Complications include scarring, obstruction, and fistula formation

Histologically, presents as solitary or confluent ulcerated mucosal lesions, usually in the region of the ureteral orifices (trigone), with caseating granulomatous inflammation and fibrosis involving the lamina propria

Frequently associated with the ulceration of the overlying mucosa

Special stains (auramine–rhodamine or other AFB stain) demonstrate acid-fast bacilli

“Malakoplakia” means “soft plaque” in Greek

This benign process was first described by Michaelis and Gutmann and by von Hansemann in 1902 and 1903

There is a female predilection, with peak incidence in the fifth decade

Patients typically present with symptoms of urinary tract infection

Symptoms include recurrent fever, hematuria, pyuria, urgency, pain, and weight loss

Others organs may be involved

Multiple small yellow mucosal nodules or plaques, usually in the area of the trigone with a yellow to yellow-brown discoloration, not more than 2 cm in maximum dimension

The lesion is characterized by mixed inflammatory infiltrate in the lamina propria

Large numbers of epithelioid histiocytes (von Hansemann histiocytes) with abundant granular eosinophilic cytoplasm and intracytoplasmic inclusions (Michaelis–Gutmann bodies, 3–10 μm) are present (Fig. 36.6A)

Michaelis–Gutmann bodies are concentrically laminated basophilic round to oval calcospherites and may be PAS+, iron+, and calcium (von Kossa stain)+, either freely in the stroma or as intracytoplasmic inclusions (Fig. 36.6B)

Concentrically laminated structures with a central electron dense core and radially oriented spicules hydroxyapatite crystals (Fig. 36.6C)

Adenocarcinomas, including signet ring cell adenocarcinoma

Endemic in some parts of Africa and Southwest Asian countries, especially Egypt

Granulomatous inflammation and fibrosis of lamina propria or muscularis propria

Identification of schistosomal eggs (100 μm), frequently calcified in the bladder wall, is diagnostic (Fig. 36.7)

Inflammatory condition (with acute and chronic phases) associated with pelvic radiation treatment

Patients have a previous history of radiation, not necessarily for bladder cancer, sometimes for prostate or cervical cancer

Highly dose dependent (50% risk if receiving 70 Gy but only 5% risk with 60 Gy)

Cystoscopy may show small papillary lesions, slight mucosal irregularities, or nonspecific findings

Early changes appear after 3–6 weeks and include acute cystitis and desquamation of the urothelial cells associated with hyperemia

Later, there is epithelial hyperplasia producing a pseudoinfiltrative appearance

Budding off single cells may also be seen, and the nests may show squamous differentiation, raising the suspicion of a malignant process

These cells show mild to severe cytologic atypia with nuclear hyperchromasia; however, nucleoli are inconspicuous, the nuclear-to-cytoplasmic (N/C) ratio is preserved or increased, and mitotic figures are typically absent—features that are not characteristic of a malignant process (Fig. 36.8A)

Other helpful features are the finding of scattered enlarged fibroblasts (Fig. 36.8B) in the lamina propria associated with nuclear hyperchromasia, hemorrhage or fibrin deposition, edema, inflammatory cells, and ectatic vessels. Some vessels may show myointimal thickening and eccentric accumulation of amorphous pink material

Acute phase occurs within 6 months (usually manifests within 6 weeks of treatment); subacute phase occurs from 6 months to 2 years after treatment; chronic phase usually takes 2–5 years to appear

Main entity entering differential diagnosis is carcinoma in situ (CIS), which has high N/C ratio, nuclear pleomorphism, and hyperchromasia

Clinical history is critical in determining the etiology of this increasingly frequent lesion

BCG is used to treat patients with superficial high-grade bladder carcinoma or CIS

Symptoms include dysuria, frequency, fever, and other systemic reactions (e.g., pneumonitis, hepatitis, rash, and arthralgia)

There is erosion and ulceration of the mucosa and a sarcoid-like nonnecrotizing granuloma with giant cells (Fig. 36.9)

Edema, congestion, and chronic inflammatory infiltrate in the lamina propria are associated features

Occurs in up to 8% of patients treated with cyclophosphamide (Cytoxan) and is secondary to toxic metabolite acrolein (an aldehyde and oxidizing agent from tobacco and systematic inflammation) that is excreted in the urine

May result in severe, intractable hematuria, which may require cystectomy

At endoscopy, there is a diffuse, severe hyperemia with edema and erosion or ulceration of the mucosa (Fig. 36.10A)

Urothelial denudation/ulceration leads to regeneration with reparative urothelial changes that results in atypical urothelium covering a lamina propria with edema and extensive hemorrhage (Fig. 36.10B)

A frequent finding is the activation of polyomavirus or adenovirus infection that should not be mistaken for malignancy

History of prior surgery or instrumentation.

