Pathology of Cystitis

Cystitis describes a broad range of diseases with diverse etiology and pathologic mechanisms but with similar clinical presentations. The leading symptoms are dysuria, frequency, urgency, and, occasionally, suprapubic pain. However, these symptoms are nonspecific and may also be associated with infection of the lower genitourinary tract (urethra, vagina) or with noninfectious conditions such as bladder carcinoma, urethral diverticulum, and calculi.

The incidence of different types of cystitis varies wildly by etiology and the affected patient population. Although acute cystitis—most commonly due to ascending bacterial infection—leads to 0.5-0.7 episode/person of symptomatic urinary tract infections (UTIs) in sexually active women annually, ^[1] other variants are extremely rare. For example, approximately 20 cases of xanthogranulomatous cystitis have been reported. ^[2]

Furthermore, certain types of cystitis have a high incidence in a particular patient population (eg, radiation cystitis, hemorrhagic cystitis) or have a unique geographic distribution. For example, cystitis from schistosomiasis is common in Africa and the Middle East.

Acute infectious cystitis

Bacterial cystitis is most commonly the result of an ascending infection through the urethra caused by the patient’s own enteric microbiota. Hematologic dissemination of organisms in immunocompromised patients, however, is also possible. The most common pathologic agents are the coliform Escherichia coli, Proteus, Klebsiella, and Enterobacter. The presence of anaerobic bacteria, such as Bacteroides fragilis, suggests communication between the intestinal and urinary tracts.

Infection with the obligate intracellular organism Chlamydia trachomatis (immunotypes D-K) frequently associates with other lower genitourinary (GU) tract infections. C trachomatis infection has also been linked to painful bladder syndrome (PBS). ^[3] Fungi (Blastomyces and Candida species) and viruses (polyomavirus, adenovirus, cytomegalovirus [CMV]) can also be responsible for acute inflammation, primarily in immunosuppressed patients.

Emphysematous cystitis, a special form of bacterial cystitis, is caused by gas-producing bacteria and is characterized by gas-filled cysts in the bladder wall. This entity is usually seen in association with poorly controlled diabetes, chronic cystitis, neurogenic bladder, and immunocompromise. ^[4]

Cystitis cystica and cystitis glandularis

Cystitis cystica et glandularis (CCCG) is a common, usually incidental microscopic finding. Its development has been linked to long-standing mucosal irritation (urethral reimplantation, neurogenic bladder, bladder exstrophy). This condition is thought to be reversible, with possible regression upon the elimination of the provoking cause. The association between CCCG with urothelial adenocarcinoma has been suggested but has not been shown conclusively. ^[5]

Eosinophilic cystitis

Eosinophilic cystitis, a rare condition, can be associated with allergic and autoimmune diseases such as lupus, parasitic infection, and systemic peripheral eosinophilia, such as in idiopathic hypereosinophilic syndrome.

Follicular cystitis

Follicular cystitis is typically seen in the background of chronic cystitis. The underlying etiology can be infectious in nature, such as Salmonella infection in the urinary tract, ^[6] but follicular cystitis can also be seen during intravesical chemotherapy, with bacillus Calmette-Guerin (BCG) therapy (eg, prophylaxis after transurethral resection of bladder tumor ^[7] ), or following irradiation to the pubic area.

Granulomatous cystitis

Granulomatous inflammation can arise from bacterial, fungal, or parasitic infection. In the bladder, however, it most commonly arises secondary to BCG immunotherapy (eg, in the treatment of high-grade papillary carcinoma or carcinoma in situ) or following transurethral resection of bladder tumor (TURBT). Granulomatous cystitis due to Mycobacterium tuberculosis infection is often secondary to primary kidney involvement.

Hemorrhagic cystitis

Classic hemorrhagic cystitis is most commonly seen as a side effect of cyclophosphamide, especially if it is combined with radiation therapy. Methotrexate therapy has also been linked to hemorrhagic cystitis. ^[8] In immunocompromised patients, viral infection, such as with adenovirus, ^[9] CMV, polyomavirus (BK virus), or herpes virus, may result in a similar clinical presentation.

Interstitial (Hunner) cystitis/painful bladder syndrome

This uncommon form of cystitis predominantly affects middle-aged white women, with a slightly higher prevalence in the Jewish population. The etiology of interstitial cystitis is not fully understood. Epidemiologic studies, however, have shown that affected individuals are more likely to have a history of childhood bladder problems or urinary tract infections.

