystitis are edematous and broad based in contrast to thin, delicate fibrovascular cores of papillary urothelial neoplasms. In addition, the papillary fronds in polypoid cystitis do not branch into smaller papillae as can be seen in papillary urothelial neoplasms. Although isolated papillary fronds in polypoid cystitis may closely resemble those seen in a papillary urothelial neoplasm, one must interpret these fronds in the context of the rest of the lesion and diagnose the entire case as polypoid cystitis.

Prognosis and Treatment

Polypoid cystitis is a benign lesion with no risk of evolving into carcinoma. It usually disappears after removal of the irritant.

Clinical Features

Interstitial cystitis is an enigmatic, essentially incurable condition characterized by a constellation of symptoms that includes urinary frequency, urgency, nocturia, suprapubic pressure, and pelvic and bladder pain. Greater than 90% of patients are women, and the disease predominantly affects middle-aged and old women. Many patients have history of autoimmune diseases. The urine is sterile, and the etiology remains unknown. Immunologic dysregulation, infection, trauma, and structural defects have been hypothesized to play a role in pathogenesis.

The diagnosis of interstitial cystitis is primarily based on the clinical findings and exclusion of other possible etiologies, including other forms of cystitis and carcinoma. The role of pathologists in the management of interstitial cystitis is to rule out carcinoma in situ (CIS) and other forms of cystitis and to correlate pathologic results with clinical findings.

Interstitial cystitis is categorized as nonulcerative (early, nonclassic) and ulcerative (late, classic; so called Hunner ulcer) diseases based on cystoscopic findings. Transition from nonulcerative to ulcerative disease is rare, and the two types may be completely separate entities pathologically.

Pathologic Features

Gross Findings

The nonulcerative disease exhibits glomerulations, which are petechial submucosal hemorrhage after hydrodistension of the bladder ( Fig. 3-19 , A ). The ulcerative disease manifests as single or multiple patches of reddened mucosa with small vessels radiating from a central scar called Hunner ulcer ( Fig. 3-19 , B ). However, glomerulations are neither specific nor sensitive, and ulceration is extremely uncommon (<5%) in interstitial cystitis.

Microscopic Findings

There are no characteristic histologic features for interstitial cystitis. The nonulcerative disease has a relatively unaltered mucosa with a sparse inflammatory response. The main feature is multiple small mucosal ruptures and suburothelial hemorrhages ( Fig. 3-20 , A ). The bladder mucosa may be completely normal in some cases and denuded in other cases. In patients with Hunner ulcer, the ulcer varies in thickness but usually involves the upper half of the lamina propria. It is often covered by debris, fibrin, inflammatory cells, and erythrocytes. The ulcer base is composed of granulation tissue. The rest of the lamina propria is moderately or markedly inflamed with lymphoid

INTERSTITIAL CYSTITIS—FACT SHEET

Definition

• ▪

  Chronic inflammatory process of the urinary bladder of uncertain etiology

Incidence and Location

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  Female: 18.1 per 100,000

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  Male: 1.2 per 100,000

Gender, Race, and Age Distribution

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  >90% patients are women

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  Affects middle-aged and older patients

Clinical Features

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  Constellation of symptoms: urinary frequency, urgency, nocturia, suprapubic pressure, and pelvic and bladder pain

• ▪

  No evidence of urothelial carcinoma or other forms of cystitis

Prognosis and Treatment

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  Incurable with protracted course of exacerbations and remissions

• ▪

  Palliative treatment for symptomatic relief

aggregates. Perineural inflammation ( Fig. 3-20 , B ), or chronic perineuritis, is seen in 70% of patients. In long-standing diseases, fibrosis and inflammation may be seen in the muscularis propria ( Fig. 3-20 , C ), a finding that correlates with the reduced bladder capacity seen in advanced disease. The perivesical fat usually lacks significant inflammation.

Mast cells have frequently been associated with interstitial cystitis. Activated mast cells may play an important role in the pathogenesis of interstitial cystitis. A high mast cell count in the detrusor muscle, however, is not diagnostically useful because the mast cell counts in interstitial cystitis overlap with those seen in patients with bladder inflammation of other etiologies and they do not correlate with clinical symptoms, cystoscopic findings, or response to therapy.

Differential Diagnosis

A wide range of other diseases should be excluded before a diagnosis of interstitial cystitis is rendered. CIS is the most important diagnostic consideration. Cystoscopically, extensively denuded CIS (denuding cystitis) can mimic interstitial cystitis. Histologically, denuding CIS exhibits ulceration, vascular congestion, and inflammation that resembles interstitial cystitis. Multiple tissue sections should be examined to search for atypical cells. Other forms of cystitis, including hemorrhagic cystitis, radiation cystitis, eosinophilic cystitis, and infectious cystitis, should be ruled out based on urinalysis, cytology, culture, and histologic examination.

Prognosis and Treatment

Interstitial cystitis is incurable. Treatment offers symptomatic palliation. Most patient conditions can be maintained in a satisfied, although not asymptomatic, state punctuated by exacerbations and remissions.

Clinical Features

Eosinophilic cystitis is characterized by dense eosinophilic infiltrates in the bladder wall and lamina propria. It occurs in two clinical settings. It most commonly reflects a nonspecific, localized, self-limited subacute inflammatory reaction to injury, such as associated with transurethral resection, catheterization, or invasive cancer. Rarely, eosinophilic cystitis is associated with allergic diseases, and in most cases, patients also have asthma, eosinophilic gastroenteritis, or rarely parasitic infection. Patients can be seen at all ages, ranging from newborn to elderly, and the female-to-male ratio is 2 to 1. Patients commonly present with frequency, dysuria, and hematuria. They may also have peripheral eosinophilia.

Pathologic Features

Microscopic Findings

The lamina propria is edematous with a mixed inflammatory infiltrate in which eosinophils predominate ( Fig. 3-21 ). Tissue eosinophilia is also commonly seen in the vicinity of an invasive urothelial carcinoma.

Prognosis and Treatment

In eosinophilic cystitis associated with allergic disease, therapy is targeted towards the underlying disease.