The etiology is related to immunologic recognition of altered antigen induced by the procedure (also known as necrobiotic granuloma)

Hemorrhage, necrosis, and mucosal irregularities are common

The granulomas include a central zone of fibrinoid necrosis surrounded by a peripheral rim of palisading epithelioid histiocytes (Fig. 36.11)

Chronic inflammatory infiltrate composed of histiocytes, giant cells, lymphocytes, plasma cells, and eosinophil s

Uncommon inflammatory process seen in middle-aged women (30–50 years) that presents with dysuria, urgency, frequency, hematuria, or generalized pelvic pain

The diagnosis is made clinically based on symptoms and cystoscopic examination. There is also negative testing for bacterial, fungal, or viral pathogens

Some cases are associated with allergic and autoimmune disorders (rheumatoid arthritis, systemic lupus erythematosus, or autoimmune thyroiditis)

Antinuclear antigen test is positive in >50% of cases

Scattered petechial hemorrhages

Wedge-shaped ulceration (Hunner ulcer)

There are two main histologic forms:

Mast cell infiltration in the lamina propria and muscularis propria is common in both forms of interstitial cystitis

Discontinuous uroplakin III immunostaining in superficial (umbrella) cells of patients with interstitial cystitis and continuous immunostaining in urothelium of patients without disease has been reported

Other forms of cystitis, including tuberculous cystitis and eosinophilic cystitis or nonspecific acute or chronic cystitis, should be considered in the differential diagnosis

Inflammatory process found in women and children; seen with allergic disorders and other diseases associated with peripheral eosinophilia

Uncommonly seen in elderly men with bladder injury or history of transurethral resection

Symptoms include severe frequency, urgency, dysuria, and hematuria, with periods of remission and exacerbation

Spontaneous resolution is common

Diffuse mucosal edema and erythema or velvety yellow plaque

Tumorlike polypoid growths that appear erythematous and may demonstrate ulceration or necrosis

Mononuclear and eosinophilic infiltrate in the lamina propria and muscularis is the main histological finding (Fig. 36.13)

Early disease is characterized by marked edema, congestion, and a mixed mononuclear and eosinophilic infiltrate, but in severe cases, muscle necrosis may be seen

As the disease progresses, the inflammatory infiltrate tends to subside, and varying degrees of fibrosis may be seen in the lamina propria and muscularis

Flat urothelial hyperplasia is characterized by marked thickening of the mucosa usually to ten or more cell layers (Fig. 36.14)

The true incidence of flat hyperplasia is not known due to lack of large-scale screening studies

This is a controversial entity with unknown clinical significance.

Some investigators consider it as a precursor to grade 1 papillary urothelial carcinoma.

Most cases of papillary urothelial hyperplasia are discovered incidentally on followup cystoscopy for previous papillary tumors.

The lesion displays undulating folds of urothelium that may have increased vascularity at the base of papillary folds, but lacks well-developed fibrovascular cores of a papillary neoplasm (Fig. 36.15).

Although considered “hyperplastic,” papillary hyperplasia is typically surfaced by normal-appearing urothelium between four and seven cells in thickness.

Cytologically, the urothelial cells in papillary hyperplasia lack atypia and maintain nuclear polarity.

The primary differential diagnosis includes papilloma, low-grade papillary neoplasm, and papillary cystitis.

In contrast to papillary neoplasms, papillary hyperplasia lacks arborization and detached papillary fronds.

Papillary hyperplasia also lacks the broad-based stalks and inflammation seen in papillary–polypoid cystitis.

More commonly seen in men, with a male-to-female ratio (M:F) of 4:1.

Usually occurs in the setting of longstanding chronic inflammation, but may be focally present in noninflamed bladders.

Associated conditions include exstrophy, neurogenic bladder, indwelling catheter, previous surgery or biopsy, recurrent infection (e.g., schistosomiasis), and calculi.

Nonkeratinizing squamous metaplasia of the trigone in women is a normal finding secondary to estrogen stimulation and does not need to be reported.

Keratinizing squamous metaplasia is considered a putative precursor to carcinoma.

Nonkeratinizing squamous metaplasia is not associated with increased risk of carcinoma.

It may appear as mature or immature keratinizing squamous epithelium (Fig. 36.16).

Usually occurs in middle-aged men (M:F, 2:1; mean age, 41 years)

In most cases, it is an incidental finding, but in one-third of cases, lesions are sizable and 10% are 4 cm or larger

Frequently occurs in the setting of longstanding chronic irritation

20% of cases occur in children and adolescents

8% of patients have undergone kidney transplantation

Approximately, 80% of the lesions occur in the bladder, with the remainder involving the urethra (15%) or ureter (5%) and, rarely, the renal pelvis

Nephrogenic adenoma may recur, but malignant transformation has not been unequivocally documented

Papillary or polypoid small solitary yellow nodules (usually <1 cm)

Erythematous irregular mucosa with a predilection for the trigone

The lesion is composed of a well-circumscribed proliferation of small compact tubules, cysts, and delicate filiform papillae lined by columnar or cuboidal hobnail or flattened cells (Fig. 36.17)