It has also been demonstrated that the prevalence of allergies, fibromyalgia, inflammatory bowel disease, and certain autoimmune diseases (eg, rheumatoid arthritis) is higher in this patient group. ^{[10, 11]} These data, along with twin studies, suggest that genetic predisposition may play a role in the manifestation of interstitial cystitis. ^{[12, 13]}

Other etiologies have also been suggested, such as an unidentified infectious agent or a defective epithelial cell layer, with the latter allowing toxic substances to enter the bladder wall and trigger the symptoms. Furthermore, the role of mast cells and abnormalities in the central nervous system (CNS) has been proposed in the pathogenesis of interstitial cystitis as well. ^{[14, 15, 16]}

In a study designed to identify toxic factors, urinary cationic metabolites, in patients with interstitial cystitis (IC), Parsons et al found metabolites were twice as high in the patients with IC compared to a control group (3.1 (0.2) vs 6.3 (0.5) mAU*min/μg creatinine (P < 0.001)). HTB-4 urothelial cells were used to determine cytotoxicity with and without Tamm-Horsfall protein (THP). The cytotoxicity of the cationic metabolites in patients with IC was significantly higher than in control subjects: 1-methyladenosine (51%), 5-methylcytidine (36%), 1-methyl guanine (31%), N(4)-acetylcytidine (24%), N(7)-methylguanosine (20%) and L-Tryptophan (16%), and the presence of THP effectively lowered cytotoxicity in the metabolites. ^[17]

Papillary-polypoid cystitis

This rare, nonspecific mucosal reaction occurs secondary to chronic inflammation of the bladder and is marked by polypoid lesions and edema or by papillary lesions. Papillary cystitis is the chronic phase of polypoid cystitis.

The development of papillary or polypoid cystitis has been linked to frequent or prolonged bladder catheterization. Most patients are middle-aged men.

Radiation cystitis

Radiation may directly cause rapid cell death from mitotic arrest, point mutations in deoxyribonucleic acid (DNA), and cell membrane damage. Radiation can also cause vascular changes. Subendothelial proliferation, edema, and medial thickening may progressively deplete the blood supply to the irradiated tissue.

Radiation cystitis can develop acutely or as long as 14 years after completion of radiation therapy. ^[18] The severity of the disease correlates with the dose and the duration of the exposure.

Malakoplakia

Malakoplakia is an unusual granulomatous process that commonly manifests in the GU tract. It is more frequently seen in women and in immunocompromised patients. ^[19] Malakoplakia is believed to result from defective phagolysosomal activity of histiocytes in response to infection with gram-negative coliforms. According to this theory, the inappropriately digested bacterial glycolipids, along with calcium and iron, are deposited in the histiocytes (Michaelis-Gutmann bodies).

Schistosomiasis-associated cystitis

Infection with the trematode flatworm Schistosoma haematobium is common in Africa and the Middle East. Humans become infected through contact with contaminated water containing the larval form of the parasite (cercaria), which penetrates the skin. The parasite then matures to the adult form and resides in the venous plexus of the bladder wall. Eggs released by the adult worm traverse the bladder wall, causing inflammation and ulceration.

Xanthogranulomatous cystitis

Xanthogranulomatous cystitis is a rare, benign, inflammatory condition. The etiology is unknown; however, the condition has been linked to the following ^[20] :

• Anaerobic urinary tract infection

• Presence of suture material

• Urachal adenoma

• Malignancy

The gross findings are not specific in cystitis. Most commonly, the findings of edema, hyperemia, petechiae, hemorrhage, or ulceration may be evident on cystoscopic examination. Findings in specific variants include the following:

• Cystitis cystica et glandularis and eosinophilic cystitis: Visible irregularity and, rarely, papillary fronds

• Follicular cystitis: Mild nodularity of the mucosa; cystoscopic findings may also include mass lesions, yellow plaques, and surface erythema ^[21]

• Interstitial cystitis: Hunner ulcer in fewer than 10% of patients

• Papillary-polypoid cystitis: Papillary projections, which either are thin and delicate in papillary cystitis or are broad and edematous in polypoid cystitis

• Malakoplakia: Soft, yellow-white plaques, usually in the trigone area

Although urine is easily accessible for cytologic examination, its use in the differentiation of the different types of cystitis is limited. The main utility of urine cytology is to rule out malignancy; it can also be very useful in guiding the clinician to the correct diagnosis of certain infectious processes.

Tissue sampling in the acute phase of infectious cystitis is contraindicated; however, chronic and recurrent cases may need histologic evaluation to rule out underlying malignancy. The microscopic findings are edema and nonspecific acute and/or chronic inflammatory infiltrate in the lamina propria. Various degrees of reactive atypia may be also present in the overlying epithelium (see the image below). ^[22]

Cytologic examination of the urine is much more universal. Along with the typical inflammatory cells, cytologic features may include atypical urothelial cells and necrotic debris (see the image below). In viral cystitis, the following cytopathic effects can also be appreciated:

• Herpes: Multinucleation, margination, molding

• Cytomegalovirus (CMV): Intracytoplasmic and intranuclear inclusion

• Polyomavirus: Decoy cells or comet cells

  Pathology of Cystitis. Acute cystitis. Cytologic examination of the urine shows inflammatory cells and reactive, sometimes atypical, urothelial cells. Necrotic debris may also be present.

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Furthermore, parasites (eg, Trichomonas, schistosomal ova) or fungi (eg, Candida, Blastomyces, Cryptococcus, Aspergillus) can be recognized in urine specimens. ^[23]

Emphysematous cystitis is characterized by cystic, gas-filled spaces in the bladder wall—usually in the background of acute and/or chronic inflammation. The cysts are often lined by multinucleated giant cells.

Cystitis cystica and cystitis glandularis

Cystitis cystica et glandularis (CCCG) arises from the von Brunn nests in the lamina propria by developing slitlike and cystic spaces, as shown in the image below. The spaces are lined by cuboidal to columnar epithelium, which may be surrounded by a ring of transitional epithelium.

In cystitis glandularis of the common type, the glands have a cuboidal to low columnar lining. The less common form of cystitis glandularis (which may coexist with the common type) is the intestinal variety. In the intestinal form, the glands are lined by metaplastic, tall columnar epithelium with abundant intracellular mucin. Occasional goblet cells, Paneth cells, and argentaffin cells may also be present.

Features favoring cystitis glandularis of the intestinal type versus adenocarcinoma are more superficial and evenly spaced glands in the lamina propria with no cytologic atypia or increased mitotic activity. Extracellular mucin pools may be seen in both scenarios. In cases of cystitis glandularis, however, no floating epithelial clusters are present. Adenocarcinoma may arise from long-standing cystitis glandularis of the intestinal type; therefore, careful examination for features of malignancy is essential. ^[24]

Furthermore, the distinction of von Brunn nests and CCCG from invasive urothelial carcinoma, particularly the nested variant, may also be difficult. The smooth, round contour of the nests, consisting of numerous cells, with no cytologic atypia, and the consistent localization in depth in the lamina propria (bandlike appearance) support the diagnosis of CCCG. However, it has to be noted that reactive atypia or hyperplasia may be present in von Brunn nests and also in CCCG similarly as in the surface epithelium.

Eosinophilic cystitis

Eosinophilic cystitis is microscopically characterized by dense, mixed, chronic inflammatory infiltrate, predominantly eosinophils, in the bladder wall (see the image below). Fibrosis and muscle necrosis may also be present. Similar histologic findings are commonly seen adjacent to invasive transitional cell carcinoma. ^[25]

Follicular cystitis

Follicular cystitis refers to a special form of chronic cystitis that demonstrates lymphoid aggregates with well-formed germinal centers in the lamina propria, as depicted in the images below.

Granulomatous cystitis

The histologic features of granulomatous cystitis depend on the etiology. Infection with tuberculosis presents as caseating granulomas with Langerhans giant cells predominantly in the lamina propria. Mucosal ulceration may be also present. The presence of noncaseating granulomas with the background of acute and chronic inflammation and superficial ulceration is suggestive of bacillus Calmette-Guerin (BCG) treatment (see the following images).

Postresection changes may lead to the formation of foreign body–type granulomas or may resemble rheumatoid nodules (see the image below). Special stains for acid-fast bacilli (AFB; Fite) or fungal organisms (GMS) are helpful to determine the underlying etiology.

Hemorrhagic cystitis

Hemorrhagic cystitis is characterized by extensive ulceration and denudation of the surface epithelium. Fibrinopurulent exudate may also be present. Edema and hemorrhage are usually evident in the lamina propria, as depicted in the image below.

Interstitial (Hunner) cystitis

Interstitial cystitis is a diagnosis of exclusion and requires strong clinical correlation. The histologic findings are nonspecific, mixed inflammatory infiltrate in the lamina propria, commonly involving the muscularis propria and nerves. Thus, bladder inflammation, urothelium denudation, eosinophil and plasma cell infiltration, lamina propria hemorrhage, and granulation may be present. ^[26] An increased number of mast cells are usually present in the bladder wall and also in the bladder washing specimen. Superficial ulceration is a classic finding (Hunner ulcer) but is not always present. ^[23] The key from the histologic aspect is to rule out other conditions that may present with similar symptomatology.