Cells have clear to eosinophilic cytoplasm and uniform nuclei with inconspicuous mitotic figures

Intracytoplasmic vacuoles (glycogen+) may be seen, imparting a signet ring cell appearance

Tubules have thickened PAS+ basement membrane and may contain eosinophilic PAS+ secretions

Often accompanied by chronic inflammation and associated with squamous metaplasia, cystitis cystica, and cystitis glandularis

Cytologic atypia including nuclear enlargement, nuclear hyperchromasia, and enlarged nucleoli may be focally seen (atypical nephrogenic adenoma); however, these lesions are benign and do not need further treatment

A rare variant of nephrogenic adenoma with myxoid stroma has been reported (fibromyxoid nephrogenic adenoma)

The tubules of nephrogenic adenoma may occasionally be intermixed with muscle fibers of the muscularis mucosa in the bladder. This should not be mistaken for malignancy

Strong positivity for wide-spectrum keratin, cytokeratin 7 (CK7), EMA, vimentin, PAX2, PAX8, and alpha-methylacyl-CoA racemase (P504S)

p53 and Ki67 are typically negative

Clear cell adenocarcinoma

Urothelial c arcinoma with tubuloglandular pattern

Signet ring cell adenocarcinoma of the bladder or adenocarcinoma metastatic to the bladder

See discussion below on cystitis glandularis with intestinal metaplasia

Most papillomas are solitary lesions, occurring in younger patients than carcinoma (mean age, 46 years; range, 22–89 years)

Accounts for 1–2% of papillary urothelial neoplasms in some series

Hematuria is the most common presenting symptom

Urothelial papilloma may arise as a de novo neoplasm, or it may occur in patients with a clinical history of bladder cancer, as a secondary papilloma

Urothelial papilloma may recur; however, it does not progress; aggressive behavior has been reported in a patient with urothelial papilloma on immunosuppressive therapy secondary to a renal transplant

The cystoscopic appearance is identical to that of low-grade papillary neoplasms

Exophytic solitary small papillary lesion (<2 cm)

Urothelial papilloma is a benign exophytic neoplasm composed of a delicate fibrovascular cores lined by normal-appearing urothelium (Fig. 36.30)

Key features

The superficial (umbrella) cells are often prominent and may display increased cytoplasm, vacuolization, and degenerative nuclear atypia

The stroma may show edema and/or lymphoid inflammatory cells

Rarely, urothelial papilloma shows extensive multifocal involvement of the mucosa; a phenomenon referred to as diffuse papillomatosi s

Papillomas are diploid and show frequent FGFR3 (75%) mutation

A recent study found FGFR3 mutations in urothelial papilloma with a frequency comparable to that of papillary urothelial neoplasia of low malignant potential and low-grade papillary urothelial carcinoma

Papilloma shows low proliferation and uncommon p53 nuclear accumulation

CK20 expression is limited to the superficial (umbrella) cells in the usual expression pattern for normal urothelium

Papillary urothelial neoplasm of low malignant potential and low-grade papillary carcinoma enter the differential diagnosis

Tumors typically have longer slender papillae covered by urothelium with a variable degree of hyperplasia (>7 cell layers) and some degree of cytologic atypia.

Urothelial papillomas show discrete papillary fronds with occasional branching but without fusion and are covered by normal urothelium .

Rare benign urothelial neoplasm that comprises less than 1% of urothelial tumors

Presents with hematuria and irritative symptoms

M:F, 4.5:1; age range, 10–94 years

Some cases may be multifocal

Inverted papilloma diagnosed according to strictly defined criteria is a benign urothelial neoplasm not related to urothelial carcinoma

Recurrence rate is 1%, most apparently due to incomplete surgical excision

Previous reported cases of inverted papillomas that coexist with carcinoma have been questioned. The majority of those reported cases probably represent urothelial carcinoma with inverted growth according to current diagnostic criteria

Most cases are solitary nodular or sessile lesions, smaller than 3 cm, and arise in the bladder trigone/bladder neck region

I nverted papilloma has a smooth surface covered by normal urothelium and endophytic growth of urothelial cells arborizing extensively from the surface urothelium into the lamina propria but not into the muscularis propria (Fig. 36.31)

Most cases show anastomosing cords, columns, and trabeculae of invaginated urothelium separated by thin fibrovascular septa

Foci of nonkeratinizing squamous metaplasia and neuroendocrine differentiation have been reported

Recent molecular studies indicate that inverted papilloma represents a clonal proliferation characterized by frequent FGFR3 mutations

Florid proliferation of von Brunn nests rarely represents a diagnostic concern

Low-grade urothelial carcinoma has cytologic atypia, variable mitotic figures, and exophytic papillary growth

Inverted variant of urothelial carcinoma has thicker and more irregular columns with loss of polarity and absence of peripheral palisading basaloid cells