Papillary-polypoid cystitis

Fingerlike projections are observed, which can be thin and delicate or broad and edematous, representing the morphologic spectrum of papillary-polypoid cystitis (see the image below). These polypoid lesions are lined by nonneoplastic urothelium with surface umbrella cells.

The underlying lamina propria can be fibrotic (papillary cystitis) or edematous (polypoid cystitis) with a variable amount of chronic inflammatory infiltrate. The inflammation is very helpful to make the distinction between this entity and papillary urothelial carcinoma, in which inflammation in the lamina propria is not present. ^[24]

Radiation cystitis

Radiation cystitis is characterized by nonspecific acute and chronic inflammation, dilated blood vessels, hemorrhage, and edema in the lamina propria (see the image below). The endothelial cells are usually swollen; microthrombi and fibrin deposition are frequently present.

Hemosiderin deposition and the presence of atypical fibroblasts (radiation fibroblasts) suggest a long-standing process. The surface epithelium may show atypia, metaplastic (squamous metaplasia) or degenerative changes; cytoplasmic vacuolization and karyorrhectic debris are commonly seen.

An emphasized radiation-related injury of the bladder is the pseudocarcinomatous proliferation composed of irregularly shaped aggregates of epithelial cells in the lamina propria with or without atypia. ^[27] Small projections of these nests with surrounding retraction artifact around them may resemble invasive carcinoma or may be confused with vascular invasion. Radiation-related changes may persist for an extended period after treatment completion.

Malakoplakia

Sheets of epithelioid histiocytes (occasional multinucleated giant cells) with granular, periodic acid–Schiff (PAS)–positive cytoplasm (von Hansemann histiocytes) are seen in malakoplakia. Characteristic round, laminated, intracytoplasmic inclusions (Michaelis-Gutmann bodies) are present in the histiocytes, which can be highlighted with iron (Prussian blue) and calcium (von Kossa) stains. On electron microscopy, Michaelis-Gutmann bodies are phagosomes filled with undigested bacterial residues, and their presence is considered pathognomonic for the disease.

Schistosomiasis-associated cystitis

Eggs in the veins of the muscularis propria and in the muscularis mucosa, surrounded by inflammatory response consisting predominantly of eosinophils, can be demonstrated with schistosomiasis-associated cystitis. Necrosis and mucosal ulceration may also be present.

Later on, chronic inflammatory infiltrate and a foreign body–type granulomatous reaction in association with fibrosis dominate the picture. Because schistosomiasis has a strong association with squamous cell carcinoma of the bladder, vigilant assessment of the mucosa is crucial (see the following images).

Xanthogranulomatous cystitis

In xanthogranulomatous cystitis, sheets of lipid-laden macrophages in the lamina propria can be demonstrated. Chronic suppurative infection may be present in the background. Because xanthogranulomatous cystitis is an aggressive, locally infiltrative process, foamy histiocytes, multinucleated giant cells, and cholesterol clefts may also be seen in the bladder wall.

This condition has been described in association with malignant neoplasms, such as urachal adenocarcinoma, and transitional cell carcinoma. Therefore, the occurrence of related neoplasm should be considered when this rare diagnosis is made. ^[20]

Immunohistochemistry is not routinely necessary in cystitis, but it may be helpful if differential diagnostic dilemmas arise. In viral cystitis, the diagnostic cytomorphologic changes may be confirmed with immunohistochemical staining (herpes, cytomegalovirus, polyomavirus, adenovirus).

Primary bladder lymphoma, although very rare, can mimic follicular or chronic cystitis. A panel of immunohistochemical studies, in correlation with the morphology, may be required to exclude lymphoproliferative disorders. ^[28]

One study has suggested that certain polymorphisms in the Toll-like receptor (TLR) pathway genes (particularly TLR5) are associated with increased susceptibility to recurrent urinary tract infection in adult women. ^[29]

Gene expression profiles from bladder biopsies in patients with ulcerative interstitial cystitis have shown a similar expression pattern to those of patients with immune system, lymphatic, and autoimmune diseases. The majority of the upregulated genes were expressed in the leukocytes, suggesting that leukocyte invasion of the bladder wall is important in the pathomechanism of ulcerative interstitial cystitis. ^[30]

Heterozygous polymorphisms in the drug-metabolizing enzyme alleles ALDH3A1*2 and ALDH1A1*2, members of the aldehyde dehydrogenase gene family, have been linked to an increased risk of developing hemorrhagic cystitis and liver toxicity in patients treated with high doses of combination chemotherapy, including cyclophosphamide, thiotepa, and carboplatin. ^[31]